5B 3 In Vitro Synergy Testing of Two New Antimicrobial Combination Therapies for Gonorrhea

Thursday, June 12, 2014: 8:20 AM
Dogwood A
Olusegun Soge, PhD1, Lindley Barbee, MD, MPH2, Matthew Golden, MD, MPH3 and King Holmes, MD, PhD1, 1Neisseria Reference Laboratory, Center for AIDS and STD, Departments of Global Health and Medicine, University of Washington, Seattle, WA, 2Department of Medicine, Division of Allergy and Infectious Disease, University of Washington & Public Health -- Seattle & King County HIV/STD Program, Seattle, WA, 3Department of Medicine, Division of Allergy and Infectious Disease, and Public Health - Seattle & King County HIV/STD Program, University of Washington, Seattle, WA

Background: A recent clinical trial found that azithromycin plus either gemifloxacin or gentamicin is effective in the treatment of uncomplicated gonorrhea.  These regimens could be useful in a future era of more widespread gonococcal resistance.  However, the efficacy of these treatments against gonococci with resistance to azithromycin and/or gemifloxacin is unknown.  We evaluated in vitro activities of these new antimicrobial combinations, including among isolates with resistance or elevated minimum inhibitory concentrations (MICs) to azithromycin, gemifloxacin, and gentamicin.

Methods: We selected a panel of 78 N. gonorrhoeae strains with varying susceptibility profiles including 15 reference strains and 63 clinical isolates collected from patients in Seattle, Washington, 2007 - 2013. We determined MICs for azithromycin, gentamicin and gemifloxacin individually and in combination by Etest, and calculated the fractional inhibitory concentration index (FICI) to assess synergy and antagonism.

Results: Azithromycin MICs ranged from 0.032 - 16 µg/mL; gemifloxacin, ≤0.002 to 12 µg/mL, and gentamicin, 2 -16 µg/mL. The overall mean FICI observed with the combination of azithromycin and gentamicin was 1.12, SD 0.21, with 13 (16.7%) of the isolates exhibiting partial synergy (FICI 0.63 – 0.99). The mean FICI for the combination of azithromycin and gemifloxacin was 1.20, SD 0.20, with only 2 (2.6%) of the isolates indicating partial synergy.  No antagonism was observed for either combination.  Among 20 isolates with intermediate susceptibility to gentamicin (MIC 8–16 µg/mL), all appeared to be susceptible to combination of azithromycin and gentamicin. In contrast, among 49 gemifloxacin-resistant isolates (MIC ≥1 µg/mL), only 33% showed laboratory evidence of susceptibility to a combination of azithromycin and gemifloxacin.

Conclusions: The combinations of azithromycin and either gemifloxacin or gentamicin showed partial synergy or indifference.  Compared to gemifloxacin and azithromycin, the combination of azithromycin plus gentamicin had superior in vitro activity against relatively resistant gonococci; the clinical significance of this observation is uncertain.