What is the next best step when GeneXpert (Genetic Expert) results show Rifampicin (RIF) resistance is indeterminate?

Management of Indeterminate Rifampicin Resistance on GeneXpert

When GeneXpert shows indeterminate rifampicin resistance, immediately send a new specimen (preferably pleural biopsy if extrapulmonary TB, or repeat sputum if pulmonary) to a reference laboratory for comprehensive drug susceptibility testing, and if the patient is clinically ill or has positive AFB smears, start an expanded empirical regimen without waiting for results. 1

Understanding the Indeterminate Result

An indeterminate rifampicin resistance result means GeneXpert detected Mycobacterium tuberculosis but could not definitively determine resistance status—this is NOT the same as "resistant" or "susceptible," it indicates a technically inconclusive result. 2

Common causes include:

• Low bacterial load in the specimen 2
• Uncommon rpoB gene mutations (particularly at codon 432, Lys446Gln, or Pro439Leu) that the assay cannot reliably interpret 3
• Technical assay limitations 2

Critical point: Indeterminate results increase the post-test probability of rifampicin resistance to an unknown extent, as they may indicate underlying rpoB mutations within the rifampicin-resistance determining region. 3

Immediate Diagnostic Actions

Obtain new specimens immediately:

• For pulmonary TB: Repeat sputum sample 1
• For pleural TB: Pleural biopsy (superior to pleural fluid alone for detecting M. tuberculosis and determining resistance patterns) 2
• Send specimens for BOTH molecular testing AND phenotypic culture-based drug susceptibility testing to first- and second-line agents 2, 1

Treatment Decision Algorithm

For Seriously Ill Patients or Positive AFB Smears

Start expanded empirical regimen immediately without waiting for repeat testing: 1

Regimen components (all given as directly observed therapy):

• Standard 4 drugs: Isoniazid + Rifampicin + Pyrazinamide + Ethambutol 1
• PLUS Fluoroquinolone (levofloxacin 500-1000 mg daily or moxifloxacin) 1
• PLUS Injectable agent (amikacin, kanamycin, or capreomycin) 1
• PLUS Consider additional oral agent (cycloserine, ethionamide, or PAS) depending on disease severity 1

Never add a single drug to an uncertain regimen—this leads to acquired resistance. Always add at least 2-3 new drugs. 1

For Clinically Stable Patients

You may defer starting the expanded regimen until repeat susceptibility results are available, BUT continue standard 4-drug therapy (INH, RIF, PZA, EMB) while awaiting results. 4

However, if any high-risk features are present, treat as seriously ill:

• Previous TB treatment history 2
• Known exposure to MDR-TB case 2
• HIV co-infection 2
• Origin from high MDR-TB prevalence area 2
• Severe respiratory compromise or life-threatening disease 2

Adjusting Treatment Based on Final Results

If Repeat Testing Confirms Rifampicin Susceptibility

De-escalate to standard 6-month rifampicin-containing regimen (2 months INH/RIF/PZA/EMB, then 4 months INH/RIF). 1

If Repeat Testing Confirms Isolated Rifampicin Resistance

Treat with isoniazid + pyrazinamide + ethambutol for 2 months, then isoniazid + ethambutol for 16 additional months (total 18 months). 2

If Repeat Testing Confirms MDR-TB (Rifampicin + Isoniazid Resistance)

• Refer immediately to specialized MDR-TB treatment center 1
• Continue expanded regimen with minimum 5 effective drugs for at least 18-24 months total 1
• Include bedaquiline and linezolid if available (Group A priority drugs) 1
• Alternative: Shorter 9-11 month regimen if patient meets eligibility criteria 2

Critical Monitoring During Uncertain Period

Monthly sputum cultures to assess treatment response 1

Monitor for adverse effects from expanded regimen:

• Hepatotoxicity 1
• Nephrotoxicity 1
• Ototoxicity 1
• QTc prolongation 1

Reassess regimen immediately once definitive susceptibility results are available 1

Common Pitfalls to Avoid

False-negative rifampicin resistance on GeneXpert occurs more frequently with mixed M. tuberculosis infections (containing both drug-sensitive and drug-resistant strains), particularly when <90% of organisms are rifampicin-resistant. 5 These false-negative results are strongly associated with poor clinical outcomes (treatment failure, default, death). 5

False-positive rifampicin resistance can also occur, though less commonly. 6 This is why phenotypic confirmation is essential before committing to prolonged MDR-TB treatment.

In high-burden settings where mixed infections are common, indeterminate or negative GeneXpert results for rifampicin resistance may need further confirmation with repeat testing. 5