title: Improvement in plasma drug activity during the early treatment interval among Tanzanian patients with multidrug-resistant tuberculosis.
abstract: BACKGROUND
  Individual pharmacokinetic variability may be common in patients treated for multidrug-resistant tuberculosis (MDR-TB) but data are sparse from resource-limited settings and across the early treatment interval.
  
  
  METHODS
  Plasma drug activity, as measured by the TB Drug Activity (TDA) assay at 2 and 4 weeks of treatment with a standardized MDR-TB regimen was performed in patients with pulmonary MDR-TB from Tanzania. TDA values were correlated with measures of early treatment outcome including every two week collection of sputum for time-to-positivity (TTP) in liquid culture from the MGIT 960 automated system. Patients were evaluated at 24 weeks and those surviving without delayed sputum culture conversion (>8 weeks), culture reversion after previously negative, or weight loss were defined as having a favorable outcome.
  
  
  RESULTS
  Twenty-five patients were enrolled with a mean age of 37 ±12 years. All were culture positive from the pretreatment sputum sample with a mean TTP in MGIT of 257 ±134 hours, and the median time to culture conversion on treatment was 6 weeks. Twenty patients (80%) had an increase in TDA, with the overall mean TDA at 2 weeks of 2.1 ±0.7 compared to 2.4 ±0.8 at 4 weeks (p = 0.005). At 2 weeks 13 subjects (52%) had a TDA value > 2-log killing against their own M. tuberculosis isolate compared to 17 subjects (68%) at 4 weeks (McNemar's exact test p = 0.29). An interim treatment outcome was able to be determined in 23 patients (92%), of whom 7 had a poor outcome (30%). An increase in TDA from week 2 to week 4 was associated with favorable outcome, [unadjusted OR = 20.0, 95% CI: 1.61-247.98, exact p = 0.017 and adjusted OR = 19.33, 95% CI: 1.55-241.5, exact p = 0.023].
  
  
  CONCLUSIONS
  The majority of patients with MDR-TB in Tanzania had an increase in plasma drug activity from week 2 to week 4 of treatment as measured by the TDA assay. Understanding the etiology and full impact of this dynamic may inform therapeutic intervention.
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors: Norah D
authors: ND
authors: Ndusilo
authors: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, United States of America; Kibong'oto Infectious Diseases Hospital, Sanya Juu, Tanzania.
authors: Scott K
authors: SK
authors: Heysell
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania; Kibong'oto Infectious Diseases Hospital, Sanya Juu, Tanzania.
authors: Stellah G
authors: SG
authors: Mpagama
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania; Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, United States of America.
authors: Jean
authors: J
authors: Gratz
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors: Farida H
authors: FH
authors: Segesela
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors: Saumu J
authors: SJ
authors: Pazia
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, United States of America.
authors: Xin-Qun
authors: XQ
authors: Wang
authors: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, United States of America.
authors: Eric R
authors: ER
authors: Houpt
authors: Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors: Gibson S
authors: GS
authors: Kibiki
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013183:Sputum / Q000382:microbiology; D013636:Tanzania; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents