Evidence Behind the 4-Hour Rule for Initiation of Antibiotic Therapy in Community-Acquired Pneumonia

Abstract

US regulatory authorities mandate delivery of antibiotics within 4 hours of arrival for patients being admitted to the hospital with community-acquired pneumonia. This evidence-based emergency medicine review examines the scientific evidence pertaining to this requirement. We searched MEDLINE, EMBASE, the Cochrane Library, other databases, and bibliographies. We selected articles allowing comparison of inpatient or 30-day mortality among patients receiving early versus delayed antibiotics. We prospectively categorized studies according to whether they were retrospective or prospective and whether they adjusted for severity with the Pneumonia Severity Index. We evaluated the precision with which the interval to initiation of antibiotic therapy was defined and the compliance of retrospective studies with standard reporting criteria for chart reviews. We identified 13 observational studies reporting comparative outcomes in patients receiving early versus delayed antibiotic initiation, of which 10 allowed calculation of our primary outcome. Of the 4 prospective studies, 1 allowed severity adjustment using the Pneumonia Severity Index score. Among the retrospective studies, definition of time to antibiotic therapy was frequently imprecisely defined, and compliance with standard reporting criteria for chart review was scanty in the subgroup lacking severity adjustment. Odds ratios (ORs) for mortality varied widely. One methodologically weak study reported a large benefit of early antibiotics (OR for mortality antibiotics <4 hours versus >4 hours 0.24; 95% confidence interval [CI] 0.08 to 0.71). The one study that used prospective enrollment and severity adjustment using the Pneumonia Severity Index observed a contrary result (adjusted OR for mortality, antibiotics <4 hours versus >4 hours 1.99; 95% CI 1.22 to 13.45). Results from studies reporting an 8-hour cutoff also varied in magnitude and direction of effect. Evidence from observational studies fails to confirm decreased mortality with early administration of antibiotics in stable patients with community-acquired pneumonia. Although timely administration of antibiotics to patients with confirmed community-acquired pneumonia should be encouraged, an inflated sense of priority of the 4-hour time frame is not justified by the evidence.