Antimicrobial combinations

Abstract

The present invention provides an antimicrobial combination comprising three different antimicrobial agents. The first antimicrobial agent is selected from the group consisting of ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; the second antimicrobial agent is selected from the group consisting of zidovudine, doxycycline, fosfomycin and pharmaceutically acceptable derivatives thereof; and the third antimicrobial agent is selected from the group consisting of levofloxacin, doxycycline, fosfomycin, meropenem, rifampicin, gentamicin, polymyxin B / E, and pharmaceutically acceptable derivatives thereof; wherein the combination comprises at least one of levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; with the proviso that the combination is not (1) polymyxin E / B, zidovudine and rifampicin or (2) ceftazidime, zidovudine and fosfomycin. Also provided are antimicrobial combinations comprising three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof.

Description

Field of the Invention

[0001] The present invention relates to a synergistic combination of three or four antimicrobial agents. The first, second, and third agents (and the fourth agent, when present) are selected from their respective groups as defined herein, and the combination has a synergistic effect against Gram-negative bacteria and / or Gram-positive bacteria, meaning that it is suitable for treating microbial infections caused by said bacteria. Specifically, the present invention relates to the use of this combination to kill microorganisms in the proliferative (i.e., logarithmic phase) associated with a bacterial infection (such as a Gram-negative bacterial infection).

[0002] Background

[0003] Before the introduction of antibiotics, patients suffering from acute microbial infections (such as tuberculosis or pneumonia) had a very low chance of survival. For example, the mortality rate of tuberculosis was about 50%. The introduction of antimicrobial agents in the 1940s and 1950s quickly changed this scenario, and today about 100 antibiotics are used to treat different bacterial infections. This contributed to the birth of modern medicine, as bacterial infections in millions of patients with, for example, cancer, organ transplantation, kidney dialysis, immunosuppression, and surgery can be effectively prevented and treated.

[0004] However, bacteria have responded to the widespread use of antibiotics by gradually acquiring resistance. Today, antibiotic-resistant bacteria exist in every country in the world, and this resistance increases year by year, thus reducing the effectiveness of all antibiotics. By 2040 - 2050, deaths from antimicrobial-resistant infections are expected to exceed 10 million per year (The Review on Antimicrobial Resistance, chaired by Jim O’Neill, May 2016).

[0005] The increase in antimicrobial resistance is expected to occur in poorer countries by 2040 - 2050 and this has become a real and practical medical problem in Europe and the United States. In fact, in the United States, more than 70% of the bacteria that cause hospital-acquired infections are resistant to at least one of the main antimicrobial agents commonly used to combat infections (Nature Reviews, Drug Discovery, 1, 895 - 910 (2002)). As a result, the World Health Organization has classified antibiotic resistance as a "serious threat, [which] is no longer a prediction for the future, it is happening in every region of the world and has the potential to affect anyone, of any age, in any country" ("Antimicrobial resistance: global report on surveillance", World Health Organization, April 2014). If not addressed, life expectancy could return to pre-antibiotic levels, which is about 20 years less than it is now.

[0006] Accordingly, there is an urgent need for solutions to the problem of increasingly drug-resistant bacteria. In essence, the medical community needs to replace approximately 100 antibiotics with products that are effective against microbial agent-resistant infections while avoiding the development of future antimicrobial resistance.

[0007] Current efforts to address this problem have mainly focused on the development of new chemical entities (NCEs). Each NCE requires more than 10 years of development and costs over $600 million to complete the necessary safety and clinical testing. A large number will fail and thus it typically takes approximately $3.8 billion to deliver one NCE antibiotic. Ironically, as antibiotic use increases, the development of antimicrobial resistance also occurs more rapidly, meaning that all NCEs have a limited lifespan, usually less than 10 years. Therefore, replacing the currently used antibiotics with NCEs over a 10-year period would require approximately $3.8 trillion, and even if successful, these products would then need ongoing programs to replace them as each antimicrobial resistance emerges over their 10-year lifespan. This is clearly unsustainable, even for high-income countries.

[0008] The applicant has identified a solution to this major, global problem. Specifically, combinations of three or more known antibiotics have surprisingly been shown to have a synergistic effect against Gram-negative bacteria and / or Gram-positive bacteria. Such combinations have been found to kill antimicrobial-resistant bacteria (also known as drug-resistant bacteria) and avoid the development of antimicrobial resistance. The three or more known antibiotics are defined in the appended claims and described herein.

[0009] The synergistic effect demonstrated means that the composition has higher biological activity at the stated dose levels than would be expected from the additive effects of the individual agents. This means that less of the antibiotic (e.g. 5 to 20 times less) is more effective in combination therapy than any of the individual antibiotics.

[0010] In addition, by combining approved drugs (CADs), the approval time and cost involved are much lower than for new chemical entities (NCEs). For example, the time is approximately 5 years and it costs no more than $50 million to produce a new product. With far fewer failures in development, the cumulative success / failure cost for a CAD is approximately $130 million, compared to $3.8 billion for each NCE. To replace the approximately 100 individual antibiotics currently in use, the number of combinations required can be reduced since CADs have activity against a wide range of different infecting species, and individual antibiotics that are unavailable due to antimicrobial resistance in the CAD can be revitalized, with the CAD having higher activity against these antimicrobial-resistant strains and avoiding the development of future antimicrobial resistance. As a percentage of GDP, CAD technology moves the 4% of GDP accounted for by NCEs in high-income countries to approximately 0.005%, enabling all high, middle and even low-income countries to contribute and benefit.

[0011] Currently, the global focus is only on repetitive NCE projects, which have a higher cost / time / failure probability and a shorter remaining useful life, and it is predicted that effective antibiotics will be exhausted within twenty years and antimicrobial resistance deaths will set back 200 years. Even investing 0.1% of the NCE development cost in CAD approaches would provide a practical, affordable and more durable solution, offering a viable option for continuing to provide available antibiotic products - effective and affordable globally - and bringing hope for "antibiotics for all, forever and affordably".

[0012] Over the past decade, the applicant, a small UK company and a non-profit organization (GARDP) have been actively developing CAD - antibiotic combinations of existing drugs. In the present application, the applicant has developed a new approach for replacing all antibiotics by discovering a synergistic combination of three antimicrobial agents. The combination is effective against at least extended-spectrum beta-lactamase (ESBL), carbapenemase-producing (CPE) and carbapenem-resistant (CRE) Gram-negative bacteria. Even more surprisingly, the applicant has revealed that the active concentrations of each antimicrobial agent in the combination are at very low concentrations, e.g. as low as 1 / 16 of the MIC of the agent. mono Thus, compared to, for example, monotherapy, it may be possible to advantageously reduce any potential toxic burden by using less of each antimicrobial agent in the combination.

[0013] WO2015 / 114340 describes the use of a combination of zidovudine with a polymyxin selected from colistin or polymyxin B, an anti-tuberculosis antibiotic selected from rifampicin, rifapentine or rifabutin, and optionally piperine for the treatment of microbial infections. WO2018 / 011562 describes a combination comprising zidovudine and a carbapenem, and optionally a polymyxin selected from polymyxin B and polymyxin E. Accordingly, the present invention does not cover combinations previously identified by these applicants.

[0014] When two or more active agents are used in combination, the synergistic effect is unpredictable or unexpected. Synergism in the context of antimicrobial agents is measured in a variety of ways, which is in line with the generally accepted view that "synergism is an effect greater than additive". One of the methods for assessing whether synergism has been observed is the use of the "checkerboard" technique. This is a widely accepted method that results in the generation of a value known as the fractional inhibitory concentration index (FICI). Orhan et al. J. Clin. Microbiol. 2005, 43(1):140 describe the checkerboard method and analysis in the bridging paragraph on pages 140-141.

[0015] The FICI (or fractional inhibitory concentration index) refers to the sum of the FICs (or fractional inhibitory concentrations) of each antimicrobial agent when used in combination. The FIC (or fractional inhibitory concentration) of an antimicrobial agent in a combination is equal to the MIC of the antimicrobial agent in the combination divided by the MIC of the same antimicrobial agent when used alone. The minimum inhibitory concentration in the art is defined as the lowest concentration of an antimicrobial agent that will inhibit visible growth of a microorganism after overnight incubation.

[0016] The combination is active against drug-resistant bacteria (see the examples herein). In many cases, the individual antimicrobial agents in these combinations have significant activity at concentrations significantly lower than the MICs when used alone. However, there does not appear to be a method in the art for defining synergism for a 3-mer (including a combination of three antimicrobial agents) or a 4-mer (including a combination of four antimicrobial agents) expressed in terms of fractional inhibitory concentration. In fact, there has been very little prior work in this area. Accordingly, the present inventors have devised such a method. The method is applicable to any combination of more than two antimicrobial agents, provided that only two antimicrobial agents differ in their concentrations.

[0017] In the 3 - drug combination method, one antibiotic is "fixed" as part of the backbone, while the other two antibiotics vary on a doubling concentration scale starting from the MIC (x1) of the effective dose of the single - drug treatment against the test microorganism. Then, ΣFIC is calculated as shown below. In the 4 - drug combination method, two antibiotics are "fixed" as part of the backbone, while the other two antibiotics start from the MIC (x1) of the effective dose of the single - drug treatment against the test microorganism and vary on a doubling concentration scale.

[0018] Divide ΣFIC by "0.5 / n", where n = the number of antimicrobials in the combination to provide the FIC. The inventors chose this representation because it is closer to the 2 - drug synergy level. The same FIC scale used for 2 - drug combinations is applied: Synergy is observed when FIC < 0.5. "Additive" effect is observed when FIC is 0.5 to < 1. Indifference is observed when FIC is 1 to < 2. Antagonism is observed when FIC is 2 to 4.

[0019] Synergy can be expressed as "ΣFIC ≤ 0.25 x n".

[0020]

[0021] The above - mentioned method was used in the examples herein. Summary of the Invention

[0023] In one aspect, the present invention provides an antimicrobial combination comprising three antimicrobials, wherein (i) the first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; (ii) the second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and (iii) the third antimicrobial agent is selected from levofloxacin, doxycycline, fosfomycin, meropenem, rifampicin, gentamicin, polymyxin B / E, and pharmaceutically acceptable derivatives thereof. The first, second, and third antimicrobial agents in the combination are different from each other, and the combination comprises at least one of levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof, provided that the combination is not (1) polymyxin E / B, zidovudine, and rifampicin, or (2) ceftazidime, zidovudine, and fosfomycin. In a further embodiment of this aspect, the combination comprises a fourth antimicrobial agent, which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0024] On the other hand, the present invention provides an antimicrobial combination comprising three antimicrobial agents. The first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, and the third antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof. In a further embodiment of this aspect, the combination comprises a fourth antimicrobial agent which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0025] On the other hand, the present invention provides an antimicrobial combination comprising three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

[0026] On the other hand, the present invention provides a combination for treating infections caused by Gram-negative bacteria or Gram-positive bacteria.

[0027] On the other hand, the present invention provides a pharmaceutical composition comprising the combination defined herein and pharmaceutically acceptable excipients, diluents and carriers. The pharmaceutical composition is preferably for treating infections caused by Gram-negative bacteria or Gram-positive bacteria.

[0028] On the other hand, the present invention provides a product comprising an antimicrobial combination comprising three antimicrobial agents, wherein: the first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; the second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and the third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, fosfomycin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof; wherein the first, second, and third antimicrobial agents in the combination are different from each other; wherein the combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; provided that the combination is not (1) polymyxin E / B, zidovudine, and rifampicin, or (2) ceftazidime, zidovudine, and fosfomycin; the product being a combined preparation for simultaneous, separate, or sequential use in treating infections caused by Gram-negative bacteria or Gram-positive bacteria. In a further embodiment of this aspect, the combination comprises a fourth antimicrobial agent which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0029] On the other hand, the present invention provides a product comprising an antimicrobial combination of three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof, and the product is used as a combined preparation for simultaneous, separate or sequential treatment of infections caused by Gram-negative bacteria or Gram-positive bacteria. In a further embodiment of this aspect, the combination includes a fourth antimicrobial agent, which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0030] On the other hand, the present invention provides a product comprising an antimicrobial combination of three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof, and the product is used as a combined preparation for simultaneous, separate or sequential treatment of infections caused by Gram-negative bacteria or Gram-positive bacteria.

[0031] On the other hand, the present invention provides the use of a first antimicrobial agent in combination with at least second and third antimicrobial agents in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof. The third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof. The combination includes at least levofloxacin, rifampicin, doxycycline, fosfomycin, or a pharmaceutically acceptable derivative thereof, and the first, second, and third antimicrobial agents are different from each other, provided that the combination is not polymyxin E / B, zidovudine, and rifampicin. In a further embodiment of this aspect, the combination includes a fourth antimicrobial agent, which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0032] On the other hand, the present invention provides the use of a second antimicrobial agent in combination with at least a first and a third antimicrobial agent in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof. The third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof. The combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof, and the first, second, and third antimicrobial agents are different from each other, provided that the combination is not polymyxin E / B, zidovudine, and rifampicin. In a further embodiment of this aspect, the combination comprises a fourth antimicrobial agent which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0033] On the other hand, the present invention provides the use of a third antimicrobial agent in combination with at least a first and a second antimicrobial agent in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof. The third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof. The combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof, and the first, second, and third antimicrobial agents are different from each other, provided that the combination is not polymyxin E / B, zidovudine, and rifampicin. In a further embodiment of this aspect, the combination comprises a fourth antimicrobial agent which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0034] On the other hand, the present invention provides the use of ceftazidime or a pharmaceutically acceptable derivative thereof in combination with zidovudine or a pharmaceutically acceptable derivative thereof and polymyxin E or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. In a further embodiment of this aspect, the combination further comprises a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0035] On the other hand, the present invention provides the use of zidovudine or a pharmaceutically acceptable derivative thereof, in combination with ceftazidime or a pharmaceutically acceptable derivative thereof, and polymyxin E or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. In a further embodiment of this aspect, the combination further comprises a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0036] On the other hand, the present invention provides the use of polymyxin E or a pharmaceutically acceptable derivative thereof, in combination with zidovudine or a pharmaceutically acceptable derivative thereof, and ceftazidime or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections. In a further embodiment of this aspect, the combination further comprises a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0037] On the other hand, the present invention provides the use of ceftazidime or a pharmaceutically acceptable derivative thereof, in combination with zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof, and meropenem or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections.

[0038] On the other hand, the present invention provides the use of zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof, in combination with ceftazidime or a pharmaceutically acceptable derivative thereof, and meropenem or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections.

[0039] On the other hand, the present invention provides the use of meropenem or a pharmaceutically acceptable derivative thereof, in combination with zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof, and ceftazidime or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for the synergistic treatment of Gram-negative or Gram-positive bacterial infections.

[0040] In another aspect, the present invention provides a method for treating Gram-negative or Gram-positive bacterial infections, the method comprising administering a pharmaceutically effective amount of a combination comprising three antimicrobial agents, wherein the first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; the second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and the third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof; wherein the first, second, and third antimicrobial agents in the combination are different from each other; wherein the combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; provided that the combination is not polymyxin E / B, zidovudine, and rifampicin. In a further embodiment of this aspect, the combination further comprises a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

[0041] In another aspect, the present invention provides a method for treating Gram-negative or Gram-positive bacterial infections, the method comprising administering a pharmaceutically effective amount of a combination comprising three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

[0042] These aspects and their embodiments are set forth in the appended independent and dependent claims. It will be understood that the features of the dependent claims may be combined with each other and may be combined with the features of the independent claims in combinations other than those explicitly set forth in the claims. Furthermore, the present disclosure is not limited to the specific embodiments set forth below, but includes and encompasses any combination of the features presented herein.

[0043] The foregoing and other aspects, embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description. In this regard, the specific parts of the specification should not be read in isolation from the other parts.

[0044] Detailed Description

[0045] Although various exemplary embodiments are described or presented herein, other exemplary embodiments that employ various methods and materials similar or equivalent to those described or presented herein are also encompassed within the general inventive concept. For the sake of brevity, those features or embodiments that are implemented in a conventional manner may not be discussed or described in detail. Accordingly, it will be understood that features not described in detail in the devices, products, or methods described herein may be implemented according to any conventional techniques used to implement such features in the respective circumstances.

[0046] As used herein, the phrases "combination of..." and "in combination with..." encompass administering the drugs separately, sequentially, or simultaneously. Unless otherwise specified, these phrases are also intended to exclude any additional active ingredients. For example, "a synergistic combination comprising three antimicrobial agents" means that the defined antimicrobial agents are administered separately, sequentially, or simultaneously, but no other active agents (i.e., antimicrobial agents) are administered.

[0047] When the agents are administered sequentially, the first, second, or third antimicrobial agent may be administered first. When the administration is simultaneous, the agents may be administered in the same or different pharmaceutical compositions. In a preferred embodiment, the agents are administered sequentially or simultaneously.

[0048] The combinations of the present invention can be used to treat Gram-positive or Gram-negative bacterial infections. Specifically, they can be used to kill proliferating and / or clinically latent bacteria associated with such infections, preferably proliferating bacteria associated with such infections, such as proliferating bacteria associated with Gram-negative bacterial infections. Thus, the treatment of bacterial infections as referred to herein includes killing proliferating and / or clinically latent microorganisms associated with such infections.

[0049] As used herein, "kill" refers to the loss of viability as assessed by the lack of metabolic activity.

[0050] As used herein, "clinically latent bacteria" refers to bacteria that are metabolically active but have a growth rate below the threshold for the manifestation of an infectious disease. The threshold for the manifestation of an infectious disease refers to the growth rate threshold below which no symptoms of an infectious disease appear in the host.

[0051] The metabolic activity of clinically latent bacteria can be determined by several methods known to those skilled in the art; for example, by measuring the mRNA levels in the bacteria or by determining their uridine uptake rate. In this regard, clinically latent bacteria have a reduced but still significant level of the following substances compared to bacteria under logarithmic growth conditions (in vitro or in vivo):

[0052] (I) mRNA (e.g., mRNA levels of 0.0001% to 50%, such as 1% to 30%, 5% to 25% or 10% to 20%); and / or

[0053] (II) Uridine (e.g., [3H]uridine) uptake (e.g., [3H]uridine uptake levels of 0.0005% to 50%, such as 1% to 40%, 15% to 35% or 20% to 30%).

[0054] Clinically latent bacteria typically have a number of recognizable characteristics. For example, they may be viable but non-culturable; that is, they generally cannot be detected by standard culturing techniques, but can be detected and quantified by techniques such as broth dilution counting, microscopy or molecular techniques (e.g., polymerase chain reaction). In addition, clinically latent bacteria are phenotypically drug-resistant and are thus sensitive (in the logarithmic phase) to the biostatic effect of conventional antimicrobial agents (i.e., bacteria for which the minimum inhibitory concentration (MIC) of a conventional antimicrobial agent remains essentially constant); but have a sharply decreased susceptibility to drug-induced killing (e.g., for any given conventional antimicrobial agent, the ratio of the minimum bactericidal concentration (e.g., minimum bactericidal concentration, MBC) to the MIC is 10 or higher).

[0055] In various embodiments of the invention, one or more of the foregoing combinations are used to treat bacterial infections, in particular the combination can be used to kill proliferating and / or clinically latent bacteria associated with a bacterial infection. As used herein, the term "bacteria" (and its derivatives, e.g., "bacterial infection") includes, but is not limited to, reference to the following classes and specific types of microorganisms (or infections due to microorganisms):

[0056] Gram-positive cocci, such as Staphylococcus spp. (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus auricularis, Staphylococcus capitis capitis, Staphylococcus capitis ureolyticus, Staphylococcus caprae, Staphylococcus cohnii cohnii, Staphylococcus cohnii urealyticus, Staphylococcus equorum, Staphylococcus gallinarum, Staphylococcus haemolyticus, Staphylococcus hominis hominis, Staphylococcus hominis novobiosepticius, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pasteuri, Staphylococcus saccharolyticus, Staphylococcus schleiferi schleiferi, Staphylococcus schleiferi coagulans, Staphylococcus sciuri, Staphylococcus simulans, Staphylococcus warneri, and Staphylococcus xylosus)); Streptococcus spp. (e.g., β-hemolytic Streptococcus pyogenes (e.g., Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae dysgalactiae, Streptococcus dysgalactiae equisimilis, Streptococcus equi equi, Streptococcus equi zooepidemicus, Streptococcus iniae, Streptococcus porcinus, and Streptococcus pyogenespyogenes), microaerophilic Streptococcus pyogenes (“Streptococcus “milleri”), such as Streptococcus anginosus, Streptococcus constellatus constellatus, Streptococcus constellatus pharyngidis, and Streptococcus intermedius), “mitis” oral streptococci (alpha-haemolytic “viridans” streptococci, such as Streptococcus mitis, Streptococcus oralis, Streptococcus sanguinis, Streptococcus cristatus, Streptococcus gordonii, and Streptococcus parasanguinis), “salivarius” (non-haemolytic, such as Streptococcus salivarius and Streptococcus vestibularis), and “mutans” (tooth surface streptococci, such as Streptococcus criceti, Streptococcus mutans, Streptococcus ratti, and Streptococcus sobrinus) groups, Streptococcus acidominimus, Streptococcus bovis, Streptococcus faecalis, Streptococcus equinus, Streptococcus pneumoniae, and Streptococcus suisStreptococcus suis), or alternatively streptococci that can be classified into groups A, B, C, D, E, G, L, P, U or V; Enterococcus spp. (e.g., Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus, and Enterococcus solitarius); Bacillaceae, such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus, and Bacillus cereus;.

[0057] Gram-negative cocci, such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava, and Neisseria weaveri; Enterobacteriaceae such as Escherichia coli; Enterobacter spp. (e.g., Enterobacter aerogenes, Enterobacter agglomerans, and Enterobacter cloacae); Citrobacter spp. (such as Citrob. freundii and Citrob. divernis); Hafnia spp. (e.g., Hafnia alvei); Erwinia spp. (e.g., Erwinia persicinus); Morganella spp. (e.g., Morganella morganii); Salmonella spp. (Salmonella enterica and Salmonella typhi); Shigella spp. (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei); Klebsiella spp. (e.g., Klebs. Pneumoniae, Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs. granulomatis (Calymmatobacteriumgranulomatis)) and Klebsiella rhinoscleromatis; Proteus spp. (e.g., Proteus mirabilis, Proteus rettgeri, and Proteus vulgaris), Providencia spp. (e.g., Providencia alcalifaciens, Providencia rettgeri, and Providencia stuartii); Serratia spp. (e.g., Serratia marcescens and Serratia liquifaciens) and Yersinia spp. (e.g., Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis); Helicobacter spp. (e.g., Helicobacter pylori, Helicobacter cinaedi, and Helicobacter fennelliae); Acinetobacter spp. (e.g., Acinetobacter baumanii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter lwoffii, and Acinetobacter radioresistens); Pseudomonas spp. (e.g., Pseudomonas aeruginosa, Pseudomonas maltophilia (StenotrophomonasPseudomonas maltophilia), Pseudomonas alcaligenes, Pseudomonas chlororaphis, Pseudomonas fluorescens, Pseudomonas luteola, Pseudomonas mendocina, Pseudomonas monteilii, Pseudomonas oryzihabitans, Pseudomonas pertocinogena, Pseudomonas pseudalcaligenes, Pseudomonas putida, and Pseudomonas stutzeri); Bacteroides fragilis; Peptococcus spp. (e.g., Peptococcus nigerniger)); Peptostreptococcus; Clostridium (e.g., Clostridium perfringens, Clostridium difficile, Clostridium botulinum, Clostridium tetani, Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium beijerinckii, Clostridium butyricum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridioforme clostridium, Clostridium cochlearium, Clostridium cocleatum, Clostridium fallax, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium innocuum, Clostridium irregulare, Clostridium leptum, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium piliforme, Clostridium putrefasciens, Clostridium ramosum, Clostridium septicum, Clostridium sordelii, Clostridium sphenoides, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, and Clostridium tertium)); Mycoplasma (e.g., Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma genitalium, and Mycoplasma urealyticum)); Mycobacterium (e.g., Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitumfortuitum), Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmatis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacteriumlentiflavum), Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi, and Mycobacterium xenopi)); Haemophilus spp. (such as Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus, and Haemophilus parahaemolyticus)); Actinobacillus spp. (such as Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillushominis), Actinobacillus lignieresii, Actinobacillus suis, and Actinobacillus ureae); Actinomyces (e.g., Actinomyces israelii); Brucella (e.g., Brucella abortus, Brucella canis, Brucella melitensis, and Brucella suis); Campylobacter (e.g., Campylobacter jejuni, Campylobacter coli, Campylobacter lari, and Campylobacter fetus); Listeria monocytogenes; Vibrio (e.g., Vibrio cholerae, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus, and Vibrio vulnificus); Erysipelothrix rhusopathiae; Corynebacteriaceae (e.g., Corynebacterium diphtheriae, Corynebacterium jeikeum, and Corynebacterium urealyticum); Spirochaetaceae, such as Borrelia (e.g., Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii,garinii), Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri, Borrelia persica, Borrelia turicatae, and Borrelia venezuelensis) and the genus Treponema (Treponema pallidum ssp. pallidum, Treponema pallidum ssp. endemicum, Treponema pallidum ssp. pertenue, and Treponema carateum); the genus Pasteurella (e.g., Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septicaseptica), Pasteurella pneumotropica, and Pasteurella stomatis); Bordetella spp. (such as Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis, and Bordetella trematum); Nocardiaceae, such as Nocardia spp. (e.g., Nocardia asteroides and Nocardia brasiliensis); Rickettsia (e.g., Ricksettsii or Coxiella burnetii); Legionella spp. (such as Legionella anisa, Legionella birminghamensis, Legionella bozemanii, Legionella cincinnatiensis, Legionella dumoffii, Legionella feeleii, Legionella gormanii, Legionella hackeliae, Legionella israelensis, Legionella jordanis, Legionella lansingensis, Legionella longbeachae, Legionella maceachernii, Legionella micdadei, Legionella oakridgensis, Legionella pneumophila, Legionella saintelensi, Legionella tucsonensis, and Legionella wadsworthii); Moraxellacatarrhalis); Cyclospora cayetanensis; Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; Toxoplasma gondii; Stenotrophomonas maltophilia; Burkholderia stenotrophomonas; Burkholderia cepacia; Burkholderia mallei and Burkholderia pseudomallei; Francisella tularensis; Gardnerella spp. (such as Gardnerella vaginalis and Gardnerella mobiluncus); Streptobacillus moniliformis; Flavobacteriaceae, such as Capnocytophaga spp. (e.g., Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea, and Capnocytophaga putigena)); Bartonella spp. (Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana, and Bartonella vinsonii arupensis); Leptospira spp. (e.g., LeptospiraLeptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai, and Leptospira weilii); Spirillum (e.g., Spirillum minus); Bacteroides (e.g., Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, and Bacteroides vulgatus); Prevotella (e.g., Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella peptolytica, PrevotellaPrevotella (e.g., Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis, and Prevotella zoogleoformans)); Porphyromonas (e.g., Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levii, and Porphyromonas macacae)); Fusobacterium (e.g., F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatumF. nucleatum), Fusobacterium nucleatum fusiforme, Fusobacterium nucleatum polymorphum, Fusobacterium nucleatum vincentii, Fusobacterium periodonticum, Fusobacterium russii, Fusobacterium ulcerans, and Fusobacterium varium); Chlamydia (e.g., Chlamydia trachomatis); Cryptosporidium (e.g., Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium canis, Cryptosporidium felis, Cryptosporidium meleagridis, and Cryptosporidium muris); Chlamydophila (e.g., Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae (Chlamydia pneumoniae), and Chlamydophila psittaci (Chlamydia psittaci)); Leuconostoc (e.g., Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides, and Leuconostoc pseudomesenteroides); Gemella (e.g., Gemella bergeri, Gemella haemolysans, Gemella morbillorum, and Gemella sanguinis); Aeromonas (Aeromonas hydrophila, Aeromonas caviae, and Aeromonas veronii biovar sobria) and Ureaplasma (e.g., Ureaplasma parvum and Ureaplasma urealyticum).

[0058] Preferably, the combination of the present invention has a synergistic effect on Gram-positive bacteria or Gram-negative bacteria selected from the following:

[0059] Gram-negative bacteria: Enterobacteriaceae, Enterobacter spp, Pseudomonas spp, Acinetobacter spp, Shigella spp, Salmonella spp, Burkholderia stenotrophomonas, Citrobacter spp, Serratia spp, Proteus spp, Morganella spp, Providencia spp, Haemophilus spp, Aeromonas spp, Pasteurella spp, Brucella spp, Helicobacter spp, Campylobacter spp, Francisella tularensis, Legionella spp, Vibrio spp, Neisseria spp, Mycobacterium spp, Yersinia pestis, Rickettsia spp.

[0060] Gram-positive bacteria: Staphylococcus spp, Enterococcus spp, Streptococcus spp, Bacillus anthracis.

[0061] Gram-negative bacteria can be, for example: Enterobacteriaceae bacteria, such as Escherichia coli; Enterobacter spp. (such as Enterobacter aerogenes, Enterobacter agglomerans, and Enterobacter cloacae); Citrobacter spp. (such as Citrobacter freundii and Citrobacter divergens); Pseudomonas spp. (such as Pseudomonas aeruginosa, Pseudomonas maltophilia (Stenotrophomonas maltophilia), Pseudomonas alcaligenes, Pseudomonas chlororaphis, Pseudomonas fluorescens, Pseudomonas luteola, Pseudomonas mendocina, Pseudomonas monteilii, Pseudomonas oryzihabitans, Pseudomonas pertocinogena, Pseudomonas pseudalcaligenes, Pseudomonas putida, and Pseudomonas stutzeri); Yersinia spp. (such as Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis); Helicobacter spp. (such as Helicobacter pylori, Helicobacter cinaedi, and Helicobacter fennelliae); Acinetobacter spp. (such as Acinetobacter baumanii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter lwoffii, and Acinetobacter radioresistens); Morganella spp. (such as Morganella morganii); Salmonella spp. (Salmonella enterica and SalmonellaSalmonella typhi)); Shigella spp. (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei)); (e.g., Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ornitholytica, Klebsiella planticola, Klebsiella ozaenae, Klebsiella terrigena, Klebsiella granulomatis (Calymmatobacterium granulomatis), and Klebsiella rhinoscleromatis)); Stenotrophomonas maltophilia; Francisella tularensis; Serratia spp. (e.g., Serratia marcescens and Serratia liquifaciens)); Proteus spp. (e.g., Proteus mirabilis, Proteus rettgeri, and Proteus vulgaris)); Providencia spp. (e.g., Providencia alcalifaciens, Providencia rettgeri, and Providencia stuartii)); Haemophilus spp. (e.g., Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus, and Haemophilus parahaemolyticus)); Aeromonas spp. (Aeromonas hydrophila, Aeromonas caviae, and Aeromonas veronii biovarsobria)); Pasteurella (e.g., Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica, and Pasteurella stomatis); Brucella (e.g., Brucella abortus, Brucella canis, Brucella melintensis, and Brucella suis); Campylobacter (e.g., Campylobacter jejuni, Campylobacter coli, Campylobacter lari, and Campylobacter fetus); Legionella (e.g., Legionella anisa, Legionella birminghamensis, Legionella bozemanii, Legionella cincinnatiensis, Legionella dumoffii, Legionella feeleii, Legionella gormanii, Legionella hackeliae, Legionella israelensis, Legionella jordanis, Legionella lansingensis, Legionella longbeachae, Legionella maceacherniimaceachernii), Legionella micdadei, Legionella oakridgensis, Legionella pneumophila, Legionella sainthelensi, Legionella tucsonensis, and Legionella wadsworthii); Vibrio spp. (e.g., Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus, and Vibrio vulnificus)); Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava, and Neisseria weaveri; Mycobacterium spp. (e.g., Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmatissmegmitis), Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium lentiflavum, Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicumnonchromogenicum), Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi, and Mycobacterium xenopi); Rickettsia (e.g., Ricksettsii or Coxiella burnetii).

[0062] Gram-positive bacteria can be, for example, of the genus Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus auricularis, Staphylococcus capitis capitis, Staphylococcus capitis ureolyticus, Staphylococcus caprae, Staphylococcus cohnii cohnii, Staphylococcus cohnii ureolyticus, Staphylococcus equorum, Staphylococcus gallinarum, Staphylococcus haemolyticus, Staphylococcus hominis hominis, Staphylococcus hominis novobiosepticius, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pasteuri, Staphylococcus saccharolyticus, Staphylococcus schleiferi schleiferi, Staphylococcus schleiferi coagulans, Staphylococcus sciuri, Staphylococcus simulans, Staphylococcus warneri, and Staphylococcus xylosus); of the genus Streptococcus (e.g., β-hemolytic Streptococcus pyogenes (e.g., Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae dysgalactiae, Streptococcus dysgalactiae equisimilis, Streptococcus equi equi, Streptococcus equi zooepidemicus, Streptococcus iniae, Streptococcus porcinus, and Streptococcus pyogenespyogenes), microaerophilic Streptococcus pyogenes (“Streptococcus “milleri”), such as Streptococcus anginosus, Streptococcus constellatus constellatus, Streptococcus constellatus pharyngidis, and Streptococcus intermedius), “mitis” oral streptococci (alpha-haemolytic “viridans” streptococci, such as Streptococcus mitis, Streptococcus oralis, Streptococcus sanguinis, Streptococcus cristatus, Streptococcus gordonii, and Streptococcus parasanguinis), “salivarius” (non-haemolytic, such as Streptococcus salivarius and Streptococcus vestibularis) and “mutans” (tooth surface streptococci, such as Streptococcus criceti, Streptococcus mutans, Streptococcus ratti, and Streptococcus sobrinus) groups, Streptococcus acidominimus, Streptococcus bovis, Streptococcus faecalis, Streptococcus equinus, Streptococcus pneumoniae, and Streptococcus suisStreptococcus suis), or alternatively streptococci that can be classified into groups A, B, C, D, E, G, L, P, U or V; Enterococcus spp. (such as Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus, and Enterococcus solitarius); Bacillus anthracis).

[0063] The bacterial infections treated by the combinations described herein are Gram-negative bacterial infections or Gram-positive bacterial infections. Specific Gram-negative bacteria that can be treated using the combination of the present invention include:

[0064] Enterobacteriaceae, such as Escherichia coli, Klebsiella spp. (e.g., Klebsiella pneumoniae and Klebsiella oxytoca), and Proteus spp. (e.g., Proteus mirabilis, Proteus rettgeri, and Proteus vulgaris); Haemophilus influenzae; Mycobacterium spp. (e.g., Mycobacterium tuberculosis); and Enterobacter spp. (e.g., Enterobacter cloacae). Preferably, the bacterium is Enterobacteriaceae, such as Escherichia coli, Klebsiella spp. (e.g., Klebsiella pneumoniae and Klebsiella oxytoca). Particularly preferred are Escherichia coli and Klebsiella pneumoniae (e.g., Klebsiella pneumoniae subsp. pneumoniae).

[0065] The combination of the present invention is particularly beneficial in treating (multi)-drug resistant ((M)DR) bacteria. For Enterobacteriaceae, resistance most often progresses to carbapenemases, i.e., carbapenemase-resistant strains and "extended-spectrum β-lactamase" (ESBL) strains, such as New Delhi Metallo-beta-lactamase-1 (NDM-1)-resistant Klebsiella pneumoniae and NDM-1 Escherichia coli. The combination therapy of the present invention is also particularly effective against carbapenemase-producing Enterobacteriaceae (CPE). Other resistant strains can also be used, such as colistin-resistant strains, and carbapenemase-resistant strains outside Enterobacteriaceae, which include carbapenem-resistant Acinetobacter and carbapenem-resistant Pseudomonas spp. microorganisms carrying the blaKPC gene.

[0066] In various embodiments, the combinations of the invention are beneficial against ESKAPE pathogens. These six highly virulent and typically antibiotic-resistant bacterial pathogens include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. This group of Gram-positive and Gram-negative bacteria can evade or "escape" commonly used antibiotics due to their enhanced multi-drug resistance. Thus, the combinations of the invention are beneficial against (M)DR strains of ESKAPE pathogens.

[0067] Advantageously, in various embodiments, the combinations of the invention have a broader range of activity than monotherapy or combinations of only two active agents. Specifically, the various combinations can be effective against at least Acinetobacter, Pseudomonas, and Enterobacteriaceae, which bacteria have been identified by the World Health Organization as including multi-drug resistant bacteria for which there is an urgent need for new antibiotics.

[0068] It should be remembered that although combinations (such as the claimed combinations) may initially be shown to be effective in treating (M)DR strains, they can additionally be used to treat non-resistant strains. This is of great value in the context of the currently claimed combinations, where the primary therapies for Enterobacteriaceae such as Escherichia coli and Klebsiella spp. (such as Klebsiella pneumoniae and Klebsiella oxytoca) are expensive antimicrobial drugs due to existing patent protection. From a therapeutic perspective as well as from a financial / economic perspective (at a time when governments are seeking to reduce healthcare costs), the substitution of such "prescription" drugs by combinations of "generic" antibiotics is considered beneficial.

[0069] The combinations of the invention can be used to treat infections associated with any of the bacterial microorganisms mentioned above, and in particular they can be used to kill proliferating and / or clinically latent microorganisms associated with such an infection (such as an ESKAPE pathogen bacterial infection).

[0070] In various embodiments, the combinations of the invention are effective in treating infections caused by: (1) carbapenem-resistant Escherichia coli, Klebsiella, Acinetobacter, Pseudomonas aeruginosa, Serratia, or Proteus; (2) MRSA, vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant Enterococcus faecium (VRE), clarithromycin-resistant Helicobacter pylori, or quinolone-resistant Salmonella; or (3) penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, or quinolone-resistant Shigella.

[0071] Specific medical conditions for which the combination therapy of the present invention can be used include tuberculosis (such as pulmonary tuberculosis, non-pulmonary tuberculosis (such as scrofula, genitourinary tuberculosis, osteoarticular tuberculosis, tuberculous meningitis), and miliary tuberculosis), anthrax, abscess, acne vulgaris, actinomycosis, asthma, bacillary dysentery, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, botulism, Buruli ulcer, bone and joint infections, bronchitis (acute or chronic), brucellosis, burn wounds, cat-scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffuse panbronchiolitis, diphtheria, dental caries, upper respiratory diseases, eczema, empyema, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, erysipelas, erysipeloid, erythrasma, eye infections, furuncle, gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhea, granuloma inguinale, Haverhill fever, burn infections, dental postoperative infections, oral cavity infections, prosthesis-related infections, intra-abdominal abscesses, Legionnaires' disease, leprosy, leptospirosis, listeriosis, liver abscesses, Lyme disease, lymphogranuloma venereum, mastitis, mastoiditis, meningitis and nervous system infections, mycetoma, nocardiosis (such as Madura foot), non-specific urethritis, ophthalmia (such as neonatal ophthalmia), osteomyelitis, otitis (such as otitis externa and otitis media), orchitis, pancreatitis, paronychia, pelvic peritonitis, peritonitis, peritonitis with appendicitis, pharyngitis, cellulitis, pinta, plague, pleural effusion, pneumonia, postoperative wound infections, postoperative gas gangrene, prostatitis, pseudomembranous colitis, psittacosis, pulmonary emphysema, pyelonephritis, pyoderma (such as impetigo), Q fever, rat-bite fever, reticulocytosis, ricin poisoning, Ritter's disease, salmonellosis, salpingitis, septic arthritis, septic infections, septicemia, sinusitis, skin infections (such as skin granulomas, impetigo, folliculitis, and furunculosis), syphilis, systemic infections, tonsillitis, toxic shock syndrome, trachoma, tularemia, typhoid fever, typhus (such as epidemic typhus, murine typhus, scrub typhus, and spotted fever), urethritis, wound infections, yaws, aspergillosis, candidiasis (such as oropharyngeal candidiasis, vaginal candidiasis, or balanitis), cryptococcosis, favus, histoplasmosis, intertrigo, mucormycosis, tinea (such as tinea corporis, tinea capitis, tinea cruris, tinea pedis, and onychomycosis), onychomycosis, pityriasis versicolor, trichomycosis, and sporotrichosis;or infections by MSSA, MRSA, Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, and Acinetobacter baumanii;

[0072] Specific medical conditions that can be treated using the combinations of the invention also include those caused by Gram-negative bacteria, such as abscess, asthma, bacillary dysentery, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, bone and joint infections, bronchitis (acute or chronic), brucellosis, burn wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cystic fibrosis, cystitis, nephritis, diffuse panbronchiolitis, dental caries, upper respiratory diseases, empyema, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, eye infections, furuncle, gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhea, granuloma inguinale, haverhill fever, burn infections, post-dental infections, oral cavity infections, prosthesis-related infections, intra-abdominal abscesses, legionnaires' disease, leptospirosis, listeriosis, liver abscess, lyme disease, lymphogranuloma venereum, mastitis, mastoiditis, meningitis and nervous system infections, non-specific urethritis, ophthalmia (e.g., neonatal ophthalmia), osteomyelitis, otitis (such as otitis externa and otitis media), orchitis, pancreatitis, paronychia, pelvic peritonitis, peritonitis, peritonitis with appendicitis, pharyngitis, pleural effusion, pneumonia, post-operative wound infections, post-operative gas gangrene, prostatitis, pseudomembranous colitis, psittacosis, pyelonephritis, Q fever, Ritter's disease, salmonellosis, salpingitis, septic arthritis, septic infections, sepsis, systemic infections, tonsillitis, trachoma, typhoid, urethritis, urinary tract infections, wound infections; or infections by Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, and Enterobacter cloacae.

[0073] Preferably, the combinations of the invention are used for the treatment of acute or complicated urinary tract infections, acute or complicated skin and soft tissue infections, intra-abdominal infections, upper respiratory tract infections, community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, or bloodstream infections.

[0074] It will be understood that the term "treatment" as referred to herein extends to prophylaxis as well as the treatment of established diseases or symptoms.

[0075] As used herein, the term "pharmaceutically acceptable derivative" means: (a) a pharmaceutically acceptable salt; (b) a solvate (including a hydrate) and / or (c) a prodrug, where appropriate.

[0076] Pharmaceutically acceptable salts of the compounds included in the combinations of the present invention include their appropriate acid addition salts or base salts. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977).

[0077] Suitable acid addition salts include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, octanoate, stearate, acrylate, hexanoate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, octanedioate, decanedioate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate), halide salts (e.g., chloride, bromide or iodide salts), sulfonate salts (e.g., benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2-naphthalenesulfonate or 1,5-naphthalenedisulfonate) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, or nitrate. Suitable base salts include metal salts, such as sodium salts, calcium salts and amine salts.

[0078] For example, ceftazidime pentahydrate, colistin sulfate, polymyxin B sulfate, doxycycline hyclate (doxycycline hemihydrochloride hemihydrate), doxycycline hydrochloride, doxycycline monohydrate, fosfomycin tromethamine, fosfomycin calcium, fosfomycin sodium, fosfomycin disodium, levofloxacin hemihydrate, meropenem trihydrate, rifampicin N-oxide, gentamicin sulfate hydrate and gentamicin sulfate are commercially available from Sigma Aldrich. Other suppliers are also known in the art.

[0079] As used herein, the term "prodrug" refers to an antimicrobial compound in which one or more groups have been modified such that the modification can be reversed after administration to a human or mammalian subject. This reversal is typically carried out by enzymes that are naturally present in the subject, but a second agent may also be administered together with such a prodrug in order to effect the reversal in vivo. Examples of such modifications include the formation of esters (e.g., any of those described above), where the reversal can be effected by esterases and the like. Other such systems will be known to those of skill in the art.

[0080] For example, zidovudine is a prodrug that must be phosphorylated to its active 5'-triphosphate metabolite.

[0081] Polymyxin E or colistin is commercially available as a methanesulfonic acid derivative: colistimethate sodium or colistin sodium methanesulfonate (CMS). Colistimethate sodium is a prodrug. It is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which results in the addition of a sulfomethyl group to the primary amine of colistin. In aqueous solution, it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives and colistin.

[0082] The present invention includes the use of these pharmaceutically acceptable derivatives and prodrugs. Specifically, the present invention includes the use of colistin and its pharmaceutically acceptable derivatives (including colistin sulfate, colistimethate sodium, and colistin sodium methanesulfonate).

[0083] The present invention also includes all enantiomers and tautomers (where appropriate) of the compounds. Those of skill in the art will recognize compounds having optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be separated or prepared by methods known in the art.

[0084] Certain compounds included in the combinations of the present invention may exist as stereoisomers and / or geometric isomers - for example, they may have one or more asymmetric centers and / or geometric centers and thus may exist in two or more stereoisomeric and / or geometric isomeric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of those inhibitors and mixtures thereof. The terms used in the claims cover such forms provided that said forms retain the appropriate functional activity (although not necessarily to the same degree).

[0085] The present invention also encompasses all suitable isotopic variants of the compounds or their pharmaceutically acceptable salts. Isotopic variants or their pharmaceutically acceptable salts are defined as those in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from that typically found in nature. Examples of isotopes that can be incorporated include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Certain isotopic variants, such as those in which a radioactive isotope (e.g., 3H or 14C) is incorporated, can be used in drug and / or substrate tissue distribution studies. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred because of their ease of preparation and detection. In addition, replacement with an isotope such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may thus be preferred in certain cases. Isotopic variants can generally be prepared by conventional procedures using appropriate isotopic variants of suitable reagents.

[0086] The compounds for use in the combinations of the present invention, including their pharmaceutically acceptable derivatives or prodrugs, are commercially available and / or can be prepared by synthetic methods known in the art. Zidovudine, ceftazidime, polymyxin E, polymyxin B, doxycycline, fosfomycin, levofloxacin, meropenem, rifampicin, gentamicin, ceftazidime pentahydrate, colistin sulfate, colistimethate sodium, colistin methylsulfate, polymyxin B sulfate, doxycycline hyclate (doxycycline hemihydrochloride hemihydrate), doxycycline hydrochloride, doxycycline monohydrate, fosfomycin trometamol, fosfomycin calcium, fosfomycin sodium, fosfomycin disodium, levofloxacin hemihydrate, meropenem trihydrate, rifampicin N-oxide, gentamicin sulfate hydrate, and gentamicin sulfate are commercially available from SigmaAldrich, e.g., from Sigma- obtained. Other commercial suppliers are known in the art.

[0087] Zidovudine is 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione and is available by prescription under the trade name obtained. It is also known as 3'-azido-3'-deoxythymidine or "AZT" and has the following chemical structure:

[0088]

[0089] Ceftazidime is sold under the trade name Fortaz, etc., and is a third-generation cephalosporin antibiotic used to treat a variety of bacterial infections. It has the following chemical structure:

[0090]

[0091] Polymyxin E is also known as colistin. It is an antibiotic drug used as a last resort for treating infections including multi-drug resistant Gram-negative bacteria (including pneumonia). These infections may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be administered intravenously, intramuscularly, or by inhalation; and colistin sulfate is mainly applied to the skin or taken orally. It has the following chemical structure:

[0092]

[0093] Polymyxin B, sold under trade names such as Poly-Rx, is an antibiotic used to treat meningitis, pneumonia, sepsis, and urinary tract infections. It can be administered by intravenous injection, intramuscular injection, or intracerebroventricular injection, or by inhalation. It has the following chemical structure:

[0094]

[0095] Doxycycline is a broad-spectrum tetracycline antibiotic used to treat infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, and syphilis. Doxycycline can be taken orally or by intravenous injection. It has the following chemical structure:

[0096]

[0097] Fosfomycin, sold under trade names such as Monurol, is an antibiotic mainly used to treat lower urinary tract infections (lower UTI). It is usually taken orally and has the following chemical structure:

[0098]

[0099] Levofloxacin, sold under trade names such as Levaquin, is an antibiotic drug used to treat a variety of bacterial infections, including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and certain types of gastroenteritis. It is available by oral, intravenous injection, and in the form of eye drops. It is the (S)-isomer of ofloxacin and has the following chemical structure:

[0100]

[0101] Meropenem, sold under trade names such as Merrem, is an intravenous β-lactam antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infections, pneumonia, sepsis, and anthrax. It is in the carbapenem drug family and has the following chemical structure:

[0102]

[0103] Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis, Mycobacterium avium complex disease, leprosy, and Legionnaires' disease. Rifampicin can be administered orally or by intravenous injection and has the following chemical structure:

[0104]

[0105] Gentamicin is an antibiotic used to treat several types of bacterial infections, including bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis. It can be administered intravenously, intramuscularly, or topically. It has the following chemical structure:

[0106]

[0107] The synergistic combination of the present invention comprises three antimicrobial agents. These agents are grouped in the appended claims so as to cover the exemplified combinations in the most effective manner.

[0108] The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and the third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof. The first, second, and third antimicrobial agents are different from each other. The combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; provided that the combination is not polymyxin E / B, zidovudine, and rifampicin, or ceftazidime, zidovudine, and fosfomycin.

[0109] In various embodiments, the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof. In some embodiments, the second antimicrobial agent is preferably zidovudine or a pharmaceutically acceptable derivative thereof. More preferably, ceftazidime and zidovudine, or pharmaceutically acceptable derivatives thereof are combined with a third antimicrobial agent, which is levofloxacin, doxycycline, rifampicin, or a pharmaceutically acceptable derivative thereof. For example, the combination can be:

[0110] Ceftazidime or a pharmaceutically acceptable derivative thereof; zidovudine or a pharmaceutically acceptable derivative thereof; and levofloxacin or a pharmaceutically acceptable derivative thereof;

[0111] Ceftazidime or a pharmaceutically acceptable derivative thereof; zidovudine or a pharmaceutically acceptable derivative thereof; and doxycycline or a pharmaceutically acceptable derivative thereof; or

[0112] Ceftazidime or a pharmaceutically acceptable derivative thereof; zidovudine or a pharmaceutically acceptable derivative thereof; and rifampicin or a pharmaceutically acceptable derivative thereof.

[0113] In various embodiments, the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof. In some embodiments, the second antimicrobial agent is preferably doxycycline, fosfomycin, or a pharmaceutically acceptable derivative thereof. More preferably, ceftazidime and doxycycline or fosfomycin, or a pharmaceutically acceptable derivative thereof are combined with a third antimicrobial agent, which is levofloxacin, doxycycline (when the second antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof), meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, or a pharmaceutically acceptable derivative thereof. For example, the combination can be:

[0114] Ceftazidime or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and levofloxacin or a pharmaceutically acceptable derivative thereof;

[0115] Ceftazidime or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and meropenem or a pharmaceutically acceptable derivative thereof;

[0116] Ceftazidime or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and rifampicin or a pharmaceutically acceptable derivative thereof;

[0117] Ceftazidime or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and gentamicin or a pharmaceutically acceptable derivative thereof;

[0118] Ceftazidime or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; polymyxin E / B or a pharmaceutically acceptable derivative thereof;

[0119] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and levofloxacin or a pharmaceutically acceptable derivative thereof;

[0120] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and doxycycline or a pharmaceutically acceptable derivative thereof;

[0121] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and meropenem or a pharmaceutically acceptable derivative thereof;

[0122] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and rifampicin or a pharmaceutically acceptable derivative thereof;

[0123] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and gentamicin or a pharmaceutically acceptable derivative thereof; or

[0124] Ceftazidime or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; polymyxin E / B or a pharmaceutically acceptable derivative thereof.

[0125] In various embodiments, the first antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof, and the second antimicrobial agent is doxycycline, fosfomycin or a pharmaceutically acceptable derivative thereof. In such embodiments, the third antimicrobial agent is preferably selected from levofloxacin, doxycycline (when the second antimicrobial agent is fosfomycin), meropenem, rifampicin, gentamicin, or a pharmaceutically acceptable derivative thereof. For example, the combination can be:

[0126] Polymyxin E or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and levofloxacin or a pharmaceutically acceptable derivative thereof;

[0127] Polymyxin E or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and meropenem or a pharmaceutically acceptable derivative thereof;

[0128] Polymyxin E or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and rifampicin or a pharmaceutically acceptable derivative thereof;

[0129] Polymyxin E or a pharmaceutically acceptable derivative thereof; doxycycline or a pharmaceutically acceptable derivative thereof; and gentamicin or a pharmaceutically acceptable derivative thereof;

[0130] Polymyxin E or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and levofloxacin or a pharmaceutically acceptable derivative thereof;

[0131] Polymyxin E or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and doxycycline or a pharmaceutically acceptable derivative thereof;

[0132] Colistin E or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and meropenem or a pharmaceutically acceptable derivative thereof;

[0133] Colistin E or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and rifampicin or a pharmaceutically acceptable derivative thereof; or

[0134] Colistin E or a pharmaceutically acceptable derivative thereof; fosfomycin or a pharmaceutically acceptable derivative thereof; and gentamicin or a pharmaceutically acceptable derivative thereof.

[0135] In various embodiments, the first antimicrobial agent is colistin E / B or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, and the third antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof.

[0136] The present invention also provides an antimicrobial combination containing three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, and the third antimicrobial agent is colistin E or a pharmaceutically acceptable derivative thereof.

[0137] The combination of the present invention can be grouped by one or more common antimicrobial agents. In one embodiment, the combination includes ceftazidime or a pharmaceutically acceptable derivative thereof as the first antimicrobial agent, and zidovudine or a pharmaceutically acceptable derivative thereof as the second antimicrobial agent, provided that the third antimicrobial agent is not fosfomycin. For example, one aspect of the present invention provides an antimicrobial combination containing three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

[0138] In one embodiment, the combination includes ceftazidime or a pharmaceutically acceptable derivative thereof as the first antimicrobial agent and levofloxacin or a pharmaceutically acceptable derivative thereof as the second antimicrobial agent; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

[0139] In another embodiment, the combination includes ceftazidime or a pharmaceutically acceptable derivative thereof as the first antimicrobial agent, fosfomycin / doxycycline or a pharmaceutically acceptable derivative thereof as the second antimicrobial agent, and fosfomycin / doxycycline or a pharmaceutically acceptable derivative thereof as the third antimicrobial agent.

[0140] In another embodiment, the combination comprises ceftazidime or a pharmaceutically acceptable derivative thereof as a first antimicrobial agent, and doxycycline or a pharmaceutically acceptable derivative thereof as a second antimicrobial agent.

[0141] In another embodiment, the combination comprises polymyxin E / B or a pharmaceutically acceptable derivative thereof as a first antimicrobial agent, and fosfomycin, doxycycline or a pharmaceutically acceptable derivative thereof as a second antimicrobial agent.

[0142] In various embodiments, any combination disclosed herein may include a fourth antimicrobial agent. In a preferred embodiment, the fourth antimicrobial agent is a carbapenem or a pharmaceutically acceptable derivative thereof. More preferably, the fourth antimicrobial agent is selected from imipenem, meropenem, ertapenem, doripenem, panipenem, biapenem, razupenem, tebipenem, lenapenem, tomopenem, and thienpenem or a pharmaceutically acceptable derivative thereof, such as meropenem trihydrate. Even more preferably, the fourth antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

[0143] In one embodiment, the first antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, the third antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof, and the fourth antimicrobial agent is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably the carbapenem is selected from imipenem, meropenem, ertapenem, doripenem, panipenem, biapenem, razupenem, tebipenem, lenapenem, tomopenem, and thienpenem, or a pharmaceutically derivative thereof, such as meropenem trihydrate; more preferably it is meropenem or a pharmaceutically acceptable derivative thereof.

[0144] In one embodiment, the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; the third antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof, and the fourth antimicrobial agent is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably the carbapenem is selected from imipenem, meropenem, ertapenem, doripenem, panipenem, biapenem, asupenem, temocillin, lenapenem, tomopenem and thienamycin, or a pharmaceutically derivative thereof, such as meropenem trihydrate; more preferably it is meropenem or a pharmaceutically acceptable derivative thereof.

[0145] In one embodiment, the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; the third antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof; and the fourth antimicrobial agent is a carbapanem or a pharmaceutically acceptable derivative thereof, preferably the carbapenem is selected from imipenem, meropenem, ertapenem, doripenem, panipenem, biapenem, asupenem, temocillin, lenapenem, tomopenem and thienamycin, or a pharmaceutically derivative thereof, such as meropenem trihydrate; more preferably it is meropenem or a pharmaceutically acceptable derivative thereof.

[0146] The compounds for use according to the invention may be administered in the form of the raw material, but are preferably provided in the form of a pharmaceutical composition. The compounds may be used as separate formulations or as a single combined formulation. When combined in the same formulation, it will be understood that the two compounds must be stable and compatible with each other and with the other components in the formulation.

[0147] The formulations of the invention include those suitable for oral, parenteral (including subcutaneous, e.g. by injection or depot tablets, intrathecal, intramuscular, e.g. by depot formulation and intravenous) and rectal, or suitable for administration by inhalation or insufflation. The most suitable route of administration may depend on the condition and disorder of the patient. Preferably, the compositions of the invention are formulated for oral administration.

[0148] The pharmaceutical compositions can be conveniently presented in unit dosage form and can be prepared by any methods well-known in the art of pharmacy, such as those described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21st Edition, (2005). Suitable methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more excipients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. It will be understood that when two active ingredients are administered independently, each may be administered by a different route.

[0149] When formulated with excipients, the active ingredient may be present in a concentration of from 0.1% to 99.5% by weight of the total mixture (e.g. 0.5% to 95%); suitably from 30% to 95% for tablets and capsules, and from 0.01% to 50% (e.g. 3% to 50%) for liquid formulations.

[0150] The concentration of each antimicrobial agent in the synergistic combination is equal to or lower than the minimum inhibitory concentration in monotherapy with that agent against the bacteria targeted by the combination (i.e. MIC mono ). Thus, "MIC" as referred to herein should be understood as MIC mono , unless otherwise specified. Preferably, the concentration of at least one antimicrobial agent in the synergistic combination is lower than MIC mono , more preferably, the concentrations of at least two antimicrobial agents in the synergistic combination are lower than MIC mono . Using such concentrations is advantageous because it avoids toxicity problems and reduces the likelihood of development of antimicrobial resistance as compared to one or more agents in the combination.

[0151] In various embodiments, the concentration of ceftazidime against the bacteria targeted by the combination is 1xMIC or lower, where MIC is the minimum inhibitory concentration of ceftazidime alone against said bacteria, i.e. MIC mono . Preferably, the concentration of ceftazidime against the bacteria targeted by the combination can be at 0.5xMIC mono or lower. More preferably, the concentration of ceftazidime against the bacteria targeted by the combination is 0.25xMIC mono or lower. Most preferably, the concentration of ceftazidime against the bacteria targeted by the combination is 0.125xMIC mono or lower. In some embodiments, the concentration of ceftazidime against the bacteria targeted by the combination is as low as 0.0625xMIC mono - equivalent to 1 / 16 MICmono In fact, an unexpected enhanced efficacy is obtained by the combination of the present invention, such that in certain embodiments, for example those embodiments comprising four antimicrobial agents, the concentration of ceftazidime for the bacteria targeted by the use of the combination can be as low as 1 / 512 MIC. mono .

[0152] As an example, in a combination showing synergy against ESBL E. coli, the concentration of ceftazidime can be about 32 mg / L or lower. In a preferred embodiment, in a combination showing synergy against ESBL E. coli, the concentration of ceftazidime can be about 0.5 to about 32 mg / L. More preferably, in a combination showing synergy against ESBL E. coli, the concentration of ceftazidime can be about 0.5 to about 16 mg / L. Most preferably, in a combination showing synergy against ESBL E. coli, the concentration of ceftazidime can be about 0.5 to about 4 mg / L.

[0153] As a further example, in a combination showing synergy against Klebsiella pneumoniae CPE, the concentration of ceftazidime can be about 4 mg / L or lower. In a preferred embodiment, in a combination showing synergy against Klebsiella pneumoniae CPE, the concentration of ceftazidime can be about 0.25 to about 4 mg / L. More preferably, in a combination showing synergy against Klebsiella pneumoniae CPE, the concentration of ceftazidime can be about 0.25 to about 2 mg / L.

[0154] As a further example, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of ceftazidime can be about 512 mg / L or lower. In a preferred embodiment, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of ceftazidime can be about 0.015625 to about 512 mg / L. More preferably, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of ceftazidime can be about 0.5 to about 4 mg / L.

[0155] As a further example, in a combination showing synergy against Acinetobacter baumannii, the concentration of ceftazidime can be about 512 mg / L or lower. In a preferred embodiment, in a combination showing synergy against Acinetobacter baumannii, the concentration of ceftazidime can be about 32 to about 512 mg / L. More preferably, the concentration of ceftazidime can be about 32 to about 128 mg / L.

[0156] As a further example, in a combination showing synergy against MRSA, the concentration of ceftazidime can be about 32 mg / L or lower. In a preferred embodiment, in a combination showing synergy against MRSA, the concentration of ceftazidime can be about 1 to about 32 mg / L.

[0157] In various embodiments, the concentration of zidovudine against the bacteria targeted by the combination is 1xMIC mono or lower. Preferably, the concentration of zidovudine against the bacteria targeted by the combination is 0.5xMIC mono or lower. More preferably, the concentration of zidovudine against the bacteria targeted by the combination is 0.25xMIC mono or lower. Most preferably, the concentration of zidovudine against the bacteria targeted by the combination is 0.125xMIC mono or lower.

[0158] As an example, in a combination showing synergy against ESBL Escherichia coli, the concentration of zidovudine can be about 1 mg / L or lower, preferably about 0.03 to about 1 mg / L, more preferably about 0.125 to about 1 mg / L.

[0159] As a further example, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of zidovudine can be about 512 mg / L or lower, preferably in a combination showing synergy against Pseudomonas aeruginosa the concentration of zidovudine is about 128 mg / L or lower, or more preferably about 64 mg / L or lower. For example, in various embodiments, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of zidovudine can be 0.5 to about 512 mg / L, about 1 to about 512 mg / L, about 2 to about 512 mg / L, or about 8 to about 512 mg / L. In a further embodiment, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of zidovudine can be 0.5, 1, 2 or 8 mg / L to about 128 mg / L, more preferably to about 64 mg / L.

[0160] As a further example, in a combination showing synergy against Acinetobacter baumannii, the concentration of zidovudine can be about 512 mg / L or lower, preferably about 128 mg / L or lower. In different embodiments, in a combination showing synergy against Acinetobacter baumannii, the concentration of zidovudine can be about 0.5 to about 512 mg / L, preferably about 2 to about 512 mg / L, about 2 to about 128 mg / L, or about 4 to about 128 mg / L.

[0161] As will be understood by those skilled in the art, the concentration range of zidovudine as the second antimicrobial agent can be combined with the concentration range of ceftazidime as the first antimicrobial agent, and further combined with the following concentration ranges of levofloxacin, doxycycline and rifampicin each as the third antimicrobial agent as defined below. Those skilled in the art will also understand that all concentration ranges herein apply to pharmaceutically acceptable derivatives of the compounds mentioned.

[0162] In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, and zidovudine is used at a concentration of about 0.03 to about 1 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, and the zidovudine concentration can be about 0.03 to about 1 mg / L. Most preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 4 mg / L, and the zidovudine concentration is about 0.03 to about 1 mg / L.

[0163] In various embodiments, in combinations showing synergy against Pseudomonas aeruginosa, ceftazidime is used at a concentration of about 0.015625 to about 512 mg / L, and zidovudine is used at a concentration of about 0.5 to about 512 mg / L. Preferably, in combinations showing synergy against Pseudomonas aeruginosa, the ceftazidime concentration can be about 0.5 to about 512 mg / L, and the zidovudine concentration can be about 2 to about 512 mg / L. More preferably, in combinations showing synergy against Pseudomonas aeruginosa, the ceftazidime concentration can be about 0.5 to about 4 mg / L, and the zidovudine concentration can be about 8 to about 128 mg / L, more preferably about 64 mg / L.

[0164] In various embodiments, in combinations showing synergy against Acinetobacter baumannii, ceftazidime is used at a concentration of about 32 to about 512 mg / L, and zidovudine is used at a concentration of about 0.5 to about 512 mg / L. Preferably, in combinations showing synergy against Acinetobacter baumannii, the ceftazidime concentration can be about 32 to about 512 mg / L, and the zidovudine concentration can be about 0.5, 2, or 4 mg / L to about 512 mg / L. More preferably, in combinations showing synergy against Acinetobacter baumannii, the ceftazidime concentration can be about 32 to about 128 mg / L, and the zidovudine concentration can be about 0.5, about 2 or about 4 mg / L to about 128 mg / L.

[0165] In various embodiments, for the bacteria targeted by the use of the combination, the concentration of levofloxacin is 1xMIC mono or lower. Preferably, for the bacteria targeted by the use of the combination, the concentration of levofloxacin can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by the use of the combination, the concentration of levofloxacin can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by the use of the combination, the concentration of levofloxacin is 0.125xMIC mono or lower.

[0166] As an example, in combinations showing synergy against ESBL E. coli, the levofloxacin concentration can be about 8 mg / L or lower, preferably about 0.25 to about 8 mg / L, more preferably about 0.25 to about 4 mg / L.

[0167] As a further example, in combinations showing synergy against MRSA, the levofloxacin concentration can be about 1 mg / L or lower, preferably about 0.125 to about 1 mg / L, more preferably about 0.25 to about 1 mg / L.

[0168] As described above, the concentration ranges of levofloxacin can be combined with the respective concentration ranges of ceftazidime and zidovudine. In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, zidovudine is used at a concentration of about 0.03 to about 1 mg / L, and levofloxacin is used at a concentration of about 0.25 to about 8 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, the zidovudine concentration can be about 0.03 to about 1 mg / L, and the levofloxacin concentration can be about 1 to about 8 mg / L. Most preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the zidovudine concentration can be about 0.03 to about 1 mg / L, and the levofloxacin concentration can be about 4 to about 8 mg / L, most preferably about 8 mg / L.

[0169] In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, zidovudine is used at a concentration of about 0.25 to about 1 mg / L, and levofloxacin is used at a concentration of about 0.25 to about 8 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, ceftazidime can be used at a concentration of about 0.5 to about 4 mg / L, zidovudine can be used at a concentration of about 0.5 to about 1 mg / L, and levofloxacin can be used at a concentration of about 1 to about 8 mg / L.

[0170] The respective concentrations of ceftazidime, zidovudine, and levofloxacin can also be expressed as multiples of the MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, zidovudine can be used at a concentration of 1xMIC mono or lower, and levofloxacin can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 1xMIC monoor lower concentrations, levofloxacin can be used at 1xMIC mono or lower concentrations, and zidovudine can be used at 0.5 to 1xMIC mono of the concentration. Alternatively, ceftazidime can be used at 0.5xMIC mono or lower concentrations, levofloxacin can be used at 1xMIC mono of the concentration, and zidovudine at 1xMIC mono or lower concentrations.

[0171] In various embodiments, for the bacteria targeted by the use of the combination, the concentration of doxycycline is 1xMIC mono or lower. Preferably, for the bacteria targeted by the use of the combination, the concentration of doxycycline can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by the use of the combination, the concentration of doxycycline can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by the use of the combination, the concentration of doxycycline can be 0.125xMIC mono or lower.

[0172] As an example, in the combination showing synergy against ESBL Escherichia coli, the concentration of doxycycline can be about 1 mg / L or lower, preferably about 0.03 to about 1 mg / L, more preferably about 0.03 to about 0.5 mg / L.

[0173] As described above, the concentration range of doxycycline can be combined with the respective concentration ranges of ceftazidime and zidovudine. The concentration range of doxycycline can also be combined with the respective concentration ranges of polymyxin E / B and levofloxacin / meropenem / rifampicin / gentamicin, or with the respective concentration ranges of polymyxin E / B and zidovudine.

[0174] In various embodiments, in the combination showing synergy against ESBL Escherichia coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, zidovudine is used at a concentration of about 0.03 to about 1 mg / L, and doxycycline is used at a concentration of about 0.03 to about 2 mg / L. Preferably, in the combination showing synergy against ESBL Escherichia coli, the concentration of ceftazidime can be about 0.5 to about 16 mg / L, the concentration of zidovudine can be about 0.03 to about 1 mg / L, and the concentration of doxycycline can be about 0.06 to about 1 mg / L. Most preferably, in the combination showing synergy against ESBL Escherichia coli, the concentration of ceftazidime can be about 0.5 to about 4 mg / L, the concentration of zidovudine can be about 0.03 to about 1 mg / L, and the concentration of doxycycline can be about 0.5 to about 1 mg / L, most preferably about 1 mg / L.

[0175] In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, zidovudine is used at a concentration of about 0.25 to about 1 mg / L, and doxycycline is used at a concentration of about 0.03 to about 1 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, ceftazidime can be used at a concentration of about 0.5 to about 4 mg / L, zidovudine can be used at a concentration of about 0.5 to about 1 mg / L, and doxycycline is used at a concentration of about 0.06 to about 1 mg / L, more preferably about 0.5 to about 1 mg / L.

[0176] The concentrations of ceftazidime, zidovudine, and doxycycline can also be expressed as multiples of the MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and zidovudine can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and zidovudine can be used at a concentration of 0.25 to 1xMIC mono Alternatively, ceftazidime can be used at a concentration of 0.5xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono and zidovudine at a concentration of 1xMIC mono or lower.

[0177] The concentration range of doxycycline can alternatively be combined with the concentration ranges of ceftazidime and levofloxacin, respectively. In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, doxycycline is used at a concentration of about 0.0625 to about 1 mg / L, and levofloxacin is used at a concentration of about 0.25 to about 8 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, the doxycycline concentration can be about 0.0625 to about 1 mg / L, and the levofloxacin concentration can be about 2 to about 4 mg / L. Alternatively, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, the doxycycline concentration can be about 0.0625 to about 0.5 mg / L, and the levofloxacin concentration can be about 0.5 to about 4 mg / L. Most preferably, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the doxycycline concentration can be about 0.125 to about 1 mg / L, and the levofloxacin concentration can be about 2 to about 8 mg / L.

[0178] The concentrations of ceftazidime, doxycycline, and levofloxacin can also be expressed as multiples of the MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and levofloxacin can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and levofloxacin can be used at a concentration of 1xMIC mono or lower. More preferably, ceftazidime can be used at a concentration of 0.5xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and levofloxacin can be used at a concentration of 1xMIC mono or lower.

[0179] As a further example, in combinations showing synergy against Klebsiella pneumoniae CPE, the doxycycline concentration can be 0.5 mg / L or lower, preferably 0.03 to 0.5 mg / L, more preferably 0.03 to 0.25 mg / L.

[0180] In various embodiments, for the bacteria targeted by using the combination, the concentration of rifampicin can be 1xMIC monoor lower. Preferably, for the bacteria targeted by the use of the combination, the concentration of rifampicin can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by the use of the combination, the concentration of rifampicin can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by the use of the combination, the concentration of rifampicin can be 0.125xMIC mono or lower.

[0181] As an example, in a combination showing synergy against ESBL Escherichia coli, the rifampicin concentration can be about 4 mg / L or lower, preferably about 0.125 to about 4 mg / L, more preferably about 0.25 to about 4 mg / L.

[0182] The concentration range of rifampicin can be combined with the concentration ranges of ceftazidime or polymyxin E / B and zidovudine, doxycycline or fosfomycin, respectively.

[0183] In various embodiments, in a combination showing synergy against ESBL Escherichia coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, zidovudine is used at a concentration of about 0.03 to about 1 mg / L, and rifampicin is used at a concentration of about 0.125 to about 4 mg / L. Preferably, in a combination showing synergy against ESBL Escherichia coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, the zidovudine concentration can be about 0.03 to about 1 mg / L, and the rifampicin concentration can be about 0.5 to about 4 mg / L. Most preferably, in a combination showing synergy against ESBL Escherichia coli, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the zidovudine concentration can be about 0.03 to about 1 mg / L, and the rifampicin concentration can be about 0.5 to about 4 mg / L, most preferably about 1 mg / L to about 4 mg / L.

[0184] In various embodiments, in a combination showing synergy against ESBL Escherichia coli, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, zidovudine is used at a concentration of about 0.125 to about 1 mg / L, and rifampicin is used at a concentration of about 0.5 to about 4 mg / L. Preferably, in a combination showing synergy against ESBL Escherichia coli, ceftazidime can be used at a concentration of about 0.5 to about 4 mg / L, zidovudine can be used at a concentration of about 0.125 to about 1 mg / L, and rifampicin is used at a concentration of about 1 to about 4 mg / L.

[0185] The concentrations of ceftazidime, zidovudine and rifampicin can also be expressed as multiples of MIC mono For example, ceftazidime can be at 1xMIC monoor at a lower concentration, zidovudine can be used at 1xMIC mono or at a lower concentration, and rifampicin can be used at 1xMIC mono or at a lower concentration. Preferably, ceftazidime can be used at 1xMIC mono or at a lower concentration, zidovudine can be used at 1xMIC mono or at a lower concentration, and rifampicin can be used at a concentration of 0.125 to 1xMIC mono Preferably, ceftazidime can be used at 0.5xMIC mono or at a lower concentration, zidovudine can be used at 1xMIC mono or at a lower concentration, and rifampicin at a concentration of 0.25 to 1xMIC mono of the concentration.

[0186] In various embodiments, for the bacteria targeted by the use of the combination, the concentration of polymyxin E or polymyxin B can be 1xMIC mono or lower. Preferably, for the bacteria targeted by the use of the combination, the concentration of polymyxin E or polymyxin B can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by the use of the combination, the concentration of polymyxin E or polymyxin B can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by the use of the combination, the concentration of polymyxin E or polymyxin B can be 0.125xMIC mono or lower.

[0187] As an example, in a combination showing synergy against ESBL Escherichia coli, the concentration of polymyxin E or polymyxin B can be about 2 mg / L or lower, preferably about 0.06 to about 2 mg / L.

[0188] As a further example, in a combination showing synergy against Klebsiella pneumoniae CPE, the concentration of polymyxin E or polymyxin B can be about 4 mg / L or lower, preferably about 0.25 to about 4 mg / L.

[0189] As a further example, in a combination showing synergy against Pseudomonas aeruginosa, the concentration of polymyxin E or polymyxin B can be about 512 mg / L or lower, preferably about 0.03125 to about 512 mg / L, more preferably about 0.5 to about 512 mg / L, even more preferably about 0.5 to about 64 mg / L.

[0190] As a further example, in combinations showing synergy against Acinetobacter baumannii, the polymyxin E or polymyxin B concentration can be about 256 mg / L or lower, preferably about 128 mg / L or lower. In various embodiments, the polymyxin E or polymyxin B concentration can be from about 0.125 to about 256 mg / L, more preferably from about 8 to about 256 mg / L. In various embodiments, the polymyxin E or polymyxin B concentration can be from about 0.125 to about 128 mg / L, more preferably from about 8 to about 128 mg / L.

[0191] The concentration range of polymyxin E / B can be combined with the respective concentration ranges of ceftazidime and zidovudine described above. Alternatively, the concentration range of polymyxin E / B can be combined with each of the zidovudine / doxycycline / fosfomycin and levofloxacin / doxycycline / meropenem / gentamicin / rifampicin combinations defined herein.

[0192] In various embodiments, in combinations showing synergy against ESBL Escherichia coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, zidovudine is used at a concentration of about 0.03 to about 1 mg / L, and polymyxin E / B is used at a concentration of about 0.06 to about 2 mg / L. Preferably, in combinations showing synergy against ESBL Escherichia coli, the ceftazidime concentration can be from about 0.5 to about 16 mg / L, the zidovudine concentration can be from about 0.03 to about 1 mg / L, and the polymyxin E / B concentration can be from about 0.5 to about 2 mg / L. Most preferably, in combinations showing synergy against ESBL Escherichia coli, the ceftazidime concentration can be from about 0.5 to about 4 mg / L, the zidovudine concentration can be from about 0.03 to about 1 mg / L, and the polymyxin E / B concentration can be from about 0.5 to about 2 mg / L, most preferably from about 1 mg / L to about 2 mg / L.

[0193] In various embodiments, in combinations showing synergy against ESBL Escherichia coli, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, zidovudine is used at a concentration of about 0.125 to about 1 mg / L, and polymyxin E / B is used at a concentration of about 0.5 to about 2 mg / L. Preferably, in combinations showing synergy against ESBL Escherichia coli, ceftazidime can be used at a concentration of about 0.5 to about 4 mg / L, zidovudine can be used at a concentration of about 0.5 to about 1 mg / L, and polymyxin E / B is used at a concentration of about 0.06 to about 2 mg / L.

[0194] In various embodiments, in combinations that exhibit synergy against Pseudomonas aeruginosa, ceftazidime is used at a concentration of about 0.015625 to about 512 mg / L, zidovudine is used at a concentration of about 0.5 to about 512 mg / L, and polymyxin E / B is used at a concentration of about 0.03125 to about 512 mg / L. Preferably, in combinations that exhibit synergy against Pseudomonas aeruginosa, the ceftazidime concentration can be about 0.5 to about 512 mg / L, the zidovudine concentration can be about 2 to about 512 mg / L, and the polymyxin E / B concentration can be about 0.5 to about 512 mg / L. Most preferably, in combinations that exhibit synergy against Pseudomonas aeruginosa, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the zidovudine concentration can be about 8 to about 512 mg / L, and the polymyxin E / B concentration can be about 0.5 to about 512 mg / L, most preferably about 0.5 mg / L to about 64 mg / L.

[0195] In various embodiments, in combinations that exhibit synergy against Acinetobacter baumannii, ceftazidime is used at a concentration of about 32 to about 512 mg / L, zidovudine is used at a concentration of about 0.5 to about 512 mg / L, and polymyxin E / B is used at a concentration of about 0.125 to about 256 mg / L. Preferably, in combinations that exhibit synergy against Acinetobacter baumannii, the ceftazidime concentration can be about 32 to about 512 mg / L, the zidovudine concentration can be about 0.5, 2 or 4 mg / L to about 512 mg / L, and the polymyxin E / B concentration can be about 0.125 to about 256 mg / L, more preferably about 8 to about 256 mg / L. More preferably, in combinations that exhibit synergy against Acinetobacter baumannii, the ceftazidime concentration can be about 32 to about 512 mg / L, the zidovudine concentration can be about 0.5, 2 or 4 mg / L to about 128 mg / L, and the polymyxin E / B concentration can be about 0.125 to about 256 mg / L, more preferably about 8 to about 256 mg / L. Even more preferably, in combinations that exhibit synergy against Acinetobacter baumannii, the ceftazidime concentration can be about 32 to about 128 mg / L, the zidovudine concentration can be about 0.5, 2 or 4 mg / L to about 128 mg / L, and the polymyxin E / B concentration can be about 0.125 to about 256 mg / L, more preferably about 8 to about 256 mg / L.

[0196] The concentrations of ceftazidime, zidovudine, and polymyxin E individually can also be expressed as multiples of the MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, zidovudine can be used at a concentration of 0.5 to 1xMIC mono and polymyxin E can be used at a concentration of 1xMIC monoor at a lower concentration. Preferably, ceftazidime can be used at 1xMIC mono or at a lower concentration, zidovudine can be used at 0.5 to 1xMIC mono or at a lower concentration, and polymyxin E can be used at 0.125 to 1xMIC mono of the concentration. Alternatively, ceftazidime can be used at 0.5xMIC mono or at a lower concentration, zidovudine can be used at 1xMIC mono or at a lower concentration, and polymyxin E at 0.5 to 1xMIC mono of the concentration.

[0197] In various embodiments, for the bacteria targeted by using this combination, the concentration of meropenem can be 1xMIC mono or lower. Preferably, for the bacteria targeted by using this combination, the concentration of meropenem can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by using this combination, the concentration of meropenem can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by using this combination, the concentration of meropenem can be 0.125xMIC mono or lower.

[0198] As an example, in a combination that shows synergistic effect against ESBL Escherichia coli, the concentration of meropenem can be about 0.02 mg / L or lower, preferably about 9x10 -4 to about 0.02 mg / L.

[0199] As a further example, in a combination that shows synergistic effect against Pseudomonas aeruginosa, the concentration of meropenem can be about 32 mg / L or lower, preferably about 2 to about 32 mg / L, more preferably about 4 to about 32 mg / L.

[0200] As a further example, in a combination that shows synergistic effect against MRSA, the concentration of meropenem can be about 32 mg / L or lower, preferably about 4 to about 32 mg / L.

[0201] The concentration range of meropenem can be combined with the respective concentration ranges of ceftazidime / polymyxin E / B and doxycycline / fosfomycin / zidovudine defined herein.

[0202] In various embodiments, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, ceftazidime is used at a concentration of from about 0.015625 to about 512 mg / L, zidovudine is used at a concentration of from about 0.5 to about 512 mg / L, and meropenem is used at a concentration of from about 2 to about 32 mg / L. Preferably, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, the concentration of ceftazidime can be from about 0.015625 to about 512 mg / L, the concentration of zidovudine can be from about 2 to about 512 mg / L, and the concentration of meropenem can be from about 2 to about 32 mg / L. Most preferably, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, the concentration of ceftazidime can be from about 0.015625 to about 512 mg / L, the concentration of zidovudine can be from about 8 to about 512 mg / L, and the concentration of meropenem can be from about 2 to about 32 mg / L, most preferably from about 4 to about 32 mg / L.

[0203] In various embodiments, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, ceftazidime is used at a concentration of from about 0.5 to about 512 mg / L, zidovudine is used at a concentration of from about 1 to about 512 mg / L, and meropenem is used at a concentration of from about 2 to about 32 mg / L. Preferably, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, the concentration of ceftazidime can be from about 0.5 to about 512 mg / L, the concentration of zidovudine can be from about 2 to about 512 mg / L, and the concentration of meropenem can be from about 2 to about 32 mg / L. More preferably, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, the concentration of ceftazidime is from about 0.5 to about 512 mg / L, the concentration of zidovudine is from about 8 to about 512 mg / L, and the concentration of meropenem can be from about 2 to about 32 mg / L, more preferably from about 4 to about 32 mg / L. Most preferably, in combinations that exhibit synergistic activity against Pseudomonas aeruginosa, the concentration of ceftazidime can be from about 0.5 to about 4 mg / L, the concentration of zidovudine can be from about 8 to about 64 mg / L, and the concentration of meropenem can be from about 4 to about 32 mg / L.

[0204] The concentrations of ceftazidime, zidovudine, and meropenem can also be expressed as multiples of the MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, zidovudine can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 0.5xMIC mono or lower, zidovudine can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of from 0.25 to 1xMIC monofor use at a concentration. More preferably, ceftazidime can be used at a concentration of 0.25xMIC mono or lower, zidovudine can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 0.25 to 1xMIC mono . Most preferably, ceftazidime is used at a concentration of 0.125xMIC mono or lower (e.g., 0.0625MIC mono ), zidovudine can be used at a concentration of 0.5 to 1xMIC mono , and meropenem can be used at a concentration of 0.25 to 1xMIC mono .

[0205] The lower limit of the MIC mono range defined herein is not restricted. In the case where it is not specified, it is preferably 1 / 512MIC mono , 1 / 256MIC mono , 1 / 128MIC mono , 1 / 64MIC mono , 1 / 32MIC mono or 0.0625MIC mono . For example, "0.5x MIC mono or less" becomes "0.5xMIC mono to 0.0625MIC mono ".

[0206] The concentration range of meropenem can be combined with the respective concentration ranges of levofloxacin and ceftazidime. In various embodiments, in a combination showing synergistic effect against MRSA, ceftazidime is used at a concentration of about 1 to about 32 mg / L, the concentration of levofloxacin is about 0.03125 to about 1 mg / L, and the concentration of meropenem is about 4 to about 32 mg / L. Preferably, in a combination showing synergistic effect against MRSA, the concentration of ceftazidime is about 1 to about 32 mg / L, the concentration of levofloxacin is about 0.125 to about 1 mg / L, and the concentration of meropenem is about 4 to about 32 mg / L.

[0207] The respective concentrations of ceftazidime, levofloxacin, and meropenem can also be expressed as multiples of MIC mono . For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, levofloxacin can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 0.5xMIC monoor lower concentrations, levofloxacin can be used at 1xMIC mono or lower concentrations, and meropenem can be used at 0.25 to 1xMIC mono concentrations. More preferably, ceftazidime can be used at 0.25xMIC mono or lower concentrations, levofloxacin can be used at 1xMIC mono or lower concentrations, and meropenem can be used at 0.25 to 1xMIC mono or lower concentrations. Most preferably, ceftazidime is at 0.125xMIC mono or lower (e.g., 0.0625MIC mono ) concentrations, levofloxacin can be used at 0.5 to 1xMIC mono concentrations, and meropenem can be used at 0.25 to 1xMIC mono concentrations. In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 32 mg / L, doxycycline is used at a concentration of about 0.0625 to about 1 mg / L, and meropenem is used at a concentration of about 9x10 -4 to about 0.02 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 16 mg / L, the doxycycline concentration can be about 0.0625 to about 1 mg / L, and the meropenem concentration can be about 0.0156 mg / L. Most preferably, in combinations showing synergy against ESBL E. coli, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the doxycycline concentration can be about 0.625 to about 1 mg / L, and the meropenem concentration can be about 0.156 mg / L.

[0208] In various embodiments, in combinations showing synergy against ESBL E. coli, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, doxycycline is used at a concentration of about 0.25 to about 1 mg / L, and meropenem is used at a concentration of about 3x10 -3 to about 0.02 mg / L. Preferably, in combinations showing synergy against ESBL E. coli, ceftazidime can be used at a concentration of about 0.5 to about 2 mg / L, doxycycline can be used at a concentration of about 0.25 to about 1 mg / L, and meropenem is at a concentration of about 3x10 -3 to about 0.02 mg / L (e.g., 7x10 -3 to about 0.02 mg / L) concentrations.

[0209] The concentrations of ceftazidime, doxycycline, and meropenem can also be expressed as MIC monomultiple. For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Preferably, ceftazidime can be used at a concentration of 0.5xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 0.25 to 1xMIC mono More preferably, ceftazidime can be used at a concentration of 0.25xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 0.25 to 1xMIC mono or lower. Most preferably, ceftazidime is used at a concentration of 0.125xMIC mono or lower (e.g., 0.0625MIC mono ), doxycycline can be used at a concentration of 0.5 to 1xMIC mono , and meropenem can be used at a concentration of 0.25 to 1xMIC mono .

[0210] The lower limit of the MIC mono range defined herein is not limited. In cases where it is not specified, it is preferably 1 / 512MIC mono , 1 / 256MIC mono , 1 / 128MIC mono , 1 / 64MIC mono , 1 / 32MIC mono or 0.0625MIC mono . For example, "0.5xMIC mono or less" becomes "0.5xMIC mono to 0.0625MIC mono ".

[0211] In various embodiments, for the bacteria targeted by using the combination, the concentration of fosfomycin can be 1xMIC mono or lower. Preferably, for the bacteria targeted by using the combination, the concentration of fosfomycin can be 0.5xMIC mono or lower. More preferably, for the bacteria targeted by using the combination, the concentration of fosfomycin can be 0.25xMIC mono or lower. Most preferably, for the bacteria targeted by using the combination, the concentration of fosfomycin can be 0.125xMIC mono or lower.

[0212] As an example, in combinations showing synergy against Klebsiella pneumoniae CPE, the fosfomycin concentration can be about 64 mg / L or lower, preferably about 4 to about 64 mg / L.

[0213] As a further example, in combinations showing synergy against Pseudomonas aeruginosa, the fosfomycin concentration can be about 256 mg / L or lower, preferably about 128 mg / L or lower. Preferably, in combinations showing synergy against Pseudomonas aeruginosa, the fosfomycin concentration can be about 4 to about 256 mg / L, more preferably about 16 to about 128 mg / L.

[0214] As a further example, in combinations showing synergy against Acinetobacter baumannii, the fosfomycin concentration can be about 256 mg / L or lower, preferably about 32 to about 256 mg / L.

[0215] As a further example, in combinations showing synergy against MRSA, the fosfomycin concentration can be about 16 mg / L or lower, preferably about 2 to about 16 mg / L.

[0216] The concentration range of fosfomycin can be combined with the respective concentration ranges of ceftazidime / polymyxin E / B, zidovudine / doxycycline, and / or levofloxacin / doxycycline / meropenem / rifampicin / gentamicin / polymyxin E / B as defined herein.

[0217] In various embodiments, in combinations showing synergy against Klebsiella pneumoniae CPE, ceftazidime is used at a concentration of about 0.25 to about 32 mg / L, doxycycline is used at a concentration of about 0.0625 to about 0.5 mg / L, and fosfomycin is used at a concentration of about 4 or about 16 to about 64 mg / L. Preferably, in combinations showing synergy against Klebsiella pneumoniae CPE, the ceftazidime concentration can be about 0.25 to about 16 mg / L, the doxycycline concentration can be about 0.125 to about 0.5 mg / L, and the fosfomycin concentration can be about 4 or about 16 to about 64 mg / L. Most preferably, in combinations showing synergy against Klebsiella pneumoniae CPE, the ceftazidime concentration can be about 0.5 to about 4 mg / L, the doxycycline concentration can be about 0.5 mg / L, and the fosfomycin concentration can be about 4 to about 64 mg / L.

[0218] The concentrations of ceftazidime, doxycycline, and fosfomycin can also be expressed as multiples of MIC mono For example, ceftazidime can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and fosfomycin can be used at a concentration of 1xMICmono or at a lower concentration. Preferably, ceftazidime can be used at 0.5xMIC mono or at a lower concentration, doxycycline can be used at 1xMIC mono or at a lower concentration, and fosfomycin can be used at a concentration of 0.25 to 1xMIC mono More preferably, ceftazidime can be used at 0.25xMIC mono or at a lower concentration, doxycycline can be used at 1xMIC mono or at a lower concentration, and fosfomycin can be used at a concentration of 0.25 to 1xMIC mono or at a lower concentration. Most preferably, ceftazidime is used at 0.125xMIC mono at a concentration, doxycycline can be used at a concentration of 0.125 to 1xMIC mono or at a lower concentration, and fosfomycin can be used at a concentration of 0.25 to 1xMIC mono at a concentration.

[0219] In various embodiments, in combinations showing synergy against Klebsiella pneumoniae CPE, ceftazidime is used at a concentration of about 0.25 to about 32 mg / L, fosfomycin is used at a concentration of about 4 to about 64 mg / L, and rifampicin is used at a concentration of about 1 to 8 mg / L. Preferably, in combinations showing synergy against Klebsiella pneumoniae CPE, the concentration of ceftazidime can be about 0.25 to about 16 mg / L, the concentration of fosfomycin can be about 4 to 64 mg / L, and the concentration of rifampicin can be about 1 to 8 mg / L. Most preferably, in combinations showing synergy against Klebsiella pneumoniae CPE, the concentration of ceftazidime can be about 0.5 to about 4 mg / L, the concentration of fosfomycin can be about 4 to about 64 mg / L, and the concentration of rifampicin can be about 1 to 8 mg / L.

[0220] In various embodiments, in combinations showing synergy against Klebsiella pneumoniae CPE, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, the concentration of fosfomycin can be about 4 to about 64 mg / L, and the concentration of rifampicin can be about 2 to 8 mg / L. More preferably, in combinations showing synergy against Klebsiella pneumoniae CPE, ceftazidime is used at a concentration of about 0.5 to about 4 mg / L, the concentration of fosfomycin is about 8 to about 64 mg / L, and the concentration of rifampicin can be about 2 to 8 mg / L.

[0221] The concentrations of ceftazidime, fosfomycin, and rifampicin can also be expressed as multiples of MIC mono For example, ceftazidime can be used at 1xMIC mono or at a lower concentration, fosfomycin can be used at 1xMIC monoor lower concentrations, and rifampicin can be used at 1xMIC mono or lower concentrations. Preferably, ceftazidime can be used at 0.5xMIC mono or lower concentrations, fosfomycin can be used at concentrations from 0.125 to 1xMIC mono and rifampicin can be used at 1xMIC mono or lower concentrations. More preferably, ceftazidime can be used at 0.25xMIC mono or lower concentrations, fosfomycin can be used at concentrations from 0.25 to 1xMIC mono or lower concentrations, and rifampicin can be used at 1xMIC mono or lower concentrations. Most preferably, ceftazidime is used at 0.125xMIC mono and fosfomycin can be used at concentrations from 0.5 to 1xMIC mono (e.g., 0.5MIC mono ) and rifampicin can be used at 1xMIC mono or lower concentrations.

[0222] As described above, the concentration range of fosfomycin can be combined with the respective concentration ranges of ceftazidime and levofloxacin.

[0223] In various embodiments, in combinations showing synergy against MRSA, ceftazidime is used at concentrations of about 1 to about 32 mg / L, fosfomycin is used at concentrations of about 2 to about 16 mg / L, and levofloxacin is used at concentrations of about 0.0625 to about 1 mg / L. Preferably, in combinations showing synergy against MRSA, the ceftazidime concentration can be about 1 to about 32 mg / L, the fosfomycin concentration can be about 2 to about 16 mg / L, and the levofloxacin concentration can be about 0.125 to about 1 mg / L.

[0224] The concentrations of ceftazidime, fosfomycin, and levofloxacin can also be expressed as multiples of MIC mono For example, ceftazidime can be used at 1xMIC mono or lower concentrations, fosfomycin can be used at 1xMIC mono or lower concentrations, and levofloxacin can be used at 1xMIC mono or lower concentrations. Preferably, ceftazidime can be used at 0.5xMIC mono or lower concentrations, fosfomycin can be used at concentrations from 0.125 to 1xMIC mono and levofloxacin can be used at 1xMIC mono or lower concentrations. More preferably, ceftazidime can be used at 0.25xMIC monoUsed at a concentration of 0.25 to 1xMIC or lower, fosfomycin mono Used at a concentration of 1xMIC or lower, and levofloxacin can be at 1xMIC mono Used at a concentration of or lower. Most preferably, ceftazidime is used at a concentration of 0.125xMIC mono Used at a concentration of 0.5 to 1xMIC, fosfomycin mono (e.g., 0.5MIC mono ) Used at a concentration of, and levofloxacin can be at 1xMIC mono Used at a concentration of or lower.

[0225] In various embodiments, in combinations showing synergy against Pseudomonas aeruginosa, polymyxin E / B is used at a concentration of about 0.03125 to about 512 mg / L, zidovudine is used at a concentration of about 0.03125 to about 512 mg / L, and fosfomycin is used at a concentration of about 4 to about 256 mg / L. Preferably, in combinations showing synergy against Pseudomonas aeruginosa, the concentration of polymyxin E / B can be about 0.03125 to about 512 mg / L, the concentration of zidovudine can be about 0.5 to about 512 mg / L, and the concentration of fosfomycin can be about 4 to about 256 mg / L. More preferably, in combinations showing synergy against Pseudomonas aeruginosa, the concentration of polymyxin E / B can be about 0.5 to about 512 mg / L, the concentration of zidovudine can be about 0.5 to about 512 mg / L, and the concentration of fosfomycin can be about 16 to about 128 mg / L. Most preferably, in combinations showing synergy against Pseudomonas aeruginosa, the concentration of polymyxin E / B can be about 0.5 to about 1 mg / L, the concentration of zidovudine can be about 0.5 to about 1 mg / L, and the concentration of fosfomycin can be about 16 to about 128 mg / L.

[0226] In various embodiments, in combinations showing synergy against Acinetobacter baumannii, polymyxin E / B is used at a concentration of about 0.06 to about 128 mg / L, zidovudine is used at a concentration of about 0.03125 to about 512 mg / L, and fosfomycin is used at a concentration of about 32 to about 256 mg / L. Preferably, in combinations showing synergy against Acinetobacter baumannii, the concentration of polymyxin E / B can be about 0.5 to about 128 mg / L, the concentration of zidovudine can be about 0.5 to about 512 mg / L, and the concentration of fosfomycin can be about 32 to about 256 mg / L. More preferably, in combinations showing synergy against Acinetobacter baumannii, the concentration of polymyxin E / B can be about 0.5 to about 2 mg / L, the concentration of zidovudine can be about 0.5 to about 1 mg / L, and the concentration of fosfomycin can be about 32 to about 256 mg / L.

[0227] The concentrations of polymyxin E / B, zidovudine, and fosfomycin can also be expressed as multiples of MIC. mono For example, polymyxin E / B can be used at a concentration of 1xMIC mono or lower, zidovudine can be used at a concentration of 1xMIC mono or lower, and fosfomycin can be used at a concentration of 1xMIC mono or lower. Preferably, polymyxin E / B can be used at a concentration of 0.5xMIC mono or lower, zidovudine can be used at a concentration of 0.125 to 1xMIC mono and fosfomycin can be used at a concentration of 1xMIC mono or lower. More preferably, polymyxin E / B can be used at a concentration of 0.25xMIC mono or lower, zidovudine can be used at a concentration of 0.25 to 1xMIC mono or lower, and fosfomycin can be used at a concentration of 1xMIC mono or lower. Most preferably, polymyxin E / B is used at a concentration of 0.125xMIC mono and zidovudine can be used at a concentration of 0.5 to 1xMIC mono (e.g., 0.5MIC mono ) and fosfomycin can be used at a concentration of 1xMIC mono or lower.

[0228] In various embodiments, in combinations showing synergy against Escherichia coli ESBL, colistin / polymyxin E is used at a concentration of about 0.125 to about 4 mg / L, doxycycline is used at a concentration of about 0.0625 to about 1 mg / L, and rifampicin is used at a concentration of about 0.25 to 4 mg / L. Preferably, in combinations showing synergy against Escherichia coli ESBL, the colistin concentration can be about 0.125 to about 2 mg / L, the doxycycline concentration can be about 0.0625 to about 1 mg / L, and the rifampicin concentration can be about 0.25 to 4 mg / L. Most preferably, in combinations showing synergy against Escherichia coli ESBL, the colistin concentration can be about 0.25 to about 0.5 mg / L, the doxycycline concentration can be about 0.0625 to about 1 mg / L, and the rifampicin concentration can be about 0.25 to 4 mg / L.

[0229] The concentrations of colistin, doxycycline, and rifampicin can also be expressed as multiples of MIC mono For example, colistin can be used at a concentration of 1xMIC mono or lower, doxycycline can be used at a concentration of 1xMIC mono or lower, and rifampicin can be used at a concentration of 1xMICmono or at a lower concentration. Preferably, colistin can be used at 0.5xMIC mono or at a lower concentration, doxycycline can be used at 1xMIC mono or at a lower concentration, and rifampicin can be used at 1xMIC mono or at a lower concentration. More preferably, colistin can be used at 0.125xMIC mono or at a lower concentration, doxycycline can be used at 0.125 to 1xMIC mono or at a lower concentration, and rifampicin can be used at 1xMIC mono or at a lower concentration. Most preferably, colistin is used at 0.125xMIC mono at a concentration, doxycycline can be used at 0.125 to 1xMIC mono at a concentration, and rifampicin can be used at 1xMIC mono or at a lower concentration.

[0230] In various embodiments, in combinations showing synergy against Escherichia coli ESBL, colistin / polymyxin E is used at a concentration of about 0.125 to about 4 mg / L, fosfomycin is used at a concentration of about 4 to 64 mg / L, and levofloxacin is used at a concentration of about 0.1565 to 0.25 mg / L. Preferably, in combinations showing synergy against Escherichia coli ESBL, the colistin concentration can be about 0.125 to about 2 mg / L, the fosfomycin concentration can be about 4 or about 16 to 64 mg / L, and the levofloxacin concentration can be about 0.0156 to 0.25 mg / L. Most preferably, in combinations showing synergy against Escherichia coli ESBL, the colistin concentration can be about 0.5 mg / L, the fosfomycin concentration can be about 4 or 16 to 64 mg / L, and the levofloxacin concentration can be about 0.03 or 0.125 to 0.25 mg / L.

[0231] The concentrations of colistin, fosfomycin, and levofloxacin can also be expressed as multiples of MIC mono For example, colistin can be used at 1xMIC mono or at a lower concentration, fosfomycin can be used at 1xMIC mono or at a lower concentration, and levofloxacin can be used at 1xMIC mono or at a lower concentration. Preferably, colistin can be used at 0.5xMIC mono or at a lower concentration, fosfomycin can be used at 0.5 to 1xMIC mono at a concentration, and levofloxacin can be used at 0.625 to 0.5xMIC mono at a concentration. Most preferably, colistin is at 0.125xMIC monoFor use at a concentration of fosfomycin can be from 0.5 to 1xMIC mono For use at a concentration of levofloxacin can be at 1xMIC mono Or at a lower concentration, for example, from 0.0625 to 0.5xMIC mono .

[0232] In various embodiments, for the bacteria targeted by the use of the combination, the concentration of gentamicin can be 1xMIC mono Or lower. Preferably, for the bacteria targeted by the use of the combination, the concentration of gentamicin can be 0.5xMIC mono Or lower. More preferably, for the bacteria targeted by the use of the combination, the concentration of gentamicin can be 0.25xMIC mono Or lower. Most preferably, for the bacteria targeted by the use of the combination, the concentration of gentamicin is 0.125xMIC mono Or lower.

[0233] As an example, in a combination showing synergy against Klebsiella pneumoniae CPE, the gentamicin concentration can be about 2 mg / L or lower, preferably from about 0.125 to about 2 mg / L, more preferably from about 0.25 to about 2 mg / L.

[0234] In various embodiments, in a combination showing synergy against Klebsiella pneumoniae CPE, colistin / polymyxin E is used at a concentration of from about 0.125 to about 4 mg / L, fosfomycin is used at a concentration of from about 4 to 64 mg / L, and gentamicin is used at a concentration of from about 0.125 to 2 mg / L. Preferably, in a combination showing synergy against Klebsiella pneumoniae CPE, the colistin concentration can be from about 0.125 to about 2 mg / L, the fosfomycin concentration can be about 4 or about 16 to 64 mg / L, and the gentamicin concentration can be from about 0.125 to 2 mg / L. Most preferably, in a combination showing synergy against Klebsiella pneumoniae CPE, the colistin concentration can be about 0.5 mg / L, the fosfomycin concentration can be about 4 or 16 to 64 mg / L, and the gentamicin concentration can be from about 0.125 to 2 mg / L.

[0235] The concentrations of colistin, fosfomycin and gentamicin can also be expressed as multiples of MIC mono For example, colistin can be used at a concentration of 1xMIC mono Or lower, fosfomycin can be used at a concentration of 1xMIC mono Or lower, and gentamicin can be used at a concentration of 1xMIC mono Or lower. Preferably, colistin can be at 0.5xMIC monoFor use at a concentration of 0.0625 or 0.5 to 1xMIC, fosfomycin can be used mono at a concentration of, and gentamicin can be used at a concentration of 0.625 to 0.5xMIC mono For use at a concentration of. More preferably, colistin can be used at a concentration of 0.125xMIC mono or lower, fosfomycin can be used at a concentration of 0.5 to 1xMIC mono and gentamicin can be used at a concentration of 1xMIC mono or lower. Most preferably, colistin is used at a concentration of 0.125xMIC mono and fosfomycin can be used at a concentration of 0.5 to 1xMIC mono and gentamicin can be used at a concentration of 1xMIC mono or lower, such as 0.0625 to 0.5xMIC mono .

[0236] The concentration range of meropenem can also be combined with the respective concentration ranges of ceftazidime / fosfomycin, zidovudine, and polymyxin E / colistin; for example, in a combination of four antimicrobial agents that shows synergistic activity against Pseudomonas aeruginosa.

[0237] In various embodiments, in a combination that shows synergistic activity against Pseudomonas aeruginosa, zidovudine is used at a concentration of about 1 to about 512 mg / L, colistin is used at a concentration of about 2 to about 512 mg / L, ceftazidime is used at a concentration of about 1 to about 512 mg / L, and meropenem is used at a concentration of about 1 to about 32 mg / L. Preferably, in a combination that shows synergistic activity against Pseudomonas aeruginosa, the concentration of zidovudine can be about 1 to about 64 mg / L, the concentration of colistin is about 2 to about 512 mg / L, the concentration of ceftazidime is about 1 to 512 mg / L, and the concentration of meropenem is about 1 to about 32 mg / L. More preferably, in a combination that shows synergistic activity against Pseudomonas aeruginosa, the concentration of zidovudine can be about 1 to about 64 mg / L, the concentration of colistin is about 2 to about 512 mg / L, the concentration of ceftazidime is about 1 to 512 mg / L, and the concentration of meropenem is about 1 to about 4 mg / L.

[0238] The concentrations of zidovudine, colistin, ceftazidime, and meropenem can also be expressed as multiples of MIC mono For example, zidovudine can be used at a concentration of 1xMIC mono or lower, colistin can be used at a concentration of 1xMIC mono or lower, ceftazidime can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC monoused at a concentration of 1xMIC or lower. Preferably, zidovudine can be used at a concentration of 1xMIC mono or lower, colistin can be used at a concentration of 1xMIC mono or lower, ceftazidime can be used at a concentration of 1xMIC mono and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 0.5 to 1xMIC mono and colistin can be used at a concentration of 1xMIC mono and ceftazidime at a concentration of 1xMIC mono or lower and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 1xMIC mono and colistin can be used at a concentration of 0.5 to 1xMIC mono and ceftazidime at a concentration of 1xMIC mono or lower and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 1xMIC mono and colistin can be used at a concentration of 1xMIC mono and ceftazidime at a concentration of 0.5 to 1xMIC mono or lower and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 1xMIC mono and colistin can be used at a concentration of 1xMIC mono and ceftazidime at a concentration of 1xMIC mono or lower and meropenem can be used at a concentration of 0.5 to 1xMIC mono or lower.

[0239] The lower limit of the MIC range defined herein is not restricted. In cases where it is not specified, it is preferably 1 / 512 MIC mono 、1 / 256 MIC mono 、1 / 128 MIC mono 、1 / 64 MIC mono 、1 / 32 MIC mono 、1 / 16 MIC mono or 0.0625 MIC mono 。For example, "0.5xMIC mono or below" becomes "0.5xMIC mono to 0.0625xMIC mono ".

[0240] In various embodiments, in combinations showing synergy against Pseudomonas aeruginosa, zidovudine is used at a concentration of about 1 to about 512 mg / L, colistin is used at a concentration of about 16 to about 512 mg / L, fosfomycin is used at a concentration of about 4 to about 256 mg / L, and meropenem is used at a concentration of about 1 to about 32 mg / L. Preferably, in combinations showing synergy against Pseudomonas aeruginosa, zidovudine is used at a concentration of about 1 to about 512 mg / L, colistin is used at a concentration of about 32 to about 512 mg / L, fosfomycin is used at a concentration of about 4 to about 256 mg / L, and meropenem is used at a concentration of about 1 to about 32 mg / L. More preferably, in combinations showing synergy against Pseudomonas aeruginosa, zidovudine is used at a concentration of about 1 to about 512 mg / L, colistin is used at a concentration of about 32 to about 64 mg / L, fosfomycin is used at a concentration of about 4 to about 256 mg / L, and meropenem is used at a concentration of about 1 to about 32 mg / L. Even more preferably, in combinations showing synergy against Pseudomonas aeruginosa, zidovudine is used at a concentration of about 1 to about 64 mg / L, colistin is used at a concentration of about 32 to about 64 mg / L, fosfomycin is used at a concentration of about 4 to about 128 mg / L, and meropenem is used at a concentration of about 1 to about 32 mg / L, more preferably 1 to about 4 mg / L.

[0241] The concentrations of zidovudine, colistin, fosfomycin, and meropenem can also be expressed as multiples of MIC mono For example, zidovudine can be used at a concentration of 1xMIC mono or lower, colistin can be used at a concentration of 1xMIC mono or lower, fosfomycin can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Preferably, zidovudine can be used at a concentration of 1xMIC mono or lower, colistin can be used at a concentration of 1xMIC mono or lower, fosfomycin can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 0.5 to 1xMIC mono or lower, colistin can be used at a concentration of 1xMIC mono or lower, fosfomycin can be used at a concentration of 1xMIC mono or lower, and meropenem can be used at a concentration of 1xMIC mono or lower. Alternatively, zidovudine can be used at a concentration of 1xMIC mono or lower, colistin can be used at a concentration of 0.5 to 1xMICmono is used at a concentration, and the concentration of fosfomycin is at 1xMIC mono or a lower concentration, and meropenem can be at 1xMIC mono or a lower concentration. Alternatively, zidovudine can be at 1xMIC mono at a concentration, and colistin can be at 1xMIC mono at a concentration, fosfomycin at 0.5 to 1xMIC mono or a lower concentration, and meropenem can be at 1xMIC mono or a lower concentration. Alternatively, zidovudine can be at 1xMIC mono at a concentration, and colistin can be at 1xMIC mono at a concentration, fosfomycin at 1xMIC mono or a lower concentration, and meropenem can be at 0.5 to 1xMIC mono or a lower concentration.

[0242] Preparations suitable for oral administration may be presented as: discrete units such as capsules, cachets or tablets (e.g. chewable tablets especially for paediatric administration), each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or water-in-oil or oil-in-water liquid emulsions. The active ingredient may also be presented as boluses, lozenges or pastes.

[0243] Tablets may be made by compression or moulding, optionally containing one or more excipients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in free-flowing form such as a powder or granules, optionally mixed with other conventional excipients such as binders (e.g. syrup, gum acacia, gelatin, sorbitol, tragacanth, starch mucilage, polyvinylpyrrolidone and / or hydroxypropylmethylcellulose), fillers (e.g. lactose, sugar, microcrystalline cellulose, maize starch, calcium phosphate and / or sorbitol), lubricants (e.g. magnesium stearate, stearic acid, talc, polyethylene glycol and / or silica), disintegrants (e.g. potato starch, croscarmellose sodium and / or sodium starch glycolate) and wetting agents (e.g. sodium lauryl sulphate). Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active ingredient and an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide controlled release (e.g. extended, sustained or pulsatile release, or a combination of immediate release and controlled release) of the active ingredient.

[0244] Alternatively, the active ingredient may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Preparations containing the active ingredient may also be presented as dry products to be constituted with water or another suitable vehicle before use.

[0245] Such liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and / or hydrogenated edible oils), emulsifying agents (e.g., lecithin, sorbitan monooleate, and / or gum arabic), non-aqueous carriers (e.g., edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and / or ethanol), and preservatives (e.g., methyl or propyl paraben and / or sorbic acid).

[0246] The compositions used according to the present invention may be presented in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may for example comprise a metal or plastic foil, such as a blister pack. When the composition is intended to be administered as three separate compositions, these may be presented in a dual pack form.

[0247] The pharmaceutical composition may also be prescribed to a patient in the form of a "patient pack" containing the entire course of treatment in a single package, usually a blister pack. The patient pack has the advantage over traditional prescriptions in that the pharmacist separates the patient's drug supply from the bulk supply, as the patient always receives the package insert contained in the patient pack, which is usually lost in traditional prescriptions. It has been shown that including a package insert improves patient compliance with the physician's instructions.

[0248] Administering the combination of the present invention by including a single patient pack or a patient pack for each composition that instructs the patient on the correct use of the package insert of the present invention is a desirable feature of the present invention.

[0249] A further embodiment according to the present invention provides a patient pack comprising at least one active agent of the combination according to the present invention and an information insert containing instructions for the use of the combination of the present invention. In another embodiment of the present invention, there is provided a dual pack jointly comprising an antimicrobial agent (preferably having biological activity against clinically latent microorganisms) for separate administration and one or more compounds disclosed herein (preferably having biological activity against clinically latent microorganisms).

[0250] The amount of the active ingredient required for treatment will vary depending on the nature of the condition to be treated, as well as the age and condition of the patient, and will ultimately be determined by the attending physician. However, generally, the dose for adult treatment will typically be in the range of 0.02 to 5000 mg per day, preferably 1 - 1500 mg per day. The desired dose may conveniently be presented as a single dose or as separate doses administered at appropriate intervals, such as two, three, or more sub-doses per day.

[0251] Thus, those skilled in the art will readily obtain and understand this information.

[0252] Biological tests

[0253] Test procedures for determining the biological (e.g., bactericidal or antimicrobial) activity of an active ingredient include those known to persons skilled in the art for determining the following:

[0254] (a) Bactericidal activity against clinically latent bacteria; and

[0255] (b) Antimicrobial activity against log-phase bacteria.

[0256] Regarding the above (a), methods for determining the activity against clinically latent bacteria include determining the Minimum Stationary-cidal Concentration (“MSC”) or Minimum Dormicidal Concentration (“MDC”) of the test compound under conditions known to persons skilled in the art (e.g., those described in Nature Reviews, Drug Discovery 1, 895-910 (2002), the disclosure of which is hereby incorporated by reference).

[0257] For example, WO2000028074 describes suitable methods for screening compounds to determine their ability to kill clinically latent microorganisms. Typical methods may include the following steps:

[0258] (1) Growing a bacterial culture to the stationary phase;

[0259] (2) Treating the stationary-phase culture with one or more antimicrobial agents at a concentration and / or for a time sufficient to kill the growing bacteria, thereby selecting a phenotypically resistant subpopulation;

[0260] (3) Incubating a sample of the phenotypically resistant subpopulation with one or more test compounds or agents; and

[0261] (4) Evaluating the antimicrobial effect on the phenotypically resistant subpopulation.

[0262] According to this method, the phenotypically resistant subpopulation can be regarded as representative of clinically latent bacteria that retain metabolic activity in vivo and can cause disease recurrence or onset.

[0263] Regarding the above (b), methods for determining the activity against log-phase bacteria include determining the Minimum Inhibitory Concentration (“MIC”) or Minimum Bactericidal Concentration (“MBC”) of the test compound under standard conditions (i.e., conditions known to persons skilled in the art, such as those described in WO 2005014585, the disclosure of which is hereby incorporated by reference). Specific examples of such methods are described below. Examples

[0264] The antimicrobial agents were sourced from commercial channels. They were weighed and dissolved in water, PBS, DMSO, or acidified water to achieve a final concentration of 1 - 10 mg / mL. The antimicrobial agent solution was diluted 10 - fold to the highest concentration used in the experiment and then serially diluted 2 - fold in a series of no more than 11 consecutive dilutions. This left the operator with up to 12 different, decreasing concentrations of the selected antimicrobial agent.

[0265] The bacteria were obtained from Ninewells Hospital and Medical School in Dundee, Scotland. They were obtained as patient strains and characterized by Vitek2 screening. To prepare the following examples, the bacteria were cultured overnight or until confluent in Mueller Hinton cation - adjusted broth in the presence or absence of supplements. The OD of the bacteria was measured 600 , and bacteria with a reading < 0.25 were returned to the incubator. The bacterial culture was diluted in the medium until the OD 600 register reading = < 0.01, which indicated that the culture was approximately 10 6 CFU / ml.

[0266] All data in this article were generated using the same checkerboard test.

[0267] 20 μL of antibiotic A (backbone) was pipetted as a single dilution into all wells of a 96 - well plate for use.

[0268] 20 μL of the lowest concentration of antibiotic B (first variable) was pipetted into column 1 of the 96 - well plate. The second concentration (2 - fold concentration) was pipetted into column 2. This process was repeated until all concentrations of antibiotic B to be used were added.

[0269] 20 μL of the lowest concentration of antibiotic C (second variable) was pipetted into row A of the 96 - well plate. The second concentration (2 - fold concentration) was pipetted into row B. This process was repeated until all concentrations of antibiotic C to be used were added.

[0270] 120 μL of sterile medium (BHI / MHB2) was added.

[0271] 20 μL of the prepared bacterial culture was added.

[0272] The culture plate was sealed with a lid and incubated for 16 hours, overnight.

[0273] The culture plate was read in a 96 - well plate reader at OD 600 These are the values reported in the following checkerboard.

[0274] For the triple combinations, the concentrations of two antibiotics vary while one remains constant, with the latter being the "backbone". For the quadruple combinations, the concentrations of two antibiotics vary while the remaining two remain constant, with the latter being the "backbone". The above method was explained, together with the calculation of FICI and the indicative values for synergy, indifference, and antagonism.

[0275] The backbone for Comparative Examples 1 and 2 and Examples 3 to 5 was ceftazidime at 4 mg / L. The isolates in these examples were resistant to cephalosporins and to ceftazidime at ≥ 32 mg / L. Thus, the concentration of 4 mg / L ceftazidime corresponded to 1 / 8 of the MIC of the isolate. This fell within the dosage guidance recommended by EUCAST (European Committee on Antimicrobial Susceptibility Testing). EUCAST compiled a breakpoint table for the interpretation of MICs and zone diameters, see for example version 12.

[0276] Comparative Example 1: Indifference of ceftazidime, fosfomycin, and zidovudine

[0277] In the tests outlined above, the triple combination of ceftazidime, fosfomycin, and zidovudine was tested. Ceftazidime at 4 mg / L was the backbone and the combination was tested against ESBL Escherichia coli. In each experiment, the highest concentration was equal to 1xMIC of the test isolate but this failed to inhibit growth. The following concentrations of zidovudine (AZT - x - axis) and fosfomycin (fosfo - y - axis) were used.

[0278]

[0279]

[0280] The results reported in the above table were OD600 values determined as described herein.

[0281] ΣFIC was calculated in the same manner as in Example 3 shown below. ΣFIC for Comparative Example 1 = 3 and FIC = 2. Thus, the combination of ceftazidime, fosfomycin, and zidovudine was indifferent or antagonistic to ESBL Escherichia coli.

[0282] The bold values in the above table (and similarly in the corresponding tables of subsequent examples) represent bacterial growth and are considered to represent ineffective killing of bacteria (i.e., lack of synergy).

[0283] Comparative Example 2: Indifference between ceftazidime, meropenem, and zidovudine

[0284] The method and the strain were the same as in Comparative Example 1. The effect of the combination was tested with ceftazidime at 4 mg / L as the backbone. The same trend as in Comparative Example 1 was observed.

[0285]

[0286] The results reported in the above table are reported as OD600 values measured as described herein.

[0287] The MICs of each drug alone and in combination were also calculated in the same manner as in Example 3. ΣFIC = 3 and FIC = 2 indicate no or antagonistic effects between the three antimicrobial agents.

[0288] Example 3: Synergistic effect between ceftazidime, zidovudine, and doxycycline

[0289] The method and strain were the same as in Comparative Examples 1 and 2. Using 4 mg / L of ceftazidime as the backbone, the effect of the combination of the present invention was tested. The following concentrations (mg / L) of AZT (zidovudine - x-axis) and doxycycline (doxy - y-axis) were used:

[0290]

[0291]

[0292] The results reported in the above table are reported as OD600 values measured as described herein.

[0293] The MICs of each drug alone and in combination were calculated in the same manner as in Comparative Example 1. ΣFIC = 0.75 and FIC = 0.5. Contrary to Examples 1 and 2, this indicates borderline synergistic effect.

[0294]

[0295] Example 4: Synergistic effect between ceftazidime, zidovudine, and rifampicin

[0296] The method and strain were the same as in Comparative Examples 1 and 2. Using 4 mg / L of ceftazidime as the backbone, the effect of the combination of the present invention was tested. The following concentrations (mg / L) of zidovudine (AZT - x-axis) and rifampicin (Rif - y-axis) were used:

[0297]

[0298] The results reported in the above table are reported as OD600 values measured as described herein.

[0299] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.75 and FIC = 0.5, which indicates borderline synergistic effect.

[0300] Example 5: Synergistic effect between ceftazidime, zidovudine, and colistin

[0301] The method and strain were the same as in Comparative Examples 1 and 2. Ceftazidime at 4 mg / L was used as the backbone to test the effect of the combinations of the present invention. Zidovudine (AZT - x - axis) and colistin (CSS - y - axis) were used at the following concentrations (mg / L):

[0302]

[0303] The results reported in the above table were reported as OD600 values measured as described herein.

[0304] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.65625 and FIC = 0.4375, indicating synergy.

[0305] Comparative Examples 1 and 2 vs. Examples 3 to 5 support the general understanding in the art that synergy is unpredictable or unforeseeable. Although ceftazidime and zidovudine may be a potent combination against (M)DR Gram - negative bacteria (illustrated herein with ESBL - producing E. coli as an example), they did not exemplify synergy when combined with any third antimicrobial agent. Synergy was only observed when ceftazidime and zidovudine were combined with doxycycline, levofloxacin, rifampin, and colistin / polymyxin E.

[0306] As shown in each of Examples 3 to 5, synergy is particularly difficult to predict at concentrations below the MIC or against (M)DR bacteria (ESBL - producing E. coli); this means that the combination represents an important advance in combating antimicrobial resistance. Surprisingly, they were successfully against bacteria found to have the enzyme (ESBL) in the strain, which are known not to be killed by many antibiotics that would be used by those skilled in the art to treat infections.

[0307] Example 6: Synergy between ceftazidime, doxycycline, and meropenem

[0308] The backbone in Example 6 was ceftazidime at 1 mg / L. The isolate in this example was resistant to cephalosporins and to ceftazidime at ≥32 mg / L. Thus, a concentration of 1 mg / L of ceftazidime was equivalent to 1 / 16 of the MIC of this isolate.

[0309] The method and strain were the same as in Comparative Example 1. The effect of the combinations of the present invention was tested with 1 mg / L ceftazidime as the backbone. Doxycycline (x - axis) and meropenem (y - axis) were tested at the following concentrations (mg / L):

[0310]

[0311]

[0312] The results reported in the above table are reported as OD600 values measured as described herein.

[0313] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.438 and FIC = 0.2917, indicating synergy.

[0314] Example 7: Synergy of ceftazidime, doxycycline, and fosfomycin

[0315] The method was the same as in Comparative Example 1. The effect of the combination of the present invention was assayed using 0.5 mg / L ceftazidime as the backbone against Klebsiella pneumoniae CPE. The isolates in this example were resistant to cephalosporins and to 4 mg / L ceftazidime. Thus, a ceftazidime concentration of 0.5 mg / L was equivalent to 1 / 8 of the MIC of this isolate. The following concentrations (mg / L) of doxycycline (doxy - y - axis) and fosfomycin (Fosfo - x - axis) were tested:

[0316]

[0317] The results reported in the above table are reported as OD600 values measured as described herein.

[0318] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.630 and FIC = 0.42, indicating synergy.

[0319] Example 8: Synergy between ceftazidime, doxycycline, and levofloxacin

[0320] The method and the strain were the same as in Comparative Example 1. The effect of the combination of the present invention was assayed using 2 mg / L (i.e., 1 / 8 MIC) of ceftazidime as the backbone. The following concentrations (mg / L) of doxycycline (x - axis) and levofloxacin (y - axis) were tested:

[0321]

[0322]

[0323] The results reported in the above table are reported as OD600 values measured as described herein.

[0324] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.590 and FIC = 0.393, indicating synergy.

[0325] Example 9: Synergy of ceftazidime, rifampicin, and fosfomycin

[0326] This method is the same as Comparative Example 1. Ceftazidime at 0.5 mg / L was used as the backbone to test the effect of the combination of the present invention against Klebsiella pneumoniae CPE. A ceftazidime concentration of 0.5 mg / L is equivalent to 1 / 8 MIC of the test isolate. The following concentrations (mg / L) of fosfomycin (x-axis) and rifampicin (y-axis) were tested:

[0327]

[0328] The results reported in the above table were reported as OD600 values measured as described herein.

[0329] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.354 and FIC = 0.236, indicating synergy.

[0330] Example 10: Synergy between colistin, doxycycline, and rifampicin

[0331] The backbone of Example 10 was colistin at 0.25 mg / L. This is equivalent to 1 / 8 MIC of the test isolate (the method and strain were the same as in Comparative Example 1). The following concentrations (mg / L) of doxycycline (x-axis) and rifampicin (y-axis) were tested:

[0332]

[0333]

[0334] The results reported in the above table were reported as OD600 values measured as described herein.

[0335] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.146 and FIC = 0.0973, indicating synergy.

[0336] Example 11: Synergy between colistin, fosfomycin, and gentamicin

[0337] The backbone of Example 11 was colistin at 0.5 mg / L. The isolate in this example was Klebsiella pneumoniae CPE and was resistant to ≥ 8 mg / L of colistin. Therefore, a colistin concentration of 0.5 mg / L was equivalent to 1 / 16 of the MIC. The method was the same as in Comparative Example 1.

[0338] The following concentrations (mg / L) of fosfomycin (x-axis) and gentamicin (y-axis) were tested:

[0339]

[0340] The results reported in the above table were reported as OD600 values measured as described herein.

[0341] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.625 and FIC = 0.417, indicating synergy.

[0342] Example 12: Synergy between colistin, fosfomycin, and levofloxacin

[0343] The method and strain were the same as in Example 11. The effect of the combinations of the present invention was tested with 0.5 mg / L colistin as the backbone. This corresponds to 1 / 16 MIC of this isolate. The following concentrations (mg / L) of fosfomycin (Fosfo - y - axis) and levofloxacin (x - axis) were tested:

[0344]

[0345] The results reported in the above table were reported as OD600 values determined as described herein.

[0346] The MICs of each drug alone and in combination were calculated in the same manner as in Example 3. ΣFIC = 0.615 and FIC = 0.417, indicating synergy.

[0347] Example 13: Synergy between zidovudine, colistin, meropenem, and ceftazidime

[0348] The method was the same as in Comparative Example 1, except that the isolate was Pseudomonas aeruginosa. This isolate was resistant to ceftazidime up to at least 512 mg / L, colistin up to at least 512 mg / L, fosfomycin up to and including 64 mg / L, meropenem up to and including 64 mg / L, and AZT up to at least 512 mg / L. The effect of the combinations of the present invention was tested with 2 mg / L colistin and 1 mg / L ceftazidime as the backbone. This corresponds to 1 / 256 MIC of colistin and 1 / 512 MIC of ceftazidime for this isolate. The following concentrations (mg / L) of meropenem and zidovudine (AZT) were tested:

[0349]

[0350] The results reported in the above table were reported as the percentage of bacteria killed values based on OD600 values relative to the positive control.

[0351]

[0352] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.0703 and FIC = 0.0352, indicating synergy.

[0353] Example 14: Synergy between zidovudine, colistin, meropenem, and fosfomycin

[0354] This method was the same as Comparative Example 1. The isolate was Pseudomonas aeruginosa and was the same as in Example 13. The effect of the combination of the present invention was tested with 4 mg / L of zidovudine and 4 mg / L of meropenem as the backbone. This corresponded to 1 / 128 MIC of zidovudine and 1 / 8 MIC of meropenem for this isolate. The following concentrations (mg / L) of fosfomycin (y-axis) and colistin (x-axis) were tested:

[0355]

[0356] The results reported in the above table were reported as the percentage of bacteria killed based on the OD600 value relative to the positive control.

[0357]

[0358] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.205 and FIC = 0.103, which indicated synergy.

[0359] Example 15: Synergy between zidovudine (AZT), colistin (CSS), and fosfomycin (fosfo)

[0360] This method was the same as Comparative Example 1. The isolate was Acinetobacter baumannii. This isolate was resistant to up to at least 512 mg / L of ceftazidime, up to and including 64 mg / L of colistin, up to and including 128 mg / L of fosfomycin, up to and including 128 mg / L of meropenem, and resistant to up to at least 512 mg / L of zidovudine. The effect of the combination of the present invention was tested with 32 mg / L of fosfomycin as the backbone. This corresponded to 1 / 8 MIC of this isolate. The following concentrations (mg / L) of zidovudine (x-axis) and colistin (y-axis) were tested:

[0361]

[0362] The results reported in the above table were reported as the percentage of bacteria killed based on the OD600 value relative to the positive control.

[0363]

[0364] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.130 and FIC = 0.0866, which indicated synergy.

[0365] The combination of zidovudine, colistin, and fosfomycin was also tested against a Pseudomonas aeruginosa isolate, with 16 mg / L of fosfomycin as the backbone. This isolate was the same as that in Example 13. The fosfomycin concentration was equivalent to 1 / 8 MIC of this isolate. The following concentrations (mg / L) of zidovudine (x-axis) and colistin (y-axis) were tested:

[0366]

[0367] The results reported in the above table were reported as the percentage of bacterial killing based on the OD600 value relative to the positive control.

[0368]

[0369] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.127 and FIC = 0.846, indicating synergy.

[0370] Example 16: Synergy between zidovudine (AZT), ceftazidime (ceft), and meropenem (mero)

[0371] The method was the same as that in Comparative Example 1. The isolate was Pseudomonas aeruginosa, the same as that in Example 13. The effect of the combination of the present invention was tested with 4 mg / L of meropenem as the backbone. This was equivalent to 1 / 8 MIC of this isolate. The following concentrations (mg / L) of ceftazidime (x-axis) and zidovudine (y-axis) were tested:

[0372]

[0373]

[0374] The results reported in the above table were reported as the percentage of bacterial killing based on the OD600 value relative to the positive control.

[0375]

[0376] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.142 and FIC = 0.0944, indicating synergy.

[0377] Example 17: Synergy between zidovudine (AZT), colistin (CSS), and ceftazidime (ceft)

[0378] The method was the same as that in Comparative Example 1. The isolate was Acinetobacter baumannii, the same as that in Example 15. The effect of the combination of the present invention was tested with 32 mg / L of ceftazidime as the backbone. This was equivalent to 1 / 16 MIC of this isolate. The following concentrations (mg / L) of colistin (x-axis) and zidovudine (y-axis) were tested:

[0379]

[0380] The results reported in the above table are reported as the percentage value of bacterial killing based on the OD600 value relative to the positive control.

[0381]

[0382] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.320 and FIC = 0.214, which indicate synergistic effect.

[0383] The combination of zidovudine, colistin and ceftazidime was also tested against Pseudomonas aeruginosa, with 4 mg / L of colistin as the backbone. This corresponds to 1 / 128 MIC of this isolate. This isolate is the same as that in Example 13. The following concentrations (mg / L) of ceftazidime (x-axis) and zidovudine (y-axis) were tested:

[0384]

[0385] The results reported in the above table are reported as the percentage value of bacterial killing based on the OD600 value relative to the positive control.

[0386]

[0387] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.0137 and FIC = 0.00912, which indicate synergistic effect.

[0388] Example 18: Synergistic effect between ceftazidime (ceft), levofloxacin (levo) and fosfomycin (fosfo)

[0389] The method is the same as that in Comparative Example 1. This isolate is methicillin-resistant Staphylococcus aureus (MRSA). The effect of the combination of the present invention was tested with 2 mg / L of fosfomycin as the backbone. This corresponds to 1 / 8 MIC of this isolate. The following concentrations (mg / L) of ceftazidime (x-axis) and levofloxacin (y-axis) were tested:

[0390]

[0391] The results reported in the above table are reported as the percentage value of bacterial killing based on the OD600 value relative to the positive control.

[0392]

[0393] The MICs of each drug alone and in combination were calculated as shown above. ΣFIC = 0.75 and FIC = 0.5, which indicate synergistic effect.

[0394] Example 19: Synergy between Ceftazidime (ceft), Levofloxacin (levo) and Meropenem (mero)

[0395] This method was the same as Comparative Example 1. The isolate was MRSA (the same as in Example 18). 4 mg / L meropenem was used as the backbone to test the effect of the combinations of the present invention. This corresponds to 1 / 8 MIC of this isolate. The following concentrations (mg / L) of ceftazidime (x-axis) and levofloxacin (y-axis) were tested:

[0396]

[0397] The results reported in the table above were reported as the percentage value of bacterial killing based on the OD600 value relative to the positive control.

[0398]

[0399] The MICs of the individual drugs and the combinations were calculated as shown above. ΣFIC = 0.406 and FIC = 0.271, which indicates synergy.

[0400] The examples support that the combinations of the present invention have synergy. When combining antimicrobial agents, synergy is not an expected result, and especially when combining three or more antimicrobial agents and / or against multi-drug resistant bacteria (such as ESBL and CPE strains) or among ESKAPE pathogens, synergy is undoubtedly not an expected result. The examples support that the combinations of the present invention have synergy against drug-resistant bacteria, including ESKAPE pathogens, and thus provide a solution to the global antimicrobial resistance problem discussed above. This is a significant advancement in the art. The various embodiments described herein are presented only to assist in understanding and teaching the claimed features. These embodiments are provided only as representative samples of embodiments and are not exhaustive and / or exclusive. It should be understood that the advantages, embodiments, examples, functions, features, structures, and / or other aspects described herein should not be considered as limitations on the scope of the invention defined by the claims or on equivalents of the claims, and that other embodiments may be used and modifications may be made without departing from the scope of the claimed invention. The various embodiments of the present invention may suitably comprise, consist of, or consist essentially of a suitable combination of the disclosed elements, components, features, parts, steps, devices, etc., in addition to those specifically described herein. Furthermore, the present disclosure may include other inventions that are not currently claimed but may be claimed in the future.

Claims

1. An antimicrobial combination comprising three antimicrobial agents, wherein: i. The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; ii. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and iii. The third antimicrobial agent is selected from levofloxacin, doxycycline, fosfomycin, meropenem, rifampicin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof; wherein the first, second, and third antimicrobial agents in the combination are different from each other; wherein the combination comprises at least one of levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; provided that the combination is not (1)(i) polymyxin E / B, (ii) zidovudine, and (iii) rifampicin or (2)(i) ceftazidime, (ii) zidovudine, and (iii) fosfomycin.

2. The combination according to claim 1, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof.

3. The combination according to claim 1 or claim 2, wherein the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof.

4. The combination according to any one of claims 1 to 3, wherein the third antimicrobial agent is selected from levofloxacin, doxycycline, rifampicin, polymyxin E, and pharmaceutically acceptable derivatives thereof, preferably wherein the third antimicrobial agent is selected from doxycycline, rifampicin, polymyxin E, and pharmaceutically acceptable derivatives thereof.

5. The combination according to claim 1 or claim 2, wherein the second antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof.

6. The combination according to any one of claims 1, 2, or 5, wherein the third antimicrobial agent is rifampicin, doxycycline, or a pharmaceutically acceptable derivative thereof.

7. The combination according to claim 1 or claim 2, wherein the second antimicrobial agent is doxycycline or a pharmaceutically acceptable derivative thereof.

8. The combination according to any one of claims 1, 2, or 7, wherein the third antimicrobial agent is meropenem, levofloxacin, or a pharmaceutically acceptable derivative thereof.

9. The combination according to claim 1, wherein the first antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is doxycycline or a pharmaceutically acceptable derivative thereof, and the third antimicrobial agent is rifampicin or a pharmaceutically acceptable derivative thereof, or wherein the first antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, and the third antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof.

10. An antimicrobial combination comprising three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof.

11. The combination according to claim 1 or claim 10, wherein the combination includes a fourth antimicrobial agent which is a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

12. The combination according to claim 11, wherein the first antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof, the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof, the third antimicrobial agent is fosfomycin or a pharmaceutically acceptable derivative thereof, and the fourth antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

13. The combination according to claim 11, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; the third antimicrobial agent is polymyxin E / B or a pharmaceutically acceptable derivative thereof, and the fourth antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

14. An antimicrobial combination comprising three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof.

15. The combination according to any one of claims 1, 4, and 9 to 14, wherein the pharmaceutically acceptable derivative of polymyxin E is colistin sulfate, colistin mesylate, or colistin mesylate sodium.

16. The combination according to any one of claims 1 to 15 for the treatment of infections caused by Gram-negative bacteria or Gram-positive bacteria.

17. A pharmaceutical composition comprising the combination according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient, diluent, or carrier, the pharmaceutical composition being preferably for the treatment of infections caused by Gram-negative bacteria or Gram-positive bacteria.

18. The combination for use according to claim 16, or the pharmaceutical composition for use according to claim 17, wherein the infection is a urinary tract infection, skin and soft tissue infection, intra-abdominal infection, upper respiratory tract infection, pneumonia, or bloodstream infection.

19. The combination for use according to claim 16 or claim 18, or the pharmaceutical composition for use according to claim 17 or claim 18, wherein the infection is caused by Enterobacteriaceae, Acinetobacter, Pseudomonas, or Staphylococcus.

20. The combination for use or pharmaceutical composition for use according to claim 19, wherein the infection is caused by Escherichia coli or Klebsiella pneumoniae or Acinetobacter baumannii or Pseudomonas aeruginosa or MRSA.

21. The combination for use according to claim 16 or any one of claims 17 to 20, or the pharmaceutical composition for use according to any one of claims 17 to 20, wherein the infection is caused by a drug-resistant strain of bacteria.

22. A product comprising an antimicrobial combination of three antimicrobial agents, wherein: i. The first antimicrobial agent is selected from ceftazidime, polymyxin E, polymyxin B, and pharmaceutically acceptable derivatives thereof; ii. The second antimicrobial agent is selected from zidovudine, doxycycline, fosfomycin, and pharmaceutically acceptable derivatives thereof; and iii. The third antimicrobial agent is selected from levofloxacin, doxycycline, meropenem, rifampicin, fosfomycin, gentamicin, polymyxin B, polymyxin E, and pharmaceutically acceptable derivatives thereof; wherein the first, second, and third antimicrobial agents are different from each other in the combination; wherein the combination comprises at least levofloxacin, doxycycline, rifampicin, fosfomycin, or a pharmaceutically acceptable derivative thereof; provided that the combination is not (1) polymyxin E / B, zidovudine, and rifampicin or (2) ceftazidime, zidovudine, and fosfomycin; the product as a combined preparation for use simultaneously, separately, or sequentially for treating infections caused by Gram-negative bacteria or Gram-positive bacteria.

23. A product comprising an antimicrobial combination of three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is polymyxin E or a pharmaceutically acceptable derivative thereof, the product as a combined preparation for use simultaneously, separately, or sequentially for treating infections caused by Gram-negative bacteria or Gram-positive bacteria.

24. The product according to claim 22 or 23, wherein the combination comprises a fourth antimicrobial agent, the fourth antimicrobial agent being a carbapenem or a pharmaceutically acceptable derivative thereof, preferably meropenem or a pharmaceutically acceptable derivative thereof.

25. A product comprising an antimicrobial combination of three antimicrobial agents, wherein the first antimicrobial agent is ceftazidime or a pharmaceutically acceptable derivative thereof; the second antimicrobial agent is zidovudine, levofloxacin, or a pharmaceutically acceptable derivative thereof; and the third antimicrobial agent is meropenem or a pharmaceutically acceptable derivative thereof, the product as a combined preparation for use simultaneously, separately, or sequentially for treating infections caused by Gram-negative bacteria or Gram-positive bacteria.

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