Deciphering the Efficacy of the β-Lactams in the Face of Metallo-β-lactamase Derived Resistance in Enterobacterales: Supraphysiologic Zinc in the Broth is the Culprit

Abstract

In vitro-in vivo discordance in β-lactams activities against metallo-ß-lactamase (MBL)-producing Enterobacterales has been described. We aimed to assess whether this discordance was attributed to the supra-physiologic zinc concentration in the in vitro testing media. A clinical and microbiological observational study of patients with bloodstream infections due to New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae was performed. Outcomes of patients treated empirically with non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam +aztreonam) were documented. The patients’ isolates were used to induce septicemia in mice and survival upon meropenem treatment was recorded. Meropenem MICs were determined in standard media and in presence of physiological zinc concentrations. Twenty-nine patients receiving empiric non-MBL-active β-lactams (median duration 4 days) were compared to 29 receiving MBL-active β-lactams. The 14-day-mortality rates were 21% and 14%, respectively. In the murine septicemia model, meropenem treatment resulted in protection from mortality(P < 0.0001). Meropenem MICs in the physiologic zinc concentration broth were 1- to >16-fold lower versus MICs in zinc-unadjusted broth (≥64 mg/L). Our data provide foundational support to establish PK/PD relationships using MICs derived in physiologic zinc concentration which may better predict β-lactam therapy outcome.