In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae

Antimicrobial-resistant Neisseria gonorrhoeae is a major public health threat. Current CDC treatment guidelines for uncomplicated gonorrhoea recommend only ceftriaxone plus either azithromycin or doxycycline. Additional treatment options are needed. We used antibiotic gradient synergy testing (the Etest) to evaluate antimicrobial combinations that included a third-generation cephalosporin (cefixime or ceftriaxone) plus azithromycin, doxycycline, gentamicin, rifampicin or fosfomycin. We tested each combination against 28 clinical N. gonorrhoeae isolates and four control strains of varying susceptibility profiles, and compared the results with those obtained using combination antimicrobial testing using agar dilution. We calculated the fractional inhibitory concentration index (FICI) for each combination to determine synergy, the results being interpreted as follows: FICIaEuroSa parts per thousand currency signaEuroS0.5aEuroS=aEuroSsynergy; FICIaEuroS > aEuroS4.0aEuroS=aEuroSantagonism; and FICIaEuroS > aEuroS0.5-4aEuroS=aEuroSindifference. The combinations of a third-generation cephalosporin plus azithromycin, doxycycline, rifampicin, gentamicin or fosfomycin produced FICIs of indifference. The Etest and agar dilution methods produced comparable results. Combinations of ceftriaxone plus rifampicin, gentamicin or fosfomycin may warrant further clinical investigation as treatments for gonorrhoea. Using the Etest for synergy testing is a viable method that has practical advantages over agar dilution.