Pharmacodynamics of Piperacillin-Tazobactam/Amikacin Combination versus Meropenem against Extended-Spectrum beta-Lactamase-Producing Escherichia coli in a Hollow Fiber Infection Model

Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum beta-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli; however, due to selection of carbapenem resistance, there is an increasing interest in alternative treatment regimens including the use of beta-lactam-aminoglycoside combinations. We compared the pharmacodynamic activity of piperacillin-tazobactam and amikacin as mono and combination therapy versus meropenem monotherapy against extended-spectrum beta-lactamase (ESBL)-producing, piperacillin-tazobactam resistant E. coli using a dynamic hollow fiber infection model (HFIM) over 7 days. Broth-microdilution was performed to determine the MIC of E. coli isolates. Whole genome sequencing was conducted. Four E. coli isolates were tested in HFIM with an initial inoculum of similar to 10(7) CFU/mL. Dosing regimens tested were piperacillin-tazobactam 4.5 g, 6-hourly, plus amikacin 30 mg/kg, 24-hourly, as combination therapy, and piperacillin-tazobactam 4.5 g, 6-hourly, amikacin 30 mg/kg, 24-hourly, and meropenem 1 g, 8-hourly, each as monotherapy. We observed that piperacillin-tazobactam and amikacin monotherapy demonstrated initial rapid bacterial killing but then led to amplification of resistant subpopulations. The piperacillin-tazobactam/amikacin combination and meropenem experiments both attained a rapid bacterial killing (similar to 4-5 log(10)) within 24 h and did not result in any emergence of resistant subpopulations. Genome sequencing demonstrated that all ESBL-producing E. coli clinical isolates carried multiple antibiotic resistance genes including bla(CTX-M-15), bla(OXA-1), bla(EC), bla(TEM-1), and aac(6')-Ib-cr. These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.