title: At the threshold: defining clinically meaningful resistance thresholds for antibiotic choice in community-acquired pneumonia.
abstract: 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% credible interval, 0.5%-3.1%) for death, 1.6% (95% credible interval, 0.5%-3.2%) for bacteremia, and 3.3% (95% credible 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Clinical Evaluative Sciences, Sunnybrook Health Sciences Centre, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Daneman
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: Alison
authors.initials: A
authors.lastname: McGeer
authors.forename: Karen A
authors.initials: KA
authors.lastname: Green
authors.forename: David N
authors.initials: DN
authors.lastname: Fisman
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017714:Community-Acquired Infections / Q000188:drug therapy* / Q000473:pathology; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides