Combinations as Treatments for Anaerobic Pathogens

Abstract

The combinations and / or formulations of co-agents herein unexpectedly exhibit significantly better antimicrobial activity (e.g., greater efficacy and / or greater potency) against anaerobic pathogens that were not previously considered as targets. When using three or more co-agents selected from the group consisting of fosfomycin, diaminopyridine, sulfonamides, beta-lactam antibacterial agents, bacterial beta-lactamase inhibitors, bacterial fosfomycin modifying enzymes, and bacterial peptidoglycan synthesis inhibitors, the therapeutic potential of the three or more co-agents is expanded by targeting a broader spectrum of pathogens. The co-agents are active and effective herein against pathogenic anaerobic organisms that are difficult to treat (including anaerobic organisms that cannot utilize oxygen and / or inhabit anaerobic environments and are in part inhibited by oxygen) due to an unexpected synergistic effect in the anaerobic environment, as well as against pathogens that are considered to be resistant or intolerant to at least one of the co-agents when used separately in the anaerobic environment. Some combinations and / or formulations of co-agents contain one or more existing antibiotic drugs that are repurposed for their usefulness against difficult-to-treat anaerobic pathogens.

Description

【Technical Field】 【0001】 【0002】 This application describes a plurality of novel combinations and / or formulations that each contain a plurality of agents (co-agents), each of which is unexpectedly difficult to treat pathogenic anaerobic organisms that cannot utilize oxygen and some of which are inhibited by oxygen, and provides an antimicrobial effect against them. Each co-agent in the combination or formulation interferes with or inhibits the enzymes of anaerobic pathogens. The plurality of co-agents are selected for their synergistic properties and exhibit and have a synergistic effect that enhances or otherwise promotes sufficient and / or effective antimicrobial activity against anaerobic pathogens that are difficult to treat in an anaerobic environment. However, many anaerobic organisms are intrinsically resistant when the co-agents are used separately, and many co-agents are inactive against the same anaerobic organisms when used separately. 【Background Art】 【0002】 【0003】With the continuous increase of more complex infectious diseases and, in particular, the further increase in the rate of antibiotic resistance of particularly highly used classes of antibiotics, there remains a need to find antimicrobial agents effective against pathogenic anaerobic bacteria and to combat adequately and effectively biological or mixed infections (including one or more species of anaerobic pathogens and one or more species of aerobic pathogens) with broad-spectrum activity. The WHO has referred to the shortage of new antibiotics due to the reduction in research and development, combined with the global increase in both antibiotic-resistant pathogens and the infections caused by such resistant pathogens. (World Health Organization, "Lack of new antibiotics threatens global efforts to contain drug-resistant infections", January 17, 2020, https: / / www.who.int / news / item / 17-01-2020-lack-of-new-antibiotics-threatens-global-efforts-to-contain-drug-resistant-infections). This leads to an over-reliance on certain classes of antibiotics, accelerating the accumulation of resistance selection and the spread of resistance, both of which will further increase the limitation of treatment options. 【0003】 【0004】Infections caused by anaerobic microorganisms are increasing (among other reasons, in part due to the increasing overall age of the population, the increasing incidence of certain predisposing diseases such as inflammatory diseases and cancer that increase the risk of gastrointestinal perforation and peritonitis, and the increasing number of surgical procedures, accidents, injuries, and deep penetrating wounds). Many current antibiotics used to treat aerobic microorganisms (those capable of using oxygen for metabolism) are not tolerated for use against anaerobic organisms (e.g., having little or no effectiveness in inhibiting anaerobic bacterial growth and / or removing anaerobic bacteria, especially when used against strict anaerobes or obligate anaerobes). Therefore, treatment options available for use against more severe infections, including nosocomial infections, are limited, and there is no predictability regarding effective treatment against pathogenic anaerobic organisms involved in such infections, including anaerobic organisms identified as strict anaerobes or obligate anaerobes. Obligate anaerobes, which are the most difficult to treat due to their inability to perform aerobic metabolism. Obligate anaerobes cannot utilize oxygen, some are actually inhibited by oxygen, and survive and are pathogenic in the absence of oxygen. Obligate anaerobes rely on other substances (other than oxygen; i.e., final electron acceptors) as well as alternative (different) enzymatic pathways for energy conversion (for growth, metabolism, and activity) compared to aerobic microorganisms that utilize and convert oxygen for energy production. 【0004】 【0005】In fact, drug therapies or treatment plans for pathogenic anaerobic organisms (including obligate anaerobic organisms and / or especially obligate anaerobic organisms) and / or infections that may have arisen or are suspected of having arisen from one or more pathogenic anaerobic organisms are still empirical. The options for antibiotics currently available against pathogenic anaerobic organisms, especially obligate anaerobic organisms, are severely limited. This is due in part to the ineffectiveness of many antibiotic drugs under anaerobic conditions. As the resistance of microorganisms (including anaerobic organisms) to the few antibiotic agents used against anaerobic organisms has further increased, even previously used antibiotics are no longer recommended in empirical treatment against such pathogenic anaerobic organisms (including clindamycin, many penicillins, second-generation cephalosporins, and quinolones, for example). The inability to directly treat pathogenic anaerobic organisms is a common reason for clinical failure. 【0005】 【0006】There remains a need for a direct and novel option for drug therapy effective against pathogenic anaerobic organisms, including pathogenic obligate anaerobic organisms. There also remains a need for a direct and novel option for drug therapy effective against pathogenic anaerobic organisms, including pathogenic obligate anaerobic organisms, in an anaerobic environment and / or in an environment with very low oxygen (e.g., under low or very low oxygen pressure that is not toxic to such pathogens and / or does not generally promote sustained energy production using oxygen and / or provides an alternative source of energy other than oxygen, such as through fermentation). In addition, or alternatively, there remains a need for an option for drug therapy that is effective not only against one or more pathogenic anaerobic organisms, including pathogenic obligate anaerobic organisms, but also against at least one pathogenic anaerobic organism and one or more pathogenic aerobic microorganisms (gram-positive aerobic organisms and / or gram-negative aerobic organisms) and can be used in their mixed population and / or in an infectious disease. In addition, or alternatively, there remains a need for an option for drug therapy that provides sustained growth inhibitory activity and / or sustained elimination against one or more pathogenic anaerobic organisms, including one or more that are considered resistant to one or more separate antibiotic formulations when used separately, and / or one or more pathogenic obligate anaerobic organisms. In addition, or alternatively, there remains a need for an option for drug therapy that provides appropriate care for an infectious disease suspected to be derived from, resulting from, or having developed from one or more pathogenic anaerobic organisms, including one or more that are considered resistant to one or more separate antibiotic formulations when used separately.Moreover, there remains a need for options for drug therapy that are active against one or more pathogenic anaerobic organisms, including one or more pathogenic obligate anaerobic organisms and / or one or more that are considered resistant to one or more separate antibiotic formulations when used separately, that cross the blood-brain barrier and have activity against such organisms upon and / or after crossing the blood-brain barrier (e.g., in subjects in need of options for drug therapy). 【0006】 【0007】 One or more, and / or all, of the needs are met by one or more of the following combinations and / or formulations herein, and when utilized, provide one or more of the benefits described herein due to the synergistic action of the agents utilized in said one or more combinations and / or formulations. 【SUMMARY OF THE INVENTION】 【0007】 【0008】In this specification, a plurality of unpredictable combinations of antimicrobial agents (co-agents) for use against one or more types or species of pathogenic anaerobic microorganisms (anaerobes), some of which are such that at least one of the co-agents in the unpredictable combination itself is ineffective against the one or more types or species of pathogenic anaerobes in an anaerobic environment as an antimicrobial agent and / or is either not active against the one or more types or species of pathogenic anaerobes (due to acquired or intrinsic resistance to at least one of the co-agents by the one or more types or species of pathogenic anaerobes), and each unpredictable combination is not predicted to be effective against the one or more types or species of pathogenic anaerobes. Additionally, or alternatively, at least one unpredictable combination is not predicted to be effective against the one or more types or species of pathogenic anaerobes, at least in part because the pathogenic anaerobes are in an anaerobic environment. Additionally, or in place of, at least one unpredictable combination is not predicted to have been effective against the one or more types or species of pathogenic anaerobes, at least in part because the one or more types or species of pathogenic anaerobes are intrinsically resistant to at least one of the co-agents of the at least one unpredictable combination. Using the unpredictable combinations of co-agents, the combination is not only effective against the one or more types or species of pathogenic anaerobes in an anaerobic environment, but the action of the combination is synergistically unexpected and has or causes an antimicrobial effect, inhibiting the growth of the one or more pathogenic anaerobes at least sufficiently. 【0008】 【0009】In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of pathogenic obligate anaerobic organism. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of gram-negative obligate anaerobic organism (GNOA). In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of gram-positive obligate anaerobic organism (GPOA). In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of drug-resistant pathogenic anaerobic organism. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of drug-resistant pathogenic anaerobic organism, and when the co-agent is used alone against the pathogenic anaerobic organism, the drug (against which the anaerobic organism is resistant) is at least one co-agent in an unpredictable combination herein. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of intrinsically resistant drug-resistant pathogenic anaerobic organism, and at least one type or species of pathogenic anaerobic organism is intrinsically resistant to at least one co-agent in an unpredictable combination herein. For intrinsic resistance, the drug (or co-agent) is not predicted to possess antimicrobial activity against at least one type or species of pathogenic anaerobic organism as a whole. Intrinsic resistance (or intrinsically resistant) may also be referred to as predicted phenotypic resistance or intrinsic non-susceptibility and is not acquired resistance. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of drug-resistant GNOA, and the drug resistance is intrinsic or acquired. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of drug-resistant GPOA, and the drug resistance is intrinsic or acquired. In one or more embodiments, the pathogenic anaerobic organism is at least two types or species of microorganisms, also referred to as a mixed population of organisms, including at least one type or species of pathogenic anaerobic organism and at least one type or species of pathogenic aerobic organism. In one or more embodiments, the pathogenic anaerobic organism is a mixed population containing at least one type or species of drug-resistant pathogenic anaerobic organism, and the drug (against which the anaerobic organism is resistant) is at least one co-agent in an unpredictable combination.In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of pathogenic anaerobic organism that is intrinsically resistant to at least two co-agents in an unpredictable combination. In one or more embodiments, the pathogenic anaerobic organism is at least one type or species of pathogenic anaerobic organism that is intrinsically resistant to at least three co-agents in an unpredictable combination. Being intrinsically resistant to at least one or at least two or at least three co-agents in an unpredictable combination means that such agents would never (or would never have been) considered effective against any of the one or more unpredictable combinations and / or formulations described herein. It is understood that any combination of pathogenic anaerobic organisms as described herein (or above) can be targeted by the unpredictable combinations and / or formulations herein. 【0009】 【0010】 As used herein, susceptibility and / or resistance to at least one or at least two or at least three or at least four co-agents in the unpredictable combinations and / or formulations herein is identified by susceptibility breakpoints established and / or identified by a practice organization establishing the criteria, such as EUCAST (European Committee on Antimicrobial Susceptibility Testing, Vaxjo, Sweden) or CLSI (Clinical and Laboratory Standards Institute, Pennsylvania, U.S.A). An acceptable standardized test for anaerobic organisms can be a culture-based or agar-based in vitro antimicrobial susceptibility test (AST) by CLSI; EUCAST does not currently provide a standardized test for anaerobic organisms. 【0010】 【0011】As used herein, a pathogenic anaerobic organism is any type or species of anaerobic organism, or any combination thereof, supra or infra, that requires pharmacological interference or intervention with at least one unpredictable combination and / or formulation of antimicrobial agents herein, such pharmacological interference or intervention being for inhibiting or reducing or alleviating or managing or eliminating pathogenicity (at least in part due to one or more pathogenic anaerobic organisms), and / or for inhibiting or reducing or alleviating or managing or eliminating an infection caused or suspected of being caused by one or more pathogenic anaerobic organisms herein (e.g., in a host or subject having or suspected of having an infectious disease). When referring to any of the terms such as providing, and / or treating, and / or delivering, and / or conveying, and / or presenting, and / or dispensing, etc., involved in pharmacological interference or intervention with any combination and / or formulation herein (including multiple co-agents or active co-agents or synergists), whether the term "pathogenic" (or any suitable equivalent technical term as understood by one of ordinary skill in the art) is included in the expression or in the claims, and / or whether the phrase "one or more types or species" or "one or more types and / or species" (provided interchangeably herein in reference to pathogenic anaerobic organisms) is included in the expression or in the claims, and / or whether the phrase "pharmacological interference or intervention" (or any suitable equivalent technical term as understood by one of ordinary skill in the art) is included in the expression or in the claims, a pharmacological interference or intervention directed to or against at least one or more types and / or species of pathogenic anaerobic organisms as described herein includes an unpredictable combination and / or formulation herein. 【0011】 【0012】Unpredictable combinations and / or formulations (each containing multiple co-agents) each exhibit or demonstrate an unexpected response and antimicrobial activity as described herein. The antimicrobial activity is sufficient and / or appropriate against one or more pathogenic anaerobic organisms in the present specification, which may include pathogenic anaerobic organisms that cannot utilize oxygen and / or are inhibited by oxygen, and such activity is therapeutically beneficial (effective) at least to the same extent as alternative and known antibiotics currently approved for use against aerobic bacteria in many embodiments. In some embodiments, the activity is stronger than or includes an activity stronger than alternative and known antibiotics that are sufficient and currently approved for use against aerobic bacteria and are inactive against pathogenic anaerobic organisms that cannot utilize oxygen or are inhibited by oxygen. The activity of the unpredictable combinations and / or formulations herein is due to the synergy of the co-agents, which provides an unexpected and unforecasted antimicrobial activity against one or more pathogenic anaerobic organisms, including those in an anaerobic environment, as further disclosed. The synergy positively affects and confers one or more responses and activities of the co-agents against one or more (types and / or species of) pathogenic anaerobic organisms.An activity shown or caused by an unpredictable combination and / or formulation in this specification, which is active against an anaerobic pathogen or an infectious disease caused by or suspected of being caused by an anaerobic pathogen, and includes the following: (i) growth inhibitory activity against one or more pathogenic anaerobic organisms; (ii) sustained growth inhibitory activity against one or more pathogenic anaerobic organisms; (iii) removal (and / or destruction) of one or more pathogenic anaerobic organisms; (iv) sustained removal (and / or destruction) of one or more pathogenic anaerobic organisms; (v) prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vi) sustained prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vii) alleviation of an infectious disease caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of alleviation of an infectious disease); (viii) management of an infectious disease caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of management of an infectious disease); (ix) prevention of an infectious disease that may be caused by, derived from, or develop from one or more pathogenic anaerobic organisms (e.g., before and / or after surgery in a subject in need of prevention of an infectious disease); (x) reduction of the infection rate of an infectious disease caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of reduction of the infection rate of an infectious disease), or any combination thereof.Accordingly, the synergistic and antimicrobial activities of the co-agent combinations and / or formulations herein can be sufficient and / or effective as a drug therapy, for treating infectious diseases, for preventing possible infectious diseases (e.g., related to surgery), for reducing the systemic nosocomial infection rate, for reducing the adjustment / change of the first antibiotic treatment or therapy, for reducing or eliminating empirical antibiotic therapy, for improving the overall in-hospital outcome indicators, for reducing the hospital stay period, and / or for reducing the length of antibiotic treatment or therapy. 【0012】 【0013】 Unexpectedly, in some embodiments, the unpredictable co-agent combinations and / or formulations herein can revive the therapeutic potential of at least one co-agent such that, where at least one co-agent provided in the unpredictable co-agent combination and / or formulation is a known antibiotic currently approved for use as an antibiotic, the co-agent can be provided here for new uses and / or broader spectrum activity and / or better outcomes. 【0013】 【0014】Unexpectedly, the unpredictable combinations and / or formulations of co-agents herein have synergistic and effective antimicrobial activity against one or more pathogenic anaerobic organisms (e.g., as shown by any one or more of activities (i)-(x)), and are active against an unexpected group of pathogens including obligate anaerobic organisms (Gram-positive and / or Gram-negative); obligate anaerobic organisms in a mixed population; drug-resistant obligate anaerobic organisms that are intrinsically resistant; non-susceptible anaerobic organisms. Unexpectedly, the unpredictable combinations and / or formulations of co-agents herein (having synergistic and antimicrobial activity against one or more anaerobic organisms shown as one or more of activities (i)-(x)) are active in an anaerobic environment, but are selectively active and are inactive, unexpectedly, against certain facultative (non-responsive) anaerobic bacteria that are identified by those skilled in the relevant art as beneficial or symbiotic anaerobic organisms (e.g., symbiotic with the microbiota or the bacterial flora of a normal or disease-free mammalian host).Non-responsive common facultative anaerobic organisms are any of Lactobacillus spp., Leuconostoc spp., and Pediococcus spp., none of which have been found to be responsive to the unpredictable combinations and / or formulations of co-agents herein when the combination and / or formulation of co-agents contains at least the following co-agents: (1) phosphomycin (F), or an inhibitor of the microbial (bacterial) MurA enzyme, which itself has antibacterial activity (against aerobic bacteria in an aerobic environment) and includes any suitable phosphate, salt, acid, amine, and / or ester thereof, any of which may interfere with or inhibit the microbial (bacterial) UDP-N-acetylglucosamine (UDP-GlcNAc) enolpyruvate transferase (or MurA enzyme); (2) diaminopyrimidine (D), or an inhibitor of the microbial (bacterial) dihydrofolate reductase (DHFR), which itself has antibacterial activity (against aerobic bacteria in an aerobic environment) and includes any suitable phosphate, salt, acid, and / or ester thereof, any of which may interfere with or inhibit the microbial (bacterial) dihydrofolate reductase (DHFR); and (3) sulfonamide (S), or an inhibitor of the microbial (bacterial) dihydropteroate synthase (DHPS), which itself has antibacterial activity (against aerobic bacteria in an aerobic environment) and includes any suitable phosphate, salt, acid, and / or ester thereof, any of which may interfere with or inhibit the microbial (bacterial) dihydropteroate synthase (DHPS). 【0014】 【0015】In one form, the unexpected combinations and / or formulations of co-agents herein having synergistic and antimicrobial activity (e.g., as any one or more of activities (i)-(x)) against one or more pathogenic anaerobic organisms have an unanticipated post-antibiotic effect (PAE), as revealed by in vitro testing against responsive facultative anaerobic organisms (and when compared to the PAEs of the co-agents tested separately). In one or more embodiments, the PAE is longer for the combinations and / or formulations of co-agents herein against responsive anaerobic organisms when compared to the PAEs of the co-agents provided alone (separately) against responsive anaerobic organisms. In one or more embodiments, when the co-agents are provided alone (separately) against responsive facultative anaerobic organisms, the PAE after delivery of the combinations and / or formulations of co-agents is sufficiently the same as or similar to the PAEs of the co-agents (from the combination and / or formulation), and a sufficiently same or similar PAE for the combinations and / or formulations of co-agents can occur at a lower concentration of at least one co-agent or all co-agents (when the co-agents are provided separately). The PAE of the combinations and / or formulations of co-agents can be 30 minutes (min) longer or 1 hour longer or 2 hours longer or more than 2 hours longer than the PAE when the co-agents of the combination are provided separately. The PAE of the combinations and / or formulations of co-agents can unexpectedly be longer than can be predicted based on the PAEs of one co-agent (when provided separately) from the combination or two sets of co-agents from the combination (when provided as two sets) against the same pathogenic anaerobic organism. The responsive pathogenic anaerobic organisms can be facultative anaerobic organisms. The responsive pathogenic anaerobic organisms can be obligate anaerobic organisms. 【0015】 【0016】In some forms, unexpectedly, combinations and / or formulations of unpredicted co-agents herein having synergistic and sufficient and / or effective (e.g., as shown as one or more of activities (i)-(x)) antimicrobial activity against one or more pathogenic anaerobic organisms herein exhibit better antimicrobial activity (or greater potency) than the individual co-agents from the combinations and / or formulations when the co-agents act alone or separately against the same pathogenic anaerobic organisms (which can be evaluated using in vitro anaerobic AST). In some forms, unexpectedly, combinations and / or formulations of unpredicted co-agents herein having synergistic and sufficient and / or effective (e.g., as one or more of any of activities (i)-(x)) antimicrobial activity against one or more pathogenic anaerobic organisms herein exhibit better antimicrobial activity (or greater potency) than pairs of co-agents from the combinations and / or formulations when the pairs are provided against the same pathogenic anaerobic organisms (which can be evaluated using in vitro anaerobic AST). Benefits of the combinations and / or formulations of co-agents herein include meaningful efficacy (potency) against pathogenic anaerobic organisms, particularly those that cannot utilize oxygen and / or are inhibited by oxygen, compared to the activity of at least one co-agent from the combinations and / or formulations when used separately against the pathogenic anaerobic organisms (which can be evaluated using in vitro anaerobic AST). Another benefit of the combinations and / or formulations of co-agents herein includes safe and effective activity against pathogenic anaerobic organisms, particularly those that cannot utilize oxygen and / or are inhibited by oxygen, compared to currently approved antibiotics when used as prescribed against the same pathogenic anaerobic organisms in an anaerobic environment (which can be evaluated using in vitro anaerobic AST).Combinations of co-agents and / or other benefits of the formulations herein include inducing reversal of co-agent resistance to one or more pathogenic anaerobic organisms, particularly those that cannot utilize oxygen and / or are inhibited by oxygen, and those that are resistant or non-susceptible to the co-agents from the combination and / or formulation, when the co-agents are used separately against the pathogenic anaerobic organisms (which can be evaluated using in vitro anaerobic AST). In some embodiments, such pathogenic anaerobic organisms include at least one type or species of obligate anaerobic organisms in an anaerobic environment. In some embodiments, such pathogenic anaerobic organisms do not include non-responsive facultative anaerobic organisms of the genus Lactobacillus, Leuconostoc, and / or Pediococcus that do not respond (are non-susceptible) to the combinations of co-agents and / or formulations herein. 【0016】 【0017】One or more combinations and / or formulations of unpredicted co-agents herein having synergistic effects against one or more pathogenic anaerobic organisms and sufficient and / or effective (e.g., as shown as one or more of activities (i)-(x)) antimicrobial activity, when provided to the pathogenic anaerobic organisms herein, restore the activity (or efficacy) of at least one co-agent in the combination and / or formulation of co-agents, where at least one co-agent is not active against the pathogenic anaerobic organisms when used separately (or as a pair) (which can be evaluated using in vitro anaerobic AST). One or more combinations and / or formulations of unpredicted co-agents herein having synergistic effects against one or more pathogenic anaerobic organisms and sufficient and / or effective (e.g., as shown as any one or more of activities (i)-(x)) antimicrobial activity, when provided to the pathogenic anaerobic organisms herein, establish the activity of at least one co-agent in the combination and / or formulation of co-agents, where at least one co-agent is not active against the pathogenic anaerobic organisms when used separately (or as a pair) (which can be evaluated using in vitro anaerobic AST). The lack (or insufficient efficacy) of the activity of at least one co-agent against the pathogenic anaerobic organisms when acting individually (or as a pair) can be due to its intrinsic resistance, acquired resistance, and / or the phenotype of the pathogenic anaerobic organisms. In some embodiments, reversing or restoring or establishing the activity of the novel combinations and / or formulations of co-agents herein is due, at least in part, to the synergy of the co-agents, causing a synergistic effect of the co-agents that could not or did not previously exist, between or among the co-agents.In some embodiments, reversing or restoring or establishing the activity of at least one co-agent in the novel co-agent combinations and / or formulations herein causes or provides sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms that may include those that cannot utilize oxygen and / or are inhibited by oxygen in an anaerobic environment, where the sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms has not been previously observed by at least one co-agent when used anaerobically and separately (or as a pair). 【0017】 【0018】 In some embodiments, an unpredictable co-agent combination and / or formulation has a synergistic effect and sufficient and / or effective (e.g., as shown as any one or more of activities (i) - (x)) antimicrobial activity against one or more pathogenic anaerobic organisms when co-administered during the same period or overlapping periods, and the co-administration provides good antimicrobial efficacy and / or better antimicrobial efficacy compared to at least one co-agent in the combination when at least one of its co-agents is used separately (or as a pair) against pathogenic anaerobic organisms. In some embodiments, such pathogenic anaerobic organisms include at least one type or species of obligate anaerobic organisms in an anaerobic environment. In some embodiments, such pathogenic anaerobic organisms do not include non-responsive facultative anaerobic organisms of the genus Lactobacillus, Leuconostoc, and / or Pediococcus that do not respond (are not sensitive) to the co-agent combinations and / or formulations herein. 【0018】 【0019】In some embodiments, the combination and / or formulation of co-agents herein consists of, consists essentially of, or comprises a plurality of active co-agents consisting of, consisting essentially of, or comprising three active co-agents. In some embodiments, the plurality of active co-agents consists of, consists essentially of, or comprises four active co-agents. In some embodiments, the plurality of active co-agents consists of, consists essentially of, or comprises five active co-agents. In some embodiments, the plurality of active co-agents consists of, consists essentially of, or comprises six active co-agents. In some embodiments, the plurality of active co-agents consists of, consists essentially of, or comprises from three to five active co-agents. In some embodiments, the plurality of active co-agents consists of, consists essentially of, or comprises from three to six active co-agents. Co-agent or active co-agent is used interchangeably to define the co-agent herein in the combination and / or formulation, and when in the combination and / or formulation of co-agents, said co-agents are synergistic, have a synergistic effect, and are understood to cause sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms. (For example, when provided to one or more of the pathogenic anaerobic organisms described herein, shown as any one or more of activities (i)-(x), the synergistic effect and / or antimicrobial activity can be evaluated using standardized in vitro anaerobic AST, which at least identifies the minimum inhibitory concentration (MIC) for separate co-agents or pairs of two tested against pathogenic anaerobic organisms in an anaerobic environment, as well as for the combinations of co-agents described herein).In embodiments herein, the MIC and calculated fractional inhibitory concentration (FIC) index (to identify antimicrobial interactions such as synergistic (S), additive (A), indifferent (I), and antagonistic (X)) for the combinations and / or formulations of the three co-agents herein against pathogenic anaerobic organisms are obtained, and the MIC and / or FIC index (FICI) with the three co-agents herein is better than the additive activity of each co-agent when provided separately (individually) to the pathogenic anaerobic organisms (utilizing standardized anaerobic AST). In some embodiments herein, the MIC and / or FICI for the four co-agents herein against pathogenic anaerobic organisms herein is better than the additive activity of each co-agent when provided separately (individually) to the pathogenic anaerobic organisms (utilizing standardized anaerobic AST). In some embodiments herein, the MIC and / or FICI for the five co-agents herein against pathogenic anaerobic organisms herein is better than the additive activity of each co-agent when provided separately (individually) to the pathogenic anaerobic organisms (utilizing standardized anaerobic AST). In some embodiments herein, the MIC and / or FICI for the six co-agents herein against pathogenic anaerobic organisms herein is better than the additive activity of each co-agent when provided separately (individually) to the pathogenic anaerobic organisms (utilizing standardized anaerobic AST). In some embodiments, at least one co-agent is a known antibiotic (currently approved for use as an antibiotic). In some embodiments, at least two co-agents are known antibiotics, each currently approved for use as an antibiotic. In some embodiments, at least three co-agents are known antibiotics, each currently approved as an antibiotic. In some embodiments, at least four co-agents are known antibiotics, each currently approved for use as an antibiotic. In some embodiments, at least five co-agents are known antibiotics, each currently approved for use as an antibiotic.In some embodiments, at least six co-agents are known antibiotics, each of which is currently approved as an antibiotic. 【0019】 【0020】 In one or more embodiments, the unpredictable co-agent combinations and / or formulations described herein consist of, or consist essentially of, or comprise at least three co-agents selected from the group consisting of: (1) an inhibitor of F (identified above) or the microbial (bacterial) MurA enzyme (e.g., sodium phosphonomycin, fosfomycin trometamol, fosfomycin tromethamine, calcium phosphonomycin, sodium phosphonomycin, monobasic or dibasic water-soluble phosphonomycin salts, and phosphonic acid derivatives thereof, anything having some activity against aerobic bacteria in an aerobic environment, each of these being merely illustrative and representative for the purposes herein); (2) an inhibitor of D (identified above) or the microbial (bacterial) DHFR (e.g., pyrimethamine, trimethoprim, iclaprim, trimetrexate, methotrexate, pirithioxime, tetroxoprim, metioprim, brodimoprim, 3,4-diaminopyrimidine, 2,4-diaminopyrimidine, 4-desmethyltrimethoprim, 2,4-diamino-5-aryl-6-substituted pyrimidine derivatives having at least one R 2 substituent, a diaminopyrimidine having at least a more hydrophobic group at the 6-position of 2,4-diaminopyrimidine, at least one R 2 substituent, a diaminopyrimidine having at least one R 2 substituent having a hydroxy group: (type 1), a diaminopyrimidine having at least one R 2 substituent having an alkoxy group: (type 2), a diaminopyrimidine having at least one R 2 substituent having a thiazole group: (type 3), a diaminopyrimidine having at least one R 2Substituents, each of which is merely illustrative and representative for the purposes herein and can be anything having some activity against aerobic bacteria in an aerobic environment); (3) S (identified above) or an inhibitor of microbial (bacterial) DHPS (e.g., sulfisoxazole, sulfamethoxazole, sulfadiazine, sulfasalazine, sulfadimethoxine, sulfadoxine, sulfacetamide, zonisamide, para-aminomethylbenzenesulfonamide, sulfacetamide, sulfafurazole, sulfadimidazine, sulfaisodimidazine, sulfamoxole, sulfanitran, sulfamethoxypyridazine, sulfamethoxydiazine, sulfamethopyrazine, terephthalyl, sulfatroxazole, sulfamerazine, sulfamethazine, sulfapyrazole, sulfachinoxaline, sulfachloropyridazine, sulfaguanidine, sulfalen, sulfamethine, sulfamethoxine, sulfamethylphenazole, sulfethoxypyridazine, sulfabromomethazine, sulfaphenazole, sulfamoxole, sulfapyrazine, sulfapyridazine, sulfapyridine, sulfasymazine, sulfathiazole, sulfametrole, sulfanilimide, sulfasomidine, each of which is merely illustrative and representative for the purposes herein and can be anything having some activity against aerobic bacteria in an aerobic environment); (4) at least one antimicrobial agent quinazoline (Q) that itself has antimicrobial activity (against aerobic bacteria in an aerobic environment) and includes any suitable phosphate, salt, acid, and / or ester thereof, any of which interferes with and / or inhibits microbial (bacterial) DHFR (e.g., SCH79797, eristidin-16, anilinokynazoline (gefitinib, lapatinib), aminokynazoline (erlotinib, afatinib), and can be anything having some activity against aerobic bacteria in an aerobic environment);(5) An inhibitor (FMEI) of microbial (bacterial) phosphomycin modifying enzymes that inhibits or inactivates phosphomycin modifying enzymes (FME), such as FosA, FosB, FosC, FosX, or bacterial metalloenzymes (such as glutathione S-transferase, thiol S-transferase, epoxide hydrolase), or bacterial kinases (such as FomA and FomB, functionally related to FME) (for example, phosphonoformate, phosphonoacetate, acetylphosphonate, 2-phosphonobutyrate, 4-phosphonobutyrate, 2-phosphonopropionate, 2-phosphonopropionate, 3-phosphonopropionate, methylphosphonate, ethylphosphonate, phenylphosphonate, phosphonoacetaldehyde, sodium phosphonoformate, trisodium phosphonoformate hexahydrate, triethyl phosphonofomate, each of which is merely illustrative and representative for the purposes herein), and includes any suitable phosphate, salt, acid and / or ester thereof;(6) At least one inhibitor of microbial (bacterial) peptidoglycan synthesis (PGSI) that itself has some antimicrobial property (against aerobic bacteria in an aerobic environment) and includes any suitable phosphate, salt, acid, and / or ester thereof, all of which bind to the outer wall of bacteria (e.g., peptidoglycan) and inhibit or interfere with peptidoglycan synthesis as well as cell wall synthesis, or bind to an enzyme and inhibit cell wall polymerization or cross-linking, belonging to the class of glycopeptide / lipoglycopeptide antibiotics (e.g., including second generation, third generation, fourth generation, fifth generation, and sixth generation, such as ceftazidime, cefuroxime, cefoxitin, cefoperazone, ceftolozane, cephalexin, cefdinir, ceftriaxone, ceftaroline, cefixime, cefpodoxime, cefazolin, cefibuten, ceftaroline, cefuroxime, cefotaxime, cefoperazone, cefepime, ceftolozane, ceftriaxone, ceftobiprole, cefiderocol, cefoxitin, moxalactam, S-64922, etc.), vancomycin, teicoplanin, oritavancin, dalbavancin, telavancin, bleomycin, ramoplanin, decaplanin, dimycin A, coromyin, amoxicillin, meropenem, imipenem, which can be used alone or in combination with a BLI (as generally approved for use), and all examples herein are merely illustrative or representative for the purposes herein); (7) An inhibitor of microbial (bacterial) beta-lactamase (BLI) (from the class of beta-lactamase inhibitors) that includes any suitable phosphate, salt, acid, and / or ester thereof and is used alone or, more often, in combination with an antibiotic, e.g., an antibiotic of the beta-lactam class or other PGSI (e.g., avibactam, clavulanate / clavulanic acid (CA), relebactam, sulbactam, tazobactam, baloxavir, nacubactam, didemnibactam, QPX7728, ETX0282, VNRX5236, all of which are merely illustrative or representative for the purposes herein), either alone or in combination with a beta-lactam antibiotic (as generally indicated).; 【0020】 【0021】In some forms, unexpectedly having a synergistic effect of the co-agents, providing or causing antimicrobial activity (at least growth inhibitory activity and / or as any of activities (i)-(x) herein) against one or more pathogenic anaerobic organisms herein are the unexpected co-agent combinations and / or formulations herein that include at least the following co-agents: antimicrobial agent F (as described herein), antimicrobial agent D (as described herein), and antimicrobial agent S (as described herein). In some forms, unexpectedly having a synergistic effect of the co-agents, providing or causing antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein are the unexpected co-agent combinations and / or formulations herein that include at least the following co-agents: antimicrobial agent F, antimicrobial agent Q, antimicrobial agent S. In some embodiments, Q can replace D, and unexpectedly having a synergistic effect of the co-agents, provides yet further unexpected co-agent combinations and / or formulations that provide or cause antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms. In some forms, unexpectedly having a synergistic effect of the co-agents, providing or causing antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein are the unexpected co-agent combinations and / or formulations herein that include at least the co-agents: F, D, S, and PGSI. In some forms, unexpectedly having a synergistic effect of the co-agents, providing or causing antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein are the unexpected co-agent combinations and / or formulations herein that include at least the co-agents: F, D, S, and FMEI.In one form, combinations and / or formulations of agents that unexpectedly have a synergistic effect and provide or cause antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein are at least agent: F, D, S, and BLI when BLI itself has antimicrobial activity. 【0021】 【0022】 In one or more embodiments, combinations and / or formulations of agents that unexpectedly have a synergistic effect and provide or cause antimicrobial activity (at least growth inhibitory activity and / or any of activities (i)-(x) as described herein) against one or more pathogenic anaerobic organisms herein, wherein the agents are inhibitors of bacterial MurA enzymes having some antibacterial property; inhibitors of bacterial DHFR having some antibacterial property; and inhibitors of DHPS having some antibacterial property or include them. Optionally, the agents also include PGSI. Optionally, the agents include BLI when BLI itself has antimicrobial activity. Optionally, the agents include FMEI. Optionally, the agents include PGSI and BLI. Optionally, the agents include BLI and a beta-lactam antibiotic (PGSI). 【0022】 【0023】The combination and / or formulation of co-agents in any specification targets one or more pathogenic anaerobic organisms, the co-agents act synergistically as synergists, promoting or causing sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms herein (initiating at least one of the activities (i)-(x) and / or bacteriostatic activity and / or bacterial interference or removal described herein), where the targeted anaerobic organisms are at least certain types and / or species of pathogenic anaerobic organisms, including but not limited to obligate anaerobic organisms, obligate anaerobic organisms in mixed populations, GPOA, GNOA, GPOA in mixed populations, GNOA in mixed populations, drug-resistant obligate anaerobic organisms (intrinsic and / or acquired resistance), and any combination or arrangement thereof. In some embodiments, the targeted anaerobic organisms are in an anaerobic environment. In some embodiments, the targeted anaerobic organisms are in a pH-neutral environment. In some embodiments, the targeted anaerobic organisms are in a basic pH environment (e.g., above neutral pH and / or about pH 8 or about pH 9, or within any pH range therebetween). In some embodiments, the targeted anaerobic organisms are in an acidic pH environment (e.g., below neutral pH and / or about pH 5 or about pH 6, or within any pH range therebetween). Unexpectedly, the combination and / or formulation of co-agents herein effectively targets one or more pathogenic anaerobic organisms, the co-agents act synergistically as synergists, and it has been found to promote or cause sufficient and / or effective antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein in any or all of (aa) neutral pH; (bb) acidic pH; and (cc) basic pH. 【0023】 【0024】To promote or cause the synergistic effects and synergy of co-agents that promote or cause sufficient and / or effective antimicrobial activity (as at least one of activities (i)-(x) herein and / or bacteriostatic activity and / or at least bacterial interference or elimination of colony formation) against one or more pathogenic anaerobic organisms herein, three or more co-agents herein are delivered or dispensed (or administered or conveyed or presented) in a suitable manner such that the synergistic effects and synergy of the co-agents occur. In some embodiments, the delivery or dispensing (or administration or conveyance or presentation) is co-administration of three or more co-agents, and the co-administration occurs at the same time or approximately the same time to obtain synergy, synergistic effects, and sufficient and / or effective antimicrobial activity. In some embodiments, the delivery or dispensing (or administration or conveyance or presentation) is co-administration of three or more co-agents, and the co-administration occurs over a period of time to obtain synergy, synergistic effects, and sufficient and / or effective antimicrobial activity. In some embodiments, the delivery or dispensing (or administration or conveyance or presentation) is co-administration of three or more co-agents, and the co-administration occurs over an overlapping period of time to obtain synergy, synergistic effects, and sufficient and / or effective antimicrobial activity. The three or more co-agents may be provided as a whole or as one or more portions (e.g., doses), and each delivery or dispensing (or administration or conveyance or presentation) is independent or sequential, and the co-agents are provided simultaneously, sequentially, or within an acceptable period of time. The three or more co-agents may be in the same vehicle, or in different vehicles, or in two or more vehicles, or in three or more vehicles, or in four or more vehicles.In one or more embodiments, to cause or initiate a synergistic effect with a co-agent that is active against one or more pathogenic anaerobic organisms herein, and to promote or cause sufficient and / or effective antimicrobial activity (as described herein), three or more co-agents herein are in or provided by or maintained by or supported by or continue to be delivered or dispensed or administered or conveyed or presented in at least one vehicle that may also be for the delivery or dispensing or administration or conveyance or presentation of the co-agent, or the co-agents may be delivered or dispensed or administered or conveyed or presented in approximately the same period or substantially the same period (simultaneously or sequentially in one or more vehicles). In one or more embodiments, to cause or initiate a synergistic effect with a co-agent that is active against one or more pathogenic anaerobic organisms herein, and to promote or cause sufficient and / or effective antimicrobial activity (as described herein), three or more co-agents herein are in at least one vehicle that is also for the delivery or dispensing or administration or conveyance or presentation of the co-agent, or provided by or maintained by or supported by it, or the co-agents continue to be delivered or dispensed or administered or conveyed or presented (simultaneously or sequentially in one or more vehicles) for a period or overlapping periods that are any one of several minutes, about or up to about 15 minutes, about or up to about 30 minutes, about or up to about 1 hour, about or up to about 2 hours, about or up to about 3 hours, or any period or any range therebetween. 【0024】 【0025】In some embodiments, the use of combinations of co-agents and / or three or more co-agents in a formulation herein as a drug therapy or medicament provides a new use for at least one co-agent or more than one co-agent. In some embodiments, the use of combinations of co-agents and / or three or more co-agents in a formulation herein as a drug therapy or medicament resurrects at least one co-agent or more than one co-agent. In some embodiments, the use of combinations of co-agents and / or three or more co-agents in a formulation herein as a drug therapy or medicament provides enhanced therapeutic potential (or efficacy) for at least one co-agent or more than one co-agent. In some embodiments, the use of combinations of co-agents and / or three or more co-agents in a formulation herein as a drug therapy or medicament reverses the inactivity of at least one co-agent or more than one co-agent that is itself inactive against one or more pathogenic anaerobic organisms herein. 【0025】 【0026】In embodiments herein, delivery or dispensing (or administration or conveyance or presentation) of the active co-agent as herein or as above starts or causes or results in a response that includes any one or more of the following: (a) reduction (or growth reduction) of the growth of one or more pathogenic anaerobic organisms; (b) inhibition (or growth inhibition) of the growth of one or more pathogenic anaerobic organisms; (c) cessation (or growth cessation) of the growth of one or more pathogenic anaerobic organisms; (d) removal (or microbial removal) of all or part of one or more pathogenic anaerobic organisms; (e) reduction (or microbial reduction) of all or part of one or more pathogenic anaerobic organisms; (f) interference (or microbial interference) in all or part of one or more pathogenic anaerobic organisms; (g) change and / or enhancement and / or facilitation of the sensitivity of one or more pathogenic anaerobic organisms (which may or may not include one or more previously non-susceptible pathogenic anaerobic organisms and / or one or more intrinsically resistant pathogenic microorganisms) through the synergy of the active co-agent, where one or more active co-agents promote or cause a synergy for sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms (which may be currently susceptible to the active combinations and / or formulations described herein but may include those that are not susceptible to one or more co-agents when used separately or as a pair). In some embodiments, the pathogenic anaerobic organisms are or include obligate anaerobic organisms (GPOA and / or GNOA) in an anaerobic environment. 【0026】 【0027】In some embodiments, when a co-agent composition and / or formulation herein (including multiple co-agents or three or more active co-agents herein) is provided as a drug therapy to a host or subject having or suspected of having one or more pathogenic anaerobic organisms, or an infection caused or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in need of drug therapy), the co-agents initiate or cause a synergistic effect and sufficient and / or effective antimicrobial activity against one or more susceptible pathogenic anaerobic organisms, where one or more of responses (a)-(g) occur. Generally, one or more of reactions (a)-(g) occur within approximately one day or several days to several weeks after providing the multiple co-agents via at least one delivery or dispensing means. In many embodiments, the provision of multiple co-agents to a host or subject in need thereof is daily via one or more vehicles (containing one or more co-agents) by a delivery or dispensing means, and the multiple co-agents are co-administered over a period of time (the co-agents are in one or more formulations and are contained in one or more vehicles for delivery and / or dispensing). The co-administration of one or more formulations over a period of time via the delivery or dispensing of one or more vehicles over a period of time allows for the association and admixture of the co-agents to initiate or cause a synergistic effect and sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms (e.g., in an anaerobic environment). In some embodiments, the provision of multiple co-agents is for the treatment or treatment of a host or subject having or suspected of having at least one pathogenic anaerobic organism that is considered or found to be resistant (acquired resistance or intrinsic resistance) to one or more antibiotics, and the multiple co-agents are active against at least one pathogenic anaerobic organism considered or found to be resistant to antibiotics so as to overcome or reverse the resistance.In some embodiments, the provision of multiple co-agents is for the treatment or treatment of a host or subject having or suspected of having at least one pathogenic anaerobic organism that is considered or found to be resistant (acquired resistance or intrinsic resistance) to at least one of the co-agents, and the multiple co-agents are active against at least one pathogenic anaerobic organism that is considered or found to be resistant to at least one of the co-agents so as to overcome or reverse the resistance. Resistance can be evaluated via established in vitro AST against anaerobic organisms. In many embodiments, one or more susceptible pathogenic anaerobic organisms or at least one pathogen (having acquired or intrinsic resistance) in or on the host or subject (or suspected thereof) are obligate anaerobic organisms in an anaerobic environment. Obligate anaerobic organisms can be in a mixed population. In many embodiments, one or more susceptible pathogenic anaerobic organisms or at least one pathogen (having acquired resistance or intrinsic resistance) in or on the host or subject (or suspected thereof) are GPOA and / or GNOA and are not non-responsive facultative anaerobic organisms selected from one or more of the genus Lactobacillus, the genus Leuconostoc, and / or the genus Pediococcus. One or more susceptible pathogenic anaerobic organisms or at least one pathogen (having acquired or intrinsic resistance) in or on the host or subject (or suspected thereof) can be one or more or a combination of GPOA, GNOA, gram-positive facultative anaerobic organisms, gram-negative facultative anaerobic organisms, all of which may or may not be (individually) resistant to at least one co-agent due to acquired or intrinsic resistance. In some embodiments, one or more susceptible pathogenic anaerobic organisms or at least one pathogen (having acquired or intrinsic resistance) are in an anaerobic environment. The environment can be neutral pH, or acidic pH (less than 7 and as low as about 5 or as low as about 6) or basic pH (greater than 7 and as high as about 8 or as high as about 9) without significantly changing the synergistic effect of the co-agents.Three or more co-agents can be in one form and / or formulation, each being a therapeutically effective amount, and the co-agents are at least F, D, S, or F, Q, S. Three or more co-agents can be in one or more other forms and / or formulations, each being a therapeutically effective amount, and the co-agents are at least F, D, S, or F, Q, S. Three or more co-agents can be in one form and / or formulation, each being a therapeutically effective amount, and the co-agents are at least F, D, S, FMEI or F, Q, S, FMEI. Three or more co-agents can be in one or more other forms and / or formulations, each being a therapeutically effective amount, and the co-agents are at least F, D, S, FMEI or F, Q, S, FMEI. Three or more co-agents can be in one form and / or formulation, each being a therapeutically effective amount, and the co-agents are at least F, D, S, PGSI or F, Q, S, PGSI. Three or more co-agents can be in one or more other forms and / or formulations, each being a therapeutically effective amount, and the co-agents are at least F, D, S, PGSI or F, Q, S, PGSI. Three or more co-agents can be in one form and / or formulation, each being a therapeutically effective amount, and the co-agents are, when BLI itself has antimicrobial activity, at least F, D, S, BLI or F, Q, S, BLI. Three or more co-agents can be in one or more other forms and / or formulations, each being a therapeutically effective amount, and the co-agents are, when BLI itself has antimicrobial activity, at least F, D, S, BLI or F, Q, S, BLI. Three or more co-agents can be in one form and / or formulation, each being a therapeutically effective amount, and the co-agents are at least F, D, S, PGSI, BLI or F, Q, S, PGSI, BLI (generally when PGSI is from the class of beta-lactam antibiotics). Three or more co-agents can be in one or more other forms and / or formulations, each being a therapeutically effective amount, and the co-agents are at least F, D, S, PGSI, BLI or F, Q, S, PGSI, BLI (generally when PGSI is from the class of beta-lactam antibiotics).Three or more co-agents can be in one form and / or formulation or in more than one different form and / or formulation, each co-agent being in a therapeutically effective amount, the co-agents being at least: an inhibitor of bacterial MurA enzyme and having some antibacterial property in an aerobic environment; an inhibitor of bacterial DHFR and having some antibacterial property in an aerobic environment; and an inhibitor of bacterial DHPS and having some antibacterial property in an aerobic environment. Q as an inhibitor of bacterial DHFR having some antibacterial property in an aerobic environment can be replaced by D (or an inhibitor of bacterial DHFR herein) when in a therapeutically effective amount, the replacement initiating or causing synergy and sufficient and / or effective antimicrobial activity against one or more susceptible pathogenic anaerobic organisms or at least one pathogen (having acquired or intrinsic resistance) in an anaerobic environment. 【0027】 【0028】 When the combination and / or formulation of co-agents comprises F, D, S or F, Q, S, a further co-agent is provided, the further co-agent being at least PGSI and the pathogenic anaerobic organisms being at least GPOA and / or GNOA or including the same. In some embodiments, when BLI has antimicrobial activity, the further co-agent is at least BLI and the pathogenic anaerobic organisms are at least GPOA and / or GNOA or include the same. In some embodiments, the further co-agent is at least FMEI and the pathogenic anaerobic organisms are at least GPOA and / or GNOA or include the same. In some embodiments, the further co-agent is at least PGSI (as a beta-lactam antibiotic) and BLI and the pathogenic anaerobic organisms are at least GPOA and / or GNOA or include the same. In some forms, the further co-agent is amoxicillin and clavulanate and the pathogenic anaerobic organisms are at least GPOA and / or GNOA or include the same. In some forms, the further co-agent is vancomycin and at least one pathogenic anaerobic organism is at least GPOA and / or GNOA or includes the same. 【0028】 【0029】In one embodiment, a method of utilizing an effective amount of fosfomycin or an inhibitor of the microbial (bacterial) MurA enzyme (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, amines, and / or esters, and any combination thereof having activity against aerobic bacteria) as a synergist or active co-agent for a combination of antibiotics, wherein the combination of antibiotics comprises: (1) a diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR, and (2) a sulfonamide or an inhibitor of the microbial (bacterial) DHPS, the method comprising the steps of providing an effective amount and / or a sufficient amount of the combination of antibiotics to a host or subject in need thereof; and including an effective amount and / or a sufficient amount of the synergist or active co-agent, wherein the combination of antibiotics and the synergist or active co-agent are provided together or within a period including about 1 hour or 2 hours or 3 hours, and the host or subject has or is suspected of having an infection from one or more species and / or types of obligate anaerobic bacteria that are of one kind and / or species or different kinds and / or species, the diaminopyrimidine or inhibitor of the microbial (bacterial) DHFR being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, the sulfonamide or inhibitor of the microbial (bacterial) DHPS being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, and the diaminopyrimidine and the sulfonamide each having some antibacterial activity against aerobic bacteria individually / separately in an aerobic environment. 【0029】 【0030】In one embodiment, a method of utilizing an inhibitor of microbial (bacterial) peptidoglycan synthesis (PGSI) (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphate salts, acids and / or esters, and any combination thereof) as a synergist or active co-agent for a combination of antibiotics, wherein the combination of antibiotics comprises: (1) phosphomycin or an inhibitor of the microbial (bacterial) MurA enzyme; (2) a diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR, and (3) a sulfonamide or an inhibitor of the microbial (bacterial) DHPS, each of which, when alone, has some antibacterial activity against aerobic bacteria; the method comprising the step of providing an effective and / or sufficient amount of the combination of antibiotics to a host or subject in need of the combination of antibiotics; and the step of including an effective amount and / or sufficient amount of the synergist or active co-agent, wherein the combination of antibiotics and the synergist or active co-agent are provided together or within a period including about 1 hour or 2 hours or 3 hours, and the host or subject has or is suspected of having an infection from one or more types and / or species of anaerobic bacteria that are one type and / or species or different types and / or species, the inhibitor of the diaminopyrimidine or the microbial (bacterial) DHFR being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, the inhibitor of the sulfonamide or the microbial (bacterial) DHPS being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, and the inhibitor of phosphomycin or the microbial (bacterial) MurA enzyme being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and any combination thereof. 【0030】 【0031】In some embodiments, a method of utilizing an inhibitor of a microbial (bacterial) phosphomyein modifying enzyme (FMEI) (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof) as a synergist or active co-agent for a combination of antibiotics, wherein the combination of antibiotics comprises: (1) phosphomyein or an inhibitor of a microbial (bacterial) MurA enzyme; (2) a diaminopyrimidine or an inhibitor of a microbial (bacterial) DHFR; and (3) a sulfonamide or an inhibitor of a microbial (bacterial) DHPS, each of which, when alone, has some antibacterial activity against aerobic bacteria; the method comprising the step of providing to a host or subject in need an effective and / or sufficient amount of the combination of antibiotics; and the step of including an effective amount and / or sufficient amount of a synergist or active co-agent, wherein the combination of antibiotics and the synergist or active co-agent are provided together or within a period including about 1 hour or 2 hours or 3 hours, and the host or subject has or is suspected of having an infection from one or more types and / or species of anaerobic bacteria that are one or different types and / or species, the inhibitor of the diaminopyrimidine or the microbial (bacterial) DHFR being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, the inhibitor of the sulfonamide or the microbial (bacterial) DHPS being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, and the inhibitor of phosphomyein or the microbial (bacterial) MurA enzyme being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and any combination thereof. 【0031】 【0032】In one embodiment, a method of utilizing an effective amount of a microbial (bacterial) beta-lactamase inhibitor (BLI) (when the BLI itself has antibacterial properties, including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof) as a synergist or active co-agent for a combination of antibiotics, wherein the combination of antibiotics comprises: (1) fosfomycin or an inhibitor of the microbial (bacterial) MurA enzyme; (2) a diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR, and (3) a sulfonamide or an inhibitor of the microbial (bacterial) DHPS, each of which, when alone, has some antibacterial activity against aerobic bacteria; the method comprising the step of providing an effective and / or sufficient amount of the combination of antibiotics to a host or subject in need of the combination of antibiotics; and the step of including an effective amount and / or sufficient amount of the synergist or active co-agent, wherein the combination of antibiotics and the synergist or active co-agent are co-administered, together, or provided within 1 hour or 2 hours or 3 hours or a period including about 1 hour or 2 hours or 3 hours, and the host or subject has or is suspected of having an infection from one or more types and / or species of anaerobic bacteria that are of one or different types and / or species, the diaminopyrimidine or inhibitor of the microbial (bacterial) DHFR being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, the sulfonamide or inhibitor of the microbial (bacterial) DHPS being its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, and the fosfomycin or inhibitor of the microbial (bacterial) MurA enzyme being stereoisomers, its geometric isomers, its tautomers, its hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, amines, and / or esters, and any combination thereof. 【0032】 【0033】In one or more of the methods herein, the steps of providing and including promote or initiate or cause the synergistic action of a co-agent as a synergist. Due to the steps of providing and including, and the combination or co-administration of a synergist or co-agent and an antibiotic within a period, it promotes or initiates or causes the synergistic enhancement of the activity of a combination or co-agent of antibiotics as a drug therapy against one or more pathogenic anaerobic organisms. The steps of providing and including may involve co-administration within a period of all co-agents and synergists, which may be up to 12 daily periods until it is appropriate to discontinue from one period. The steps of providing and including occur together or substantially together or occur during a period, the period including within about 1 hour or less, or within about 2 hours or less, or within 3 hours or less, or being continuous. The steps of providing and including can lead to or result in or induce sufficient and / or effective antimicrobial activity of a combination or combination of antibiotics containing a co-agent and / or synergist against one or more types and / or species of anaerobic bacteria. In one or more of the methods herein, the further including step occurs together or substantially together with or during the same period as the steps of providing and / or including, the period including within about 1 hour or less, or within about 2 hours or less, or within 3 hours or less. Additionally, or alternatively, the steps of providing and including a combination or combination of antibiotics containing a co-agent and / or synergist and / or a further co-agent and / or a further synergist can occur in one of a neutral pH environment, an acidic pH environment, or a basic pH environment that neither disrupts nor interferes with synergistic action and / or sufficient and / or effective antimicrobial activity. 【0033】 【0034】Also provided herein are a plurality of co-agents for use as antimicrobial pharmaceutical agents against one or more pathogenic anaerobic organisms in an anaerobic environment, the co-agents comprising phosphomycin in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, amines, and esters, wherein phosphomycin alone is active against aerobic bacteria in an aerobic environment and can be replaced by an inhibitor of bacterial UDP-GlcNAc enolpyruvyl transferase having some activity against aerobic bacteria in an aerobic environment; a diaminopyrimidine in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, and esters, wherein the diaminopyrimidine is active against aerobic bacteria in an aerobic environment and can be replaced by an inhibitor of bacterial dihydrofolate reductase having some activity against aerobic bacteria in an aerobic environment; and a sulfonamide in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, and esters, wherein the sulfonamide is active against aerobic bacteria in an aerobic environment and can be replaced by an inhibitor of bacterial dihydropteroate synthase having some activity against aerobic bacteria in an aerobic environment, the plurality of co-agents being provided to a subject in need thereof for at least one period, one or more of the plurality of co-agents acting as synergists to cause antibacterial activity against one or more pathogenic anaerobic organisms in an anaerobic environment, the at least one period being selected from the group consisting of about 3 hours or less, about 2 hours or less, and about 1 hour or less. The plurality of co-agents can be active against at least one of one or more pathogenic anaerobic organisms when at least one of the one or more pathogenic anaerobic organisms is at any of acidic pH, neutral pH, and basic pH, with acidic pH being about pH 5 or lower and basic pH being about pH 8 or higher. When at least one co-agent is used separately against at least one of one or more pathogenic anaerobic organisms, at least one of the one or more pathogenic anaerobic organisms is considered resistant to at least one of the plurality of co-agents, and at least one of the one or more pathogenic anaerobic organisms is an obligate anaerobic bacterium.A plurality of co-agents can be provided as a drug therapy to a subject, the plurality of co-agents are provided during a period by co-administration, and the co-administration is further selected from the group consisting of the same time, substantially the same time, overlapping time spreads within the period, and sequences within the period. The co-administration within the period can be selected from one of the group consisting of once, twice, three times, four times, six times, eight times, twelve times, and continuously within 24 hours. The plurality of co-agents can be provided as a drug therapy to a subject having or suspected of having an infectious disease caused by or suspected of being caused by one or more Gram-positive obligate anaerobic bacteria in an anaerobic environment in or on the subject. The plurality of co-agents can be provided as a drug therapy to a subject having or suspected of having an infectious disease caused by or suspected of being caused by one or more Gram-negative obligate anaerobic bacteria in an anaerobic environment in or on the subject. The plurality of co-agents can be provided as a drug therapy to a subject having or suspected of having an infectious disease caused by or suspected of being caused by one or more challenging anaerobes selected from microaerophilic streptococci including one or more of S. anginosus, S. constellatus, S. intermedius, S. mutans, and viridans streptococci, and the plurality of co-agents are active against one or more microaerophilic streptococci.The plurality of co-agents can be provided as drug therapy to a subject having or suspected of having an infection caused by or suspected of being caused by one or more gram-positive obligate anaerobic bacteria selected from the group consisting of Actinomyces spp., Arcanobacterium spp., Atopobium spp., Bifidobacterium spp., Bilophila spp., Clostridioides spp., Clostridium spp., Collinsella spp., Eggerthella spp., Eubacterium spp., Finegoldia spp., Parvimonas spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp. and Cutibacterium spp., and the plurality of co-agents are active against one or more gram-positive obligate anaerobic bacteria.A plurality of co-agents can be provided as a drug therapy to a subject in need of drug therapy who has or is suspected of having an infection caused by or suspected of being caused by one or more Gram-negative obligate anaerobic bacteria selected from the group consisting of Aggretibacter spp., Bacteroides spp., Parabacteroides spp., Dethiosulfovibrio spp., Fusobacterium spp., Phocaeicola spp., Porphyromonas spp., Prevotella spp., Sutterella spp., Veillonella spp. The plurality of co-agents are active against one or more Gram-negative obligate anaerobic bacteria. The plurality of co-agents, when provided as a drug therapy to a subject, are neither active nor effective against one or more symbiotic anaerobic bacterial species selected from the group consisting of Lactobacillus spp., Pediococcus spp., and Leuconostoc spp. 【0034】 【0035】In other embodiments, a synergist for a combination of antibiotics, wherein the combination of antibiotics is a diaminopyrimidine in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids and esters, which can be replaced by an inhibitor of bacterial dihydrofolate reductase, and when any of them is used separately: (a) has some activity against aerobic bacteria in an aerobic environment; (b) has no activity against one or more obligate anaerobic bacteria in an anaerobic environment, a diaminopyrimidine; and a sulfonamide in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids and esters, which can be replaced by an inhibitor of bacterial dihydropteroate synthase, and when any of them is used separately, (a) has some activity against aerobic bacteria in an aerobic environment; (b) has no activity against one or more obligate anaerobic bacteria in an anaerobic environment, a sulfonamide; the diaminopyrimidine and the inhibitor of bacterial dihydrofolate reductase inhibit or inactivate the dihydrofolate reductase enzyme of one or more obligate anaerobic bacteria, the sulfonamide and the inhibitor of bacterial dihydropteroate synthase inhibit or inactivate the dihydropteroate synthase enzyme of one or more obligate anaerobic bacteria, the synergist comprises at least a phosphomycin in a pharmaceutically acceptable form selected from one or more of salts, phosphates, amines, acids and esters, which can be replaced by an inhibitor of bacterial UDP-GlcNAc enolpyruvyl transferase (MurA), and when any of them is used separately, (a) has some activity against aerobic bacteria in an aerobic environment; (b) has no activity against one or more obligate anaerobic bacteria in an anaerobic environment, a phosphomycin; the synergist with the combination of antibiotics causes a synergistic effect to convert the therapeutic potential of the combination of antibiotics, and as a result, the synergist with the combination of antibiotics is active against one or more obligate anaerobic bacteria in an anaerobic environment.The combination of the synergist and the antibiotic can be in the same formulation or in different formulations. For synergistic effect, the combination of the synergist and the antibiotic is provided within the same period, and the period is selected from one of the group consisting of within about 1 hour or less, within about 2 hours or less, and within about 3 hours or less. The combination of the synergist and the antibiotic as a drug therapy for a subject in need thereof is provided to the subject within a period, and the period for providing the combination of the synergist and the antibiotic is selected from one of the group consisting of the same period, substantially the same period, overlapping time spreads within the period, and sequences within the period. Phosphomycin or an inhibitor of bacterial MurA can be selected from one or more of the group consisting of phosphonates, phosphoric acid, derivatives of phosphonates, derivatives of phosphoric acid, its stereoisomers, its geometric isomers, its tautomers, its hydrates, its solvates, and a representative example of phosphomycin is a water-soluble phosphomycin salt. Diaminopyrimidine or an inhibitor of bacterial dihydrofolate reductase can be selected from one or more of the group consisting of 2,4-diaminopyrimidine, derivatives of 2,4-diaminopyrimidine, its stereoisomers, its geometric isomers, its tautomers, its hydrates, its solvates, and a representative example of diaminopyrimidine is selected from one or more of trimethoprim, pyrimethamine, diaveridine, brodimoprim, tetroxoprim, methioprim, and iclaprim.Inhibitors of sulfonamides or bacterial dihydropteroate synthase can be selected from one or more of the group consisting of sulfanilamides, derivatives of sulfanilamides, sulfamides, derivatives of sulfamides, sulfonamides, derivatives of sulfonamides, disulfonimides, derivatives of disulfonimides, their stereoisomers, their geometric isomers, their tautomers, their hydrates, and their solvates. Representative examples of sulfonamides include sulfadiazine, sulfamethoxazole, sulfatroxazole, sulfamerazine, sulfadoxine, sulfadimethoxine, sulfamethazine, sulfapyrazole, sulfachinoxaline, sulfachloropyridazine, sulfaguanidine, sulfalen, sulfamethine, sulfamethoxine, sulfamethoxypyridazine, sulfamethylphenazole, sulfamethoxypyridazine, sulfethoxypyridazine, sulfabromomethazine, sulfaphenazole, sulfamoxole, sulfapyridazine, sulfapyrimidine, sulfapyridine, sulfachloropyridazine, sulfathiazole, sulfametrole, sulfanilylimide, sulfasomidine, and sulfisoxazole. The synergist may further include a co-agent, and the co-agent is an inhibitor of bacterial phosphomycin modification (FME) enzyme selected from one or more of the group consisting of phosphonformate, phosphonoacetate, methylphosphonate, ethylphosphonate, phenylphosphonate, acetylphosphonate, phosphonoacetaldehyde, its stereoisomers, its geometric isomers, its tautomers, its hydrates, and its solvates. Representative examples include sodium phosphonoformate, sodium phosphonoformate tribasic hexahydrate, triethylphosphonformate, 2-phosphonobutyrate, 4-phosphonobutyrate, 2-phosphonopropionate, 2-phosphonopropionate, and 3-phosphonopropionate. The inhibitor of bacterial FME inhibits or inactivates the FME of one or more obligate anaerobic bacteria.The synergist may further contain a co-agent, and the co-agent is: (a) an inhibitor of bacterial peptidoglycan synthesis selected from antibiotics of the glycopeptide or lipoglycopeptide class, which binds to the lipid II precursor of the outer wall of one or more obligate anaerobic bacteria, inhibits peptidoglycan synthesis, and inhibits the synthesis of the cell wall of one or more obligate anaerobic bacteria; (b) a beta-lactam antibiotic selected from the class of beta-lactam antibiotics, which binds to the penicillin-binding protein enzyme and inhibits peptidoglycan synthesis of one or more obligate anaerobic bacteria; and (c) an inhibitor of bacterial beta-lactamase, which inhibits or inactivates the beta-lactamase enzyme of one or more obligate anaerobic bacteria, and is one or more from the group of co-agents consisting of inhibitors of bacterial beta-lactamase. The co-agent is provided as a combination with the synergist and the antibiotic within the same period, and the period is selected from one of the group consisting of within about 1 hour or less, within about 2 hours or less, and within about 3 hours or less. The combination of the synergist and the antibiotic and the co-agent are provided one, two, three, four, six, eight, twelve times, or continuously within 24 hours, selected from one of the group consisting of one, two, three, four, six, eight, twelve times, and continuously. 【0035】 【0036】Also provided herein is a kit containing a co-agent for use as an antimicrobial agent against one or more pathogenic anaerobic organisms in an anaerobic environment, the kit comprising at least: a therapeutically effective amount of a first co-agent for delivery within 24 hours of the first co-agent, which is fosfomycin in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, amines, and esters, and which is an inhibitor of bacterial UDP-GlcNAc enolpyruvate transferase when used alone in an aerobic environment; a therapeutically effective amount of a second co-agent for delivery within 24 hours of the second co-agent, which is a diaminopyrimidine in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, and esters, and which is an inhibitor of bacterial dihydrofolate reductase when used alone in an aerobic environment; a therapeutically effective amount of a third co-agent for delivery within 24 hours of the third co-agent, which is a sulfonamide in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, and esters, and which is an inhibitor of bacterial dihydropteroate synthase when the second co-agent is used alone in an aerobic environment; and optionally, at least one diluent for any one or more of the first co-agent, the second co-agent, and the third co-agent, wherein the first co-agent, the second co-agent, and the third co-agent are in one or more vehicles, and the one or more vehicles contain a sufficient amount for at least one delivery within 24 hours, the kit being for delivery of a therapeutically effective amount of the first co-agent and a therapeutically effective amount of the second co-agent and a therapeutically effective amount of the third co-agent for treatment or prevention of an infection from one or more obligate anaerobic bacteria to a subject in at least one delivery. 【0036】 【0037】Also provided herein is a synergist or co-agent or active co-agent for a combination of antibiotics, comprising at least an effective amount or a therapeutically effective amount of a diaminopyrimidine or an inhibitor of microbial (bacterial) DHFR; and an effective amount or a therapeutically effective amount of a sulfonamide or an inhibitor of microbial (bacterial) DHPS, each of which, when alone, has some antibacterial activity against aerobic bacteria; the synergist or co-agent or active co-agent comprising an effective amount or a therapeutically effective amount of fosfomycin or an inhibitor of microbial (bacterial) MurA enzyme (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and combinations thereof, which have some antibacterial activity against aerobic bacteria), the synergist or co-agent or active co-agent for a combination of antibiotics initiating, causing or imparting a synergistic effect and effective and / or sufficient antimicrobial activity against one or more pathogenic anaerobic organisms, the combination of antibiotics and the synergist or co-agent or active co-agent being in the same formulation or different formulations, the combination of antibiotics and the synergist or co-agent or active co-agent being provided for the same period or a substantially same period, the period being within about 1 hour or less, or within about 2 hours or less, or within about 3 hours or less, the diaminopyrimidine or the inhibitor of microbial (bacterial) DHFR being its stereoisomers, its geometric isomers, its tautomers, its hydrates, its solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and combinations thereof, and the sulfonamide or the inhibitor of microbial (bacterial) DHPS being its stereoisomers, its geometric isomers, its tautomers, its hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and combinations thereof, which is a synergist or co-agent or active co-agent. 【0037】 【0038】In some embodiments, a synergist or co-agent or active co-agent for converting the therapeutic potential of a combination of antibiotics when used against at least one or more anaerobic bacteria, wherein the combination of antibiotics comprises at least an effective amount or a therapeutically effective amount of a diaminopyrimidine or an inhibitor of microbial (bacterial) DHFR; and at least an effective amount or a therapeutically effective amount of a sulfonamide or an inhibitor of microbial (bacterial) DHPS, each of which has some activity against aerobic bacteria when alone, and the synergist comprises an effective amount or a therapeutically effective amount of phosphomycin or an inhibitor of microbial (bacterial) MurA enzyme (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and any combination thereof, and having some activity against aerobic bacteria), so that the synergist or co-agent or active co-agent accompanied by the combination of antibiotics is therapeutically effective against one or more anaerobic bacteria in an anaerobic environment, or an infectious disease caused by or suspected of being caused by one or more anaerobic bacteria in an anaerobic environment, wherein the combination of antibiotics alone without the synergist or co-agent or active co-agent is less therapeutically effective or therapeutically ineffective against one or more anaerobic bacteria and / or the infectious disease, the combination of antibiotics and the synergist or co-agent or active co-agent are in the same formulation or different formulations, the combination of antibiotics and the synergist or co-agent or active co-agent are provided within the same period or a substantially same period, or within about 1 hour or 2 hours or 3 hours, the diaminopyrimidine or the inhibitor of microbial (bacterial) DHFR is its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and combinations thereof, and the sulfonamide or the inhibitor of microbial (bacterial) DHPS is its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and combinations thereof, which is a synergist or co-agent or active co-agent. 【0038】 【0039】In some embodiments, a synergist or co-agent or active co-agent for converting the therapeutic potential of a combination of antibiotics when used against at least one or a plurality of anaerobic bacteria in an anaerobic environment, wherein the combination of antibiotics comprises at least: (aa) an effective amount or a therapeutically effective amount of fosfomycin or an inhibitor of the microbial (bacterial) MurA enzyme, either of which comprises its stereoisomers, its geometric isomers, its tautomers, its hydrates, its solvates, its pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and any combination thereof; (bb) an effective amount or a therapeutically effective amount of a diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR, either of which comprises its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof, and (cc) an effective amount or a therapeutically effective amount of a sulfonamide or an inhibitor of the microbial (bacterial) DHPS, either of which comprises its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof, wherein each of (aa), (bb), and (cc) has some activity against aerobic bacteria alone, and the synergist or co-agent or active co-agent comprises an effective amount or a therapeutically effective amount of any one or combination of: (dd) an inhibitor of microbial (bacterial) peptidoglycan synthesis from the class of glycopeptide / lipoglycopeptide antibiotics that binds to the outer wall of the bacterium and inhibits or interferes with bacterial peptidoglycan synthesis and the synthesis of its cell wall, comprising its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and combinations thereof; (ee) an inhibitor of the microbial (bacterial) fosfomycin modifying enzyme, comprising its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof;(ff) It contains an inhibitor of microbial (bacterial) beta-lactamase (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and combinations thereof), and thus a synergist or co-agent or active co-agent accompanied by a combination of antibiotics is therapeutically effective against one or more anaerobic bacteria, or an infectious disease caused by or suspected of being caused by one or more anaerobic bacteria, and a combination of antibiotics alone without a synergist or co-agent or active co-agent is less therapeutically effective or therapeutically ineffective against one or more anaerobic bacteria and / or the infectious disease, and the combination of antibiotics and the synergist or co-agent or active co-agent are in the same formulation or different formulations, and the combination of antibiotics and the synergist or co-agent or active co-agent are provided during the same period or substantially the same period, or within a period of about 1 hour or about 2 hours or about 3 hours, and it is a synergist or co-agent or active co-agent.; 【0039】 【0040】Also provided herein are a plurality of co-agents or active co-agents as a combination for use against at least one or more obligate anaerobic organisms or for use against at least one or more obligate anaerobic organisms, the plurality of co-agents or active co-agents comprising at least: an effective or therapeutically effective amount of a diaminopyrimidine or an inhibitor of microbial (bacterial) DHFR in a pharmaceutically acceptable form (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof); an effective or therapeutically effective amount of a sulfonamide or an inhibitor of microbial (bacterial) DHPS in a pharmaceutically acceptable form (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combination thereof); and an effective or therapeutically effective amount of phosphomycin or an inhibitor of microbial (bacterial) MurA enzyme in a pharmaceutically acceptable form (including its stereoisomers, geometric isomers, tautomers, hydrates, solvates, its pharmaceutically acceptable phosphates, salts, acids, amines and / or esters, and any combination thereof), wherein each co-agent, when used alone, has some activity against aerobic bacteria, and the plurality of co-agents are therapeutically effective and active against one or more obligate anaerobic organisms in an anaerobic environment, where one or more obligate anaerobic organisms are suspected of causing or causing an infectious disease in a host or subject, and the plurality of co-agents are provided to the host or subject by co-administration within a period of about 1 hour or about 2 hours or about 3 hours. 【0040】 【0041】In some embodiments, the invention herein is a combination of co-agents (or at least three active co-agents) in at least one pharmaceutically acceptable formulation as a drug therapy against one or more pathogenic anaerobic organisms (e.g., gram-positive and / or gram-negative anaerobic bacteria), wherein the co-agents are active and effective in an anaerobic environment, the co-agents are synergistic agents, and in an anaerobic environment, reverse at least one resistance of one or more pathogenic anaerobic organisms to at least one of the co-agents (e.g., reverse resistance in one or more gram-negative pathogens or obligate anaerobic organisms that exhibit bacterial resistance to F separately, and / or reverse resistance in one or more gram-negative and / or gram-positive pathogens or obligate anaerobic organisms that exhibit bacterial resistance to either D or S separately, or to D and S as a pair). In some forms, the one or more pathogenic anaerobic organisms are in and / or on a host or subject, and the at least one pharmaceutically acceptable formulation is delivered to or dispensed within the host or subject in one or more therapeutically acceptable conveyances or vehicles and in a therapeutically effective amount.Delivery or dispensing of at least one pharmaceutically acceptable formulation causes or facilitates an effect at several subsequent times, and the effect is at least one of the following: (i) growth inhibitory activity against one or more pathogenic anaerobic organisms; (ii) sustained growth inhibitory activity against one or more pathogenic anaerobic organisms; (iii) removal (and / or destruction) of one or more pathogenic anaerobic organisms; (iv) sustained removal (and / or destruction) of one or more pathogenic anaerobic organisms; (v) prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vi) sustained prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vii) alleviation of an infection caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a host or subject); (viii) management of an infection caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a host or subject); (ix) prevention of an infection that would be suspected of being caused by, derived from, or developing from one or more pathogenic anaerobic organisms (e.g., in a host or subject); (x) reduction or alleviation of the infection rate of an infection caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a host or subject). 【0041】 【0042】In the methods or combinations involving combinations of antibiotics herein, there may be a synergist or co-agent or additional synergist or additional co-agent which is any one or any combination of an inhibitor of a phosphomycin modifying enzyme; an inhibitor of microbial (bacterial) peptidoglycan synthesis from the class of glycopeptide / lipoglycopeptide antibiotics that bind to the outer wall of bacteria and inhibit or interfere with bacterial peptidoglycan synthesis and cell wall synthesis; an inhibitor of microbial (bacterial) beta-lactamase, an antimicrobial beta-lactam antibiotic; and an antimicrobial agent, any of which may be its stereoisomer, its geometric isomer, its tautomer, its hydrate, its solvate, its pharmaceutically acceptable phosphate, salt, acid, and / or ester, and combinations thereof, each being in a pharmaceutically acceptable amount and / or effective amount. In any method or combination herein, quinazoline (Q) herein replaces diaminopyrimidine (D) herein, unexpectedly causing a synergistic effect of the co-agent and providing additional unexpected combinations and / or formulations of co-agents that provide antimicrobial activity (as described herein) against one or more pathogenic anaerobic organisms herein. 【0042】 【0043】For the combinations or combinations of antibiotics and / or methods herein, the synergist or co-agent or additional synergist or additional co-agent or combination or combination of antibiotics is provided in a pharmaceutically acceptable amount and / or an effective amount for synergy. For the combinations or combinations of antibiotics and / or methods herein, the synergist or co-agent or additional synergist or additional co-agent or combination or combination of antibiotics is provided in a pharmaceutically acceptable amount and / or an effective amount for sufficient and / or effective antimicrobial activity against the target anaerobic organisms. For the combinations or combinations of antibiotics and / or methods herein, the synergist or co-agent or additional synergist or additional co-agent or combination or combination of antibiotics is (a) reducing the growth of one or more pathogenic anaerobic organisms; (b) inhibiting the growth of one or more pathogenic anaerobic organisms; (c) interrupting the growth of one or more pathogenic anaerobic organisms; (d) removing all or part of one or more pathogenic anaerobic organisms; (e) reducing all or part of one or more pathogenic anaerobic organisms; (f) interfering with all or part of one or more pathogenic anaerobic organisms; and (g) changing or enhancing or promoting the sensitivity of one or more pathogenic anaerobic organisms through the synergistic effect of the active co-agent (e.g., the active co-agent is a synergist and has a synergistic effect, and when in the described combination and / or formulation, the pathogenic anaerobic organisms are sufficiently interfered with in such a way that the pathogenic anaerobic organisms become sensitive to the active co-agent), can cause or initiate or promote one or more of the responses, and when used independently and separately against pathogenic anaerobic organisms, one or more pathogenic anaerobic organisms may or may not be insensitive and / or intrinsically resistant to at least one co-agent. For the methods or combinations and / or combinations of antimicrobial agents herein, effective and / or sufficient antibacterial activity can be reflected in any one or more of the activities (i)-(x) herein. 【0043】 【0044】In the combinations or combinations of antibiotics and / or methods herein, the plurality of co-agents or synergists or co-agents can include or further include any one or more of an inhibitor of a microbial (bacterial) phosphomycin modifying enzyme (FMEI); an inhibitor of microbial (bacterial) peptidoglycan synthesis (PGSI) (e.g., from the class of glycopeptide / lipoglycopeptide antibiotics that bind to the outer wall of bacteria and inhibit or interfere with bacterial peptidoglycan synthesis and the synthesis of its cell wall); an inhibitor of microbial (bacterial) beta-lactamase (BLI); and a beta-lactam antibiotic (e.g., PGSI as a beta-lactam antibiotic having antimicrobial activity), any of which can be in a pharmaceutically acceptable form including its stereoisomers, its geometric isomers, its tautomers, its hydrates, its solvates, its pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof. 【0044】 【0045】In the combinations or combinations of antibiotics and / or methods herein, when used independently or separately against anaerobic bacteria or pathogenic anaerobic organisms, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms is not sensitive or responsive to at least one co-agent or synergist, which can be evaluated by standardized in vitro AST for anaerobic organisms. In the combinations or combinations of antibiotics and / or methods herein, when evaluated independently or separately against anaerobic bacteria or pathogenic anaerobic organisms, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms is resistant to at least one co-agent or synergist, which can be determined or identified by standardized in vitro AST for anaerobic organisms. In the methods or combinations and / or combinations of antimicrobial agents herein, clinical samples or specimens can be used to evaluate the sensitivity or resistance of at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms in response to the co-agent or synergist or combination or combination of antibiotics or multiple co-agents (via standardized in vitro AST for anaerobic organisms) herein, and the clinical samples can be obtained from the site of infection or a site suspected of having or containing an infection, and the site is from one or more of blood, urine, wound, sputum, rectum, feces, pharynx, and / or biopsy under direct vision. In the combinations or combinations of antibiotics and / or methods herein, one or more types and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be pathogenic obligate anaerobic organisms.In the combinations or combinations of antibiotics and / or methods herein, one or more types and / or species of anaerobic bacteria or pathogenic anaerobic organisms are certain types and / or species of obligate anaerobic organisms, certain types and / or species of obligate anaerobic organisms in a mixed population, certain types and / or species of GPOA, certain types and / or species of GNOA, certain types and / or species of GPOA in a mixed population, certain types and / or species of GNOA in a mixed population, certain types and / or species of drug-resistant anaerobic organisms (when evaluated independently and separately from the anaerobic organisms, having intrinsic resistance to at least one co-agent or active co-agent or synergist, which can be identified by in vitro testing and can be or include an obligate anaerobic organism), certain types and / or species of drug-resistant anaerobic organisms (when provided independently and separately from the anaerobic organisms, having acquired resistance to at least one co-agent or active co-agent, which is identified by in vitro testing and can be or include an obligate anaerobic organism), and at least one of any combination or arrangement thereof. In the combinations or combinations of antibiotics and / or methods herein, one or more types and / or species of anaerobic bacteria or pathogenic anaerobic organisms are in (e.g., survive in) an anaerobic environment. In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be GPOA in an anaerobic environment.In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be one or more of Actinomyces species, Alkanobacterium species, Atopobium species, Bifidobacterium species, Bifidobacterium species, Clostridioides species, Clostridium species, Collinsella species, Eggerthella species, Eubacterium species, Finegoldia species, Parvimonas species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, and / or Cutibacterium species, and / or microaerophilic Streptococcus species (including one or more of S. anginosus, S. constellatus, S. intermedius, S. mutans, and one or more of green streptococci) in an anaerobic environment. In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be one or more of Actinomyces species, Alkanobacterium species, Atopobium species, Bifidobacterium species, Bifidobacterium species, Collinsella species, Eggerthella species, Eubacterium species, Finegoldia species, Parvimonas species, Peptococcus species, Peptostreptococcus species, Propionibacterium species, and / or Cutibacterium species, and / or microaerophilic Streptococcus species (including one or more of S. anginosus, S. constellatus, S. intermedius, S. mutans) in an anaerobic environment. In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be GNOA in an anaerobic environment. In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms can be one or more of Aggregatibacter species, Bacteroides species, Parabacteroides species, Desulfovibrio species, Fusobacterium species, Focaeicola species, Porphyromonas species, Prevotella species, Sutterella species, Veillonella species in an anaerobic environment.In the combinations or combinations of antibiotics and / or methods herein, at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms are obligate pathogenic anaerobic organisms (Gram-positive and / or Gram-negative) and are not any one or more of the Lactobacillus species, Pediococcus species or Leuconostoc species. In the combinations or combinations of antibiotics and / or methods herein, when the co-agent and / or synergist is F, D, S or F, Q, S, each of Lactobacillus, Pediococcus and Leuconostoc is non-responsive or insensitive to a plurality of co-agents or combinations or combinations of antibiotics herein with a synergist. In the combinations or combinations of antibiotics and / or methods herein, the anaerobic bacteria are at any one of neutral pH, acidic pH and basic pH, the pH is between about 5-8, or any range therebetween, without disturbing the synergistic effect of the co-agent. 【0045】 【0046】In the combinations or combinations of antibiotics and / or methods herein, the synergist or co-agent or co-agents enhance or augment or facilitate the antibacterial activity to an effective level in a synergistic manner, which can be evaluated from clinical samples obtained from or taken from a host or subject having or suspected of having pathogenic anaerobic organisms, in vitro or in a clinical setting, which require one or more of the methods and / or combinations or combinations of antibiotics described herein. In the combinations or combinations of antibiotics and / or methods herein, the combination or combination of antibiotics or co-agents provide or facilitate a growth inhibitory effect against at least one type and / or species of anaerobic bacteria or pathogenic anaerobic organisms, which is greater than the growth inhibitory effect of one synergist or one co-agent or one active co-agent when individually (separately) evaluated against pathogenic anaerobic organisms. In the combinations or combinations of antibiotics and / or methods herein, the synergist or co-agent or active co-agent can be in a pharmaceutically acceptable formulation and / or pharmaceutical active formulation intended for the treatment of an infection suspected to be in or within the host or subject. In the combinations or combinations of antibiotics and / or methods herein, the combination or combination of antibiotics can be in a pharmaceutically acceptable form or formulation intended for the treatment of an infection suspected to be in or within the host or subject that requires the combination or combination of antibiotics. In the combinations or combinations of antibiotics and / or methods herein, an infection from (or suspected of) pathogenic anaerobic organisms or anaerobic bacteria may not resolve in the absence of a synergist (without at least one synergist) or in the absence of co-agents. In the combinations or combinations of antibiotics and / or methods herein, the combination of synergist and antibiotic or co-agents can be provided to a host or subject that requires the combination of synergist and antibiotic or co-agents in substantially the same manner and / or form.In the combinations or combinations of antibiotics and / or methods herein, the synergist and the combination of antibiotics or multiple co-agents can be provided to a host or subject in need thereof in different ways and / or forms. In the combinations or combinations of antibiotics and / or methods herein, the synergist and / or the combination of antibiotics and / or multiple co-agents are provided to a host or subject in need thereof by one or more routes (for delivery or dispensing or administration), which may be the same route or different routes, and the one or more routes include one (or a combination thereof) of concentrated water enema, suppository, enteral, intravenous, intraperitoneal, inhalation, intramuscular, subcutaneous, and oral. 【0046】 【0047】In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and the synergist or multiple co-agents can be provided to a subject or host in need thereof once (e.g., before or after surgery, or prophylactically) or on a schedule, where the schedule can be every 2 hours, and / or every 3 hours, and / or every 4 hours, and / or every 6 hours, and / or every 8 hours, and / or every 10 hours, and / or every 12 hours or once a day, until the infection is resolved in whole or in part, or can be continued as needed. In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and the synergist or multiple co-agents can be provided daily in a suitable and acceptable form for delivery. Fosfomycin or an inhibitor of the microbial (bacterial) MurA enzyme is provided at about 500 mg to about 4 g per dose every 4 hours, or every 6 hours, or every 8 hours daily. Diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR is provided at about 80 mg to about 640 mg every 4 hours, or every 6 hours, or every 8 hours daily. Sulfonamide or an inhibitor of the microbial (bacterial) DHPS is provided at about 360 mg to about 3.6 g every 4 hours, or every 6 hours, or every 8 hours daily. In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and the synergist are provided daily in a suitable and acceptable form for delivery. Fosfomycin or an inhibitor of the microbial (bacterial) MurA enzyme is provided at about 0.7 g to about 3.3 g per dose every 4 hours, or every 6 hours, or every 8 hours daily. Diaminopyrimidine or an inhibitor of the microbial (bacterial) DHFR is provided at about 80 mg to about 160 mg every 4 hours, or every 6 hours, or every 8 hours daily. Sulfonamide or an inhibitor of the microbial (bacterial) DHPS is provided at about 360 mg to about 800 mg every 4 hours, or every 6 hours, or every 8 hours daily.In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and the synergist or co-agents are provided daily in a suitable and acceptable form for delivery, and the phosphomycin or inhibitor of the microbial (bacterial) MurA enzyme is provided at about 1.8 g to about 7.5 g per dose every 4 hours or every 6 hours or every 8 hours daily, and the diaminopyrimidine or inhibitor of the microbial (bacterial) DHFR is provided at about 5 mg to about 20 mg every 4 hours or every 6 hours or every 8 hours daily, and the sulfonamide or inhibitor of the microbial (bacterial) DHPS is provided at about 25 mg to about 100 mg every 4 hours or every 6 hours or every 8 hours daily. In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and the synergist or co-agents are provided daily in a suitable and acceptable form, such as an oral form, for delivery, and the phosphomycin or inhibitor of the microbial (bacterial) MurA enzyme is provided at about 1.5 g to about 3 g per day twice a day, and the diaminopyrimidine or inhibitor of the microbial (bacterial) DHFR is provided at about 160 mg to about 320 mg per day twice a day, and the sulfonamide or inhibitor of the microbial (bacterial) DHPS is provided at about 800 mg to about 1600 mg per day every 4 hours or every 6 hours or every 8 hours. In the combinations or combinations of antibiotics and / or methods herein, the combination of antibiotics and / or the synergist or co-agents are provided daily in a suitable and acceptable form for delivery, and the delivery of the combination of antibiotics and / or the co-agent or synergist is at an effective concentration and continuous to facilitate the consistent delivery of at least one co-agent at or above its MIC against at least one type and / or species of anaerobic or pathogenic bacteria. 【0047】 【0048】 These and other embodiments are further described and / or contemplated below. 【DETAILED DESCRIPTION OF THE INVENTION】 【0048】 【0049】The making and use of various embodiments are described below and in the accompanying tables, but many inventive concepts can be embodied herein. It should be understood that the exemplary embodiments serve as representative embodiments and have no undue limitation on the present invention. The embodiments discussed herein are novel and inventive, but those skilled in the art will recognize that various replacements and modifications can be made without departing from what is described herein and defined by the scope of the appended claims. 【0049】 【0050】 In drug therapy, there is a great benefit to the public as a whole if existing antimicrobial agents can be revived in new and more useful combinations. This is due to the enhanced therapeutic potential of existing antimicrobial agents when such revival is not expected and is provided in a new combination; and / or the new and more effective use of existing antimicrobial agents when provided in a new combination (compared to the reduced effectiveness or inactivity of the existing agents when used alone or in alternative and less effective combinations). When disclosed herein, in one or more embodiments, new and more effective combinations of antibiotics are provided, some of which include at least one existing antimicrobial agent (which is currently approved for use as an antimicrobial agent), and all combinations herein include multiple co-agents, at least one of which plays a role in the synergistic enhancement of the activity of the co-agent as a treatment for infections, complications, diseases or disorders affected by and / or affecting anaerobic pathogens. 【0050】 【0051】Further disclosed herein are additional unexpected and unique benefits for combinations and / or formulations that include a new and previously undescribed mode of action, an expanded spectrum of activity (including, for example, types or species that are intrinsically resistant, and thereby activity against intrinsically insensitive resistant anaerobic organisms), greater efficacy, and improved or better antimicrobial efficacy. Any of the unexpected findings described herein expand the importance and utility of the combinations and / or formulations herein, each of which includes a plurality of co-agents, each of which is active due to an evaluated synergistic effect, and the plurality of co-agents includes at least an inhibitor of microbial (bacterial) MurA, an inhibitor of microbial (bacterial) DHFR, and an inhibitor of microbial (bacterial) DPTS. The co-agents herein generally include at least three co-agents or three or more co-agents, each of which is from a different class of antibiotics. It is understood that the co-agents herein (for the combinations and / or formulations herein) can be extended to these particular classes of antibiotics of new members (when having antibacterial properties against at least aerobic bacteria). 【0051】 【0052】In one or more embodiments, at least one of the plurality of co-agents can be a known antibiotic formulation (currently approved for use as an antibiotic and active against aerobic bacteria) that is revived and / or repurposed for new or expanded uses herein. More than one of the plurality of co-agents can be known and revived and / or repurposed for new or expanded uses herein. Each of the plurality of co-agents can be known and revived and / or repurposed for new or expanded uses herein. At least one of the plurality of co-agents can be a functional equivalent (e.g., its functional analog, its functional derivative) of a known antibiotic and can be in the same class as the known antibiotic (active against aerobic bacteria). More than one of the plurality of co-agents can be a functional equivalent of a known antibiotic, each being in the same class as its known antibiotic (each being active against aerobic bacteria), or each of the plurality of co-agents can be a functional equivalent of a known antibiotic, each being in the same class as its known antibiotic (each being active against aerobic bacteria). The plurality of co-agents can be three known antibiotics, each being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be four known antibiotics, each being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be five known antibiotics, each being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be three active co-agents, one being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be three active co-agents, two being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be four active co-agents, one being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be four active co-agents, two being known and revived and / or repurposed for new or expanded uses. The plurality of co-agents can be four active co-agents, three being known and revived and / or repurposed for new or expanded uses.The plurality of co-agents can be five active co-agents, one of which is known and is revived and / or diverted for new or expanded uses. The plurality of co-agents can be five active co-agents, two of which are known and are revived and / or diverted for new or expanded uses. The plurality of co-agents can be five active co-agents, three of which are known and are revived and / or diverted for new or expanded uses. The plurality of co-agents can be five active co-agents, four of which are known and are revived and / or diverted for new or expanded uses. 【0052】 【0053】 In some embodiments, the plurality of novel and unpredictable compositions and / or formulations (including the plurality of co-agents herein) have antibacterial activity and are effective against one or more pathogenic anaerobic bacteria (pathogenic anaerobic organisms). The plurality of novel and unpredictable compositions and / or formulations have antibacterial activity and efficacy against one or more pathogenic anaerobic organisms in an anaerobic environment. In some forms, the pathogenic anaerobic organisms are also referred to as targets. In some forms, the pathogenic anaerobic organisms are one or more types or species of pathogen-obligate anaerobic bacteria. In some forms, the pathogenic anaerobic organisms are one or more types or species of gram-positive anaerobic bacteria. In some forms, the pathogenic anaerobic organisms are one or more types or species of GPOA bacteria. In some forms, the pathogenic anaerobic organisms are one or more types or species of gram-negative anaerobic bacteria. In some forms, the pathogenic anaerobic organisms are one or more types or species of GNOA bacteria. In some forms, the pathogenic anaerobic organisms are in a mixed population that includes at least one or more types and / or species of pathogenic anaerobic organisms; and one or more types and / or species of pathogenic aerobic organisms. In one or more forms, the pathogenic anaerobic organisms are or include one or more types and / or species of facultative anaerobic organisms. 【0053】 【0054】In one or more forms, one or more types or species of pathogenic anaerobic organisms are or include at least one type or species of anaerobic organisms that cannot utilize oxygen and / or are inhibited by oxygen. In one or more forms, pathogenic anaerobic organisms are present in an anaerobic environment and / or an environment poor in oxygen (e.g., where oxygen and / or free oxygen is limited or absent, e.g., where blood supply is impeded, which can result from trauma, injury, occlusion, perforation, aspiration, and / or surgical procedures). In one or more forms, one or more types or species of pathogenic anaerobic organisms are or include at least one type or species of pathogens that do not require oxygen for respiration. In one or more forms, one or more types or species of pathogens are or include at least one type or species of pathogens that do not have the ability to metabolize aerobically. In one or more forms, one or more types or species of pathogens are or include at least one type or species of pathogens that cannot utilize oxygen, some are inhibited by oxygen, and instead rely on other substances (other than oxygen) and alternative enzymatic pathways for growth, metabolism, and activity. In one or more forms, one or more types or species of pathogens are or include at least one type or species of pathogens that undergo energy conversion and metabolism using alternative (different) enzymes and enzymatic pathways compared to aerobic microorganisms that utilize and convert oxygen for energy. In one or more forms, one or more types or species of pathogens are or include at least one type or species of pathogens that have the ability to metabolize in the absence of oxygen and / or undergo sustained metabolism in the absence of oxygen. 【0054】 【0055】Pathogenic obligate anaerobic organisms are absolute anaerobes, unable to utilize oxygen and some are inhibited by oxygen. For obligate anaerobic organisms, oxygen can be toxic and / or affect the main enzymes in said organisms. Obligate anaerobic organisms are impaired over time in the presence of oxygen and thus do not function properly or are unable to function and then die. One or more, or in some forms, one or more types or species of pathogens are capable of sustaining growth in an environment that provides a source of energy other than oxygen and / or are capable of sustaining growth through fermentation and / or include at least one type or species of pathogen that is capable of doing so. In one or more embodiments, any combination of said one or more types or species of pathogens can be one or more types or species of pathogens that inhabit or are supported by an anaerobic environment as a target. 【0055】 【0056】In one or more forms, an anaerobic environment includes an environment that supports the pathogenic anaerobic organisms described herein and is an environment with low oxygen saturation or low oxygen pressure. Atmospheric oxygen may be absent or substantially absent (e.g., anoxic or substantially anoxic), and in in vitro tests, including the tests herein, can support the pathogenic anaerobic organisms herein, particularly one or more obligate anaerobic organisms. Similarly, atmospheric oxygen can be 0.5 percent or about 0.5 percent or up to about 0.5 percent (and can support pathogenic anaerobic organisms, e.g., one or more obligate anaerobic organisms), or atmospheric oxygen can be between about 0.5 percent oxygen to 2 percent oxygen (and can support one or more obligate anaerobic organisms), or oxygen can be 2 percent or about 2 percent or up to about 2 percent oxygen (and can support one or more obligate anaerobic organisms), or oxygen can be between about 2 - 8 percent oxygen (and can support one or more obligate anaerobic organisms). In some cases, atmospheric oxygen can be up to about 8 percent oxygen and can support one or more pathogenic anaerobic organisms. It is understood that in blood, fully oxygenated blood is bound (not free), the oxygen saturation is 95 - 100%, and oxygen is considered scarce when the saturation is below 90 or 91%. Tissue oxygenation varies widely depending on the tissue type and / or location, and the median or average value for a "normal" oxygenated tissue is generally greater than or well above 20 mmHg, while the median or average value for an affected or cancerous tissue is generally below 20 mmHg or about 16 mmHg or below (except for rectal disorders or cancers where about 25 mmHg can be measured). For the purposes herein, an anaerobic environment is generally considered (as understood in the art) to be a poor or low oxygen environment, or in some cases, an anoxic or substantially anoxic environment. In some embodiments, the anaerobic environment supports pathogenic anaerobic organisms and generally does not promote sustained energy production that utilizes oxygen.In addition, or alternatively, in some forms, the anaerobic environment supports pathogenic anaerobic organisms and is not toxic to the pathogen, while having a low oxygen pressure or a low oxygen saturation or no oxygen, or having only an amount of oxygen that is not toxic to the pathogenic anaerobic organism. In addition, or alternatively, in one or more forms, the anaerobic environment supports pathogenic anaerobic organisms and is not toxic to the anaerobic organisms, and if there is oxygen in the environment, this is less than an appropriate amount for sustained aerobic metabolism (e.g., as a percentage or saturation level). In addition, or alternatively, the anaerobic environment supports pathogenic obligate anaerobic organisms and provides an alternative source of energy other than oxygen for the pathogen to obtain sustained energy. In addition, or alternatively, in some forms, the anaerobic environment is a state that makes the host or subject prone to anaerobic infections. Certain conditions found in a host or subject with an anaerobic infection include tissue necrosis; foul-smelling discharge; an environment leading to or existing thrombophlebitis; no (symptomatic and / or physical) improvement after providing alternative antibiotics, and / or no response to alternative antibiotics; the presence of pathogenic factors associated with anaerobic infections (e.g., adhesion factors (e.g., fimbriae, lectins), invasion factors (e.g., phospholipase C, lipopolysaccharide, protease), factors involved in tissue destruction (e.g., fibrinolysis, acetylglucosaminidase, collagenase), and / or capsular resistance to phagocytosis); immunocompromised hosts; and / or sites suspected of anaerobic activity (e.g., the intestinal / gut lumen, local trauma sites, surgical sites, sites of visceral or other perforations, sites of tissue necrosis, sites of clearance impairment of sterile sites (such as chronic rhinosinusitis and / or pneumonia), and / or ulcers). 【0056】 【0057】Pathogenic anaerobic organisms are targeted by any combination and / or formulation described herein. In one or more forms, the pathogenic anaerobic organisms targeted by the combinations and / or formulations described herein are or include one or more types or species of anaerobic organisms in the anaerobic environments described above. In one or more forms, the pathogenic anaerobic organisms targeted by the combinations and / or formulations described herein are or include one or more types or species of anaerobic organisms that are oxygen-intolerant. In one or more forms, the pathogenic anaerobic organisms targeted by the combinations and / or formulations described herein are or include one or more types or species of anaerobic organisms that do not utilize oxygen and can survive in the absence of oxygen and can be pathogenic. In one or more forms, the pathogenic anaerobic organisms targeted by the combinations and / or formulations described herein are or include one or more types or species of anaerobic organisms that do not utilize oxygen and are inhibited by oxygen. In one or more forms, the pathogenic anaerobic organisms targeted by the combinations and / or formulations described herein are or include one or more types or species of obligate anaerobic organisms in anaerobic environments. 【0057】 【0058】In mammals, anaerobic organisms exist and inhabit anoxic or very oxygen-poor habitats such as those described above. Such habitats include, without limitation, the oral mucosa (mouth), as well as the upper and lower respiratory tracts, intra-abdominal, lower gastrointestinal (GI) tract and pelvic (pelvic cavity), as well as areas such as the gingival sulcus, tonsillar crypts, tooth surfaces, nasal folds, hair follicles, colon, urethra and vagina. When one or more anaerobic organisms in the host are transferred from these normal habitats or induced to other locations (e.g., when consumed, or when there is a breakdown of the skin-mucosal barrier, or when there is immunosuppression), the anaerobic organisms can become pathogenic and cause local or systemic infections and / or sites of infection. The sites of infection are often anaerobic and acidic.Without limitation, the site of infection can include one or more of the following: the brain (e.g., abscess from an infection or perforation or surgery or shunt, subdural abscess, meningitis); the blood (e.g., hematogenous spread from an infection or perforation or surgery, sepsis, abscess, bacteremia, wound); the oral cavity (e.g., abscess from an infection or perforation or surgery, cellulitis, otitis media, mastoiditis); the dental region (e.g., abscess from an infection or perforation or surgery or root canal, root canal infection, sinusitis); the pulmonary cavity (e.g., bronchial and / or in the blood from aspiration or infection or perforation or surgery, pneumonia, hematogenous spread, abscess, bronchiectasis, nosocomial and / or necrotizing pneumonia, empyema); the skin and soft tissues (e.g., abscess from an infection or perforation or surgery, acne vulgaris, pressure ulcer, impetigo contagiosa, gangrene, degenerated tissue, dead or dying tissue, necrotizing cellulitis, necrotizing fasciitis, bite, diabetic foot); the intra-abdominal region (e.g., abscess from an infection or perforation or surgery, appendicitis, peritonitis, wound infection); the pelvic region (e.g., female genital tract infection from an infection or perforation or surgery of pelvic organs or sites and / or malignancy, urinary tract (UT) infection, colitis); the muscle (e.g., abscess, wound, gangrene, cancer from an infection or perforation or surgery and / or in immunocompromised subjects); and the cardiac region (e.g., endocarditis, bacteremia from an infection or perforation or surgery and / or malignancy). 【0058】 【0059】In one or more embodiments, the unexpected combinations and / or formulations (including multiple co-agents) contemplated and / or described herein, through synergy, as a response, initiate or cause or result in or induce at least one of the following: (a) reduction of growth (or growth reduction) of one or more pathogenic anaerobic organisms; (b) inhibition of growth (or growth inhibition) of one or more pathogenic anaerobic organisms; (c) cessation of growth (or growth cessation) of one or more pathogenic microorganisms; (d) removal of all or part of one or more pathogenic anaerobic organisms (or microbial removal); (e) reduction of all or part of one or more pathogenic anaerobic organisms (or microbial reduction); (f) interference in all or part of one or more pathogenic anaerobic organisms (or microbial interference); (g) changing and / or enhancing and / or promoting the sensitivity of one or more pathogenic anaerobic organisms (which may or may not include one or more previously non-sensitive pathogenic anaerobic organisms and / or one or more intrinsically resistant pathogenic anaerobic organisms). In one or more embodiments, the responses (a)-(g) occur through the synergy and / or synergistic action of the co-agents, one or more co-agents are or become active, at least one co-agent is a synergist, and in the combination, the synergistic co-agents initiate or affect or cause the synergistic action, providing sufficient and / or effective antimicrobial activity against one or more pathogenic anaerobic organisms (including those that were considered insensitive and / or intrinsically resistant to at least one co-agent in previously used combinations and / or formulations when at least one co-agent was provided independently (separately) to the pathogenic anaerobic organisms).In one or more embodiments, susceptibility (to at least one of one or more unexpected combinations and / or formulations) is identified by in vitro susceptibility testing of anaerobic organisms, which, as reported by other skilled artisans, has clinical outcomes that sufficiently correlate with the results of in vitro susceptibility testing, and is of note because higher mortality has been found when an inert treatment (inert treatment is identified, for example, by non-susceptibility and / or misdiagnosis of anaerobic organisms to that treatment) is provided. From the perspective of such reports, improving clinical outcomes may include providing one or more active combinations and / or formulations to a host or subject in need thereof, and performing one or more in vitro susceptibility tests on clinical cultures of clinical specimens or samples obtained from the host or subject, where the clinical specimen or sample has or is suspected of having at least one anaerobic pathogen that causes or is suspected of causing an infectious disease in the host or subject. When the in vitro activity of a clinical specimen is investigated or analyzed, using the information therefrom may be useful for better treatment outcomes, and the effective combinations and / or formulations described herein will serve as a meaningful explanation of good clinical outcomes. 【0059】 【0060】Anaerobic pathogens that are at least clinically relevant absolute or obligate anaerobes are represented by, but not limited to, the following: Actinomyces species, Atopobium species, Bacteroides species and Parabacteroides species, Bifidobacterium species, Dialister species, Clostridioides species, Clostridium species, Collinsella species, Cutibacterium species (some currently Cutibacterium species), Desulfovibrio species, Eggerthella species, Eubacterium species, Finegoldia species, Fusobacterium species, Parvimonas species, Peptococcus species, Peptostreptococcus species, Phocaeicola species, Porphyromonas species, Propionibacterium species (some currently Cutibacterium species), Prevotella species, Sutterella species and Veillonella species, and / or certain microaerophilic Streptococcus species (e.g., S. anginosus, S. constellatus, S. intermedius, S. mutans, one or more of the viridans group streptococci). Such anaerobic organisms as pathogens have unexpectedly been found to be responsive to one or more unexpected combinations and / or formulations contemplated and / or described herein, and if the combinations and / or formulations described herein promote or initiate or cause at least one or any combination of (a)-(g) identified above as a response, such combinations and / or formulations (including multiple co-agents) are active against anaerobic organisms as described herein. 【0060】 【0061】In fact, and unexpectedly, while the obligate anaerobic organisms described herein are responsive to the active combinations and / or formulations contemplated and / or described herein, most obligate anaerobic organisms are generally non-responsive (or insensitive) to current antibiotics that are indicated and approved for aerobic bacteria or infections caused by them. It is not uncommon for such current antibiotics to be inactive against obligate anaerobic organisms. And most current antibiotics are not active in anaerobic environments. Importantly, most of the obligate anaerobic organisms described herein are also non-responsive (or insensitive) to at least one co-agent utilized in the active combinations and / or formulations described herein (when the co-agent is used individually or separately against obligate anaerobic organisms in an anaerobic environment, as determined using in vitro susceptibility testing). 【0061】 【0062】Gram-positive anaerobic organisms that are pathogenic, at least in clinical settings, are represented by, but not limited to, one or more or any combination of obligate anaerobic organisms: Actinomyces spp., Alkanobacterium spp., Atopobium spp., Bifidobacterium spp., Dialister spp., Clostridioides spp., Clostridium spp., Collinsella spp., Eggerthella spp., Eubacterium spp., Finegoldia spp., Parvimonas spp., Peptococcus spp., Peptostreptococcus spp., Propionibacterium spp., and / or Cutibacterium spp.; certain microaerophilic Streptococcus spp. (e.g., S. anginosus, S. constellatus, S. intermedius, S. mutans, one or more of the viridans group streptococci) can also be mentioned. All GPOAs tested were responsive to unexpected combinations and / or formulations (including multiple co-agents), and the multiple co-agents, as a response, promoted or initiated or caused at least one or any combination of (a)-(g) identified above. Additional data are provided in the attached table, showing that each combination and / or formulation tested herein was active against all pathogenic GPOAs tested and that each combination and / or formulation tested against GPOAs showed an antibacterial synergistic effect. It is clear that the combination and / or formulation (when including multiple co-agents as described herein) is an active antibacterial agent, the co-agents are synergists, and they have a synergistic effect as well as sufficient and / or effective antibacterial activity against pathogenic GPOAs. Neither the strong synergistic effect nor the degree of activity (using various co-agent combinations and / or formulations against GPOAs) could be predicted. This is particularly relevant because the GPOAs tested were either not sensitive or intrinsically resistant to at least one co-agent used in the combination tested (non-sensitivity or intrinsic resistance was identified (shown in the data or table or explained by other persons skilled in the art) when one co-agent (in an unexpected combination) was used independently and separately against the GPOA).Furthermore, the determined activity levels and better potencies (for each GPOA tested in an anaerobic environment) are extremely beneficial for co-agents designed to target anaerobic sites, since such sites can be compromised, can have lower blood flow, and can have lower tissue oxygenation, and such combinations and / or formulations appear to be optimized (very active and very potent) even in anaerobic environments, and thus none of these affect the efficacy of the unexpected combinations and / or formulations described herein. 【0062】 【0063】GNOA, which is pathogenic at least in clinical situations, is represented by or includes any one or more or any combination of Aggregatibacter species, Bacteroides species, Parabacteroides species, Desulfovibrio species, Fusobacterium species, Phocaeicola species, Porphyromonas species, Prevotella species, Sutterella species, Veillonella species, but is not limited thereto. All GNOA tested were responsive to unexpected combinations and / or formulations (including multiple co-agents), and the multiple co-agents, as a response, promoted or initiated or caused at least one or any combination of (a)-(g) identified above. Additional data are provided in the attached table, showing that each unexpected combination and / or formulation tested herein was active against pathogenic GNOA and that each combination and / or formulation tested against GNOA exhibited an antibacterial synergistic effect. Therefore, it is clear that the combination and / or formulation (when including multiple co-agents as described herein) is an active antibacterial agent, the co-agents are synergists, and have a synergistic effect and sufficient and / or effective antibacterial activity against pathogenic GNOA. The strong synergistic effect and degree of activity (using various co-agent combinations and / or formulations against GNOA) could not be predicted. Of particular relevance is the fact that each GNOA tested was either not sensitive to at least one co-agent from the combinations tested or was intrinsically resistant (when one co-agent (in an unexpected combination) was used independently and separately against GNOA, non-sensitivity or intrinsic resistance (shown in the data or table or explained by other persons skilled in the art)).Furthermore, the levels of activity and better efficacy found herein (for each GNOA tested in an anaerobic environment) are extremely beneficial for co-agents designed to target anaerobic sites, especially since such sites can be compromised, can have lower blood flow, and can have lower tissue oxygenation, and such combinations and / or formulations appear to be optimized (very active and very potent) even in anaerobic environments, and thus none of these affect the efficacy of the unexpected combinations and / or formulations described herein. 【0063】 【0064】 It has been reported by other persons skilled in the art that species of Bacteroides (some of which are currently Porphyromonas gingivalis), Prevotella, Porphyromonas, and Fusobacterium can constitute one-third or more of the clinical isolates from specimens obtained from infections in a host (e.g., that mammal or subject having an infectious disease), which represents the importance of the findings herein that the unexpected combinations and / or formulations herein are therapeutically effective against most clinically relevant anaerobic organisms, which is due to the finding of a strong synergistic effect of all of the combinations tested by the inventors and / or provided herein, all of which are shown to have antibacterial activity effective against all of the obligate anaerobic organisms tested (as any one or more of the responses (a)-(g) above). Utilizing the unexpected combinations and / or formulations herein thereby provides an effective antibacterial agent in a host or subject having or suspected of having an infection caused by one or more obligate anaerobic organisms, such obligate anaerobic organisms likely inhabiting and / or being supported by an anaerobic environment. And based on the findings from the inventors' and / or the data herein, the combinations are not only synergistic, but all have antibacterial activity effective against all obligate anaerobic organisms in an anaerobic environment (as any one or more of the responses (a)-(g) above). 【0064】 【0065】Interestingly, and unexpectedly, there are certain anaerobic organisms that are not responsive to any of the tested unexpected combinations and / or formulations (and none of the co-agent combinations and / or formulations are active in these non-responsive anaerobic organisms and cannot initiate, promote, or cause a response). Non-responsive (non-susceptible) anaerobic organisms include facultative species of the genus Lactobacillus (Gram-positive bacilli), species of Leuconostoc (Gram-positive cocci), and species of Pediococcus (Gram-positive cocci), each of which is a facultative anaerobic organism and is considered by those skilled in the relevant art to be a bacterium that is beneficial and / or symbiotic to a mammalian host (inhabiting the microbiota of a normal or disease-free mammalian host, e.g., non-pathogenic). From the perspective of such data, it is clear that the unexpected combinations and / or formulations herein are not active against bacteria that are beneficial and / or symbiotic to a mammalian host and thus do not provide an antimicrobial function against them. Notably, unexpectedly and unpredictably, there are other facultative anaerobic organisms that are responsive (sensitive) to the unexpected combinations and / or formulations described herein (the co-agent combinations and / or formulations tested against responsive facultative anaerobic organisms cause, promote, or initiate at least one or any combination of (a)-(g) as identified above as a response), and are generally considered pathogenic to a mammalian host (e.g., in a clinical setting). Responsive facultative anaerobic organisms include those identified by those skilled in the art as not being beneficial and not considered symbiotic to a mammalian host. Anaerobic organisms are appropriate or responsive targets for any of the compositions and / or formulations of the unexpected inventions herein if they are pathogenic and / or are suspected of causing or causing an infection in a host and / or subject. Responsive targets include obligate anaerobic organisms that are sensitive to one or more of the co-agent combinations and / or formulations herein. Responsive targets include responsive facultative anaerobic organisms (e.g., considered pathogenic in a clinical setting) that are sensitive to the co-agent combinations and / or formulations herein. 【0065】 【0066】 The unexpected and unforeseen findings herein regarding the responsiveness and sensitivity of only certain (facultative) facultative anaerobes (but not all facultative anaerobes) provide further evidence of the unpredictability of the invention disclosed herein, while all obligate anaerobes are strongly responsive (sensitive) to the combinations and / or formulations herein in an anaerobic environment. Further, some pathogenic anaerobic organisms (obligate or facultative facultative anaerobes) were sensitive to all of the co-agents of the combinations and / or formulations described herein (when each co-agent was individually tested against the pathogen using in vitro sensitivity testing for anaerobic organisms), but there were some pathogenic anaerobic organisms (obligate or facultative facultative anaerobes) that were not sensitive to one of the co-agents when tested individually, and other pathogenic anaerobic organisms (obligate or facultative facultative anaerobes) that were not sensitive to two co-agents when tested individually (using in vitro sensitivity testing for anaerobic organisms). Still other pathogenic anaerobic organisms (obligate or facultative facultative anaerobes) were not sensitive to three co-agents when tested individually (using in vitro sensitivity testing for anaerobic organisms). Without being bound by theory, it is contemplated that the synergistic effect of the co-agents may correlate with the accumulation of by-products and / or toxic metabolites formed in the anaerobic organisms, which is presumably due at least in part to the absence of certain enzymes in obligate anaerobes, and / or changes in the enzyme pathways for energy production or metabolite conversion, which are thought to increase in some way in obligate anaerobes. However, this concept does not explain the reason for the difference in responsiveness (and difference in sensitivity to co-agents) for certain pathogenic facultative anaerobes, while there is a complete lack of responsiveness (non-sensitivity) in symbiotic or beneficial facultative anaerobes (e.g., at high levels in the flora of normal or disease-free mammalian hosts). The higher and more effective synergistic effect may in part be due to different membrane characteristics that may differ in obligate anaerobes, especially when multiple co-agents are combined. 【0066】 【0067】Facultative anaerobic organisms that are responsive to one or more unexpected combinations and / or formulations in the present specification in an aerobic (atmosphere) environment and that can be pathogenic at least in clinical situations include: Gram-positive facultative anaerobic organisms, such as Arcanobacterium (branching bacillus), Bacillus (rod-shaped bacteria), such as Bacillus cereus, Bacillus subtilis, Bacillus anthracis; Enterococcus (cocci, such as E. faecalis, E. faecium, Staphylococcus aureus (cocci)); and Gram-negative facultative anaerobic organisms, such as Acinetobacter baumannii (coccobacilli), Burkholderia (rod-shaped bacteria, such as B. thailandensis, B. cepacia, B. mallei, B. pseudomallei), Enterobacter (rod-shaped bacteria), Escherichia (rod-shaped bacteria, coliforms, such as Escherichia coli), Klebsiella (rod-shaped bacteria, such as K. pneumoniae), Pseudomonas aeruginosa (rod-shaped bacteria), Yersinia (rod-shaped bacteria, such as Y. pseudotuberculosis, Y. pestis). It should further be noted that many of the facultative anaerobic organisms tested were drug-resistant or multi-drug resistant to one or more drugs that are currently approved or shown for use as antibiotics against aerobic bacteria. 【0067】 【0068】It has been reported (e.g., by reported tests of clinical isolates from specimens obtained from infections in mammals) that it is not uncommon for other persons skilled in the art for an infection (or the site of that infection) in a mammal or host to contain more than one type or species of anaerobic organism. Cooperative activity among obligate anaerobic pathogens has been found among certain species of Clostridioides, Clostridium, Bacteroides, Veillonella, Fusobacterium, Porphyromonas gingivalis, and Prevotella, any of which have, to date, been particularly virulent and have unpredictable susceptibility patterns. From the perspective of the data and information herein, it is clear that utilizing one or more unexpected combinations and / or formulations herein will, in one or more embodiments, inhibit or be inhibitory to cooperative activity among obligate anaerobic organisms. And utilizing one or more unexpected combinations and / or formulations herein provides an inhibitory effect at the site of infection (e.g., inhibiting growth, inhibiting colony formation) by inhibiting cooperative activity among pathogenic obligate anaerobic organisms in a mammal or host that contains, has, or is suspected of having an infection. 【0068】 【0069】It is not uncommon for an infection in a mammal or host (or the site of infection in a mammal or host) to have, include, comprise, or be caused by one or more types or species of organisms referred to herein as a mixed population. In a mixed anaerobic infection, different anaerobic metabolic pathogens can be present. Such mixed populations can be successfully targeted using one or more of the combinations and / or formulations herein found to be effective as antimicrobial agents against a broad spectrum of anaerobic pathogens. In other mixed infections, different metabolic pathogens can be present, some anaerobic and some aerobic. As previously identified by the inventors, these mixed populations can also be successfully targeted using one or more of the combinations and / or formulations herein, since they have been found to be effective as antimicrobial agents against a broad spectrum of anaerobic as well as aerobic pathogens. In one or more embodiments, utilizing one or more of the unexpected combinations and / or formulations herein promotes, initiates, or causes, as a response, at least one or any combination of (a)-(g) as identified above, where the target is a mixed population that includes a mixed population of anaerobic organisms that are responsive in an anaerobic environment (e.g., obligate and / or facultative anaerobic organisms supported by and / or persisting in an anaerobic environment). 【0069】 【0070】Generally, the unexpected inventive compositions and / or formulations herein include multiple co-agents as active co-agents. The multiple ones can consist of, or consist essentially of, or include three co-agents as active agents for an antimicrobial synergistic effect (synergism), or can consist of, or consist essentially of, or include four co-agents as active agents for an antimicrobial synergistic effect (synergism), or can consist of, or consist essentially of, or include five co-agents as active agents for an antimicrobial synergistic effect (synergism). In some embodiments, the unexpected compositions and / or formulations herein consist of, or consist essentially of, or include three co-agents as active agents for an antimicrobial synergistic effect (synergism) for antimicrobial purposes, or in some embodiments, the unexpected compositions and / or formulations herein include three or more co-agents as active agents for a synergistic effect (synergism) for antimicrobial purposes. In some embodiments, the unexpected compositions and / or formulations herein include at least three co-agents or three or more co-agents as active agents for an antimicrobial synergistic effect (synergism), and in use, the at least three co-agents or three or more co-agents are provided against anaerobic pathogens in a pathogenic environment. In many embodiments, the pathogen environment is an anaerobic environment as described elsewhere herein. 【0070】 【0071】In the inventors' findings and the data provided herein, three or more co-agents are combined as a composition and / or formulation and delivered to a pathogenic anaerobic organism or a host or subject in need of three or more co-agents, where the host or subject has or is suspected of having an infection caused by or suspected of being caused by one or more pathogenic anaerobic organisms or such anaerobic organisms. When the pathogenic anaerobic organism is an obligate anaerobic organism, all combinations of co-agents are antibacterial, exhibit antibacterial activity, and as a response or effect, at least promote, initiate, or cause growth inhibition.In one or more embodiments, the antibacterial activity exhibited or caused by the unpredictable combinations and / or formulations herein against anaerobic pathogens or infectious diseases caused by or suspected of being caused by anaerobic pathogens includes at least one or any combination of the following outcomes or effects: (i) growth inhibitory activity against one or more pathogenic anaerobic organisms; (ii) sustained growth inhibitory activity against one or more pathogenic anaerobic organisms; (iii) removal (and / or destruction) of one or more pathogenic anaerobic organisms; (iv) sustained removal (and / or destruction) of one or more pathogenic anaerobic organisms; (v) prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vi) sustained prophylactic activity against the formation of microbial colonies of one or more pathogenic anaerobic organisms; (vii) alleviation or improvement of an infectious disease (or its symptoms) caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of alleviation or improvement of the infectious disease (or its symptoms)); (viii) management of an infectious disease (or its symptoms) caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of management of the infectious disease (or its symptoms)); (ix) prevention of an infectious disease that is caused by, derived from, or suspected of developing from one or more pathogenic anaerobic organisms (e.g., in a subject in need of prevention of the infectious disease); (x) reduction of the infection rate of an infectious disease caused by, derived from, or suspected of being caused by one or more pathogenic anaerobic organisms (e.g., in a subject in need of reduction of the infection rate of the infectious disease). These, when utilized in combinations and / or formulations, are synergistic and are due to the co-agent synergists herein having beneficial synergistic effects.The inventors using the co-agent synergist in this specification have also unexpectedly, unpredictably, and not obviously found that in some embodiments, there is a reversal in the sensitivity or activity of at least one co-agent that was ineffective or inactive as an antibacterial agent when provided individually to the anaerobic organisms described in this specification. 【0071】 【0072】When the co-agents were tested separately using standardized in vitro test methods, considering that many of the responsive anaerobic pathogens tested were resistant (intrinsic or acquired) rather than sensitive to any one, two, or three co-agents, the level of co-agent synergistic effect found by the inventors is strong, unexpected, and particularly unpredictable. Each of the co-agents provided is unexpected and unpredictable because most are considered by other persons skilled in the art to lack a spectrum of activity against many anaerobic organisms and, in particular, to lack antimicrobial activity against strict anaerobic or obligate anaerobic organisms. For any co-agent utilized herein against strict anaerobic or obligate anaerobic organisms, susceptibility breakpoints have not actually been reported. However, cumulative data have been obtained from extensive and thorough testing conducted by the inventors, which shows that the multiple active co-agents herein have an unexpected synergistic effect (having synergy) and excellent antimicrobial efficacy (compared to co-agents used separately or compared to current antibiotics approved for use as single or two-drug combinations) against a broad spectrum of anaerobic organisms, including all strict or obligate anaerobic organisms tested and responsive facultative anaerobic organisms considered to be non-symbiotic or non-beneficial to the normal flora in a mammalian host. Also unexpectedly, the synergistic effect, synergy, and antimicrobial activity of the co-agent combinations tested against obligate anaerobic organisms are much greater than against responsive facultative anaerobic organisms, and in particular, when required in anaerobic or oxygen-poor environments where obligate anaerobic organisms inhabit, they assist the overall effectiveness and efficacy of the co-agent combinations and / or formulations herein. The co-agent combinations and / or formulations herein cross the blood-brain barrier and are particularly beneficial considering that many currently approved antibiotics cannot cross the blood-brain barrier or do not function or are ineffective in anaerobic environments.In some cases, the excellent antibacterial activity and synergy of the co-agents as identified herein may allow the concentration of each co-agent in the compositions and / or formulations herein required to inhibit growth to be at or below that which would be required to correlate with and provide clinical cure (e.g., as evaluated by area under the concentration-time curve (AUC) and maximum concentration (Cmax) from a clinical pharmacokinetic and / or pharmacodynamic perspective). In some cases, reducing the effective and / or therapeutic amount of at least one co-agent due to its synergy with the co-agent(s) may reduce the toxicity of that one co-agent. Reducing the effective and / or therapeutic amount of at least one co-agent due to its synergy with the co-agent(s) may, in one or more embodiments, reduce or eliminate previous safety concerns when there are safety concerns with at least one co-agent in the combination and / or formulation. 【0072】 【0073】The data in this specification, and in the accompanying tables, clearly demonstrate the excellent antimicrobial activity and synergy of combinations of co-agents tested against anaerobic pathogens. In severe infections (e.g., in a hospital, caused by or suspected of being caused by one or more pathogenic anaerobic organisms), susceptibility testing of clinical specimens can still be performed, and is recommended at any time before the introduction of co-agent therapy described herein, or before a change in therapy and before providing a combination and / or formulation of co-agents as therapy, or during co-agent therapy. Some examples of some severe or serious or life-threatening infections that can benefit from one or more susceptibility tests are brain abscess, bacteremia or endocarditis, or infections that were initially treated with other agents under a poor empirical treatment and did not respond to that poor empirical treatment, or infections that recurred after initial treatment and did not respond to a poor empirical treatment that initially responded to another agent, or infections where an antibacterial agent has a special role in the outcome or where the host requires long-term treatment with an antibacterial agent (e.g., by way of example, sepsis, septic arthritis, osteomyelitis, undrained abscess, infection of a graft or prosthesis, toxic megacolon). 【0073】 【0074】Since anaerobic organisms are fastidious pathogens, they are difficult to grow anaerobically unless appropriate culture methods are used. In fact, other skilled artisans are recommended to perform isolation tests on very virulent pathogens for which susceptibility cannot be predicted, including at least species of Bacteroides, Fusobacterium, Prevotella, Porphyromonas, Clostridioides, Clostridium, and Veillonella. Appropriate culture methods (agar dilution or microbroth dilution methods) were used for data collection including the data provided herein. Standardized anaerobic organism AST was utilized for susceptibility testing, designated as M11, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, from CLSI, to enable comparison of the data and findings herein or when evaluated before or during treatment in a clinical setting. 【0074】 【0075】Briefly, the agar dilution method was utilized for the AST of obligate anaerobes, and Brucella agar plates (supplemented with 5% lysed sheep blood, 5 μg / mL hemin, 1 μg / mL vitamin K1, and 50 mg / L glucose 6-phosphate (G6P) according to CLSI recommendations) were used. The co-drugs were incorporated into a two-fold geometric dilution scheme. Incubation was carried out anaerobically for approximately 48 hours at 35 °C (e.g., using a Coy anaerobic chamber with 0 ppm oxygen or a BD GasPak EZ Anaerobe system). The checkerboard variants for each matrix were utilized to evaluate the combinations of co-drugs. Anaerobic colonies (suspended in saline after removal from the anaerobic culture) were seeded onto the plates using a turbidity of 0.5 McFarland standard from a 48-hour incubated pure culture and replica stamped. After incubation of the plates for 48 - 72 hours in an anaerobic (oxygen-free) environment, the plates were read (growth or no growth) and visually compared. The minimum concentration of the drug that inhibits the growth of a given bacterial strain was defined as the MIC. For facultative anaerobes, a similar agar dilution scheme was utilized, replacing the medium with Mueller-Hinton agar supplemented with 50 mg / L G6P and setting the conditions to aerobic. All microbroth dilution and agar dilution methods are very labor-intensive. The synergistic effect between co-drugs was determined using a checkerboard matrix as understood by those skilled in the art in the relevant technical field. When confirming the synergistic effect, a series of replicates of a series of checkerboard plates were prepared, including additional co-drugs (three-dimensional synergistic effect layout). The FICI was calculated using known methods. For three co-drugs, FICI = FIC(A) + FIC(B) + FIC(C) = (A / MIC A )+(B / MIC B )+(C / MIC C )(where MIC A and MIC Bis the MIC of the co-agent alone, and A, B, and C are the MICs of each co-agent in combination, respectively). If two co-agents are combined before the test (in a specific example, for example, a two-component combination, such as a two-component combination of D and S), FICI = FIC(A) + FIC(B) = (A / MIC A )+(B / MIC B )(where MIC A is the MIC of the co-agent alone, MIC B is the MIC of the two-component co-agent, and A and B are the MICs of each co-agent / two-component co-agent in a fixed ratio combination (for three co-agents), respectively. The FIC index defines the antibacterial interaction as synergistic (S) when ≤ 0.5; additive (A) when > 0.5 to 1; irrelevant (I) when > 1 but ≤ 4; or antagonistic (X) when > 4). 【0075】 【0076】 Unexpectedly, unpredictably, and not obvious, the inventors have found that the co-agents in the combinations and / or formulations herein against certain responsive (e.g., pathogenic) facultative anaerobic organisms described herein have a longer PAE compared to the PAE of one co-agent when used separately. Additionally, or alternatively, the combinations and / or formulations of co-agents herein have the same PAE with a lower concentration of at least one co-agent compared to the PAE and concentration of one co-agent when used separately against responsive facultative anaerobic organisms. 【0076】 【0077】 One or more co-agents in unexpected combinations and / or formulations are as follows. 【0078】1. An antibacterial phosphomycin or an inhibitor of bacterial MurA (UDP-GlcNAc enolpyruvate transferase). The phosphomycin (F) or inhibitor of bacterial MurA herein is provided in a suitable and pharmaceutically acceptable form, such as a salt, phosphate, acid, amine, and / or ester. Currently, phosphomycin is the only inhibitor of MurA, an enzyme specific to bacteria. The phosphomycin or MurA inhibitor can be a phosphonate or phosphonic acid derivative, and representative and non-limiting forms include salts such as the disodium salt, or a monobasic water-soluble salt, mono-salt, di-salt (e.g., sodium, potassium, calcium, magnesium), salts formed with amines (e.g., α-phenethylamine, quinine, lysine, procaine, tromethamine), or salts formed as (-)(cis-1,2-epoxy-propyl)phosphonic acid. A suitable phosphomycin or inhibitor of bacterial MurA may have some antibacterial activity (meaning being active against at least one aerobic bacterium or at least one facultative anaerobic organism in an aerobic environment), behaves as a phosphoenolpyruvate (PEP) substitute, binds to MurA, irreversibly inactivates and / or inhibits the MurA enzyme in peptidoglycan biosynthesis, and / or inhibits or inactivates the MurA enzyme to interfere with peptidoglycan synthesis, thereby showing inhibitory activity against bacterial cell wall synthesis. Any new and / or functionally equivalent analogs or derivatives (as inhibitors of bacterial MurA with or without one or more acceptable substitutions) that are still in the same class as phosphomycin herein can be replaced by phosphomycin and used as phosphomycin as long as they function in the same way as described above, including their stereoisomers, geometric isomers, tautomers, hydrates, solvates, and their pharmaceutically acceptable phosphates, salts, acids, amines, and / or esters, and any combinations thereof.Representative examples include fosfomycin trometamol, and phosphonic acid derivatives such as cis-1,2-epoxypropylphosphonic acid, monobasic water-soluble fosfomycin salts or fosfomycin-tromethol, but are not limited thereto. Fosfomycin or an inhibitor of bacterial MurA (or an acceptable analog or derivative thereof) should penetrate into various mammalian tissues and reach at least body fluids (blood, mucus, urine, plasma, cerebrospinal fluid), membranes (peritoneal, pericardial, mucosal) and tissues of the central nervous system (CNS), soft tissues, bone and lung. 【0077】 【0079】 Fosfomycin as monotherapy is not recommended for pathogenic anaerobic organisms, in part due to the intrinsic microbial resistance to fosfomycin due to MurA mutations and because fosfomycin has not been found to deliver sufficient activity against many anaerobic organisms. The rapid development of resistance to fosfomycin in vitro against some facultative anaerobic organisms including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella spp. and some multi-drug resistant pathogens has been reported by other persons skilled in the art. 【0078】 【0080】2. Antibacterial Diaminopyrimidines as Inhibitors of Bacterial DHFR. The diaminopyrimidines (D) or inhibitors of bacterial DHFR herein are provided in a suitable and pharmaceutically acceptable form, such as salts, phosphates, acids, and / or esters. Suitable diaminopyrimidines may have some antibacterial activity (meaning being active against at least one aerobic bacterium or at least one facultative anaerobic organism in an aerobic environment), inhibit DHFR, and interfere with folate synthesis in pathogens. Suitable D or inhibitors of bacterial DHFR generally contain at least two amine groups on the pyrimidine ring (sometimes referred to as diaminopyrimidines). Any new and / or functionally equivalent diaminopyrimidine analogs or derivatives that are still in the same class as the diaminopyrimidines herein (as inhibitors of bacterial DHFR with or without one or more acceptable substitutions and interfering with folate synthesis) may be replaced by diaminopyrimidines and used as diaminopyrimidines, including their stereoisomers, geometric isomers, tautomers, hydrates, solvates, and their pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combinations thereof, as long as they function in the same way as described above.Representative examples include, but are not limited to: 2,4-diaminopyrimidine; 2,4-diamino-5-benzyl-pyrimidine; 2,4-diamino-5-(4-amino-3,5-dichlorobenzyl)-pyrimidine; 2,4-diamino-5-(3,5-dichloro-4-methylaminobenzyl)-pyrimidine; 2,4-diamino-5-(3,5-dichloro-4-ethylaminobenzyl)-pyrimidine; 2,4-diamino-5-(3,5-dichloro-4-dimethylaminobenzyl)-pyrimidine; 4-diamino-5-(4-acetamido-3,5-dichlorobenzyl)-pyrimidine; 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine; 2,4-diamino-5-[3,5-diethoxy-4-pyrrol-1-yl)-benzyl]-pyrimidine, 2,4-diamino-5-(3,4-dimethoxybenzyl)-pyrimidine (diamveridine); 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (pyrimethamine); 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl)-pyrimidine; (RS)-5-[(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl]pyrimidine-2,4-diamine (iclaprim), and 5-[(4-bromo-3,5-dimethoxyphenyl)methyl]pyrimidine-2,4-diamine (brodimoprim). Diaminopyrimidines may also include diaminopyrimidines having substitutions in the phenyl ring, such as 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine (trimethoprim), 2,4-diamino-5-[3,5-dimethoxy-4-(2-methoxyethoxy)benzyl]-pyrimidine (tetroxoprim), and 2,4-diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine (methioprim). The diaminopyrimidine (or an acceptable analog or derivative thereof) as an inhibitor of bacterial DHFR should penetrate various mammalian tissues and reach at least body fluids (blood, mucus, urine, plasma, cerebrospinal fluid), membranes (peritoneal, pericardial, mucosal) and CNS tissues, soft tissues, bone and lung. 【0079】 【0081】Certain specific diaminopyrimidines are provided as monotherapy, although the representative diaminopyrimidine trimethoprim is more often prescribed together with sulfamethoxazole. In the present specification, diaminopyrimidines can be provided together with sulfonamides as a two-component co-drug herein. Resistance to trimethoprim alone is increasing, which is plasmid-mediated or from chromosomal gene or promoter mutations and / or highly mobile transposons. The development of resistance to trimethoprim in vitro and in vivo has been reported by other persons skilled in the art. In vitro resistance is frequent in aerobic and facultative anaerobic organisms including species of Acinetobacter, Brucella, Escherichia coli, Haemophilus influenzae, Enterobacteriaceae (e.g., E. coli; Enterobacteriaceae), Neisseria spp, Staphylococcus aureus, Chlamydia spp., Coxiella spp., Rickettsia spp., Mycobacterium tuberculosis, Mycoplasma, and Treponema, as well as most pseudomonads (intrinsically resistant), and some multi-drug resistant pathogens. 【0080】 【0082】3. Antibacterial sulfonamides or inhibitors of bacterial DHPS. The sulfonamide (S) or inhibitor of bacterial DHPS is provided in a suitable and pharmaceutically acceptable form, such as a salt, phosphate, acid and / or ester. The sulfonamide or inhibitor of bacterial DHPS is derived from sulfanilamide and is modified by one or more functional groups for the amino group or one or more substituents on the amino group, and some are in the form of alkali metal salts. Suitable sulfonamides or inhibitors of bacterial DHPS may have some antibacterial activity (meaning active against at least one aerobic bacterium or at least one facultative anaerobic organism in an aerobic environment), inhibit DHPS, and interfere with folic acid synthesis (or synthesis of folate). In one or more embodiments, the sulfonamide is represented by the structure shown by the following Structure I (wherein R is an organic group). 【0081】 【0083】 RSO2NH2I. 【0084】 The sulfonamide may also be in a cyclic form (such as sultam), which is an N 1 -heterocyclically substituted sulfonamide, such as a 5- or 6-membered heterocycle (such as pyrimidine, pyrazine, pyridazine, oxazole, isoxazole, thiazole or thiadiazole ring). The sulfonamide may also be a sulfinamid as an amide of sulfinic acid represented by the structure shown by the following Structure II, where R and R’ are some organic groups, and may further include a chiral form (such as tert-butanesulfinamide, p-toluenesulfinamide, 2,4,6-trimethylbenzenesulfinamide). 【0082】 【0085】 R(S=O)NH)R II. 【0086】 The sulfonamide may also be a disulfonimide represented by the structure shown by the following Structure III, where two sulfonyl groups are adjacent to the amine and R and R’ are organic groups. 【0083】 【0087】R-S(=O)2-N(H)-S(=O)2-R’ III. 【0088】 Any new and / or functionally equivalent analogs or derivatives that are still in the same class as the sulfonamides herein, as well as inhibitors of bacterial DHPS (having one or more acceptable substitutions), including their stereoisomers, geometric isomers, tautomers, hydrates, solvates, and / or their pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combinations thereof, may be replaced by sulfonamides and used as sulfonamides as long as they function in the same way as described above. Representative and non-limiting examples include: sulfadiazine, sulfamethoxazole, sulfatroxazole, sulfamerazine, sulfadoxine, sulfadimethoxine, sulfamethazine, sulfapyrazole, sulfachinoxaline, sulfachloropyridazine, sulfaguanidine, sulfalen, sulfamethine, sulfamethoxine, sulfamethoxypyridazine, sulfamethylphenazole, sulfamethoxypyridazine, sulfethoxypyridazine, sulfabromomethazine, sulfaphenazole, sulfamoxole, sulfapyridazine, sulfapyrimidine, sulfapyridine, sulfachloropyridazine, sulfathiazole, sulfameter, sulfanilylamide, sulfisomidine, and sulfisoxazole. The sulfonamide or inhibitor of bacterial DHPS (or its acceptable analogs or derivatives) should penetrate various mammalian tissues and reach at least body fluids (blood, mucus, urine, plasma, cerebrospinal fluid), membranes (peritoneal, pericardial, mucosal) and CNS tissues, soft tissues, bone and lung. 【0084】 【0089】Some sulfonamides can be provided as monotherapy, but sulfonamides, such as sulfamethoxazole, are often prescribed with trimethoprim. Resistance to sulfonamides alone has increased significantly, limiting their use as monotherapy and restricting their clinical usefulness. Resistance is generally plasmid-mediated or chromosome-mediated. Cross-resistance is common. In vitro acquired resistance is frequent as reported by other persons skilled in the art and is found in many facultative anaerobic organisms including Escherichia coli, Neisseria spp., Shigella spp., Staphylococcus aureus, gonococci, meningococci, and pneumococci. Obligate anaerobic organisms are not considered sensitive to sulfonamides. 【0085】 【0090】4. Antibacterial quinazolines as inhibitors of bacterial DHFR. Quinazoline (Q) is an alternative inhibitor of bacterial DHFR and is provided in a suitable and pharmaceutically acceptable form, such as a salt, phosphate, acid and / or ester, and the acid form includes hydrochloride or dihydrochloride. Quinazoline may have some antibacterial activity (meaning being active against at least one aerobic bacterium or at least one facultative anaerobic organism in an aerobic environment), and inhibits DHFR and / or bacterial thymidylate synthase in pathogens. Suitable Q or inhibitors of bacterial DHFR are derived from naphthalene, have a bicyclic aromatic heterocyclic structure, and have two fused 6-membered rings (a benzene ring and a pyrimidine ring). Suitable quinazolines can be provided as alternatives to diaminopyrimidines, and the provided alternative quinazolines are inhibitors of bacterial DHFR. Any new and / or functionally equivalent quinazoline analogs or derivatives that are still in the same class as the quinazolines herein (as inhibitors of bacterial DHFR with or without one or more acceptable substitutions and that interfere with folate synthesis), including stereoisomers, their geometric isomers, their tautomers, their hydrates, their solvates, and their pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combinations thereof, can be replaced with and utilized as quinazolines as long as they function in the same way as described above. Representative examples include 3-benzyl-2-cinnamylthio-6-(methyl or nitro)-quinazolin-4(3H)-one, derivatives of 4(3H)-quinazolinone or 4(3H)-quinazoline, 7-[(4-phenylphenyl)methyl]pyrrolo[3,2-f]quinazoline-1,3-diamine (Iressistin-16) and N 3 -cyclopropyl-7-[[4-(1-methylethyl)phenyl]methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, or dihydrochloride (SCH79797), anilinok quinazolines (gefitinib, lapatinib), aminok quinazolines (erlotinib, afatinib). A few quinazolines are mainly under investigation for non-bacterial interventions. Resistance data are not available and the activity against obligate anaerobic organisms is not clinically known. 【0086】 【0091】 5. Inhibitors of Bacterial FME. Inhibitors of bacterial FME (or FMEIs) are provided in a suitable and pharmaceutically acceptable form, such as phosphates, salts, acids and / or esters, and prevent the inhibition or inactivation of phosphomycin herein. FME inactivates phosphomycin and behaves similarly to a metalloenzyme. FME is FosA (glutathione S-transferase or GST), FosB (bacillithiol S-transferase), FosC (GST), FosX (Mn 2+It includes dependent epoxide hydrolase, kinase FomA, kinase FomB, and other related GSTs (FosA-type enzymes retained on the plasmid, such as FosA3, FosA4, FosA5, and FosC2). Inhibitors of bacterial FME are generally small molecule inhibitors or chelating agents having a C-P bond (carbon and phosphorus as a phosphate or phosphonate group), generally lacking an amine group, including but not limited to phosphonoformate, phosphonoacetate, 2-phosphonobutyrate, 4-phosphonobutyrate, 2-phosphonopropionate, 2-phosphonopropionate, 3-phosphonopropionate, methylphosphonate, ethylphosphonate, phenylphosphonate, acetylphosphonate, phosphonoacetaldehyde, sodium phosphonoformate, sodium phosphonoformate tribasic hexahydrate, triethylphosphonoformate. Another example is a small molecule active site inhibitor of FosA: 3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one. Any new and / or functionally equivalent analogs or derivatives (having one or more acceptable substitutions) that act as inhibitors of bacterial FME can be replaced with inhibitors of FME and utilized as inhibitors of FME as long as they function in the same way as described above, including their stereoisomers, geometric isomers, tautomers, hydrates, solvates, and their pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combinations thereof. 【0087】 【0092】6. Antibacterial inhibitors of bacterial peptidoglycan synthesis. Inhibitors of bacterial peptidoglycan synthesis (PGSIs) are represented herein as glycopeptide / lipoglycopeptide antibiotics and beta-lactam antibiotics and are provided in a suitable and pharmaceutically acceptable form, such as salts, phosphates, acids, and / or esters. These inhibitors bind to the lipid II precursor (e.g., peptidoglycan) of the bacterial outer wall, inhibit peptidoglycan synthesis, either inhibit the synthesis of the bacterial cell wall (glycopeptide / lipoglycopeptide) or bind to the penicillin-binding protein enzyme that cross-links the cell wall and inhibits peptidoglycan synthesis (beta-lactam). Beta-lactam antibiotics have a beta-lactam ring (e.g., as examples, amoxicillin, ceftazidime, meropenem, and include four groups or classes: penicillin, cephalosporin, carbapenem, monobactam). Here, PGSIs can include penams (beta-lactamase-sensitive (e.g., penicillin G, amoxicillin, piperacillin) or beta-lactamase-resistant (e.g., methicillin, temocillin, oxacillin, cloxacillin)), cephems (more than 6 generations, exemplified below), carbapenems and penams (e.g., meropenem), monobactams (e.g., aztreonam). Novel and / or functionally equivalent analogs or derivatives (as inhibitors of bacterial peptidoglycan synthesis having one or more acceptable substitutions) in the same class, as long as they function in the same way as described above, including their stereoisomers, their geometric isomers, their tautomers, their hydrates, their solvates, and their pharmaceutically acceptable phosphates, salts, acids, and / or esters, and any combination thereof, can be replaced by PGSIs and utilized as PGSIs.Representative and non-limiting examples include cephems (such as cefazidime, cefuroxime, cefoxitin, cefoperazone, ceftolozane, cephalexin, cefdinir, ceftriaxone, ceftaroline, cefixime, cefpodoxime, cefazolin, cefibuten, ceftaroline, cefuroxime, cefotaxime, cefoperazone, cefepime, ceftolozane, ceftriaxone, cefibuprole, cefiderocol, cefoxitin, moxalactam, S-64922, etc., including second-generation, third-generation, fourth-generation, fifth-generation, and sixth-generation cephems), vancomycin, teicoplanin, oritavancin, dalbavancin, telavancin, bleomycin, ramoplanin, decaplanin, dimycin A, colomycin, amoxicillin (other penicillins such as, merely as representative examples, ampicillin, carbenicillin, dicloxacillin, oxacillin, piperacillin, nafcillin, ticarcillin), any of which can be utilized in drug therapy as a co-agent for the purposes of the invention described herein. 【0088】 【0093】 Many PGSIs are prescribed or used in combination with a beta-lactamase inhibitor (BLI) and can be provided herein as two-component co-agents or as independent co-agents. Amoxicillin is prescribed or used with clavulanic acid (CA). Piperacillin is often prescribed with tazobactam. Ceftolozane is often prescribed with tazobactam. Cefazidime can be prescribed / used with avibactam. Ceftaroline can be prescribed / used with avibactam. Cefpodoxime or cefibuten or cefixime or other cephalosporins can be used with CA. The activity of these PGSIs is more effective against Gram-positive bacteria (mainly aerobic or facultative anaerobic organisms). In general, resistance to a class of PGSIs can occur via the expression of certain genes and / or transposons in microorganisms that can transfer to other Gram-positive bacteria. Resistance has been found against many facultative Gram-positive facultative anaerobic organisms, including species of Enterococcus, Streptococcus, Staphylococcus, and Listeria. 【0089】 【0094】 7. Inhibitors of bacterial beta-lactamases. A beta-lactamase inhibitor (BLI) is a class of inhibitors provided in a suitable and pharmaceutically acceptable form, such as salts, phosphates, acids and / or esters. The inhibitors in the class act as substrates that bind to the bacterial beta-lactamase enzyme with high affinity, or create or cause sterically unfavorable interactions when binding to the bacterial beta-lactamase enzyme, and in the binding or interference with the enzyme, the bacterial beta-lactamase is inhibited or inactivated. New and / or functionally equivalent analogs or derivatives (as inhibitors of bacterial beta-lactamases having one or more acceptable substitutions) in this same class, including their stereoisomers, geometric isomers, tautomers, hydrates, solvates, and their pharmaceutically acceptable phosphates, salts, acids and / or esters, and any combinations thereof, can be replaced with and utilized as a BLI as long as they function in the same manner as described above. Representative and non-limiting examples are avibactam, relebactam, sulbactam, tazobactam, baloxavir, CA, nacubactam, didebactam, QPX7728, ETX0282 and VNRX5236. 【0090】 【0095】BLIs that do not have antibacterial activity beneficial per se are utilized in combination with PGSIs (e.g., beta-lactam antibiotics or penicillin-binding protein antibiotics) and are provided herein as two-component combinations of co-agents or as independent co-agents. Avibactam can be used herein together with ceftazidime or meropenem. CA can be utilized together with amoxicillin or ticarcillin. Relebactam can be utilized together with imipenem-cilastatin (indicated as a three-component combination). Sulbactam can be used together with ampicillin or cefoperazone. Tazobactam can be used together with piperacillin or ceftolozane. Vaborbactam can be used together with meropenem. Didebactam can be used together with cefepime. Nacubactam can be used together with meropenem. Intrinsic and acquired resistance to some BLIs in certain facultative anaerobic organisms has been reported by other persons skilled in the art, and the emergence of continuous resistance to BLIs has been reported when these are combined with beta-lactam antibiotics.Intrinsic resistance to CA - amoxicillin occurs at least in the following: Citrobacter freundii, Enterobacter cloacae complex, Hafnia alvei, Klebsiella aerogenes, Morganella morganii, Plesiomonas shigelloides, Providencia rettgeri, Providencia stuartii, Serratia marcescens, Yersinia enterocolitica, Aeromonas hydrophila, Aeromonas veronii, Aeromonas dhakensis, Aeromonas caviae, and Aeromonas jandaei. Sulbactam - ampicillin is not active against Pseudomonas aeruginosa. Avibactam is not active against many metallo - beta - lactamase (class B) - producing bacterial strains, or against A. baumannii. Zidebactam does not appear to be active against A. baumannii. Relbactam with imipenem - cilastatin is not active against bacteria with metallo - beta - lactamases, and the triple combination has poor activity against many Gram - negative bacteria that produce beta - lactamases known as oxacillinase or OXA - 48. Nacubactam has a profile similar to that of avibactam. 【0091】 【0096】When using the above co-agent classifications (1-7), a plurality of co-agents for use against one or more anaerobic pathogens may comprise, consist of, consist essentially of, or include three co-agents, and the co-agents are F, D, and S; or F, Q, and S or include them. The plurality of co-agents may comprise, consist of, consist essentially of, or include four co-agents, and the co-agents are F, D, S, and FMEI; or F, Q, S, and FMEI; or F, D, S, and BLI (when BLI has its own antibacterial activity); or F, Q, S, and BLI (when BLI has its own antibacterial activity); or F, D, S, and PGSI; or F, Q, S, and PGSI or include them. The plurality of co-agents may comprise, consist of, consist essentially of, or include five co-agents, and the co-agents are F, D, S, FMEI, and PGSI; or F, Q, S, FMEI, and PGSI; or F, D, S, BLI, and PGSI; or F, Q, S, BLI, and PGSI; or F, D, S, PGSI, and FMEI; or F, Q, S, PGSI, and FMEI or include them. In one or more embodiments, at least one co-agent is a co-agent that is currently approved for use as an antibacterial agent and is revived and / or diverted for use in the combinations and / or formulations herein. Or, more than one co-agent may be a co-agent that is currently approved for use as an antibacterial agent and is revived and / or diverted for use in the combinations and / or formulations herein. 【0092】 【0097】When using any of such multiple co-agents as described above, the co-agent is a synergist and has synergism and a synergistic effect, providing or causing or promoting sufficient and / or effective antibacterial activity (as any one or more of (i)-(x) described herein) against pathogenic anaerobic organisms in an anaerobic environment. Unexpectedly, such pathogenic anaerobic organisms include at least one or more obligate anaerobic organisms or one or more obligate anaerobic organisms in a mixed population. Also unexpectedly, some facultative anaerobic organisms are responsive to such multiple co-agents, but the responsiveness is selective, and there are non-responsive facultative anaerobic organisms selected from the group consisting of at least one of Lactobacillus, Leuconostoc, and Pediococcus (where 100% of the isolates of Lactobacillus, Leuconostoc, and Pediococcus are not responsive to or sensitive to any of the tested co-agent combinations). A co-agent combination and / or formulation comprising any of the multiple co-agents, wherein the co-agent is a synergist and has synergism and a synergistic effect, providing or causing or promoting sufficient and / or effective antibacterial activity, is evaluated by in vitro AST for at least anaerobic organisms, whereby MIC and FIC values are determined.Unexpectedly, when identified and evaluated herein by MIC and FICI values, a combination agent having synergy and a synergistic effect, where the plurality of combination agents are three combination agents, is less active than when the plurality of combination agents are four combination agents (or five combination agents). This means that when the plurality of combination agents are three combination agents (e.g., F, D, and S; or F, Q, and S), using four combination agents (or five combination agents) is more synergistic than three combination agents. The three combination agents continue to be effective as antibacterial agents and are highly effective, acting synergistically through a synergistic effect and having strong antibacterial activity against the pathogenic anaerobic organisms described herein (e.g., against 100% of the obligate anaerobic organism isolates tested and being active and having growth inhibitory activity against the responsive facultative anaerobic organism isolates tested), and are not active against non-responsive facultative anaerobic isolates of Lactobacillus, Leuconostoc, or Pediococcus (at least when the combination agents are F, D, S, or F, Q, S). And despite the fact that it has been found by reports of other persons skilled in the relevant art that neither fosfomycin (as representative F), nor trimethoprim (as representative D), nor sulfamethoxazole (as representative S) is individually considered an effective antibiotic against obligate anaerobic organisms, the plurality of combination agents are at least three combination agents (e.g., F, D, S; or F, Q, S), and at least three combination agents may be highly active and effective together as an antibacterial agent. 【0093】 【0098】Considering that there is a strong correlation between the bacterial susceptibility evaluated in vitro and the clinical outcome of a subject or host having or suspected of having an infectious disease caused by or suspected of being caused by bacteria, the findings herein provide evidence that any of the plurality of co-agents herein against pathogenic anaerobic organisms, when utilized as a pharmaceutically acceptable drug therapy agent against a pathogenic anaerobic organism that is or is suspected of being in a subject or host (or an infectious disease suspected of being present in the subject or host), may provide sufficient and / or effective antimicrobial activity against the pathogenic anaerobic organism in the subject or host (having or suspected of having an infectious disease caused by or suspected of being caused by the pathogenic anaerobic organism). The pharmaceutically acceptable forms may be provided via the delivery or dispensing means described herein, and without targeting non-responsive facultative anaerobic isolates of Lactobacillus, Leuconostoc, and / or Pediococcus, an effective amount of the plurality of co-agents is delivered or dispensed or distributed, for example, to a pathogenic anaerobic organism that is or is suspected of being in a subject or host (or an infectious disease suspected of being present in the subject or host) to target one or more types and / or species of obligate anaerobic organisms, or pathogenic organisms that are one or more types and / or species of obligate anaerobic organisms in a mixed population. The combined pharmaceutically acceptable forms should be particularly effective against pathogenic anaerobic organisms involved in, causing, or suspected of causing severe infectious diseases (e.g., requiring hospitalization and / or parenteral antimicrobial therapy of the host or subject) or co-infections (e.g., having underlying and / or predisposing conditions in the host or subject and / or being non-responsive or resistant to previous alternative therapies). The delivery or dispensing means for delivering or dispensing or distributing an effective amount of the plurality of co-agents to the pathogenic anaerobic organism provides the co-agents in the same formulation or carrier, or in one or more different formulations or carriers.Delivery or dispensing means for delivering, dispensing or distributing a plurality of co-agents in an effective amount to pathogenic anaerobic organisms delivers the co-agents: each co-agent simultaneously; at least two co-agents simultaneously (and provides any other co-agent by any means herein within a certain period); at least three co-agents simultaneously (and provides any other co-agent by any means herein within a certain period); each co-agent together; at least two co-agents together (and provides any other co-agent by any means herein within a certain period); at least three co-agents together (and provides any other co-agent by any means herein within a certain period); each co-agent in a series, each co-agent in the same or overlapping cycle or schedule; each co-agent within a period that is any of about 15 minutes, or 30 minutes, or 45 minutes, or 1 hour (hr), or 2 hours, or 3 hours, or 4 hours, or 5 hours or less thereof. 【0094】 【0099】 In one or more embodiments, an F that exceeds a sufficient amount or sufficient concentration in any of the plurality of co-agents provided within a certain period improves the efficacy of the combination and / or formulation (e.g., is improved or better than F when used separately against one or more obligate anaerobic organisms, one or more GPOA and / or one or more GNOA; is improved or better than when F in the combination of co-agents and / or formulation is provided in a sufficient amount or sufficient concentration). In one or more embodiments, a D that exceeds a sufficient amount or sufficient concentration in any of the plurality of co-agents provided within a certain period improves the efficacy of the combination and / or formulation (e.g., is improved or better than D when used separately against one or more obligate anaerobic organisms, one or more GPOA and / or one or more GNOA; is improved or better than when D in the combination of co-agents and / or formulation is provided in a sufficient amount or sufficient concentration). 【0095】 【0100】The attached table provides evidence of the synergy of the combinations and / or formulations herein, any of which contain 3 or more active co-agents as described (e.g., at least F, D, S or at least F, Q, S), and the MIC assays described are for obligate anaerobic bacteria (gram positive or gram negative, either of which grows in the absence of oxygen, grows anaerobically and is not a facultative anaerobic organism) in an anaerobic environment; and facultative anaerobic bacteria (gram positive or gram negative, either of which grows in oxygen, grows aerobically and is not an obligate anaerobic organism) in an aerobic environment as the core of the susceptibility assessment against pathogens. Note that bacteria sensitive or resistant to one or more co-agents were included in the analysis. For convenience, unless otherwise specified, the diaminopyrimidine and sulfonamide were prepared as separate stocks and provided together as a pair. Generally, such pairs were in a fixed ratio (e.g., 1:19 for D / S, which is the usual ratio in clinical situations). Other known pairs are often prepared as pairs and provided together if available as such. Using known techniques, an oxygen-free (anaerobic) environment was provided and maintained using either a GasPak EZ anaerobic system (7-liter anaerobic box) or a Coy anaerobic chamber containing 0% oxygen and metered with 90% N2 - 10% H2. 【0096】 【0101】Referring to Table 1, the antibacterial synergistic effect was achieved using a combination of three co-agents when tested against many different GPOA bacteria and many different GNOA bacteria in an anaerobic environment: phosphomycin (F), here sodium phosphomycin; diaminopyrimidine (D), here trimethoprim; and sulfonamide (S), here sulfamethoxazole). Five different strains of C. perfringens were tested, three different strains of C. difficile were tested, and numerous strains of Bacteroides species or Porphyromonas gingivalis were tested. The co-agents were significantly effective against all representative obligate anaerobic pathogens, reducing the MIC values significantly. A complete co-agent synergistic effect was shown against all strains tested, and the MIC for each co-agent combination was reduced to a level understood by other persons skilled in the art as a synergist. Table 1 shows that in a true anaerobic environment, the combination of the three co-agents (F, D, S) has exceptional antibacterial activity against all GNOA, including but not limited to at least Bacteroides, Parabacteroides, Porphyromonas gingivalis, Prevotella, Porphyromonas, and Aggregatibacter, exhibits synergy (as a synergist), and is effective. When F is provided separately to GNOA, almost all GNOA in Table 1 are non-responsive and / or not sensitive to F, which means that F does not have antibacterial activity separately against most GNOA and would be ineffective (not therapeutically useful as a separate treatment) against infections having or suspected of having GNOA, such as Bacteroides, Porphyromonas gingivalis, Parabacteroides, Prevotella, and / or Porphyromonas. Similarly, when provided without F, GNOA were generally non-responsive and / or not sensitive to one or both of D and S. This means that when one or both of D and S are provided without F in an anaerobic situation, they do not have antibacterial activity against most GNOA and are thus ineffective (and not therapeutically useful as a treatment) for infections having or suspected of having GNOA, such as Bacteroides, Parabacteroides, Porphyromonas gingivalis, Prevotella, and / or Porphyromonas, when provided separately or as a pair.In the table, the susceptibility is based on the extrapolation of the MIC breakpoint for facultative anaerobic bacteria or aerobic bacteria in an aerobic (atmospheric oxygen) environment, which is ≤ 32 μg / ml for F (e.g., fosfomycin sodium), and ≤ 2 μg / ml for D (e.g., trimethoprim), and ≤ 38 μg / ml for S (e.g., sulfamethoxazole), and the resistance to F (e.g., fosfomycin) is > 64 μg / ml, and the resistance to D (e.g., trimethoprim) is > 2 μg / ml (or 4 μg / μl or greater), and the resistance to S (e.g., sulfamethoxazole) is > 38 μg / ml (or 76 μg / ml or greater). 【0097】 【0102】Table 1 also shows that in an anaerobic environment, the combination of three co-agents (F, D, and S) has exceptional antibacterial activity against all GPOAs including, but not limited to, at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium, and microaerophilic Streptococcus (e.g., Streptococcus mutants), exhibits synergy (as a synergist), and is effective. When F is provided separately to GPOA, some GPOAs in Table 1 are non-responsive and / or insensitive to F, which means that F does not have antibacterial activity against these GPOAs separately, and thus would be ineffective (not therapeutically useful as a separate treatment) against them (or in a host that may have or be suspected of having them). And when provided without F, GPOA is generally non-responsive and / or insensitive to one or both of D and S. This is because in a true anaerobic environment, one or both of D and S do not have antibacterial activity against most GPOAs when provided without F, and thus one or both of D and S provided separately or as a pair of two are ineffective (and not therapeutically useful as a treatment) against many GPOAs, such as Clostridioides, Clostridium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium, and / or microaerophilic Streptococcus (e.g., Streptococcus mutants). In summary, this means that when tested separately or as a pair of two, each obligate anaerobic organism was non-responsive to at least one of F or D or S, which by itself is sufficient to rule out any reason to expect a synergistic effect of F and D and S. In addition, the ineffectiveness of the co-agents against many obligate anaerobic organisms when delivered separately or as a pair of two means that there is no reason or justification to expect a high level or high degree of antibacterial activity with a co-agent containing at least F, D, and S. 【0098】 【0103】Tables 2, 3, 5, 6, 8, and 9 show that sulfonamides are sufficient and effective co - agents as long as they have some antibacterial activity (against aerobic bacteria) and are inhibitors of bacterial DHPS, and thus provide outstanding antibacterial activity as co - agents with F and D. In every case, the FIC values showed a complete synergistic effect against all the strains tested (where the MICs of the co - agent combinations in the said tables were all significantly reduced and the FIC indices were all identified as synergistic herein), emphasizing that such co - agents exhibit synergy (as synergists). Tables 2, 3, 5, 6, 8, and 9, like Table 1, show that the co - agents (at least F, D, and S) are synergistic and have sufficient and / or effective antibacterial activity against all the Gram - negative and GPOA tested, and thus are effective (and therapeutically useful as a treatment) against infections having or suspected of having GPOA (such as at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium, and / or microaerophilic S. mutans) and / or GNOA (such as at least Bacteroides, Porphyromonas gingivalis, Parabacteroides, Prevotella, Porphyromonas, and / or Aggregatibacter). In Tables 2, 5, and 8, S is sulfisoxazole. In Tables 3, 6, and 9, S is sulfadoxine. Tables 2, 3, 5, 6, 8, and 9 show that the substitution of one sulfonamide for another still initiates or causes or promotes the synergistic effect with the F and D co - agents, and thus the effectiveness of these as synergists with at least three co - agents and as synergists having activity against one or more obligate anaerobic organisms in an anaerobic environment is maintained. 【0099】 【0104】Tables 4-9 show that as long as the diaminopyrimidine has some antibacterial activity (against aerobic bacteria) and is an inhibitor of bacterial DHFR, it is a sufficient and effective co-agent, and thus provides extraordinary antibacterial activity as a co-agent with F and S. In every case, the FICI showed a complete synergistic effect against all the strains tested (the MICs of all co-agent combinations were significantly reduced, and all the FICIs identified herein were synergistic), providing evidence that the co-agent exhibits synergy (as a synergist). Similar to Table 1, Tables 4-9 each show that the co-agent (at least F, D, S) is synergistic and has sufficient and / or effective antibacterial activity against all the GNOA and GPOA tested, and thus is effective (and therapeutically useful as a treatment) against infections having or suspected of having GPO (e.g., at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium, and / or microaerophilic S. mutans) and / or GNOA (e.g., at least Bacteroides, Parabacteroides, Porphyromonas gingivalis, Prevotella, Porphyromonas, and / or Aggregatibacter). In Tables 4-6, D is pyrimethamine. In Tables 7-9, D is iclaprim. In summary, Tables 4-9 show that the substitution of one diaminopyrimidine for another still initiates or causes or promotes the synergistic effect with the F and D co-agents, and thus the effectiveness of these as synergists with at least three co-agents and as synergists having activity against one or more obligate anaerobic organisms in an anaerobic environment is maintained. 【0100】 【0105】In Tables 1-9, the co-agent synergist promotes and enhances antibacterial activity (e.g., at least inhibition of bacterial growth and / or inhibition of colony formation and / or reduction of bacteria) in an anaerobic environment even when the co-agent synergist, with one exception, all GN0A exhibits resistance to F, and almost all GPOA and almost all GN0A exhibit resistance to one or both of D and S. Tables 1-9 provide evidence that one or both of D and S are generally ineffective against both GPOA and GN0A in an anaerobic environment. F has also been shown to be ineffective against GN0A in an anaerobic environment, which is consistent with other reports by those skilled in the art that there is a lack of sufficient activity when F or D and / or S are administered separately or as a pair at safe concentrations against more difficult or pathogenic obligate anaerobic organisms. Nevertheless, despite the individual resistance profiles and lack of activity of the co-agents (F when delivered separately, or D and S as a pair), it is clear from Tables 1-9 that a synergistic effect always occurs when the co-agents F and D and S are delivered to any obligate anaerobic pathogen in an anaerobic environment. Importantly, the synergistic effect appears to be involved, at least in part, in reversing the resistance in one or more GN0A that exhibit bacterial resistance to F separately, and / or in reversing the resistance in one or more GN0A and / or GPOA that exhibit bacterial resistance to either D or S separately or to D and S as a pair. Therefore, from the perspective of Tables 1-9, there are a number of different sulfonamides and a number of different diaminopyrimidines that can serve as suitable co-agents while achieving the same or similar (and sufficient) outcomes that result in meaningful antibacterial activity against obligate anaerobic pathogens in an anaerobic environment as long as the F co-agent is present. 【0101】 【0106】Referring to Table 10A, the combined data shows that there is a replacement of the diamino pyrimidine with a quinazoline (represented by Q, SCH79797) such that the co-agent is at least F, Q, and S, which is consistent with the findings from Tables 1 - 9. In Table 10A, in every case, a complete synergistic effect was identified for all the strains tested (where the MIC was significantly reduced in all cases and the FIC indices identified herein and by other persons skilled in the art were all synergistic), so the co-agents that are at least F, Q, and S are synergistic. This means that the co-agents of F, Q, and S have sufficient and effective antibacterial activity against all the GNOA and GPOA tested, and are effective (and therapeutically useful as a treatment) against infections that have or are suspected of having GPOA (such as at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium, and / or microaerophilic S. mutans) and / or GNOA (such as at least Bacteroides, Parabacteroides, Fusobacterium nucleatum and / or Prevotella, and / or Porphyromonas, and / or Aggregatibacter). Without being bound by theory, if Q has some activity against aerobic bacteria and inhibits bacterial DHFR, then Q is a suitable alternative to D. This inhibitory activity against DHFR may not be the only explanation for the synergy between D, S, and F, but it suggests that the inhibitory effect on bacterial DHFR is, at least in part, related to how the replacement with Q provides similar and effective synergy. Considering this and extrapolating the susceptibility breakpoint based on D (trimethoprim), Table 10A also shows that Q is ineffective against the GPOA tested and many of the GNOA tested when delivered separately. It should be noted that despite the lack of individual activity of Q when delivered separately, it is clear from Table 10A that a synergistic effect always occurs when the co-agents F, Q, and S are delivered to any obligate anaerobic pathogen in an anaerobic environment.The MIC values for the co-agents F, Q, and S indicate that the co-agents are an effective antibacterial agent combination against GPOA and GNOA in an anaerobic environment. As found in Tables 1-9, as long as the F co-agent is present, there are at least a number of different sulfonamides and a number of different quinazolines that can serve as suitable co-agents with synergy while achieving the same or similar and / or sufficient outcomes with meaningful antibacterial activity against obligate anaerobic pathogens in an anaerobic environment. This is evident from Table 10A. 【0102】 【0107】 Table 10B confirms the synergy of the co-agents and the antibacterial activity of the F, Q, and S co-agents against gram-positive and gram-negative facultative anaerobic organisms in an aerobic environment (data not shown, also reported in an anaerobic environment). Table 10C confirms that when each pair is delivered against different strains of methicillin-resistant gram-positive facultative anaerobic organisms and multiple drug-resistant gram-negative anaerobic organisms in an aerobic environment, the synergistic effect of the pair Q with S is consistent with the synergistic effect of the pair D with S. Tables 10A-10C suggest that if other discovered inhibitors of bacterial DHFR are identified (e.g., inhibiting bacterial DHFR and having at least some activity against aerobic bacteria under aerobic conditions), the other discovered inhibitors can be suitable for synergy with at least F and S when replacing D (or Q). 【0103】 【0108】Table 11 shows the unexpected synergism caused by combinations of more than three co-agents, where the co-agents are F, D, S, PGSI, and BLI, five co-agents that generally exhibit better synergy and synergistic effects compared to F, D, S or F, Q, S. In Table 11, the co-agent synergists promote and enhance antibacterial activity (e.g., at least inhibition of growth and / or inhibition of colony formation) in an anaerobic environment, and when the co-agents further include PGSI (here amoxicillin) and BLI (here CA) along with F, D, and S, more than three co-agents are more effective as antibacterial agents against both GPOA (e.g., at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium) and GNOA (e.g., at least Bacteroides, Parabacteroides, Fusobacterium nucleatum, and / or Prevotella). In Table 11, when using two additional co-agents, the MIC values against all tested obligate anaerobic organisms are dramatically reduced, at least in part due to the five co-agents that are better synergists, showing better synergistic effects compared to three co-agents in an in vitro anaerobic environment. Having more than three co-agents may provide a broader spectrum of activity than F, D, S or F, Q, S. 【0104】 【0109】As shown in Table 11, Table 12 shows the unexpected synergistic effects caused by combinations of more than three co-agents, where the co-agents are F, D, S and PGSI, four co-agents that generally exhibit better synergy and synergistic effects compared to F, D, S or F, Q, S. In Table 12, the co-agent synergists promote and enhance antibacterial activity (e.g., at least inhibition of growth and / or inhibition of colony formation) in an anaerobic environment, and when the co-agent further contains PGSI (here vancomycin) together with F, D and S, more than three co-agents are more effective as antibacterial agents against both GPOA (e.g., at least Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, and / or Cutibacterium) and GNOA (e.g., at least Bacteroides, Parabacteroides, Fusobacterium nucleatum and / or Prevotella). In Table 11, when using additional co-agents, the MIC values are reduced, at least in part due to the four co-agents that are better synergists, and show better synergistic effects compared to three co-agents in an in vitro anaerobic environment. Again, having more than three co-agents may also provide a broader spectrum of activity than F, D, S or F, Q, S. 【0105】 【0110】The bacterial strains in Tables 1-9, 10A, 11, and 12 are representatives of the types and / or species of obligate anaerobic bacteria that cause about 95% or more than about 95% of anaerobic bacterial infections that are more difficult to treat in humans. As reported by other persons skilled in the art, it is known that in vitro MIC susceptibility values correlate with good or effective clinical outcomes, which means that the tables and data herein showing the susceptibility of all obligate anaerobic organisms to the co-agent combinations herein are not only useful, but also serve as effective predictors of in vivo efficacy in a host or subject in need of a co-agent (e.g., having or suspected of having at least one obligate anaerobic organism, or having or suspected of having an infection caused or suspected of being caused by at least one obligate anaerobic organism). Therefore, Tables 1-9, 10A, 11, and 12 each represent co-agent combinations that may be useful as drug therapies for infections involving or suspected of involving obligate anaerobic organisms, which obligate anaerobic organisms include Clostridioides, Clostridium, Bifidobacterium, Peptostreptococcus, Propionibacterium, Cutibacterium, Bacteroides, Parabacteroides, Fusobacterium nucleatum, Prevotella, Porphyromonas, and / or Aggregatibacter, and / or microaerophilic Streptococcus (e.g., Streptococcus mutants), or at least one or more of any combination thereof, including Gram-negative and / or Gram-positive bacteria. Because of the species and / or types of bacteria for which the co-agent combinations are antibacterial effective and because of the high effectiveness that exists in an anaerobic environment, this finding provides evidence that the co-agent combinations herein not only provide an enhancement of one or more existing antibacterial agents, but also broaden the spectrum of activity for appropriate antimicrobial activity and high efficacy against challenging anaerobic organisms and / or antibiotic-resistant anaerobic pathogens that are thought to be the cause of substantial and severe (complicated) infections.Therefore, the combinations of co-agents herein can be used as drug therapies for mixed infections (including one or more obligate anaerobic organisms) and / or co-infections, such as, but not limited to, the infections identified elsewhere herein (e.g., as representative examples, abscesses, UTs, airways, skin and skin / soft tissue, those located intra-abdominally), and / or those from secondary infections (e.g., as representative examples, nosocomial infections, ventilator-associated infections, and / or severe or co-viral infections, such as those responsive to and / or subsequent to SARS-CoV, HIV and / or influenza virus). From the perspective of the increasingly higher synergy and synergism found herein (where the combination of five co-agents shows higher synergism than the combination of four co-agents with a lower FICI value, and the combination of four co-agents shows higher synergism than the combination of three co-agents with a lower FICI value, which does not need to be in a fixed ratio), the addition of further co-agents (or two further co-agents or three further co-agents) to a combination of three co-agents can also enable a reduction in the dose (of at least one co-agent in the combination of co-agents) and / or a reduction in the duration of dosing, both of which are noted to be beneficial to the host or subject in need, particularly when safety and / or side effects are a concern. 【0106】 【0111】Importantly, in light of the useful, valuable, and highly effective synergistic effects of the co-agent combinations (either 3 co-agents, 4 co-agents, 5 co-agents, or 6 co-agents) herein, the further benefits of co-agent synergy and synergy action are to increase the exposure of at least one co-agent (or 2 co-agents or 3 co-agents or 4 agents or 5 co-agents or 6 co-agents) by providing each of said 1 co-agent or 2 co-agents or 3 co-agents or 4 co-agents or 5 co-agents or 6 co-agents in combination above its MIC, thereby ensuring synergistic effects and synergy action (as well as excellent antibacterial efficacy) throughout the dosing schedule and / or dosing regimen while achieving the activity and antibacterial benefits from each of that 1 co-agent or 2 co-agents or 3 co-agents or 4 co-agents or 5 co-agents or 6 co-agents respectively. 【0107】 【0112】Interestingly, as shown in Table 13, combinations of co-agents containing at least F, D, and S are selective antibacterial agents and do not exhibit antibacterial activity against commensal or symbiotic Gram-positive facultative anaerobic bacteria (e.g., symbiotic under normal or disease-free conditions) including species of Lactobacillus, Pediococcus, and Leuconostoc. When the combination was at least F, D, and S, none of the following were inhibited by the combination of co-agents: Lactobacillus acidophilus, Lactobacillus delbrueckii, Lactobacillus gasseri, Lactobacillus paracasei, Lactobacillus plantarum, Leuconostoc mesenteroides, Pediococcus acidilactici, or Pediococcus pentosaceus. Similar findings were observed with other combinations of co-agents (data not shown). Since such symbiotic and / or commensal Gram-positive facultative anaerobic bacteria are beneficial to the host (e.g., the GI tract), it is possible to intentionally make the selectivity of the combination of co-agents herein, and the combination of co-agents herein enhances antibacterial activity (e.g., any one or more of antibacterial responses (i)-(x) herein) against obligate anaerobic pathogens while maintaining at least a portion of the GI tract microbiota without showing general interference with symbiotic and / or commensal Gram-positive facultative anaerobic bacteria. Preservation of any one or more symbiotic / commensal Gram-positive facultative anaerobic bacteria of Lactobacillus, Pediococcus, and / or Leuconostoc can also be beneficial in preventing secondary infections by pathogenic bacteria.For example, if the commensal flora of the GI tract is inhibited, its numbers are reduced, or it is eliminated, the GI tract has a predisposition to abnormal growth and diseases associated with Clostridioides (e.g., C. difficile) or Clostridium and experiences them. These benefits are best when the pathogenic bacteria are targeted by at least F, D, S or F, Q, S, and optionally further co-agents (e.g., if the pathogenic bacteria are suspected to be non-resistant or resistant to the further co-agent, any one or more of PGSI, BLI, FMEI). If resistance to a further co-agent is suspected or known, no further co-agent herein should be utilized. 【0108】 【0113】 Such unexpected findings indicate that the combination of co-agents has multiple beneficial effects including: the synergistic effect and synergy of the co-agent when delivered to one or more obligate anaerobic organisms; sufficient and / or effective antibacterial activity against one or more obligate anaerobic organisms, or its reduction or inhibition or elimination; the lack of synergy when delivered to commensal and / or mutualistic Gram-positive facultative anaerobic bacteria selected from any one or a combination of Lactobacillus, Pediococcus, and / or Leuconostoc; the lack of antibacterial activity against commensal and / or mutualistic Gram-positive facultative anaerobic bacteria selected from any one or a combination of Lactobacillus, Pediococcus, and / or Leuconostoc; and the preservation of commensal and / or mutualistic Gram-positive facultative anaerobic bacteria selected from any one or a combination of Lactobacillus, Pediococcus, and / or Leuconostoc. 【0109】 【0114】Tables 14A, 14B and 15 support the findings identified at least in Tables 1-9, 10A, 11 and 12, and the synergistic action of the co-agents and the antibacterial activity of the co-agent combinations are enhanced by including at least one additional co-agent. Tables 14A and 14B show unexpected improvements when the additional co-agent is FMEI (or an inhibitor of bacterial FME; here phosphonoformate). FME is thought to mediate resistance to phosphomycin (i.e., by adding a glutathione moiety to the antibacterial phosphomycin to inactivate it), and not only is it unaffected by combinations of three co-agents containing F, but including FMEI further improves the synergistic effect of the co-agents (see further shifts and lower FIC values for combinations of four co-agents), which is also reflected in better MIC values for at least D and S when FMEI is included in the combination against both phosphomycin-susceptible and phosphomycin-resistant responsive Gram-positive and responsive Gram-negative facultative anaerobic organisms in aerobic environments. Tables 14A and 14B show that combinations of four co-agents (including FMEI) are active against at least Staphylococcus aureus and Escherichia coli. The activity against Staphylococcus aureus is particularly unexpected (and unforecast) because Staphylococcus aureus strains are not known to express FME with a glutathione moiety and such FME inhibitors have not been found to be effective against Staphylococcus aureus to date. 【0110】 【0115】In Table 15, further co-agents are PGSIs with or without BLI, either of which enhances the synergistic effect of the co-agents and the antibacterial activity of the combination of co-agents when at least one further co-agent is included in a combination of at least three co-agents of F, D and S. Unexpectedly better efficacy is found with further co-agents that are PGSIs, such as vancomycin or telavancin or meropenem. Further co-agents that are PGSIs and BLIs, such as amoxicillin-clavulanate or ceftazidime-avibactam, also exhibit better efficacy when used. Table 15 shows that combinations of four co-agents (including PGSIs) and combinations of five co-agents (including PGSIs and BLIs) are all synergistic and have antibacterial activity against responsive facultative anaerobic organisms (at least one or more of Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii in an aerobic environment). With each of the clavulanates, further PGSI and / or BLI co-agents are provided as described herein, and it should be noted that the expected dosage for each is at least its approved dosage currently indicated for antibacterial efficacy. 【0111】 【0116】Table 16 discloses PAEs using combination agents F, D, S that are at least as long as or longer than when provided separately or in pairs against responsive facultative anaerobic pathogens in an aerobic environment. When the PAEs of combination agents F, D, S are the same length as the PAEs for the individual combination agents, the concentrations are not the same, and thus it should be noted that when using combination agents F, D, S (the three combination agents), the concentration is 1 / 4 of the amount used for the individual agents. And when four or five combination agents are used, the amount of each combination agent used to achieve the PAEs shown in the table is 1 / 8 to 1 / 16 less than the amount used for the equivalent PAEs using the individual combination agents. Thus, the PAEs using four combination agents (F, D, S, PGSI) or five combination agents (F, D, S, PGSI, BLI) are at least as long as or longer than the combination agents when provided separately or in pairs against responsive facultative anaerobic pathogens in an aerobic environment, while the amount of each combination agent in the combination is significantly less than the amount of the individual combination agents (e.g., 1 / 8 to 1 / 16 less). PAE is a measure of the length of time that growth is inhibited after the antibiotic has disappeared, indicating the continuation of growth inhibition (and / or bacterial suppression and / or reduction and / or elimination, and / or reduction or elimination of colony formation) after the full life at a single dose or trough concentration in the treated host or subject. Using each combination of combination agents, Table 16 also shows that the improvement in PAE is synergistic and occurs even when the concentration of each combination agent in the combination of combination agents is lower (or substantially lower) than the concentration used separately to show the individual PAEs. This is evidence of another strong role of the synergistic effect of the combination agents, where the combination of combination agents sustains (or continues) growth inhibition (and / or bacterial suppression and / or reduction and / or elimination, and / or reduction or elimination of colony formation) at a lower concentration when each combination agent is in the combination and is able to sustain or continue growth for at least the same length of time or a longer time by the lower concentration.Such findings are notable and unexpected, similar to the finding that there is no PAE while two co-agents as a pair (PGSI + BLI, here ceftazidime-avibactam) are used (beta-lactams do not exhibit PAE). When these co-agents are accompanied by a combination of three co-agents (F, D, S) against responsive facultative anaerobes (E. coli), PAE is observed, which is at least in part due to the synergy and synergistic action of co-agents that are identified unexpectedly in this specification. Table 16 shows that a combination of four co-agents (PGSI, here including vancomycin) is not only an effective antibacterial agent against beta-lactam and methicillin-resistant Staphylococcus aureus (at lower concentrations of each co-agent), but is also sufficient to maintain PAE at much lower concentrations of each co-agent. 【0112】 【0117】 The clinical significance of the finding that combinations of co-agents herein (e.g., having at least F, D, S or F, Q, S) may extend the period for growth inhibition (and / or bacterial suppression and / or reduction and / or elimination, and / or reduction or elimination of colony formation), even after the level of the co-agent has decreased below the MIC, is its favorable impact due to the reduction of its resistant mutation selection at the trough concentration (e.g., before dosing, or during spaced dosing, e.g., spaced longer than the PAE). Extending the PAE is associated with or correlates with a lower likelihood of selected resistance due to exposure, and thus these findings predict that resistance is less likely to occur with the combinations and / or formulations of co-agents herein. 【0113】 【0118】PAE was determined by incubating overnight (< 12 h) at 37 °C with shaking (ca. 200 rpm) in log-phase facultative anaerobic bacteria in vitro in an aerobic environment in cation-adjusted Mueller-Hinton broth (CAMHB), then diluting 1:6 in fresh pre-warmed CAMHB supplemented with 50 mg / L G6P and incubating for an additional 2 h, followed by exposure to various concentrations of the co-agent (2×, 4× or 8× MIC) identified in Table 16 for 1 h, then washing (to remove the co-agent), re-suspending in pre-warmed growth medium, and monitoring until each condition returned to logarithmic growth. Aliquots from each condition were removed at time 0 and at 30 min intervals, serially diluted 10-fold, spread on Mueller-Hinton agar plates and incubated for 48 h to grow colonies. Colonies were counted and multiplied by the reciprocal of the dilution to obtain the plate count and PAE value (plate counts were used to generate growth curves and to determine the time required for a 1-log increase in the bacterial count after removal of the antibiotic). PAE was quantified by viable cell count. PAE was defined by the following formula: PAE = (number of hours for a 1-log increase in cell number for each culture condition after removal of the co-agent) − (number of hours required for a 1-log increase for a control culture without co-agent (treated separately individually)). 【0114】 【0119】Table 17 provides an exemplary summary of the susceptibility of certain obligate anaerobic organisms tested in an anaerobic environment, separately with each co-agent (F), or with two-agent combinations (D, S) of co-agents, or with a combination of representative co-agents (F, D, S). The table summarizes the fact that most of the tested GPOA were sensitive (+) to F used separately, while they were not sensitive but resistant (-) to the two-agent combinations (D, S) of co-agents. Interestingly, Bifidobacterium is generally a GPOA that is sensitive to the two-agent combinations (D, S) of co-agents and, instead, had no sensitivity to F used separately. All of the tested GNOA were not sensitive to F used separately and were also not sensitive to the two-agent combinations (D, S) of co-agents, with the exception of Porphyromonas gingivalis (ATCC 33277), which was sensitive to the two-agent combination (D, S). And despite the lack of activity of F and / or the two-agent combinations (D, S) of co-agents against the obligate anaerobic organisms, all of the tested obligate anaerobic organisms were sensitive to at least three co-agent combinations (here F, D, S), where the three co-agents were synergistic (as identified by FICI ≤ 0.5), acting synergistically to cause or promote sufficient and / or effective antibacterial activity (at least growth inhibitory activity and / or provided by any of the above responses (i)-(x)) by the co-agent combination against each of the tested obligate anaerobic organisms. Low FIC calculated values are also presented in Table 17. 【0115】 【0120】Tables 18 - 21 are provided because other persons skilled in the art have reported that the pH can vary depending on the site of infection and can be reduced or increased from the systemic homeostatic pH (which is neutral pH or near it). For example, an abscess can be acidic (e.g., pH about 5), the skin can be acidic (e.g., pH 5 or 6, or about 5 or about 6, or between about pH 5 and 6.5), but urine can have a pH anywhere between 5 and 8. Antibiotics often malfunction in acidic conditions. Therefore, for facultative anaerobic organisms in an aerobic environment, a representative combination of co - agents (here F, D, S) was tested for synergy and antibacterial activity at different pH conditions (pH 5, 7, 8 as shown in Tables 18, 19 and 20 respectively) and compared with the data when the co - agents were used separately (F) or as two - drug combinations (D, S). Generally, regardless of the pH condition (acidic (pH 5) or neutral (pH 7) or basic (pH 8)), many Gram - positive facultative anaerobic organisms were responsive to F alone, while many Gram - negative facultative anaerobic organisms (e.g., certain Pseudomonas aeruginosa, K. pneumoniae and Burkholderia thailandensis) were resistant to F alone. Only two Gram - negative strains (Acinetobacter baumannii 918857, Burkholderia thailandensis ATCC700388) were impaired at basic pH and did not grow at pH 8. E. faecium (Gram - positive) and some types and / or strains of Gram - negative facultative anaerobic organisms were resistant to the two - drug combinations (D, S) at pH 5. More Gram - positive and Gram - negative facultative anaerobic organisms were resistant to D, S at neutral or basic pH (e.g., all strains of Pseudomonas aeruginosa). On the other hand, unlike many currently approved antibiotics, the combination of co - agents (including at least F, D, S) maintained these synergies throughout the pH range and, with the exception of the two impaired Gram - negative strains that did not grow at pH 8, was surprisingly active as an antibacterial agent against all facultative anaerobic organisms tested at acidic pH as well as neutral and basic pH conditions (in an aerobic environment).Consistently, as shown in Table 21, the MIC values of the co-agent combinations were significantly lower at all pH conditions against all facultative anaerobic organisms tested (considered responsive facultative anaerobic organisms and not considered non-responsive or commensal and / or symbiotic facultative anaerobic organisms of any of the Lactobacillus spp., Leuconostoc spp. and Pediococcus spp.). Thus, the table shows that many of the responsive facultative anaerobic organisms tested are drug-resistant or multi-drug resistant strains (resistant to one or more of the existing approved antibiotics and / or at least one of F, D and / or S), but a synergistic effect with the co-agent was observed under all tested pH conditions (e.g., pH 5-8) at any pH at which anaerobic pathogens can grow, regardless of tissue or body fluid or pathological condition. Table 21 shows that at all pH conditions, the co-agent combinations herein are synergistic, active and effective against drug-resistant strains and responsive anaerobic organisms (here responsive facultative anaerobic organisms) including strains found to be resistant to at least one of the co-agents when tested and used separately (F) and in pairs (D, S). Similar findings are likely in anaerobic organisms that are difficult to treat or considered obligate anaerobes. 【0116】 【0121】In summary, the tables and the attached information in this specification show that the co-agent combinations and / or formulations in this specification are active as antimicrobial agents (e.g., containing at least F, D, S or at least F, Q, S), and have at least the following properties: a synergistic effect that provides a significantly lower (or better) MIC as a synergist for effective antibacterial activity against obligate anaerobic organisms; a synergistic effect that provides a significantly lower MIC as a synergist for effective antibacterial activity against facultative anaerobic organisms that respond; a synergistic effect that provides a significantly lower MIC as a synergist for effective antibacterial activity against obligate anaerobic organisms in a mixed population; and no synergistic effect or antibacterial activity against commensal and / or symbiotic (non-responsive) facultative anaerobic organisms consisting of Lactobacillus species, Leuconostoc species and / or Pediococcus species. Such properties cause or promote any one or more or any reasonable combination of the actions (i) to (x) as described above, such as growth inhibitory activity, and / or growth suppression activity, and / or reduction and / or destruction and / or removal of bacteria, and / or reduction and / or prevention and / or removal of colony formation. The co-agent combinations and / or formulations in this specification are selectively synergistic, and no antibacterial activity against Lactobacillus species, Leuconostoc species and Pediococcus species is observed (e.g., no growth inhibitory activity), which is not only unexpected but also not predictable. The pharmaceutically acceptable co-agents in one or more of the co-agent combinations and / or formulations in this specification exhibit a synergistic effect against pathogenic anaerobic organisms including obligate anaerobic organisms in an anaerobic environment and are antimicrobially effective. 【0117】 【0122】The information herein is for the synergistic effect of a combination of three co-agents that causes or promotes antimicrobial activity (with a significantly lower MIC) even against fastidious anaerobic organisms that provide synergy and are more difficult to treat, indicating that the combination is truly beneficial and superior to many existing treatments currently available for more difficult-to-treat pathogens, fastidious anaerobic organisms. By including additional co-agents in the combination of three co-agents, when tested against fastidious anaerobic organisms that are difficult to treat, the synergy of the co-agents is amplified and the MIC is further reduced. Importantly, the said action and activity occur in an anaerobic environment, indicating the versatility and effective utility of the combination of co-agents and / or formulations herein (having three or more co-agents as described herein). The evidence and data support a combination drug therapy approach using the combination of co-agents herein across two strategies commonly implemented in hospitals: the mixed strategy (random treatment of half of the subjects or patients with a first antibiotic and the other half with a different antibiotic) or the cycle strategy (rotation of temporary treatments with each antibiotic over different periods). Importantly, the synergistic effect of the co-agents as identified herein not only allows for a possible reduction in the concentration of at least one co-agent when safety is a concern, but also (as shown herein, resistant strains continue to be sensitive to the combination of co-agents herein regardless of whether they are acquired, endogenous or predicted phenotypic resistance to one or more drugs) particularly against resistant anaerobic strains by causing sufficient and / or effective activity of the (combination of co-agents and / or formulation), and by providing such enhanced antibacterial activity in an anaerobic environment, and by amplifying the co-agent efficacy, and by extending the PAE, which will necessarily reduce the case of SMF.The inventors determined that the SMF of the combination of three co-agents (F, D, S) against strains of responsive facultative anaerobic organisms (E. coli, S. aureus, and E. faecalis) was at least two orders of magnitude or 100-fold lower compared to the separate co-agent (F) or two-agent combinations (D, S) against the same strains, and that the finding occurred even when the co-agents (F or D, S) were tested at higher concentrations. 【0118】 【0123】 The observations and findings by the inventors strongly suggest and provide that the killing of obligate anaerobic organisms and facultative anaerobic organisms responsive to the co-agent combinations and / or formulations herein excludes non-responsive and commensal and / or symbiotic facultative anaerobic organisms of the genus Lactobacillus or Leuconostoc or Pediococcus. And, using even lower MIC and FIC values, when more than three co-agents are utilized and administered to tested anaerobic organisms that are obligate anaerobic organisms and facultative anaerobic organisms responsive to the co-agent combinations and / or formulations herein and are not non-responsive or commensal and / or symbiotic facultative anaerobic organisms of the genus Lactobacillus or Leuconostoc or Pediococcus, the bactericidal activity may be such that any of the co-agent combinations and / or formulations herein are delivered in a pharmaceutically sufficient amount as an effective antibacterial agent against obligate anaerobic organisms and facultative anaerobic organisms responsive to such antimicrobial co-agents. 【0119】 【0124】The combinations and / or formulations herein are a plurality of co-agents (e.g., 3 co-agents, 4 co-agents, 5 co-agents, 6 co-agents), the co-agents are provided in one or more pharmaceutically acceptable forms, the co-agents are in an effective amount for synergistic effect, and the co-agents are provided via one or more delivery and / or dispensing means as an effective drug therapy, for example, in an anaerobic environment. The plurality of co-agents can be in the same formulation or in one or more different formulations. The plurality of co-agents can be in the same vehicle or carrier for delivery and / or dispensing or in one or more different vehicles or carriers for delivery and / or dispensing. The dispensing or delivery means is a method or manner of providing or administering the combinations and / or formulations herein, and representative examples include, but are not limited to, intravenous, intramuscular, oral, intraoral, dental, dermal, subcutaneous, endocervical, intranasal, intratracheal, epidural, enteral, intraperitoneal, intracerebral, intradermal, intraspinal, intrauterine, intranasal, parenteral, rectal, sublingual, intravaginal. The co-agents for delivery and / or dispensing are provided in the same vehicle or carrier in many cases, for example, except when one or more co-agents in a kit are individualized and later delivered or dispensed in the same formulation or by the same or similar delivery and / or dispensing means. Representative examples of vehicles or carriers available for the co-agents herein include, for the purposes herein, pills, tablets, capsules, gels, medicinal candies, aerosols, sprays, liquids, suspensions, sachets, bags, suppositories, vials, implants, lotions, creams, ointments. In at least one embodiment, the plurality of co-agents are in the same type or similar types of vehicles, and the vehicle is any vehicle or carrier described and / or contemplated herein. In at least one embodiment, at least a part or all of the plurality of co-agents are of the same type or similar types of vehicles, the vehicle is any vehicle or carrier described and / or contemplated herein, and in the case of the same type of vehicle, some or all of the co-agents are compartmentalized and mixed when delivered or dispensed into or onto a subject in need of the co-agents.In at least one embodiment, at least two co-agents are in the same vehicle, and the vehicle is any vehicle or carrier described and / or contemplated herein. In at least one embodiment, at least three co-agents are in the same vehicle, and the vehicle is any vehicle or carrier described and / or contemplated herein. In at least one embodiment, at least four co-agents are in the same vehicle, and the vehicle is any vehicle or carrier described and / or contemplated herein. In at least one embodiment, at least five co-agents are in the same vehicle, and the vehicle is any vehicle or carrier described and / or contemplated herein. In at least one embodiment, at least six co-agents are in the same vehicle, and the vehicle is any vehicle or carrier described and / or contemplated herein. In one or more embodiments, the co-agents are in the same pharmaceutically acceptable formulation. In one or more embodiments, the co-agents are in different pharmaceutically acceptable formulations and in the same vehicle (e.g., in one or more layers or coatings or films or sections or segments by way of example). All co-agents can be formulated either in the same preparation or in one or more different preparations (e.g., in one or more particles or solids or droplets) and can be in the same aerosol or spray. All co-agents can be formulated either in the same preparation or in one or more different preparations (e.g., in one or more concentrates) and can be in the same liquid / fluid or suspension. All co-agents can be formulated either in the same sachet or bag or suppository or vial or implant or in the same preparation or in one or more different preparations (e.g., in one or more sections or segments or layers). In one or more embodiments, all co-agents can be formulated either in the same lotion or cream or ointment or balm or in the same preparation or in one or more different preparations (e.g., in one or more emulsions or layers). Additionally or alternatively, at least one co-agent can be formulated into another pill or tablet or capsule or gel or medicinal candy.Additionally, or alternatively, at least one co-agent can be formulated into another aerosol or spray. Additionally, or alternatively, at least one co-agent can be formulated into another liquid / fluid or suspension. Additionally, or alternatively, at least one co-agent can be formulated into another sachet or bag or suppository or vial or implant. Additionally, or alternatively, at least one co-agent can be formulated into another lotion or cream or ointment or balm. Thus, any one of the vehicle or carrier can have or contain one or more co-agents. In one or more embodiments, any one of the vehicle or carrier can have or contain all of the co-agents. In one or more embodiments, any one of the vehicles can be compartmentalized and contain one or more co-agents within a compartment or layer or section or subsection or film or emulsion or suspension or solid or particle. In one or more embodiments, any one of the vehicles can have one or more co-agents therein, each or some of the co-agents being independent and / or independently formed (e.g., independent beads or grains or liposomes or colloids or particles or nanoparticles or solids or emulsions or films or layers). 【0120】 【0125】In general, the co-agent compositions and / or formulations (e.g., pharmaceutical or veterinary) herein are formulated, as representative examples, for an administration route (e.g., systemic delivery or dispensing means) selected from topical, transdermal, enteral, oral, subcutaneous, enema, rectal, inhalation, parenteral, intranasal, intravenous, intramuscular, intraperitoneal, and / or intraocular. Additionally, or alternatively, the compositions and / or formulations (pharmaceutical or veterinary) herein, when formulated, include one or more pharmaceutically acceptable excipients (e.g., inert ingredients) appropriate for the acceptable manufacturing practices and processes for pharmaceutical therapy pharmaceuticals, as well as the desired means of delivery or dispensing. The excipients may facilitate one or more of binding, stability, density, texture, flavor, and / or release. The co-agent compositions and / or formulations (e.g., having one or more pharmaceutically acceptable excipients) herein, when formulated, are provided to a host or provided according to its prescription (e.g., with or without a diluent or other components for systemic delivery). In some forms, administration is by at least the intravenous / injection route. In some forms, administration is by at least the oral or inhalation route. In some forms, administration is by at least the parenteral route. In some forms, administration is by at least suppository. Administration can be by at least enema or concentrated aqueous enema. 【0121】 【0126】For one or more pharmaceutically acceptable forms of solid or liquid compositions and / or formulations, vehicles or carriers can include, but are not limited to, tablets, capsules, caplets, powders, granules, beads, liquids, suspensions, solutions, emulsions, syrups, elixirs, droplets, semi-solids (e.g., waxinates, gums, gummies, creams, lotions, balms, suppositories), any of which can be off-the-shelf products or concentrates. In some forms, the solid or liquid can be a concentrate (dry or liquid or semi-solid), which is later solubilized, resuspended and / or diluted, usually prior to administration, using sterile water, saline, particles, powders, or any other suitable sterile media known in the art for solubilization, resuspension and / or dilution. Non-toxic solid carriers and / or diluents can be included in any form herein, represented at least by pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcan, cellulose, glucose, sucrose, magnesium, carbonate, etc. One or more binders can be included that impart cohesive qualities to the powder (e.g., for compressed forms or tablets); binders are represented at least by pharmaceutical grade starch, gelatin, one or more sugars (e.g., lactose, dextrose), natural gums, synthetic gums. One or more disintegrants can be included that enhance disintegration; disintegrants are represented at least by pharmaceutical grade starch, clay, cellulose, algin, gum, cross-linked polymers. One or more lubricants and / or glidants can be included to prevent adhesion to the surface (e.g., during the manufacturing process and / or at the time of administration and / or to improve the flow characteristics for manufacturing and / or administration). Lubricants are represented at least by pharmaceutical grade colloidal silicon dioxide. Glidants are represented at least by pharmaceutical grade talc, stearic acid. 【0122】 【0127】The solid or liquid may or may also contain, by way of example, solubilizing agents, emulsifying agents, buffers, antimicrobial preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity regulators, stabilizers and / or osmotic regulators. Liquids for enteral administration may include water (containing one or more additives, such as cellulose (or its derivatives)), sodium carboxymethylcellulose solution, alcohols (such as monohydric alcohols, polyhydric alcohols, glycols) and / or oils (such as fractionated coconut oil and groundnut oil). Liquids for parenteral administration may include oily esters (such as ethyl oleate, isopropyl myristate). For oral and / or inhalation, other solutes and / or suspending agents and / or oils and / or fats may or may also be included (such as sufficient physiological saline and / or glucose to make the solution or suspension isotonic, and / or other additives, and / or at least one or more of pharmaceutical grade salts, phosphates, gelatin, oleic acid esters of sorbitol, and / or anhydrides thereof copolymerized with ethylene oxide (such as sorbitan monooleate, polysorbate 80)). 【0123】 【0128】 For topical and / or transdermal compositions and / or formulations in one or more pharmaceutically acceptable forms (such as semi-solid, vaccinate, cream, gel, foam), the vehicle or carrier may include, but is not limited to, ointments, creams, lotions, balms and gels. One or more suitable penetration enhancers and / or detergents for enhancing penetration may be included, represented by at least pharmaceutical grade dimethyl sulfoxide, dimethylacetamide and dimethylformamide. 【0124】 【0129】For transmucosal compositions and / or formulations in one or more pharmaceutically acceptable forms (e.g., liquid, suspension, emulsion, solid, semi-solid, particle), vehicles or carriers include, but are not limited to, nasal sprays, oral sprays, concentrated aqueous enemas, rectal and / or vaginal suppositories. As is known in the art, one or more base compounds of the type utilized transdermally may be included, represented at least by pharmaceutical grade cocoa butter, polyethylene glycol (carbowax), polyethylene sorbitan monostearate or mixtures thereof, with or without other materials for modifying melting point and / or dissolution rate known in the art. 【0125】 【0130】Co-agent compositions and / or formulations, when formulated, can be prepared according to methods known in the art that substantially release one or more components in the formulation upon or immediately after administration. In one or more forms, any co-agent composition and / or formulation, when formulated, releases components in the formulation at a predetermined time and / or for a predetermined period after administration and / or at a predetermined location on or in a host or subject in need of the co-agent composition and / or formulation, according to methods known in the art. A method of controlling or inhibiting or destroying or removing one or more pathogenic anaerobic organisms or their colony formation in or on a host or subject comprises: providing or delivering or dispensing (for administration) to the host or subject an effective amount or a therapeutically effective amount of a combination of co-agents comprising a plurality of co-agents that are at least three active co-agents herein, the co-agents exhibiting a synergistic effect, the synergistic effect causing or promoting antimicrobial activity, the co-agents being effective to cause or promote a response in at least one or more pathogens, the response being selected from one or more of the following: (a) inhibiting the growth of one or more pathogenic anaerobic organisms; (b) inhibiting the growth of one or more pathogenic anaerobic organisms for a sustained period; (c) interrupting the growth of one or more pathogenic anaerobic organisms; (d) removing all or part of one or more pathogenic anaerobic organisms; (e) destroying all or part of one or more pathogenic anaerobic organisms; (f) interfering with one or more pathogenic anaerobic organisms as a whole; (g) changing and / or enhancing and / or affecting and / or reversing the sensitivity of one or more pathogenic anaerobic organisms that are not sensitive and / or are intrinsically resistant to at least one co-agent when used separately (or as a pair) against one or more pathogenic anaerobic organisms. The pathogenic anaerobic organisms can be in an anaerobic environment. 【0126】 【0131】In some embodiments, a method for individualized drug therapy or treatment for a host or subject (e.g., an individual) in need of individualized drug therapy or treatment for an infection caused by or suspected of being caused by anaerobic bacteria, comprising: i) obtaining a biological sample from the host or subject and identifying at least one anaerobic bacterium suspected of being a pathogen in the biological sample; and ii) providing or delivering or dispensing to the host or subject a pharmaceutically acceptable combination agent comprising a plurality of combination agents that are at least three active combination agents in the same or different formulations, wherein the providing or delivering or dispensing can be at the same or similar times, or at different times within a period of at most about 2 hours or less than about 2 hours, and wherein the providing or delivering or dispensing can be continuous. The biological sample can include types and / or species of pathogenic and / or non-pathogenic anaerobic bacteria, and after the providing or delivering or dispensing, at least one pathogenic anaerobic organism (and / or its colonies) on or in the host or subject is inhibited or removed or controlled, while a sufficient amount of non-pathogenic bacterial types and / or species (and / or their colonies) is not substantially impaired. 【0127】 【0132】A pharmaceutically acceptable medicine for use as a drug therapy for a host or subject having or suspected of having one or more pathogenic anaerobic organisms, the medicine comprising a plurality of co-agents in the same or different formulations, and being an antimicrobial agent effective against one or more pathogenic anaerobic organisms, at least some of the pathogenic anaerobic organisms being in an anaerobic environment, the plurality of active co-agents being at least three co-agents (e.g., F, D, S or F, Q, S) in use as a drug therapy, being synergistic, causing effective antimicrobial activity as compared to the active co-agents (separately or as pairs), and the co-agents (separately or as pairs) being less effective or ineffective when provided separately or as pairs against one or more pathogens (which can be identified by in vitro AST and by calculation of FICI). At least one active co-agent in use as a drug therapy is a synergist for promoting or causing a synergistic effect with other active co-agents in use as a drug therapy, inducing a reversal effect on at least one co-agent (e.g., a co-agent that is inactive or ineffective when provided separately or as pairs against one or more pathogens, which can be identified by in vitro AST and by calculation of FICI). At least one active co-agent in use as a drug therapy is a synergist for promoting or causing a synergistic effect with other active co-agents in use as a drug therapy, inducing a reversal effect on resistance to at least one co-agent against one or more pathogenic anaerobic organisms (e.g., reversal of resistance to at least one active co-agent when used separately or as pairs against one or more pathogenic anaerobic organisms). The plurality of co-agents or the medicine can be provided empirically or after in vitro testing. 【0128】 【0133】In some embodiments, in a period of time and in the same or different formulations, the in situ synergistic effect of multiple co-agents in the use as a drug therapy as an antimicrobial agent against a target comprising one or more pathogenic anaerobic organisms to be delivered or dispensed to a required host or subject, which promotes or causes or induces a response, the response being: (a) reducing the growth of the target; (b) inhibiting the growth of the target; (c) interrupting the growth of the target; (d) removing all or part of the target; (f) metabolically interfering with all or part of the target; (g) changing or enhancing or promoting or reversing the sensitivity of the target, including one or more or any combination thereof, and the target may or may not be resistant (acquired, endogenous or phenotypically) to at least one active co-agent when at least one active co-agent is used separately against the target, and the period is one or more of less than about 1 hour or less, or less than about 2 hours or less, or less than about 3 hours or less, which is an in situ synergistic effect. In some embodiments, the target is one or more of at least one GNOA bacterium, at least one GPOA bacterium, at least one GNOA bacterium in a mixed population, at least one GPOA bacterium in a mixed population, and any combination thereof. The target may be in or inhabit an anaerobic environment. In some embodiments, more than one of the multiple co-agents to be delivered or dispensed is by the same means of delivery or dispensing, and the means is one or more of the delivery or dispensing routes described herein. In some embodiments, more than one of the multiple co-agents to be delivered or dispensed is by different means of delivery or dispensing, and the means is one or more of the delivery or dispensing routes described herein. The host or subject has or is suspected of having the target in or on the target.The host or subject may have an infectious disease caused or suspected of being caused by the target, or may be at risk of developing an infectious disease caused or suspected of being caused by the target, or may have a disorder and / or disease attributable or suspected of being attributable at least in part to the target. Diagnostic and / or analytical methods, including in vitro methods, for the target, infectious disease, disorder and / or disease, or related thereto, are well known and / or known to those of ordinary skill in the relevant art for diagnosing or determining and / or analyzing the target. In one or more embodiments, the target, infectious disease, disorder and / or disease exhibits or is suspected of exhibiting resistance to treatment or previous pharmacotherapy. In some embodiments, the target, infectious disease, disorder and / or disease exhibits or is suspected of exhibiting antibiotic resistance (to one or more currently approved antibiotics). In one or more embodiments, the target, infectious disease, disorder and / or disease exhibits or is suspected of exhibiting resistance to at least one co-agent (when tested independently or separately against the target). In some embodiments, the host or subject has not been treated prior to one or more active co-agents being delivered or dispensed. In some embodiments, the host or subject has received at least one treatment prior to one or more active co-agents being delivered or dispensed. In some embodiments, one or more active co-agents are delivered or dispensed daily (e.g., according to established clinical and / or hospital guidelines) until the target and / or infectious disease and / or disorder and / or disease is inhibited and / or reduced and / or controlled and / or removed or resolved to a clinically acceptable level for that target and / or infectious disease and / or disorder and / or disease. In some embodiments, one or more active co-agents are delivered or dispensed on a daily schedule of once a day, or twice a day, or three times a day, or four times a day, or five times a day, or six times a day, within a period of time. In some embodiments, one or more active co-agents are delivered or dispensed continuously within a period of time.In some embodiments, more than one active co-agent is delivered or dispensed on a daily schedule for a period of time until a target anaerobic organism, infection, disorder and / or disease (suspected or not) persists or treatment is contemplated or resolved, or as long as it is so. More than one active co-agent can be at least three co-agents herein (at least F, D, S or at least F, Q, S), or at least four co-agents herein (including at least F, D, S or including at least F, Q, S and accompanied by any one of PGSI, BLI or FMEI), or at least five co-agents herein (including at least F, D, S or including at least F, Q, S and accompanied by any two of PGSI, BLI, and / or FMEI), or at least six co-agents herein (including at least F, D, S or including at least F, Q, S and accompanied by any three of PGSI, BLI, and / or FMEI). 【0129】 【0134】In any of the embodiments described herein, a plurality of co-agents (also referred to as active co-agents and / or three or more co-agents) may have the same daily dosing schedule or a similar daily dosing schedule or an overlapping daily dosing schedule, and / or its own dialing dosing schedule, each of which is delivered or dispensed over a period (e.g., any one or more of less than or within about 1 hour, or less than or within about 2 hours, or less than or within about 3 hours) and can be in the same form or different forms (e.g., by means or route of delivery or dispensing). In any of the embodiments herein, the co-agents are in the same vehicle or different vehicles for each co-agent and are in a form for delivery (e.g., solid form or liquid form or semi-solid form, and / or one or more of dry or wet) in either the same form or different forms, and are delivered via at least one of the described vehicles. Using one or more means or routes for delivery or dispensing of a plurality of co-agents (e.g., three or four or five or six co-agents described herein), an effective amount of the co-agents is provided to a host or subject in need thereof by the one or more means or routes for delivery or dispensing (e.g., as representative examples, intravenous, intramuscular, oral, intraoral, dental, dermal, subcutaneous, endocervical, intranasal, intratracheal, epidural, enteral, intraperitoneal, intracerebral, intradermal, intraspinal, intrauterine, nasal, parenteral, rectal, topical, sublingual, intravaginal), and the effective amount is sufficient for a synergistic effect and action against pathogenic anaerobic organisms of one or more types and / or species herein and for effective antibacterial activity. In some embodiments, the effective amount also exhibits or induces or causes any one or more of (a)-(g) herein in response in an anaerobic environment.Moreover, the multiple co-agents continue to be selective because they have no synergistic effect and thereby have no antibacterial activity or inhibitory activity (nor any synergistic action) against certain specific symbiotic and / or beneficial facultative anaerobic organisms (such as symbiotic bacteria in normal or resident or disease-free bacterial flora) that are any one or a combination of Lactobacillus species, Leuconostoc species, and Pediococcus species. 【0130】 【0135】 For example, some infections in a host or subject may have a higher number of pathogenic bacterial cells that can cause an inoculation-like effect, so the MIC can increase in the presence of a higher bacterial load, and thus more drug may be required. Such situations are more likely in co-infections or severe infections. In a clinical situation, especially for co-infections or severe infections, higher antibiotic exposure is better. For example, a severe infection that requires IV administration may have a higher initial dosing schedule to increase the certainty of clinical cure and result in a reduced hospital stay. Therefore, in one or more embodiments, the dosing of one or more co-agents for the combination of co-agents and / or formulations herein is greater than or significantly greater than the MIC for high co-agent exposure to one or more pathogenic anaerobic organisms (such as one or more obligate anaerobic organisms herein or including them). Fortunately, the co-agents described herein have good tissue penetration, and due to the unexpected but beneficial synergy of the co-agents described herein, even in more difficult or severe infections (such as co-UTI and / or pyelonephritis as examples), the co-agents can be used to promote antimicrobial activity (such as any one or more of activities (i)-(x)) at an acceptable and sufficient co-agent level and / or without drug toxicity, much higher than the MIC co-agent level, and can be treated. In some embodiments, a certain level of reversible toxicity may be tolerated due to the shorter duration of use provided herein, which is also understood to result from the benefit of the synergy of the co-agents in the combinations and / or formulations herein. 【0131】 【0136】 Exemplary and representative dosing schedules are described, where the plurality of co-agents herein (e.g., 3 or more co-agents, and up to 6 co-agents) can be either in the same formulation or in 2 or more separate formulations, any of which can be provided by the same or different modes or means of delivery or dispensing, at the same time or period, or at substantially the same or similar times or periods, or at one or more times within a period (e.g., within 3 hours, within 2 hours, within 1 hour, within 30 minutes, within 15 minutes, as representative examples) or continuously. Delivery or dispensing of the plurality of co-agents within a period ensures overlapping delivery or dispensing for synergistic effects and actions. For such a plurality of co-agents herein, the overlapping periods of delivery or dispensing ensure a response (e.g., any one or more of responses (a)-(g)). For such a plurality of co-agents herein, the overlapping periods of delivery or dispensing ensure sufficient and / or effective antimicrobial activity (e.g., any one or more of activities (i)-(x)). For the purposes herein, the overlapping periods of delivery or dispensing can also be referred to as co-administration. 【0132】 【0137】In embodiments herein, delivery or dispensing of the pharmaceutically acceptable combinations and / or formulations herein involves providing a plurality of co-agents (e.g., containing at least 3 active co-agents herein, or at least 4 active co-agents herein, or at least 5 active co-agents herein, or at least 6 active co-agents herein in the same or more than one different form and / or formulation), in amounts for synergistic effect and / or antibacterial activity in an anaerobic environment, and providing is at the same time or substantially the same or similar time or within a period (e.g., within about 3 hours, within about 2 hours, within about 1 hour, within about 30 minutes, within about 15 minutes as representative examples) or is continuous. For sufficient and / or effective antibacterial activity of the plurality of co-agents, the plurality of co-agents includes dosing with at least one of F, D, S or F, Q, S (in the same or different form and / or formulation) during 24 hours, and optionally with any of a therapeutically effective amount of FMEI, PGSI, and / or BLI. At least one dosing during 24 hours can be provided 1, 2, 3, 4, 6, 8 or 12 times and can be a dosing for only 1 day or can be extended for several days or weeks and / or until discontinuation is appropriate. Generally, for synergistic effect and / or antibacterial activity, the amount of F is at least about 2.4 g and at most about 36 g (or any amount within this range during 24 hours), the amount of D (or Q) is at least about 130 mg and at most about 1110 mg (or any amount within this range during 24 hours), and the amount of S is at least about 650 mg and at most about 5600 mg (or any amount within this range during 24 hours). In many cases, and from the perspective of the significant synergistic effects disclosed herein that provide benefit from exposure exceeding the MIC of the co-agents herein, the dosing strategy can include one or more of the plurality of co-agents at higher doses.For example, for sufficient and / or effective synergistic effect and antibacterial activity over 24 hours, the amount of co-agent F can be from about 20 g to about 36 g (or any range therein), the co-agent D (or Q) can be from about 500 mg to about 1110 mg (or any range therein), and the co-agent S can be from about 2000 mg to about 5600 mg (or any range therein). Over 24 hours, the maximum amount of F is about 36 g or up to about 36 g, the maximum amount of D (or Q) is about 1110 mg or up to about 1110 mg, and the maximum amount of S is about 5600 mg or up to about 5600 mg, all of which are historically safe amounts. 【0133】 【0138】For a sufficient and / or effective drug therapy (e.g., for synergistic and / or antimicrobial efficacy), any of FMEI, PGSI, and / or BLI, if included, is provided in a clinically or hospital-approved daily amount and / or schedule. Vancomycin (PGSI) is often provided at about 500 mg or up to about 500 mg (IV) every 6 hours (4 times a day), or about 1 g or up to about 1 g (IV) every 12 hours (2 times a day), and would be beneficial if included in a schedule of 4 times a day or 2 times a day with F, D, S or F, Q, S. Meropenem (PGSI) is often provided at up to about 2 or about 2 (IV) every 8 hours (3 times a day), and would be beneficial if included in a schedule of 3 times a day with F, D, S or F, Q, S. Meropenem-vaborbactam (a PGSI-BLI combination) is often provided at up to about 4 g or about 4 g (IV) every 8 hours (3 times a day), and would be beneficial if included in a schedule of 3 times a day with F, D, S or F, Q, S. Imipenem-relebactam-silasastatin (a PGSI-BLI combination) is often provided at up to about 1.5 g or about 1.5 g (IV) every 6 hours (4 times a day), and would be beneficial if included in a schedule of 4 times a day with F, D, S or F, Q, S. Amoxicillin-clavulanate (a PGSI-BLI combination) is often provided at up to about 1 g or about 1 g (total, IV) every 8 hours (3 times a day), or up to about 500 mg (total, oral) every 8 hours, or up to about 2 g (total, oral) every 12 hours (2 times a day), and would be beneficial if included in a schedule of 2 times a day or 3 times a day with F, D, S or F, Q, S. Ceftazidime-avibactam (a PGSI-BLI combination) is often provided at up to about 2.5 g or about 2.5 g (total, IV) every 8 hours (3 times a day), and would be beneficial if included in a schedule of 3 times a day with F, D, S or F, Q, S. Ceftolozane-tazobactam (a PGSI-BLI combination) is often provided at up to about 1.5 g or about 1.5 g (total, IV) every 8 hours (3 times a day), and would be beneficial if included in a schedule of 3 times a day with F, D, S or F, Q, S.Ticarcillin-clavulanate (a two-component PGSI-BLI) is often provided at a maximum of about 3.2 g or about 3.2 g (total, IV) every 4 to 6 hours (6 or 4 times a day) and would be beneficial when included in a schedule of 4 or 6 times a day with F, D, S or F, Q, S. Ampicillin-sulbactam (a two-component PGSI-BLI) is often provided at a maximum of about 3 g or about 3 g (total, IV or IM) every 6 to 8 hours (4 or 3 times a day) and would be beneficial when included in a schedule of 4 or 3 times a day with F, D, S or F, Q, S. Piperacillin-tazobactam is often provided at a maximum of about 4.5 g or about 4.5 g (total, IV or IM) every 6 to 8 hours (4 or 3 times a day) and would be beneficial when included in a schedule of 4 or 3 times a day with F, D, S or F, Q, S. Two-component or three-component combinations of pre-made or not pre-made PGSI, BLI and / or FMEI can be utilized according to clinical and / or hospital practice and would be beneficial when provided according to these daily schedules and when co-administered or continuously dosed with a plurality of co-drugs including at least F, D, S or at least F, Q, S. 【0134】 【0139】In some embodiments, the daily co - administration (in any amount within the range) is provided once a day, or calculated to provide the co - agent (co - administer) in more than one dose per day (e.g., in any amount within the range, 2, 3, 4, 6, 8, or 12 times a day), or calculated to provide the co - agent continuously (in any amount within the range). In some embodiments, the daily co - administration is an amount for a sufficient and / or effective drug therapy against one or more pathogenic anaerobic organisms in an anaerobic environment, e.g., in a host or subject, or against an infection having or suspected of having one or more pathogenic anaerobic organisms, and is a sufficient and / or effective amount of F, and a sufficient and / or effective amount of D (or Q), and a sufficient and / or effective amount of S, or comprises them. In some embodiments, the daily co - administration for antimicrobial drug therapy is at least 2.4 g or about 2.4 g and up to about 36 g of F as a once - daily amount, and 130 mg or about 130 mg and up to about 1110 mg of D (or Q) as a once - daily amount, and 650 mg or about 650 mg and up to about 5600 mg of S as a once - daily amount, or comprises it. In other embodiments, the daily co - administration for antimicrobial drug therapy is at least 1.2 g or about 1.2 g and up to about 18 g (per dose, 2 doses / day) of F as a twice - daily amount, and 65 mg or about 65 mg and up to about 555 mg (per dose, 2 doses / day) of D (or Q) as a twice - daily amount, and 325 mg or about 325 mg and up to about 2800 mg (per dose, 2 doses / day) of S as a twice - daily amount, or comprises it. In further embodiments, the daily co - administration for antimicrobial drug therapy is at least 0.8 g or about 0.8 g and up to about 12 g (per dose, 3 doses / day) of F as a three - times - daily amount, and 43 mg or about 43 mg and up to about 370 mg (per dose, 3 doses / day) of D (or Q) as a three - times - daily amount, and 215 mg or about 215 mg and up to about 1870 mg (per dose, 3 doses / day) of S as a daily amount, or comprises it.In a further embodiment, the daily co - administration for antimicrobial drug therapy is at least F in an amount of 0.6 g or about 0.6 g and up to about 9 g (4 doses / day at 1 dose each) as a four - times - daily dose, and D (or Q) in an amount of 32 mg or about 32 mg and up to about 280 mg (4 doses / day at 1 dose each) as a four - times - daily dose, and S in an amount of 162 mg or about 162 mg and up to about 1400 mg (4 doses / day at 1 dose each) as a four - times - daily dose, or includes it. In a further embodiment, the daily co - administration for antimicrobial drug therapy is at least F in an amount of 0.4 g or about 0.4 g and up to about 6 g (6 doses / day at 1 dose each) as a six - times - daily dose, and D (or Q) in an amount of 21 mg or about 21 mg and up to about 185 mg (6 doses / day at 1 dose each) as a six - times - daily dose, and S in an amount of 108 mg or about 108 mg and up to about 935 mg (6 doses / day at 1 dose each) as a six - times - daily dose, or includes it. In a further embodiment, the daily co - administration for antimicrobial drug therapy is at least F in an amount of 0.3 g or about 0.3 g and up to about 4.5 g (8 doses / day at 1 dose each) as an eight - times - daily dose, and D (or Q) in an amount of 16 mg or about 16 mg and up to about 139 mg (8 doses / day at 1 dose each) as an eight - times - daily dose, and S in an amount of 81 mg or about 81 mg and up to about 700 mg (8 doses / day at 1 dose each) as an eight - times - daily dose, or includes it. In a further embodiment, the daily co - administration for antimicrobial drug therapy is at least F in an amount of 0.2 g or about 0.2 g and up to about 3 g (12 doses / day at 1 dose each) as a twelve - times - daily dose, and D (or Q) in an amount of 10 mg or about 10 mg and up to about 92 mg (12 doses / day at 1 dose each) as a twelve - times - daily dose, and S in an amount of 54 mg or about 54 mg and up to about 468 mg (12 doses / day at 1 dose each) as a twelve - times - daily dose, or includes it. 【0135】 【0140】The plurality of active co-agents can include at least F, D, and S (each being separately active against aerobic bacteria in an aerobic environment, and at least one being separately inactive against anaerobic organisms in an anaerobic environment), and are co-administered (e.g., parenterally) every 4 hours or every 6 hours daily, where F is about 1.8 to about 7.5 grams (per dose), D is about 5 to about 20 mg / kg (per dose), and S is about 20 to about 100 mg / kg (per dose). The plurality of active co-agents can include at least F, D, and S (each being separately active against aerobic bacteria in an aerobic environment, and at least one being separately inactive against anaerobic organisms in an anaerobic environment), and are co-administered (e.g., orally and / or oro-nasal-gastrically) every 4 hours or every 6 hours daily, where F is about 0.7 to about 3.3 grams (per dose), D is about 80 to about 160 mg (per dose), and S is about 360 to about 800 mg (per dose). The plurality of active co-agents can include at least F, D, and S (each being separately active against aerobic bacteria in an aerobic environment, and at least one being separately inactive against anaerobic organisms in an anaerobic environment), and are co-administered (e.g., orally and / or oro-nasal-gastrically) every 8 hours or every 12 hours daily, where F is about 1.4 to about 6.7 grams (per dose), D is about 160 to about 320 mg (per dose), and S is about 700 to about 1800 mg (per dose). The plurality of active co-agents can include at least F, D, and S, and are co-administered (e.g., by enema or retention enema) every 6 hours daily, where F is about 500 to about 4 grams (per dose), D is about 80 to about 640 mg (per dose), and S is about 360 mg to about 3.2 g (per dose). D and S can be provided as a two-component combination (e.g., D is trimethoprim and S is sulfamethoxazole). One or more of FMEI, PGSI, and / or BLI herein are co-administered with F, D, S. In some embodiments, PGSI and BLI can be provided as a two-component or three-component combination (e.g., when indicated and / or presented / prepared as a two-component or three-component combination for approved use). 【0136】 【0141】Exemplary delivery or dispensing is provided where daily co-therapy for one or more pathogenic anaerobic organisms (obligate anaerobes in an anaerobic environment or including such) is at least F, D, S or F, Q, S or includes such and continues until the infection and / or symptoms improve, are controlled or resolved or due to safety concerns. For parenteral delivery or dispensing, F can be provided in dry / powder or liquid form in a vial and is or can be fosfomycin trometamol salt or fosfomycin disodium (or hydrolysable) salt (as representative examples only for the purposes herein). D can be provided in dry / powder or liquid form in a vial and is or can be trimethoprim, iclaprim, pyrimethamine (as representative examples only for the purposes herein). S can be provided in dry / powder or liquid form in a vial and is or can be sulfamethoxazole, sulfisoxazole, sulfadoxine (as representative examples only for the purposes herein). D can be replaced by Q which is or can be SCH79797, iregistrin, gefitinib, lapatinib, erlotinib, afatinib (as representative examples only for the purposes herein) provided in dry / powder or liquid form in a vial or as a tablet. The form in the vial is dissolved and / or reconstituted and / or diluted (e.g., using 5% dextrose, buffered saline, sterile water or other suitable diluent) for injection / IV. The vial can be provided in a kit with or without one or more diluents. More than two co-agents can be in the same vial. Daily co-administration via the IV route utilizes a peripheral and / or central line.The co-administration can be on the same or different IV lines (e.g., different if the forms are not compatible), and includes at least F at about 1.8 - 7.5 g every 6 hours (4 times / day), and D at about 5 - 20 mg / kg every 6 hours (4 times / day), and S at about 25 - 100 mg / kg every 6 hours (4 times / day). The IV infusion is metered over a period of time (e.g., up to 60 minutes or about 60 minutes, or up to 90 minutes or about 90 minutes, or up to 120 minutes or about 120 minutes) for delivery or dispensing (e.g., via a pump). If the co-administration further includes FMEI, PGSI and / or BLI, FMEI, PGSI and / or BLI are on a similar schedule (e.g., every 6 hours for the same or substantially the same period as F, D, S or F, Q, S). 【0137】 【0142】For oral or oro-nasal-gastric delivery or dispensing, F can be provided in dry / powder or liquid or solid form (the dry / powder can be in sachets or vials, in solid form as tablets or capsules, or in some equivalents), and can be or can be phosphomycin trometamol salt or phosphomycin disodium salt (exemplified only for the purposes herein). D can be provided in dry / powder or liquid or solid form (the dry / powder can be in sachets or vials, in solid form as tablets or capsules, or in some equivalents), and can be or can be trimethoprim, iclaprim, pyrimethamine (exemplified only for the purposes herein). S can be provided in dry / powder or liquid or solid form (the dry / powder can be in sachets or vials, in solid form as tablets or capsules, or in some equivalents), and can be or can be sulfamethoxazole, sulfisoxazole, sulfadoxine (as a representative example only for the purposes herein). D can be replaced by Q, which can be or can be SCH79797, eristostatin, gefitinib, lapatinib, erlotinib, afatinib provided in vials, in dry / powder or liquid form in sachets, or as tablets or capsules (exemplified only for the purposes herein). For example, the form in vials or sachets in dry / powder form is dissolved and / or reconstituted and / or diluted (e.g., using 5% dextrose, buffered saline, sterile water or other diluents) prior to delivery or dispensing via the oral route or via the oral or nasogastric tube. Vials and / or solids and / or sachets can be in kits with or without one or more diluents. More than two co-agents can be in the same vehicle (e.g., by way of example, vials or sachets or pills or capsules or elixirs or concentrates).Co - administration can be in the same solid or liquid or different solids or liquids (e.g., if the forms are not compatible). A first representative embodiment includes at least F at about 0.7 - 3.4 g every 6 hours (4 times / day), and D at about 80 - 160 mg every 6 hours (4 times / day), and S at about 360 - 800 mg every 6 hours (4 times / day), and the delivery or dispensing is within the same or substantially the same period (e.g., up to 15 minutes or about 15 minutes, or up to 30 minutes or about 30 minutes, or up to 45 minutes or about 45 minutes). In another example, co - administration includes at least F at about 1.4 - 6.7 g every 12 hours (2 times / day), and D at about 160 - 320 mg every 12 hours (2 times / day), and S at about 700 - 1200 mg every 12 hours (2 times / day), and the delivery or dispensing is within the same or substantially the same period (e.g., up to 15 minutes or about 15 minutes, or up to 30 minutes or about 30 minutes, or up to 45 minutes or about 45 minutes). When co - administration further includes FMEI, PGSI and / or BLI, FMEI, PGSI and / or BLI are on a similar schedule (e.g., every 6 hours or every 12 hours in the same or substantially the same period as F, D, S or F, Q, S). 【0138】 【0143】For the delivery or dispensing of enemas or retention enemas, F can be provided in dry / powder or liquid form (the dry / powder can be in sachets or vials), and is or can be fosfomycin trometamol salt or fosfomycin disodium (or hydrolyzable) salt (representative examples only for the purposes herein). D can be provided in dry / powder or liquid form (the dry / powder can be in sachets or vials), and is or can be trimethoprim, iclaprim, pyrimethamine (representative examples only for the purposes herein). S can be provided in dry / powder or liquid form (the dry / powder can be in sachets or vials), and is or can be sulfamethoxazole, sulfisoxazole, sulfadoxine (as representative examples only for the purposes herein). D can be replaced by Q, which is or can be, for example, SCH79797, eristostatin, gefitinib, lapatinib, erlotinib, afatinib provided in dry / powder or liquid form (representative examples only for the purposes herein). For example, the form in vials or sachets in dry / powder form is dissolved and / or reconstituted and / or diluted (e.g., using 5% dextrose, buffered saline, sterile water or other suitable diluents). Co-agents of the same or different volumes are diluted to a fixed volume (e.g., up to 100 ml or about 100 ml, up to 250 ml or about 250 ml, up to 500 ml or about 500 ml). Vials and / or sachets can be provided in a kit with or without one or more diluents, and with or without a bag or balloon and / or catheter and / or inflation means. More than two co-agents can be in the same vehicle (e.g., by way of example, vials or sachets or elixirs or concentrates).Co - administration can be in the same bag or balloon or in different bags or balloons (e.g., when the forms are not compatible), insert a catheter with a bag or balloon into the rectum, inflate it, instill a fixed volume containing one or more co - agents, and subsequently clamp the catheter for a period (e.g., up to 60 minutes or about 60 minutes, or up to 90 minutes or about 90 minutes, or up to 120 minutes or about 120 minutes). F is about 500 mg to 4 g, D is about 80 - 640 mg, S is about 360 mg to 3.2 g, and each is provided every 6 hours (4 times / day). When using different bags or balloons, delivery or dispensing is in series. Co - administration can further include FMEI, PGSI and / or BLI, and FMEI, PGSI and / or BLI are in the same or subsequent bag or balloon as one or more of F, D, S (or F, Q, S). 【0139】 【0144】In one embodiment, a kit comprising one or more vehicles (e.g., by way of representative example only, vials, syringes, pills, tablets, suppositories), wherein at least one pharmaceutically acceptable co-agent (pre-weighed, pre-measured for at least one dosage per vehicle, generally with one or more excipients and with a dosage for one or more days) is in one or more of the vehicles in the kit. In one or more embodiments, a kit comprising a separate vehicle for each co-agent (e.g., one for F, one for D (or Q), one for S, etc.), wherein each co-agent (pre-weighed, pre-measured for at least one dosage per vehicle and / or for one day's dosage, generally with one or more excipients) is in its vehicle in the kit. In one or more embodiments, a kit comprising the same vehicle for a plurality of co-agents, wherein the plurality of co-agents (pre-weighed, pre-measured for at least one dosage per vehicle, generally with one or more excipients and with a dosage for one or more days) is in one or more of the vehicles in the kit. In one or more embodiments, the kit further comprises information / instructions. In one or more embodiments, the kit further comprises a suitable diluent for one or more of the vehicles. 【0140】 【0145】The inventors have demonstrated that the antimicrobial agents (including a plurality of co-agents co-administered within a period) herein can be present in a mixed infection in an anaerobic environment, cannot utilize oxygen, and / or are inhibited by oxygen, and are active against target anaerobic organisms (i.e., obligate anaerobic organisms) that are difficult to treat. When combined to be synergistic herein, it has also been shown that the antimicrobial agents increase the activity or efficiency of the co-agents. Furthermore, alternative inhibitors of bacterial dihydrofolate reductase can be successfully replaced by diaminopyrimidines to achieve synergistic agent activity equally effective against such anaerobic organisms. Unexpectedly, the antimicrobial agents of the invention herein have been demonstrated to be selectively active. It is possible to target and be active against all obligate anaerobic organisms tested, but the co-agent compositions and / or formulations herein are considered normal GI tract commensal or beneficial symbiotic bacteria, or facultative anaerobic organisms Lactobacillus species, Pediococcus species and / or Leuconostoc that are not inhibited by the antimicrobial agents of the invention herein and have not been found to be responsive (or sensitive). Such unique and unexpected findings herein provide a means for targeted drug therapy against selected pathogenic anaerobic organisms and indicate a new and novel approach particularly applicable to the treatment of anaerobic pathogenic organisms. (According to reports by other persons skilled in the art) The inability to address or the inappropriate use of treatment against anaerobic organisms can lead to clinical failure, and in many cases to clinical failure, so the importance of such findings means the reduction of clinical failure.In addition, considering that the use of many alternative approved antibiotics is associated with harmful phenomena known as dysbiosis (GI side effects resulting from the death of protective GI flora or symbiotic and / or those considered beneficial, and an increase in GI infections including an increased risk of infection from one or more obligate anaerobic organisms such as C. difficile), the findings herein regarding selective inactivation of at least some of the symbiotic or beneficial commensal bacteria of the normal GI system mean that the use of the antimicrobial agents of at least some of the inventions herein results in an overall reduction of GI side effects and GI infections and is suitable for use in hosts (e.g., patients) having existing GI problems or prone to recurrence of GI infections. 【0141】 【0146】Based on the in vitro activities of a plurality of tested active co-agents, providing any of the active co-agents herein in a combination and / or formulation (by co-administration within a certain period), and / or utilizing any such combination and / or formulation against one or more pathogenic anaerobic organisms in a host or subject known or suspected to have said one or more anaerobic organisms, it is evident that it is a truly effective antimicrobial agent and provides a good clinical outcome, thereby improving the treatment time and reducing the mortality rate. In addition, based on the in vitro activities of a large number of tested active co-agents, the active co-agents herein in the combination and / or formulation are as effective as or more effective than metronidazole, which is unreliable against Gram-positive anaerobic organisms, particularly GPOA, as reported by other persons skilled in the art. Based on the in vitro activities of a large number of tested active co-agents, overall, clindamycin is less reliable than metronidazole as reported by other persons skilled in the art, continues to show an increase in resistance to certain obligate anaerobic organisms including Bacteroides, and moreover, clindamycin does not penetrate the central nervous system, but the active co-agents herein (e.g., at least F, D, S or F, Q, S) have been found to pass through the blood-brain barrier and enter the CNS, so it is evident that the active co-agents herein in the combination and / or formulation are more effective against GNOA than clindamycin. Based on the in vitro activities of a large number of tested active co-agents, it is evident that the active co-agents herein in the combination and / or formulation are more effective than penicillin, and as reported by other persons skilled in the art, penicillin has become unreliable due to its increasing resistance profile and these inactivities against anaerobic organisms producing beta-lactamase (referring to most Gram-negative anaerobic organisms), but the co-agents herein are active against beta-lactamase-producing anaerobic organisms.Based on the in vitro activities of a large number of tested active co-agents, the active co-agents herein in combinations and / or formulations are clearly more effective than second-generation cephalosporins (such as cefoxitin, cefotetan, cefmetazole), and as reported by other persons skilled in the art, second-generation cephalosporins have become unreliable and are not recommended as empirical treatment due to these increasing resistance profiles. Based on the in vitro activities of a large number of tested active co-agents, the active co-agents herein in combinations and / or formulations are clearly more effective than fluoroquinolones (such as levofloxacin, moxifloxacin), and as reported by other persons skilled in the art, fluoroquinolones have become unreliable due to these increasing resistance profiles and are generally left as salvage therapy for those after the failure of other drugs or for those with beta-lactam allergies. 【0142】 【0147】 Unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a", "and", and "the" may include plural referents. For example, "combination" or "formulation" may include plural and their equivalents as known to persons skilled in the art. It is understood that the term "comprising" (and related terms, such as "comprise", "comprises", "having", or "including") is not intended to exclude embodiments where, for example, a particular described combination, composition, method, or process, etc. may "consist of" or "consist essentially of" a certain described property. 【0143】 [Table 1-1] 【0144】 [Table 1-2] 【0145】 [Table 2] 【0146】 [Table 3] 【0147】 [Table 4] 【0148】 [Table 5] 【0149】 [Table 6] 【0150】 [Table 7] 【0151】 [Table 8] 【0152】 [Table 9] 【0153】 [Table 10A] 【0154】 [Table 10B-1] 【0155】 [Table 10B-2] 【0156】 [Table 10B-3] 【0157】 [Table 11] 【0158】 [Table 12] 【0159】 [Table 13] 【0160】 [Table 14A] 【0161】 [Table 14B] 【0162】 [Table 14C] 【0163】 [Table 15-1] 【0164】 [Table 15-2] 【0165】 [Table 16] 【0166】 [Table 17-1] 【0167】 [Table 17-2] 【0168】 [Table 18] 【0169】 [Table 19] 【0170】 [Table 20] 【0171】 [Table 21]

Claims

[Claim 1] Multiple co-agents for use as antimicrobial pharmaceuticals against one or more pathogenic anaerobic organisms in an anaerobic environment: Fosfomycin in a pharmaceutically acceptable form selected from one or more of salts, phosphates, acids, amines, and esters, wherein fosfomycin alone is an antimicrobial agent having antimicrobial activity in an aerobic environment as an inhibitor of bacterial UDP-GlcNAc enolpyruvirtransferase (MurA), and can be replaced by an alternative antimicrobial agent having antimicrobial activity in an aerobic environment as an inhibitor of bacterial UDP-GlcNAc enolpyruvirtransferase (MurA); Diaminopyrimidines in pharmaceutically acceptable forms selected from one or more salts, phosphates, acids, and esters, which are antimicrobial agents having antimicrobial activity in an aerobic environment as inhibitors of bacterial dihydrofolate reductase, and which can be replaced by alternative antimicrobial agents having antimicrobial activity in an aerobic environment as inhibitors of bacterial dihydrofolate reductase; and A pharmaceutically acceptable form of sulfonamide selected from one or more of salts, phosphates, acids, and esters, wherein the sulfonamide alone is an antimicrobial substance having antimicrobial activity in an aerobic environment as an inhibitor of bacterial dihydropteroic acid synthase, and can be replaced by an alternative antimicrobial substance having antimicrobial activity in an aerobic environment as an inhibitor of bacterial dihydropteroic acid synthase. Includes, The plurality of co-agents are provided to a target requiring them for at least one period of time, and one or more of the plurality of co-agents act as synergistic agents to produce antimicrobial activity against the one or more pathogenic anaerobic organisms in the anaerobic environment, wherein at least one of the one or more pathogenic anaerobic organisms is an obligate anaerobic bacterium in the anaerobic environment, and the at least one period is selected from the group consisting of about three hours or less, about two hours or less, and about one hour or less. [Claim 2] The plurality of co-agents according to claim 1, wherein if at least one of the one or more pathogenic anaerobic organisms is at an acidic pH, a neutral pH, or a basic pH, the plurality of co-agents are active against at least one of the one or more pathogenic anaerobic organisms, where the acidic pH is a low pH of about pH 5 and the basic pH is a high pH of about pH 8. [Claim 3] The plurality of co-agents according to claim 1, wherein when at least one co-agent is used alone against at least one of the one or more pathogenic anaerobic organisms, at least one of the one or more pathogenic anaerobic organisms is considered to be resistant to at least one co-agent of the plurality of co-agents, and at least one of the one or more pathogenic anaerobic organisms is an obligate anaerobic bacterium. [Claim 4] The plurality of co-agents used as co-agents are provided as one or more selected from the group consisting of (a), (b), and (c) below, according to Claim 1: (a) pharmacotherapy to the subject, wherein the plurality of co-agents are provided by co-administration during the period, the co-administration being further selected from a group consisting of the same time, substantially the same time, overlapping temporal spans within the period, and sequences within the period, and the co-administration within the period being selected from one of the groups consisting of 1, 2, 3, 4, 6, 8, 12, and consecutive doses within a 24-hour period; (b) Pharmacological treatment for subjects having or suspected to have an infection caused by or suspected to be caused by one or more Gram-positive obligate anaerobic bacteria in an anaerobic environment; and (c) Pharmacotherapy for subjects having or suspected to have an infection caused by or suspected to be caused by one or more Gram-negative obligate anaerobic bacteria in an anaerobic environment. [Claim 5] The plurality of co-agents used as co-agents are provided as one or more selected from the group consisting of (a), (b), and (c) below, according to Claim 1: (a) A drug therapy for a subject having or suspected of having an infection caused by or suspected of being caused by one or more challenging anaerobic organisms selected from one or more microaerophilic Streptococcus species, including S. anginosus, S. constellatus, S. intermethius, S. mutans, and Streptococcus viridans, wherein the plurality of co-agents are active against the one or more microaerophilic Streptococcus species; (b) Pharmacotherapy for subjects having or suspected of having an infection caused by or suspected of being caused by one or more Gram-positive obligate anaerobic bacteria selected from one or more of the group consisting of Actinomyces, Arcanobacterium, Atopovium, Bifidobacterium, Virophila, Clostridioides, Clostridium, Cholinella, Egasella, Eubacterium, Finegordia, Parvimonas, Peptococcus, Peptostreptococcus, Propionibacterium and Cutibacterium, wherein the plurality of co-agents are active against the one or more Gram-positive obligate anaerobic bacteria; and (c) A drug therapy for a subject who has or is suspected of having an infection caused by or suspected of having an infection caused by or suspected of being caused by one or more Gram-negative obligate anaerobic bacteria selected from one or more species of the group consisting of Aggregatibacter, Bacteroides, Parabacteroides, Dethiosulfovibrio, Fusobacterium, Focaeicola, Porphyromonas, Prevotella, Saterella, and Veillonella, wherein the plurality of co-agents are active against the one or more Gram-negative obligate anaerobic bacteria. [Claim 6] The plurality of co-agents according to claim 1, wherein when the plurality of co-agents are provided to the subject as pharmacotherapy, they are not effective as antimicrobial agents against one or more symbiotic anaerobic bacterial species selected from the group consisting of Lactobacillus species, Pediococcus species, and Leuconostoc species. [Claim 7] A synergistic agent for a combination of antibiotics, wherein the combination of antibiotics is: Diaminopyrimidines in pharmaceutically acceptable forms selected from one or more salts, phosphates, acids, and esters, which are antimicrobial agents as inhibitors of bacterial dihydrofolate reductase when used alone in an aerobic environment, and which are not effective antimicrobial agents against one or more obligate anaerobic bacteria in an anaerobic environment when used alone; and A pharmaceutically acceptable form of sulfonamide selected from one or more salts, phosphates, acids, and esters, which is an antimicrobial agent as an inhibitor of bacterial dihydropteroic acid synthase when used alone in an aerobic environment, but is not an effective antimicrobial agent against one or more obligate anaerobic bacteria in an anaerobic environment when used alone. Including; The synergistic agent comprises at least, A pharmaceutically acceptable form of fosfomycin selected from one or more salts, phosphates, amines, acids, and esters, which is an antimicrobial agent that acts as an inhibitor of bacterial UDP-GlcNAc enolpyruvirtransferase (MurA) when used alone in an aerobic environment, comprises fosfomycin; A synergistic agent wherein the synergistic agent, in combination with the aforementioned antibiotics, induces a synergistic effect that transforms the therapeutic potential of the combination of antibiotics, and as a result, the synergistic agent, in combination with the aforementioned antibiotics, is active against one or more obligate anaerobic bacteria in the anaerobic environment. [Claim 8] The synergistic agent according to claim 7, wherein the combination of the synergistic agent and the antibiotic is provided as one or more selected from the group consisting of (i), (ii), and (iii): (i) The combination of the synergistic agent and the antibiotic is in the same formulation, and for synergistic effect, the combination of the synergistic agent and the antibiotic is provided within the same period of time, the period of time being selected from one of the groups consisting of about one hour or less, about two hours or less, and about three hours or less; (ii) The combination of the synergistic agent and the antibiotic is in different formulations, and for synergistic effect, the combination of the synergistic agent and the antibiotic is provided within the same period of time, the period of time being selected from one of the groups consisting of about one hour or less, about two hours or less, and about three hours or less; (iii) A drug therapy for a subject in need, provided within a certain period, wherein the period for providing the combination of the synergistic agent and the antibiotic is selected from one of the group consisting of the same period, substantially the same period, overlapping temporal spans within the period, and a series within the period. [Claim 9] The synergistic agent according to claim 7 or the plurality of co-agents according to claim 1, wherein the fosfomycin or bacterial MurA inhibitor is selected from one or more of the group consisting of phosphonates, phosphates, derivatives of phosphonates, derivatives of phosphates, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and each of them has antibacterial activity when used alone in an aerobic environment, and a typical example of the fosfomycin is a water-soluble fosfomycin salt. [Claim 10] The synergistic agent according to claim 7 or the plurality of co-agents according to claim 1, wherein the diaminopyrimidine or bacterial dihydrofolate reductase inhibitor is selected from one or more of the group consisting of 2,4-diaminopyrimidine, derivatives of 2,4-diaminopyrimidine, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and each of them has antimicrobial activity when used alone in an aerobic environment, and a typical example of the diaminopyrimidine is selected from one or more of trimethoprim, pyrimethamine, diaveridine, brodimoprim, tetroxoprim, methioprim, and ikuraprim. [Claim 11] The sulfonamide or bacterial dihydropteroic acid synthase inhibitor is selected from one or more of the group consisting of sulfanilamide, sulfanilamide derivatives, sulfam, sulfam derivatives, sulfonamide, sulfonamide derivatives, disulfonimide, disulfonimide derivatives, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and any of them has antibacterial activity when used alone in an aerobic environment, and typical examples of the sulfonamide are sulfadiazine, sulfamethoxazole, sulfatroxazole, sulfamerazine, sulfadoxine, sulfadimethoxine, sulf A synergistic agent according to claim 7 or a plurality of co-agents according to claim 1, selected from one or more of the following: amethazine, sulfapyrazole, sulfaquinoxaline, sulfachloropyridazine, sulfaguanidine, sulfarene, sulfametine, sulfamethine, sulfamethoxyline, sulfamethoxypyridazine, sulfamethylphenazole, sulfamethoxypyridazine, sulfaethoxypyridazine, sulfabromomethazine, sulfafenazole, sulfamoxol, sulfapyrazine, sulfapyridine, sulfasimazine, sulfathiozol, sulfametrol, sulfanilimide, sulfasomidine, and sulfisoxazole. [Claim 12] The synergistic agent according to claim 7, wherein the synergistic agent further comprises a co-agent, the co-agent being an inhibitor of bacterial phosphomycin modifying enzyme (FME) selected from one or more of the group consisting of phosphonoformate, phosphonoacetate, methylphosphonate, ethylphosphonate, phenylphosphonate, acetylphosphonate, phosphonoacetaldehyde, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, a typical example being selected from one or more of sodium phosphonoformate, sodium phosphonoformate tribasic hexahydrate, triethylphosphonoformate, 2-phosphonobutyrate, 4-phosphonobutyrate, 2-phosphonopropionate, 2-phosphonopropionate, and 3-phosphonopropionate, and the bacterial FME inhibitor inhibits or inactivates the FME of one or more obligate anaerobic bacteria. [Claim 13] The synergistic agent further comprises a co-agent, the co-agent being: (a) a bacterial peptidoglycan synthesis inhibitor selected from the class of glycopeptides or lipoglycopeptides, which binds to the lipid II precursor of the outer wall of one or more obligate anaerobic bacteria, inhibiting peptidoglycan synthesis and inhibiting cell wall synthesis of the one or more obligate anaerobic bacteria; (b) a beta-lactam antibiotic selected from the class of beta-lactam antibiotics, which binds to penicillin-binding protein enzymes and inhibits peptidoglycan synthesis of the one or more obligate anaerobic bacteria; and (c) a fine The synergistic agent according to claim 7, which is a bacterial beta-lactamase inhibitor, one or more from a group of co-agents comprising bacterial beta-lactamase inhibitors that inhibit or inactivate the beta-lactamase enzyme of one or more obligate anaerobic bacteria, wherein the co-agent is provided as a combination of the synergistic agent and the antibiotic within the same period, the period being selected from one of the groups consisting of about 1 hour or less, about 2 hours or less, and about 3 hours or less, and the combination of the synergistic agent and the antibiotic and the co-agent are provided within 24 hours in one of the groups consisting of 1, 2, 3, 4, 6, 8, 12, and consecutively. [Claim 14] A kit containing a pharmaceutically acceptable co-agent for use as a drug therapy for one or more pathogenic anaerobic organisms in an anaerobic environment, wherein at least, The first co-agent is a therapeutically effective dose of the first co-agent for delivery within 24 hours, and is a pharmaceutically acceptable form of fosfomycin selected from one or more of salts, phosphates, acids, amines, and esters, and is an inhibitor of bacterial UDP-GlcNAc enolpyruvirtransferase when used alone in an aerobic environment; The second co-agent is a therapeutically effective dose of the second co-agent for delivery within 24 hours, and is a pharmaceutically acceptable form of diaminopyrimidine selected from one or more salts, phosphates, acids, and esters, and is an inhibitor of bacterial dihydrofolate reductase when used alone in an aerobic environment; A third co-agent, a therapeutically effective dose of the third co-agent for delivery within 24 hours, which is a sulfonamide in a pharmaceutically acceptable form, selected from one or more salts, phosphates, acids, and esters, and which, when used alone in an aerobic environment, is an inhibitor of bacterial dihydropteroic acid synthase; and Depending on the circumstances, the mixture may include at least one diluent for one or more of the first co-agent, the second co-agent, or the third co-agent. The first co-agent, the second co-agent, and the third co-agent are contained in one or more vehicles, and the one or more vehicles contain a sufficient amount for at least one delivery within 24 hours. The kit is for the delivery of therapeutically effective amounts of the first co-agent, therapeutically effective amounts of the second co-agent, and therapeutically effective amounts of the third co-agent for at least one delivery to a subject for the treatment or prevention of an infection caused by one or more obligate anaerobic bacteria, The fosfomycin is selected from one or more of the group consisting of phosphonates, phosphoric acid, derivatives of phosphonates, derivatives of phosphoric acid, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and each of these has antibacterial activity when used alone in an aerobic environment, and a typical example of the fosfomycin is a water-soluble fosfomycin salt. The diaminopyrimidine is selected from one or more of the group consisting of 2,4-diaminopyrimidine, derivatives of 2,4-diaminopyrimidine, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and each of them has antimicrobial activity when used alone in an aerobic environment, and a typical example of the diaminopyrimidine is selected from one or more of trimethoprim, pyrimethamine, diaveridine, brodimoprim, tetroxoprim, methioprim, and ikuraprim, and The sulfonamide is selected from one or more of the group consisting of sulfanilamide, sulfanilamide derivatives, sulfam, sulfam derivatives, sulfonamide, sulfonamide derivatives, disulfonimide, disulfonimide derivatives, stereoisomers thereof, geometric isomers thereof, tautomers thereof, hydrates thereof, and solvates thereof, and any of them has antibacterial activity when used alone in an aerobic environment, and typical examples of the sulfonamide are sulfadiazine, sulfamethoxazole, sulfatroxazole, sulfamerazine, sulfadoxine, sulfadimethoxine, and Selected from one or more of the following: rufamethazine, sulfapyrazole, sulfaquinoxaline, sulfachloropyridazine, sulfaguanidine, sulfarene, sulfametine, sulfamethine, sulfamethoxyline, sulfamethoxypyridazine, sulfamethylphenazole, sulfamethoxypyridazine, sulfaethoxypyridazine, sulfabromomethazine, sulfafenazole, sulfamoxol, sulfapyrazine, sulfapyridine, sulfasimazine, sulfapyridine, sulfasimazine, sulfathiosol, sulfametol, sulfanilimide, sulfasomidine, sulfisoxazole. kit.