Anti-Anaerobic Antibiotics Linked to Higher Mortality in Bloodstream Infection

Antibiotics with anaerobic activity were associated with higher 90-day mortality and gut microbiome disruption among patients with bloodstream infection who lacked a clinical indication for anaerobic coverage, according to a study published in Clinical Infectious Diseases. The planned observational sub-study of the BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) randomized clinical trial does not establish causation.

The parent BALANCE trial enrolled 3,631 participants with bacteremia at more than 70 hospitals in seven countries; 2,851 met the criteria for this analysis. All survived beyond seven days after the index blood culture and had no anaerobic organism or intra-abdominal or hepatobiliary infection indicating anaerobic coverage. Exposure required at least one dose of an anti-anaerobic antibiotic from three days before through seven days after the index culture.

Overall, 2,106 patients (74%) received anti-anaerobic antibiotics, most commonly piperacillin-tazobactam or meropenem. After inverse probability of treatment weighting, exposure was associated with higher odds of 90-day mortality. Each additional exposure day across all participants was also associated with higher mortality odds. Exposure was not significantly associated with Clostridium difficile infection or bacteremia relapse.

Among 94 participants, 135 rectal-swab samples collected after treatment began underwent metagenomic sequencing. Anti-anaerobic exposure was associated with a lower relative abundance of obligate anaerobes. Shannon diversity and total bacterial load were numerically lower but did not differ significantly.

The authors identified confounding by indication as the primary limitation, noting that residual confounding could remain despite statistical adjustment. Other limitations included the absence of pretreatment microbiome samples, inclusion only of seven-day survivors, and the small microbiome analysis. They concluded that randomized trials are needed to determine whether limiting anti-anaerobic exposure when anaerobic coverage is not clinically indicated improves outcomes.

Source: Armstrong E, Pinto R, Kulikova M, et al. Association of anti-anaerobic antibiotics with mortality and the gut microbiome: a sub-study of the BALANCE randomized clinical trial. Clin Infect Dis. Published online August 4, 2026. doi:10.1093/cid/ciag460