US 2010.0062974A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0062974 A1 LaRonde et al. (43) Pub. Date: Mar. 11, 2010

(54) COMBINATION THERAPY FOR THE Publication Classification TREATMENT OF BACTERAL INFECTIONS (51) Int. Cl. (75) Inventors: Frank LaRonde, Toronto (CA); st 4.5 CR Hanje Chen, Toronto (CA); Selva ( .01) Sinnadurai, Scarborough (CA) A63/496 (2006.01) A63L/7048 (2006.01) Correspondence Address: A63L/43 (2006.01) CLARK & ELBNG LLP A6II 3/42 (2006.01) 101 FEDERAL STREET A63L/464 (2006.01) A6IP3 L/10 (2006.01) (73) Assignee: Interface Biologics, Inc., Toronto (CA) (52) U.S. Cl...... 514/8: 514/635: 514/253.08: 514/40: 514/197; 514/380: 514/399 (21) Appl. No.: 12/419,733 (22) Filed: Apr. 7, 2009 (57) ABSTRACT O O The invention features a method for treating a Subject diag Related U.S. Application Data nosed with, or at risk of developing, a bacterial infection by (60) Provisional application No. 61/123,231, filed on Apr. administering to the Subject a combination of biologically 7, 2008. active agents. US 2010/0062974 A1 Mar. 11, 2010

COMBINATION THERAPY FOR THE ond agent selected from fluoroquinolones, aminoglycosides, TREATMENT OF BACTERAL INFECTIONS B-lactams, glycopeptide antibiotics, Sulfonamides, and anti fungal azoles. CROSS-REFERENCE TO RELATED 0008. The invention further features a composition includ APPLICATIONS ing a biodegradable polymer having a first repeating unit and 0001. This application claims benefit from U.S. Provi a second repeating unit, the first repeating unit including a sional Application No. 61/123,231, filed Apr. 7, 2008, hereby membrane active biocide and the second repeating unit incorporated by reference. including a second agent selected from fluoroquinolones, aminoglycosides, B-lactams, glycopeptide antibiotics, Sul BACKGROUND OF THE INVENTION fonamides, and antifungal azoles. 0009. The invention also features a composition including 0002 The present invention relates to the field of antibac (i) a biodegradable polymer including a repeating unit includ terial therapy. ing a membrane active biocide and (ii) a second agent 0003. The use of antibiotics by humans can be seen as an selected from fluoroquinolones, aminoglycosides, B-lactams, evolutionary experiment of enormous magnitude, a window glycopeptide antibiotics, Sulfonamides, and antifungal from which to view not-quite-natural selection operating in azoles. real time. Within 50 years, the number of species and strains 0010. In a related aspect the invention features a compo of pathogenic and commensal bacteria resistant to antibiotics sition including (i) a biodegradable polymer including a and the number of antibiotics to which they are resistant has repeating unit including a second agent selected from fluoro increased virtually monotonically world-wide. As a result, quinolones, aminoglycosides, B-lactams, glycopeptide anti infections that had been readily treatable by chemotherapy biotics, Sulfonamides, and antifungal azoles and (ii) a mem may no longer be so. It is clear that the evolution and spread brane active biocide. of resistance can be attributed to the use and overuse of antibiotics. Increased resistance of bacterial infections to 0011. The invention further features a composition includ antibiotic treatment has been extensively documented and has ing (i) a first biodegradable polymer including a repeating now become a generally recognized medical problem, par unit including a membrane active biocide and (ii) a second ticularly with nosocomial infections. See, for example, Jones biodegradable polymer including a repeating unit including a et al., Diagn. Microbiol. Infect. Dis. 31:379-388, 1998; Mur second agent selected from fluoroquinolones, aminoglyco ray, Adv. Intern. Med. 42:339-367, 1997; and Nakae, Micro sides, B-lactams, glycopeptide antibiotics, Sulfonamides, and biologia 13:273-284, 1997. antifungal azoles. 0004 Throughout the developed world there is public and 0012. The invention further features a method of reducing governmental concern about the increasing prevalence of bacterial growth on a Surface by contacting the Surface with a antimicrobial resistance to chemotherapy in bacteria that composition including a membrane active biocide and a sec cause diseases in humans. Many pathogens exist for which ond agent selected from fluoroquinolones, aminoglycosides, there are few effective treatments, and the number of strains B-lactams, glycopeptide antibiotics, Sulfonamides, and anti resistant to available drugs is continually increasing. New fungal azoles in amounts that together are effective to reduce antimicrobial agents and improved methods are thus needed bacterial growth. for the treatment and prevention of infections by such patho 0013 The invention also features a method of reducing genS. bacterial growth on a surface by coating the Surface with a biodegradable polymer including a first repeating unit and a SUMMARY OF THE INVENTION second repeating unit, the first repeating unit including a 0005 We have discovered that a combination of a mem membrane active biocide and the second repeating unit brane active biocide (e.g., chlorhexidine) and a second agent including a second agent selected from fluoroquinolones, selected from fluoroquinolones, aminoglycosides, B-lactams, aminoglycosides, B-lactams, glycopeptide antibiotics, Sul glycopeptide antibiotics, Sulfonamides, and antifungal azoles fonamides, and antifungal azoles. is more effective in treating bacterial infections and reducing 0014. The invention further features a method of reducing bacterial growth than either agent alone. We have also dis fungal growth on a Surface by contacting the Surface with a covered that a combination of a Sulfonamide (e.g., Sul composition including a membrane active biocide and a sec famethoxazole) and a second agent selected from B-lactams ond agent selected from fluoroquinolones, aminoglycosides, and antifungal azoles is more effective in treating bacterial B-lactams, glycopeptide antibiotics, Sulfonamides, and anti infections and reducing bacterial growth than either agent fungal azoles in amounts that together are effective to reduce alone. Thus, the invention features compositions, methods, fungal growth. and kits including these effective combinations, which can be 0015 The invention also features a method of reducing useful for the treatment and prevention of infections. fungal growth on a surface by coating the Surface with a 0006. Accordingly, in a first aspect the invention features a biodegradable polymer including a first repeating unit and a composition including a membrane active biocide and a sec second repeating unit, the first repeating unit including a ond agent selected from fluoroquinolones, aminoglycosides, membrane active biocide and the second repeating unit B-lactams, glycopeptide antibiotics, Sulfonamides, and anti including a second agent selected from fluoroquinolones, fungal azoles in amounts that together are sufficient in vivo to aminoglycosides, B-lactams, glycopeptide antibiotics, Sul treat a bacterial infection. fonamides, and antifungal azoles. 0007. In a related aspect, the invention features a biode 0016. In certain embodiments of the above methods, the gradable polymer including a first repeating unit and a second Surface is, for example, a surface of an implantable medical repeating unit, the first repeating unit including a membrane device (e.g., a cardiac-assist device, a catheter, a stent, a active biocide and the second repeating unit including a sec prosthetic implant, a Suture, a cuff, a mesh, a hernia patch, a US 2010/0062974 A1 Mar. 11, 2010

wound dressing, a bandage, an artificial sphincter, or a drug 0025. The invention also features a kit including: (i) an delivery device) or any other surface described herein. implantable medical device; (ii) a composition including a 0017. The invention also features a method of treating a membrane active biocide and a second agent selected from bacterial infection in a Subject, the method including admin fluoroquinolones, aminoglycosides, 3-lactams, glycopeptide istering a membrane active biocide and a second agent antibiotics, Sulfonamides, and antifungal azoles; and (iii) selected from fluoroquinolones, aminoglycosides, B-lactams, instructions for coating the implantable medical device with glycopeptide antibiotics, Sulfonamides, and antifungal azoles the composition. to the Subject in amounts that together are sufficient in vivo to 0026. In certain embodiments of the kits of the invention, treat the bacterial infection. the composition is a biodegradable polymer including a first 0018. The invention also features a method of treating a repeating unit and a second repeating unit, the first repeating fungal infection in a Subject, the method including adminis unit including a membrane active biocide and the second tering a membrane active biocide and a second agent selected repeating unit including the second agent. Alternatively, the from fluoroquinolones, aminoglycosides, 3-lactams, glyco composition is a mixture of (i) a biodegradable polymer peptide antibiotics, Sulfonamides, and antifungal azoles to the including a repeating unit including a membrane active bio Subject in amounts that together are sufficient in Vivo to treat cide and (ii) the secondagent, a mixture of (i) a biodegradable the fungal infection. polymer including a repeating unit including the secondagent and (ii) a membrane active biocide; or a mixture of (i) a first 0019. In certain embodiments, the membrane active bio biodegradable polymer including a repeating unit including a cide and the second agent are administered for prophylaxis membrane active biocide and (ii) the second biodegradable against an infection resulting from a Surgical procedure or polymer including a repeating unit including the second implantation of a medical device (e.g., a cardiac-assist device, agent. a catheter, a stent, a prosthetic implant, a Suture, a cuff, a 0027. In still another related aspect, the invention features mesh, a hernia patch, a wound dressing, abandage, an artifi a composition including a Sulfonamide and a second agent cial sphincter, a drug delivery device, or any other medical selected from B-lactams and antifungalazoles in amounts that device described herein). together are sufficient in vivo to treat a bacterial infection. 0020. In still other embodiments, the method of treating 0028. In a related aspect, the invention features a biode includes contacting the Subject with a biodegradable polymer gradable polymer including a first repeating unit and a second including a first repeating unit and a second repeating unit, the repeating unit, the first repeating unit including a sulfonamide first repeating unit including a membrane active biocide and and the second repeating unit including a second agent the second repeating unit including a second agent selected selected from B-lactams and antifungal azoles. from fluoroquinolones, aminoglycosides, 3-lactams, glyco 0029. The invention further features a composition includ peptide antibiotics, Sulfonamides, and antifungal azoles. ing a biodegradable polymer having a first repeating unit and 0021. In certain embodiments, the method of treating a second repeating unit, the first repeating unit including a includes contacting the Subject with (i) a biodegradable poly Sulfonamide and the second repeating unit including a second mer including a repeating unit including a membrane active agent selected from B-lactams and antifungal azoles. biocide and (ii) and a second agent selected from fluoroqui 0030 The invention also features a composition including nolones, aminoglycosides, 3-lactams, glycopeptide antibiot (i) a biodegradable polymer including a repeating unit includ ics, Sulfonamides, and antifungal azoles. Alternatively, the inga Sulfonamide and (ii) a second agent selected from B-lac method of treating includes contacting the Subject with (i) a tams and antifungal azoles. biodegradable polymer including a repeating unit including a 0031. In a related aspect the invention features a compo second agent selected from fluoroquinolones, aminoglyco sition including (i) a biodegradable polymer including a sides, B-lactams, glycopeptide antibiotics, Sulfonamides, and repeating unit including a second agent selected from 3-lac antifungal azoles and (ii) a membrane active biocide. tams and antifungal azoles and (ii) a Sulfonamide. 0022. In still other embodiments, the method of treating 0032. The invention further features a composition includ includes contacting the Subject with (i) a first biodegradable ing (i) a first biodegradable polymer including a repeating polymer including a repeating unit including a membrane unit including a Sulfonamide and (ii) a second biodegradable active biocide and (ii) a second biodegradable polymer polymer including a repeating unit including a second agent including a repeating unit including a second agent selected selected from B-lactams and antifungal azoles. from fluoroquinolones, aminoglycosides, 3-lactams, glyco 0033. The invention further features a method of reducing peptide antibiotics, Sulfonamides, and antifungal azoles. bacterial growth on a Surface by contacting the Surface with a 0023 The invention features a kit including: (i) a compo composition including a sulfonamide and a second agent sition including a membrane active biocide and a second selected from B-lactams and antifungalazoles in amounts that agent selected from fluoroquinolones, aminoglycosides, together are effective to reduce bacterial growth. B-lactams, glycopeptide antibiotics, Sulfonamides, and anti 0034. The invention also features a method of reducing fungal azoles; and (ii) instructions for administering the com bacterial growth on a surface by coating the Surface with a position to a subject diagnosed with or at risk of developing a biodegradable polymer including a first repeating unit and a bacterial infection. second repeating unit, the first repeating unit including a 0024. The invention further features a kit including: (i) a Sulfonamide and the second repeating unit including a second membrane active biocide; (ii) a second agent selected from agent selected from B-lactams and antifungal azoles. fluoroquinolones, aminoglycosides, 3-lactams, glycopeptide 0035. The invention further features a method of reducing antibiotics, Sulfonamides, and antifungal azoles; and (iii) fungal growth on a Surface by contacting the Surface with a instructions for administering the membrane active biocide composition including a sulfonamide and a second agent and the fluoroquinolone to a subject diagnosed with or at risk selected from B-lactams and antifungalazoles in amounts that of developing a bacterial infection. together are effective to reduce fungal growth. US 2010/0062974 A1 Mar. 11, 2010

0036. The invention also features a method of reducing antifungal azoles; and (iii) instructions for coating the fungal growth on a surface by coating the Surface with a implantable medical device with the composition. biodegradable polymer including a first repeating unit and a 0047. In certain embodiments of the kits of the invention, second repeating unit, the first repeating unit including a the composition is a biodegradable polymer including a first Sulfonamide and the second repeating unit including a second repeating unit and a second repeating unit, the first repeating agent selected from B-lactams and antifungal azoles. unit including a sulfonamide and the second repeating unit 0037. In certain embodiments of the above methods, the including the second agent. Alternatively, the composition is Surface is, for example, a Surface of an implantable medical a mixture of (i) a biodegradable polymer including a repeat device (e.g., a cardiac-assist device, a catheter, a stent, a ing unit including a Sulfonamide and (ii) the second agent; a prosthetic implant, a Suture, a cuff, a mesh, a hernia patch, a mixture of (i) a biodegradable polymer including a repeating wound dressing, a bandage, an artificial sphincter, or a drug unit including the second agent and (ii) a Sulfonamide; or a delivery device) or any other surface described herein. mixture of (i) a first biodegradable polymer including a 0038. The invention also features a method of treating a repeating unit including a Sulfonamide and (ii) the second bacterial infection in a Subject, the method including admin biodegradable polymer including a repeating unit including istering a Sulfonamide and a second agent selected from the second agent. B-lactams and antifungal azoles to the Subject in amounts that 0048 Bacterial and fungal infections that can be treated together are sufficient in vivo to treat the bacterial infection. using the methods of the invention include, without limita 0039. The invention also features a method of treating a tion, group consisting of a community-acquired pneumonia, fungal infection in a Subject, the method including adminis upper and lower respiratory tract infection, skin and soft tering a Sulfonamide and a second agent selected from 3-lac tissue infection, bone and joint infection, hospital-acquired tams and antifungal azoles to the Subject in amounts that lung infection, acute bacterial otitis media, bacterial pneumo together are sufficient in vivo to treat the fungal infection. nia, complicated infection, noncomplicated infection, pyelo 0040. In certain embodiments, the sulfonamide and the nephritis, intra-abdominal infection, deep-seated abcess, bac second agent are administered for prophylaxis against an terial sepsis, central nervous system infection, bacteremia, infection resulting from a Surgical procedure or implantation wound infection, peritonitis, meningitis, infections after of a medical device (e.g., a cardiac-assist device, a catheter, a burn, urogenital tract infection, gastro-intestinal tract infec stent, a prosthetic implant, a Suture, a cuff, a mesh, a hernia tion, pelvic inflammatory disease, endocarditis, intravascular patch, a wound dressing, a bandage, an artificial sphincter, a infection, and any other bacterial infections described herein. drug delivery device, or any other medical device described The infections to be treated may be caused by Gram-positive bacteria. These include, without limitation, infections by, Sta herein). phylococcus aureus, Staphylococcus epidermidis, Entero 0041. In still other embodiments, the method of treating coccus faecalis, Enterococcus faecium, Clostridium perfirin includes contacting the Subject with a biodegradable polymer gens, Clostridium difficile, Streptococcus pyogenes, including a first repeating unit and a second repeating unit, the Streptococcus pneumoniae, other Streptococcus spp., and first repeating unit including a Sulfonamide and the second other Clostridium spp. More specifically, the infections may repeating unit including a second agent selected from 3-lac be caused by a Gram-positive coccus, or by a drug-resistant tams and antifungal azoles. Gram-positive coccus. Exemplary Gram-positive cocci are, 0042. In certain embodiments, the method of treating without limitation, S. aureus, S. epidermidis, S. pneumoniae, includes contacting the Subject with (i) a biodegradable poly S. pyogenes, M. Catarrhalis, C. difficile, H. pylori, Chlamydia mer including a repeating unit including a sulfonamide and spp., and Enterococcus spp. Furthermore, the methods and (ii) and a secondagent selected from B-lactams and antifungal compositions described herein are useful for treating an azoles. Alternatively, the method of treating includes contact infection by multi-drug resistant bacteria. Resistant strains of ing the Subject with (i) a biodegradable polymer including a bacteria include penicillin-resistant, methicillin-resistant, repeating unit including a second agent selected from 3-lac quinolone-resistant, macrollide-resistant, and/or Vancomy tams and antifungal azoles and (ii) a Sulfonamide. cin-resistant bacterial strains. The multi-drug resistant bacte 0043. In still other embodiments, the method of treating rial infections to be treated using the methods of the invention includes contacting the Subject with (i) a first biodegradable include, for example, infections by penicillin-, methicillin-, polymer including a repeating unit including a sulfonamide macrollide-, Vancomycin-, and/or quinolone-resistant Strep and (ii) a second biodegradable polymer including a repeat tococcus pneumoniae; penicillin-, methicillin-, macrollide-, ing unit including a secondagent selected from B-lactams and Vancomycin-, and/or quinolone-resistant Staphylococcus antifungal azoles. aureus; penicillin-, methicillin-, macrollide-, Vancomycin-, 0044) The invention features a kit including: (i) a compo and/or quinolone-resistant Streptococcus pyogenes; and sition including a Sulfonamide and a second agent selected penicillin-, methicillin-, macrollide-, Vancomycin-, and/or from B-lactams and antifungal azoles; and (ii) instructions for quinolone-resistant enterococci. The infections to be treated administering the composition to a subject diagnosed with or may be caused by Gram-negative bacteria. The infections to at risk of developing a bacterial infection. be treated may be fungal infections caused by Candida spp. 0045. The invention further features a kit including: (i) a 0049. The invention further features a shaped article Sulfonamide; (ii) a second agent selected from 3-lactams and including a composition of the invention. antifungal azoles; and (iii) instructions for administering the 0050. In a related aspect, the invention features a shaped Sulfonamide and the fluoroquinolone to a subject diagnosed article including a biodegradable polymer of the invention. with or at risk of developing a bacterial infection. 0051 Shaped articles of the invention can be in the form of 0046. The invention also features a kit including: (i) an an implantable medical device (e.g., a cardiac-assist device, a implantable medical device; (ii) a composition including a catheter, a stent, a prosthetic implant, a Suture, a cuff, a mesh, Sulfonamide and a second agent selected from 3-lactams and a hernia patch, a wound dressing, a bandage, an artificial US 2010/0062974 A1 Mar. 11, 2010

sphincter, or a drug delivery device), self-supporting film, fathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy fiber, or any other shaped article described herein. ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadi 0052. In the methods, kits, compositions, and biodegrad cramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, able polymers of the invention, the membrane active biocide Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic acid, Sul can be selected from chlorhexidine, polymyxin B-nonapep famerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sul tide, bacitracin, aztreonam, benzalkonium salts, metal chela famethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, tors, and any other membrane active biocide described herein. Sulfametrole, Sulfamidochrysoidine, SulfamoXole, Sulfanil In certain embodiments, the membrane active biocide is chlo amide, Sulfanilamidomethanesulfonic acid triethanolamine rhexidine. salt, 4-sulfanilamidosalicyclic acid, N4-sulfanilylsulfanil 0053. In the methods, kits, compositions, and biodegrad amide, sulfanily lurea, N-sulfanilyl-3,4-xylamide, sulfanit able polymers of the invention, the fluoroquinolone can be ran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyra selected from ciprofloxacin, enrofloxacin, enoxacin, gati Zine, Sulfapyridine, Sulfasomizole, Sulfasymazine, floxacin, gemifloxacin, levofloxacin, lomefloxacin, moxi Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine and floxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, Sulfisoxazole. In certain embodiments, the Sulfonamide is difloxacin, cinofloxacin, pefloxacin, toSufloxacin, temafloxa Sulfamethoxazole. cin, fleroxacin, amifloxacin, binfloxacin, danofloxacin, mar 0058. In the methods, kits, compositions, and biodegrad bofloxacin, ruflocaxin, Sarafloxacin, and any other fluoroqui able polymers of the invention, the antifungal azole can be nolone described herein. In certain embodiments, the selected from miconazole, ketoconazole, clotrimazole, flu fluoroquinolone is ciprofloxacin. conazole, Voriconazole, ravuconazole, azaconazole, bromu 0054. In the methods, kits, compositions, and biodegrad conazole bitertanol, propiconazole, difenoconazole, dini able polymers of the invention, the aminoglycoside can be conazole, cyproconazole, epoxiconazole, fluguinconazole, selected from amikacin, apramycin, arbekacin, bambermy flusilaZole, flutriafol, hexaconazole, itraconazole, imazalil, cins, butirosin, dibekacin, dihydrostreptomycin, fortimicin imibenconazole, ipconazole, tebuconazole, tetraconazole, (s), fradiomycin, gentamicin, ispamicin, kanamycin, micro fenbuconazole, metconazole, myclobutanil, perfurazoate, nomicin, neomycin, neomycin undecylenate, netilmicin, penconazole, posaconazole, pyrifenox, prochloraz, tercona paromomycin, ribostamycin, Sisomicin, spectinomycin, Zole, triadimefon, triadimenol, triflumizole, and triticona streptomycin, Streptonicozid, and tobramycin. In certain Zole. In certain embodiments, the antifungal azole is micona embodiments, the aminoglycoside is gentamicin. Zole. 0055. In the methods, kits, compositions, and biodegrad 0059. As used herein, the term "aminoglycosides” refers able polymers of the invention, the B-lactam can be selected to a class of antibiotics derived at least part from a saccharide from amidinocillin, amdinocillin, pivoxil, amoxicillin, ampi or polysaccharide and having the empirical formula cillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, ben CHNO (where m, n, p, and q are appropriate integers). Zylpenicillinic acid, benzylpenicillin, carbenicillin, carfecil For instance, the aminoglycosides are oligosaccharides con lin, carindacillin, clometocillin, cloxacillin, cyclacillin, sisting of an aminocyclohexanol moiety glycosidically linked dicloxacillin, diphenicillin, epicillin, fenbenicillin, floxicil to other amino Sugars. Streptomycin, one of the best studied lin, hetacillin, lenampicillin, metampicillin, methicillin, of the group, is produced by Streptomyces griseus. Strepto meZlocillin, nafcillin, oxacillin, penamecillin, penethamate mycin, and many other aminoglycosides, inhibits protein hydriodide, penicillin G benethamine, penicillin G benza synthesis in the target organisms. Aminoglycosides include, thine, penicillin G benzhydrylamine, penicillin G calcium, without limitation, amikacin, apramycin, arbekacin, bamber penicillin G hydragamine, penicillin G potassium, penicillin mycins, butirosin, dibekacin, dihydrostreptomycin, fortimi G, procaine, penicillinN, penicillin O, penicillinV, penicillin cin(s), fradiomycin, gentamicin, ispamicin, kanamycin, V benzathine, penicillin V hydrabamine, penimepicycline, micronomicin, neomycin, neomycin undecylenate, netilmi phenethicillin, piperacillin, pivapicillin, propicillin, quinacil cin, paromomycin, ribostamycin, Sisomicin, spectinomycin, lin, Sulbenicillin, talampicillin, temocillin and ticarcillin. In streptomycin, Streptonicozid, and tobramycin. In certain certain embodiments, the B-lactam is amoxicillin. embodiments, the aminoglycoside is gentamicin. 0056. In the methods, kits, compositions, and biodegrad 0060. By “an amount sufficient' is meant the amount of a able polymers of the invention, the glycopeptide antibiotic compound, a combination of compounds, or a biodegradable can be selected from actaplanin, actinoidin, ardacin, avopar polymer used in the methods, compositions, and/or kits of the cin, azureomycin, balhimycin, chloroorientiein, chlo invention, required to treat or prevent a bacterial or fungal ropolysporin, decaplanin, N-demethylvancomycin, eremo infection in a clinically relevant manner. A Sufficient amount mycin, galacardin, helvecardin, iZupeptin, kibdelin, of a compound, a combination of compounds, or a biodegrad orenticin, parvodicin, ramoplanin, ristocetin, ristomycin, able polymer used to practice the present invention for thera Synmonicin, teicoplanin, Vancomycin, and Vancomycin B. In peutic treatment of conditions caused by or contributing to a certain embodiments, the glycopeptide antibiotic is Vanco bacterial or fungal infection can vary depending upon the mycin. manner of administration, the age, body weight, and general 0057. In the methods, kits, compositions, and biodegrad health of the subject. Ultimately, the prescribers will decide able polymers of the invention, the sulfonamide can be the appropriate amount and dosage regimen. selected from acetyl sulfamethoxypyrazine, acetyl sulfisoX 0061. As used herein, the term “antifungal azoles' refers azole, azosulfamide, benzylsulfamide, chloramine-B, to any member of the class of anti-fungal compounds having chloramine-T. dichloramine-T, formosulfathiazole, a five-membered ring of three carbonatoms and two nitrogen N2-formyl-sulfisomidine, N4-B-D-glucosylsulfanilamide, atoms (imidazoles) or two carbon atoms and three nitrogen mafenide, 4'-(methyl-Sulfamoyl)sulfanilanilide, p-nitrosul atoms (triazoles). Antifungal azoles include, without limita fathiazole, noprylsulfamide, phthalylsulfacetamide, tion, miconazole, ketoconazole, clotrimazole, fluconazole, phthalylsulfathiazole, Salazosulfadimidine, Succinylsul Voriconazole, ravuconazole, azaconazole, bromuconazole US 2010/0062974 A1 Mar. 11, 2010

bitertanol, propiconazole, difenoconazole, diniconazole, (commercially available as Factive(R), levofloxacin (com cyproconazole, epoxiconazole, fluguinconazole, flusilaZole, mercially available as Levacquin R), lomefloxacin (commer flutriafol, hexaconazole, itraconazole, imazalil, imibencona cially available as Maxaquin R.), moxifloxacin (commercially Zole, ipconazole, tebuconazole, tetraconazole, fenbucona available as Avelox.R.), norfloxacin (commercially available Zole, metconazole, myclobutanil, perfurazoate, penconazole, as Noroxin R.), ofloxacin (commercially available as posaconazole, pyrifenox, prochloraz, terconazole, triadime Floxin R.), sparfloxacin (commercially available as Zagam.R.), fon, triadimenol, triflumizole, and triticonazole. trovafloxacin (commercially available as Trovan(R), difloxa 0062 By “bacterial infection' is meant the invasion of a cin, cinofloxacin, pefloxacin, to Sufloxacin, temafloxacin, host by pathogenic bacteria. For example, the infection may fleroxacin, amifloxacin, binfloxacin, danofloxacin, marbof include the excessive growth of bacteria that are normally loxacin, ruflocaxin, and Sarafloxacin. present in or on the body of a Subject (i.e., an animal or human 0.066 By “fungal infection is meant the invasion of a host Subject) or growth of bacteria that are not normally present in by pathogenic fungi. For example, the infection may include or on a Subject. More generally, a bacterial infection can be the excessive growth of fungi that are normally present in or any situation in which the presence of a bacterial population on the body of a subject (i.e., an animal or human Subject) or (s) is damaging to a host body. Thus, a subject is “suffering growth of fungi that are not normally present in or on a from a bacterial infection when an excessive amount of a Subject. More generally, a fungal infection can be any situa bacterial population is present in or on the person's body, or tion in which the presence of a fungal population(s) is dam when the presence of a bacterial population(s) is damaging aging to a host body. Thus, a subject is “suffering from a the cells or other tissue of the person. fungal infection when an excessive amount of a fungal popu 0063 As used herein, the term “B-lactams’ refers to a lation is present in or on the person's body, or when the class of antibiotics which a beta-lactam ring (a four-member presence of a fungal population(s) is damaging the cells or heteroatomic ring structure including three carbon atoms and other tissue of the person. one nitrogen atom and linked as a cyclic amide). B-lactams 0067. As used herein, the term “glycopeptide antibiotics’ include, without limitation, amidinocillin, amdinocillin, piv refers to a class of antibiotics which are oligopeptide (e.g., oxil, amoxicillin, amplicillin, aspoxicillin, azidocillin, heptapeptide) antibiotics, characterized by a ring peptide core aZlocillin, bacampicillin, benzylpenicillinic acid, benzyl and optionally Substituted with Saccharide groups, such as penicillin, carbenicillin, carfecillin, carindacillin, clometocil Vancomycin or Vancomycin-B. Glycopeptide antibiotics lin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin, epi include, without limitation, A477, A35512, A40926, A41030, cillin, fenbenicillin, floxicillin, hetacillin, lenampicillin, A42867, A47934, A80407, A82846, A83850, A84575, metampicillin, methicillin, meZlocillin, nafcillin, oxacillin, AB-65, actaplanin, actinoidin, ardacin, avoparcin, azureomy penamecillin, penethamate hydriodide, penicillin G beneth cin, balhimycin, chloroorientiein, chloropolysporin, decapla amine, penicillin G benzathine, penicillin G benzhydry nin, N-demethylvancomycin, eremomycin, galacardin, lamine, penicillin G calcium, penicillin Ghydragamine, peni helvecardin, izupeptin, kibdelin, LL-AM374, mannopeptin, cillin G potassium, penicillin G, procaine, penicillin N. MM45289, MM47756, MM47761, MM49721, MM47766, penicillin O, penicillinV, penicillinV benzathine, penicillinV MM55260, MM55266, MM55270, MM56597, MM56598, hydrabamine, penimepicycline, phenethicillin, piperacillin, OA-7653, orenticin, parvodicin, ramoplanin, ristocetin, ris pivapicillin, propicillin, quinacillin, Sulbenicillin, talampicil tomycin, synmonicin, teicoplanin, UK-68597, UK-69542, lin, temocillin and ticarcillin. UK-72051, Vancomycin, and Vancomycin B (see, e.g., “Gly 0064. By “effective” amount is meant the amount of a copeptides Classification, Occurrence, and Discovery.” by compound, a combination of compounds, or a biodegradable Rao R C and Crandall LW, in Drugs and the Pharmaceutical polymer used in the methods, compositions, and/or kits of the Sciences, Volume 63, Ramakrishnan N (ed.), Marcal Dekker, invention, required to reduce bacterial or fungal growth on a Inc., the entire disclosure of which is herein incorporated by Surface in comparison to the bacterial or fungal growth reference). Glycopeptide antibiotics also include the general observed for the same surface under the same conditions, but class of glycopeptides disclosed above in their aglycone in the absence of a compound, a combination of compounds, form. or a biodegradable polymer of the invention. Such amount is 0068. As used herein, the term “membrane active biocide' referred to as an “effective” amount. refers to a biocidal membrane permeabilizer. Membrane 0065. As used herein, the term “fluoroquinolones' refers active biocides include, without limitation, cationic bigu to a class of antibiotics which exert their antibacterial effects anide antibacterial agents (e.g., chlorhexidine), polymyxin by inhibiting bacterial DNA gyrase and which include a flu B-nonapeptide, bacitracin, aztreonam, quaternary ammo orinated quinolone ring system. Fluoroquinolones which can nium compounds (e.g., benzalkonium salts), and metal chela be used in the devices, compositions, and methods of the tors, such as ethylenediaminetetraacetate (EDTA). invention include, without limitation, those described in 0069. As used herein, the term “sulfonamides’ refers to a patent publications BE870576; DE3142854; EPO47005; class of antibiotics which include a sulfonamide group. Sul EP206283; BE887574; EP221463; EP1401 16; EP131839; fonamides include, without limitation, acetyl sulfamethoxy EP154780; EP078362; EP310849; EP520240; and U.S. Pat. pyrazine, acetyl Sulfisoxazole, azosulfamide, benzylsulfa Nos. 4,448,962: 4,499,091; 4,704,459; 4,795,751; 4,668,784: mide, chloramine-B, chloramine-T, dichloramine-T. and 5.532.239, each of which is incorporated herein by ref formosulfathiazole, N2-formyl-sulfisomidine, N4-B-D-glu erence. Exemplary fluoroquinolones which can be used in the cosylsulfanilamide, mafenide, 4'-(methyl-sulfamoyl)sulfa devices, compositions, and methods of the invention include, nilanilide, p-nitrosulfathiazole, noprylsulfamide, phthalyl without limitation, ciprofloxacin (commercially available as Sulfacetamide, phthalylsulfathiazole, Salazosulfadimidine, CiproR), enrofloxacin (commercially available as BaytrilR), Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sul enoxacin (commercially available as PenetrexR), gatifloxa fachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiaz cin (commercially available as Tequin R.), gemifloxacin ine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfa US 2010/0062974 A1 Mar. 11, 2010 ethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic selected from fluoroquinolones, aminoglycosides, B-lactams, acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame glycopeptide antibiotics, Sulfonamides, and antifungal azoles thizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxy is more effective in treating bacterial infections and reducing pyridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamox bacterial growth than either agent alone. We have also dis ole, Sulfanilamide, Sulfanilamidomethanesulfonic acid covered that a combination of a Sulfonamide (e.g., Sul triethanolamine salt, 4-sulfanilamidosalicyclic acid, N4-sul famethoxazole) and a second agent selected from B-lactams fanilylsulfanilamide, sulfanily lurea, N-sulfanilyl-3,4-xyla and antifungal azoles is more effective in treating bacterial mide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sulfaproxy infections and reducing bacterial growth than either agent line, Sulfapyrazine, Sulfapyridine, Sulfasomizole, alone. Thus, the invention features compositions, methods, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, and kits including these effective combinations, which can be Sulfisomidine and Sulfisoxazole. useful for the treatment and prevention of infections. 0070. As used herein, the term “treating refers to admin 0075. The invention is described in greater detail below. istering a pharmaceutical composition, or a biodegradable polymer of the invention, for prophylactic and/or therapeutic Therapy purposes. A "prophylactic' use refers to reducing the likeli hood or severity of a condition or disease in a subject who is 0076. The compositions, methods, and kits described not yet ill, but who is susceptible to, or otherwise at risk of a herein can be used to treat or prevent bacterial and/or fungal particular disease by administering treatment to the Subject. infections as well as diseases associated with bacterial and/or To “treat disease' or use for “therapeutic treatment” refers to fungal infections. administering treatment to a Subject already suffering from a 0077 Bacterial infections that can be treated or prevented disease to improve or stabilize the subject's condition. Thus, using the combinations of the invention include, for example, in the claims and embodiments, treating is the administration respiratory tract infections (e.g., inhalation anthrax), acute to a Subject either for therapeutic or prophylactic purposes. bacterial otitis media, bacterial pneumonia, urinary tract 0071. By “subject' is meant any animal (e.g., a human). infections, complicated infections, noncomplicated infec Other animals that can be treated using the methods, compo tions, pyelonephritis, intra-abdominal infections, deep sitions, and kits of the invention include horses, dogs, cats, seated abcesses, bacterial sepsis, skin and skin structure pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, infections (e.g., cutaneous anthrax), soft tissue infections mice, lizards, Snakes, sheep, cattle, fish, and birds. (e.g., endometritis), bone and joint infections (e.g., osteomy 0072 The term “pharmaceutically acceptable salt' repre elitis, septic arthritis), central nervous system infections (e.g., sents those salts which are, within the scope of sound medical meningitis), bacteremia, wound infections, peritonitis, men judgment, Suitable for use in contact with the tissues of ingitis, infections after burn, urogenital tract infections, gas humans and lower animals without undue toxicity, irritation, tro-intestinal tract infections (e.g., antibiotic-associated coli allergic response and the like, and are commensurate with a tis, gastrointestinal anthrax), pelvic inflammatory disease, reasonable benefit/risk ratio. Pharmaceutically acceptable and endocarditis. salts are well known in the art. The salts can be prepared in 0078 Fungal infections that can be treated or prevented situ during the final isolation and purification of the com using the combinations of the invention include, for example, pounds of the invention, or separately by reacting the free Superficial or systemic mycoses. Superficial mycoses include base function with a Suitable organic acid. Representative tinea capitis, tinea corporis, tinea pedis, onychomycosis, peri acid addition salts include acetate, adipate, alginate, ascor onychomycosis, pityriasis versicolor, oral thrush, and other bate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, candidoses such as vaginal, respiratory tract, biliary, eosoph butyrate, camphorate, campherSulfonate, citrate, cyclopen ageal, and urinary tract candidoses. Systemic mycoses tanepropionate, digluconate, dodecylsulfate, ethane include systemic and mucocutaneous candidosis, cryptococ Sulfonate, fumarate, glucoheptonate, glycerophosphate, cosis, aspergillosis, mucormycosis, paracoccidioidomycosis, hemisulfate, heptonate, hexanoate, hydrobromide, hydro North American blastomycosis, histoplasmosis, coccidioido chloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethion mycosis, and sporotrichosis. ate, lactobionate, lactate, laurate, lauryl Sulfate, malate, male ate, malonate, mesylate, methanesulfonate, Other Uses 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropi 0079 Combinations of the invention can be incorporated onate, phosphate, picrate, pivalate, propionate, Stearate, suc into, for example, unpreserved food, beverages, contact lens cinate, Sulfate, tartrate, thiocyanate, toluenesulfonate, unde products, food ingredients, or cosmetics, such as lotions, canoate, Valerate salts, and the like. Representative alkali or creams, gels, ointments, Soaps, shampoos, conditioners, anti alkaline earth metal salts include Sodium, lithium, potassium, perspirants, deodorants, mouthwash, contact lens products, calcium, magnesium, and the like, as well as nontoxic ammo enzyme formulations, in an amount effective for killing or nium, quaternary ammonium, and amine cations, including, inhibiting the growth of fungal or bacterial pathogens. but not limited to ammonium, tetramethylammonium, tetra 0080 Thus, a combination of the invention may be useful ethylammonium, methylamine, dimethylamine, trimethy as a disinfectant, e.g., in the treatment of acne, eye infections, lamine, triethylamine, ethylamine, and the like. Desirably, the mouth infections, fingernail infections, top nail infections, pharmaceutical salt is a Zinc salt. skin infections, wounds, or in treating infections caused by 0073. Other features and advantages of the invention will the insertion of stents. Combinations of the invention are also be apparent from the Detailed Description and the claims. useful for cleaning, disinfecting, or inhibiting fungal or bac terial growth on any hard Surface. Examples of Surfaces DETAILED DESCRIPTION which may advantageously be contacted with a combination 0.074. We have discovered that a combination of a mem of the invention are surfaces of process equipment used in brane active biocide (e.g., chlorhexidine) and a second agent dairies, chemical or pharmaceutical process plants, water US 2010/0062974 A1 Mar. 11, 2010

sanitation systems, paper pulp processing plants, water treat menoXime, cefodizime, cefonicid, cefoperaZone, ceforanide, ment plants, cooling towers, cooking utensils, or surfaces in cefotaxime, cefotiam, cefpimizole, cefpirimide, cefpo any area in which food is prepared (e.g., hospitals, nursing doXime proxetil, cefroxadine, cefsulodin, ceftazidime, homes, or restaurants). cefiteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, 0081. In addition, combinations of the invention are useful cefuroxime, cefuZonam, cephacetrile sodium, cephalexin, for cleaning, disinfecting, or inhibiting fungal or bacterial cephaloglycin, cephaloridine, cephalosporin, cephalothin, growth on or in an in-dwelling device in a patient. In-dwelling cephapirin Sodium, cephradine, pivoefalexin, cephalothin, cefaclor, cefotetan, cefprozil, loracarbef, cefetamet, and devices include, but are not limited to, Surgical and dental cefepime; cephamycins such as cefbuperaZone, cefimetazole, implants, prosthetic devices, artificial joints, heart valves, cefninox, cefetan, and cefoxitin: monobactams such as aztre pacemakers, vascular grafts, vascular catheters, stents, cere onam, carumonam, and tigemonan, oxacephems such as flo broSpinal fluid shunts, urinary catheters, and continuous moxef and moxolactam; lincosamides such as clindamycin ambulatory peritoneal dialysis (CAPD) catheters. A combi and lincomycin; macrollides Such as azithromycin, carbomy nation of the invention may be used to bathe an in-dwelling cin, clarithromycin, erythromycin(s) and derivatives, josa device immediately before insertion. Alternatively, the com mycin, leucomycins, midecamycins, miokamycin, oleando bination may be administered by injection to achieve a local mycin, primycin, rokitamycin, rosaramicin, roXithromycin, or systemic effect against relevant micro-organisms shortly spiramycin and troleandomycin; polypeptides such as before insertion of an in-dwelling device. Treatment may be amphomycin, bacitracin, capreomycin, colistin, enduracidin, continued after Surgery during the in body time of the device. enylomycin, fusafungine, gramicidin(s), gramicidinS, mika 0082 Moreover, the compositions of the invention are mycin, polymyxin, polymyxin B-methanesulfonic acid, pris useful as Veterinary products for treating Socially and/or eco tinamycin, ristocetin, teicoplanin, thiostrepton, tuberactino nomically valuable non-human vertebrate animals, such as mycin, tyrocidine, tyrothricin, Vancomycin, viomycin(s), pets and laboratory animals (horses, dogs, cats, rabbits, ham Virginiamycin and Zinc bacitracin, tetracyclines such as Spi sters, monkeys, guinea pigs, rats, mice, lizards, Snakes), live cycline, chlortetracycline, clomocycline, demeclocycline, stock, fish, captive aquatic mammals, and birds. For land doxycycline, guamecycline, lymecycline, meclocycline, based animals, the compositions can be incorporated into methacycline, minocycline, oxytetracycline, penimepicy feed, drinking water, or administered by IV, topically, or by cline, pipacycline, rollitetracycline, sancycline, Senociclin other methods Suitable for treating the particular animal in and tetracycline; and 2,4-diaminopyrimidines Such as brodi need of such treatment. For fish and other aquatic animals, the moprim, tetroXoprim and trimethoprim; nitrofurans such as compositions may be administered by, e.g., food, or added to furaltadone, furazolium, nifuradene, nifuratel, nifurfoline, aquarium or tank water, and may be combined with other nifurpirinol, nifurprazine, nifurtoinol and nitrofurantoin: Sul agents usually administered to aquatic animals, or the tank or fonamides such as acetyl sulfamethoxypyrazine, acetyl aquarium, e.g. anti-algae agents, antimolluscides, and anti Sulfisoxazole, azosulfamide, benzylsulfamide, chloramine-B, helmintics (e.g., niclosamide). chloramine-T. dichloramine-T, formosulfathiazole, N-formyl-sulfisomidine, Na-B-D-glucosylsulfanilamide, Additional Agents mafenide, 4'-(methyl-sulfamoyl)sulfanilanilide, p-nitrosul fathiazole, noprylsulfamide, phthalylsulfacetamide, 0083. The compositions, methods, and kits of the inven phthalylsulfathiazole, Salazosulfadimidine, Succinylsul tion can further include an additional antibiotic agent selected fathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy from: aminoglycosides, such as amikacin, apramycin, ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadi arbekacin, bambermycins, butirosin, dibekacin, dihydros cramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, treptomycin, fortimicin(s), fradiomycin, gentamicin, ispami Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic acid, Sul cin, kanamycin, micronomicin, neomycin, neomycin unde famerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sul cylenate, netilmicin, paromomycin, ribostamycin, sisomicin, famethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, spectinomycin, streptomycin, streptonicozid, and tobramy Sulfametrole, Sulfamidochrysoidine, SulfamoXole, Sulfanil cin; amphenicols, such as azidamfenicol, chloramphenicol, amide, Sulfanilamidomethanesulfonic acid triethanolamine chloramphenicol palmirate, chloramphenicol pantothenate, salt, 4-sulfanilamidosalicyclic acid, N-sulfanilylsulfanil florfenicol, and thiamphenicol; ansamycins, such as amide, sulfanily lurea, N-sulfanilyl-3,4-xylamide, sulfanit rifampin, rifabutin, rifapentine, and rifaximin; B-Lactams, ran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyra Such as amidinocillin, amdinocillin, pivoxil, amoxicillin, Zine, Sulfapyridine, Sulfasomizole, Sulfasymazine, ampicillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine and benzylpenicillinic acid, benzylpenicillin, carbenicillin, Sulfisoxazole, Sulfones, such as acedapsone, acediasulfone, carfecillin, carindacillin, clometocillin, cloxacillin, cyclacil acetosulfone, dapsone, diathymosulfone, glucosulfone, Sola lin, dicloxacillin, diphenicillin, epicillin, fenbenicillin, flox Sulfone, Succisulfone, Sulfanilic acid, p-sulfanilylbenzy icillin, hetacillin, lenampicillin, metampicillin, methicillin, lamine, p.p'-sulfonyldianiline-N,N'digalactoside, Sulfoxone meZlocillin, nafcillin, oxacillin, penamecillin, penethamate and thiazolsulfone; lipopeptides Such as daptomycin; hydriodide, penicillin G benethamine, penicillin G benza oxazolidones Such as lineZolid; ketolides Such as tellithromy thine, penicillin G benzhydrylamine, penicillin G calcium, cin; and miscellaneous antibiotics Such as clofoctol, hexe penicillin G hydragamine, penicillin G potassium, penicillin dine, magainins, methenamine, methenamine anhydrometh G, procaine, penicillinN, penicillin O, penicillinV, penicillin ylene-citrate, methenamine hippurate, methenamine V benzathine, penicillin V hydrabamine, penimepicycline, mandelate, methenamine Sulfosalicylate, nitroxoline, phenethicillin, piperacillin, pivapicillin, propicillin, quinacil squalamine, Xibornol, cycloserine, mupirocin, and tuberin. lin, Sulbenicillin, talampicillin, temocillin and ticarcilling car bapenems, such as imipenem; cephalosporins, such as Administration 1-carba (dethia) cephalosporin, cefactor, cefadroxil, cefa I0084. In particular embodiments of any of the methods of mandole, cefatrizine, cefaZedone, cefazolin, cefixime, cef the invention, the two components of the combination therapy US 2010/0062974 A1 Mar. 11, 2010

are administered within 10 days of each other, within five I0089. Each compound of the combination may be formu days of each other, within twenty-four hours of each other, or lated in a variety of ways that are known in the art. For simultaneously. The compounds may be formulated together example, the first and second agents may be formulated as a single composition, or may be formulated and adminis together or separately. Desirably, the first and second agents tered separately. are formulated together for the simultaneous or near simul 0085. Therapy according to the invention may be per taneous administration of the agents. Such co-formulated formed alone or in conjunction with another therapy and may compositions can include the two active agents (e.g., chlo be provided at home, the doctor's office, a clinic, a hospital’s rhexidine and ciprofloxacin) formulated together either in a outpatient department, or a hospital. Treatment optionally unit dosage form (e.g., in the same pill, capsule, or tablet) or begins at a hospital so that the doctor can observe the thera non-unit dosage form (e.g., cream, liquid, or powder). It is to py's effects closely and make any adjustments that are be understood that, when referring to the formulation of two needed, or it may begin on an outpatient basis. The duration of agents in a combination therapy, the formulation technology the therapy depends on the type of disease or disorder being employed is also useful for the formulation of the individual treated, the age and condition of the Subject, the stage and agents of the combination, as well as other combinations of type of the Subject's disease, and how the Subject responds to the invention. By using different formulation strategies for the treatment. Additionally, a person having a greater risk of different agents, the pharmacokinetic profiles for each agent developing a bacterial infection (e.g., a person who is under going a Surgical procedure) may receive prophylactic treat can also be suitably matched. ment. 0090 Controlled Release Formulations 0.086 Routes of administration for the various embodi 0091 Administration of a combination of the invention in ments include, but are not limited to, topical, transdermal, and which one or both of the active agents is formulated for systemic administration (such as, intravenous, intramuscular, controlled release is useful where one of the agents, has (i) a Subcutaneous, inhalation, rectal, buccal, vaginal, intraperito narrow therapeutic index (e.g., the difference between the neal, intraarticular, ophthalmic or oral administration). As plasma concentration leading to harmful side effects or toxic used herein, “systemic administration” refers to all nonder reactions and the plasma concentration leading to a therapeu mal routes of administration, and specifically excludes topi tic effect is Small; generally, the therapeutic index, TI, is cal and transdermal routes of administration. defined as the ratio of median lethal dose (LDso) to median effective dose (EDs)); (ii) a narrow absorption window in the 0087. In combination therapy, the dosage and frequency of gastro-intestinal tract; (iii) a short biological half-life; or (iv) administration of each component of the combination can be the pharmacokinetic profile of each component must be controlled independently. For example, one compound may modified to maximize the contribution of each agent, when be administered three times per day, while the second com used together, to an amount of that is therapeutically effective pound may be administered once per day. Combination for treating or preventing bacterial infections. Accordingly, a therapy may be given in on-and-off cycles that include rest Sustained release formulation may be used to avoid frequent periods so that the subject's body has a chance to recover from dosing that may be required in order to Sustain the plasma any as yet unforeseen side effects. The compounds may also levels of both agents at a therapeutic level. For example, in be formulated together such that one administration delivers preferable oral pharmaceutical compositions of the invention, both compounds. half-life and mean residency times from 10 to 20 hours for one or both agents of the combination of the invention are Formulation observed. 0088. The administration of a combination of the inven 0092. Many strategies can be pursued to obtain controlled tion (e.g., a membrane active biocide/fluoroquinolone com release in which the rate of release outweighs the rate of bination) may be by any suitable means that results in an metabolism of the therapeutic compound. For example, con amount Sufficient to treat a bacterial infection or an amount trolled release can be obtained by the appropriate selection of effective to reduce bacterial growth at a target site. A com formulation parameters and ingredients (e.g., appropriate pound may be contained in any appropriate amount in any controlled release compositions and coatings). Examples Suitable carrier Substance, and is generally present in an include single or multiple unittablet or capsule compositions, amount of 1-95% by weight of the total weight of the com oil solutions, Suspensions, emulsions, microcapsules, micro position. The composition may be provided in a dosage form spheres, nanoparticles, patches, and liposomes. The release that is suitable for the oral, parenteral (e.g., intravenously, mechanism can be controlled such that the one or both of the intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, agents are released at period intervals, the release could be skin (patch), or ocular administration route. Thus, the com simultaneous, or a delayed release of one of the agents of the position may be in the form of, e.g., tablets, capsules, pills, combination can be affected, when the early release of one powders, granulates, Suspensions, emulsions, solutions, gels particular agent is preferred over the other. including hydrogels, pastes, ointments, creams, plasters, 0093 Controlled release formulations may include a drenches, osmotic delivery devices, Suppositories, enemas, degradable or nondegradable polymer, hydrogel, organogel, injectables, implants, sprays, or aerosols. The pharmaceutical or other physical construct that modifies the bioabsorption, compositions may be formulated according to conventional half-life or biodegradation of the agent. The controlled pharmaceutical practice (see, e.g., Remington: The Science release formulation can be a material that is painted or other and Practice of Pharmacy, 20th edition, 2000, ed. A. R. wise applied onto the afflicted site, either internally or exter Gennaro, Lippincott Williams & Wilkins, Philadelphia, and nally. In one example, the invention provides a biodegradable Encyclopedia of Pharmaceutical Technology, eds. J. Swar bolus or implant that is Surgically inserted at or near a site of brick and J. C. Boylan, 1988-1999, Marcel Dekker, New interest (for example, proximal to placement of a catheter). In York). another example, the controlled release formulation implant US 2010/0062974 A1 Mar. 11, 2010 can be inserted into the body as part of a Surgical procedure The coupling segments can be synthesized from the groups of utilizing the combination to reduce the risk of infection at the precursor monomers selected from diols, diamines and/or a site of implantation. compounds containing both amine and hydroxyl groups. Pre 0094 Kits, Packaging, and Instructions cursors that can be incorporated into coupling segments 0095. The individually or separately formulated agents include, without limitation, ethylene glycol, butane diol, hex can be packaged together as a kit. Non-limiting examples ane diol, hexamethylene diol. 1.5 pentanediol. 2,2-dimethyl include kits that contain, e.g., two pills, a pill and a powder, a 1.3 propanediol. 1.4-cyclohexane diol, 1.4-cyclohex Suppository and a liquid in a vial, two topical creams, etc. The anedimethanol, tri(ethylene glycol), poly(ethylene glycol), kit can include optional components that aid in the adminis poly(ethylene oxide) diamine, lysine esters, silicone diols and tration of the unit dose to Subjects, such as vials for reconsti diamines, polyether diols and diamines, carbonate diols and tuting powder forms, Syringes for injection, customized IV diamines, dihydroxy vinyl derivatives, dihydroxy diphenyl delivery systems, inhalers, etc. Additionally, the unit dose kit Sulfone, ethylene diamine, hexamethylene diamine, 1,2-di can contain instructions for preparation and administration of amino-2 methylpropane, 3.3-diamino-n-methyldipropy the compositions. The kit may be manufactured as a single lamine, 1.4 diaminobutane, 1.7 diaminoheptane, 2.2.4- use unit dose for one subject, multiple uses for a particular trimethylhexamethylene diamine, and 1.8 diaminooctane. Subject (at a constant dose or in which the individual com (0099 Blends with Base Polymers pounds may vary in potency as therapy progresses); or the kit 0100 Where the biodegradable polymer of the invention may contain multiple doses Suitable for administration to does not have base polymer properties, it may be desirable to multiple Subjects (“bulk packaging”). The kit components prepare a blend with a base polymer to produce the requisite may be assembled in cartons, blisterpacks, bottles, tubes, and mechanical properties, e.g., for a shaped article. Desirably, the like. the polymer of the invention is concentrated within the nm 0096. The methods and compositions of the present inven region of the exterior polymer interface and is designed to be tion can be disclosed in the form of instructions for the admin thermodynamically compatible with the base polymer to pre istration of a combination of the invention. Typically, the vent phase separations. method is disclosed to a Subject along with the sale or distri 0101 Many materials having base polymer properties are bution of the compositions or kit. In some instances, instruc known in the art. Base polymers useful in the blends of the tions may be included on a label or on a package insert invention can include, without limitation, polyurethane, accompanying a pharmaceutical formulation containing a polysulfones, polycarbonates, polysaccharides, polyesters, combination of the invention. The method of the present polyethylene, polypropylene, polystyrene, poly(acryloni invention can be incorporated into a prepackaged therapeutic trile-butadienestyrene), polybutadiene, polyisoprene, Sty regimen designed to deliver a loading-dose regimen of a renebutadiene-styrene block copolymers, styrene-isoprenes combination of the invention to a subject using the prepack tyrene block copolymers, poly-R-methylpentene, aged regimen. For example, the two agents of the combina polyisobutylene, polymethyl-methacrylate, polyvinylac tion can be packaged in separate dosage units containing etate-polyacrylonitrile, polyvinyl chloride, polyethylene varying quantities of each agent along with instructions to the terephthalate, cellulose and its esters and derivatives, polya Subject describing the timing and order in which the dosage mides, polyester-polyethers, styrene-isoprenes, units should be administered. Such doses may consist, for styrenebutadienes, thermoplastic polyolefins, styrene-satu example, of one or more tablets, pills, capsules, or caplets. rated olefins, polyester-polyester, ethylene-vinyl acetate eth ylene-ethyl acrylate, ionomers, and thermoplastic poly Biodegradable Polymers dienes. 0097. In particular embodiments of any of the methods, compositions, and kits of the invention, the one or both agents Shaped Articles of the combination are incorporated as repeating units into a 0102 Articles of the invention can beformed from a phar pharmaceutically-active biodegradable polymer. maceutically-active polymer of the invention used either 0098. Such biodegradable polymers can be prepared alone or as a blend with a base polymer. One advantage of using, for example, the methods described in U.S. Pat. No. using a polymer of the invention alone as the base polymer to 5,798,115 and PCT Publ. No. WO20051 10485, both of which form a shaped article is that because there is no polymer are incorporated herein by reference. The biodegradable mixing, there is no reduction in entropy and no possibility of polymers of the invention optionally further include an oli phase separation. gomeric segment separating the agent(s) incorporated into 0103) Any shaped article can be made using the composi the backbone of the polymer. By "oligomeric segment” or tions of the invention. For example, articles suitable for con “Oligo' is meant a relatively short length of a repeating unit tact with bodily fluids, such as medical devices can be made or units, generally less than about 50 monomeric units and using the compositions described herein. The duration of molecular weights less than 5,000 but preferably <3,000. contact may be short, for example, as with Surgical instru Preferably, Oligo is selected from polytetramethylene oxide, ments or long term use articles Such as implants. The medical polycaprolactone, and mixtures thereof. The components devices include, without limitation, catheters, guide wires, (e.g., oligomeric segment, a first agent, and a second agent) of vascular stents, micro-particles, electronic leads, probes, sen the biodegradable polymers of the invention can be linked sors, drug depots, transdermal patches, vascular patches, directly, or via a coupling segment. By “coupling segment” is blood bags, and tubing. The medical device can be an meant a molecule or chemical bond covalently linking seg implanted device, percutaneous device, or cutaneous device. ments together in the pharmaceutically-active polymer. Typi Implanted devices include articles that are fully implanted in cally, coupling segments can have molecular weights ranging a patient, i.e., are completely internal. Percutaneous devices from 16 to 2,000 Da and have multi-functionality, but pref include items that penetrate the skin, thereby extending from erably di-functionality, to permit coupling of two segments. outside the body into the body. Cutaneous devices are used US 2010/0062974 A1 Mar. 11, 2010

Superficially. Implanted devices include, without limitation, measuring at 600 nm wavelength. This is a suspension con prostheses Such as pacemakers, electrical leads such as pac taining approximately x10 CFU/mL of microbe. The sus ing leads, defibrillators, artificial hearts, Ventricular assist pension was diluted in MH broth so that, after dilution, the devices, anatomical reconstruction prostheses such as breast tube contained approximately 5x10 CFU/mL, and after implants, artificial heart Valves, heart valve stents, pericardial inoculation, each well contains approximately 5x10 CFU/ patches, Surgical patches, coronary stents, vascular grafts, mL. vascular and structural stents, vascular or cardiovascular shunts, biological conduits, pledges, Sutures, annuloplasty 0110 Broth dilution procedure: small volumes of MH rings, stents, staples, valved grafts, dermal grafts for wound broth dispensed in sterile, polystyrene, non-pyrogenic tissue healing, orthopedic spinal implants, orthopedic pins, intrau culture plates, 96 well, flat bottoms with low evaporation lid terine devices, urinary stents, maxial facial reconstruction were prepared (each well contained 0.1 mL of MH broth) plating, dental implants, intraocular lenses, clips, sternal followed by the final two fold dilutions of antimicrobial agent wires, bone, skin, ligaments, tendons, and combination dispensed volumetrically into the broth. The MIC was deter thereof. Percutaneous devices include, without limitation, mined using concentrations derived from serial twofold dilu catheters or various types, cannulas, drainage tubes such as tions indexed to the base 2 (e.g., 1, 2, 4, 8, 16 ug/mL ... etc.). chest tubes, Surgical instruments such as forceps, retractors, 0111 Inoculation: each well of a microdilution plate was needles, and gloves, and catheter cuffs. Cutaneous devices inoculated. The purity of the inoculum Suspension was include, without limitation, burn dressings, wound dressings checked by Sub-culturing an aliquot on to MH agar plate. and dental hardware. Such as bridge Supports and bracing Colony counts on inoculum Suspensions were performed components. periodically, to ensure that the final inoculum concentration 0104. An implantable medical device as described above was approximately 5x10 CFU/mL. Both a positive (0.1 mL is generally structured from a base metallic or polymeric of MH broth with 10 uL of inoculum) and a negative (0.1 mL platform in a solid state format. The polymer of the invention of MH Broth only) control were performed with each microti within this primary platform, either alone or as a blend, con tre plate. To prevent drying, each plate was sealed with para trols the release of therapeutic agents from the device. film and the plates were kept in a moist chamber while incu 0105. The following examples are put forth so as to pro bating at 37° C. overnight, in a shaking incubator. vide those of ordinary skill in the art with a complete disclo 0112 Determining MIC endpoints: The MIC is defined as sure and description of how the methods and compounds the lowest concentration of an antimicrobial that will inhibit claimed herein are performed, made, and evaluated, and are growth of a microorganism. The in plate dilution method the intended to be purely exemplary of the invention and are not endpoint is detected by the unaided eye. If, for example, in a intended to limit the scope of what the inventors regard as two fold dilution scheme-if one detects growth at 2 Lig/mL, their invention. the MIC is reported between 4 and 2 ug/mL. The results are summarized in Table 1 and Table 2 below. Example 1 TABLE 1 Determination of the Minimum Inhibitory Concen tration (MIC) MIC Data MIC (ig/mL) 0106 Broth dilution method was used to measure quanti Microorganism tatively the in vitro activity of an antimicrobial agent against a given bacterial isolate. First, a series of tubes/wells were P prepared with a broth medium to which various concentra Agent(s) E. coi Airegenosa S. Airetts tions of the antimicrobial agents were added. The tubes/wells Monotherapy were then inoculated with standardized suspension of the test Ciprofloxacin O.OOS-O.OO78 O.156-0.25 0.156-0.2 organism. After overnight incubation at 35+2°C., the tests Polymixin B 7.8-10 3.12S-SO 62.5-1OO.O were examined and the minimum inhibitory concentration Chlorhexidine 3.13-4.O 40-50 3.125-4.O (MIC) was determined. The procedures were performed Bacitracin 1000-12SO 4OOO-SOOO 35-40 under aseptic conditions. Aztreonam O.O78-0.097 1562-19.0 625-12SO Gentamicin 1.25-2.5 O.625-12S N.D. 0107 Stock culture: Stock cultures were maintained in Vancomycin 1900-3800 N.D. N.D. Mueller Hinton Broth containing 15% Glycerol and stored at Amoxicillin N.D. 2SO-SOO 31.25-62.5 -80° C. Stock cultures were sub-cultured on to Mueller Hin Sulfamethoxazole N.D. N.D. 64 O-700 ton Agar (MHA), and incubated overnight at 37°C. Miconazole N.D. N.D. 45.O-900 0108 Preparation of inoculum: a single isolated colony of Combination Therapy the same morphologic type from the MHagar plate culture Ciprofloxacin/Bacitracin N.I. O.O78-0.125° N.I. Bacitracin/Ciprofloxacin/ N.I. 625-1250 N.I. was selected, inoculated into a sterile tube containing 25 mL Ciprofloxacin/ O.OO2S-O.OO39° N.I. N.I. of MH broth, and incubated at 37° C. overnight in a shaking Chlorhexidine incubator. Chlorhexidine? O.125-0.195 N.I. N.I. Ciprofloxacin 0109 Washing of cells: the cells were washed with PBS Ciprofloxacin/Polymixin B 0.0025-0.0039° N.I. N.I. (pH 7.1) by centrifuging at 3000 rpm for 10 minutes. A cell Polymixin B/Ciprofloxacin 1.25-1.95 N.I. N.I. suspension in Mueller Hinton broth (MHB) having a turbidity Aztreonam Chlorhexidine N.I. 0.625-0.78' N.I. equivalent to a 0.5 McFarland turbidity standard was pre Chlorhexidine, Aztreonam N.I. 7.8-9.76 N.I. pared using a Beckman Coulter DU 800 Spectrophotometer US 2010/0062974 A1 Mar. 11, 2010

TABLE 1-continued TABLE 2-continued

MIC Data MIC Data MIC (ig/mL) MIC (ig/mL) Microorganism Microorganism Agent(s) C. Albicans P Ciprofloxacin, Miconazole 0.125-0.155 Agent(s) E. coi Airegenosa S. Airetts Miconazole? Ciprofloxacin O7-14 Polymixin B/Gentamicin 3.9-5.0 2.5-3.125° N.I. The MIC of ciprofloxacin is reduced in the presence of a membrane active Gentamicin/Polymixin B O.25-0.3125 0.15-0.25 N.I. biocide. Polymixin B/Aztreonam 2.5-3.125° N.I. N.I. The data reported for each combination therapy refers to the MIC in g/mL Aztreonam Polymixin B O.O24-O.O39 N.I. N.I. of the first agent listed. The second agent of the combination therapy is Polymixin B/Vancomycin N.I. 1.56-2.5° N.I. present at a concentration some number of dilutions below the lower MIC Vancomycin/Polymixin B N.I. 16.0-250 N.I. limit observed for the use of the second agent as a monotherapy (i.e., for Bacitracin Aztreonam N.I. 2000-25OOf 17.5-2Of chlorhexidine the concentration is less than 3.13 g/mL). Thus, the second Aztreonam Bacitracin N.I. 2.44-4.88 78.1-156.2 agent is present in an amount at which no inhibition of microbial growth Polymixin B. Amoxicillin N.I. 0.975-1253 N.I. should be observed when used as a monotherapy. Amoxicillin/Polymixin B N.I. 64.O-128.O. N.I. Bacitracini Amoxicillin N.I. 1000-2000' N.I. 0113. The results provided in Tables 1 and 2 show that the Amoxicillin Bacitracin N.I. 62.5-12S.O. N.I. combinations of the invention can work together synergisti Polymixin B. Miconazole N.I. N.I. 7.8-15.6 cally to produce a composition having Superior and unex Miconazole Polymixin B N.I. N.I. 11.25-22.5 pected antibacterial and antifungal properties in comparison Bacitracin Miconazole N.I. N.I. 10.0-12.5i Miconazole Bacitracin N.I. N.I. 5.6-11.25 to the use of the individual components alone. Miconazole Sulfa N.I. N.I. 11.25-22.5 Sulfa Miconazole N.I. N.I. 16.0-25.O Example 2 Amoxicillin Sulfa N.I. N.I. 7.8-15.6 Sulfa. Amoxicillin N.I. N.I. 16.0-25.O General Synthesis of Bioactive Monomers Contain N.D. = no data. ing a Membrane Active Biocide or a Fluoroqui N.I. = no improvement over the monotherapy MIC data was observed. nolone a = Sulfamethoxazole “The MIC of ciprofloxacin is reduced in the presence of a membrane active 0114. A protocol for the general synthesis of a biological biocide. coupling agents (e.g., a membrane active biocide-containing The MIC of aztreonam is reduced in the presence of chlorhexidine. The MIC of gentamicin is reduced in the presence of a membrane active monomeric unit or a fluoroquinolone-containing monomeric biocide unit) is set forth below in steps A-D and Scheme A. The MIC of aztreonam is reduced in the presence of polymixin B. 0115 STEPA: The MIC of vancomycin is reduced in the presence of a second membrane active biocide in a gram negative organism (Note: Vancomycin not active 0116. To a dry 2 L round bottom flask flushed with nitro against gram negative bacteria.) gen was added ciprofloxacin hydrochloride (100 g, 301.8 The MIC of aztreonam is reduced in the presence of aztreonam. mmol), trityl chloride (185.1 g, 663.9 mmol) and chloroform 8The MIC of amoxicillin is reduced in the presence of polymixin B. "The MIC of amoxicillin is reduced in the presence of bacitracin. (1000 mL). To this stirring suspension triethylamine (135 The MIC of miconazole is reduced in the presence of a membrane active mL. 965.8 mmol) was added dropwise and the resulting mix biocide. ture was stirred at room temperature for 4 h, during which The MIC of sulfamethoxazole is reduced in the presence of a membrane time a homogeneous yellow solution resulted. The resulting active biocide. The data reported for each combination therapy refers to the MIC in g/mL solution was treated with methanol (500 mL) and stirred at of the first agent listed (i.e., ciprofloxacin or aztreonam). The second agent 50° C. for 1.5h. The resulting solution was washed with water of the combination therapy is present at a concentration some number of (2x2 L). The organic layer was dried over Sodium Sulphate, dilutions below the lower MIC limit observed for the use of the second agent filtered, and solvent removed under reduced pressure until as a monotherapy (i.e., for chlorhexidine the concentration is less than 3.13 IgmL). Thus, the second agent is present in an amount at which no inhibi precipitate first begins to form. A couple of drops of methanol tion of microbial growth should be observed when used as a monotherapy. was added and flask placed in refrigerator overnight. The product was collected by filtration (160 g, 90%). 0117 STEP B: TABLE 2 0118. To a dry 2 L round bottom flask flushed with nitro MIC Data gen was added 1 ((50 g., 87.16 mmol) and dichloromethane (900 mL). Reagent 1 was allowed to dissolve before the MIC (ig/mL) Microorganism addition of tri(ethyleneglycol) (6.23g, 41.45 mmol) and dim Agent(s) C. Albicans ethylaminopyridine (5.33 g, 43.59 mmol). The resulting solu tion was cooled to 0° C. before the addition of EDAC-HC1 Monotherapy (66.75 g, 348.2 mmol) and the reaction was allowed to con Ciprofloxacin >2.5 tinue overnight with warming then for a week at room tem Chlorhexidine 3.125-4.O perature. The progress of the reaction is monitored by TLC. Miconazole 1.4-2.8 Upon complete consumption of 1 as detected by TLC the Combination Therapy solvent is removed. Ciprofloxacin/Chlorhexidine O.312-0.625 0119 The product is recovered by recrystallization with Chlorhexidine/Ciprofloxacin 1.56-312S chloroform methanol. This produces 37.63 g (68%) of the desired product, C. US 2010/0062974 A1 Mar. 11, 2010 12

0120 STEP C: solution was approximately 8. Filtration of the white solid 0121 To a dry 1 L round bottom flask was added 2 (100 g, followed by washing with water (150 mL), and drying over 79.27 mmol) and dichloromethane (344 mL). To this stirring night under vacuum produced the desired product. This pro solution was added trifluoroacetic (24 mL), and water (12 duced 78.42 g (98%) of the compound 4. mL). The reaction was stirred at room temperature for 5 hours. The progress of the reaction was monitored by TLC. (0.124 'H NMR of CIPRO-TEG-CIPRO: (400 MHz, During the course of the reaction the desired STEPD: product DMSO). 8:9.16 (bs, 2H, NH R), 8.30 (s. 2H, H, ar), 7.49 precipitated from the reaction. The product was isolated by (d. 2H, J=13.2 Hz, H, ar), 7.34 (d. 2H, J=7.6 Hz, H, ar), 4.25 filtration and washed with chloroform (2x100 mL). This pro (t, 4H, J=5.2 Hz, N CH(CH)); 3.73 (t, 4H, J–4.4 Hz, duced 78.42 g (98%) of the desired product. COCH), 3.46-3.30 (m, 16H, piperazine), 1.22 (q, 4H. J–6.4 0122) STEP D: HZ, CH(CH, CH)), 1.07 (m, 4H, CH(CHCH)). 0123 To a dry 1 L round bottom flask was added 3 (100 g, (0.125 °C NMR of CIPRO-TEG-CIPRO: (400 MHz, 99.52 mmol), water (150 mL) and chloroform (200 mL). To DMSO). 8: 1719, 164.1, 158.7, 153.9, 151.5, 148.4, 143.0, this heterogeneous white mixture at room temperature was 142.9, 138.1, 122.6, 122.5, 111.9, 111.7, 109.2, 107.0, 79.6, slowly added a Saturated aqueous solution of Sodium bicar 70.5, 70.4, 68.9, 63.7, 47.0, 43.2, 35.3, 7.9. bonate. The reaction mixture effervesced upon each addition 0.126 ES-MS of CIPRO-TEG-CIPRO (m/z, %) (Positive of base. The progress of the reaction was followed by pH. The mode): Calculated for mass CHFNOs: 776 amu; found addition of bicarbonate solution was done until the pH of the 777 (M+H"): 389 (M+2H)".

Scheme A: Synthetic route for Bioactive Monomer O STEPA O F 1. TrC1/CHCl, F STEP B OH 4h OH Tri(ethylene glycol) He 2. MeOH EDACDMAPDCM r N N N RT for 1 week itsu R N R

1

r O N N F 1n-1 O N-1 no-1N1 O F

2

STEP C1% TFAf in DCM US 2010/0062974 A1 Mar. 11, 2010 13

-continued

N O Ca corr cri O 3 STEP pico

N N O O co------, rur N O 4

Example 3 and THDI (24 mL, 116.25 mmol). The reaction mixture was stirred for 4h at 65° C. before the addition of chlorhexidine Synthesis of Ciprofloxacin Polymer (18.96g, 37.5 mmol) solution in DMSO (100 mL) and dibu 0127. To a dry 1 L round bottom flask flushed with nitro tyltin dilaureate (2.7 mL, 4.5 mmol). The reaction was con gen was added polycaprolactone diol (200 g, 100 mmol). The tinued to stir for 17 hat 65° C. under inert atmosphere. The flask was heated to 70° C. for 2 hours under vacuum. The reaction was quenched with the addition of methanol (100 temperature was decreased to 65° C. before the addition of mL) and left to stir for an addition 1 hour. The polymer was DMSO (100 mL), dibutyltin dilaureate (3.2 mL, 5.0 mmol) transferred to a dropping funnel where it was added dropwise and THDI (32 mL, 155 mmol). The reaction mixture was to hexane (2L). Upon discarding the Supernatant, the polymer stirred for 1 h at 65° C. before the addition of 4 (38.84g, 50 was taken up in isopropanol and again added dropwise to mmol) solution in DMSO (500 mL) and dibutyltin dilaureate hexane (2 L). The process was repeated with water as the (1.8 mL, 3.0 mmol). The reaction was continued to stir for 17 precipitant. The resulting polymer mass is dissolved in iso h at 65° C. under inert atmosphere. The reaction was propanol. To this solution is added EDTA ammonium salt quenched with the addition of methanol (78 mL) and left to solution (described below) dropwise. The polymer is taken up stir for an addition 1 hour. The polymer was transferred to a in isopropanol and washed with water (1x1 L) and finally dropping funnel where it was added dropwise to hexane (2L). washed with hexane (2x1 L). Upon discarding the Supernatant, the polymer was taken up in isopropanol and again added dropwise to hexane (2 L). The Example 5 process was repeated with water as the precipitant. The result Article Coated with Ciprofloxacin Polymer and ing polymer mass is dissolved in isopropanol. To this solution Chlorhexidine Polymer was added EDTA ammonium salt solution (described below) dropwise. The polymer was taken up in isopropanol and I0129. The ciprofloxacin polymer and chlorhexidine poly washed with water (1x1 L) and finally washed with hexane mer described in examples 3 and 4 can be used in the methods (2x1 L). and kits of the invention. For example, the polymers can be used to coat a catheter cuff and thereby reduce the risk of Example 4 infection by locally releasing a membrane active biocide and fluoroquinolone in vivo following implantation of the cath Synthesis of Chlorhexidine Polymer eter in a Subject. 0128. To a dry 1 L round bottom flask flushed with nitro gen was added polycaprolactone diol (150 g, 75 mmol). The Other Embodiments flask was heated to 70° C. for 2 hours under vacuum. The 0.130 All publications, patent applications, and patents temperature was decreased to 65° C. before the addition of mentioned in this specification are herein incorporated by DMSO (400 mL), dibutyltin dilaureate (4.4 mL, 7.5 mmol) reference. US 2010/0062974 A1 Mar. 11, 2010

0131 While the invention has been described in connec kibdelin, orenticin, parvodicin, ramoplanin, ristocetin, risto tion with specific embodiments, it will be understood that it is mycin, Synmonicin, teicoplanin, Vancomycin, and Vancomy capable of further modifications. Therefore, this application cin B. is intended to cover any variations, uses, or adaptations of the 11. The composition of claim 10, wherein said glycopep invention that follow, in general, the principles of the inven tide antibiotic is Vancomycin. tion, including departures from the present disclosure that 12. The composition of claim 1, wherein said second agent come within known or customary practice within the art. is a Sulfonamide selected from acetyl sulfamethoxypyrazine, 0132 Other embodiments are within the claims. acetyl Sulfisoxazole, aZoSulfamide, benzylsulfamide, What we claim is: chloramine-B, chloramine-T, dichloramine-T, formosul 1. A composition comprising a membrane active biocide fathiazole, N2-formyl-sulfisomidine, N4-3-D-glucosylsulfa and a second agent selected from fluoroquinolones, ami nilamide, mafenide, 4'-(methyl-Sulfamoyl)sulfanilanilide, noglycosides, B-lactams, glycopeptide antibiotics, Sulfona p-nitrosulfathiazole, noprylsulfamide, phthalylsulfaceta mides, and antifungal azoles, wherein said membrane active mide, phthalylsulfathiazole, Salazosulfadimidine, Succinyl biocide and said second agent are present in amounts that Sulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy together are sufficient to treat a bacterial infection when ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, administered to a subject. Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethi 2. The composition of claim 1, wherein said membrane dole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic acid, active biocide is selected from chlorhexidine, polymyxin Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, B-nonapeptide, bacitracin, aztreonam, benzalkonium salts, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypy and metal chelators. ridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, 3. The composition of claim 2, wherein said membrane Sulfanilamide, Sulfanilamidomethanesulfonic acid triethano active biocide is chlorhexidine. lamine salt, 4-sulfanilamidosalicyclic acid, N4-sulfanilylsul 4. The composition of claim 1, wherein said second agent fanilamide, sulfanily lurea, N-sulfanilyl-3,4-xylamide, sul is a fluoroquinolone selected from ciprofloxacin, enrofloxa fanitran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, cin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lom Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, efloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfloxacin, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine and trovafloxacin, difloxacin, cinofloxacin, pefloxacin, to Sufloxa Sulfisoxazole. cin, temafloxacin, fleroxacin, amifloxacin, binfloxacin, dano 13. The composition of claim 12, wherein said sulfona floxacin, marbofloxacin, ruflocaxin, and Sarafloxacin. mide is Sulfamethoxazole. 5. The composition of claim 4, wherein said fluoroqui 14. The composition of claim 1, wherein said second agent nolone is ciprofloxacin. is an antifungal azole selected from miconazole, ketocona 6. The composition of claim 1, wherein said second agent Zole, clotrimazole, fluconazole, Voriconazole, raVuconazole, is an aminoglycoside selected from amikacin, apramycin, aZaconazole, bromuconazole bitertanol, propiconazole, arbekacin, bambermycins, butirosin, dibekacin, dihydros difenoconazole, diniconazole, cyproconazole, epoxicona treptomycin, fortimicin(s), fradiomycin, gentamicin, ispami Zole, fluquinconazole, flusilaZole, flutriafol, hexaconazole, cin, kanamycin, micronomicin, neomycin, neomycin unde itraconazole, imazalil, imibenconazole, ipconazole, tebu cylenate, netilmicin, paromomycin, ribostamycin, sisomicin, conazole, tetraconazole, fenbuconazole, metconazole, spectinomycin, streptomycin, streptonicozid, and tobramy myclobutanil, perfurazoate, penconazole, posaconazole, cin. pyrifenox, prochloraz, terconazole, triadimefon, triadimenol, 7. The composition of claim 6, wherein said aminoglyco triflumizole, and triticonazole. side is gentamicin. 15. The composition of claim 14, wherein said antifungal 8. The composition of claim 1, wherein said second agent azole is miconazole. is a B-lactam selected from amidinocillin, amdinocillin, piv 16. The composition of claim 1, wherein said composition oxil, amoxicillin, amplicillin, aspoxicillin, azidocillin, comprises a biodegradable polymer having a first repeating aZlocillin, bacampicillin, benzylpenicillinic acid, benzyl unit and a second repeating unit, said first repeating unit penicillin, carbenicillin, carfecillin, carindacillin, clometocil comprising a membrane active biocide and said second lin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin, epi repeating unit comprising an agent selected from fluoroqui cillin, fenbenicillin, floxicillin, hetacillin, lenampicillin, nolones, aminoglycosides, 3-lactams, glycopeptide antibiot metampicillin, methicillin, meZlocillin, nafcillin, oxacillin, ics, Sulfonamides, and antifungal azoles. penamecillin, penethamate hydriodide, penicillin G beneth 17. The composition of claim 1, wherein said composition amine, penicillin G benzathine, penicillin G benzhydry comprises (i) a biodegradable polymer comprising a repeat lamine, penicillin G calcium, penicillin Ghydragamine, peni ing unit comprising a membrane active biocide and (ii) an cillin G potassium, penicillin G, procaine, penicillin N. agent selected from fluoroquinolones, aminoglycosides, penicillin O, penicillinV, penicillinV benzathine, penicillinV B-lactams, glycopeptide antibiotics, Sulfonamides, and anti hydrabamine, penimepicycline, phenethicillin, piperacillin, fungal azoles. pivapicillin, propicillin, quinacillin, Sulbenicillin, talampicil 18. The composition of claim 1, wherein said composition lin, temocillin and ticarcillin. comprises (i) a biodegradable polymer comprising a repeat 9. The composition of claim 8, wherein said B-lactam is ing unit comprising an agent selected from fluoroquinolones, amoxicillin. aminoglycosides, B-lactams, glycopeptide antibiotics, Sul 10. The composition of claim 1, wherein said second agent fonamides, and antifungal azoles and (ii) a membrane active is a glycopeptide antibiotic selected from actaplanin, actinoi biocide. din, ardacin, avoparcin, azureomycin, balhimycin, chloroori 19. The composition of claim 1, wherein said composition entiein, chloropolysporin, decaplanin, N-demethylvancomy comprises (i) a first biodegradable polymer comprising a cin, eremomycin, galacardin, helvecardin, iZupeptin, repeating unit comprising a membrane active biocide and (ii) US 2010/0062974 A1 Mar. 11, 2010 a second biodegradable polymer comprising a repeating unit biocide and a second agent selected from fluoroquinolones, comprising an agent selected from fluoroquinolones, ami aminoglycosides, B-lactams, glycopeptide antibiotics, Sul noglycosides, B-lactams, glycopeptide antibiotics, Sulfona fonamides, and antifungal azoles, wherein said membrane mides, and antifungal azoles. 20. A shaped article comprising a composition of any of active biocide and said second agent are administered in claims 1-19, wherein said shaped article is in the form of an amounts that together are sufficient in vivo to treat said bac implantable medical device, self-supporting film, or fiber. terial infection. 21. A method of reducing bacterial growth on a surface, 23. A method of treating a fungal infectionina Subject, said said method comprising contacting said Surface with a com method comprising administering a membrane active biocide position comprising a membrane active biocide and a second and a second agent selected from fluoroquinolones, ami agent selected from fluoroquinolones, aminoglycosides, noglycosides, B-lactams, glycopeptide antibiotics, Sulfona B-lactams, glycopeptide antibiotics, Sulfonamides, and anti mides, and antifungal azoles, wherein said membrane active fungal azoles, wherein said membrane active biocide and said biocide and said second agent are administered in amounts second agent are administered in amounts that together are that together are Sufficient in vivo to treat said fungal effective to reduce bacterial growth. infection. 22. A method of treating a bacterial infection in a Subject, said method comprising administering a membrane active