title: Activities of mutant prevention concentration-targeted moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro pharmacodynamic model.
abstract: The differential effects of moxifloxacin and levofloxacin on the development of resistance in four Streptococcus pneumoniae isolates were examined by using an in vitro pharmacodynamic model. Therapeutic regimens (moxifloxacin: peak, 4.5 micro g/ml; half-life [t(1/2)], 12 h; and levofloxacin: peak, 6 micro g/ml; t(1/2), 6 h) were tested against two fluoroquinolone-susceptible isolates (strains 79 and ATCC 49619) and KD2138 and KD2139 (parC and gyrA mutants, respectively, of ATCC 49619). Mutant prevention concentration (MPC)-targeted regimens with modified pharmacokinetics of each drug were simulated to match the area under the concentration-time curve (AUC) above the MPC for the two fluoroquinolones. Moxifloxacin MICs and MPCs (MIC/MPC) for isolates 79, ATCC 49619, KD2138, and KD2139, respectively, were 0.125 and 0.5, 0.125 and 0.5, 0.25 and 8, and 0.25 and 4 micro g/ml. Levofloxacin MICs and MPCs for the same isolates were 1 and 4, 0.5 and 2, 1 and 64, and 0.5 and 32 micro g/ml, respectively. Therapeutic levofloxacin concentrations led to isolation of mutants of ATCC 49619 (S79Y in ParC), KD2138 (S81Y in GyrA), and KD2139 (S79Y in ParC). Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates. MPC-targeted moxifloxacin (lower-than-normal peak = 0.75 to 1.5 micro g/ml, administered at levofloxacin's t(1/2)) caused growth of a GyrA variant (S81Y) of KD2138 and a ParC variant (S79Y) of KD2139, while no mutants of ATCC 49619 were recovered. MPC-targeted levofloxacin (higher-than-normal peak = 14.5 to 29.5 micro g/ml, administered at moxifloxacin's t(1/2)) against KD2138 and KD2139 did not prevent the development of the mutations observed in therapeutic regimens, but resistance in the fluoroquinolone-susceptible ATCC 49619 was no longer noted. Normalization of the respective AUC/MPC ratios of moxifloxacin and levofloxacin did not eliminate differences in resistance selectivity of the two agents in all cases. We conclude that the reduced recovery of resistant mutants of S. pneumoniae following moxifloxacin exposure compared to levofloxacin may be due to intrinsic differences between the drugs. Increasing the concentration and exposure (t(1/2)) to exceed the MPC may prevent mutations from occurring in fluoroquinolone-susceptible strains. However, this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations. Further study of the MPC concept to evaluate these relationships is warranted.
authors.affiliation: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Allen
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001372:Aza Compounds; D003470:Culture Media; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D000077266:Moxifloxacin; D009154:Mutation / Q000235:genetics*; D015242:Ofloxacin / Q000494:pharmacology*; D011804:Quinolines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D003470:Culture Media; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D000077266:Moxifloxacin