What is the recommended approach for managing a drug reaction to first-line tuberculosis medications like isoniazid, rifampicin, pyrazinamide, or ethambutol?

Management of Drug Reactions to First-Line Tuberculosis Medications

When a patient experiences a drug reaction to first-line tuberculosis medications, the recommended approach is to stop the suspected medications, monitor liver function until normalized, and then sequentially reintroduce drugs one by one with careful monitoring to identify the offending agent. 1

Initial Management of Drug Reactions

• If AST/ALT levels rise to five times normal or bilirubin rises, immediately stop rifampicin, isoniazid, and pyrazinamide 1
• For non-infectious TB in stable patients, no treatment is needed until liver function normalizes 1
• For infectious TB (sputum smear positive) or clinically unwell patients, continue treatment with non-hepatotoxic drugs such as streptomycin and ethambutol until liver function normalizes 1
• For severe reactions like Stevens-Johnson syndrome, immediately stop all medications until symptoms resolve 1

Sequential Drug Reintroduction Protocol

Once liver function normalizes, reintroduce drugs in the following sequence with daily monitoring of clinical condition and liver function:

1. Isoniazid:

   • Start at 50 mg/day
   • Increase to 300 mg/day after 2-3 days if no reaction occurs
   • Continue for 2-3 more days without reaction before adding next drug 1

2. Rifampicin:

   • Start at 75 mg/day
   • Increase to 300 mg after 2-3 days
   • Further increase to weight-appropriate dose (450 mg if <50 kg, 600 mg if >50 kg) after 2-3 more days
   • Continue for 2-3 more days without reaction before adding next drug 1

3. Pyrazinamide:

   • Start at 250 mg/day
   • Increase to 1.0 g after 2-3 days
   • Further increase to weight-appropriate dose (1.5 g if <50 kg, 2.0 g if >50 kg) 1

Management Based on Reaction Type

Hepatotoxicity

• Monitor liver function tests if fever, malaise, vomiting, jaundice, or unexplained deterioration occur 1
• Consider viral hepatitis testing to exclude coexistent viral causes 1
• If AST/ALT are 2-5× normal, monitor weekly for two weeks, then biweekly until normal 1

Rash/Hypersensitivity

• For mild reactions: provide symptomatic relief 1
• For severe reactions (like the case of immediate hypersensitivity to rifampicin): permanently discontinue the offending drug and modify regimen 2
• Restart TB medications one by one every 2 days with careful monitoring 1

Alternative Regimens When a Drug Must Be Excluded

• If rifampicin cannot be used: Consider a fluoroquinolone-based regimen (particularly newer ones like moxifloxacin) 3, 4
• If isoniazid cannot be used: Treatment will need to be continued for at least 12 months with rifampicin and ethambutol, supplemented with pyrazinamide for the initial two months 1, 5
• If pyrazinamide cannot be used: Treatment should be with rifampicin and isoniazid for nine months, supplemented with ethambutol for the initial two months 1
• If ethambutol cannot be used: The six-month regimen of rifampicin and isoniazid supplemented by two months' initial pyrazinamide is satisfactory 1

Special Considerations

• For multidrug-resistant TB (resistance to both rifampicin and isoniazid), treatment should be conducted by physicians with substantial experience in managing complex resistant cases 1
• In cases where drug options are extremely limited due to resistance patterns, desensitization protocols may be considered under the cover of two other anti-tuberculosis drugs 1
• Combined drug preparations (like Rifinah, Rimactazid, and Rifater) can be useful for compliance monitoring but should be used cautiously when reintroducing drugs after reactions 1, 6

Monitoring During Reintroduction

• Daily monitoring of clinical condition and liver function during drug reintroduction 1
• If a reaction recurs, the most recently added drug should be identified as the offending agent and permanently excluded 1
• Alternative regimens should be developed under the supervision of a fully trained physician 1