Comparative in vitro and in vivo activity of the C-8 methoxy quinolone moxifloxacin and the C-8 chlorine quinolone BAY y 3118.
The C-8 methoxy quinolone moxifloxacin is highly bactericidal against wild-type and first-step gyrase- and topoisomerase IV-resistant mutants. This finding led to the hypothesis that the C-8 methoxy group may lower the propensity for resistance development compared with quinolones possessing different substituents at the C-8 position. Therefore, resistance development of the C-8 methoxy quinolone moxifloxacin was compared with that of its structural analogue BAY y 3118 (chlorine moiety at the C-8 position), with Staphylococcus aureus used as the test organism. The spontaneous emergence of resistance was quantified by counting the number of colonies growing on drug-free medium compared with moxifloxacin- or BAY y 3118-containing media. The multistep emergence of quinolone resistance was encountered by growing S. aureus over 8 passages in drug-containing medium. Human serum concentrations were simulated in an in vitro model over 84 h (dosing every 24 h), and total and resistant S. aureus were quantified. Spontaneous mutation frequencies of 6x10-11 for moxifloxacin and 4x10-7 for BAY y 3118 were observed. Multistep resistance to moxifloxacin developed slowly (2-fold rise) but rapidly against BAY y 3118 (>16-fold rise). No resistance against moxifloxacin developed in this model, whereas resistance to BAY y 3118 began to develop after 4 h. Thus, as the C-8 moiety was the only difference, the 8-methoxy group on moxifloxacin appeared to significantly lower the propensity for quinolone resistance development.
Bayer AG, Pharma Research Center Wuppertal, PH-PD SDD AI, Building 402, Aprather Weg 18, D-42113 Wuppertal, Germany. axel.dalhoff.ad@bayer-ag.de
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Dalhoff
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds; D002713:Chlorine; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D005260:Female; D024841:Fluoroquinolones; D015394:Molecular Structure; D000077266:Moxifloxacin; D011804:Quinolines; D051381:Rats; D017208:Rats, Wistar; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; C079807:Bay Y3118; D002713:Chlorine; D000077266:Moxifloxacin