What does a Genexpert (GeneXpert) test result showing rifampicin (Rifampin) resistance as indeterminate mean for a patient with tuberculosis (TB) pleural effusion?

GeneXpert Rifampicin Resistance "Indeterminate" Result in TB Pleural Effusion

An indeterminate rifampicin resistance result on GeneXpert means the test detected Mycobacterium tuberculosis but could not definitively determine whether rifampicin resistance is present or absent, requiring immediate repeat testing with pleural biopsy (preferred over fluid) and initiation of an expanded empirical regimen while awaiting confirmatory drug susceptibility testing. 1

What "Indeterminate" Actually Means

• The GeneXpert (Xpert MTB/RIF) assay successfully identified TB bacteria in your pleural fluid but encountered technical issues in analyzing the genetic mutations that indicate rifampicin resistance 1
• This is NOT the same as "rifampicin resistant" or "rifampicin susceptible"—it means the test result is inconclusive for resistance status 1
• Indeterminate results can occur due to low bacterial load (common in pleural effusions), mixed bacterial populations, or technical assay limitations 2, 3

Critical Clinical Implications

Rifampicin resistance is a marker for multidrug-resistant TB (MDR-TB) in approximately 90% of cases, meaning resistance to both rifampicin and isoniazid 1. Therefore, an indeterminate result must be treated with high suspicion until proven otherwise.

Immediate Next Steps Required:

• Obtain pleural biopsy immediately for culture and comprehensive drug susceptibility testing—this is superior to pleural fluid alone for detecting M. tuberculosis and determining resistance patterns 3
• Send specimens for both molecular testing (line probe assay for isoniazid resistance) and phenotypic culture-based drug susceptibility testing 1, 4
• Do NOT wait for results before starting treatment if the patient is clinically ill 1

Treatment Approach While Awaiting Confirmatory Testing

If Patient is Clinically Stable:

• You may continue standard four-drug therapy (isoniazid, rifampicin, pyrazinamide, ethambutol) while awaiting repeat testing results 1
• However, add two to three additional drugs to which the organism is likely susceptible until full susceptibilities are confirmed 1

If Patient is Seriously Ill or High Risk for MDR-TB:

Start an expanded empirical regimen immediately consisting of: 1, 4

• Standard four drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) PLUS
• A fluoroquinolone (levofloxacin or moxifloxacin) PLUS
• An injectable agent (amikacin, kanamycin, or capreomycin if not previously exposed to streptomycin) PLUS
• Consider an additional second-line drug depending on disease severity 1, 4

All treatment must be given as directly observed therapy (DOT) 1

High-Risk Features Requiring Expanded Empirical Regimen:

• Previous TB treatment history 1
• Known exposure to MDR-TB case 1
• HIV co-infection 1, 3
• Ethnic minority background or origin from high MDR-TB prevalence area 1, 3
• Severe respiratory compromise or life-threatening disease 1

Critical Pitfalls to Avoid:

• Never add a single new drug to a potentially failing regimen—this will create additional resistance 1, 4
• Do not assume the result means "susceptible"—indeterminate requires the same caution as suspected resistance 1
• Do not rely solely on pleural fluid for repeat testing—pleural biopsy has much higher yield 3
• Do not use intermittent therapy for suspected drug-resistant TB 1

Special Considerations for Pleural TB:

• Drug penetration into pleural fluid is variable: isoniazid penetrates well, but rifampicin and especially pyrazinamide often achieve subtherapeutic levels in pleural effusions 5
• This suboptimal penetration may contribute to treatment failure and development of resistance 5
• Approximately 6-10% of pleural TB isolates show isoniazid resistance, and 1-3% are multidrug-resistant 3
• Consider therapeutic drainage if effusion is large, as this may improve drug penetration 5

Adjusting Treatment Based on Final Results:

If Confirmed Rifampicin-Susceptible:

• Continue standard six-month regimen (2 months HRZE, then 4 months HR) 1

If Confirmed Rifampicin-Resistant (Isolated):

• Treat with isoniazid, pyrazinamide, ethambutol for 2 months, then isoniazid plus ethambutol for 16 additional months (total 18 months) 1, 6
• However, assume MDR-TB until isoniazid susceptibility is confirmed 1

If Confirmed MDR-TB:

• Refer immediately to specialized MDR-TB treatment center 1, 4
• Minimum five effective drugs for at least 20 months, or shorter 9-11 month regimen if eligible 1, 4
• Treatment must include Group A drugs (fluoroquinolone, bedaquiline, linezolid) as backbone 4, 2