Activity of temocillin against third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae bloodstream isolates from a clinical trial

Abstract

Background: Extended spectrum β-lactamase (ESBL) and AmpC-producing Gram-negative bacilli contribute significantly to the antimicrobial resistance (AMR) burden worldwide. Temocillin is an intravenous semisynthetic antibiotic that is stable to hydrolysis by ESBLs and AmpC. Temocillin may be a treatment option for serious infections due to these organisms. Methods: Third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates from the MERINO trial were collected. The majority originated from the urinary tract. Isolates had previously undergone whole genome sequencing (WGS) to identify antimicrobial resistance genes. Temocillin minimum inhibitory concentration (MIC) values were determined by broth microdilution (BMD) with a concentration range of 2 to 128 mg/L. A recent EUCAST guideline has recommended clinical breakpoints for urinary E. coli, Klebsiella spp. (except K. aerogenes) and Proteus mirabilis (resistant >16 mg/L). Results: 317 index bloodstream isolates (275 E. coli and 42 K. pneumoniae) were used. The frequency of β-lactamases among isolates was: CTX-M-15 (56%), OXA-1 (31%), CTX-M-27 (14%), CTX-M-14 (12%) and CMY-2 (8%). Overall, 95% of isolates were susceptible, increased exposure according to EUCAST clinical breakpoints v11.0. Summary MIC values were obtained: MIC50 was 8 mg/L and MIC90 was16 mg/L (range ≤2 to ≥128 mg/L) and did not differ markedly between species. Higher MIC values were seen among isolates that produced more than one β-lactamase but this did not appear to be specific to a single β-lactamase. Conclusions: Temocillin demonstrated favourable in vitro activity against ceftriaxone-resistant Enterobacterales bloodstream isolates and may be a suitable agent to be trialled for treatment of serious infections due to these organisms.