The New Antibiotic Mantra-"Shorter Is Better".

InAD321,RomanEmperorConstantine theGreat codified that therewouldbe7days in aweek.Even in themoderneraof evidence-based-medicine, this 1695-year-olddecreeremainsaprimary reference for durationof antibiotic therapy: it leadsphysicians to treat infections in intervals of 7 days. Thus, it is gratifying when clinical trials challenge the standard antibiotic duration of 7 to 14 days. In the past, community-acquired pneumonia was treated with a 7to 14-day course of antibiotics. However, clinical trials in the early 2000s demonstrated that 3 or 5 days of protocol-specified antibiotics are as efficacious as longer courses of therapy for patients with mild to moderately severe community-acquired pneumonia.1,2 To this body of literature is now added a new randomized trial, in this issue of JAMA Internal Medicine, by Uranga et al,3 comparing short-course vs longer courses of therapy for hospitalized patients with community-acquired pneumonia. The trial used a pragmatic design in that treating physicians were allowed to select their preferred antibiotic for the first 5 days of therapy. Patients were randomized such that on day 5 those in the control group continued the therapy selected by their treating physicians and those in the experimental group had their antibiotics stopped if they were afebrile for 48 hours and had no more than 1 sign of clinical instability (eg, hypotension, tachycardia, tachypnea, or hypoxia). These criteria for stopping the antibiotic applied to 70.1% of patients in the experimental arm. Although patients admitted to the intensive care unit were excluded from the trial, a substantial number (approximately 40%) of patients in both arms had Pneumonia Severity Index scores of IV to V, indicative of severe illness. In contrast, prior studies of short-course antibiotic therapy have focused primarily on patients with mild to moderate illness. The study arms were well matched, and the results were compelling.The interventionworked,aspatientswhowereadministered the short-course regimen received a median of 5 days of antibiotics vs 10 for the standard regimen. Across all endpoints, timepoints, andpopulations, short-course therapy was as effective as longer courses of therapy. Point estimates of success favoredshort-course therapyacrossmostendpoints and timepoints. In the sickest cohort (Pneumonia Severity Index scores of IV-V), 30-day rates of clinical success in the intention-to-treatpopulationwere significantlyhigher for shortcourse vs standard therapy (93.1% vs 80.3%; P = .04). Furthermore, the readmission ratewas significantly lower for patients receiving the short-course regimen (1.4% vs 6.6%; P = .02). Overall, the data are convincing that 5 days of antibiotic therapy is at least as effective as 10 days for the treatment of community-acquired pneumonia.3 In his keynote address at an annual meeting of the Infectious Diseases Society of America, Louis B. Rice,MD, pointed out that pneumonia was successfully treated with short durationsof antibiotics as longagoas the 1940s.4Physicians considered “pioneers” of penicillin customized the duration of therapy depending on the patient’s response and found that a range of 11⁄2 to 4 days of therapy resulted in high cure rates. Themodern concept that we should continue treating bacterial infections past the time when signs and symptoms have resolved canbe traced to 1945.Meads et alwrote that they administeredpenicillin topatientswithpneumonia, “until there wasdefinite clinical improvementand the temperaturehad remainedbelow 100°F for 12 hours...then given for another two to three days.”5(p748) Theperceivedneed to treat beyond resolution of symptoms was driven by a desire to prevent relapses. However, the recurrent infections seen in the case series were caused by isolates with distinct bacterial serotypes, indicative of reinfection rather than relapse. It is unclear how thisconfuseddesire toprevent reinfectionssubsequently transformed into the illogicaldogmathat antibiotic resistancecould be prevented by continuing therapy beyond resolution of symptoms.4 Nevertheless, this dogma has been reinforced by the equally illogical, often-heard statement that to prevent antibiotic resistance, it is necessary for patients to complete the entire prescribed course of therapy, even after resolution of symptoms. There is no evidence that taking antibiotics beyond thepoint atwhich apatient’s symptoms are resolved reduces antibiotic resistance. To the contrary, specifically for pneumonia, studieshaveshownthat longer coursesof therapy result in more emergence of antibiotic resistance,6,7 which is consistent with everything we know about natural selection, the driver of antibiotic resistance.8 In only a few types of infectionsdoes resistance emerge at the site of infection; rather, resistance typically emergesoff target, amongcolonizing flora away from the site of infection.9 Thus, all that is achieved by treating an infection with antibiotics for longer than the patient has symptoms is increased selectivepressuredriving antibiotic resistance among our colonizing microbial flora. Given the large number of bacterial infections that occur every year, overtreating patients who have established infection is likely a major source of selective pressure that drives antibiotic resistance in society. Other than tuberculosis— which is caused by a very slowly replicative organism that spends much of its time in a nonreplicating state—for every bacterial infection for which trials have compared shortcourse with longer course antibiotic therapy, short-course Related article Opinion