Anti-Anaerobic Antibiotics, Gut Microbiota, and Sepsis-associated Acute Kidney Injury.

Abstract

Acute kidney injury (AKI) is a common complication of sepsis. Anti-anaerobic antibiotics, which deplete gut commensal bacteria, are common in the initial management of sepsis. Recent studies have reported an association between anti-anaerobic antibiotics and mortality, but the mechanisms underlying this relationship remain unknown. To determine whether anti-anaerobic antibiotics and gut microbiome disruption increase patient susceptibility to sepsis-associated AKI. We identified a cohort of patients with sepsis and performed four complementary analyses: 1) comparing AKI incidence among patients who did and did not receive early anti-anaerobic antibiotics, 2-3) two instrumental variable analyses using the 2015-16 piperacillin-tazobactam shortage to determine the effect of anti-anaerobic antibiotics on the <i>onset</i> and <i>resolution</i> of AKI, and 4) a matched case-control study comparing gut microbiota in septic patients who did and did not develop AKI. We then modeled sepsis in genetically-identical but microbially-heterogenous mice and compared creatinine elevation with gut microbiota. In a retrospective cohort study (N=12,776), early exposure to anti-anaerobic antibiotics was independently associated with a 61% increased risk of sepsis-associated AKI (95% CI-37%-92%). In instrumental variable analyses of AKI <i>onset</i> (N=3,036) and <i>resolution</i> (N=2,177), treatment with anti-anaerobic antibiotics (piperacillin-tazobactam) was associated with an increased hazard of AKI <i>onset</i> (HR-1.65, 95% CI-1.18-2.30) and decreased AKI <i>resolution</i> (HR-0.74, 95% CI-0.61-0.88). In a matched case-control study of gut microbiota in 372 patients with sepsis, increased gut bacterial density and enrichment with <i>Enterobacteriaceae</i> and <i>Lachnospiraceae</i> spp. predicted subsequent AKI onset. In a murine model of sepsis (N=53), creatinine elevation was strongly associated with vendor and gut community composition (P<0.001 for all), with relative abundance of <i>Lachnospiraceae</i> spp. explaining 18% of variation in serum creatinine. Anti-anaerobic antibiotics are associated with increased risk of AKI in sepsis, potentially via modulation of the gut microbiome.