WHO operational handbook on tuberculosis: module 3: diagnosis: web annex B: WHO critical concentrations for pretomanid and cycloserine: systematic review and technical advisory group reports

This web annex to the WHO operational handbook on tuberculosis, Module 3: Diagnosis, presents systematic reviews and Technical Advisory Group assessments undertaken to inform WHO recommendations on critical concentrations for pretomanid and cycloserine in drug susceptibility testing for tuberculosis. The document examines available microbiological, pharmacokinetic and pharmacodynamic evidence related to these medicines, with particular emphasis on minimum inhibitory concentration distributions, epidemiological cut-off values, lineage-associated variability and implications for treatment of drug-resistant tuberculosis. It describes the methods and findings of evidence reviews, analyses of Mycobacterium tuberculosis lineage-specific susceptibility patterns, and evaluations of treatment outcomes associated with pretomanid-containing regimens.

The publication summarizes data generated from laboratory studies, clinical trials and individual-level analyses contributed by multiple international institutions and WHO reference laboratories. It discusses limitations in the current evidence base, including variability between testing media and limited data availability for some compounds and lineages. The annex also reviews pharmacokinetic and pharmacodynamic parameters relevant to dose optimization, therapeutic targets and susceptibility testing interpretation for pretomanid and cycloserine. These findings support WHO technical deliberations on establishing or refining critical concentrations and strengthening laboratory guidance for the diagnosis and management of drug-resistant tuberculosis.