Emergence of Resistance in Klebsiella aerogenes to Piperacillin-Tazobactam and Ceftriaxone

We examined the effects of piperacillin-tazobactam (TZP) concentration and bacterial inoculum on in vitro killing and the emergence of resistance in Klebsiella aerogenes The MICs for 15 clinical respiratory isolates were determined by broth microdilution for TZP and by Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistance in TZP-susceptible isolates (n = 10) was determined by serial passes over increasing concentrations of TZP-containing and CRO-containing agar plates. Isolates with growth on TZP 16/4-μg/ml and CRO 8-μg/ml plates (n = 5) were tested in high-inoculum (HI; 7.0 log₁₀ CFU/ml) and low-inoculum (LI; 5.0 log₁₀ CFU/ml) time-kill studies. Antibiotic concentrations were selected to approximate TZP 3.375 g every 8 h (q8h) via a 4-h prolonged-infusion free peak concentration (40 μg/ml [TZP40]), peak epithelial lining fluid (ELF) concentrations, and average AUC_0-24 values for TZP (20 μg/ml [TZP20] and 10 μg/ml [TZP10], respectively), the ELF FEP concentration (14 μg/ml), and the average AUC_0-24 CRO concentration (6 μg/ml). For HI, FEP exposure significantly reduced 24-h inocula against all comparators (P ≤ 0.05) with a reduction of 4.93 ± 0.64 log₁₀ CFU/ml. Exposure to TZP40, TZP20, and TZP10 reduced inocula by 0.81 ± 0.43, 0.21 ± 0.18, and 0.05 ± 0.16 log₁₀ CFU/ml, respectively. CRO-exposed isolates demonstrated an increase of 0.42 ± 0.39 log₁₀ CFU/ml compared to the starting inocula, with four of five CRO-exposed isolates demonstrating TZP-nonsusceptibility. At LI after 24 h of exposure to TZP20 and TZP10, the starting inoculum decreased by averages of 2.24 ± 1.98 and 2.91 ± 0.50 log₁₀ CFU/ml, respectively. TZP demonstrated significant inoculum-dependent killing, warranting dose optimization studies.