Faropenem resistance causes in vitro cross-resistance to carbapenems in ESBL-producing Escherichia coli

• Published in: International journal of antimicrobial agents Vol. 55; no. 3; p. 105902
• Main Authors: Gandra, Sumanth, Choi, JooHee, McElvania, Erin, Green, Stefan J., Harazin, Maureen, Thomson, Richard B., Dantas, Gautam, Singh, Kamal S., Das, Sanchita
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2020
• Subjects: Anti-Bacterial Agents - pharmacology; beta-Lactamases - biosynthesis; beta-Lactams - pharmacology; carbapenem; Carbapenems - pharmacology; cross resistance; Drug Resistance, Bacterial - drug effects; Ertapenem - pharmacology; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; faropenem; Humans; porin; Porins - biosynthesis; faropenem; carbapenem; cross resistance; porin
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2020.105902

•Faropenem resistance among Escherichia coli isolates causes cross-resistance to carbapenems•Cross-resistance was seen in extended spectrum beta-lactamase (ESBL)-producing E. coli isolates tested•ESBL E. coli isolates with reduced susceptibility to carbapenems show ompC mutations Faropenem is an oral penem drug with activity against Gram-positive and Gram-negative bacteria, including CTX-M-15-type extended spectrum beta-lactamase (ESBL)-producing Enterobacteriales and anaerobic bacteria. As there are structural similarities, there is concern for the development of carbapenem cross-resistance; however, there are no studies confirming this. This study examined whether in vitro development of faropenem resistance in Escherichia coli isolates would result in cross-resistance to carbapenems. Four well-characterized E. coli isolates from the US Centers for Disease Control and Prevention antibiotic resistance isolate bank were utilized. Three isolates (NSF1, NSF2 and NSF3) are ESBL producers (CTX-M-15) and one (NSF4) is pan-susceptible. Faropenem minimum inhibitory concentrations (MICs) were determined and resistance was induced by serial passaging in increasing concentrations of faropenem. Susceptibility to carbapenems was determined and whole-genome sequencing (WGS) was performed to identify the underlying genetic mechanism leading to carbapenem resistance. Faropenem MIC increased from 1 mg/L to 64 mg/L within 10 days for NSF2 and NSF4 isolates, and from 2 mg/L to 64 mg/L within 7 days for NSF1 and NSF3 isolates. Reduced carbapenem susceptibility (ertapenem MIC ≥8 mg/L, doripenem/meropenem ≥2 mg/L and imipenem ≥1 mg/L) developed among three CTX-M-15-producing isolates that were faropenem-resistant, but not in NSF4 isolate that lacked ESBL enzyme. WGS analysis revealed non-synonymous changes in the ompC gene among three CTX-M-15-producing isolates, and a single nucleotide polymorphism (SNP) in the envZ gene in NSF4 isolate. Induced resistance to faropenem causes cross-resistance to carbapenems among E. coli isolates containing CTX-M-15-type ESBL enzymes.