Journal Article

At the Threshold: Defining Clinically Meaningful Resistance Thresholds for Antibiotic Choice in Community-Acquired Pneumonia

Nick Daneman, Donald E. Low, Alison McGeer, Karen A. Green and David N. Fisman

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 46, issue 8, pages 1131-1138
Published in print April 2008 | ISSN: 1058-4838
Published online April 2008 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/529440
At the Threshold: Defining Clinically Meaningful Resistance Thresholds for Antibiotic Choice in Community-Acquired Pneumonia

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Background. Community-acquired pneumonia caused by Streptococcus pneumoniae is a major source of morbidity and mortality. Macrolide antibiotics are recommended as empirical first-line therapy for patients with community-acquired pneumonia. Guidelines suggest a 25% rate of high-level macrolide resistance in the community as the threshold beyond which macrolides should not be used. We evaluated the implications of this threshold for clinical failure rates.

Methods. We developed a theoretical model linking the prevalence of macrolide resistance to patient outcomes, based on the epidemiological concept of risk difference. We estimated the risk of clinical failure as a function of the likelihood and impact of discordant therapy and of the probability of clinical failure even in the presence of optimal therapy. The model was parameterized on the basis of the best available data derived from the published medical literature, and clinical failures were valued monetarily using an expected net benefit approach.

Results. Under the proposed 25% resistance threshold, the risk difference for such therapy would be 1.2% (95% confidence interval, 0.5%–3.1%) for death, 1.6% (95% confidence interval, 0.5%–3.2%) for bacteremia, and 3.3% (95% confidence interval, 1.1%–5.7%) for prolonged clinical course; excess risks of death were valued at >$10,000 per empirical treatment of community-acquired pneumonia and were further elevated in high-risk populations. Excluding low-level resistance resulted in a 4-fold underestimation of projected risks.

Conclusion. A 25% resistance threshold that fails to consider low-level resistance will result in high excess rates of morbidity and mortality because of discordant therapy. Whether projected failure rates are classified as unacceptable is an important health policy question, because risk of clinical failure needs to be weighed against other considerations.

Journal Article.  5240 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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