What is the role of antimycobacterial agents in patients with immunodeficiency due to Mendelian inheritance?

From the Guidelines

Antimycobacterial agents are crucial in managing patients with immunodeficiency due to Mendelian inheritance, particularly those with Mendelian susceptibility to mycobacterial disease (MSMD), and should be tailored to the specific mycobacterial infection and the patient's genetic defect. The choice of antimycobacterial therapy is critical in these patients due to their impaired immune response to mycobacterial infections. According to the most recent guidelines, patients with MSMD require combination antimycobacterial therapy, which may include isoniazid, rifampin, ethambutol, and pyrazinamide for Mycobacterium tuberculosis infections 1. For non-tuberculous mycobacterial infections, a combination of clarithromycin, ethambutol, and rifampin is often used, with treatment duration extending from 12-24 months.

Key Considerations

• The specific antimycobacterial regimen should be guided by the results of susceptibility testing and the patient's clinical response to treatment.
• Patients with severe MSMD may require lifelong prophylaxis with azithromycin or clarithromycin after completing initial treatment.
• Adjunctive IFN-γ therapy may benefit patients with specific genetic defects in the IFN-γ pathway, as it can enhance macrophage activation and mycobacterial killing.
• The management of patients with MSMD should be guided by consultation with persons and centers with knowledge and experience diagnosing and treating a broad range of immunodeficiencies to improve consistency in evaluation and management and to have the best outcomes with respect to patient and family health, education, and planning 1.

Treatment Regimens

• For Mycobacterium tuberculosis infections: isoniazid (5-10 mg/kg/day), rifampin (10-20 mg/kg/day), ethambutol (15-25 mg/kg/day), and pyrazinamide (15-30 mg/kg/day) for 2 months, followed by isoniazid and rifampin for an additional 4-7 months.
• For non-tuberculous mycobacterial infections: a combination of clarithromycin (7.5-15 mg/kg twice daily), ethambutol (15-25 mg/kg/day), and rifampin (10-20 mg/kg/day) is often used, with treatment duration extending from 12-24 months.
• Lifelong prophylaxis with azithromycin (250-500 mg three times weekly) or clarithromycin may be required for patients with severe MSMD.

From the Research

Role of Antimycobacterial Agents in Patients with Immunodeficiency due to Mendelian Inheritance

• Antimycobacterial agents play a crucial role in the treatment of patients with Mendelian susceptibility to mycobacterial diseases (MSMD) 2, 3, 4, 5, 6.
• MSMD is caused by inborn errors of IFN-γ immunity, which leads to increased susceptibility to mycobacterial infections 4, 5, 6.
• The use of antimycobacterial agents in patients with MSMD is guided by the identification of the underlying genetic defect and the specific mycobacterial pathogen involved 2, 6.
• Molecular diagnosis, including oligonucleotide array methods, can facilitate the identification of the primary immunodeficiency and guide antimicrobial treatment in immunodeficient patients 2.
• Patients with MSMD may require long-term treatment with antimycobacterial agents to prevent recurrent infections 3, 5.

Genetic Defects and Antimycobacterial Treatment

• Genetic defects in 18 different genes have been associated with MSMD, including IFNGR1, IFNGR2, STAT1, IL12B, and IL12RB1 4, 5, 6.
• The genetic defect underlying MSMD can influence the choice of antimycobacterial agent and the duration of treatment 6.
• For example, patients with autosomal dominant IFN-γ receptor 1 deficiency may require treatment with antimycobacterial agents that are effective against Mycobacterium tuberculosis complex and Mycobacterium abscessus 2.

Clinical Features and Antimycobacterial Treatment

• Patients with MSMD may present with a range of clinical features, including recurrent mycobacterial infections, salmonellosis, candidiasis, and tuberculosis 3, 5.
• The clinical features of MSMD can influence the choice of antimycobacterial agent and the duration of treatment 6.
• For example, patients with multifocal osteomyelitis may require treatment with antimycobacterial agents that are effective against Mycobacterium tuberculosis complex and Mycobacterium abscessus, as well as agents that inhibit osteoclast differentiation and bone resorption 6.