title: Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.
abstract: Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.
authors.affiliation: Kibong'oto National Tuberculosis Hospital, Kilimanjaro, Tanzania.
authors.forename: Stellah G
authors.initials: SG
authors.lastname: Mpagama
authors.forename: Norah
authors.initials: N
authors.lastname: Ndusilo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Stroup
authors.forename: Happiness
authors.initials: H
authors.lastname: Kumburu
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Jean
authors.initials: J
authors.lastname: Gratz
authors.forename: Eric R
authors.initials: ER
authors.lastname: Houpt
authors.forename: Gibson S
authors.initials: GS
authors.lastname: Kibiki
authors.forename: Scott K
authors.initials: SK
authors.lastname: Heysell
mesh_terms: D000293:Adolescent; D000328:Adult; D000583:Amikacin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003523:Cycloserine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005000:Ethionamide / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007612:Kanamycin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D064704:Levofloxacin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D015242:Ofloxacin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011718:Pyrazinamide / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013183:Sputum / Q000382:microbiology; D013636:Tanzania; 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; D024841:Fluoroquinolones; D011718:Pyrazinamide; D007612:Kanamycin; D064704:Levofloxacin; D000583:Amikacin; D003523:Cycloserine; D015242:Ofloxacin; D005000:Ethionamide; D000077266:Moxifloxacin