title: Population pharmacokinetics and pharmacodynamics of ofloxacin in South African patients with multidrug-resistant tuberculosis.
abstract: Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chigutsa
authors.forename: Sandra
authors.initials: S
authors.lastname: Meredith
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Nesri
authors.initials: N
authors.lastname: Padayatchi
authors.forename: Joe
authors.initials: J
authors.lastname: Harding
authors.forename: Prashini
authors.initials: P
authors.lastname: Moodley
authors.forename: William R
authors.initials: WR
authors.lastname: Mac Kenzie
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015242:Ofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013019:South Africa; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D015242:Ofloxacin