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Revisiting the mutant prevention concentration to guide dosing in childhood tuberculosis

Devan Jaganath1, H Simon Schaaf2, Peter R Donald2

  • 1Department of Paediatrics, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA.

The Journal of Antimicrobial Chemotherapy
|March 24, 2017
PubMed

Insights

Mutant prevention concentration (MPC) is crucial for tuberculosis treatment, especially in children. Incorporating MPC into pharmacokinetic studies can optimize drug dosing to prevent resistance and manage drug-resistant TB.

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Mutant prevention concentration (MPC) is established for bacterial infections but underutilized in tuberculosis (TB) treatment due to perceived toxicity and unachievable concentrations.
  • Genomics and quantitative drug susceptibility testing reveal diverse minimum inhibitory concentrations (MICs) for anti-TB agents, influenced by mutations and strain type.
  • Paediatric TB pharmacokinetics show that even with higher doses, some children do not reach target drug concentrations.

Purpose of the Study:

  • To advocate for the consideration of Mutant Prevention Concentration (MPC) in tuberculosis drug development and treatment strategies.
  • To highlight the importance of incorporating MPC into pharmacokinetic studies for paediatric TB.
  • To propose optimizing anti-TB drug dosing in children to prevent the emergence of resistant mutants.

Main Methods:

  • Review of existing literature on Mutant Prevention Concentration (MPC) in bacterial infections and tuberculosis (TB).
  • Analysis of pharmacokinetic data in paediatric TB, focusing on drug concentration targets.
  • Discussion of the role of genomics and drug susceptibility testing in understanding TB drug resistance.

Main Results:

  • Single mutations can confer high MICs to first- and second-line anti-TB drugs.
  • A significant proportion of children with TB do not achieve target drug concentrations despite dose adjustments.
  • Genomic insights suggest a complex interplay between mutations, strain type, and drug efficacy.

Conclusions:

  • Mutant Prevention Concentration (MPC) should be considered for optimizing anti-TB drug dosing, particularly in paediatric populations.
  • Integrating MPC into pharmacokinetic studies is essential for setting appropriate concentration targets in children.
  • This approach can help restrict the growth of resistant mutants and improve the management of drug-resistant TB.

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