Molecular epidemiology and associated treatment outcomes of third generation cephalosporin-resistant enterobacterales causing pneumonia in intensive care unit patients

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Abstract Background Infections caused by third generation cephalosporin (3GC)-resistant Enterobacterales (Ceph-RE) are rising in incidence. 3GC resistance may be due to production of extended-spectrum beta-lactamase (ESBL) or AmpC enzymes. However, studies evaluating the molecular epidemiology of Ceph-RE causing pneumonia and their antibiotic treatment responses are limited. We used whole genome sequencing to characterize Ceph-RE isolates causing pneumonia in intensive care unit (ICU) patients and assessed their clinical outcomes. Methods In this retrospective study, adult ICU patients with pneumonia and a positive respiratory culture for Ceph-RE between 1/2015 and 7/2022 were identified from electronic records. Patients who received definitive therapy with piperacillin/tazobactam, cefepime, or a carbapenem were included in the study. Nanopore sequencing was performed for multi-locus sequence typing and comprehensive antibiotic resistance gene detection. Piperacillin/tazobactam and cefepime minimum inhibitory concentrations were determined by broth microdilution. We then compared clinical factors and treatment outcomes between patients treated with each antibiotic and who received a carbapenem versus non-carbapenem antibiotic (cefepime or piperacillin/tazobactam) using univariable analyses. Results Of 80 included patients, 56% were treated with a carbapenem, 31% with piperacillin/tazobactam, and 13% with cefepime. Ceph-RE isolates were highly diverse. Three-quarters of isolates harbored an extended-spectrum β-lactamase (ESBL) gene, of which bla CTX−M−15 was the most common (50%). AmpC genes were identified in 19 isolates. More isolates were susceptible to piperacillin-tazobactam (88%) than cefepime (58%); however, fewer AmpC (83%) compared to ESBL-harboring isolates (93%) were piperacillin/tazobactam-susceptible. Patients treated with a non-carbapenem versus carbapenem antibiotic did not significantly differ with respect to their clinical characteristics. 14% of patients treated with piperacillin-tazobactam or cefepime died within 30 days compared to 33% of carbapenem recipients ( p = 0.09). In patients infected with ESBL-producing isolates only, mortality was 8% versus 26% ( p = 0.1). Conclusions Although recent treatment guidelines recommend carbapenems for the treatment of most patients with ESBL-producing Enterobacterales infections, piperacillin/tazobactam and cefepime were frequently used to treat pneumonia due to Ceph-RE. However, we did not identify significant differences in clinical characteristics or outcomes among patients treated with carbapenem versus non-carbapenem antibiotics, including those infected with ESBL gene-harboring isolates. Larger, prospective studies are needed to assess the use of non-carbapenem beta-lactams in this patient population.

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