Comparative serum bactericidal activity of meropenem-based combination regimens against extended-spectrum beta-lactamase and KPC-producing Klebsiella pneumoniae
Combination therapies are frequently used in the treatment of multidrug-resistant Klebsiella pneumoniae infection without consensus regarding which combination is the most effective. We compared bactericidal titres from sera collected from critically ill patients receiving meropenem plus tigecycline (n = 5), meropenem plus colistin (n = 5), or meropenem, colistin and tigecycline (n = 5) against K. pneumoniae isolates that included ESBL-producing (n = 7) and KPC-producing strains (n = 14) with varying sensitivity patterns to colistin and tigecycline. Meropenem concentrations (Cmin) were measured in all samples by LC-MS/MS, and indexed to respective pathogen MICs to explore differences in patterns of bactericidal activity for two versus three drug combination regimens. All combination regimens achieved higher SBTs against ESBL (median reciprocal titre 128, IQR 32–256) versus KPC (4, IQR 2–32) strains. Sera from patients treated with meropenem-colistin yielded higher median SBTs (256, IQR 64–512) than either meropenem-tigecycline (32, IQR 8–256; P < 0.001). The addition of tigecycline was associated with a lower probability of achieving a reciprocal SBT above 8 when meropenem concentrations were below the MIC (P = 0.04). Although the clinical significance is unknown, sera from patients receiving tigecycline-based combination regimens produce lower serum bactericidal titres against ESBL or KPC-producing K. pneumoniae. SBTs may represent a useful complimentary endpoint for comparing pharmacodynamics of combinations regimens for MDR Enterobacteriaceae.
KeywordsKlebsiella pneumoniae Serum bactericidal assay ESßL KPC Tigecycline
We would like to thank the patients, nurses, and medical residents and technicians who donated their time and energy to complete this study.
This work was partially supported by the Italian Ministry of Health (Ricerca Finalizzata, Giovani Ricercatori, GR-2018-12367572) and the Emilia-Romagna region.
Compliance with ethical standards
Conflict of interest
Russell Lewis has received research funding support from Gilead Inc., Pfizer, and served on speakers or advisory boards for Merck & Co. Inc., and Gilead.
All others declare no interests.
The study design was approved by the Institutional Research Committee.
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