What is the replacement for Isoniazid (INH) with Levofloxacin in tuberculosis treatment if INH is discontinued due to psychosis?

Isoniazid-Induced Psychosis: Replacement with Levofloxacin

Yes, levofloxacin is an appropriate replacement for isoniazid when INH must be discontinued due to psychosis, as part of a modified regimen for drug-susceptible tuberculosis. 1

Immediate Management When INH-Induced Psychosis Occurs

• Discontinue isoniazid immediately upon recognition of psychotic symptoms, as rechallenge with INH results in recurrence of psychosis in more than 80% of cases 2
• Psychotic symptoms typically occur within the first 2 months of treatment, with earlier onset in patients aged 18 years or less 2
• Common presentations include delusions, hallucinations, psychomotor disturbances, disorganized speech, and neuropsychiatric symptoms such as sleep disturbances, hostility, confusion, and anxiety 2

Recommended Replacement Regimen

The optimal replacement regimen consists of rifampin, ethambutol, pyrazinamide, and levofloxacin for 6 months total. 1

Specific Drug Dosing:

• Rifampin: 10 mg/kg daily (typically 600 mg) 1
• Ethambutol: 15 mg/kg daily 1
• Pyrazinamide: 35 mg/kg daily for patients <50 kg or 2.0 g daily for patients >50 kg (given for first 2 months only) 1
• Levofloxacin: 750 mg daily 1

Treatment Duration:

• Continue this 4-drug regimen for the first 2 months (intensive phase) 1
• Follow with rifampin, ethambutol, and levofloxacin for 4 additional months (continuation phase) to complete 6 months total 1

Evidence Supporting Fluoroquinolone Substitution

• The American Thoracic Society/CDC/IDSA guidelines specifically recommend fluoroquinolones (levofloxacin, moxifloxacin, or ofloxacin) as appropriate substitutes when INH cannot be used 1
• For isoniazid-resistant tuberculosis, the WHO recommends a regimen of rifampin, ethambutol, pyrazinamide, and levofloxacin for 6 months, which achieved treatment success rates with adjusted OR of 2.8 (95% CI: 1.1-7.3) 1
• This same regimen is appropriate when INH must be discontinued for toxicity reasons, as the organism remains susceptible to INH but the patient cannot tolerate it 1

Critical Considerations for Extended Treatment

• If cavitary disease was present on initial chest radiograph AND the 2-month culture remains positive, extend the continuation phase to 7 months (total of 9 months treatment) 1
• For patients with extensive disease, the fluoroquinolone strengthens the regimen and may compensate for the loss of INH 1
• Ethambutol should be continued throughout the entire treatment course (unlike standard regimens where it can be stopped after 2 months) because you are effectively treating with one fewer first-line drug 1

Monitoring Requirements

• Obtain monthly sputum specimens for smear and culture until two consecutive specimens are culture-negative 1
• Baseline and periodic visual acuity and red-green color discrimination testing for ethambutol 1
• Monitor for fluoroquinolone-related adverse effects including tendinopathy, QT prolongation, and CNS effects 1

Important Caveats

• Do NOT attempt to rechallenge with isoniazid, even at lower doses or with pyridoxine supplementation, as recurrence of psychosis is highly likely 2, 3
• While pyridoxine deficiency may contribute to INH-induced psychosis pathogenesis, supplementation does not reliably prevent or treat established psychosis 4, 5, 3
• Ensure drug susceptibility testing confirms the organism is susceptible to rifampin, as this is the cornerstone of the modified regimen 1
• Consider psychiatric consultation for management of acute psychotic symptoms, which may require antipsychotic medication (such as olanzapine) in addition to discontinuing INH 3