US00835.7385B2 (12) United States Patent (10) Patent No.: US 8,357,385 B2 LaRonde et al. (45) Date of Patent: *Jan. 22, 2013 (54) COMBINATION THERAPY FOR THE FOREIGN PATENT DOCUMENTS TREATMENT OF BACTERAL INFECTIONS CA 2243 649 8, 1997 CA 2417 389 2, 2002 Inventors: Frank LaRonde, Toronto (CA); Hanje CA 2438 346 3, 2004 (75) CA 2539 868 4/2005 Chen, Toronto (CA); Selva Sinnadurai, CA 2467 321 11, 2005 Scarborough (CA) CA 2611 577 9, 2007 (73) Assignee: Interface Biologics Inc., Toronto (CA) OTHER PUBLICATIONS Bu et al. A Comparison of Topical Chlorhexidine, Ciprofloxacin, and (*) Notice: Subject to any disclaimer, the term of this Fortified Tobramycin/Cefazolin in Rabbit Models of Staphylococcus patent is extended or adjusted under 35 and Pseudomonas Keratitis. Journal of Ocular Pharmacology and U.S.C. 154(b) by 377 days. Therapeutics, 1997 vol. 23, No. 3, pp. 213-220.* Martin-Navarro et al. The potential pathogenicity of chlorhexidine This patent is Subject to a terminal dis sensittive Acanthamoeba strains isolated from contact lens cases claimer. from asymptomatic individuals in Tenerife, Canary Islands, Spain. Journal of Medical Microbiology. 2008. vol. 57, pp. 1399-1404.* (21) Appl. No.: 12/419,733 Craig et al., Modern Pharmacology. 4' Edition: 545-547, 555-557. 567, 569, 583-586, 651-654, and 849-851. (1994). Filed: Apr. 7, 2009 Jones et al., “Bacterial Resistance: A Worldwide Problem.” Diagn. (22) Microbiol. Infect. Dis. 31:379-388 (1998). Murray, "Antibiotic Resistance.” Adv. Intern. Med. 42:339-367 (65) Prior Publication Data (1997). US 201O/OO62974 A1 Mar. 11, 2010 Nakae, “Multiantibiotic Resistance Caused by Active Drug Extru sion in Pseudomonas aeruginosa and Other Gram-Negative Bacte ria.” Microbiologia. 13:273-284 (1997). Related U.S. Application Data International Search Report (PCT/CA2009/000446), dated Jun. 8, Provisional application No. 61/123,231, filed on Apr. 2009. (60) International Preliminary Report on Patentability and Written Opin 7, 2008. ion of the Searching Authority (PCT/CA2009/000446), dated Oct. (51) Int. C. 21, 2010. A6DF 3/00 (2006.01) * cited by examiner A6 IK3I/74 (2006.01) (52) U.S. Cl. ..................................... 424/422; 424/78.17 Primary Examiner — Marcela M Cordero Garcia (58) Field of Classification Search ........................ None (74) Attorney, Agent, or Firm — Clark & Elbing LLP: See application file for complete search history. Kristina Bieker-Brady (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The invention features a method for treating a Subject diag 2,631,146 A * 3/1953 Weidenheimer et al. ..... 540,345 nosed with, or at risk of developing, a bacterial infection by 6,432,389 B1* 8/2002 Hansenne et al. .............. 424,59 administering to the Subject a combination of biologically 2004/0039031 A1* 2/2004 Cugnardey et al. .. 514,354 active agents. 2007/0020320 A1 1/2007 David et al. ................... 424,445 2010.0034.862 A1 2/2010 Laronde et al. ............... 424/423 6 Claims, No Drawings US 8,357,385 B2 1. 2 COMBINATION THERAPY FOR THE agent selected from fluoroquinolones, aminoglycosides, TREATMENT OF BACTERAL INFECTIONS B-lactams, glycopeptide antibiotics, Sulfonamides, and anti fungal azoles. CROSS-REFERENCE TO RELATED The invention further features a composition including a APPLICATIONS biodegradable polymer having a first repeating unit and a second repeating unit, the first repeating unit including a This application claims benefit from U.S. Provisional membrane active biocide and the second repeating unit Application No. 61/123,231, filed Apr. 7, 2008, hereby incor including a second agent selected from fluoroquinolones, porated by reference. aminoglycosides, B-lactams, glycopeptide antibiotics, Sul 10 fonamides, and antifungal azoles. The invention also features a composition including (i) a BACKGROUND OF THE INVENTION biodegradable polymer including a repeating unit including a The present invention relates to the field of antibacterial membrane active biocide and (ii) a second agent selected therapy. from fluoroquinolones, aminoglycosides, 3-lactams, glyco 15 peptide antibiotics, Sulfonamides, and antifungal azoles. The use of antibiotics by humans can be seen as an evolu In a related aspect the invention features a composition tionary experiment of enormous magnitude, a window from including (i) a biodegradable polymer including a repeating which to view not-quite-natural selection operating in real unit including a secondagent selected from fluoroquinolones, time. Within 50 years, the number of species and strains of aminoglycosides, B-lactams, glycopeptide antibiotics, Sul pathogenic and commensal bacteria resistant to antibiotics fonamides, and antifungal azoles and (ii) a membrane active and the number of antibiotics to which they are resistant has biocide. increased virtually monotonically world-wide. As a result, The invention further features a composition including (i) infections that had been readily treatable by chemotherapy a first biodegradable polymer including a repeating unit may no longer be so. It is clear that the evolution and spread including a membrane active biocide and (ii) a second biode of resistance can be attributed to the use and overuse of 25 gradable polymer including a repeating unit including a sec antibiotics. Increased resistance of bacterial infections to ond agent selected from fluoroquinolones, aminoglycosides, antibiotic treatment has been extensively documented and has B-lactams, glycopeptide antibiotics, Sulfonamides, and anti now become a generally recognized medical problem, par fungal azoles. ticularly with nosocomial infections. See, for example, Jones The invention further features a method of reducing bac et al., Diagn. Microbiol. Infect. Dis. 31:379-388, 1998; Mur 30 terial growth on a Surface by contacting the Surface with a ray, Adv. Intern. Med. 42:339-367, 1997; and Nakae, Micro composition including a membrane active biocide and a sec biologia 13:273-284, 1997. ond agent selected from fluoroquinolones, aminoglycosides, Throughout the developed world there is public and gov B-lactams, glycopeptide antibiotics, Sulfonamides, and anti ernmental concern about the increasing prevalence of antimi fungal azoles in amounts that together are effective to reduce 35 bacterial growth. crobial resistance to chemotherapy in bacteria that cause dis The invention also features a method of reducing bacterial eases in humans. Many pathogens exist for which there are growth on a Surface by coating the Surface with a biodegrad few effective treatments, and the number of strains resistant to able polymer including a first repeating unit and a second available drugs is continually increasing. New antimicrobial repeating unit, the first repeating unit including a membrane agents and improved methods are thus needed for the treat 40 active biocide and the second repeating unit including a sec ment and prevention of infections by Such pathogens. ond agent selected from fluoroquinolones, aminoglycosides, B-lactams, glycopeptide antibiotics, Sulfonamides, and anti SUMMARY OF THE INVENTION fungal azoles. The invention further features a method of reducing fungal We have discovered that a combination of a membrane 45 growth on a surface by contacting the Surface with a compo active biocide (e.g., chlorhexidine) and a second agent sition including a membrane active biocide and a second selected from fluoroquinolones, aminoglycosides, B-lactams, agent selected from fluoroquinolones, aminoglycosides, glycopeptide antibiotics, Sulfonamides, and antifungal azoles B-lactams, glycopeptide antibiotics, Sulfonamides, and anti is more effective in treating bacterial infections and reducing fungal azoles in amounts that together are effective to reduce bacterial growth than either agent alone. We have also dis 50 fungal growth. covered that a combination of a Sulfonamide (e.g., Sul The invention also features a method of reducing fungal famethoxazole) and a second agent selected from B-lactams growth on a Surface by coating the Surface with a biodegrad and antifungal azoles is more effective in treating bacterial able polymer including a first repeating unit and a second infections and reducing bacterial growth than either agent repeating unit, the first repeating unit including a membrane alone. Thus, the invention features compositions, methods, 55 active biocide and the second repeating unit including a sec and kits including these effective combinations, which can be ond agent selected from fluoroquinolones, aminoglycosides, useful for the treatment and prevention of infections. B-lactams, glycopeptide antibiotics, Sulfonamides, and anti Accordingly, in a first aspect the invention features a com fungal azoles. position including a membrane active biocide and a second In certain embodiments of the above methods, the surface agent selected from fluoroquinolones, aminoglycosides, 60 is, for example, a Surface of an implantable medical device B-lactams, glycopeptide antibiotics, Sulfonamides, and anti (e.g., a cardiac-assist device, a catheter, a stent, a prosthetic fungal azoles in amounts that together are sufficient in vivo to implant, a Suture, a cuff, a mesh, a hernia patch, a wound treat a bacterial infection. dressing, a bandage, an artificial sphincter, or a drug delivery In a related aspect, the invention features a biodegradable device) or any other surface described herein. polymer including a first repeating unit and a second repeat 65 The invention also features a method of treating a bacterial ing unit,