title: Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients.
abstract: Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0-24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0-24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0-24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R(2) = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0-24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.
authors.affiliation: Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania, USA Botswana-University of Pennsylvania Partnership, Gaborone, Botswana.
authors.forename: Chawangwa
authors.initials: C
authors.lastname: Modongo
authors.affiliation: Center for Infectious Diseases Research & Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
authors.forename: Beki T
authors.initials: BT
authors.lastname: Magazi
authors.affiliation: Center for Infectious Diseases Research & Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania, USA Botswana-University of Pennsylvania Partnership, Gaborone, Botswana Department of Medicine, University of Botswana, Gaborone, Botswana.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Zetola
authors.affiliation: Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Centro di Ricerca, Ospedale San Pietro Fatebenefratelli, Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.affiliation: Center for Infectious Diseases Research & Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA Department of Medicine, University of Cape Town, Observatory, Cape Town, South Africa Tawanda.Gumbo@BSWHealth.org.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001185:Artificial Intelligence; D001902:Botswana; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008962:Models, Theoretical; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012044:Regression Analysis; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D000583:Amikacin