Evaluation of the mutant selection window for fluoroquinolones against Neisseria gonorrhoeae.
OBJECTIVE
The availability of antimicrobials that may be used for the treatment of infections caused by Neisseria gonorrhoeae has been limited by the emergence of antimicrobial resistance, particularly fluoroquinolone resistance. Few data exist regarding the pharmacodynamics of fluoroquinolone resistance selection in N. gonorrhoeae.


METHODS
We used mutant prevention concentration (MPC) testing to define the risk of fluoroquinolone resistance induction in N. gonorrhoeae by ciprofloxacin, levofloxacin and moxifloxacin in a wild-type isolate (ATCC 49226) and its corresponding gyrA mutant (m-49226).


RESULTS
MIC/MPC values (mg/L) of ciprofloxacin, levofloxacin and moxifloxacin for ATCC 49226 were 0.0078/0.03125, 0.0078/0.125 and 0.0156/0.0625, respectively. The MIC of all fluoroquinolones for m-49226 was 0.125 mg/L; MPCs of ciprofloxacin, levofloxacin and moxifloxacin for this isolate were 4, 0.5 and 0.25 mg/L, respectively. Concentrations of all agents are predicted to exceed the MPC for ATCC 49226 for the entire dosage interval, while concentrations of moxifloxacin alone will exceed the MPC for m-49226. The hierarchy of tested agents with respect to %T(MSW) [percentage of the dosage interval that concentrations fall within the mutant selection window (MSW)] for m-49226 was ciprofloxacin > levofloxacin > moxifloxacin. Multiple-dose fluoroquinolone regimens are predicted to achieve superior pharmacodynamics in comparison with single-dose regimens for m-49226, with increased AUC/MPC values and a reduced %T(MSW).


CONCLUSIONS
Evaluation of the use of moxifloxacin against N. gonorrhoeae is warranted, as is use of multiple-dose fluoroquinolone regimens.
Allen
George P
GP
Oregon State University College of Pharmacy at Oregon Health and Science University, Portland, OR 97239-4501, USA. allenge@ohsu.edu
Hankins
Cynthia D
CD
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology*; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000187:drug effects*; D015242:Ofloxacin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012641:Selection, Genetic
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin