What is the next step if a sputum Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) result shows indeterminate resistance?

Management of Indeterminate Resistance on Sputum CBNAAT for Tuberculosis

When sputum CBNAAT shows indeterminate resistance to rifampicin, the next step is to collect additional sputum specimens for culture and comprehensive drug susceptibility testing (DST) while initiating empirical treatment based on clinical judgment.

Immediate Actions After Indeterminate CBNAAT Result

• Collect additional sputum specimens for AFB smear, culture, and comprehensive drug susceptibility testing (DST) for both first-line and second-line drugs 1
• Test for inhibitors in the specimen, as 3-7% of sputum specimens might contain substances that prevent or reduce amplification and cause false-negative or indeterminate NAA results 1
• Consider performing a repeat CBNAAT test on a fresh specimen to confirm or clarify the initial indeterminate result 1, 2
• If the patient is seriously ill or has positive sputum AFB smears, consider starting empirical TB treatment without waiting for DST results, based on clinical judgment 3

Diagnostic Algorithm for Indeterminate CBNAAT Results

• If inhibitors are detected in the specimen:

  • The CBNAAT test provides no diagnostic help for this specimen 1
  • Collect a new specimen and repeat testing 1
  • Use clinical judgment to determine treatment initiation while awaiting culture results 1

• If inhibitors are not detected:

  • Proceed with culture and comprehensive DST as the gold standard for confirmation 1
  • Consider the patient's clinical presentation and risk factors for drug-resistant TB 3
  • Use clinical judgment to determine whether to begin anti-TB treatment while awaiting culture results 1

Culture and Drug Susceptibility Testing

• Culture remains the gold standard for laboratory confirmation of TB and is required for isolating bacteria for comprehensive drug susceptibility testing 1
• Liquid culture methods (e.g., MGIT 960) have higher sensitivity (88-90%) and shorter detection time (10-14 days) compared to solid culture methods 1
• First-line drug susceptibility testing in liquid medium typically requires 1-2 weeks after growth detection 1
• Second-line drug susceptibility testing may require additional 1-4 weeks depending on the medium used 1

Treatment Considerations

• Never add a single drug to a potentially failing regimen as this leads to acquired resistance to the added drug 3
• If there is high clinical suspicion of drug-resistant TB, consider initiating an empirical retreatment regimen that includes at least three effective drugs 3
• An empirical regimen for suspected drug resistance might include a fluoroquinolone, an injectable agent, and additional oral agents 3
• Adjust the treatment regimen based on DST results when they become available 3

Special Considerations

• The positive and negative agreements between LPA (Line Probe Assay) and CBNAAT for rifampicin resistance detection are 98.9% and 92.9% respectively, making LPA a valuable follow-up test 2
• Some rifampicin resistance patterns may be mislabeled as sensitive or indeterminate based on unique RpoB gene mutation patterns 2
• For patients with HIV co-infection or paucibacillary disease, sensitivity of all TB diagnostic tests may be reduced, requiring stronger reliance on clinical judgment 4

Common Pitfalls to Avoid

• Failing to collect specimens for culture and DST before changing therapy 3
• Delaying treatment modification in seriously ill patients while waiting for DST results 3
• Assuming that an indeterminate result means absence of resistance - indeterminate results should prompt further investigation, not reassurance 1, 2
• Relying solely on CBNAAT results without considering culture, which remains essential for comprehensive drug susceptibility testing 1, 2
• Failing to consult with TB experts for complex cases with indeterminate or discordant test results 3