AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Atypical mycobacterial infection has been described in the medical literature since the mid 1950s.^{1, 2} The development and introduction of a rapid radiometric mycobacterial detection system has advanced the field of mycobacteriology over the past 20 years. This method has allowed the distinction of Mycobacterium tuberculosis from other mycobacteria and enabled the performance of antimicrobial susceptibility testing of mycobacteria. The increased frequency of atypical mycobacterial infection stems from advances in the diagnostic procedures concerning the infection paired with the prevalence of mycobacterial disease in immunocompromised patients infected with the human immunodeficiency virus (HIV).

Nontuberculous mycobacteria (NTM) are classified based on their growth rates. Rapidly growing NTM are categorized into pigmented and nonpigmented species. Mycobacterium fortuitum complex is nonpigmented and includes the M fortuitum group and the Mycobacterium chelonae/abscessus group. The pigmented species are rarely associated in clinical disease and include Mycobacterium phlei, Mycobacterium aurum, Mycobacterium flavescens, Mycobacterium vaccae, Mycobacterium neoaurum, and Mycobacterium thermoresistible. Mycobacterium smegmatis may be either pigmented or nonpigmented.^{3, 4, 5, 6}

Pathophysiology

Atypical mycobacteria are obligate aerobes that can be found in the environment in soil, water, vegetables, and even in domestic animals and dairy products. Mycobacterium avium complex (MAC) and Mycobacterium scrofulaceum are associated with lymphadenitis in immunocompetent children. All nodes in the cervical chain can be affected, but the nodes of the submandibular region appear to be the most commonly involved.⁷ Disseminated infections are usually associated with HIV infection. Host immunity seems to play a major role because a low CD4⁺ lymphocyte count (fewer than 100 cells/μL for adults and age-appropriate decreases in children) is associated with an increased frequency of disseminated MAC disease.

Some cytokines such as interleukin (IL)–1 alpha and IL-6 enhance extracellular growth of the organism. IL-6 also promotes intracellular growth of MAC, apparently by down-regulating membrane receptors for tumor necrosis factor (TNF)–alpha.^{8, 9, 10} Other cytokines, such as interferon (IFN)–gamma and IL-2, work in the other direction. IL-2 enhances lymphocyte proliferation and cytotoxic activity and upregulates production of IFN-gamma.^{11, 12, 13} Ongoing studies are establishing the additional roles of cytokines.

In immunocompromised patients, the intestinal tract is the primary route for MAC infection, followed by the respiratory tract as a secondary portal of entry.^{14, 15} CD4⁺ lymphocytes but not CD8⁺ or gamma delta+ lymphocytes are required for host protection against MAC and dissemination through the intestinal route.¹⁶ Abnormal immune response to MAC colonization may cause invasion of the epithelial cells of the gastrointestinal tract, followed by disseminated disease.¹⁵ In one series of adult patients infected with HIV with positive respiratory or stool isolates, 75% developed mycobacteremia within a year (mean 6 mo) after the isolation. A preceding stool culture positive for isolates was present in 25-36% of the patients.¹⁵ Pulmonary disease in adults without acquired immunodeficiency syndrome (AIDS) may occur.

Disseminated MAC in children without HIV has been described in the literature. It is associated in some cases with IFN-gamma receptor ligand-binding deficiency, which is a recently identified autosomal recessive inherited disorder.^{17, 18, 19} Affected children show a severe and apparently selective susceptibility to weakly pathogenic mycobacteria (either Bacillus Calmette-Guérin or NTM.²⁰ This condition has revealed the importance of IFN-gamma in the control of mycobacterial disease in humans. The importance of immune reconstitution produced by highly active antiretroviral therapy (HAART) in reducing susceptibility to MAC infection may provide clues to the critical role of the host immune defense and may establish the basis for the use of immunotherapy in disseminated MAC disease.

Frequency

United States

In the pre-HIV/AIDS era, pulmonary disease and lymphadenitis due to atypical mycobacteria were found all across the United States, with most cases located in the central and southern regions.²¹ Because infections by NTM were not reportable in the past, few systematically collected data about their frequency and distribution are available. Early in the HIV epidemic, MAC disease was quite common in patients with AIDS.²² However, frequency is decreasing among patients with HIV because of new treatment modalities, such as combination therapy with nucleoside reverse transcriptase inhibitors and protease inhibitors, as well as antimycobacterial prophylaxis.

International

Distribution of atypical mycobacterial infection is worldwide. Mycobacterium ulcerans, the agent of a chronic ulcerative skin infection called Buruli ulcer, is widespread in Ghana, Cote d'Ivoire, Senegal, Uganda, and most central African countries.^{23, 24}

Mortality/Morbidity

Disseminated MAC disease is the second most common opportunistic infection in children with HIV infection after Pneumocystis carinii pneumonia. In the era before HAART, the frequency of disseminated MAC disease varied with age, history of prior opportunistic infections, and immunologic studies.²⁵ Disseminated MAC infection may occur in children with HIV and adolescents who are severely immunocompromised after starting antiretroviral therapy.²⁶

A review of 58 deaths from a cohort monitored during a 7-year period in the pre-HAART era, with a mean age of 4.43 years, has shown that MAC was the most common isolate at the time of death, followed by P carinii pneumonia.²⁷ The risk increases in children infected with HIV with a CD4⁺ cell count fewer than 750/µL who are younger than 1 year; with a cell count fewer than 500/mL in children aged 1-2 years; with a cell count fewer than 75/µL in children aged 2-6 years; and with a cell count of 50/µL in children older than 6 years, the same threshold as in adults infected with HIV.^{28, 29, 30} Atypical mycobacterial infection has been described in children with cystic fibrosis (CF). Although MAC is more common in the United States in the population with CF, M abscessus and M avium are reported to be more common in Europe.^{31, 32}

Race

Atypical mycobacterial infection has no racial predilection.

Sex

Both sexes are affected with equal frequency.

Age

MAC and M scrofulaceum are associated with lymphadenitis in immunocompetent children aged 1-5 years.⁷ Although disseminated MAC disease rarely occurs during the first year of life, its frequency increases with age and declining CD4⁺ lymphocyte count in children infected with HIV.^{33, 34, 35}

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Suppurative cervical or submandibular lymphadenopathy that produces or does not produce systemic symptoms is the most common presentation of atypical mycobacterial infection caused by M avium-intracellulare and M scrofulaceum in the immunocompetent pediatric host. In a cohort of children infected with HIV prospectively monitored by Hoyt et al in 1992, recurrent and persistent fever and chronic anemia were the most common signs and symptoms, followed by chronic diarrhea and a history of recurrent abdominal pain with disseminated M avium complex (MAC) disease^{34, 36, 37}

Weight loss, failure to gain weight, and wasting syndrome are part of the long-term presentations of disseminated MAC disease in immunocompromised children. Other signs and symptoms include leukopenia, hepatosplenomegaly, and persistent generalized lymphadenopathies. Ulcerative lesions of the colon and mesenteric disease with abscess formation have been reported.^{37, 38, 39} Primary cutaneous infections with MAC are rare; most cases are caused by dissemination, with manifestations including scaling plaques, crusted ulcers, ecthymalike lesions, verrucous ulcers, inflammatory nodules, panniculitis, pustular lesions, and draining sinuses.⁴⁰

Buruli ulcer is a chronic ulcerative skin disease, caused by M ulcerans, that mostly affects the limbs. The lack of acute inflammatory response is typical and is likely due to an immunosuppressive toxin called mycolactone, which is produced by mycobacteria.^{24, 23} Buruli ulcer mainly affects children living in humid areas of the tropical rain forest. Following a microinjury, the organism penetrates the skin. A subcutaneous nodule develops a few weeks later, followed by necrosis of the subcutaneous fat and finally by a large dermal ulceration. Constitutional symptoms are normally absent.

Atypical mycobacteria may cause skeletal infections. A large outbreak of spinal infections after discovertebral surgery was reported in 2001.⁴¹ Tenosynovitis, multifocal osteomyelitis, septic arthritis, protracted carpal tunnel syndrome, and spondylitis implicating M chelonae, Mycobacterium kansasii, MAC, or Mycobacterium xenopi have been described in the literature.^{42, 43, 44, 45, 46} Keratitis and endophthalmitis after intravitreous injection of steroids or other ophthalmoscopic procedures secondary to M chelonae invasion have been reported. Although most of those infections secondary to atypical mycobacteria have been described in the adult population, cases of cutaneous mycobacteriosis manifesting as cellulitis, skin abscess, or sporotrichoid lesions secondary to M chelonae abscessus and M kansasii have been reported.

Catheter-related infections are the most common nosocomial nontuberculous mycobacterial infections encountered. The fast-growing atypical mycobacteria, such as M fortuitum, cause most catheter-related infections. Patients with long-term central intravenous catheters are most susceptible. However, infections have occurred in patients with peritoneal and shunt catheters. Local catheter site drainage; tunnel infections; and mycobacteremia, with or without fever, are the usual manifestations, but granulomatous hepatitis and, sometimes, pulmonary infiltrates have been observed. Case reports of atypical mycobacterial infection in transplant patients due to M chelonae and M xenopi have been described in the medical literature.^{47, 48}

Physical

Immunocompetent children with adenitis secondary to MAC present with suppurative adenitis that may or may not produce constitutional symptoms such as fever. Fistula may be present with coalescence of involved cervical or mandibular nodes. In immunocompromised children with HIV/AIDS, no pathognomonic signs are present. Physical examination may reveal that a debilitated patient has a history of failure to gain weight, chronic fatigue, chronic diarrhea, and recurrent abdominal pain. Hepatosplenomegaly may be present. Early during disseminated MAC disease, some patients may not have fever and may not appear acutely or chronically ill.⁴⁹

Causes

Numerous atypical mycobacterial infections are known. The most common forms of diseases are chronic pulmonary disease resembling tuberculosis (occurring mainly in adults), cervical adenopathy in children, skin and soft tissue infections, and disseminated disease in immunocompromised persons.^{7, 15} Lymphadenitis is the most common manifestation in children.^{7, 21} However, progressive immunodeficiency due to infection with HIV appears to be the most significant factor for disseminated MAC disease.^{50, 15, 51}

A unique MAC syndrome that develops in patients with AIDS in the first 1-2 months following the initiation of HAART has been described by 3 groups of investigators.^{52, 53, 54, 55} The symptom consists of fever and focal MAC lymphadenitis, with a blood culture negative for mycobacteria in most cases. The symptom is also known as immune reconstitution syndrome. It may occur in patients who already had subclinical MAC disease that becomes unmasked by HAART. The atypical mycobacteria observed in children are M avium-intracellulare complex, M scrofulaceum, and, rarely observed in children with AIDS, M kansasii.

Mycobacterium marinum is the causative agent of swimming pool granuloma. However, both rapidly growing and slow-growing species of NTM have been implicated in chronic granulomatous infections. Those infections mostly involve tendon sheaths, bursae, bones, and joints after direct inoculation through accidental trauma, surgical incisions, or puncture wounds.^{3, 56} Tenosynovitis of the hand secondary to MAC and M marinum has been described. Osteomyelitis of the sternum caused by M abscessus has been found in clustered and sporadic outbreaks. M fortuitum and M chelonae strains, also known as the rapidly growing organisms, have occasionally been implicated in wound, soft tissue, pulmonary, and middle ear infections.^{57, 7}

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Rule out any malignant process such as lymphoma and metastatic Kaposi sarcoma and other nonmalignant etiologies, such as bacterial adenitis, mononucleosis, toxoplasmosis, tuberculous lymphadenitis, and catscratch disease in children with suppurative lymphadenitis or persistent generalized lymphadenopathies.⁷ HIV infection per se may cause multiorgan involvement accompanied by all the systemic symptoms observed in disseminated M avium complex (MAC) disease. Other immunodeficiencies such as severe combined immunodeficiency and IFN-gamma receptor ligand-binding deficiency should be investigated, especially in patients without AIDS with disseminated MAC disease.⁵⁸

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Organisms from blood, biopsy material, bone marrow, and stools grow on routine bacterial media, but growth is best achieved using selective mycobacterial media, such as a Lowenstein-Jensen medium or Middlebrook 7K10 and 7K11 agar.^{50, 59}
• Nucleic acid hybridization probes using target sequences or ribosomal RNA are available for rapid identification of clinical isolates.⁵¹
• Species can be identified using high-performance liquid chromatography or biochemical tests.
• Polymerase chain reaction (PCR)-restriction analysis of clinical isolates have been used for the identification of M kansasii.⁶⁰
• Disseminated M avium complex (MAC) disease is most commonly diagnosed using culture of blood and bone marrow or other normally sterile tissues or body fluids. Other ancillary studies, such as acid-fast bacilli smear or radiographic imaging of the abdomen or mediastinum for detection of lymphadenopathy, may provide supportive diagnosis information.

Imaging Studies

• In patients without AIDS, the classic radiographic picture of the chest mimics reactivation tuberculosis. A second presentation includes the presence of patchy nodular infiltrates, without cavities in a nodular distribution.⁴⁹ Those features are mostly observed in adults with chronic bronchitis and emphysema. Evidence of bronchiectasis is detectable on CT scanning.⁶¹
• Multiple enlarged retroperitoneal and mesenteric lymph nodes can be observed on CT scanning of the abdomen.
• Large bulky adenopathy may be observed on autopsy findings.
• Some experts recommend fine-needle percutaneous aspiration to confirm the diagnosis.⁶²

Procedures

• Bone marrow aspirate, when biopsy is performed, may show hypocellularity and presence of foamy histiocytes.
• Acid-fast stain and culture of bone marrow specimen may reveal the presence of MAC.

Histologic Findings

The histologic findings associated with MAC vary considerably and range from granulomas to nodular foam cell lesions to purulent and necrotizing inflammations.⁶³ In 1994, Torriani et al studied a retrospective cohort of 44 AIDS patients with MAC bacteremia and complete autopsies over a period of 4 years.⁶⁴ They found that 30% had no histologic evidence of MAC. In the remaining 70%, reticuloendothelial and gastrointestinal involvement was most common. However, the number and distribution of involved sites was variable. Derived from this study's findings, MAC bacteremia may precede widespread tissue disease, and the risk of development of detectable histologic involvement was related to the duration of bacteremia.⁶⁴

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

See Medication.

Surgical Care

Pediatric neck abscesses remain common problems that are sometimes difficult to manage.⁶⁵ Surgical excision of infected nodes is recommended for immunocompetent children with suppurative adenitis secondary to M avium complex (MAC) and M scrofulaceum. The temptation is great to incise and drain the abscess cavity when fluctuant involvement is present. If this is done, a draining sinus usually persists until discharge of the involved lymph nodes beneath the skin has taken place over a period of months or years.^{21, 7} Careful attention should be paid to avoid any injury to the mandibular branch of the facial nerve because it is often adherent to the tract.²¹

Consultations

Disseminated MAC disease is best treated in collaboration with a pediatric infectious disease specialist with experience in the treatment of pediatric HIV infection.

Diet

Diet should be individualized in the presence of gastrointestinal complications such as diarrhea and vomiting. Moderate and severe dehydration should be treated accordingly. Nutritional intervention such as nasogastric feeding and hyperalimentation through a central catheter, gastrostomy tube feeding, or jejunostomy tube feeding in the presence of gastroparesis should be considered. Oral feeding can be resumed when appropriate to improve the patient's quality of life.

Activity

Patients who are acutely or chronically ill may be weak and debilitated. Caloric loss and poor intake may restrict their daily activities. Pain relief treatment in the presence of recurrent abdominal pain is necessary to keep patients comfortable.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.^{57, 66} 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.^{67, 57, 68, 29} 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.⁶⁷ Rifabutin induces CYP3A isoenzyme and, therefore, may reduce the plasma concentration of drugs metabolized by those enzymes (eg, itraconazole, clarithromycin, saquinavir).⁶⁸ 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.⁶⁷

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.²⁹ 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.⁶⁷ 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.⁴⁹ 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.

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.³¹ It may require surgical resection. Expert advice is recommended, and decisions should be made in consultation with a pediatric infectious disease specialist. Surgical debridement is also recommended for patients with Buruli ulcer.

Drug Category: Antimicrobial agents

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.

Drug Name	Clarithromycin (Biaxin)
Description	Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	500 mg PO bid; alternatively, Biaxin XL 1 g/d PO
Pediatric Dose	15-30 mg/kg/d PO divided q12h; not to exceed adult dose
Contraindications	Documented hypersensitivity; coadministration of pimozide
Interactions	Toxicity increases when coadministered with fluconazole or pimozide; effects decrease and GI adverse effects may increase when coadministered with rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, carbamazepine, ergot alkaloids, triazolam, and HMG-CoA reductase inhibitors Benzodiazepine plasma levels may increase, prolonging CNS depression; arrhythmias and increases in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents; decreases metabolism of repaglinide, thus increasing serum levels and effects Protease inhibitors may increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or protease inhibitors can be made based on existing data; efavirenz can induce metabolism of clarithromycin, and this may result in reduced serum concentration of clarithromycin but increased concentration of 14-OH clarithromycin, an active metabolite of clarithromycin Although the clinical significance of this interaction is not known, the efficacy of clarithromycin in MAC prophylaxis could be reduced because of this interaction
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Teratogen in animals and should be used with caution during pregnancy; coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; administer half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Erythromycin (EES, E-Mycin, Eryc, Ery-Tab)
Description	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.
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethyl succinate) PO q6h 1 h ac or 500 mg q12h Alternatively, 333 mg q8h; increase to 4 g/d depending on severity of infection
Pediatric Dose	30-50 mg/kg/d (15-25 mg/lb/d) PO divided q6-8h; double dose for severe infection
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis; decreases metabolism of repaglinide, thus increasing serum levels and effects
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI side effects are common (give dose pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Ciprofloxacin (Cipro)
Description	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.
Adult Dose	500-750 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Cefoxitin (Mefoxin)
Description	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.
Adult Dose	1-2 g IV q6-8h
Pediatric Dose	<3 months: Not established Infants and children: 80-160 mg/kg/d IV divided q4-6h; higher doses for severe or serious infections; not to exceed 12 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effects of cefoxitin; coadministration with aminoglycosides or furosemide may increase nephrotoxicity (closely monitor renal function)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organism may occur with prolonged use or repeated therapy

Drug Name	Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs)
Description	Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose	100 mg IV q12h with cefoxitin 2 g IV qid; continue treatment for at least 4 d and for at least 48 h after patient improves; follow by PO doxycycline (100 mg) bid for 10-14 d
Pediatric Dose	<8 years: Not recommended >8 years and <45 kg: 2-5 mg/kg/d PO qd or divided bid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Sulfamethoxazole-Trimethoprim (Bactrim, Septra)
Description	Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Adult Dose	160 mg TMP/800 mg SMZ (ie, 1 double-strength tab) PO q12h for 10-14 d
Pediatric Dose	<2 months: Contraindicated >2 months: 10-20 mg (based on trimethoprim component)/kg/d PO/IV divided q6-8h
Contraindications	Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 months
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases frequency of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Do not use during last trimester of pregnancy due to potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus) Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give leucovorin 5-15 mg/d); caution in folate deficiency (eg, those with chronic alcoholism, elderly, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Drug Name	Rifampin (Rifadin)
Description	Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Adult Dose	10 mg/kg/d mg PO/IV qd; not to exceed 600 mg/d
Pediatric Dose	10-20 mg/kg/d mg PO/IV qd; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid or pyrazinamide may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Drug Name	Rifabutin (Mycobutin)
Description	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.
Adult Dose	300 mg/d PO
Pediatric Dose	<6 years: Not established >6 years: 5-10 mg/kg/d PO; not to exceed adult dose
Contraindications	Documented hypersensitivity; WBC count <1,000/μL or platelet count <50,000/μL
Interactions	Decreases plasma concentration of methadone, verapamil, cyclosporine, digoxin, corticosteroids, PO anticoagulants, barbiturates, theophylline, quinidine, halothane, PO contraceptives, ketoconazole, and chloramphenicol; toxicity of rifabutin increases when administered concurrently with indinavir, ketoconazole, itraconazole, and erythromycin. Drugs that inhibit CYP3A (eg, delavirdine, indinavir, nelfinavir, ritonavir) may significantly increase rifabutin plasma concentration (decrease rifabutin dose)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Limited experience in pregnant women; do not administer to patients with active tuberculosis; no evidence rifabutin is effective in prophylaxis against M tuberculosis; may administer isoniazid and rifabutin concurrently in patients requiring prophylaxis against both M tuberculosis and MAC; periodically perform hematologic studies in patients receiving prophylaxis because of association with neutropenia and more rarely thrombocytopenia

Drug Name	Ethambutol (Myambutol)
Description	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.
Adult Dose	No previous antituberculous therapy: 15 mg/kg/d (7 mg/lb) PO Previous antituberculous therapy: 25 mg/kg/d (11 mg/lb) PO
Pediatric Dose	15-25 mg/kg/d PO
Contraindications	Documented hypersensitivity; optic neuritis (unless clinically indicated)
Interactions	Aluminum salts may delay and reduce absorption (allow several hours before or after ethambutol dose)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued

Drug Name	Isoniazid (Nydrazid)
Description	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.
Adult Dose	5 mg/kg/d PO (usually 300 mg/d) and 10 mg/kg/d in 1-2 divided doses in patients with disseminated disease; not to exceed 300 mg/d Directly observed therapy: 15 mg/kg twice weekly; not to exceed 900 mg/d
Pediatric Dose	10-20 mg/kg PO qd or divided bid; not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; previous isoniazid-associated hepatic injury or other severe adverse reactions
Interactions	Higher frequency of isoniazid-related hepatitis can occur with alcohol ingestion on daily basis; aluminum salts may decrease isoniazid serum levels (administer 1-2 h before taking aluminum salts); may increase anticoagulants effects with coadministration; may inhibit metabolic clearance of benzodiazepines Carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase CNS side effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram; coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor patients with active chronic liver disease or severe renal dysfunction; periodic ophthalmologic examinations during isoniazid therapy are recommended even when visual symptoms do not occur

Drug Name	Clofazimine (Lamprene)
Description	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.
Adult Dose	100 mg/d PO
Pediatric Dose	1-2 mg/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	Dapsone may inhibit anti-inflammatory activity of clofazimine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Severe abdominal symptoms may require exploratory laparotomies; caution in patients with GI problems (eg, abdominal pain, diarrhea); skin discoloration caused by drug is severe enough that depression and suicide have been reported; apply oil to skin for dryness and ichthyosis

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care is not mandatory for immunocompromised patients with M avium complex (MAC) disease unless their treatment is complicated by the presence of severe diarrhea with moderate-to-severe dehydration requiring intravenous fluid replacement and hyperalimentation, severe anemia requiring transfusion of blood products, or for further medical investigation.

Further Outpatient Care

• Decrease in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within 2-4 weeks after initiation of appropriate therapy; however, for those with more extensive disease or advanced immunosuppression, clinical response may be delayed.^{40, 51} A repeat blood culture for MAC should be obtained in 4-8 weeks after initiation of antimycobacterial therapy for patients who do not have a clinical response to their initial treatment regimen (ie, demonstrate little or no reduction in fever or systemic symptoms). Treatment failure is defined by the absence of clinical response and the persistence of mycobacteremia after 4-8 weeks of treatment.
• Testing of MAC isolates for susceptibility to azithromycin and clarithromycin is recommended for patients who do not respond microbiologically to initial therapy, who have relapse after initial response, or who develop MAC disease while receiving clarithromycin or azithromycin for prophylaxis. Results of susceptibility should be used to construct a new multidrug regimen consisting of at least 2 new drugs not previously used and to which the isolate is susceptible, including the following: ethambutol, rifabutin, ciprofloxacin or levofloxacin, or amikacin.²⁹ Resistance to clarithromycin in patients with pulmonary disease caused by MAC has been reported.⁶⁹ Data are insufficient to support the use of adjunctive treatment with immunomodulators, such as IFN-gamma, TNF-alpha, granulocyte-macrophage colony stimulating factor, and IL-12 alone or in combination with other cytokines, which appear to inhibit intracellular replication or invitrointracellular killing of M avium.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• Because optimal therapy does not guarantee a better outcome, disseminated MAC disease still carries significant morbidity. Therefore, preventing its occurrence may be the best approach. Data from multicenter studies have shown the presence of resistant strains in patients receiving prophylaxis. With a high frequency rate and a high rate of antimicrobial resistance, primary chemoprophylaxis for MAC infection, in conjunction with effective antiretroviral therapy, should be considered. Prophylaxis for prevention should be offered to children younger than 13 years with the following CD4⁺ T-lymphocyte counts:⁵⁷
• • Children aged 6 years or older with fewer than 50 cells/µL
  • Children aged 2-6 years with fewer than 75 cells/µL
  • Children aged 1-2 years with fewer than 500 cells/µL
  • Children younger than 12 months with fewer than 750 cells/µL
• Azithromycin or clarithromycin is recommended. Rifabutin is another alternative prophylactic agent. However, it should not be used until active tuberculosis has been excluded to avoid the development of rifampin-resistant tuberculosis. Disseminated MAC disease should also be excluded based on a negative blood culture result before prophylaxis is initiated.^{57, 70} Discontinuation of prophylaxis for MAC disease in adult patients infected with HIV who have a response to antiretroviral therapy is supported by some published data.⁷¹ Children with a history of disseminated MAC disease should be administered lifelong prophylaxis to prevent recurrence. The safety of discontinuing MAC prophylaxis has not been studied in children whose CD4⁺ lymphocyte counts have increased in response to HAART.²⁹

Complications

• Gastrointestinal obstruction and gastrointestinal bleeding caused by bulky intra-abdominal adenopathy or extensive ileal disease have been reported.⁴⁹ Pulmonary complications from disseminated MAC disease are uncommon in children. Culture and histologic evidence of infection have been reported in the heart, eye (keratitis), brain, skin, thyroid, tongue, adrenals, stomach, pancreas, skeletal system, and peripheral nerves.^{72, 73, 74}

Prognosis

• In the early years of the HIV epidemic, descriptive and retrospective studies were mostly aimed at defining the population of children infected with HIV at risk for MAC infection and at analyzing the predictors of survival in patients with AIDS and disseminated MAC disease.^{34, 75, 76} MAC was a contributor to mortality in HIV infection, and its presence was considered an indication that death is imminent.^{50, 77}
• The development of HAART has resulted in marked changes in the outcome of HIV disease, with reductions in hospitalizations and death as well as opportunistic infections, including MAC.⁵⁵ Established treatment, previously discussed, has reduced the morbidity and mortality caused by disseminated MAC disease. MAC infection is still a problem in developing countries where access to antiretroviral therapy is still limited and in severely immunocompromised patients whose adherence and tolerance to treatment raise a lot of questions. The prognosis for children without HIV with disseminated mycobacterial infection secondary to IFN-gamma receptor ligand-binding deficiency is poor.

Patient Education

• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles Swollen Lymph Glands and HIV/AIDS.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

Standard precautions are recommended. Patients with HIV infection should receive chemoprophylaxis and the use of sterile equipment for middle ear instrumentation, including otoscopic equipment, for the prevention of M abscessus otitis media. No specific recommendations about avoidance of exposure for people infected with HIV exist because M avium complex (MAC) organisms are common in environmental sources such as food, water, and soil. Sterile techniques should be used to avoid central catheter infections caused by fast-growing atypical mycobacteria. Patients infected with HIV at risk for MAC infection or those with MAC infection should be educated about drug interactions and the immune reconstitution syndrome when antiretroviral therapy is started.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Masson AM, Prissick FH. Cervical lymphadenitis in children caused by chromogenic Mycobacteria. Can Med Assoc J. Nov 15 1956;75(10):798-803. [Medline].
2. Weed LA, Keith HM, Needham GM. Nontuberculous acid-fast cervical adenitis in children. Mayo Clin Proc. Apr 18 1956;31(8):259-63. [Medline].
3. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis. Jan 1979;119(1):107-59. [Medline].
4. Silcox VA, Good RC, Floyd MM. Identification of clinically significant Mycobacterium fortuitum complex isolates. J Clin Microbiol. Dec 1981;14(6):686-91. [Medline].
5. Wallace RJ, Brown BA, Silcox VA, et al. Clinical disease, drug susceptibility, and biochemical patterns of the unnamed third biovariant complex of Mycobacterium fortuitum. J Infect Dis. Mar 1991;163(3):598-603. [Medline].
6. Wallace RJ, Silcox VA, Tsukamura M, et al. Clinical significance, biochemical features, and susceptibility patterns of sporadic isolates of the Mycobacterium chelonae-like organism. J Clin Microbiol. Dec 1993;31(12):3231-9. [Medline].
7. Cross JT, Jacobs R. Other mycobacteria. In: Fegin, Cherry, eds. Textbook of Pediatric Infectious Diseases. Philadelphia, Pa: WB Saunders Co; 1998.
8. Shiratsuchi H, Johnson JL, Ellner JJ. Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol. May 1 1991;146(9):3165-70. [Medline].
9. Denis M, Gregg EO. Recombinant tumour necrosis factor-alpha decreases whereas recombinant interleukin-6 increases growth of a virulent strain of Mycobacterium avium in human macrophages. Immunology. Sep 1990;71(1):139-41. [Medline].
10. Bermudez LE, Wu M, Petrofsky M, Young LS. Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immun. Oct 1992;60(10):4245-52. [Medline].
11. Newman GW, Guarnaccia JR, Vance EA 3rd, et al. Interleukin-12 enhances antigen-specific proliferation of peripheral blood mononuclear cells from HIV-positive and negative donors in response to Mycobacterium avium. AIDS. Oct 1994;8(10):1413-9. [Medline].
12. Frucht DM, Holland SM. Defective monocyte costimulation for IFN-gamma production in familialdisseminated Mycobacterium avium complex infection: abnormal IL-12regulation. J Immunol. Jul 1 1996;157(1):411-6. [Medline].
13. Bermudez LE, Wu M, Young LS. Interleukin-12-stimulated natural killer cells can activate humanmacrophages to inhibit growth of Mycobacterium avium. Infect Immun. Oct 1995;63(10):4099-104. [Medline].
14. Chin DP, Hopewell PC. Mycobacterium avium complex in the respiratory or gastrointestinal tract precedes MAC bacteremia. Front Mycobacteria. 1992;15.
15. Inderlied CB, Kemper CA, Bermudez LE. The Mycobacterium avium complex. Clin Microbiol Rev. Jul 1993;6(3):266-310. [Medline].
16. Petrofsky M, Bermudez LE. CD4+ T cells but Not CD8+ or gammadelta+ lymphocytes are required for host protection against Mycobacterium avium infection and dissemination through the intestinal route. Infect Immun. May 2005;73(5):2621-7. [Medline].
17. Levin M, Newport MJ, D'Souza S, et al. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene?. Lancet. Jan 14 1995;345(8942):79-83. [Medline].
18. Pierre-Audigier C, Jouanguy E, Lamhamedi S, et al. Fatal disseminated Mycobacterium smegmatis infection in a child withinherited interferon gamma receptor deficiency. Clin Infect Dis. May 1997;24(5):982-4. [Medline].
19. Altare F, Jouanguy E, Lamhamedi-Cherradi S, et al. A causative relationship between mutant IFNgR1 alleles and impaired cellular response to IFN-gamma in a compound heterozygous child. Am J Hum Genet. Mar 1998;62(3):723-6. [Medline].
20. Casanova JL, Newport M, Fischer A. Inherited Interferon-gamma receptor deficiency. In: Ochs HD et al, eds. Primary Immunodeficiency Diseases. Oxford, England: Oxford University Press; 1999:209-21.
21. Salyer KE, Votteler TP, Dorman GW. Surgical management of cervical adenitis due to atypical mycobacteria inchildren. JAMA. Jun 17 1968;204(12):1037-40. [Medline].
22. MacGregor RR, Hafner R, Wu JW, et al. Clinical, microbiological, and immunological characteristics in HIV-infected subjects at risk for disseminated Mycobacterium avium complex disease: an AACTG study. AIDS Res Hum Retroviruses. Aug 2005;21(8):689-95. [Medline].
23. Merone A, Saggiomo G, Severino G, et al. [Buruli ulcer. A case report]. Minerva Pediatr. Dec 2001;53(6):587-90. [Medline].
24. Thomssen H. [Buruli ulcer. A mycobacterial skin disease]. Hautarzt. May 2002;53(5):334-7. [Medline].
25. Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the humanimmunodeficiency virus managed before highly active antiretroviraltherapy. Pediatr Infect Dis J. Jan 2001;20(1):40-8. [Medline].
26. Puthanakit T, Oberdorfer P, Akarathum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children. Pediatr Infect Dis J. Jan 2006;25(1):53-8. [Medline].
27. Johann-Liang R, Cervia JS, Noel GJ. Characteristics of human immunodeficiency virus-infected children at the time of death: an experience in the 1990s. Pediatr Infect Dis J. Dec 1997;16(12):1145-50. [Medline].
28. Keller C, Kirkpatrick S, Lee K, et al. Disseminated Mycobacterium avium complex presenting as hematochezia in an infant with rapidly progressive acquired immunodeficiency syndrome. Pediatr Infect Dis J. Aug 1996;15(8):713-5. [Medline].
29. Centers for Disease Control and Prevention. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR. November 28, 2001;[Full Text].
30. Rutstein RM, Cobb P, McGowan KL, et al. Mycobacterium avium intracellulare complex infection in HIV-infected children. AIDS. Apr 1993;7(4):507-12. [Medline].
31. Le Bourgeois M, Sermet-Gaudelus I, Catherinot E, Gaillard JL. [Nontuberculous mycobacteria in cystic fibrosis]. Arch Pediatr. Aug 2005;12 Suppl 2:S117-21. [Medline].
32. Mussaffi H, Rivlin J, Shalit I, et al. Nontuberculous mycobacteria in cystic fibrosis associated with allergic bronchopulmonary aspergillosis and steroid therapy. Eur Respir J. Feb 2005;25(2):324-8. [Medline].
33. Horsburgh CR Jr, Caldwell MB, Simonds RJ. Epidemiology of disseminated nontuberculous mycobacterial disease in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J. Mar 1993;12(3):219-22. [Medline].
34. Hoyt L, Oleske J, Holland B, Connor E. Nontuberculous mycobacteria in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J. May 1992;11(5):354-60. [Medline].
35. Hartmann P, Plum G. Immunological defense mechanisms in tuberculosis and MAC-infection. Diagn Microbiol Infect Dis. Jun 1999;34(2):147-52. [Medline].
36. O'Brien RJ. The epidemiology of nontuberculous mycobacterial disease. Clin Chest Med. Sep 1989;10(3):407-18. [Medline].
37. Schonell ME, Crofton JW, Stuart AE, Wallace A. Disseminated infection with Mycobacterium avium: I. Clinical features,treatment and pathology. Tubercle. Mar 1968;49(1):12-30. [Medline].
38. Dieudonne A, McSherry, GD, Holland B. Clinical outcome and survival time in a cohort of HIV-infected children with atypical mycobacterial infections. Abstract Book. Annual Meeting of Society of Pediatric Research. 1997;Abstract 697.
39. Dieudonne A. Mycobacterium avium complex in HIV-infected infants and adolescents. Medical CME Program. Medical Word Communications. 1996;8-10.
40. Kayal JD, McCall CO. Sporotrichoid cutaneous Mycobacterium av