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.

Objective:

The potential for resistance development in Streptococcus pneumoniae (SP) secondary to varying exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin was examined at high inoculum (108.5–9 log 10 CFU/ml) over 96 hours in an in vitro pharmacodynamic model.

Methods:

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.

Results:

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 16–32 (corresponding to free doses of 50–75 mg). For each compound evaluated, a delay of first- & second-step mutants was observed with increasingly higher AUCfree/MIC ratios.

Conclusions:

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.