Revisiting the mutant prevention concentration to guide dosing in childhood tuberculosis.
The mutant prevention concentration (MPC) is a well-known concept in the chemotherapy of many bacterial infections, but is seldom considered in relation to tuberculosis (TB) treatment, as the required concentrations are generally viewed as unachievable without undue toxicity. Early studies revealed single mutations conferring high MICs of first- and second-line anti-TB agents; however, the growing application of genomics and quantitative drug susceptibility testing in TB suggests a wide range of MICs often determined by specific mutations and strain type. In paediatric TB, pharmacokinetic studies indicate that despite increasing dose recommendations, a proportion of children still do not achieve adult-derived targets. When considering the next stage in anti-TB drug dosing and the introduction of novel therapies for children, we suggest consideration of MPC and its incorporation into pharmacokinetic studies to more accurately determine appropriate concentration targets in children, to restrict the growth of resistant mutants and better manage drug-resistant TB.
Department of Paediatrics, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA.
Devan
D
Jaganath
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.
H Simon
HS
Schaaf
Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.
Peter R
PR
Donald
D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D017410:Practice Guidelines as Topic; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D014944:World Health Organization
D000995:Antitubercular Agents