Abstract
Background
Carbapenems are often used for infections due to extended-spectrum-β-lactamase (ESBL) and cephalosporinase (CSase)-producers. As increased carbapenem utilization is associated with the development of carbapenem resistance, antimicrobial stewardship has targeted non-carbapenem options. WCK 4282 (FEP 2 g-TZB 2 g) offers pharmacodynamically optimized TZB exposure and demonstrated potent activity in vitro against ESBL-phenotype isolates. We describe the pharmacodynamics of a WCK 4282 human-simulated regimen (HSR) in the neutropenic murine thigh model.
Methods
19 clinical strains harboring ESBLs or CSase (EB; n=8 and PA; n=4) or serine-carbapenemases (EB; KPC n=4 or OXA-48-like n=3) were tested in vivo. Per CLSI, 19, 18, and 17 isolates were cefepime, ceftolozane/tazobactam, and piperacillin/tazobactam (TZP) non-susceptible, respectively. Thighs of neutropenic, female, CD-1 mice (3 per group) were inoculated with ~107 CFU/mL of bacterial suspension 2 h prior to dosing. Mice received WCK 4282 HSR, FEP HSR, or saline (controls) for 24 h. WCK 4282 HSR and FEP HSR provided plasma exposures in mice that were similar in f%T > MIC and fAUC to FEP-TZB 2 g-2 g and FEP 2 g, respectively, as IV infusions over 1.5 h q8h in humans. Bacterial densities and their changes at 24 h relative to 0 h controls were determined to assess efficacy and reported as mean±SD log10 CFU/thigh.
Results
Bacterial burdens were 5.81±0.36 at 0 h and 9.29±0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/CSase producing EB and PA with WCK 4282 MIC ≤ 16 mg/L; mean change in log10 CFU from 0 h was -1.70±0.77, while growth was observed with FEP alone. WCK 4282 produced variable activity against OXA-48-like harboring EB. Against KPC-harboring EB, WCK 4282 produced stasis to growth. Mean Log10 CFU changes are reported in Table 1 and Figure 1.
Table 1. Comparative efficacy of FEP HSR and WCK 4282 HSR by genotypic β-lactamase
Figure 1. Mean Change in log10CFU/thigh for 24 h controls, FEP HSR, and WCK 4282 HSR across the tested MIC distribution.
Conclusion
WCK 4282, a novel TZB containing regimen, resulted in enhance in vitro potency against ESBL/CSase and OXA-48-like producers. Humanized exposures of WCK 4282 produced substantial kill in vivo against ESBL/CSase producers with MICs ≤ 16 mg/L including FEP resistant/TZP non-susceptible PA. These data support further evaluations of WCK 4282 as a carbapenem-sparing regimen for ESBL/cephalosporinase harboring strains.
Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)