Carbapenems are the treatment of choice for bacteremia caused by extended spectrum β-lactamase producing Enterobacteriaceae (ESBL-E). The emergence carbapenem resistance (CR) in ESBL-E isolates has been described; however, the rate of such resistance in clinical settings is unknown. We describe the frequency and mechanisms of CR in recurrent ESBL-E bacteremia at an NCI-designated cancer center.
We performed a prospective whole genome sequencing (WGS) study and retrospective cohort review of adult (age ≥18 years) patients with ESBL-E bacteremia between January 2015 and July 2016. Recurrent bacteremia was defined as identification of the same organism in blood culture at any time following initial successful treatment. CR was defined as resistance to meropenem. Carbapenemase production was assessed in the microbiology laboratory using Carba-NP. Available paired isolates underwent WGS via Illumina HiSeq for assessment of clonality and identification of CR mechanisms.
One hundred and sixteen patients with ESBL-E bacteremia were identified. E. coli was the most common organism (86%), followed by K. pneumoniae (12%), and K. oxytoca (2%). Recurrent bacteremia was identified in 17 (15%) patients (E. coli [n = 15], K. pneumoniae [n = 2]). Of these, 6 (35%) were CR and 5/6 (83%) were Carba-NP negative. All six recurrent CR isolates occurred in patients with leukemia. Five isolate pairs were available for WGS. In four of five pairs (three E. coli, one K. pneumoniae), CR emerged from the same strain causing the original infection; one recurrence was caused by a distinct E. coli with a OXA-48-like gene. Compared with parental strains, CR E. coli contained deletions in porin-encoding genes and had increased mapping depth for genes encoding CTX-M ESBLs. The K. pneumoniae was Carba-NP negative with no identifiable CR mechanism.
Emergence of CR following treatment for ESBL-E bacteremia was seen only in leukemia patients and was primarily due to porin loss and amplification of ESBL genes, rather than acquisition of exogenous carbapenemases. These are the first clinical data describing the molecular mechanism of ESBL-E transformation to CR. These data serve as the basis for future studies of antimicrobial stewardship interventions to limit the emergence of CR in ESBL-E.
S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee. Medicines Company: Scientific Advisor, Consulting fee. Merck & Co.: Scientific Advisor, Consulting fee.