How to reintroduce Anti-Tuberculosis Treatment (ATT)?

Reintroduction of Anti-Tuberculosis Treatment (ATT)

When reintroducing anti-tuberculosis treatment (ATT), the approach should be based on the patient's prior treatment history, with a standard four-drug regimen for those previously treated with directly observed therapy (DOT) for drug-susceptible TB, and an expanded regimen for those with irregular prior treatment or suspected drug resistance. 1

Assessment Before Reintroduction

• Vigorous efforts should be made to establish microbiological confirmation of relapse or treatment failure to enable testing for drug resistance 1
• Determine if the patient had previous treatment with DOT or self-administered therapy, as this influences the risk of acquired drug resistance 1
• Evaluate the timing of relapse - most relapses occur within the first 6-12 months after completion of therapy 1

Reintroduction Strategy Based on Prior Treatment

For Patients Previously Treated with DOT for Drug-Susceptible TB:

• Retreatment using the standard four-drug initial phase regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) is appropriate until susceptibility test results are available 1
• This approach is suitable because in nearly all patients with TB caused by drug-susceptible organisms who were treated with rifamycin-containing regimens using DOT, relapses occur with susceptible organisms 1

For Patients with Self-Administered or Irregular Prior Treatment:

• Begin an expanded regimen due to higher risk of acquired drug resistance 1
• The expanded regimen should generally employ isoniazid, rifampin, and pyrazinamide plus an additional three agents 1
• Additional agents typically include ethambutol, a fluoroquinolone, and an injectable agent such as streptomycin (if not used previously and the initial isolate was susceptible), amikacin, kanamycin, or capreomycin 1

Special Considerations

• NEVER ADD A SINGLE DRUG TO A FAILING REGIMEN as this risks development of resistance to the new drug 1
• For patients with impaired immunity, limited respiratory reserve, central nervous system involvement, or other life-threatening circumstances, an expanded regimen is particularly important 1
• If exogenous reinfection is suspected, the drug susceptibility pattern of the presumed source case should guide regimen selection 1

Management of Drug-Induced Adverse Effects

Hepatotoxicity Management:

• If hepatotoxicity occurs (AST/ALT more than five times normal or bilirubin rises), stop rifampin, isoniazid, and pyrazinamide immediately 1
• For non-infectious TB with hepatotoxicity, treatment can be paused until liver function normalizes 1
• For infectious or symptomatic TB with hepatotoxicity, use non-hepatotoxic drugs like streptomycin and ethambutol until liver function normalizes 1

Reintroduction After Hepatotoxicity:

• Once liver function normalizes, reintroduce drugs sequentially with careful monitoring 1:
  1. Start isoniazid at 50 mg/day, increasing to 300 mg/day after 2-3 days if no reaction
  2. Add rifampin at 75 mg/day after 2-3 more days, increasing to 300 mg after 2-3 days, then to weight-appropriate dose (450-600 mg) after another 2-3 days
  3. Finally, add pyrazinamide at 250 mg/day, increasing to 1.0 g after 2-3 days, then to weight-appropriate dose (1.5-2 g) 1

Monitoring During Reintroduction

• Perform monthly clinical monitoring for all patients 1
• Assess for signs of hepatitis (nausea, vomiting, abdominal pain, jaundice) at each visit 1
• For patients with abnormal baseline liver tests or at risk for hepatic disease, perform regular laboratory monitoring 1
• Monitor sputum cultures to assess treatment response - most patients should have negative cultures after 3 months of effective therapy 1

Treatment Duration After Reintroduction

• For drug-susceptible TB, a 6-month regimen is standard (2 months of four drugs followed by 4 months of isoniazid and rifampin) 1
• If pyrazinamide cannot be included, extend treatment to 9 months 1
• For patients with extensive disease whose cultures remain positive after 2 months, consider extending treatment 1
• For patients with cavitary pulmonary TB and positive cultures at completion of 2 months of therapy, extend the continuation phase to 7 months (total 9 months) 1

Common Pitfalls to Avoid

• Failing to obtain drug susceptibility testing before restarting treatment 1
• Adding a single drug to a failing regimen, which promotes development of resistance 1
• Ignoring the possibility of drug interactions, especially with rifampin which affects many medications 1
• Using fixed-dose combinations for intermittent dosing (they are formulated only for daily use) 1
• Discontinuing first-line drugs because of minor side effects - if gastrointestinal upset occurs, administer with food rather than splitting doses or changing to second-line drugs 1

By following these guidelines for reintroducing ATT, clinicians can maximize treatment success while minimizing the risk of developing drug resistance.