title: Relationship of Sulfamethoxazole Therapeutic Drug Monitoring to Clinical Efficacy and Toxicity: A Retrospective Cohort Study.
abstract: Trimethoprim/sulfamethoxazole (TMP/SMX) is the treatment of choice for infections caused by Pneumocystis jiroveci, Stenotrophomonas maltophilia, and Nocardia species, but the utility of therapeutic drug monitoring (TDM) is unclear. The objective of this study was to evaluate the association between peak sulfamethoxazole (SMX) serum levels and clinical outcomes to determine the utility of TDM of TMP/SMX.
  
  
  
  This study was conducted in patients receiving treatment with TMP/SMX for culture-positive infection who underwent TDM from 2003 to 2013. Peak SMX levels were classified as below target (<100 mcg/mL), within target (100-150 mcg/mL), or above target (>150 mcg/mL). The effect of initial SMX levels on clinical outcomes was compared using propensity score adjusted multivariable Cox models.
  
  
  
  A total of 279 patients had SMX monitoring performed. The primary infecting organisms were P. jiroveci (47%) and S. maltophilia (38%). A majority of patients (74%) had an SMX peak level outside of the target range. Using direct regression propensity score adjustment, there was no significant difference between rates of clinical failure and initial peak SMX level (<100 mcg/mL versus 100-150 mcg/mL: hazard ratio 0.92, 95% confidence interval, 0.28-3.07 and >150 mcg/mL versus 100-150 mcg/mL: hazard ratio 1.92, 95% confidence interval, 0.72-5.09). Similarly, there was no relationship between SMX level and toxicity (P = 0.42).
  
  
  
  Sulfamethoxazole serum levels outside the target range were not associated with increased rates of clinical failure in patients treated with TMP/SMX. There was also no association found between peak SMX levels and rates of adverse events. Although this study cannot disprove that dose adjustments after the initial SMX peak level may have affected clinical outcomes, the results suggest that the utility of SMX TDM may be limited to a subset of patients and requires further prospective investigation.
authors.affiliation: *Pharmacy Department, Spectrum Health, Grand Rapids, Michigan; †Department of Pharmacy Services, Mayo Clinic, Rochester, Minnesota; ‡Department of Clinical Pharmacy, University of California, San Francisco; Divisions of §Biomedical Statistics and Informatics, ¶Laboratory Medicine and Pathology, and ‖Infectious Diseases, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ice
authors.forename: Jason N
authors.initials: JN
authors.lastname: Barreto
authors.forename: Bao D
authors.initials: BD
authors.lastname: Dao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wolf
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dierkhising
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Jannetto
authors.forename: Loralie J
authors.initials: LJ
authors.lastname: Langman
authors.forename: Pritish K
authors.initials: PK
authors.lastname: Tosh
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination