What is the recommended treatment approach if rifampicin (RIF) resistance is indeterminate?

Treatment Approach for Indeterminate Rifampicin Resistance

When rifampicin resistance testing yields indeterminate results, treat the patient as if they have rifampicin-resistant tuberculosis with an expanded regimen until definitive susceptibility results are available, especially if the patient is seriously ill or has positive AFB smears. 1

Immediate Management Strategy

Repeat Testing is Critical

• Send a new specimen immediately to a reference laboratory for both first- and second-line drug susceptibility testing to resolve the indeterminate result and guide definitive therapy 1
• The discordance between different testing methods (molecular vs. conventional) requires clarification, as treatment outcomes differ significantly based on actual resistance patterns 2

Risk Stratification Determines Initial Approach

For seriously ill patients or those with positive AFB smears:

• Start an empirical expanded regimen immediately without waiting for repeat testing results 1
• Include at least 4-5 effective drugs: a fluoroquinolone (levofloxacin or moxifloxacin), an injectable agent (amikacin, kanamycin, or capreomycin if streptomycin was not used previously), plus pyrazinamide, ethambutol, and an additional oral agent (cycloserine, ethionamide, or PAS) 1

For stable patients who are not seriously ill:

• You may defer starting an altered regimen until repeat susceptibility results are available 1
• However, this approach carries risk if true rifampicin resistance exists, as delays can worsen outcomes 3

Critical Treatment Principles

Never Add Single Drugs

• A fundamental principle: never add a single drug to a failing or uncertain regimen - this leads to acquired resistance to the new drug 1
• Always add at least 2-3 new drugs to which susceptibility can be logically inferred 1

Consultation is Mandatory

• Patients with suspected or confirmed rifampicin resistance are at high risk for treatment failure and further acquired drug resistance and must be referred to or managed in consultation with specialized TB treatment centers 1
• Even isolated rifampicin resistance (without isoniazid resistance) carries worse prognosis than fully susceptible TB and requires expert management 1

Empirical Regimen Components While Awaiting Results

Group A Priority Drugs (Highest Priority)

• Levofloxacin 500-1000 mg daily or moxifloxacin - these are Group A priority drugs with strong evidence for MDR-TB treatment 4
• Levofloxacin is generally preferred over moxifloxacin due to fewer adverse events and less QTc prolongation 4

Injectable Agents

• Amikacin, kanamycin, or capreomycin for the initial intensive phase 1
• Streptomycin only if not used previously and the patient is not from an area with high streptomycin resistance rates 1

Additional Oral Agents

• Pyrazinamide and ethambutol should be continued 1
• Add cycloserine, ethionamide, or PAS as additional agents 1

Adjusting Treatment Based on Final Results

If Repeat Testing Confirms Rifampicin Susceptibility

• De-escalate to standard rifampicin-containing regimen 5
• Complete standard 6-month treatment (2 months HRZE, then 4 months HR) 5

If Repeat Testing Confirms Rifampicin Resistance

• Continue expanded regimen for 18-24 months total 1
• Ensure at least 4 effective drugs based on susceptibility results 1, 4
• Include bedaquiline and linezolid if available, as these are Group A priority drugs 1, 4

If Results Remain Discordant Between Testing Methods

• Patients with discordant rifampicin DST results who receive second-line regimens have better clinical response than those treated with first-line regimens 2
• Treat as rifampicin-resistant until proven otherwise, as the consequences of under-treatment are severe 2

Common Pitfalls to Avoid

• Do not continue standard first-line therapy while waiting for repeat testing if the patient has extensive disease or is clinically deteriorating - this risks treatment failure and resistance amplification 1, 3
• Do not assume indeterminate results mean susceptibility - the prevalence of second-line drug resistance among rifampicin-resistant cases is substantial, and empiric treatment must account for this 3
• Do not delay consultation with TB experts - early specialist involvement improves outcomes in drug-resistant TB 1
• Avoid fluoroquinolone monotherapy or inadequate companion drugs - this rapidly leads to fluoroquinolone resistance, which dramatically worsens prognosis 2, 6
• Remember that molecular tests (like GeneXpert) detecting rifampicin resistance have high specificity - an indeterminate result may reflect technical issues rather than true susceptibility, so err on the side of caution 2

Monitoring During Uncertain Period

• Obtain sputum cultures monthly to assess treatment response 1
• Monitor for adverse effects from the expanded regimen, particularly hepatotoxicity, nephrotoxicity, ototoxicity, and QTc prolongation 4, 6
• Reassess the regimen immediately once definitive susceptibility results are available 1