The limitations of the Cepheid GeneXpert® Mtb/Rif assay for the diagnosis and management of polyresistant pulmonary tuberculosis

Abstract

Abstract Background Tuberculosis (TB) is the leading world-wide cause of death caused by a single infectious agent. The global treatment success rate for multi-drug resistant (MDR) TB, defined as resistance to at least rifampicin and isoniazid, is estimated at 56%. Mutations in the rpoB gene predict resistance to rifampicin, and are used as a marker of MDR-TB, with standard quadruple therapy recommended in patients testing rpoB wildtype. Case report A 30-year old woman from Moldova had smear-positive pulmonary TB and was started on standard quadruple therapy after Cepheid GeneXpert® testing detected no mutations in the rpoB gene predictive of rifampicin resistance. After 14 days in hospital, she was considered to be non-infectious despite persistently smear-positive sputum samples and was discharged to continue TB medications in the community. Whole genomic sequencing (WGS) available 8 days after discharge subsequently predicted polyresistant TB (resistance to more than one first-line anti-TB drug apart from rifampicin). Results The patient was readmitted for treatment modification and required a further 82 days in hospital before sputum samples became culture-negative and respiratory isolation was lifted. Conclusions This case highlights the limitations of using the absence of mutations in the rpoB gene to predict fully susceptible TB. In cases of polyresistant TB, testing solely for rifampicin resistance may result in inadequate treatment, as resistance to first-line medications apart from rifampicin will not be detected. The lack of guidelines on appropriate de-escalation from respiratory isolation pertaining to pulmonary smear-positive polyresistant TB was also emphasised in this case. Our patient was removed from respiratory isolation when two consecutive sputum samples were culture-negative at 42 days. As sputum samples may remain smear-positive but be culture-negative, this raises the question of whether smear-positivity alone should be used as a measure for de-isolation.