Ecological effects of cefepime use during antibiotic cycling on the Gram-negative enteric flora of ICU patients

Abstract

This study examines the impact of cefepime and APP-β (antipseudomonal penicillin/ β-lactamase inhibitor combinations) on Gram-negative bacterial colonization and resistance in two Australian ICUs. While resistance did not cumulatively increase, cefepime (but not APP-β treatment) was associated with acquisition of antibiotic resistant Enterobacteriaceae, consistent with an ecological effect. Analysis of the resident gut E. coli population in a subset of patients showed an increase in markers of horizontal gene transfer after cefepime exposure that helps explain the increase in APP-β resistance and reminds us that unmeasured impacts on the microbiome are key outcome determinants that need to be fully explored.

Fig. 1

Variation in colonization patterns before and after ICU stay. a Rates of colonization with antibiotic-resistant species at admission and after ICU stay. b Change in susceptibility rates after ICU stay in different treatment cycles. Proportion of the entire study group of patients (n = 206) with positive cultures. “Any resistance” indicates any bacterial growth on antibiotic supplemented media. “All resistance” indicates any growth on ChromAgar™ supplemented with vancomycin only (to exclude Gram-positive species). *KESC, Klebsiella, Enterobacter, Serratia, Citrobacter spp. as identified on colorimetric media ChromAgar™ and confirmed by MALDI-TOF [16] as previously described [5]. Asterisks (*, **, ***) above bar charts indicate significant differences (p < 0.05)

Fig. 2

Antibiotic resistance markers detected before and after cefepime exposure in E. coli isolates from ICU patients. Resistance genes (a), plasmid replication genes (b), and plasmid transfer markers (c) were identified using the sequencing output from MiSeq sequencing (250 bp; paired-end) of pooled representatives (2–6 colonies per patient) of the E. coli population before (black) and after (white) cefepime treatment. Markers were detected by alignment with resistance genes and mobile genetic elements in the MARA database [17] and plasmids markers in our in-house database (Additional file 1 Methods). aad includes aadA1, aadA6, and aadA10; “transfer” comprises marker genes for conjugation/self-transmission (tra, nik, etc.); “mobilization” indicates relaxase genes of mobilizable plasmid types (Additional file 1: Table S1) [18]