Mutations Causing Discordant Rifampicin Susceptibility in : Retrospective Analysis of Prevalence, Phenotypic, Genotypic, and Treatment Outcomes

Background: Discordant genotypic/phenotypic rifampicin susceptibility testing in is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa.

Methods: We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDR while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes.

Results: Discordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83% of isolates. The most frequent mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes.

Conclusions: Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.