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Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study
Study Question: Is empiric, prolonged infusion of ß-lactam antibiotics for Gram-negative bacterial infections in critically ill patients associated with improved outcomes compared to intermittent infusions?
Study Description: This single-center, before-after study compared standard versus prolonged infusions (3 hours) of cefepime, meropenem, or piperacillin/tazobactam (cumulative daily doses were similar between treatment groups) for ICU patients with a presumed Gram-negative infection. The primary outcome was treatment success, which was defined as a resolution of fever for 24 hours or a WBC count decrease to less than 12,000 or by a 50% drop. Treatment failure was defined as: a persistent fever beyond 72 hours; requirement for treatment escalation; relapse of infection; or mortality attributable to the infection.
Results: Of the 2,012 patients screened, 503 were included. Baseline characteristics were similar with the exception of a greater incidence of COPD in the intermittent infusion group. The primary outcome of treatment success was 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204). Treatment failure was most commonly due to WBC count failure (intermittent infusion 29.9% and prolonged infusion 35.4%, p = 0.231). Mortality rates were not significantly different: 14-day, 30-day, and in-hospital mortality for the intermittent and prolonged infusion groups were 13.2% vs 18.0% (p = 0.141), 23.6% vs 25.7% (p = 0.582), and 19.4% vs 23.0% (p = 0.329).
Conclusion: Prolonged infusion of conventional daily doses of ß-lactam antibiotics provides no advantage over intermittent infusion therapy.
Perspective: There is conflicting literature about the presumed benefits of prolonged or continuous infusions of ß-lactams. They are thought to include theoretical advantage due to their time-dependent killing mechanism and cost-saving and adverse event benefits associated with a reduced total daily dose. However, these benefits come at the expense of more complicated administration at bedside, particularly with respect to line availability. Studies have either demonstrated the aforementioned benefits with prolonged/continuous infusions or have failed to detect a difference; this study falls into the latter category. However, there is scant evidence that prolonged/continuous infusions are clinically inferior, which some institutions will use to justify the cost-savings benefits in this era of cost consciousness. In this study, the lack of difference between treatment groups may have been produced by confounding variables (surgery, oncologic) as well as low resistance rates found among isolates (5%). Therefore, the results of this study may not be applicable to ICUs with high gram-negative resistance rates.