Differential effects of antibiotic treatment with piperacillin/tazobactam or ceftriaxone on the murine gut microbiota

Abstract

Effective antimicrobial stewardship requires a better understanding of the impact of different antibiotics on the gut microflora. Studies in humans are confounded by large inter-individual variability and difficulty in identifying control cohorts. However, controlled murine models can provide valuable information. We examined the impact of a penicillin-like antibiotic (piperacillin/tazobactam, TZP) or a third-generation cephalosporin (ceftriaxone, CRO) on the murine gut microbiota. We analyzed gut microbiome composition by 16S-rRNA amplicon sequencing and effects on the Enterobacteriaceae by qPCR and standard microbiology.Colonization resistance to multidrug resistant Escherichia coli ST131 and Klebsiella pneumoniae ST258 was also tested. Changes in microbiome composition and a significant (p<0.001) decrease in diversity occurred in all treated mice, but were more marked and longer lasting after CRO exposure with a persistent rise in Proteobacteria levels. Increases in the Enterobacteriaceae occurred in all antibiotic treated mice, but were transient and associated with direct antibiotic pressure. Co-habitation of treated and untreated mice attenuated the detrimental effect of antibiotics on treated animals, but also caused disturbance in untreated co-habitants. At the height of dysbiosis after antibiotic termination, the murine gut was highly susceptible to colonization with both multidrug resistant pathogens. The administration of a third-generation cephalosporin caused a significantly prolonged dysbiosis in the murine gut microflora, when compared to a penicillin/β-lactam inhibitor combination with comparable activity against medically important virulent bacteria. At the height of dysbiosis, both antibiotic treatments equally led to microbial imbalance associated with loss of resistance to gut colonization by antibiotic-resistant pathogens.