Combination of zidovudine and fluoroquinolone antibiotic

Abstract

To provide a combination of two active agents that reactivates specific urinary tract antibiotics in which bacterial resistance has occurred.SOLUTION: Provided is a combination comprising zidovudine or a pharmaceutically acceptable derivative thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof for use in treating a microbial infection, particularly a bacterial infection such as a urinary tract infection.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a combination of zidovudine or a pharmaceutically acceptable derivative thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof selected from the group defined herein for use in the treatment of microbial infections. In particular, the invention relates to the use of such a combination to kill vegetative (i.e., log-phase) microorganisms associated with microbial infections, such as gram-negative bacterial infections, such as urinary tract infections. [Background technology]

[0002] Before the introduction of antibiotics, patients suffering from acute microbial infections (e.g., tuberculosis or pneumonia) had a poor chance of survival. For example, the mortality rate from tuberculosis was approximately 50%. This situation changed rapidly with the introduction of antimicrobial drugs in the 1940s and 1950s, but bacteria responded by gradually developing resistance to commonly used antibiotics. Antibiotic-resistant bacteria are now found in every country in the world.

[0003] In fact, over 70% of bacteria causing hospital-acquired infections in the United States are resistant to at least one of the major antimicrobial agents typically used to fight infection (Nature Reviews, Drug Discovery, 1, 895-910(2002)). Therefore, the World Health Organization has classified antimicrobial resistance as "a serious threat that is no longer a future prediction but is occurring now in every region of the world, potentially affecting people of all ages, in every country" ("Antimicrobial resistance: global report on surveillance", The World Health Organization, April 2014).

[0004] One group of antibiotics facing significant resistance problems are compounds used to treat urinary tract infections (UTIs), specifically urogenital infections. A recent report from Public Health England noted that antimicrobial resistance was common in over one million urinary tract infections caused by bacteria identified by NHS laboratories in 2016 (<<English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR)> >(2017)).

[0005] Therefore, there is a desperate need for a solution to the growing problem of resistant bacteria causing urinary tract infections.

[0006] UTIs are often treated with a short course of oral antibiotics. Fluoroquinolones are often used to treat urogenital infections and are widely used to treat hospital-acquired infections associated with urinary catheters. One example of a fluoroquinolone is ciprofloxacin, one of the most widely used antibiotics worldwide. However, resistance to fluoroquinolones can evolve rapidly, even during treatment, and many pathogens, including Escherichia coli, commonly exhibit resistance.

[0007] Surprisingly, and of great importance to combating antimicrobial resistance in the treatment of urinary tract infections, Applicants have discovered that the antiretroviral drug zidovudine has a synergistic effect with fluoroquinolone antibiotics - in other words, the combination has a bioactivity that is greater than the expected additive effect of each drug at the dosage levels described.

[0008] Zidovudine (AZT) is a nucleoside-related reverse transcriptase inhibitor and a type of antiretroviral drug used to treat HIV / AIDS infection. In addition to its antiretroviral activity, the antibacterial effects of AZT have been demonstrated both in vitro and in vivo using experimental models of Gram-negative bacterial infection (Hermann et al., Antimicrob Agents Chemther. 1992 May; 36(5): 1081-1085). It has also been reported that zidovudine is active as an antimicrobial agent when combined with the antibiotic gentamicin (Doleans-Jordheim A. et al., Eur J Clin Microbiol Infect Dis. 2011 Oct; 30(10): 1249-56).

[0009] WO2014 / 147405 describes the use of zidovudine in combination with a polymyxin selected from colistin and polymyxin B to treat microbial infections. WO2015 / 114340 describes the use of zidovudine in combination with a polymyxin selected from colistin or polymyxin B; an antituberculosis antibiotic selected from rifampicin, rifapentine, or rifabutin; and optionally piperine to treat microbial infections. WO2018 / 011562 describes combinations comprising zidovudine and a carbapenem, optionally comprising a polymyxin selected from polymyxin B and polymyxin E.

[0010] However, when two active agents are used in combination, a synergistic effect cannot be predicted or expected. Accordingly, the present invention is based on the unexpected finding that zidovudine, or a pharmaceutically acceptable derivative thereof, when used in combination with a fluoroquinolone antibiotic, or a pharmaceutically acceptable derivative or prodrug thereof, exhibits synergistic antimicrobial activity against log-phase (i.e., vegetative) microorganisms. In particular, synergistic effects are seen when the combination is used against Gram-negative bacteria.

[0011] The surprising bioactivity of the combination of the present invention provides an opportunity to reactivate certain urinary tract antibiotics to which bacterial resistance has developed.

[0012] Synergy in the context of antimicrobial agents is measured in many ways, following the commonly accepted view that "synergy is an effect greater than additive." One way to assess whether synergy is observed is to use the "checkerboard" technique, an accepted method that generates a value called the fractional inhibitory concentration index (FICI). Orhan et al., J. Clin. Microbiol. 2005, 43(1):140, describes the checkerboard method and analysis in paragraphs 140-141, explaining that the FICI value is the ratio of the sum of the MIC (minimum inhibitory concentration) levels of each individual component alone and in the mixture. The combination is considered synergistic if the ΣFIC is ≦0.5, indifferent if the ΣFIC is >0.5 but <4.0, and antagonistic if the ΣFIC is >4.0.

[0013] Another accepted test for determining whether synergy exists is to use the time-kill method. In this method, the dynamic effect of a drug combination is compared to each drug alone when assessing the effect on logarithmic or static growth of bacteria over time. Again, possible results are in terms of synergy, additive effects, or antagonism. Summary of the Invention

[0014] In one aspect, the present invention provides a combination of zidovudine or a pharmaceutically acceptable derivative thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof for use in treating a microbial infection. In various embodiments of the present invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0015] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0016] In another aspect, the invention provides the use of zidovudine or a pharmaceutically acceptable derivative thereof in combination with a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof in the manufacture of a medicament for treating a microbial infection. In various embodiments of the invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0017] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0018] In another aspect, the invention provides the use of a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof in combination with zidovudine or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for treating a microbial infection. In various embodiments of the invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0019] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0020] In a further aspect, the present invention provides a method for treating a microbial infection comprising administering to a mammal, such as a human, zidovudine or a pharmaceutically acceptable derivative thereof in combination with a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof. In various embodiments of the present invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0021] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0022] Also provided is a pharmaceutical composition comprising a combination of zidovudine or a pharmaceutically acceptable derivative thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier, for use in treating a microbial infection, preferably wherein the microbial infection is a bacterial infection, e.g., a Gram-negative bacterial infection. In various embodiments of the invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0023] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0024] In a further aspect, the present invention relates to a product comprising zidovudine or a pharmaceutically acceptable derivative thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable derivative or prodrug thereof as a combined agent for simultaneous, separate, or sequential use in killing vegetative microorganisms associated with a microbial infection, preferably for killing vegetative bacteria associated with a bacterial infection, e.g., a Gram-negative bacterial infection. In various embodiments of the present invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0025] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. [Brief explanation of the drawings]

[0026] Having thus described aspects of the present disclosure in the foregoing general terms, reference is now made to the accompanying drawings, which are not necessarily drawn to scale, and which are merely illustrative and are not to be construed as limiting the disclosure.

[0027] [Figure 1] 1 is a checkerboard from Example 4 showing a synergy test of AZT and levofloxacin using the Escherichia coli broth microdilution checkerboard method with a 100% readout standard. The shaded areas indicate growth wells, and the thick border indicates the expected growth area. Compound concentrations (in mg / L) are shown in the top row and left column of wells, and ΣFIC values ​​are shown in bold. ΣFICmin: 0.25 at H6 (synergy). ΣFICmax: 2.00 at D12 (indifference). [Figure 2] 1 is a checkerboard from Example 4 showing a synergy test of AZT and levofloxacin using the Escherichia coli broth microdilution checkerboard method with a 100% readout standard. The shaded areas indicate growth wells, and the thick border indicates the expected growth area. Compound concentrations (in mg / L) are shown in the top row and left column of wells, and ΣFIC values ​​are shown in bold. ΣFICmin: 0.28 at H9 (synergy). ΣFICmax: 0.63 at D10 and D8. [Figure 3] 1 is a checkerboard from Example 4 showing a synergy test of AZT and levofloxacin using the Klebsiella broth microdilution checkerboard method with a 100% readout criterion. The shaded areas indicate growth wells, and the thick border indicates the expected growth area. Compound concentrations (in mg / L) are shown in the top row and left column of wells, and ΣFIC values ​​are shown in bold. ΣFICmin: 0.38 (synergy) for G8. ΣFICmax: 0.63 for H6. [Figure 4]1 is a checkerboard from Example 4 showing synergy testing of AZT and levofloxacin using the broth microdilution checkerboard method for Klebsiella pneumoniae using a 100% readout criterion. The shaded areas indicate growth wells, and the thick border indicates the expected growth area. Compound concentrations (in mg / L) are shown in the top row and left column of wells, and ΣFIC values ​​are shown in bold. ΣFICmin: 0.31 (synergy) at H8. ΣFICmax: 1.06 at D10. [Figure 5] 1 is a checkerboard from Example 4 showing a synergy test of AZT and levofloxacin using the broth microdilution checkerboard method for Klebsiella pneumoniae using a 100% readout criterion. The shaded areas indicate growth wells, and the thick border indicates the expected growth area. Compound concentrations (in mg / L) are shown in the top row and left column of wells, and ΣFIC values ​​are shown in bold. ΣFICmin: 0.38 (synergy) at F5. ΣFICmax: 1.02 (indifference) at D8. DETAILED DESCRIPTION OF THE INVENTION

[0028] As used herein, the terms "combination of" and "in combination with" are intended to encompass separate, sequential, and simultaneous administration of agents. Unless otherwise specified, the terms are also intended to exclude additional active agents; for example, "a combination of zidovudine and ciprofloxacin" means that zidovudine and ciprofloxacin are administered separately, sequentially, or simultaneously, but no other active agent is administered.

[0029] When the agents are administered sequentially, either zidovudine or the fluoroquinolone antibiotic can be administered first. When administered simultaneously, the agents can be administered in the same or different pharmaceutical compositions. Adjunctive therapy, i.e., one agent is used as the primary treatment and the other agent is used to support the primary treatment, is also an embodiment of the present invention.

[0030] The combination of the present invention can be used to treat microbial infections. In particular, it can be used to kill vegetative and / or clinically latent microorganisms associated with microbial infections, preferably vegetative microorganisms associated with microbial infections, such as vegetative bacteria associated with Gram-negative bacterial infections. Thus, when referring to the treatment of microbial infections herein, it includes killing vegetative and / or clinically latent microorganisms associated with such infections.

[0031] As used herein, "kill" means loss of viability as assessed by lack of metabolic activity.

[0032] As used herein, "clinically latent microorganism" refers to a microorganism that is metabolically active but has a growth rate below the threshold for infectious disease manifestation, which refers to the growth rate threshold below which there are no symptoms of infectious disease in the host.

[0033] The metabolic activity of clinically latent microorganisms can be measured by several methods known to those skilled in the art, for example by measuring the mRNA level in the microorganisms or by measuring the uridine incorporation rate of the microorganisms. In this respect, clinically latent microorganisms exhibit a lower, but still significant, metabolic activity compared to microorganisms under logarithmic growth conditions (in vitro or in vivo). (I) mRNA levels (e.g., 0.0001 to 50%, e.g., 1 to 30%, 5 to 25%, or 10 to 20% of the mRNA levels); and / or (II) Uridine (e.g., [ 3 H]uridine) incorporation levels (e.g., [ 3 0.0005 to 50%, e.g., 1 to 40%, 15 to 35%, or 20 to 30% of the level of [H]uridine incorporation) It has.

[0034] Clinically latent microorganisms typically have many distinguishing characteristics. For example, they may be viable but non-culturable; that is, the microorganisms are usually undetectable by standard culture techniques, but are detectable and quantifiable by techniques such as broth dilution counting, microscopy, or molecular techniques such as polymerase chain reaction. Furthermore, clinically latent microorganisms are phenotypically resistant and therefore susceptible (in log phase) to the bacteriostatic effects of conventional antimicrobial agents (i.e., microorganisms for which the minimum inhibitory concentration (MIC) of a conventional antimicrobial agent remains substantially unchanged), but are significantly reduced in susceptibility to drug-induced killing (e.g., microorganisms for which the ratio of minimum bactericidal concentration (e.g., minimum bactericidal concentration, MBC) to MIC is 10 or greater for any given conventional antimicrobial agent).

[0035] As used herein, the term "microbial" refers to fungi and bacteria. References herein to "microbial," "antimicrobial," or "antimicrobially" are to be construed accordingly. For example, the term "microbial" means "fungal" or "bacterial," and "microbial infection" refers to a fungal infection or a bacterial infection.

[0036] In various embodiments of the invention, one or more of the above combinations are used to treat bacterial infections, and in particular, the combinations can be used to kill vegetative and / or clinically latent microorganisms associated with bacterial infections, preferably vegetative bacteria associated with bacterial infections. As used herein, the term "bacteria" (and derivatives thereof, such as "microbial infection") includes, but is not limited to, reference to the following classifications and specific types of organisms (or infections by organisms):

[0037] Gram-positive cocci, for example, Staphylococci (e.g., Staph. aureus, Staph. epidermidis, Staph. saprophyticus, Staph. auricularis, Staph. capitis capitis, Staph. c. ureolyticus, Staph. caprae, Staph. cohnii cohnii, Staph. c. urealyticus, Staph. aequorum, Staph. Staphylococcus equorum, Staphylococcus gallinarum, Staphylococcus haemolyticus, Staphylococcus hominis hominis, Staphylococcus h. novobiosepticius, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pasteuri, Staphylococcus saccharolyticus, Staphylococcus schleiferi schleiferi Staphylococcus schleiferi, Staphylococcus schleiferi coagulans, Staphylococcus sciuri, Staphylococcus simulans, Staphylococcus warneri, and Staphylococcus xylosus.xylosus, Streptococci (e.g., β-hemolytic Streptococcus pyogenes (Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae dysgalactiae, Streptococcus dysgalactiae equisimilis, Streptococcus equi equi, Streptococcus equi zooepidemicus, Streptococcus iniae, Streptococcus porcinus, and Streptococcus pyogenes) pyogenes), microaerophilic pyogenic streptococci (Streptococcus "milleri", e.g., Streptococcus anginosus, Streptococcus constellatus constellatus, Streptococcus constellatus pharyngidis and Streptococcus intermedius), "mitis" (α-haemolytic Streptococcus "viridans", e.g., Streptococcus mitis, Streptococcus oralis, Streptococcus sanguinis, Streptococcus cristatus, etc.). cristatus, Streptococcus gordonii and Streptococcus parasanguinis), "salivarius" (non-hemolytic, e.g., Streptococcus salivarius and Streptococcus vestivelis).Oral streptococci of the group "mutans" (streptococci on the tooth surface, e.g., Streptococcus vestibularis) and "mutans" (streptococci on the tooth surface, e.g., Streptococcus criceti, Streptococcus mutans, Streptococcus ratti and Streptococcus sobrinus), Streptococcus acidominimus, Streptococcus bovis, Streptococcus faecalis, Streptococcus equinus, Streptococcus pneumoniae and Streptococcus suis. suis) or streptococci otherwise classified as group A, B, C, D, E, G, L, P, U or V streptococci); Gram-negative cocci, for example, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava and Neisseria weaveri; Bacillaceae, for example, Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis thuringiensis, Bacillus stearothermophilus, and Bacillus cereus; Enterobacteriaceae, e.g., Escherichia coli, Enterobacter (e.g., Enterobacter aerogenes, Enterobacter agglomerans, and Enterobacter cloacae), Citrobacter (e.g., Citrobacter freundii and Citrobacter divernis), Hafnia (e.g., Hafnia alvei), Erwinia (e.g., Erwinia persicinus), Morganella morganii, morganii), Salmonella (Salmonella enterica and Salmonella typhi), Shigella (e.g., Shigella dysenteriae),dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei), Klebsiella species (e.g., Klebs. pneumoniae, Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs. granulomatis, and Calymmatobacterium granulomatis) granulomatis and Klebsiella rhinoscleromatis), Proteus (e.g., Proteus mirabilis, Proteus rettgeri and Proteus vulgaris), Providencia (e.g., Providencia alcalifaciens, Providencia rettgeri and Providencia stuartii), Serratia (e.g., Serratia marcescens and Serratia liquifaciens), and Yersinia (e.g., Yersinia enterocolitica). enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis; enterococci (e.g., Enterococcus avium, Enterococcus casseliflavus, Enterococcus securorum,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. solitarius); 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 lwoffi, and Acinetobacter radioresistens); Pseudomonas spp. (e.g., Pseudomonas aeruginosa, aeruginosa), Pseudomonas maltophilia (Ps. maltophilia) (Stenotrophomonas maltophilia), Pseudomonas alcaligenes (Ps.alcaligenes, Pseudomonas chlororaphis, Pseudomonas fluorescens, Pseudomonas luteola, Pseudomonas mendocina, Pseudomonas monteilii, Pseudomonas oryzihabitans, Pseudomonas pertocinogena, Pseudomonas pseudalcaligenes, Pseudomonas putida, and Pseudomonas stutzeri; Bacteriodes fragilis fragilis; Peptococcus spp. (e.g., Peptococcus niger); Peptostreptococcus spp.; Clostridium spp. (e.g., Clostridium perfringens, Clostridium difficile, Clostridium botulinum, Clostridium tetani, Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium beijerinckii, Clostridium butyricum, Clostridium cadaveris, cadaveris, Clostridium carnis (C. carnis), Clostridium ceratum (C. celatum), Clostridium clostridioforme (C. clochlearium), Clostridium cocleatum (C. cocleatum), Clostridium fallax (C. fallax), Clostridium goni (C. ghonii), Clostridium glycolicum (C.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 putrefaciens putrefasciens, Clostridium ramosum, Clostridium septicum, Clostridium sordelii, Clostridium sphenoides, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, and Clostridium tertium; Mycoplasma species (e.g., Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma genitalium, and Mycoplasma urealyticum); Mycobacterium species (e.g., Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum)marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilumMycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium lentiflavum, Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex triplex), Mycobacteria Mycobacterium triviale, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi, and Mycobacterium xenopi; Haemophilus species (e.g., Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus spp.), Actinobacillus species (e.g., Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis, and Actinobacillus ureae); Actinomyces species (e.g., Actinomyces israelii); Brucella species (e.g., Brucella abortus, Brucella canis, Brucella canis, Brucella melintensis and Brucella suis);Campylobacter species (e.g., Campylobacter jejuni, Campylobacter coli, Campylobacter lari, and Campylobacter fetus); Listeria monocytogenes; Vibrio species (e.g., Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio holisae, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus, and Vibrio vulnificus; Erysipelothrix rhusopathiae; Corynebacterium species (e.g., Corynebacterium diphtheriae, Corynebacterium jeikeum, and Corynebacterium urealyticum);Spirochetaceae, for example the genus Borrelia (e.g., Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasiaca, 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 Treponema spp. (Treponema pallidum ssp. pallidum, Treponema pallidum ssp. endemicum, Treponema pallidum ssp. pertenue and Treponema carateum);Pasteurella species (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) stomatis); Bordetella genus (e.g., Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum); Nocardiaceae family, for example, Nocardia genus (e.g., Nocardia asteroides and Nocardia brasiliensis); Rickettsia genus (e.g., Ricksettsii or Coxiella burnetii);Legionella species (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 longbice) longbeachae, Legionella maceachernii, Legionella micdadei, Legionella oakridgensis, Legionella pneumophila, Legionella sainthelensi, Legionella tucsonensis, and Legionella wadsworthii; Moraxella catarrhalis; Cyclospora cayetanensis; Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis vaginalis); Toxoplasma gondii; Stenotrophomonas maltophilia; Burkholderia cepacia;Burkholderia mallei and Burkholderia pseudomallei; Francisella tularensis; Cardnerella spp. (e.g., Gardneralla vaginalis and Gardneralla mobiluncus); Streptobacillus moniliformis; Flavobacteriaceae, e.g., Capnocytophaga spp. (e.g., Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa ... granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea, and Capnocytophaga sputigena; Bartonella spp. (Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana, and Bartonella vinsonii arupensis);Leptospira (e.g., Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai, and Leptospira weilii); Spirillium (e.g., Spirillum minus);Bacteroides genus (e.g., Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes) pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vulgatus);Species of the genus Prevotella (e.g., Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, Prevotella nigrescens) nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis, and Prevotella zoogleoformans; Porphyromonas spp. (e.g., Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas spp.); Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levii, and Porphyromonas macacae); Fusobacterium species (e.g., Fusobacterium gonadiaformans (F. gonadiaformans, Fusobacterium mortiferum, Fusobacterium naviforme, Fusobacterium necrogenes, Fusobacterium necrophorum necrophorum, Fusobacterium necrophorum fundiliforme, Fusobacterium nucleatum nucleatum, Fusobacterium nucleatum fusiforme, Fusobacterium nucleatum polymorphum, Fusobacterium nucleatum vincentii vincentii), Fusobacterium periodonticum, Fusobacterium russii, Fusobacterium ulcerans, and Fusobacterium varium.varium); Chlamydia (e.g., Chlamydia trachomatis); Cryptosporidium (e.g., C. parvum, C. hominis, C. canis, C. felis, C. meleagridis, and C. muris); Chlamydophila (e.g., Chlamydophila abortus, (Chlamydia psittaci), Chlamydophila pneumoniae, (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittaci); Leuconostoc genus (e.g., Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides, and Leuconostoc pseudomesenteroides); Gemella genus (e.g., Gemella bergeri, Gemella haemolysans, Gemella haemolysans, Gemella morbillorum, and Gemella sanguinis); and Ureaplasma species (e.g., Ureaplasma parvum and Ureaplasma urealyticum).

[0038] Preferably, the bacterial infections treated by the combinations described herein are gram-negative infections. Particular gram-negative bacteria treatable using the combinations of the present invention include: Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g., Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g., Proteus mirabilis, Proteus rettgeri, and Proteus vulgaris); Haemophilis influenzae; Mycobacterium, such as Mycobacterium tuberculosis; and Enterobacter (e.g., Enterobacter cloacae). Preferably, the bacterium is an enterobacterium, such as Escherichia coli and Klebsiella (e.g., Klebs. pneumoniae and Klebs. oxytoca). Particularly preferred are Escherichia coli and Klebs. pneumoniae (e.g., Klebs. pneumoniae subsp. pneumoniae).

[0039] In all embodiments, the combination therapy is preferably synergistic compared to the administration of either component of the combination alone.

[0040] The combinations of the invention are particularly useful in the treatment of (multiple) drug-resistant ((M)DR) bacteria. For Enterobacteriaceae, drug resistance is most often developed against carbapenemases, i.e., carbapenemase-resistant strains and "extended-spectrum β-lactamase" (ESBL) strains, such as New Delhi metallo-β-lactamase-1 (NDM-1)-resistant Klebsiella pneumoniae and NDM-1 Escherichia coli.

[0041] It should be noted that while the claimed combinations can be initially shown to be functional in the treatment of (M)DR strains, they can subsequently be used to treat non-resistant strains. This is particularly beneficial because the primary therapy for Enterobacteriaceae, such as Escherichia coli and Klebsiella species (e.g., Klebs. pneumoniae and Klebs. oxytoca), is expensive, patent-protected antimicrobial drugs. Replacing such "prescription" drugs with "generic" antibiotic combinations would be beneficial from a therapeutic standpoint, as well as from a financial / economic standpoint at a time when governments are seeking to reduce healthcare costs.

[0042] The combinations of the present invention can be used to treat infections associated with any of the above bacterial organisms, and in particular they can be used to kill vegetative and / or clinically latent microorganisms associated with such infections, e.g., gram-negative bacterial infections.

[0043] Particular diseases treatable using the combinations of the present invention include those caused by gram-negative bacteria, such as abscesses, asthma, bacterial shigellosis, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, bone and joint infections, bronchitis (acute or chronic), brucellosis, burns, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cystic fibrosis, cystitis, nephritis, diffuse panbronchiolitis, dental caries, upper respiratory tract disease, empyema, endocarditis, endometritis, enteric typhoid, and the like. fever), enteritis, epididymitis, epiglottitis, eye infections, furuncles, Gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhea, granuloma groin, Haverhill fever, infected burns, infections after dental surgery, infections of the oral region, infections associated with prosthetic devices, intra-abdominal abscesses, Legionnaires' disease, leptospirosis, listeriosis, liver abscess, Lyme disease, lymphogranuloma venereum, mastitis, mastoiditis, meningitis and infections of the nervous system, nonspecific urethritis, ophthalmia (e.g., ophthalmia neonatorum) , osteomyelitis, otitis (e.g., otitis externa and otitis media), orchitis, pancreatitis, paronychia, pelvic peritonitis, peritonitis, peritonitis associated with appendicitis, pharyngitis, pleural effusion, pneumonia, postoperative wound infection, postoperative gas gangrene, prostatitis, pseudomembranous colitis, psittacosis, pyelonephritis, Q fever, rat-bite fever, Litter's disease, salmonellosis, salpingitis, septic arthritis, septic infection, septicemia, systemic infection, tonsillitis, trachoma, typhoid, urethritis, urinary tract infection, wound infection; or Escherichia coli These include infections caused by Klebsiella coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, and Enterobacter cloacae.

[0044] In one embodiment, the combination of the present invention is used to treat a urinary tract infection.

[0045] It will be clear that references herein to "treatment" extend to prophylaxis as well as the treatment of existing diseases or conditions.

[0046] In various embodiments, one or more of the combinations described herein are used to treat a microbial infection in a subject other than an HIV-infected subject. HIV refers to "human immunodeficiency virus." The term "other than an HIV-infected subject" means that the subject being treated has not been diagnosed with or is not infected with HIV, and that the subject is "HIV-negative." The purpose of this disclaimer is to exclude the use of fluoroquinolone antibiotics to treat bacterial infections in HIV-infected subjects receiving AZT as part of their HIV management. The present invention differs from such uses in that the combination of AZT and a fluoroquinolone is used to treat the same microbial infection, e.g., a bacterial infection.

[0047] As used herein, the term "pharmaceutically acceptable derivative" means (a) a pharmaceutically acceptable salt; and / or (b) a solvate (such as a hydrate). Pharmaceutically acceptable salts of the compounds included in the combination of the present invention include suitable acid addition or base salts thereof. A comprehensive list of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 1-19 (1977).

[0048] Suitable acid addition salts include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, 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, sucrose ... Suitable base salts include salts of the following compounds: benzoates, sebacates, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates, or terephthalates), halide salts (e.g., chlorides, bromides, or iodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chloro-benzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxyethanesulfonates, 1- or 2-naphthalenesulfonates, or 1,5-naphthalenedisulfonates), or sulfates, pyrosulfates, bisulfites, hydrogensulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, or nitrates. Suitable base salts include metal salts, such as sodium salts, calcium salts, and amine salts.

[0049] Examples include ciprofloxacin hydrochloride, ciprofloxacin hydrochloride hydrate, ciprofloxacin formamide, ciprofloxacin lactate, gatifloxacin sesquihydrate, gemifloxacin mesylate, levofloxacin hemihydrate, moxifloxacin hydrochloride, lomefloxacin hydrochloride, pefloxacin mesylate dihydrate, or besifloxacin hydrochloride.

[0050] As used herein, the term "prodrug" refers to an antimicrobial compound in which one or more groups have been modified such that the modifications are reversible upon administration to a human or mammalian subject. Such reversal is usually accomplished by enzymes naturally present in such subjects, although a second agent can be administered along with such a prodrug to effect reversal in vivo. Examples of such modifications include ester formation (e.g., any of those described above), where reversal can be effected by esterases, etc. Other such systems will be known in the art. Zidovudine, for example, is a prodrug that must be phosphorylated to its active 5'-triphosphate metabolite.

[0051] The present invention includes the use of these pharmaceutically acceptable derivatives and prodrugs.

[0052] The present invention also includes, where appropriate, all enantiomers and tautomers of the compounds. Compounds having optical properties (one or more chiral carbon atoms) or tautomeric characteristics will be identifiable to those skilled in the art. The corresponding enantiomers and / or tautomers may be isolated or prepared by methods known in the art.

[0053] Some of the compounds included in the combinations of the present invention can exist as stereoisomers and / or geometric isomers, e.g., they can have one or more asymmetric and / or geometric centers and therefore can exist in more than one stereoisomeric and / or geometric isomeric form. The present invention contemplates the use of all individual stereoisomers and geometric isomers of the inhibitors, as well as mixtures thereof. The terms used in the claims encompass these forms, provided that the appropriate functional activity is retained (though not necessarily to the same degree).

[0054] The present invention also encompasses all suitable isotopic forms of the compound or its pharmaceutically acceptable salts. An isotopic form or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F and 36 Cl. Certain isotopic forms, e.g. 3 H or 14 Incorporation of radioactive isotopes such as 1C is useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. 2 Substitution with isotopes such as H may be preferable in some circumstances due to the potential for greater metabolic stability and certain therapeutic advantages, such as increased in vivo half-life or reduced required dosage. Isotopic forms can be prepared by conventional procedures using appropriate isotopic forms of suitable reagents.

[0055] The compounds used 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, ciprofloxacin, ciprofloxacin hydrochloride, ciprofloxacin hydrochloride hydrate, ciprofloxacin formamide, ciprofloxacin lactate, gatifloxacin, gatifloxacin sesquihydrate, gemifloxacin, gemifloxacin mesylate, levofloxacin, levofloxacin hemihydrate, moxifloxacin, moxifloxacin hydrochloride, lomefloxacin, lomefloxacin hydrochloride, norfloxacin, ofloxacin, pefloxacin, pefloxacin mesylate dihydrate, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, besifloxacin hydrochloride and delafloxacin are available from, e.g., Sigma. Available from Sigma-Aldrich®.

[0056] Other commercial suppliers are known in the art.

[0057] 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 Retrovir®. It is also known as 3'-azido-3'-deoxythymidine or "AZT" and has the following chemical structure:

[0058] [ka]

[0059] Ciprofloxacin is an antibiotic used to treat many bacterial infections. It is a second-generation fluoroquinolone. These infections include, among others, bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections. It is also known as 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Ciprofloxacin is available commercially as a generic drug and under various trade names, including Cetraxal, Cilodex, Ciloxan, Cipro, and Neofloxin. Ciprofloxacin has the following chemical structure:

[0060] [ka]

[0061] Gatifloxacin is a fourth-generation fluoroquinolone antibiotic currently available only in the United States and Canada as an ophthalmic solution. Its chemical name is (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid anhydride. Gatifloxacin is related to the trade names Gatiflo, Tekin, and Zymar and has the following chemical structure:

[0062] [ka]

[0063] Gemifloxacin is most commonly used as its mesylate salt. Gemifloxacin mesylate is an oral, broad-spectrum, fourth-generation fluoroquinolone antibacterial agent used to treat acute bacterial exacerbations of chronic bronchitis and mild to moderate pneumonia. Gemifloxacin mesylate is commercially available and known under the trade name Factive. Gemifloxacin has the chemical name 7-[(4Z)-3-aminomethyl)-4-methoxyiminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and the following chemical structure:

[0064] [ka]

[0065] Levofloxacin is a third-generation fluoroquinolone antibiotic used to treat many bacterial infections, including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. It is the "levorotatory" or levo-isomer of racemic ofloxacin. It is therefore a chiral fluoroquinolone and the pure (-)-(S)-enantiomer of racemic ofloxacin.

[0066] Levofloxacin is commercially available and sold under the trade names Levaquin, Tavanic, Iquix, etc. Its chemical name is (2S)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.0]. 5,13 ]trideca-5(13),6,8,11-tetraene-11-carboxylic acid. The chemical structure of levofloxacin is shown below.

[0067] [ka]

[0068] Moxifloxacin is an antibiotic used to treat many bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It is a fourth-generation fluoroquinolone and is sold under the trade names Avelox, Vigamox, and Moxiflox. Its chemical name is 7-[(4aS,7aS)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid and has the following chemical structure:

[0069] [ka]

[0070] Lomefloxacin, sold as lomefloxacin hydrochloride under the trade names Maxaquin, Okacyn, and Uniquin, is a fluoroquinolone antibiotic used to treat bacterial infections such as bronchitis and urinary tract infections. The chemical name for lomefloxacin is 1-ethyl-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid, and it has the following structure:

[0071] [ka]

[0072] Norfloxacin is a first-generation fluoroquinolone used to treat urinary tract infections, gynecological infections, prostate inflammation, gonorrhea, and bladder infections. It is sold under the trade name Noroxin, among others, and has the chemical name 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid and the following chemical structure:

[0073] [ka]

[0074] Ofloxacin is a second-generation fluoroquinolone and a broader-spectrum analog of norfloxacin. It is active against both Gram-positive and Gram-negative bacteria and is sold under the trade names Floxin and Ocuflox, among others. Its chemical name is 7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.0]. 5,13 ]trideca-5(13),6,8,11-tetraene-11-carboxylic acid, the chemical structure of which is shown below.

[0075] [ka]

[0076] As mentioned above, levofloxacin is the levo-isomer of ofloxacin.

[0077] Pefloxacin is a synthetic, broad-spectrum fluoroquinolone antibacterial agent active against most Gram-positive and Gram-negative bacteria. Its chemical name is 1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid and has the following structure:

[0078] [ka]

[0079] Rufloxacin is a 7-fluoro-6-(4-methylpiperazin-1-yl)-10-oxo-4-thia-1-azatricyclo[7.3.1.0 5,13 ] It is also known as trideca-5(13),6,8,11-tetraene-11-carboxylic acid and has the following chemical structure:

[0080] [ka]

[0081] Balofloxacin is sold in Korea under the trade name Q-Roxin. It has the chemical name 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylamino)piperidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the following chemical structure:

[0082] [ka]

[0083] Grepafloxacin is an oral broad-spectrum fluoroquinolone also known as 1-cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid. It has the following chemical structure:

[0084] [ka]

[0085] Pazufloxacin is sold in Japan under the trade names Pasil and Pazucross. It has the chemical name (2S)-6-(1-aminocyclopropyl)-7-fluoro-2-methyl-10-oxo-4-oxa-1-azatricyclo[7.3.1.0]. 5,13 ]trideca-5(13),6,8,11-tetraene-11-carboxylic acid and has the following chemical structure:

[0086] [ka]

[0087] Sparfloxacin is indicated for the treatment of community-acquired lower respiratory tract infections and is marketed, inter alia, under the names Sparcin and Zagam. Its chemical name is 5-amino-1-cyclopropyl-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid and has the following structure:

[0088] [ka]

[0089] Sitafloxacin is a fluoroquinolone antibiotic that shows promise for the treatment of Buruli ulcer. Sitafloxacin is currently sold in Japan under the trade name Gracevit, and its chemical name is 7-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]4-oxoquinoline-3-carboxylic acid. The chemical structure of sitafloxacin is as follows:

[0090] [ka]

[0091] Besifloxacin is a fourth-generation fluoroquinolone antibiotic sold as its hydrochloride salt under the trade name Besivance. It is indicated for the treatment of bacterial conjunctivitis caused by susceptible bacteria and for the prevention of infectious complications in patients undergoing laser therapy for the treatment of cataracts. Besifloxacin has the chemical name (R)-7-(3-aminohexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and the following chemical structure:

[0092] [ka]

[0093] Delafloxacin, known by the trade name Baxdela, is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin and structure infections. Injectable forms of delafloxacin are sold as the meglumine salt of the active ingredient. Its chemical name is 1,(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid, and it has the following structure:

[0094] [ka]

[0095] Ulifloxacin is also known as 6-fluoro-1-methyl-4-oxo-7-piperazin-1-yl-1H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.

[0096] In various embodiments of the invention, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, ulifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0097] In a preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, ofloxacin, pefloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a more preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, balofloxacin, grepafloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof. In a most preferred embodiment, the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, levofloxacin, moxifloxacin, and pharmaceutically acceptable derivatives and prodrugs thereof.

[0098] The compounds for use according to the present invention can be administered as bulk substances, but are preferably provided in the form of pharmaceutical compositions. The compounds can be used as separate formulations or as a single combined formulation. When combined in the same formulation, it will be clear that the two compounds must be stable and compatible with each other and with the other components of the formulation.

[0099] The formulations of the present invention include those suitable for oral, parenteral (e.g., subcutaneous, intrathecal, intramuscular, and intravenous administration, e.g., by injection or depot tablet), and rectal administration, or in a form suitable for inhalation or insufflation administration. The most suitable route of administration may depend on the condition and disorder of the patient. Preferably, the compositions of the present invention are formulated for oral administration.

[0100] The formulations can conveniently be presented in unit dosage forms and can be prepared by any method known in the pharmaceutical industry, for example, as described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21st Edition, (2005). A suitable method includes combining the active ingredient with a carrier, which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the mixture into the desired formulation. It will be apparent that when these two active ingredients are administered independently, they can be administered by different means.

[0101] When formulated with excipients, the active ingredient may be present in a concentration of 0.1 to 99.5% by weight (such as 0.5 to 95% by weight) of the total mixture, conveniently 30 to 95% for tablets and capsules, and 0.01 to 50% (e.g., 3 to 50%) for liquid formulations.

[0102] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets (e.g., chewable tablets, particularly for pediatric administration), each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0103] Tablets can be made by compression or molding, optionally with one or more excipients. Compressed tablets can be made by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with other conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, starch paste, polyvinylpyrrolidone, and / or hydroxymethylcellulose), fillers (e.g., lactose, sugar, microcrystalline cellulose, corn 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 sulfate). Molded tablets can be made by molding, 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 so as to provide controlled release of the active ingredient, for example delayed, sustained or pulsed release, or a combination of immediate and controlled release.

[0104] Alternatively, the active ingredient can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Formulations containing the active ingredient can also be presented as a dry product for reconstitution with water or another suitable vehicle before use.

[0105] Such liquid formulations may contain conventional additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, and / or hydrogenated edible fats and oils), emulsifiers (e.g., lecithin, sorbitan monooleate, and / or acacia), non-aqueous vehicles (e.g., edible oils such as almond oil, coconut oil, oily esters, propylene glycol, and / or ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and / or sorbic acid).

[0106] The combinations for use according to the invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may, for example, comprise metal or plastic foil, such as a blister pack. When the compositions are intended to be administered as two separate compositions, they may be presented in the form of a twin pack.

[0107] Pharmaceutical compositions may also be prescribed to patients in "patient packs" that contain the entire course of treatment in a single package, usually a blister pack. Patient packs have the advantage over traditional prescriptions, in which a pharmacist dispenses a patient's supply of medication from a bulk supply, that the patient always has access to the package insert contained in the patient pack, which is typically lost with traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with physician instructions.

[0108] Administration of the combination of the present invention in a single patient pack or patient packs for each composition containing package inserts instructing the patient on the correct use of the present invention is a desirable feature of the present invention.

[0109] According to another embodiment of the invention there is provided a patient pack comprising at least one active agent of the combination according to the invention and an instruction leaflet providing instructions for the use of the combination according to the invention.In another embodiment of the invention there is provided a double pack comprising, in separate administrations, an antimicrobial agent, preferably biologically active against clinically latent microorganisms, and one or more compounds disclosed herein, preferably biologically active against clinically latent microorganisms.

[0110] The amount of active ingredient required for treatment will vary depending on the nature of the disease being treated and the age and condition of the patient, and is ultimately at the discretion of the attending physician. In general, however, doses used for adult treatment will typically range from 0.02 to 5000 mg / day, preferably 1 to 1500 mg / day. The desired dose can conveniently be expressed as a single dose or as divided doses administered at appropriate intervals, for example, as two, three or more subdoses per day.

[0111] Suitable dosages and formulations for administration of zidovudine are described in the product labeling for Retrovir® oral solution or capsules, available at http: / / www.medicines.org.uk / emc / medicine / 12444 / SPC / Retrovir+250mg+Capsules / .

[0112] Suitable dosages and formulations for administration of fluoroquinolone antibiotics are described, for example, in the product labeling of ciprofloxacin tablets or infusion solution, levofloxacin tablets or infusion solution, moxifloxacin tablets or infusion solution, or ofloxacin tablets or infusion solution. Such labels can be readily found by one of skill in the art, for example, by searching for fluoroquinolone antibiotics at "https: / / www.medicines.org.uk / emc / browse-ingredients#."

[0113] Accordingly, it is believed that this information would be readily obtained and understood by one of ordinary skill in the art.

[0114] Biological testing Test procedures that can be used to determine the biological activity (e.g., bactericidal or antimicrobial activity) of an active ingredient include: (a) bactericidal activity against clinically latent bacteria; and (b) Antimicrobial activity against logarithmic-phase bacteria These include those known to those skilled in the art for measuring

[0115] With regard to (a) above, methods for measuring activity against clinically latent bacteria include measuring the minimum stationary bactericidal concentration ("MSC") or minimum dormant bactericidal concentration ("MDC") for a test compound under conditions known to those of skill in the art (such as those described in Nature Reviews, Drug Discovery 1, 895-910 (2002), the disclosure of which is incorporated herein by reference).

[0116] For example, WO2000 / 028074 describes a suitable method for screening compounds to determine their ability to kill clinically latent microorganisms. A typical method comprises the following steps: (1) growing the bacterial culture to stationary phase; (2) selecting for a phenotypically resistant subpopulation by 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; (3) incubating samples of the phenotypically resistant subpopulation with one or more test compounds or drugs; and (4) Evaluating antimicrobial efficacy against phenotypically resistant subpopulations may include:

[0117] According to this method, the phenotypically resistant subpopulation can be viewed as representing clinically latent bacteria that remain metabolically active in vivo and can cause recurrent or progressive disease.

[0118] With regard to (b) above, methods for measuring activity against log-phase bacteria include determining the minimum inhibitory concentration ("MIC") or minimum bactericidal concentration ("MBC") for the test compound under standard conditions (i.e., conditions known to those of skill in the art, such as those described in WO2005 / 014585, the disclosure of which is incorporated herein by reference). Specific examples of such methods are described below. [Example]

[0119] Example 1: In vitro synergistic effects of zidovudine (AZT) and ciprofloxacin The checkerboard assay used in Example 1 followed the protocol described in detail in Antimicrob Chemo (2013) 68, 374-384. Zidovudine and ciprofloxacin were obtained from commercial sources. The bacteria used were BAA2469 NDM-1 Escherichia coli, BAA2470 NDM-1 Klebsiella pneumoniae, BAA2471 NDM-1 Escherichia coli, BAA2472 NDM-1 Klebsiella pneumoniae, and NCTC13443 NDM-1 Klebsiella pneumoniae. All strains were obtained from commercial sources, and logarithmic phase growth of the bacteria was performed using methods known in the art.

[0120] The efficacy of the combinations of the present invention was investigated by calculating the fractional inhibitory concentration index (FICI) for each combination as follows: (MIC of drug A, tested in combination) / (MIC of drug A, tested alone) + (MIC of drug B, tested in combination) / (MIC of drug B, tested alone)

[0121] Combination interactions were defined as follows: an FICI of ≤0.5 indicated synergy, an FICI of >0.5 but <4.0 indicated no interaction, and an FICI of >4.0 indicated antagonism.

[0122] [Table 1]

[0123] [Table 2]

[0124] [Table 3]

[0125] [Table 4]

[0126] [Table 5]

[0127] [Table 6]

[0128] A ≥4-fold reduction in MIC indicates synergy. For ciprofloxacin + AZT, synergy was observed for all strains tested; for example, for strain BAA2469 NDM-1, the ciprofloxacin MIC for that strain was 64 mg / L, but when combined with 0.5 mg / L AZT, the MIC decreased to 0.125, a 512-fold reduction.

[0129] Example 2: In vitro synergistic effect of zidovudine in combination with levofloxacin The methods and bacterial strains were the same as in Example 1. Zidovudine and levofloxacin were obtained from commercial sources. The effect of the combination of the present invention was investigated by calculating the MIC for each agent alone and in combination in the same manner as in Example 1.

[0130] [Table 7]

[0131] [Table 8]

[0132] [Table 9]

[0133] [Table 10]

[0134] [Table 11]

[0135] [Table 12]

[0136] In the case of levofloxacin + AZT, a synergistic effect was observed for all strains tested. For example, in the case of the BAA2469 NDM-1 strain, the levofloxacin MIC against that strain was high at 8 mg / L, but when combined with 0.5 mg / L AZT, the MIC decreased to 0.25, a 1 / 32 reduction.

[0137] Example 3: In vitro synergistic effect of zidovudine in combination with moxifloxacin The methods and bacterial strains were the same as in Example 1. Zidovudine and moxifloxacin were obtained from commercial sources. The effect of the combination of the present invention was investigated by calculating the MIC for each agent alone and in combination in the same manner as in Example 1.

[0138] [Table 13]

[0139] [Table 14]

[0140] [Table 15]

[0141] [Table 16]

[0142] [Table 17]

[0143] [Table 18]

[0144] In the case of moxifloxacin + AZT, a synergistic effect was observed in all strains tested, with a 1 / 16 to 1 / 128 reduction in the MIC of moxifloxacin.

[0145] Example 4: Further studies on zidovudine (AZT) in combination with levofloxacin Further testing of the AZT-levofloxacin combination against carbapenem-resistant and ESBL-phenotype E. coli and K. pneumoniae confirmed the combination's ability to exert synergistic effects. MIC testing standards published by the Clinical and Laboratory Standards Institute (CLSI. 2018. M07Ed11. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eleventh edition. Clinical and Laboratory Standards Institute, Wayne, PA.; CLSI. 2019. M100Ed29. Performance standards for antimicrobial susceptibility testing: 29 thSynergy testing was performed using the levofloxacin-resistant Escherichia coli (ESC) and levofloxacin-resistant K. pneumoniae isolates according to the method described in Clinical Microbiology Procedures Handbook (Leber AL, editor. 2016. Clinical Microbiology Procedures Handbook, 4th Ed. ASM Press, Washington, DC) using the levofloxacin-resistant K. pneumoniae isolates (ESC information supplement, Clinical and Laboratory Standards Institute, Wayne, PA).

[0146] Isolates were classified as carbapenem-resistant (CRE) if they were resistant to at least one of the following antimicrobials: doripenem, imipenem, or meropenem. Isolates were classified as exhibiting an ESBL phenotype if they had MIC values ​​>2 mg / L for at least one of the following antimicrobials: aztreonam, ceftazidime, or ceftriaxone. Levofloxacin-resistant Enterobacteriaceae isolates were defined as isolates exhibiting levofloxacin MIC values ​​≥2 mg / L.

[0147] Isolates were tested for antimicrobial susceptibility using the broth microdilution method according to CLSI guidelines. The test medium was cation-adjusted Mueller-Hinton broth.

[0148] Zidovudine and levofloxacin were obtained from commercial sources.

[0149] result The results of the checkerboard analysis are summarized by isolate and antimicrobial agent in the following table.

[0150] [Table 19]

[0151] Consistent with previous examples, these results support a synergistic effect between AZT and levofloxacin. Notably, these results include previously untested levofloxacin-resistant Enterobacteriaceae isolates. Synergistic effects of the AZT-levofloxacin combination were observed with E. coli and K. pneumoniae isolates, as well as isolates displaying either ESBL or CRE phenotypes.

Claims

1. A therapeutic agent for bacterial infections caused by drug-resistant strains of Enterobacteriaceae, comprising a combination of zidovudine or a pharmaceutically acceptable salt and / or solvate thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable salt and / or solvate thereof.

2. The therapeutic agent of claim 1, wherein the bacterial infection is a urinary tract infection.

3. The therapeutic agent according to claim 1 or 2, wherein the bacterial infection is caused by E. coli or Klebsiella pneumoniae.

4. The therapeutic agent described in claim 3, wherein the bacterial infection is caused by Klebsiella pneumoniae (K. pneumoniae).

5. A therapeutic agent according to any one of claims 1 to 4, wherein the bacterial infection is in a subject other than an HIV-infected subject receiving zidovudine as part of HIV management.

6. The therapeutic agent according to any one of claims 1 to 5, wherein the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, and ulifloxacin.

7. A pharmaceutical composition comprising zidovudine or a pharmaceutically acceptable salt and / or solvate thereof, a fluoroquinolone antibiotic or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment of bacterial infections caused by drug-resistant strains of the family Enterobacteriaceae.

8. A pharmaceutical composition comprising zidovudine or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, used in combination with a fluoroquinolone antibiotic or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of bacterial infections caused by drug-resistant strains of the family Enterobacteriaceae.

9. A pharmaceutical composition comprising a fluoroquinolone antibiotic or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier, used in combination with zidovudine or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of bacterial infections caused by drug-resistant strains of the family Enterobacteriaceae.

10. A pharmaceutical composition described in any one of claims 7 to 9, wherein the bacterial infection is a urinary tract infection.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein the bacterial infection is caused by Escherichia coli (E. coli) or Klebsiella pneumoniae (K. pneumoniae).

12. The pharmaceutical composition of claim 11, wherein the bacterial infection is caused by Klebsiella pneumoniae.

13. The pharmaceutical composition of any one of claims 7 to 12, wherein the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, and ulifloxacin.

14. The pharmaceutical composition of any one of claims 7 to 13, wherein the bacterial infection is in a subject other than an HIV-infected subject receiving zidovudine as part of HIV management.

15. The pharmaceutical composition according to any one of claims 7 to 14, wherein the pharmaceutical composition is in the form of a tablet suitable for oral administration or suitable for parenteral administration.

16. A product comprising zidovudine or a pharmaceutically acceptable salt and / or solvate thereof and a fluoroquinolone antibiotic or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of bacterial infections caused by drug-resistant strains of the family Enterobacteriaceae.

17. The product described in claim 16, wherein the bacterial infection is a urinary tract infection.

18. The product of claim 16 or 17, wherein the bacterial infection is caused by Escherichia coli (E. coli) or Klebsiella pneumoniae (K. pneumoniae).

19. The product of claim 18, wherein the bacterial infection is caused by Klebsiella pneumoniae.

20. 20. The product of any one of claims 16 to 19, wherein the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, sitafloxacin, besifloxacin, delafloxacin, and ulifloxacin.

Images