Antibiotics for Acute Respiratory Tract Infections (Ed.)

Linder JA. Antibiotics for treatment of acute respiratory tract infections: decreasing benefit, increasing risk, and the irrelevance of antimicrobial resistance. Clin Infect Dis 2008 Aug 11; DOI: 10.1086/591149. (Editorial)

http://www.journals.uchicago.edu/doi/full/10.1086/591149

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Clinical Infectious Diseases 2008;47:000–000
© 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4706-00XX$15.00
DOI: 10.1086/591149
EDITORIAL COMMENTARY
Antibiotics for Treatment of Acute Respiratory Tract Infections: Decreasing Benefit, Increasing Risk, and the Irrelevance of Antimicrobial Resistance
Jeffrey A. Linder
Division of General Medicine and Primary Care, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Received 4 June 2008; accepted 13 June 2008; electronically published 11 August 2008.
(See the article by Shehab et al. at http://www.journals.uchicago.edu/doi/full/10.1086/591126)
Reprints or correspondence: Dr. Jeffrey A. Linder, Div. of General Medicine and Primary Care, Brigham and Women's Hospital, 1620 Tremont St., BC-3-2X, Boston, MA 02120 (jlinder@partners.org).

Despite little microbiological reason indicating that it would be helpful, antibiotic prescribing for treatment of predominantly viral acute respiratory tract infections remains nearly as popular as ever. Acute bronchitis in adults is an instructive example. According to guidelines and performance measures, the right antibiotic prescribing rate should be close to 0% [1, 2]. However, in the United States, physicians prescribed antibiotics to 77% of adults with acute bronchitis in 1995, to 59% of adults in 2000, and to 67% of adults in 2005 (unpublished data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey). Overall, acute respiratory tract infections other than pneumonia account for 50% of antibiotic prescribing to adults and 75% of antibiotic prescribing to children [3].
Microbiology aside, clinicians may prescribe antibiotics and patients may use antibiotics with the intention of reducing symptoms or preventing complications. Research does not validate these rationales. Systematic reviews from the Cochrane Collaboration have found marginal to no benefit of antibiotics for treatment of the common cold, acute otitis media in children, maxillary sinusitis, sore throat, and acute bronchitis [4–8]. Recent randomized, controlled trials that carefully measured patient symptoms found no symptomatic benefit of antibiotics for treatment of acute bronchitis or sinusitis [9, 10].
To see whether randomized, controlled trials were missing rare complications of acute respiratory tract infections, Petersen et al. [11] recently provided an analysis of 3.4 million respiratory tract infection visits from the United Kingdom General Practice Research Database. With the exception of “chest infections,” which likely included cases of pneumonia, the number needed to treat with antibiotics to prevent 1 complication was >4000 cases. No differences in outcomes were found for smokers or patients with chronic respiratory disease. A number needed to treat of 4000 cases is much higher than the numbers of cases most commonly used in interventions, especially considering that most complications of acute respiratory tract infections are treatable. Other studies [12, 13] have not found an increase in the number of complications in instances of significant reductions in antibiotic prescribing rates.
Thus, for most acute respiratory tract infections, antibiotics appear to have little benefit. However, if the risks for individual patients are minimal, it might make sense to use antibiotics to treat acute respiratory tract infections. However, evidence of the risks associated with antibiotics continues to increase. Depending on the antibiotic, 5%-25% of patients will develop antibiotic-associated diarrhea [14]. Clostridium difficile infection is an increasingly recognized adverse event associated with antibiotic treatment. Quantifying the risk of adverse events related to antibiotic exposure is challenging, but the antibiotics most commonly associated with C. difficile infection are clindamycin, cephalosporins, and fluoroquinolones [15]. Of the patients who receive antibiotics, 2% will develop a skin reaction [16] and 1 of 5000 patients will have an anaphylactic reaction [17].
In addition, in studies examining drug-related adverse events, antibiotics continue to emerge as a common cause of these events. Penicillins are one of the most common causes of drug-related adverse events in ambulatory practice [18]. Antibiotics are the second most common cause of drug-related adverse drug events in elderly patients [19] and are one of the most common causes of such events after hospital discharge [20]. Furthermore, adverse events attributable to antibiotics often lead to hospital admission [21]. Antibiotics are one of the most common classes of medication associated with malpractice claims [22].
In this issue of Clinical Infectious Diseases, using the National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, and National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance, Shehab et al. [23] analyzed the risk of an emergency department visit for an adverse event associated with antibiotics. The authors found that antibiotics were responsible for nearly 20% of emergency department visits for drug-related adverse events and caused 10.5 emergency department visits for drug-related adverse events per 10,000 outpatient visits at which an antibiotic was prescribed. Because the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey only capture antibiotic prescribing that occurs in the context of a visit, Shehab et al. [23] likely underestimated the rate of antibiotic prescribing. However, the authors also underestimated the number of emergency department visits for drug-related adverse events; the sensitivity of the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance program for detecting adverse events is 45% [24]. What is most striking is that the risks associated with antibiotic treatment, especially sulfonamides and clindamycin, are comparable to those for insulin, warfarin, and digoxin, medications that are perceived to be relatively dangerous.
By focusing on only emergency department visits, Shehab et al. [23] detected the tip of the iceberg. Many more patients have mild drug-related adverse events that lead them to seek nonemergency ambulatory care or to simply stop use of the antibiotic. Strom [25] noted that the present US drug safety system focuses on rare effects of new drugs instead of common adverse effects of older drugs. Indeed, according to the US Food and Drug Administration Adverse Event Reporting System, a collection of voluntary reports, antibiotics do not emerge as a top cause of serious drug-related adverse events [26]. However, depending on several factors, the sensitivity of the Adverse Event Reporting System is estimated to be as low as 0.3%, and there has been widespread agreement that the time needed to identify “problem drugs” and quantify risks of older drugs is too long. Consistent with recommendations by the Committee on the Assessment of the US Drug Safety System [27], proactive, automated reporting imbedded within electronic health records may more rapidly identify problems with new drugs and allow more careful quantification of the risks of older drugs.
Shehab et al. [23] indicated that antibiotic-associated adverse events occur when antibiotics are taken as prescribed and as intended; the only error with respect to many antibiotic prescriptions is that they are prescribed at all. If as many as one-half of antibiotic prescriptions are unnecessary, what interventions will be effective in reducing the frequency of inappropriate antibiotic prescribing? Clearly, finger wagging in the medical literature is not working. Potential interventions to decrease the frequency of inappropriate antimicrobial prescribing for treatment of acute respiratory tract infections include physician education, physician audit and feedback, patient education, multidimensional interventions, delayed antimicrobial prescriptions, health information technology solutions, and financial or regulatory incentives. Unfortunately, most interventions result in only modest absolute reductions (10%) in the frequency of inappropriate antimicrobial prescribing. A recent systematic review found that multidimensional interventions involving physicians and patients appeared more effective than clinician educational interventions, which in turn, were more effective than interventions that used audit and feedback [28]. However, for acute bronchitis, even successful interventions in the United States have caused a reduction in the antimicrobial prescribing rate to only 40%–50% [13, 29, 30].
When considering an antibiotic prescription, physicians may feel a need to balance individual benefit with the societal risks of increasing antimicrobial resistance [31]. This is not necessary. First, treating a viral illness with antibiotics does not make sense microbiologically. Second, according to the literature, the benefit of antibiotics for treatment of most acute respiratory tract infections appears to be decreasing. Third, the real risks of antibiotic prescribing are becoming clearer. The article by Shehab et al. [23] is part of increasing evidence that antibiotic therapy is associated with greater risk than was previously appreciated. For everything clinicians do, they have an obligation to weigh and clearly explain the benefits and risks to patients. The decision and discussion about antibiotic prescribing should focus on benefits and risks for the individual patient. Physicians should be comfortable with making the following statement to most of their patients with acute respiratory tract infections: “For your infection, there is an 1 in 4000 chance that an antibiotic will prevent a serious complication, a 5%–25% chance that it will cause diarrhea, and an 1 in 1000 chance that you will require a visit to the emergency department because of a bad reaction to the antibiotic.”
For most acute respiratory tract infections, antimicrobial resistance is irrelevant. For an individual patient, the risks are greater than the benefits, and the discussion should stop there.

Acknowledgments
Financial support.  Agency for Healthcare Research and Quality Career Development Award (K08 HS014563).
Potential conflicts of interest.  J.A.L. has received grant support from Roche and Pfizer.

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