Opinion

EDITORIAL

The New Antibiotic Mantra—“Shorter Is Better”

Brad Spellberg, MD

In AD 321, Roman Emperor Constantine the Great codified that biotic therapy is at least as effective as 10 days for the treat-
there would be 7 days in a week. Even in the modern era of evi- ment of community-acquired pneumonia.3
dence-based-medicine, this 1695-year-old decree remains a pri- In his keynote address at an annual meeting of the Infec-
mary reference for duration of antibiotic therapy: it leads phy- tious Diseases Society of America, Louis B. Rice, MD, pointed
sicians to treat infections in intervals of 7 days. Thus, it is out that pneumonia was successfully treated with short du-
gratifying when clinical trials challenge the standard antibi- rations of antibiotics as long ago as the 1940s.4 Physicians con-
otic duration of 7 to 14 days. sidered “pioneers” of penicillin customized the duration of
In the past, community-acquired pneumonia was treated therapy depending on the patient’s response and found that
with a 7- to 14-day course of antibiotics. However, clinical a range of 1½ to 4 days of therapy resulted in high cure rates.
trials in the early 2000s demonstrated that 3 or 5 days of The modern concept that we should continue treating bacte-
protocol-specified antibiotics are as efficacious as longer rial infections past the time when signs and symptoms have
courses of therapy for patients with mild to moderately resolved can be traced to 1945. Meads et al wrote that they ad-
severe community-acquired ministered penicillin to patients with pneumonia, “until there
pneumonia.1,2 To this body was definite clinical improvement and the temperature had re-
Related article of literature is now added a mained below 100°F for 12 hours…then given for another two
new randomized trial, in this to three days.”5(p748) The perceived need to treat beyond reso-
issue of JAMA Internal Medicine, by Uranga et al,3 comparing lution of symptoms was driven by a desire to prevent re-
short-course vs longer courses of therapy for hospitalized lapses. However, the recurrent infections seen in the case se-
patients with community-acquired pneumonia. The trial ries were caused by isolates with distinct bacterial serotypes,
used a pragmatic design in that treating physicians were indicative of reinfection rather than relapse. It is unclear how
allowed to select their preferred antibiotic for the first 5 days this confused desire to prevent reinfections subsequently trans-
of therapy. Patients were randomized such that on day 5 formed into the illogical dogma that antibiotic resistance could
those in the control group continued the therapy selected by be prevented by continuing therapy beyond resolution of
their treating physicians and those in the experimental group symptoms.4
had their antibiotics stopped if they were afebrile for 48 Nevertheless, this dogma has been reinforced by the
hours and had no more than 1 sign of clinical instability (eg, equally illogical, often-heard statement that to prevent anti-
hypotension, tachycardia, tachypnea, or hypoxia). These cri- biotic resistance, it is necessary for patients to complete the
teria for stopping the antibiotic applied to 70.1% of patients entire prescribed course of therapy, even after resolution of
in the experimental arm. Although patients admitted to the symptoms. There is no evidence that taking antibiotics be-
intensive care unit were excluded from the trial, a substantial yond the point at which a patient’s symptoms are resolved re-
number (approximately 40%) of patients in both arms had duces antibiotic resistance. To the contrary, specifically for
Pneumonia Severity Index scores of IV to V, indicative of pneumonia, studies have shown that longer courses of therapy
severe illness. In contrast, prior studies of short-course anti- result in more emergence of antibiotic resistance,6,7 which is
biotic therapy have focused primarily on patients with mild consistent with everything we know about natural selection,
to moderate illness. the driver of antibiotic resistance.8 In only a few types of in-
The study arms were well matched, and the results were fections does resistance emerge at the site of infection; rather,
compelling. The intervention worked, as patients who were ad- resistance typically emerges off target, among colonizing flora
ministered the short-course regimen received a median of 5 away from the site of infection.9 Thus, all that is achieved by
days of antibiotics vs 10 for the standard regimen. Across all treating an infection with antibiotics for longer than the pa-
end points, time points, and populations, short-course therapy tient has symptoms is increased selective pressure driving an-
was as effective as longer courses of therapy. Point estimates tibiotic resistance among our colonizing microbial flora.
of success favored short-course therapy across most end points Given the large number of bacterial infections that occur
and time points. In the sickest cohort (Pneumonia Severity In- every year, overtreating patients who have established infec-
dex scores of IV-V), 30-day rates of clinical success in the in- tion is likely a major source of selective pressure that drives
tention-to-treat population were significantly higher for short- antibiotic resistance in society. Other than tuberculosis—
course vs standard therapy (93.1% vs 80.3%; P = .04). which is caused by a very slowly replicative organism that
Furthermore, the readmission rate was significantly lower for spends much of its time in a nonreplicating state—for every
patients receiving the short-course regimen (1.4% vs 6.6%; bacterial infection for which trials have compared short-
P = .02). Overall, the data are convincing that 5 days of anti- course with longer course antibiotic therapy, short-course

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 Opinion Editorial

shorter courses of antibiotic therapy is therefore greatly

Table. Infections for Which Short-Course Therapy Has Been Shown
to Be Equivalent in Efficacy to Longer Therapy preferable to longer courses of therapy.
Of course, the ultimate goal is to customize duration of
Treatment, Days
therapy to the patient’s response. So what should we do
Disease Short Long
when patients are given a prescription for a fixed duration of
Community-acquired pneumonia1-3 3-5 7-10
therapy and their symptoms resolve before they complete
Nosocomial pneumonia6,7 ≤8 10-15
the course? Here we need to change the dogma: patients
Pyelonephritis10 5-7 10-14
should no longer be told to keep taking the antibiotic.
Intraabdominal infection11 4 10 Patients should be told that if their symptoms resolve before
Acute exacerbation of chronic bronchitis and COPD12 ≤5 ≥7 completing the antibiotic they should communicate with
Acute bacterial sinusitis13 5 10 their physician to determine if they can stop therapy early.
Cellulitis14 5-6 10 Health care professionals should be encouraged to allow
Chronic osteomyelitis15 42 84 patients to stop antibiotic treatment as early as possible on
Abbreviation: COPD, chronic obstructive pulmonary disease. resolution of symptoms of infection. Ultimately, we should
replace the old dogma of continuing therapy past resolution
therapy has been just as effective, and with reduced selec- of symptoms with a new, evidence-based dogma of “shorter
tive pressure driving resistance (Table). 1-3,6,7,10-15 Use of is better.”

ARTICLE INFORMATION treatment after three days versus eight days in mild a novel ostensibly resistance-avoiding approach for
Author Affiliations: Los Angeles to moderate-severe community acquired treating infections. J Infect Dis. 2016;213(6):901-903.
County+University of Southern California Medical pneumonia: randomised, double blind study. BMJ. 10. Eliakim-Raz N, Yahav D, Paul M, Leibovici L.
Center, Los Angeles; Department of Medicine, Keck 2006;332(7554):1355. Duration of antibiotic treatment for acute
School of Medicine at University of Southern 2. Dunbar LM, Wunderink RG, Habib MP, et al. pyelonephritis and septic urinary tract infection—7
California, Los Angeles. High-dose, short-course levofloxacin for days or less versus longer treatment: systematic
Corresponding Author: Brad Spellberg, MD, community-acquired pneumonia: a new treatment review and meta-analysis of randomized controlled
Los Angeles County+University of Southern paradigm. Clin Infect Dis. 2003;37(6):752-760. trials. J Antimicrob Chemother. 2013;68(10):
California Medical Center, 2051 Marengo St, 3. Uranga A, España PP, Bilbao A, et al. Duration of 2183-2191.
Office Number C2K122, Los Angeles, CA 90033 antibiotic treatment in community-acquired 11. Sawyer RG, Claridge JA, Nathens AB, et al. Trial
([email protected]). pneumonia: a multicenter randomized clinical trial of short-course antimicrobial therapy for
Published Online: July 25, 2016. [published online July 25, 2016]. JAMA Internal Med. intraabdominal infection. N Engl J Med. 2015;372
doi:10.1001/jamainternmed.2016.3646. doi:10.1001/jamainternmed.2016.3633. (21):1996-2005.

Conflict of Interest Disclosures: Dr Spellberg 4. Rice LB. The Maxwell Finland Lecture: for the 12. El Moussaoui R, Roede BM, Speelman P, Bresser
reported receiving consulting fees from Cempra, duration-rational antibiotic administration in an era P, Prins JM, Bossuyt PM. Short-course antibiotic
The Medicines Company, MedImmune/ of antimicrobial resistance and clostridium difficile. treatment in acute exacerbations of chronic
AstraZeneca, PTC Therapeutics, Entasis, Clin Infect Dis. 2008;46(4):491-496. bronchitis and COPD: a meta-analysis of
Tetraphase, Merck, and Genentech; and Data and 5. Meads M, Harris HW, Finland M, Wilcox C. double-blind studies. Thorax. 2008;63(5):415-422.
Safety Monitoring Board fees from Dipexium; and Treatment of pneumococcal pneumonia with 13. Falagas ME, Karageorgopoulos DE,
reported owning equity in Motif, BioAIM, and penicillin. N Engl J Med. 1945;232:747-755. Grammatikos AP, Matthaiou DK. Effectiveness and
Synthetic Biologics. 6. Chastre J, Wolff M, Fagon JY, et al; PneumA Trial safety of short vs. long duration of antibiotic
Funding/Support: This work was supported by Group. Comparison of 8 vs 15 days of antibiotic therapy for acute bacterial sinusitis: a meta-analysis
grants R01AI117211, R01AI103342, and therapy for ventilator-associated pneumonia in of randomized trials. Br J Clin Pharmacol. 2009;67
UM1AI104681 from the National Institutes of Health adults: a randomized trial. JAMA. 2003;290(19): (2):161-171.
and National Institute of Allergy and Infectious 2588-2598. 14. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW,
Diseases. 7. Singh N, Rogers P, Atwood CW, Wagener MM, Starnes WF, Hasewinkle WC. Comparison of
Role of the Funder/Sponsor: The funding source Yu VL. Short-course empiric antibiotic therapy for short-course (5 days) and standard (10 days)
had no role in the design and conduct of the study; patients with pulmonary infiltrates in the intensive treatment for uncomplicated cellulitis. Arch Intern
collection, management, analysis, and care unit: a proposed solution for indiscriminate Med. 2004;164(15):1669-1674.
interpretation of the data; preparation, review, or antibiotic prescription. Am J Respir Crit Care Med. 15. Bernard L, Dinh A, Ghout I, et al; Duration of
approval of the manuscript; and decision to submit 2000;162(2, pt 1):505-511. Treatment for Spondylodiscitis (DTS) study group.
the manuscript for publication. 8. Spellberg B, Bartlett JG, Gilbert DN. The future Antibiotic treatment for 6 weeks versus 12 weeks in
of antibiotics and resistance. N Engl J Med. 2013; patients with pyogenic vertebral osteomyelitis: an
REFERENCES 368(4):299-302. open-label, non-inferiority, randomised, controlled
trial. Lancet. 2015;385(9971):875-882.
1. el Moussaoui R, de Borgie CA, van den Broek P, 9. Russo TA, Spellberg B, Johnson JR. Important
et al. Effectiveness of discontinuing antibiotic complexities of the antivirulence target paradigm:

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