title: Plasma drug activity assay for treatment optimization in tuberculosis patients.
abstract: Low antituberculosis (TB) drug levels are common, but their clinical significance remains unclear, and methods of measurement are resource intensive. Subjects initiating treatment for sputum smear-positive pulmonary TB were enrolled from Kibong'oto National TB Hospital, Tanzania, and levels of isoniazid, rifampin, ethambutol, and pyrazinamide were measured at the time of typical peak plasma concentration (C(2 h)). To evaluate the significance of the effect of observed drug levels on Mycobacterium tuberculosis growth, a plasma TB drug activity (TDA) assay was developed using the Bactec MGIT system. Time to detection of plasma-cocultured M. tuberculosis versus time to detection of control growth was defined as a TDA ratio. TDA assays were later performed using the subject's own M. tuberculosis isolate and C(2 h) plasma from the Tanzanian cohort and compared to drug levels and clinical outcomes. Sixteen subjects with a mean age of 37.8 years ± 10.7 were enrolled. Fourteen (88%) had C(2 h) rifampin levels and 11 (69%) had isoniazid levels below 90% of the lower limit of the expected range. Plasma spiked with various concentrations of antituberculosis medications found TDA assay results to be unaffected by ethambutol or pyrazinamide. Yet with a range of isoniazid and rifampin concentrations, TDA exhibited a statistically significant correlation with drug level and drug MIC, and a TDA of ~1.0 indicated the presence of multidrug-resistant TB. In Tanzania, low (≤ 2.0) TDA was significantly associated with both lower isoniazid and rifampin C(2 h) levels, and very low (≤ 1.5) TDA corresponded to a trend toward lack of cure. Study of TDA compared to additional clinical outcomes and as a therapeutic management tool is warranted.
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia 22908-1337, USA. scott.heysell@gmail.com
authors.forename: Scott K
authors.initials: SK
authors.lastname: Heysell
authors.forename: Charles
authors.initials: C
authors.lastname: Mtabho
authors.forename: Stellah
authors.initials: S
authors.lastname: Mpagama
authors.forename: Solomon
authors.initials: S
authors.lastname: Mwaigwisya
authors.forename: Suporn
authors.initials: S
authors.lastname: Pholwat
authors.forename: Norah
authors.initials: N
authors.lastname: Ndusilo
authors.forename: Jean
authors.initials: J
authors.lastname: Gratz
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Gibson S
authors.initials: GS
authors.lastname: Kibiki
authors.forename: Eric R
authors.initials: ER
authors.lastname: Houpt
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood*; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000097:blood; D008826:Microbial Sensitivity Tests / Q000592:standards; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development*; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood; D013636:Tanzania; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin