Expression of CTX-M-15 limits the efficacy of ceftolozane/tazobactam against Escherichia coli in a high-inoculum murine peritonitis model

J Canovas; G Petitjean; F Chau; A Le Monnier; B Fantin; A Lefort

doi:10.1016/j.cmi.2020.06.032

Expression of CTX-M-15 limits the efficacy of ceftolozane/tazobactam against Escherichia coli in a high-inoculum murine peritonitis model

Clin Microbiol Infect. 2020 Oct;26(10):1416.e5-1416.e9. doi: 10.1016/j.cmi.2020.06.032. Epub 2020 Jul 3.

Authors

J Canovas¹, G Petitjean², F Chau¹, A Le Monnier², B Fantin³, A Lefort⁴

Affiliations

¹ IAME, UMR 1137, INSERM, F-75018, Université de Paris, Paris, France.
² Department of Microbiology, Hôpital Saint-Joseph, Paris, France.
³ IAME, UMR 1137, INSERM, F-75018, Université de Paris, Paris, France; Internal Medicine Department, Hôpital Beaujon, AP-HP, Clichy, France.
⁴ IAME, UMR 1137, INSERM, F-75018, Université de Paris, Paris, France; Internal Medicine Department, Hôpital Beaujon, AP-HP, Clichy, France. Electronic address: [email protected].

PMID: 32629024
DOI: 10.1016/j.cmi.2020.06.032

Abstract

Objectives: Among carbapenem-sparing therapies, ceftolozane/tazobactam has been proposed for the treatment of infections due to CTX-M-15-producing Escherichia coli. However, few data exist on its in vivo activity in infections associated with a high bacterial inoculum.

Methods: We analysed ceftolozane/tazobactam activity against susceptible E. coli CFT073-RR and its CTX-M-15-producing transconjugant E. coli CFT073-RR Tc bla_CTX-M-15, in vitro at low and high inocula, and in a high-inoculum murine model of peritonitis.

Results: Against E. coli CFT073-RR Tc bla_CTX-M-15, ceftolozane/tazobactam bactericidal effect was impaired in vitro with only a minor inoculum effect; this translated into reduced activity compared with imipenem in the mouse peritonitis model.

Conclusions: Combination of extended spectrum β-lactamase expression and high inoculum size may be a clinical situation at risk of reduced bactericidal activity of ceftolozane/tazobactam.

Keywords: Carbapenem alternatives; Ceftolozane/tazobactam; Extended-spectrum β-lactamase; Inoculum effect; Mouse peritonitis model.

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology*
Bacterial Load
Carbapenem-Resistant Enterobacteriaceae / drug effects
Carbapenem-Resistant Enterobacteriaceae / genetics
Carbapenem-Resistant Enterobacteriaceae / metabolism
Cephalosporins / pharmacology*
Disease Models, Animal
Escherichia coli / drug effects*
Escherichia coli / genetics
Escherichia coli / metabolism
Escherichia coli Infections / drug therapy
Imipenem / pharmacology*
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Peritonitis / drug therapy*
Peritonitis / microbiology
Tazobactam / pharmacology*
beta-Lactamase Inhibitors / pharmacology
beta-Lactamases / metabolism*

Substances

Anti-Bacterial Agents
Cephalosporins
beta-Lactamase Inhibitors
ceftolozane, tazobactam drug combination
Imipenem
beta-lactamase CTX-M-15
beta-Lactamases
Tazobactam