In vitro evaluation of antimicrobial resistance selection in Neisseria gonorrhoeae

Gonococcal infections represent an urgent public-health threat as >50% of cases caused by Neisseria gonorrhoeae strains display reduced susceptibility to at least one antimicrobial agent. We evaluated the pharmacodynamics of a number of antimicrobials against N. gonorrhoeae in order to assess the likelihood of mutant selection by these agents. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, doxycycline, ertapenem, gentamicin, ciprofloxacin, levofloxacin and moxifloxacin against a wild-type strain of N. gonorrhoeae (ATCC 49226) and a gyrA mutant of ATCC 49226. Pharmacokinetic parameters, including peak concentration (C_max), half-life (t_1/2) and area under the plasma concentration-time curve over 24 h (AUC), associated with each agent were used to calculate the time within the MSW (T_MSW, percentage of the dosing interval that antimicrobial concentrations fall within the MSW), C_max/MPC ratio and AUC/MPC ratio for each antimicrobial agent. Concentrations of ceftriaxone (500 mg), ertapenem, ciprofloxacin, levofloxacin and moxifloxacin surpass the MPC for both strains. Results of pharmacodynamic analyses suggest that ertapenem, ciprofloxacin, levofloxacin and moxifloxacin may be most likely to prevent mutant selection in N. gonorrhoeae. Use of ceftriaxone, azithromycin, doxycycline or gentamicin for gonorrhoea is expected to lead to the ongoing emergence of resistance to these agents. There is a clear need to develop novel treatment regimens for gonococcal infections in order to limit the dissemination of resistance in N. gonorrhoeae.