Multiple antibiotic resistance in Gram-negative bacteria causing life-threatening sepsis, heavily impacts the ICU where antibiotic usage is high and patients more vulnerable, leading to increased morbidity and mortality.1 Timely antibiotic intervention is critical in improving survival,2 and preservation of susceptibility to broad-spectrum antibiotics for effective empiric therapy is paramount. Controlled antibiotic usage (“stewardship”) has thus become a primary public health agenda.3 Different antibiotics are known to have different effects on the composition of the gut microbiome,4, 5 and better understanding of these effects is needed to guide stewardship decisions. Cefepime has been advocated as effective empiric therapy but its in vivo efficacy and impact on resistance are still disputed.6,7
In this study, we compared cefepime treatment with anti-pseudomonal penicillin combinations (APP-β) by determining Enterobacteriaceae colonization and resistance rates at admission and after antibiotic therapy in 206 ICU patients. We also characterized the E. coli population in a subset of 12 patients by sequencing (paired-end MiSeq) representative pools of perineal clones before and after cefepime therapy. Reads were run against the NCBI database (BLAST8) and genetic features linked to transmissible resistance were carefully annotated (Attacca9).
Cefepime treatment was the main driver of both acquisition of resistant Enterobacteriaceae after therapy (p=0.027) and increased APP-β resistance (p=0.027). Accordingly, we observed that in the 'after' cefepime E. coli sample, the frequency of specific genes with strong links to multiple resistance (e.g. strAB, sul2) increased, while other genes (e.g. blaCMY-2) and markers of transmissible resistance (e.g. IncI1rep) were detected exclusively in the 'after' sample.
This study shows that in vivo APP-β is superior to cefepime in curtailing resistance development in Gram-negative Enterobacteriaceae. For truly effective stewardship intervention, the type of antibiotics used must be carefully considered due to possible implications for both the transmission of antibiotic resistance determinants and establishment of resistant populations.