Management of Indeterminate Rifampicin Resistance on GeneXpert

Immediate Actions and Treatment Decisions

When GeneXpert returns an indeterminate rifampicin resistance result, immediately repeat the GeneXpert test on a new specimen and simultaneously send samples for phenotypic drug susceptibility testing (DST) via liquid culture, while initiating standard first-line TB treatment pending confirmatory results, as recommended by the European Respiratory Society 1
Simultaneously send specimens for liquid culture and phenotypic DST, as molecular results must always be confirmed by culture-based methods, according to the European Respiratory Society 1
Start standard first-line therapy (rifampicin, isoniazid, pyrazinamide, ethambutol) and monitor closely, as recommended by the European Respiratory Society 1
Add ethambutol at 15 mg/kg as a fourth drug for additional protection, as recommended by the European Respiratory Society 1
Treat as rifampicin-susceptible TB with standard four-drug therapy while awaiting phenotypic DST, as recommended by the European Respiratory Society 1

Assess the patient's pretest probability of rifampicin resistance to guide clinical decision-making while awaiting confirmatory results, as recommended by the Infectious Diseases Society of America 2, 3
High-risk patients (previous TB treatment, born in/lived ≥1 year in country with MDR-TB prevalence ≥2%, contact of MDR-TB patient, HIV-infected) warrant more aggressive monitoring, as recommended by the Infectious Diseases Society of America 2, 3, 4
Starting MDR-TB treatment without confirmation can cause unnecessary toxicity and is not recommended, as stated by the European Respiratory Society 1
Rapid molecular DST is an adjunct, not a replacement for culture-based DST, as recommended by the Infectious Diseases Society of America 2, 3

Perform monthly sputum smear and culture while awaiting final DST results, as recommended by the European Respiratory Society 1
If sputum remains positive at 2 months, repeat molecular testing and comprehensive DST, as recommended by the European Respiratory Society 1
Refer immediately to a physician with substantial experience in managing drug-resistant TB if confirmed rifampicin resistant, as recommended by the European Respiratory Society and the British Thoracic Society 1, 5
Rifampicin resistance is a marker for MDR-TB in approximately 90% of cases, and treatment requires individualized regimens with minimum 5 effective drugs for at least 20 months, as stated by the British Thoracic Society 5

The European Respiratory Society/ECDC guidelines explicitly recommend GeneXpert as the WHO-endorsed rapid molecular test for initial TB diagnosis, due to its ability to immediately identify M. tuberculosis and rifampicin resistance within hours rather than weeks 6, 7, 8
The World Health Organization recommends GeneXpert as the standard of care for TB diagnosis and rifampicin resistance detection, with high diagnostic accuracy and excellent rifampicin resistance detection sensitivity and specificity 6, 7, 9

Whole genome sequencing (WGS) is available in some EU countries but is not yet the standard of care, and is currently used as a confirmatory tool when discrepant results occur between molecular and phenotypic testing 6, 7, 8
Targeted amplification followed by next-generation sequencing can detect resistance to 15 anti-TB drugs with <48h turnaround time, but these are emerging technologies 10, 11, 12

For initial diagnosis in suspected pulmonary TB, the European Respiratory Society recommends collecting at least 2 sputum specimens for microscopy and 1 for GeneXpert testing, and sending samples for liquid culture simultaneously 6, 9, 13
For drug resistance assessment, GeneXpert detects rifampicin resistance immediately, and all molecular results must be confirmed by phenotypic culture-based drug susceptibility testing 6, 14

The guidelines anticipate that sequencing will become the reference standard in the near future, but currently GeneXpert remains the WHO-recommended rapid diagnostic assay for rifampicin and isoniazid resistance identification 6, 7, 9
Quality-assured phenotypic DST confirmation is mandatory for all molecular results, and direct communication between laboratory and clinicians is essential to determine which second-line drugs are tested 6, 7, 14