In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes

Abstract

Background: Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, 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-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious (Klebsiella pneumoniae and Staphylococcus aureus pneumonia) and noninfectious (hyperoxia) injury models.

Results: Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06-1.45), infection-free survival (HR 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.

FIGURE 1

Retrospective cohort overview. We identified a cohort of 3032 mechanically ventilated patients treated with i.v. antibiotics admitted to the University of Michigan Hospital in 2016–2019. We excluded patients transferred from an outside facility, patients with chronic ventilator dependence and those who received mechanical ventilation for a period <72 h.

FIGURE 2

Anti-anaerobic antibiotic therapy predicts decreased ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival in critically ill patients. In a cohort of 3032 mechanically ventilated patients treated with i.v. antibiotics, the use of anti-anaerobic antibiotic therapy prior to day 3 of mechanical ventilation was associated with a) decreased VAP-free survival at 30 days (p=0.00074 by log-rank test), b) infection-free survival at 30 days (p=0.00044 by log-rank test) and c) overall survival at 30 days (p=0.00064 by log-rank test). There were 842 deaths, 89 cases of VAP and 472 cases of nosocomial infection in the cohort.

FIGURE 3

Anti-anaerobic antibiotic therapy is independently associated with decreased ventilator-associated pneumonia (VAP)-free survival. We constructed a multivariable Cox proportional hazards regression model including Acute Physiology and Chronic Health Evaluation (APACHE) IV score, Charlson Comorbidity Index, demographics, intensive care unit (ICU) of admission and anti-anaerobic antibiotic treatment to predict VAP-free survival. The model was highly significant (concordance of 0.63; p<2.2×10⁻⁶ for both Wald test and likelihood ratio test). Anti-anaerobic antibiotic treatment was independently associated with increased hazard of VAP or death (HR 1.24, 95% CI 1.06–1.45).

FIGURE 4

Administration of anti-anaerobic antibiotics is associated with increased identification of gut-associated bacteria in respiratory cultures. a) We compared the distribution of pathogens causing ventilator-associated pneumonia (VAP) among treatment groups and found an increased identification of Enterobacteriaceae spp. in patients treated with anti-anaerobic antibiotics (48% of cases of VAP in anti-anaerobic-treated versus 21% of cases of VAP without anaerobic treatment; p=0.0090 by t-test). b) We compared the distribution of pathogens causing fatal nosocomial infection among treatment groups and again found an increased identification of Enterobacteriaceae in patients treated with anti-anaerobic antibiotics (29% of cases in anti-anaerobic-treated versus 3% of cases without anaerobic treatment; p=0.0004 by t-test). *: p<0.05; **: p<0.01; ***: p<0.001.

FIGURE 5

Administration of antibiotics with anti-anaerobic activity is associated with decreased gut bacterial density among hospitalised patients. We compared the bacterial density of rectal swabs collected at the time of admission for a subset of 116 hospitalised patients and compared patients based on the spectrum of coverage of antibiotics administered in the emergency department. a) Patients who received antibiotics with anti-anaerobic activity had lower gut bacterial density than patients who did not receive antibiotics (95% CI for difference −1.39– −0.13 log 16S copies per sample; p=0.010 by t-test) or who received antibiotics without anaerobic activity (95% CI for difference −1.97– −0.78 log 16S copies per sample; p=1.5×10⁻⁸ by t-test). b) We found no significant association between spectrum of Pseudomonas coverage and bacterial density of admission rectal swab (Kruskal–Wallis test, p=0.52) nor any significant difference in mean bacterial density when comparing groups. ns: nonsignificant; *: p<0.05; ****: p<0.0001 after correcting for multiple comparisons with Tukey's method.

FIGURE 6

Changes in gut microbiota during hospitalisation among patients with and without exposure to anti-anaerobic antibiotic treatment. We measured the bacterial density and relative abundance of Enterobacteriaceae spp. in a subset of 116 subjects with a rectal swab specimen collected at the time of intensive care unit (ICU) admission and ICU discharge. a) Patients treated with anti-anaerobic antibiotics exhibited an increase in gut bacterial density over time, while other antibiotic-treated patients exhibited a decrease in gut bacterial density over time (β for interaction 0.089 log 16S copies per day of hospitalisation; p=0.011). Mixed models were used for statistical analysis; change regression is depicted in this figure for ease of visualisation. b) Patients treated with anti-anaerobic antibiotics exhibited an increase in Enterobacteriaceae relative abundance over time (β for interaction 0.26% relative abundance per day of hospitalisation; p=0.042).

FIGURE 7

The effects of gut anaerobe depletion on infectious and noninfectious lung injury in mice. We experimentally modulated gut microbiota in female C57BL/6 mice using intraperitoneal piperacillin–tazobactam (PT) (anti-anaerobic), cefepime (not anti-anaerobic) and saline sham controls. We compared alveolar inflammation and bacterial clearance in a, b) two infectious models (intratracheal Klebsiella pneumoniae and Staphylococcus aureus) and c–e) a noninfectious model (hyperoxia). a, b) In the pneumonia models, gut anaerobe depletion decreased clearance of a) K. pneumoniae but not b) S. aureus. In the hyperoxia model, gut anaerobe depletion had no significant effect on c, d) day 3 lung injury but e) increased day 4 mortality. F_IO2: inspiratory oxygen fraction. ns: nonsignificant; *: p<0.05; ***: p<0.001; ****: p<0.0001. Significance determined using Kruskal–Wallis rank sum test with Dunn's multiple comparisons test.