Background: Mycobacterium avium complex (MAC) consists of 2

predominant species, M avium and Mycobacterium intracellulare. More than

95% of infections in patients with AIDS are caused by M avium, while 40% of
infections in immunocompetent patients are caused by M intracellulare.

An environmental source of infection is difficult to determine. MAC has been

recovered from potable water supplies in hospitals where patients were
admitted prior to infection. It has also been isolated from household water
supplies. Other potential associations include ingestion of raw fish or hard
cheese, daily showering, and occupational exposure to water.

Pathophysiology: The modes of transmission include inhalation through the

respiratory tract and ingestion via the gastrointestinal tract. Colonization of
either site in patients with AIDS has been associated with an increased risk of
developing MAC bacteremia. Approximately 60% of patients colonized in one
series progressed to develop bacteremia; however, screening cultures from
the respiratory or gastrointestinal tract is not useful because the majority of
patients who develop bacteremia are not colonized prior to developing
disseminated disease.

The most important risk factor for MAC infection in patients negative for HIV
is underlying lung disease. Pulmonary infection is the most common
manifestation in these patients. It can also cause lymphadenitis in children.
MAC has surpassed Mycobacterium scrofulaceum as the most common
cause of cervical adenitis in developed countries.

Frequency:

 In the US: Prior to the availability of more potent antiretroviral

medications, 30% of patients positive for HIV developed disseminated
MAC (DMAC). In a 1996 study, patients taking highly active
antiretroviral therapy (HAART), including a protease inhibitor, had an
incidence of only 2%.

Mortality/Morbidity:

 Prior to the availability of clarithromycin, the life expectancy of a

patient with AIDS and DMAC was 4 months. In a 1999 study, patients
treated with rifabutin, ethambutol, and clarithromycin had a median
survival time of 9 months. Life expectancy is longer now with the
advent of HAART. The most common complication of DMAC is anemia
that may require transfusion.

 The clinical course of pulmonary MAC in patients positive for HIV is

usually indolent. Approximately 50% of patients in one study were still
alive 5 years after diagnosis. Patients with extensive parenchymal
 involvement may die of progressive respiratory failure, but patients
with more limited disease have a low mortality rate.

 In children, lymphadenitis has a benign course.

Race:

 MAC infection has no predilection for any race.

 HIV infection affects different groups at different rates because of

socioeconomic reasons and possibly genetic factors.

Sex: MAC infection has no predilection for either sex.

Age:

 Male patients with chronic obstructive pulmonary disease (COPD) may

have a higher probability of contracting MAC disease.

 Elderly women may have a higher probability of contracting pulmonary

MAC disease of the middle lobe and/or the lingula. This is known as
Lady Windermere syndrome.

  CLINICAL Section 3 of 10   

Author Information Introduction Clinical Differentials Workup Treatment
Medication Follow-up Miscellaneous Bibliography

History:

 Symptoms of MAC infection in patients with AIDS include fever,

sweats, weight loss, fatigue, diarrhea, and shortness of breath.

 Symptoms of pulmonary MAC infection in patients negative for HIV

with lung disease include cough, sputum production, weight loss,
fever, and hemoptysis.

 The most common symptom of lymphadenitis in children is unilateral,

nontender, enlarged lymph nodes.
Physical:

 MAC infection in patients with AIDS can cause wasting, tender

hepatosplenomegaly, lymphadenopathy, and skin pallor.

 Pulmonary MAC infection in patients with lung disease can cause

crackles, rhonchi, and dullness in chest percussion.

 Lymphadenitis in children can cause unilateral enlargement of

submandibular, preauricular, parotid, or postauricular lymph nodes.

Causes:

 MAC infection in patients with AIDS is associated with CD4 +

lymphocyte count of less than 50 cells per L.

 Pulmonary MAC infection in patients with lung disease is associated

with COPD, chronic bronchitis, bronchiectasis, cystic fibrosis, mitral
valve prolapse, skeletal abnormalities (eg, pectus excavatum, mild
scoliosis, straight back), or lung cancer.

  DIFFERENTIALS Section 4 of 10   

Author Information Introduction Clinical Differentials Workup

Treatment Medication Follow-up Miscellaneous Bibliography

Aspergillosis
Benign Lung Tumors
Catscratch Disease
Cryptococcosis
Fatty Liver
Infectious Mononucleosis
Lung Cancer, Non-Small Cell
Lung Cancer, Oat Cell (Small Cell)
Lymphoma, B-Cell
Lymphoma, Mediastinal
Lymphoma, Non-Hodgkin
Pneumonia, Aspiration
Pneumonia, Bacterial
Pneumonia, Fungal
Tuberculosis
Other Problems to be Considered:

Chronic cough
Lung cancer, large cell
Lung cancer, squamous cell
Mumps
Parotid stone
Parotid tumor
HIV wasting

  WORKUP Section 5 of 10   

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography

Lab Studies:

 Several laboratory studies are recommended for patients with AIDS.

o A CBC count is recommended to test for anemia and neutropenia.

o A liver panel detects elevated transaminases and alkaline phosphatase.

o Blood culture should employ special mycobacterial and/or fungal media. These techniques
may consist of inoculating 5 mL of blood into a vial of BACTEC (such as TB 13A) or 7-10
mL into an Isolator bottle. The average time for cultures to turn positive is 5-12 days. Early
in the course of infection, bacteremia may be low level or intermittent, in which case blood
cultures may not be positive. Later in the course of infection, blood cultures are invariably
positive.

 A sputum culture in patients with lung disease and pulmonary MAC infection may be difficult to
interpret because, in these patients, MAC can colonize the respiratory tract without causing
clinical infection. The American Thoracic Society states that at least 3 positive sputum cultures or
2 cultures with 1 positive smear should be present to entertain a diagnosis of pulmonary MAC
disease. One culture of usually sterile fluid such as blood or cerebrospinal fluid may also be
sufficient.

Imaging Studies:

 Imaging studies are recommended for patients with AIDS.

o CT scanning of the chest reveals mediastinal lymphadenopathy. High-resolution CT

scanning may reveal parenchymal involvement.

o CT scanning of the abdomen reveals retroperitoneal or periaortic lymphadenopathy and

 hepatosplenomegaly.

 Chest radiography in patients with pulmonary MAC infection may reveal thin-walled cavitary
infiltrates, nodular infiltrates without cavities in the upper lobes, lingula or middle lobe infiltrates,
and isolated nodules.

Procedures:

 Several procedures are indicated for patients with AIDS and MAC infection, including lymph node
biopsy, bone marrow biopsy, liver biopsy, and transbronchial biopsies.

 Procedures for pulmonary MAC infection in patients with lung disease include bronchoscopy and
CT-guided needle biopsy.

 Procedures for lymphadenitis in children include lymph node biopsy, needle aspiration, or
complete excision of lymph nodes at the point they overlay the facial nerve.

Histologic Findings: Histologic findings include necrotizing and nonnecrotizing granulomas and positive
acid-fast bacilli (AFB) smears. The number of AFB is usually higher compared to Mycobacterium
tuberculosis infection.
  TREATMENT Section 6 of 10   
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography

Medical Care:

 Treatment for patients with AIDS and MAC infection involves antimicrobial agents with activity
against MAC, including clarithromycin, azithromycin, rifabutin, ethambutol, levofloxacin, and/or
amikacin. Second-line antituberculosis (anti-TB) drugs may also rarely play a role.

o Treatment should consist of at least 2 drugs. The macrolide antibiotics (clarithromycin,

azithromycin) are the most active agents. Clear evidence demonstrates the efficacy of
clarithromycin, and it (or azithromycin) should be included in any regimen. Monotherapy
with clarithromycin has led to resistance. Fewer published data establish the efficacy of
azithromycin for MAC infection. Ethambutol appears to be the best second choice to
combine with clarithromycin. If a third drug is needed, use rifabutin. A study comparing
clarithromycin and ethambutol with clarithromycin, ethambutol, and rifabutin showed
improved microbiological clearance and survival in the triple-therapy arm. One problem
with rifabutin is drug interactions. Higher doses of clarithromycin (1000 mg bid) are
associated with higher mortality rates. Higher doses of rifabutin (600 mg per d) are
associated with higher rates of uveitis.

o Fever should improve within 2-4 weeks of beginning therapy. If patients remain febrile
longer than expected, repeat blood cultures and perform susceptibilities to clarithromycin.
Studies have not shown a correlation between clinical outcome and in-vitro susceptibilities
 to drugs other than clarithromycin. If the isolate is susceptible to clarithromycin and the
patient is not responding to therapy, consider adding amikacin.

 Chemoprophylaxis is recommended for patients positive for HIV with a CD4 + lymphocyte count of
less than 50 cells per L. The ideal time to stop prophylaxis in patients starting HAART is unclear.
If a patients' CD4 count rises above 50 for a sustained period and viral load response is good,
prophylaxis can possibly be discontinued.

o The drug of choice is either clarithromycin or azithromycin. One study comparing

clarithromycin with placebo revealed an incidence of MAC bacteremia of 5.6% in patients
taking clarithromycin and 15.5% in those taking placebo. An improved survival rate was
also observed in patients taking clarithromycin. More than 50% of patients taking
clarithromycin who developed bacteremia were infected with isolates resistant to
clarithromycin.
o Azithromycin also is superior to placebo (incidence of MAC 8.2% vs 23.3%). Patients
taking azithromycin had no survival advantage, but the study was not powered to detect a
survival difference. Azithromycin resistance was not detected in treated patients who
developed bacteremia.
o Rifabutin is an alternative to the macrolides for MAC prophylaxis. In one study, the
combination of azithromycin and rifabutin was more effective than either drug alone, but
cost and increased incidence of adverse effects precludes using these 2 drugs together.
The combination of clarithromycin and rifabutin may not be more effective than
clarithromycin alone.

 Treatment of pulmonary MAC infection in patients with lung disease involves a combination of
clarithromycin, ethambutol, and rifabutin. Streptomycin may be used for the first 6-12 weeks in
patients with cavitary disease.
o Six months of therapy is recommended.
o Clarithromycin is probably useful for treating pulmonary MAC, but fewer data support
clarithromycin in this setting compared to studies of patients with AIDS. However,
extrapolating the data and substituting clarithromycin for the more toxic streptomycin
seems reasonable.
 Antibiotics are not required to treat lymphadenitis in children.

Surgical Care:

 Pulmonary MAC infection in patients with lung disease may require surgical excision of focal
pulmonary nodules. Lobectomy has also been recommended for more extensive lung infection in
patients who have not responded to antibiotics in the past. This, however, does not occur as often
now that more potent antibiotics are available.

 Surgical excision of the infected nodes is curative in more than 95% of children with
lymphadenitis.
Consultations:

 Consultants for MAC infections in patients with AIDS include an infectious diseases specialist, a
general surgeon for lymph node biopsy, a gastroenterologist for liver biopsy, and a hematologist-
oncologist for bone marrow biopsy.

 Consultants for patients with lung disease who develop pulmonary MAC infection include an
infectious diseases specialist, a pulmonologist, and a cardiothoracic surgeon.

 Consultants for lymphadenitis in children include an infectious diseases specialist, a general

surgeon, and an ear, nose, and throat (ENT) specialist.

  MEDICATION Section 7 of 10   

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography

The drugs used most often for treatment of MAC are clarithromycin, ethambutol, and rifabutin. Amikacin
is used for refractory cases. Combination therapy is important to enhance efficacy and prevent
resistance. Duration of treatment is not established. If it is too short, relapse may occur. If it is too long,
medication adverse effects are of concern.
Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive.

Clarithromycin (Biaxin) -- Inhibits bacterial growth,

possibly by blocking dissociation of peptidyl tRNA from
Drug Name
ribosomes, arresting RNA-dependent protein
synthesis.
Adult Dose 500 mg PO bid or 1 g PO qd if Biaxin XL
Pediatric Dose 15 mg/kg/d PO divided bid
Documented hypersensitivity; coadministration of
Contraindications
pimozide
Toxicity increases with coadministration of fluconazole
and pimozide; clarithromycin effects decrease and GI
adverse effects may increase with coadministration of
rifabutin or rifampin; may increase toxicity of
anticoagulants, cyclosporine, tacrolimus, digoxin,
omeprazole, carbamazepine, ergot alkaloids,
Interactions triazolam, and HMG CoA-reductase inhibitors; serious
cardiac arrhythmias may occur with coadministration
of cisapride; plasma levels of certain benzodiazepines
may increase, prolonging CNS depression;
arrhythmias and increase in QTc intervals occur with
disopyramide; coadministration with omeprazole may
increase plasma levels of both agents
C - Safety for use during pregnancy has not been
Pregnancy
established.
Coadministration with ranitidine or bismuth citrate is
not recommended with CrCl <25 mL/min; administer
half dose or increase dosing interval if CrCl <30
Precautions
mL/min; diarrhea may be sign of pseudomembranous
colitis; superinfections may occur with prolonged or
repeated antibiotic therapies
Ethambutol (Myambutol) -- Impairs cell metabolism by
inhibiting synthesis of 1 or more metabolites, which in
turn causes cell death. No cross-resistance
Drug Name demonstrated. Mycobacterial resistance is frequent
with previous therapy. Use in these patients in
combination with second-line drugs that have not been
administered previously.
Patients with AIDS: 15 mg/kg/d PO
Adult Dose Patients with lung disease: 25 mg/kg/d PO for 2
months then 15 mg/kg/d for pulmonary MAC infection
Pediatric Dose 15 mg/kg/d PO
 Documented hypersensitivity; optic neuritis (unless
Contraindications
clinically indicated)
Aluminum salts may delay and reduce absorption
Interactions (administer several hours before or after ethambutol
dose)
C - Safety for use during pregnancy has not been
Pregnancy
established.
Reduce dose in patients with low CrCl; monitor visual
acuity and color vision monthly; clarithromycin can
Precautions
rarely lead to elevation in uric acid levels and cause
acute gout
Rifabutin (Mycobutin) -- Ansamycin antibiotic derived
from rifamycin S. Inhibits DNA-dependent RNA
Drug Name polymerase, preventing chain initiation, in susceptible
bacterial strains. If GI upset occurs, administer dose
bid with food.
Adult Dose 300 mg/d PO
Pediatric Dose Not established; suggested dose is 5 mg/kg/d PO
Contraindications Documented hypersensitivity
Steady-state zidovudine plasma levels may decrease
after repeated rifabutin dosing but does not affect
inhibition of HIV by zidovudine; decreases activity of
dapsone, narcotics, anticoagulants, steroids,
Interactions
cyclosporine, PO contraceptives, quinidine, PO
hypoglycemics, ketoconazole, beta-blockers,
mexiletine, theophylline, anticonvulsants, and
chloramphenicol
Pregnancy B - Usually safe but benefits must outweigh the risks.
Perform hematologic studies periodically because of
association with neutropenia and, more rarely,
Precautions
thrombocytopenia; monitor visual acuity because it
may cause uveitis; monitor liver function
Amikacin (Amikin) -- Irreversibly binds to 30S subunit
of bacterial ribosomes; blocks recognition step in
Drug Name
protein synthesis; causes growth inhibition. Use the
patient's IBW for dosage calculation.
Adult Dose 10-15 mg/kg/d IV
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; renal insufficiency
Interactions Coadministration with other aminoglycosides and
amphotericin B increases nephrotoxicity; enhances
 effects of neuromuscular blocking agents; causes
respiratory depression; irreversible hearing loss may
occur with coadministration of loop diuretics
Pregnancy D - Unsafe in pregnancy
Monitor renal function; prolonged very high
aminoglycoside serum levels have been associated
Precautions with ototoxicity, vestibular toxicity, difficulty in walking,
and acute muscular paralysis; avoid administering
concurrently with loop diuretics
Azithromycin (Zithromax) -- Inhibits bacterial growth,
possibly by blocking dissociation of peptidyl tRNA from
Drug Name
ribosomes, arresting RNA-dependent protein
synthesis.
Adult Dose 500 mg PO/IV qd
Pediatric Dose 10 mg/kg PO qd
Documented hypersensitivity to azithromycin,
Contraindications
erythromycin, or any macrolide antibiotic
Aluminum- and magnesium-containing antacids
reduce the peak serum levels but not the AUC of PO
administered azithromycin; although no drug
interactions have been reported in clinical trials with
azithromycin, because interactions have been
documented with other macrolides, careful monitoring
is recommended with the following drugs: digoxin
Interactions
(elevated digoxin levels), ergotamine or
dihydroergotamine (acute ergot toxicity), triazolam
(increased pharmacologic effect of triazolam by
decreasing the clearance of triazolam), and drugs
metabolized by the cytochrome P450 system
(elevated levels of carbamazepine, terfenadine,
cyclosporine, hexobarbital, and phenytoin)
Pregnancy B - Usually safe but benefits must outweigh the risks.
Coadministration with ranitidine or bismuth citrate is
not recommended with CrCl <25 mL/min; administer
half dose or increase dosing interval if CrCl <30
Precautions
mL/min; diarrhea may be sign of pseudomembranous
colitis; superinfections may occur with prolonged or
repeated antibiotic therapies
Levofloxacin -- Fluorinated quinolone that inhibits
Drug Name
bacterial DNA gyrase and topoisomerase IV.
Adult Dose 500 mg PO/IV qd
Pediatric Dose Not for pediatric use
 Documented hypersensitivity to levofloxacin or other
Contraindications
quinolone antibiotics
Concurrent administration with antacids containing
aluminum or magnesium as well as sucralfate, iron,
buffered didanosine, and multivitamins containing zinc
may interfere with the GI absorption of levofloxacin,
resulting in lower than desired systemic levels;
Interactions concomitant administration of NSAIDs and
levofloxacin may increase the risk of seizures;
disturbances of blood glucose, including hypoglycemia
and hyperglycemia, have been reported in patients
treated concomitantly with levofloxacin and
antidiabetic medications
C - Safety for use during pregnancy has not been
Pregnancy
established.
Because of possible hypotension with rapid or bolus
IV infusion, levofloxacin should be infused over a 60-
to 90-min period; levofloxacin should be administered
with caution in patients with renal insufficiency, and
patients should maintain adequate hydration;
Precautions
moderate-to-severe phototoxicity has been observed
in patients taking this class of antibiotics; levofloxacin
should be used with caution in patients with known or
suspected CNS disorders; some quinolones have
been associated with prolonged QT intervals
  FOLLOW-UP Section 8 of 10   
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography

Further Inpatient Care:

 Patients with AIDS may need to be admitted for blood transfusions, or they may need IV amikacin
if they do not respond to oral antibiotics.

 Patients with lung disease who develop pulmonary MAC infection may need to be admitted for
surgical resection of infected lung.

 Children with lymphadenitis may need to be admitted for surgical excision of infected lymph
nodes.

Further Outpatient Care:

 Carefully monitor patients with AIDS for adverse effects of medications and for anemia that may
 require transfusion.

 Carefully monitor patients with lung disease who develop pulmonary MAC infection for adverse
effects of medications.

In/Out Patient Meds:

 Clarithromycin, ethambutol, rifabutin, and amikacin may be administered on an inpatient or

outpatient basis.

Transfer:

 Patients with AIDS may need to be transferred to a facility with an infectious diseases or HIV
specialist for workup and treatment.

 Patients with pulmonary infection may need to be transferred to a facility that offers bronchoscopy.
They may also require transfer for surgical resection of infected lung tissue.

Complications:

 Patients with AIDS may develop anemia or weight loss, or they may die.

 Patients with lung disease may develop respiratory insufficiency or weight loss, or they may die.

Prognosis:

 In recent studies, life expectancy for patients with AIDS and MAC infection is 9 months, but with
HAART, it is probably much longer.

 Patients with lung disease and pulmonary MAC infections with focal nodules usually have a
benign course. Patients with more extensive disease have a 90% chance of recovery and a 20%
chance of relapse.

Patient Education:

 Instruct patients with AIDS on how to monitor for potential adverse effects of their medications as
well as how to recognize signs of anemia that might indicate the need for a transfusion.

 Educate patients with lung disease who develop pulmonary MAC infection about potential adverse
effects of their medications.

 For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center
and Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

  MISCELLANEOUS Section 9 of 10   

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography

Medical/Legal Pitfalls:

 Failing to offer prophylaxis to patients positive for HIV with a CD4 + lymphocyte count of fewer than
50 cells per L may cause problems.

 Ethambutol may cause optic neuritis and blindness, especially with coexisting renal dysfunction.

 Rifampin and rifabutin may decrease the effectiveness of contraceptives. Advise patients of this
potential effect.

  BIBLIOGRAPHY Section 10 of 10   

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up
Miscellaneous Bibliography
 Chaisson RE, Benson CA, Dube MP: Clarithromycin therapy for bacteremic Mycobacterium avium
complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS
Clinical Trials Group Protocol 157 Study Team. Ann Intern Med 1994 Dec 15; 121(12): 905-
11[Medline].
 Gordin FM, Sullam PM, Shafran SD: A randomized, placebo-controlled study of rifabutin added to
a regimen of clarithromycin and ethambutol for treatment of disseminated infection with
Mycobacterium avium complex. Clin Infect Dis 1999 May; 28(5): 1080-5[Medline].
 Havlik JA Jr, Metchock B, Thompson SE 3d: A prospective evaluation of Mycobacterium avium
complex colonization of the respiratory and gastrointestinal tracts of persons with human
immunodeficiency virus infection. J Infect Dis 1993 Oct; 168(4): 1045-8[Medline].
 Havlir DV, Dube MP, Sattler FR: Prophylaxis against disseminated Mycobacterium avium complex
with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N
Engl J Med 1996 Aug 8; 335(6): 392-8[Medline].
 Horsburgh CR Jr, Chin DP, Yajko DM: Environmental risk factors for acquisition of Mycobacterium
avium complex in persons with human immunodeficiency virus infection. J Infect Dis 1994; 170(2):
362-7[Medline].
 Nightingale SD, Cameron DW, Gordin FM: Two controlled trials of rifabutin prophylaxis against
Mycobacterium avium complex infection in AIDS. N Engl J Med 1993; 329(12): 828-33[Medline].
 Oldfield EC 3rd, Fessel WJ, Dunne MW: Once weekly azithromycin therapy for prevention of
Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind,
placebo-controlled multicenter trial. Clin Infect Dis 1998 Mar; 26(3): 611-9[Medline].
 Pierce M, Crampton S, Henry D: A randomized trial of clarithromycin as prophylaxis against
disseminated Mycobacterium avium complex infection in patients with advanced acquired
immunodeficiency syndrome. N Engl J Med 1996; 335: 384-91[Medline].
 Reich JM, Johnson RE: Mycobacterium avium complex pulmonary disease presenting as an
isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992 Jun; 101(6):
1605-9[Medline].
 Sison JP, Yao Y, Kemper CA: Treatment of Mycobacterium avium complex infection: do the
results of in vitro susceptibility tests predict therapeutic outcome in humans? J Infect Dis 1996;
 173: 677-83[Medline].

 von Reyn CF, Maslow JN, Barber TW: Persistent colonisation of potable water as a source of
Mycobacterium avium infection in AIDS. Lancet 1994 May 7; 343(8906): 1137-41[Medline].