Evaluation of various fluoroquinolones against S. pneumoniae with 1st step mutations of parC

Abstract number: 1733_1561

Chin J., Rybak M., Kaatz G.

Objectives: To compare the resistance (R) potential, AUC/MIC breakpoints, and activity of moxifloxacin (MOX), gemifloxacin (GEM), levofloxacin (LEV) and gatifloxacin (GAT) against 1st Step Mutations of parC (SP1), which have been shown in previous studies to be predisposed to 2nd-step gyrA mutations (MUT) upon re-exposure to older fluoroquinolones (FQ) leading to high-level R.

Methods: A clinical strain of SP1 (KD2138) was evaluated in an in vitro PK/PD model over 96 hours with a starting inoculum of 10⁷ CFU/mL. MOX, GEM, LEV, and GAT were dosed to simulate from 50–800, 60–640, 500–1500, and 100–800 mg QD with their respective fAUC/MIC exposures. Samples were drawn from models to determine emergence/absence of further R. In the event of R, dose and fAUC/MIC exposure were increased until R was prevented or a dose was reached that was not clinically feasible. MICs for resistant organisms (RO) were determined by Etest or microdilution according to CLSI. ROs with elevated MICs post FQ-exposure underwent PCR amplification of the gyrA quinolone resistance-determining region for DNA sequence analysis.

Results: Pre-exposure MICs for LEV, MOX, GEM, & GAT were 2, 0.5, 0.125, & 0.5 mg/mL. R occurred with MICs up to 128 mg/mL from LEV 500–1500 mg QD (fAUC/MIC of 21–62 mg/mL/h). ROs emerged as early as 24 h and beyond with a delay in R in the higher fAUC/MIC (at 96 h with 62 mg/mL/h). This was also consistent with GAT 100–400 mg QD (fAUC/MIC of 12–41 mg/mL/h) with MICs up to 32 mg/mL. R also occurred with GEM 150–320 mg QD (fAUC/MIC 18–32 mg/mL/h), resulting in MIC increases at 1–2 mg/mL. However, R was prevented at 2X the therapeutic dose with GEM 640 mg QD (fAUC/MIC of 64 mg/mL/h) & GAT 800 mg QD (fAUC/MIC of 82 mg/mL/h). In addition, ROs were only derived from MOX 200 mg QD (fAUC/MIC of 24 mg/mL/h) with MICs up to 32 mg/mL, but not from the therapeutic dose of MOX 400 mg QD (fAUC/MIC of 48 mg/mL/h). All MIC increases ≤ 4-fold were associated with efflux. MIC elevations ≥32 mg/mL were associated with the following MUTs in gyrA: S81L, S81F, and E85A.

Conclusions: Additional R resulting in gyrA MUTs in SP1 occurred with LEV and GAT at therapeutic fAUC/MIC but not with MOX. Changes in MICs to GEM were observed, but this was attributed to efflux, not to gyrA mutations.