Abstract
Background Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. Yet in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure, and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients.
Methods We conducted a retrospective single-center cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared ICU outcomes (ventilator-associated pneumonia[VAP]-free survival, infection-free survival, overall survival) in all patients, and changes in gut microbiota in a 116-patient subcohort. In murine models, we studied the effects of anaerobe depletion in infectious (K. pneumoniae and S. aureus pneumonia) and noninfectious (hyperoxia) injury models.
Results Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (HR 1.24, 95% CI 1.06–1.45), infection-free survival (1.22, 95% CI 1.09–1.38), and overall survival (HR 1.14, 95% CI 1.02–1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011), and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic treated patients (p<2.2×10−16). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (p<0.05) and increased the lethality of hyperoxia (p=0.0002).
Conclusions In critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: All authors have nothing to disclose.
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- Received May 4, 2022.
- Accepted September 16, 2022.
- Copyright ©The authors 2022.
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