Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment

Objectives: The clinical significance of the emergence of Mycobacterium tuberculosis (MTB) isolates that contain rpoB mutations (genotypic resistance), but are phenotypically susceptible to rifampicin (RIF G(R) P-S), remains uncertain. The aim of this study was to determine the prevalence of MTB cases that demonstrate this discordant rifampicin resistance pattern and to establish whether these patients have poorer treatment outcomes with rifampicin-based regimens. Methods: rpoB sequencing was performed on all MTB isolates demonstrating phenotypic resistance to one or more first-line antituberculosis agents (excluding rifampicin). Rifampicin MICs were determined for rpoB mutation-positive isolates and clinical case notes were reviewed to identify treatment outcomes in these patients. Results: Of the 214 phenotypically drug (excluding rifampicin)-resistant isolates tested, 5 contained rpoB mutations (4 isoniazid resistant and 1 pyrazinamide resistant). These isolates demonstrated elevated rifampicin MICs (low-level resistance), despite testing susceptible using phenotypic broth-based methods. One patient experienced a relapse of tuberculosis (TB) 2 years after completion of a rifampicin-containing regimen. These findings are consistent with a recent study that reported treatment failure with rifampicin-based regimens in patients with isoniazid-resistant MTB and genotypic rifampicin resistance. Conclusions: While MTB RIF G(R) P-S strains remain relatively uncommon, they can be associated with low-level rifampicin resistance and poorer treatment outcomes with rifampicin-based regimens. This recently recognized form of multidrug-resistant TB should be adequately detected and managed.