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Published on: February 15, 2022
Anti-Anaerobic Antibiotics, Gut Microbiota, and Sepsis-associated Acute Kidney Injury
Katherine M Winner1, Rishi Chanderraj2, Mark Nuppnau2
1University of Michigan Health System, Internal Medicine, Ann Arbor, Michigan, United States.
Rationale:
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.
Objective:
To determine whether anti-anaerobic antibiotics and gut microbiome disruption increase patient susceptibility to sepsis-associated AKI.
Methods:
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 onset and resolution 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.
Measurements And Main Results:
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 onset (N=3,036) and resolution (N=2,177), treatment with anti-anaerobic antibiotics (piperacillin-tazobactam) was associated with an increased hazard of AKI onset (HR-1.65, 95% CI-1.18-2.30) and decreased AKI resolution (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 Enterobacteriaceae and Lachnospiraceae 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 Lachnospiraceae spp. explaining 18% of variation in serum creatinine.
Conclusions:
Anti-anaerobic antibiotics are associated with increased risk of AKI in sepsis, potentially via modulation of the gut microbiome.
Insights
Anti-anaerobic antibiotics increase the risk of acute kidney injury (AKI) in sepsis patients by disrupting the gut microbiome. This finding highlights potential mechanisms linking antibiotic use to sepsis complications.
Area of Science:
- Microbiology
- Nephrology
- Pharmacology
Background:
- Sepsis frequently leads to acute kidney injury (AKI).
- Anti-anaerobic antibiotics are commonly used in sepsis management and alter the gut microbiome.
- Previous studies suggest a link between anti-anaerobic antibiotics and mortality, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate if anti-anaerobic antibiotics and gut microbiome changes increase susceptibility to sepsis-associated AKI.
- To explore the relationship between specific gut bacteria and AKI development in sepsis.
Main Methods:
- Retrospective cohort study of 12,776 sepsis patients to assess AKI incidence with early anti-anaerobic antibiotic exposure.
- Instrumental variable analyses using a piperacillin-tazobactam shortage to evaluate the impact on AKI onset and resolution.
- Matched case-control study of gut microbiota in 372 sepsis patients.
- Murine model of sepsis to correlate creatinine elevation with gut microbiota composition.
Main Results:
- Early anti-anaerobic antibiotic use was linked to a 61% increased risk of sepsis-associated AKI.
- Anti-anaerobic antibiotic treatment (piperacillin-tazobactam) was associated with higher AKI onset hazard and reduced AKI resolution.
- Increased gut bacterial density and specific bacterial families (Enterobacteriaceae, Lachnospiraceae) predicted AKI onset in sepsis patients.
- In mice, gut microbiota composition, particularly Lachnospiraceae, significantly correlated with creatinine elevation.
Conclusions:
- Anti-anaerobic antibiotics are associated with an elevated risk of AKI in sepsis.
- Gut microbiome modulation by anti-anaerobic antibiotics may be a key mechanism driving sepsis-associated AKI.
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