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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 log(10) CFU/ml) and low-inoculum (LI; 5.0 log(10) 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 log(10) CFU/ml. Exposure to TZP40, TZP20, and TZP10 reduced inocula by 0.81 ± 0.43, 0.21 ± 0.18, and 0.05 ± 0.16 log(10) CFU/ml, respectively. CRO-exposed isolates demonstrated an increase of 0.42 ± 0.39 log(10) 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 log(10) CFU/ml, respectively. TZP demonstrated significant inoculum-dependent killing, warranting dose optimization studies. |
