Resistance in Streptococcus pneumoniae: AUC/MIC breakpoints differ between gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin
Abstract number: 1134_02_218
LaPlante K., Rybak M., Tsuji B., Kaatz G.
The potential for resistance development in Streptococcus pneumoniae (SP) secondary to varying exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin was examined at high inoculum (108.59 log 10 CFU/ml) over 96 hours in an in vitro pharmacodynamic model.
Various AUCfree/MIC exposures, 16 through 449 of the tested fluoroquinolones (FQ), were evaluated against two clinical (WT) FQ-susceptible isolates of SP (ATCC 49619; BSP 2443). Pharmacokinetics of each drug were simulated to match various areas under the concentration-time curve (AUCfree) for each FQ. The QRDR regions of GyrA and ParC of isolates with raised MICs were sequenced to identify mutations, if any.
Gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin MICs for ATCC 49619 were 0.19, 0.03, 0.75, and 0.125 mg/L, respectively, and for BSP 2443, the corresponding results were 0.25, 0.03 0.75, 0.25 mg/L. Simulated free gatifloxacin exposure led to S52G, S79Y, and N91D parC & S81Y and S114G gyrA mutations at AUCfree/MIC of 35 & 60, (corresponding to doses of 100 & 198 mg). Gemifloxacin exposure led to S52G, S79Y, and N91D parC & S114G gyrA mutations at AUCfree/MIC of 37 (corresponding to a free dose of 50 mg). Leqwvofloxacin AUCfree/MIC of 55 through 86 (corresponding to doses of 500 mg through 843.5 mg/day) led to isolation of S79Y parC & S81Y and E85G gyrA mutants as early as 32 hrs. Moxifloxacin exposure led to S52G, S79Y, and N91D parC & S81Y gyrA mutations at AUCfree/MIC of 1632 (corresponding to free doses of 5075 mg). For each compound evaluated, a delay of first- & second-step mutants was observed with increasingly higher AUCfree/MIC ratios.
Recovery of topoisomerase mutations in SP was related to the AUCfree/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceed the AUC/MICfree resistance breakpoint against WT SP. The cited exposure breakpoints differed between FQs & may be related to structural differences within the class.
|Session name:||XXIst ISTH Congress|
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