Duration of Exposure to Antipseudomonal β-Lactam Antibiotics in the Critically Ill and Development of New Resistance

Study Objective: Minimizing the duration of broad-spectrum antimicrobial exposure in the critically ill is a commonly used strategy aimed at preventing resistance. Our objective was to correlate the duration of exposure to antipseudomonal β-lactam antibiotics with the development of new resistance in critically ill patients.

Design: Single-center, retrospective cohort study.

Setting: A large, academic, tertiary care hospital.

Patients: A total of 7118 adults with a discharge diagnosis of severe sepsis or septic shock who received at least one dose of cefepime, meropenem, or piperacillin-tazobactam during their hospitalization between 2010 and 2015.

Measurements And Main Results: Cohort entry was defined as the first day of any antipseudomonal β-lactam initiation, and exposure was defined as the cumulative days of any antipseudomonal β-lactam exposure during the 60-day follow-up period. The primary outcome was development of new resistance to any antipseudomonal β-lactam > 3 days after cohort entry. New resistance was defined as detection of resistance to any antipseudomonal β-lactam not identified within 180 days before cohort entry. Patients without an outcome (i.e., did not develop new resistance) or who died by day 60 were censored. Cox proportional hazards models were performed to assess the risk of development of new resistance to any antipseudomonal β-lactam with each additional day of exposure. Analyses of each individual antipseudomonal β-lactam were evaluated as secondary outcomes. Each additional day of exposure to any antipseudomonal β-lactam resulted in an adjusted hazard ratio (aHR) of 1.04 (95% confidence interval [CI] 1.04-1.05) for new resistance development. The risk of developing new resistance to cefepime, meropenem, and piperacillin-tazobactam for each additional day of exposure resulted in an aHR of 1.08 (95% CI 1.07-1.09), 1.02 (95% CI 1.01-1.03), and 1.08 (95% CI 1.06-1.09), respectively.

Conclusion: Among critically ill patients who receive antipseudomonal β-lactam antibiotics, each additional day of exposure to cefepime, meropenem, and piperacillin-tazobactam is associated with an increased risk of new resistance development.