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. 2024 Apr 23;11(5):ofae228.
doi: 10.1093/ofid/ofae228. eCollection 2024 May.

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

Kamilia Abdelraouf  1 , Christian M Gill  1 , Matthew Gethers  1 , Giusy Tiseo  2 , Simona Barnini  3 , Marco Falcone  2 , Francesco Menichetti  2 , David P Nicolau  1
Affiliations

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

Kamilia Abdelraouf et al. Open Forum Infect Dis. .

Abstract

Background: 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 is attributed to the supra-physiologic zinc concentration in in vitro testing media.

Methods: 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 minimum inhibitory concentrations (MICs) were determined in standard media and in the presence of physiological zinc concentrations.

Results: Twenty-nine patients receiving empiric non-MBL-active β-lactams (median duration, 4 days) were compared with 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 < .0001). Meropenem MICs in the physiologic zinc concentration broth were 1- to >16-fold lower vs MICs in zinc-unadjusted broth (≥64 mg/L).

Conclusions: Our data provide foundational support to establish pharmacokinetic/pharmacodynamic relationships using MICs derived in physiologic zinc concentration, which may better predict β-lactam therapy outcome.

Keywords: Klebsiella pneumoniae; NDM; bloodstream infections; carbapenem; zinc.

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Conflict of interest statement

Potential conflict of interest. K.A. has received research grants from the FDA, Evopoint Biosciences, Venatorx Pharmaceuticals, and Toscana Life Sciences Foundation. C.M.G. received research funding from Cepheid, Everest Medicines, Shionogi, and Entasis. M.F. received unconditional grants from MSD and grants or speaker honoraria from Angelini, Shionogi, Pfizer, Menarini, Gilead, and Nordic Pharma. G.T. received honoraria for educational meetings for Shionogi. D.P.N. is a consultant, speaker bureau member, and has received other research grants from AbbVie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, and Shionogi. All other authors report no potential conflicts. Declared conflicts of interest are outside the submitted work and did not affect the scientific objectivity of this study.

Figures

Figure 1.
Figure 1.
The distribution of modal meropenem (top) and plazomicin (bottom) MICs of the 58 clinical NDM-producing K. pneumoniae isolates in conventional and physiologic zinc concentration in CAMHB. Abbreviations: CAMHB, cation-adjusted Mueller Hinton Broth; MIC, minimum inhibitory concentration; NDM, New Delhi metallo-ß-lactamase.
Figure 2.
Figure 2.
Spleens’ bacterial densities among saline controls and meropenem-treated groups infected with the 3 non-carbapenemase-producing control Enterobacterales isolates (top) and the 2 serine carbapenemase-producing control K. pneumoniae isolates (bottom). Abbreviations: CAMHB, cation-adjusted Mueller Hinton Broth; MIC, minimum inhibitory concentration.
Figure 3.
Figure 3.
Survival curves for saline controls (black) and mice treated with meropenem (purple) and infected with (A) the 3 non-carbapenemase-producing control Enterobacterales isolates, (B) the 2 serine carbapenemase-producing control K. pneumoniae isolates, (C) the 58 clinical NDM-producing K. pneumoniae (pooled data). MEM-S: n = 30 mice for saline controls and 10 for each meropenem group. Serine: n = 20 mice for saline controls and 10 for each meropenem group. MBL: n = 576 mice for saline controls and 580 for the meropenem group. Abbreviations: CAMHB, cation-adjusted Mueller Hinton Broth; MBL, metallo-ß-lactamase; MIC, minimum inhibitory concentration; MEM-S, meropenem-susceptible; NDM, New Delhi metallo-ß-lactamase.
Figure 4.
Figure 4.
Spleens’ bacterial densities among (A) saline controls and meropenem-treated mice infected with 38 NDM-producing K. pneumoniae, (B) saline controls, meropenem- and plazomicin-treated mice infected with 10 plazomicin-resistant NDM-producing K. pneumoniae, (C) saline controls, meropenem- and plazomicin-treated mice infected with 10 plazomicin-susceptible NDM-producing K. pneumoniae. Abbreviations: CAMHB, cation-adjusted Mueller Hinton Broth; MEM, meropenem; MIC, minimum inhibitory concentration; NDM, New Delhi metallo-ß-lactamase; PLZ, plazomicin.
Figure 5.
Figure 5.
Pooled survival curves for the saline controls (black) and plazomicin-treated mice (green) infected with (A) the 10 plazomicin-resistant NDM-producing K. pneumoniae, (B) the 10 plazomicin-susceptible NDM-producing K. pneumoniae. PLZ-R: n = 98 mice for saline controls, 100 for plazomicin group. PLZ-S: n = 100 mice for each of saline controls and plazomicin groups. Abbreviations: CAMHB, cation-adjusted Mueller Hinton Broth; MIC, minimum inhibitory concentration; NDM, New Delhi metallo-ß-lactamase; PLZ, plazomicin.
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