Antimycobacterial Agents¶
Chapter 186 | Part 5: Infectious Diseases
KEY CLINICAL POINTS¶
- Latent TB infection (LTBI) is treated with isoniazid-rifapentine (3 months) or rifampin (4 months), with isoniazid alone (6–9 months) as an alternative.
- Active TB treatment involves a 6-month regimen of HRZE (isoniazid, rifampin, pyrazinamide, ethambutol) with continuation phase HR (4–7 months).
- Drug-resistant TB (DR-TB) requires second-line agents like bedaquiline, pretomanid, and linezolid, with WHO-recommended regimens like BPaLM (bedaquiline, pretomanid, linezolid, moxifloxacin).
- NTM infections require prolonged therapy with macrolides, aminoglycosides, and other agents, with surgical resection for localized disease.
- Monitoring for hepatotoxicity, drug interactions, and resistance is critical, with specific regimens for HIV co-infected patients and pediatric populations.
1. DEFINITION & OVERVIEW¶
Antimycobacterial agents target Mycobacterium tuberculosis (TB) and non-tuberculous mycobacteria (NTM). TB is a major global health burden, while NTM infections are increasingly common in immunocompromised patients and those with structural lung disease.
Table 186-1: Regimens for Latent TB Infection¶
| REGIMEN | SCHEDULE | DURATION | COMMENTS |
|---|---|---|---|
| Isoniazid plus rifapentine | 900 mg (15 mg/kg) weekly plus 900 mg (for weight >50 kg) weekly | 3 months | Directly observed therapy recommended for HIV-negative individuals; pyridoxine supplementation advised |
| Rifampin | 600 mg/d (10 mg/kg) | 4 months | |
| Isoniazid plus rifampin | 300 mg/d (5 mg/kg) plus 600 mg/d (10 mg/kg) | 3 months | Higher hepatotoxicity risk with combination |
| Isoniazid | 300 mg/d (5 mg/kg) or 900 mg twice weekly (15 mg/kg) | 6–9 months | Preferred for HIV-negative patients; pyridoxine supplementation advised |
Table 186-2: Simplified Approach to Active TB Treatment¶
| CULTURE RESULTS | INTENSIVE PHASE | CONTINUATION PHASE | EXTENSION OF TOTAL TREATMENT |
|---|---|---|---|
| Culture-positive, drug-susceptible | HRZE for 2 months, daily or 3 times/week | HR for 4 months, daily or 5 days/week | Continuation phase extended to 7 months if cavitary disease or HIV |
| CULTURE RESULTS | INTENSIVE PHASE | CONTINUATION PHASE | EXTENSION OF TOTAL TREATMENT |
|---|---|---|---|
| Extrapulmonary, drug-susceptible | HRZE for 2 months | HR for 4–7 months, daily or 5 days/week | Continuation phase extended to 10 months for TB meningitis |
1.1 Global Considerations¶
NTM infections are rising as TB rates decline. Molecular diagnostics are critical to differentiate TB from NTM. Drug resistance and treatment failure are significant challenges.
1.2 Prognosis¶
Outcomes depend on underlying conditions (e.g., IFN- γ /IL-12 defects, cystic fibrosis). Untreated NTM can lead to severe lung destruction, while TB remains a leading cause of mortality in low-resource settings.
2. EPIDEMIOLOGY¶
TB incidence has declined globally but remains high in low/middle-income countries. NTM infections are rising, especially in immunocompromised patients. M. kansasii and M. abscessus are common NTM pathogens.
2.1 Risk Factors¶
HIV co-infection, immunosuppression, structural lung disease (e.g., bronchiectasis), and prior TB exposure increase risk for NTM. M. marinum is associated with aquatic exposure.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
TB is caused by M. tuberculosis, while NTM include slow-growing (MAC, M. kansasii) and rapidly growing species (M. abscessus). Resistance mechanisms involve mutations in genes like rpoB, katG, and embB.
3.1 Drug Resistance¶
Rifampin resistance is due to rpoB mutations; isoniazid resistance involves katG and inhA mutations. Pyrazinamide resistance is linked to pncA mutations. Macrolide resistance in NTM is often due to ermB gene overexpression.
4. CLINICAL FEATURES¶
TB presents with chronic cough, fever, weight loss, and hemoptysis. NTM infections may mimic TB but often have non-specific symptoms. M. kansasii is associated with GATA2 deficiency.
4.1 NTM Subtypes¶
Slow-growing NTM (MAC, M. kansasii) cause chronic lung disease; rapidly growing NTM (M. abscessus) are more aggressive and resistant to standard TB drugs.
5. DIFFERENTIAL DIAGNOSIS¶
NTM infections must be differentiated from TB using molecular testing. M. marinum infections are often misdiagnosed as fungal or bacterial infections due to their non-specific presentation.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis involves acid-fast staining, culture, and nucleic acid amplification tests (NAAT). Molecular diagnostics are critical for rapid TB detection and NTM differentiation.
6.1 Drug Susceptibility Testing¶
Standardized testing is required for MDR-TB and NTM. Fluoroquinolone resistance is assessed via MIC testing, while macrolide resistance is evaluated using E-test or broth microdilution.
7. MANAGEMENT & TREATMENT¶
First-line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. DR-TB requires second-line agents like bedaquiline, pretomanid, and linezolid. NTM treatment is prolonged and multi-drug.
Table 186-3: Monitoring and Clinical Management of TB Treatment¶
| DRUG | ASSESSMENT | MANAGEMENT |
|---|---|---|
| Isoniazid | ALT >5× ULN or jaundice | Interrupt treatment; rechallenge after normalization |
| Rifampin | Bilirubin >2× ULN | Discontinue if jaundice; rechallenge after resolution |
| Ethambutol | Visual acuity decline | Discontinue; repeat ocular exam |
| Pyrazinamide | ALT >5× ULN | Interrupt treatment; rechallenge after normalization |
7.1 TB Treatment Regimens¶
Standard 6-month regimen (HRZE/HR). DR-TB uses BPaLM (bedaquiline, pretomanid, linezolid, moxifloxacin) or other combinations. HIV co-infected patients require careful drug interaction monitoring.
7.2 NTM Treatment¶
Combination therapy with macrolides, aminoglycosides, and other agents. Surgical resection is indicated for localized disease. Treatment duration is often >12 months.
8. PROGNOSIS & COMPLICATIONS¶
TB mortality is high in HIV-positive patients and those with drug resistance. NTM infections can lead to progressive lung damage and disseminated disease in immunocompromised hosts.
8.1 Treatment Failure¶
Adherence is critical; intermittent therapy (e.g., twice-weekly) is used to reduce toxicity. Drug resistance develops with poor adherence or suboptimal regimens.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Rifampin and isoniazid are generally safe, but pyrazinamide is contraindicated. HIV co-infected patients require ART initiation within 2 weeks of TB treatment. Pediatric dosing adjustments are needed for all drugs.
10. KEY POINTS & CLINICAL PEARLS¶
- Use isoniazid-rifapentine for LTBI in adults and children >2 years.
- Monitor for hepatotoxicity with isoniazid and pyrazinamide.
- BPaLM regimen is preferred for DR-TB.
- NTM treatment requires prolonged, multi-drug regimens.
- Surgical resection is indicated for localized NTM disease.