Medication Summary
The treatment regimen for pediatric patients infected with HIV with disseminated M avium complex (MAC) disease includes at least 2 antimicrobials, one of which should be either clarithromycin or azithromycin. [66, 77] Many experts prefer ethambutol as the second drug. Some clinicians have added a third or fourth agent from the following list: clofazimine, rifabutin, ciprofloxacin, or amikacin. [78, 66, 79, 33] The choice of therapy should be based on sensitivity reports before the combination regimen is started. Antiretroviral agents should be initiated within 1-2 weeks of MAC treatment for patients who have not previously received or are not currently receiving antiretroviral drugs.
The possible benefits of administering ciprofloxacin to a child infected with HIV who has developed disseminated MAC infection frequently outweighs cautions regarding ciprofloxacin use in children younger than 13 years. [78] Rifabutin induces CYP3A isoenzyme and, therefore, may reduce the plasma concentration of drugs metabolized by those enzymes (eg, itraconazole, clarithromycin, saquinavir). [79] Drugs that inhibit CYP3A (eg, delavirdine, indinavir, nelfinavir, ritonavir) may significantly increase rifabutin plasma concentration. In such cases, the rifabutin dose should be reduced. Therapy should continue for the lifetime of the patient if clinical and microbiologic improvement is observed. [78]
Despite multiple drug combination therapy, disseminated MAC disease treatment in children infected with HIV is still a challenge. Multiple drug-resistant strains are always present, and sensitivity rarely exceeds 2 or 3 drugs. [33] With prolonged survival time, children and adolescents develop resistance because of the duration of treatment. Clinical improvement, characterized by weight gain and absence of fever and diarrhea, may be present during the early treatment period; however, intolerance to medication, concurrent infections, and, sometimes, multiorgan failure, may impair the efficacy of a therapeutic regimen.
Therapy for disseminated MAC disease should be continued for life unless sustained immune recovery occurs with potent antiretroviral therapy. [78] Discontinuation of MAC therapy did not show resurgence in clinical symptoms and the presence of MAC in subsequent blood cultures. Ongoing clinical studies may suggest that MAC therapy may not need to be indefinitely continued. [58] In immunocompetent patients with lymphadenitis secondary to MAC, complete excision of major nodes is recommended. If excision is incomplete or disease recurs, clarithromycin or azithromycin plus ethambutol with rifampin should be used. That same regimen is recommended for pulmonary infections caused by MAC. However, management of MAC infection in HIV-negative patients without preexisting lung disease can be challenging. [80, 81]
Excision of tissue is recommended in disseminated cutaneous infection caused by M fortuitum complex. Initial therapy is amikacin plus cefoxitin intravenously, followed by erythromycin, clarithromycin, doxycycline, or ciprofloxacin orally. Doxycycline is contraindicated in children younger than 8 years. Fluoroquinolones are contraindicated in children younger than 18 years. For catheter-related infections, the usual treatment is catheter removal combined with appropriate antibiotics (amikacin plus cefoxitin) for 6-12 weeks. [3] Pulmonary infections and osteomyelitis caused by M kansasii are treated with rifampin plus ethambutol with isoniazid. Surgical debridement and prolonged antibiotic therapy may be necessary for patients with osteomyelitis.
Minor cutaneous infections caused by M marinum do not require any treatment. Rifampin, trimethoprim-sulfamethoxazole, clarithromycin, or doxycycline is used for moderate diseases. Surgical debridement may be required for extensive lesions. Patients with otitis media caused by M abscessus should receive clarithromycin plus an initial course of amikacin plus cefoxitin. Surgical debridement may be required. Pulmonary infection in patients with CF should be treated based on susceptibility testing. Some experts recommend a 1-month course of intravenous imipenem or cefoxitin plus amikacin followed by oral clarithromycin plus ethambutol for at least 12 months after negativation. [35] It may require surgical resection. Expert advice is recommended, and decisions should be made in consultation with a pediatric infectious disease specialist.
Dual therapy with rifampicin and streptomycin as well as surgical debridement is the standard treatment recommended for patients with Buruli ulcer. [82] The combination of rifampicin and streptomycin results in a rapid onset of local cellular responses associated with phagocytosis of the extracellular M ulcerans. This may be related to declining levels of the macrolide toxin mycolactone in the tissue, thus leading to an enhanced chemotherapy-induced clearance of the infection. [82]
Antibiotic
Class Summary
Indicated for treatment and prevention of disseminated MAC disease. The choice of therapy should be based on sensitivity reports before antimicrobial initiation. Regimens for treatment include 2 or more antimicrobials.
Azithromycin (Zithromax)
Macrolide that inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used in combination with at least one other drug for treatment of disseminated MAC disease and as a primary prophylactic agent in patients who are severely immunocompromised based on their CD4+ lymphocyte count.
Clarithromycin (Biaxin)
Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Erythromycin (EES, E-Mycin, Eryc, Ery-Tab)
Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest. In children, infection severity determines proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.
Ciprofloxacin (Cipro)
Fluoroquinolone with activity against pseudomonas, streptococci, MRSA, Staphylococcus epidermidis, most gram-negative organisms, and atypical mycobacteria, but no activity against anaerobes. Inhibits bacterial DNA synthesis and consequently growth.
Safety and effectiveness in pediatric patients and adolescents have not been established. Risks versus benefits should be outweighed in cases of disseminated MAC disease.
Cefoxitin (Mefoxin)
Second-generation cephalosporin indicated for gram-positive cocci and gram-negative rod infections. Used in combination with other antibiotics for infections due to rapid-growing atypical mycobacteria. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.
Combine with amikacin when used to treat M fortuitum complex.
Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs)
Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Sulfamethoxazole-Trimethoprim (Bactrim, Septra)
Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Rifampin (Rifadin)
Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Rifabutin (Mycobutin)
Ansamycin antibiotic derived from rifamycin S. Inhibits DNA-dependent RNA polymerase, preventing chain initiation in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. If GI upset occurs, administer dose bid with food. Liquid formulation suitable for children is not currently available in the United States.
Ethambutol (Myambutol)
Diffuses into actively growing mycobacterial cells, such as tubercle bacilli. Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which in turn causes cell death. No cross-resistance demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been previously administered.
Administer q24h until permanent bacteriologic conversion and maximal clinical improvement is observed. Absorption is not significantly altered by food.
Used in combination with azithromycin or clarithromycin for MAC treatment or secondary prophylaxis.
Isoniazid (Nydrazid)
Best combination of effectiveness, low cost, and minor side effects. First-line drug unless known resistance or another contraindication exists. Therapeutic regimens of < 6 mo demonstrate unacceptably high relapse rate. Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to isoniazid therapy develop. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended.
Clofazimine (Lamprene)
Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown.
Always use with other antitubercular agents. Because of severe toxicities, clofazimine should be considered only if no other effective antimycobacterial agent can be used based on resistance testing.
