Intended for healthcare professionals

Rapid response to:

Analysis

The antibiotic course has had its day

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3418 (Published 26 July 2017) Cite this as: BMJ 2017;358:j3418

Rapid Response:

Cautious interpretation of antibiotic course recommendations

We read with great interest the opinion piece authored by Llewelyn et al. in the July 26, 2017 issue of the BMJ[1]. In this article, the authors challenge the clinical recommendation that patients with a bacterial infection need to “complete the antibiotic course”, citing evidence that longer antibiotic courses can result in a higher and not lower rate of antibiotic resistance, and synthesizing evidence from clinical trials that shorter antibiotic courses are non-inferior to longer antibiotic courses[2–9]. We agree that antibiotic overuse is fueling drug resistance and threatening the efficacy of our antibiotic armamentarium. However, the authors do not discuss the evidence for the more important parent recommendation made to patients to take their antibiotic “as prescribed” i.e. not just to complete the course but more importantly not to interrupt or miss doses. There is significant laboratory evidence that growing bacteria under intermediate levels of antibiotics (i.e. not high enough to quickly kill the bacteria or stop its growth) can accelerate or potentiate the development of drug resistance[10][11]. Thus the failure to achieve appropriate tissue drug levels, as may be seen with patients who interrupt therapy or miss doses, can itself be a key driver in the development of drug resistance
While the authors correctly point out that evidence now exists for short courses of antibiotics for certain infections, this is limited to where clinical trials exist establishing non-inferiority of shorter regimens[12]. The data for pneumonia mostly derives from hospitalized patients under close observation[2,4], and in some cases there were subgroups of patients who were found to have higher infection relapse rates[3]. When reviewing the evidence on short courses vs. long courses of antibiotics, one must keep in mind the publication bias where negative results are less likely to be published.
Physicians should follow the most updated evidence and guidelines when determining appropriate courses, prescribing the shortest course of antibiotics necessary. In fact, the evidence cited by Llewelyn et al[1] is consistent with guidelines followed in the United States for treatment of pneumonia[13,14], urinary tract infections[15,16], intra-abdominal infections[17] and cellulitis[18]. While the recommendations for streptococcal pharyngitis remain at ten days[19], the authors of the Cochrane review cited also advised caution that the studies included did not give them enough power to determine effect of shorted antibiotic course on acute rheumatic fever rates[5], a sequelae of streptococcal pharyngitis that carries significant morbidity.
Prescriber education leads to adoption of shorter courses, as has been seen through antimicrobial stewardship interventions in the inpatient setting.[20,21] In the outpatient settings, joint-decision making should be encouraged, as illustrated in the guidelines for management of acute otitis media in children by the American Academy of Pediatrics and American Academy of Family Physicians.[22] Rather than messaging such as “stop when you feel better” that carries the risk of undermining the trust between the prescriber and the patient; there is a need for appropriate messaging aimed towards the prescriber for choosing shorter courses where appropriate, while the messaging to the patient should continue to encourage following their physician’s advice with open lines of communication between them.

References
1 Llewelyn MJ, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ 2017;358:j3418. doi:10.1136/bmj.j3418
2 Singh N, Rogers P, Atwood CW, et al. Short-course Empiric Antibiotic Therapy for Patients with Pulmonary Infiltrates in the Intensive Care Unit. Am J Respir Crit Care Med 2000;162:505–11. doi:10.1164/ajrccm.162.2.9909095
3 Chastre J, Wolff M, Fagon J-Y, et al. Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial. JAMA 2003;290:2588–98. doi:10.1001/jama.290.19.2588
4 Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med 2016;176:1257–65. doi:10.1001/jamainternmed.2016.3633
5 Altamimi S, Khalil A, Khalaiwi KA, et al. Short-term late-generation antibiotics versus longer term penicillin for acute streptococcal pharyngitis in children. Cochrane Database Syst Rev 2012;:CD004872. doi:10.1002/14651858.CD004872.pub3
6 Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;164:1669–74. doi:10.1001/archinte.164.15.1669
7 Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet Lond Engl 2012;380:484–90. doi:10.1016/S0140-6736(12)60608-4
8 Peterson J, Kaul S, Khashab M, et al. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology 2008;71:17–22. doi:10.1016/j.urology.2007.09.002
9 Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med 2015;372:1996–2005. doi:10.1056/NEJMoa1411162
10 Baym M, Lieberman TD, Kelsic ED, et al. Spatiotemporal microbial evolution on antibiotic landscapes. Science 2016;353:1147–51. doi:10.1126/science.aag0822
11 Safi H, Lingaraju S, Amin A, et al. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nat Genet 2013;45:1190–7. doi:10.1038/ng.2743
12 Spellberg B. The New Antibiotic Mantra—‘Shorter Is Better’. JAMA Intern Med 2016;176:1254–5. doi:10.1001/jamainternmed.2016.3646
13 Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 2007;44:S27–72. doi:10.1086/511159
14 Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61–111. doi:10.1093/cid/ciw353
15 Gupta K, Hooton TM, Naber KG, et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103–20. doi:10.1093/cid/ciq257
16 Infection S on UT, Management SC on QIA. Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months. Pediatrics 2011;:peds.2011-1330. doi:10.1542/peds.2011-1330
17 Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010;50:133–64. doi:10.1086/649554
18 Stevens DL, Bisno AL, Chambers HF, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59:e10–52. doi:10.1093/cid/ciu296
19 Shulman ST, Bisno AL, Clegg HW, et al. Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55:e86–102. doi:10.1093/cid/cis629
20 Avdic E, Cushinotto LA, Hughes AH, et al. Impact of an antimicrobial stewardship intervention on shortening the duration of therapy for community-acquired pneumonia. Clin Infect Dis Off Publ Infect Dis Soc Am 2012;54:1581–7. doi:10.1093/cid/cis242
21 Box MJ, Sullivan EL, Ortwine KN, et al. Outcomes of rapid identification for gram-positive bacteremia in combination with antibiotic stewardship at a community-based hospital system. Pharmacotherapy 2015;35:269–76. doi:10.1002/phar.1557
22 Lieberthal AS, Carroll AE, Chonmaitree T, et al. The Diagnosis and Management of Acute Otitis Media. Pediatrics 2013;:peds.2012-3488. doi:10.1542/peds.2012-3488

Competing interests: No competing interests

28 July 2017
Avika Dixit
Fellow in Pediatric Infectious Diseases
Maha R. Farhat, Assistant Professor, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA
Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA and Department of Biomedical Informatics, Harvard Medical School, Boston, MA
10 Shattuck Street, Boston, MA 02115