The New Antibiotic Mantra-"Shorter Is Better".

Abstract

InAD321,RomanEmperorConstantine theGreat codified that there would be 7 days in a week. Even in the modern era of evidence-based-medicine, this 1695-year-old decree remains aprimary reference for durationofantibiotic therapy: it leads physicians 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 witha7to 14-daycourseof antibiotics.However, clinical trials in the early 2000s demonstrated that 3 or 5 days of protocolspecified antibiotics are as efficacious as longer courses of therapyforpatientswithmildtomoderatelyseverecommunityacquiredpneumonia.1,2 To this bodyof literature isnowadded anewrandomizedtrial, in this issueof JAMAInternalMedicine, 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 physicianswere allowed to select their preferred antibiotic for the first 5daysof therapy. Patientswere randomized such that on day 5 those in the control group continued the therapy selectedby their treatingphysicians and those in theexperimental grouphad their antibiotics stopped if theywere afebrile for 48hours andhadnomore than 1 signof clinical instability (eg, hypotension, tachycardia, tachypnea,orhypoxia). Thesecriteria for stopping theantibiotic applied to70.1%ofpatients in the experimental arm.Althoughpatients admitted to the intensive careunitwereexcludedfromthetrial, asubstantialnumber (approximately40%)ofpatients inbotharmshadPneumonia 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 withmild tomoderate 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-treat population were significantly higher for short-course 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 pneumoniawas successfully treatedwith short durations of antibiotics as long ago as the 1940s.4 Physicians considered “pioneers” of penicillin customized the duration of therapydepending on thepatient’s response and found that a rangeof 11⁄2to4daysof therapy resulted inhighcure rates.The modern concept thatwe should continue treatingbacterial infectionspast the timewhensignsandsymptomshave resolved canbe traced to 1945.Meadset alwrote that theyadministered penicillin topatientswithpneumonia, “until therewasdefinite clinical improvement and the temperature had remained below 100°F for 12 hours...then given for another two to three days.”5(p748) The perceived need to treat beyond resolution of symptomswasdrivenbyadesire toprevent relapses.However, the recurrent infections seen in the case serieswere causedby isolateswithdistinct bacterial serotypes, indicativeof reinfection rather than relapse. It is unclear how this confuseddesire to prevent reinfections subsequently transformed into the illogical dogma that antibiotic resistance couldbepreventedby 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. Giventhe largenumberofbacterial infections thatoccurevery year, overtreating patients who have established infection is likely amajor source of selective pressure that drives antibiotic resistance in society. Other than tuberculosis—which is causedbyavery slowly replicativeorganismthat spendsmuch of its time inanonreplicatingstate—foreverybacterial infection forwhich trialshavecomparedshort-coursewith longercourse antibiotic therapy, short-course therapyhas been just as effective, and with reduced selective pressure driving resistance (Table).1-3,6,7,10-15 Use of shorter courses of antibiotic therapy is therefore greatly preferable to longer courses of therapy. Related article page 1257 Opinion