Atypical Mycobacterial Infection

Updated: Feb 07, 2018

Author: Arry Dieudonne, MD; Chief Editor: Russell W Steele, MD

Overview

Practice Essentials

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.[8] 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.[9, 10, 11] 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.[12, 13, 14] 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.[15, 16] CD4+ lymphocytes but not CD8+ or gamma delta+ lymphocytes are required for host protection against MAC and dissemination through the intestinal route.[17] Abnormal immune response to MAC colonization may cause invasion of the epithelial cells of the gastrointestinal tract, followed by disseminated disease.[16] 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.[16] 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.[18, 19, 20] Affected children show a severe and apparently selective susceptibility to weakly pathogenic mycobacteria (either Bacillus Calmette-Guérin or NTM.[21] 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.

MAC has also been associated with the pulmonary infection and bronchiectasis in elderly women without a preexisting lung disease. Pulmonary MAC infection in this population is believed to be due to voluntary cough suppression that results in stagnation of secretions, which is suitable for growth of the organisms. This particular type of infection is also referred to as Lady Windermere syndrome.[22]

Epidemiology

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.[23] 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.[24] 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.[25, 26, 27, 28]

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.[29] Disseminated MAC infection may occur in children with HIV and adolescents who are severely immunocompromised after starting antiretroviral therapy.[30]

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.[31] 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.[32, 33, 34] 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.[35, 36]

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.[37, 38, 39]

Presentation

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[38, 40, 41]

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.[41, 42, 43] 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.[44]

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.[26, 25] 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.[45] 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.[46, 47, 48, 49, 50] 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. M kansaii and M marinum have been reported in aquariumworkers.[51, 52] M avium– associatedtyphlitis mimicking appendicitis has been described in an immunocompetent host.[53]

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.[54, 55]

Wright et al report 18 cases of infection associated with laparoscopic gastric banding caused by Mycobacterium fortuitum and M. abscessus in Australia during 2005–2011. The authors identified cases by reviewing positive cultures at the Queensland state reference laboratory or through correspondence with clinicians, and obtained clinical and epidemiologic data. Eleven cases of M. fortuitum and 7 cases of M. abscessus infection were identified. The port was thought to be the primary site of infection in 10 of these cases. Complications included peritonitis, band erosion, and chronic ulceration at the port site. Rapidly growing mycobacteria can infect both port and band and can occur as either an early perioperative or late infection. Combination antimicrobial therapy is used on the basis of in vitro susceptibilities. The authors concluded that device removal seemed to be vital to successful therapy.[56, 57]

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.[58]

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, 16] Lymphadenitis is the most common manifestation in children.[7, 23] However, progressive immunodeficiency due to infection with HIV appears to be the most significant factor for disseminated MAC disease.[59, 16, 60]

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.[61, 62, 63, 64] 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, 65] 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.[66, 7]

A population-based study by Marras et al that included data from 417,494 patients 66 years of age and older who have been treated for COPD, asthma, or both reported that adjusted odds ratios for NTM pulmonary disease were statistically significant for current inhaled corticosteroids use overall (AOR, 1.86). Adjusted odds ratio was statically significant for fluticasone (AOR, 2.09).[67]

DDx

Diagnostic Considerations

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.[68]

Workup

Laboratory Studies

See the list below:

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.[59, 69]
Nucleic acid hybridization probes using target sequences or ribosomal RNA are available for rapid identification of clinical isolates.[60]
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.[70]
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

See the list below:

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.[58] Those features are mostly observed in adults with chronic bronchitis and emphysema. Evidence of bronchiectasis is detectable on CT scanning.[71, 72]
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.[73]

Procedures

See the list below:

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.[74] 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.[75] 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.[75]

Treatment

Medical Care

See Medication.

Surgical Care

Pediatric neck abscesses remain common problems that are sometimes difficult to manage.[76] 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.[23, 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.[23]

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

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.

Follow-up

Further Outpatient Care

See the list below:

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.[44, 60] 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.[33] Resistance to clarithromycin in patients with pulmonary disease caused by MAC has been reported.[83] 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.

Further Inpatient Care

See the list below:

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.

Inpatient & Outpatient Medications

See the list below:

See Medication.

Deterrence/Prevention

See the list below:

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:[66]
- 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.[66, 84] 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.[85] 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.[33]

Complications

See the list below:

Gastrointestinal obstruction and gastrointestinal bleeding caused by bulky intra-abdominal adenopathy or extensive ileal disease have been reported.[58] 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.[86, 87, 88]

Prognosis

See the list below:

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.[38, 89, 90] MAC was a contributor to mortality in HIV infection, and its presence was considered an indication that death is imminent.[59, 91]
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.[64] 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

See the list below:

For excellent patient education resources, visit eMedicineHealth's Sexual Health Center. Also, see eMedicineHealth's patient education articles Swollen Lymph Glands and HIV/AIDS.

Author

Arry Dieudonne, MD Associate Professor of Pediatrics, Division of Pulmonology, Allergy, Immunology and Infectious Diseases, Rutgers New Jersey Medical School; Clinical Director, Francois-Xavier Bagnold Center for Children, University Hospital

Arry Dieudonne, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Coauthor(s)

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Mark R Schleiss, MD Minnesota American Legion and Auxiliary Heart Research Foundation Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases, Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, Society for Ear, Nose and Throat Advances in Children, American Federation for Clinical Research, Surgical Infection Society, Armed Forces Infectious Diseases Society

Disclosure: Nothing to disclose.

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Atypical Mycobacterial Infection

Overview

Practice Essentials

Pathophysiology

Epidemiology

Frequency

Mortality/Morbidity

Race

Sex

Age

Presentation

History

Physical

Causes

DDx

Diagnostic Considerations

Workup

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Treatment

Medical Care

Surgical Care

Consultations

Diet

Activity

Medication

Medication Summary

Antibiotic

Class Summary

Azithromycin (Zithromax)

Clarithromycin (Biaxin)

Erythromycin (EES, E-Mycin, Eryc, Ery-Tab)

Ciprofloxacin (Cipro)

Cefoxitin (Mefoxin)

Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs)

Sulfamethoxazole-Trimethoprim (Bactrim, Septra)

Rifampin (Rifadin)

Rifabutin (Mycobutin)

Ethambutol (Myambutol)

Isoniazid (Nydrazid)

Clofazimine (Lamprene)

Follow-up

Further Outpatient Care

Further Inpatient Care

Inpatient & Outpatient Medications

Deterrence/Prevention

Complications

Prognosis

Patient Education

Contributor Information and Disclosures

References