1. Todd, Betsy MPH, RN, CIC


What if our prescribing practices are wrong?


Article Content

Resistance to antibiotics is a serious problem, and one approach has been our emphasis on completing the full course of antibiotics. But what if this doesn't help prevent antibiotic resistance? What if our prescribing practices are wrong? An article by Llewelyn and colleagues in the July issue of BMJ offers a provocative analysis of the current ap proach to antibiotic therapy.1

Figure. Pharmacists ... - Click to enlarge in new window Pharmacists are the final link in the patient education chain, reinforcing clinician instructions to complete the entire antibiotic prescription "even if you feel better." Photo by Jason Franson.

The article's authors argue that the emphasis on completing an entire course of therapy in order to prevent the development of antibiotic resistance is not evidence based and is in fact more likely to promote, rather than prevent, the development of resistant organisms. These experts trace prolonged courses of antibiotic therapy-until well past the resolution of the patient's symptoms-to the beginning of the antibiotic era. At that time, very limited supplies of penicillin necessitated short courses of treatment.2 In some patients, improvement was short lived: symptoms of infection were reversed, only to be followed, ultimately, by treatment failure. Although there is no evidence that the relapses were the result of rapidly developing antibiotic resistance, these early failures may have established the idea that only prolonged antibiotic therapy could be curative.



The BMJ authors describe two mechanisms by which bacteria develop resistance to antibiotics and suggest that we have long gone after the wrong culprit.


In target selection, resistant strains of bacteria arise during or soon after treatment for an infection (as a result of a spontaneous small-scale mutation in the target organism), and the resistant bacteria can be transmitted to others as the disease spreads. These mutations may result from inadequate dosing or from single-drug treatment of infections caused by organisms that are known to rapidly develop spontaneous resistance. Common examples of organisms with rapidly emerging resistance include Mycobacterium tuberculosis, HIV, Plasmodium species (malaria), and Neisseria gonorrhoeae (gonorrhea).


Collateral selection, on the other hand, refers to "collateral damage" during antibiotic therapy to endogenous or colonizing bacteria ("normal flora," such as are found on the skin and in the gastrointestinal tract or even in the environment)-that is, bacteria other than those that are the target of treatment. The development of this kind of resistance can transform a typical normal flora organism into an opportunistic pathogen.


Resistance that arises from collateral selection can then spread via mobile (transferrable) genetic elements from one bacterium to another (of the same species or of a different species). The longer the other ("bystander") organisms are exposed to an antibiotic, the more likely they are to become resistant.3 Examples of bacteria that develop resistance in this way include methicillin-resistant Staphylococcus aureus, extended-spectrum [beta]-lactamase-producing Escherichia coli, and carbapenem-resistant Klebsiella pneumoniae.


Importantly, resistant organisms that arise from collateral selection can then be transmitted between asymptomatic carriers, setting the stage for an infection in the future with an antibiotic-resistant organism. Collateral selection may even be an important factor in outbreaks, as is described in a review of microbiology isolates at one hospital over a five-year period.4


The medical community has long focused on target selection as the mechanism behind most antibiotic resistance, resulting in the decades-long emphasis on extending antibiotic treatment until well after symptoms of infection have resolved. However, there is little evidence to support most current recommendations for the duration of an antibiotic course of treatment. Instead, the course is "set by precedent [and] driven by fear of undertreatment." Llewelyn and colleagues argue, however, that the resistant organisms that pose the greatest threat are those that result from collateral selection.1



Studies have demonstrated that shorter courses of antibiotic therapy can be successful in treating a number of infections, including streptococcal pharyngitis,5 community-acquired pneumonia,6 nosocomial pneumonia,7, 8 cellulitis,9 pyelonephritis,10, 11 and intraabdominal sepsis.12 Comparisons of varying treatment durations are complicated, especially when comparing new drugs with older ones for the same indication. And the fact remains that with most infections, comparative studies have not been done.3 Of note, however, in comparative clinical trials that have looked at resistance as well as cure rates, no short-course treatment demonstrated an elevated risk of resistance.


Advantages and drawbacks. There are, of course, other advantages to a shorter duration of antibiotic therapy, in addition to the possibility of countering the explosion of antibiotic-resistant organisms. Costs could be reduced and hospital stays shortened, regimens are more convenient, and shorter exposure to any drug decreases the risk of adverse reactions.


Still, any new emphasis on shorter courses of antibiotics will call for careful explanation of this "new message." Already, distorted media coverage of the BMJ article has implied that consumers should stop their antibiotics as soon as they feel better, regardless of the type of infection and without having a discussion with their prescriber. Also, leftover antibiotics after a shortened course of treatment may lead some patients to save the extra pills and "prescribe" the antibiotic for themselves or family members for various complaints at a later date.



There is no one-size-fits-all duration of antibiotic therapy, especially considering the many variations in causative organism, site of infection, extent of symptoms, and comorbidities. The BMJ authors encourage a move away from the current standardized duration of therapy (until all of the antibiotics have been taken) and toward the use of more individualized courses of treatment. Clinicians can sometimes make use of various markers in monitoring infections, such as the resolution of fever and, in inpatient settings, the serum procalcitonin level.


Many factors contribute to antibiotic resistance, and it remains important to address the unnecessary prescription of antibiotics; the use of antibiotic drugs in "food" animals; and the premature discontinuation of treatment for infections, such as tuberculosis, in which antibiotic therapy that is too short can result in drug-resistant infections.




1. Llewelyn MJ, et al The antibiotic course has had its day BMJ 2017 358 j3418 [Context Link]


2. Abraham EP, et al Further observations on penicillin Lancet 1941 238 6155 177-89 [Context Link]


3. Spellberg B The new antibiotic mantra-"shorter is better." JAMA Intern Med 2016 176 9 1254-5 [Context Link]


4. Sheppard AE, et al Nested Russian doll-like genetic mobility drives rapid dissemination of the carbapenem resistance gene blaKPC Antimicrob Agents Chemother 2016 60 6 3767-78 [Context Link]


5. Altamimi S, et al Short-term late-generation antibiotics versus longer term penicillin for acute streptococcal pharyngitis in children Cochrane Database Syst Rev 2012 8 CD004872 [Context Link]


6. Uranga A, et al Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial JAMA Intern Med 2016 176 9 1257-65 [Context Link]


7. Chastre J, et al Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial JAMA 2003 290 19 2588-98 [Context Link]


8. Singh N, et al Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription Am J Respir Crit Care Med 2000 162 2 Pt 1 505-11 [Context Link]


9. Hepburn MJ, et al Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis Arch Intern Med 2004 164 15 1669-74 [Context Link]


10. Peterson J, 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 1 17-22 [Context Link]


11. Sandberg T, 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 2012 380 9840 484-90 [Context Link]


12. Sawyer RG, et al Trial of short-course antimicrobial therapy for intraabdominal infection N Engl J Med 2015 372 21 1996-2005 [Context Link]