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Mycobacterium avium complex infection in AIDS: Clinical features, treatment, and prevention
Mycobacterium Avium Complex Infection in AIDS: Clinical Features, Treatment, and Prevention Elizabeth Eccles, MS, RN; and Judy Ptak, MSN, RN
Infection with Mycobacterium avium complex (MAC) may cause a serious disseminated
Elizabeth Eccles,MS, RN, and Judy Ptak, MSN, RN, are Infectious DiseaseNurse Clinicians, Dartmouth-Hitchcock Medical Center, Lebanon,Nit.
bacterial infection in up to 40% of patients with advanced HIV infection. Disseminated MAC has a negative impact on quality of life and contributes significantly to morbidity and mortality. Prompt diagnosis and aggressive treatment can diminish those effects. Disseminated disease can be prevented in many patients with the use of rifabutin prophylaxis. Nurses play an important role in evaluating symptoms and educating patients about the prevention and treatment of disseminated MAC. Key w o r d s : AIDS, mycobacterium avium
complex, patient education
T h e term Mycobacteriumavium complex (MAC) refers to a g r o u p of closely related bacteria, i n c l u d i n g Mycobacterium avium and Mycobacterium intracellulare. Researchers first described human disease caused by MAC about 40 years ago. Most reports concerned localized pulmonary infection in adults with chronic lung disease or cervical adenitis in children. Descriptions of disseminated infection were rare, and most of these cases occurred in patients with leukemia or l y m p h o m a (Horsburgh, 1991). The HIV epidemic brought new awareness and interest in MAC infection as it became apparent that disseminated infection with MAC (dMAC) was a common and serious complication of late-stage HIV infection in both adults and children. Disseminated MAC causes a disabling syndrome of fever and wasting and contributes significantly to mortality in persons with HIV/A1DS (Horsburgh, 1991). Nurses in the United States who care for patients with late-stage HIV infection see dMAC infection in up to 40% of these patients (Nightingale et al., 1992). In the United States, dMAC is the most common disseminated bacterial infection seen in patients with AIDS. More HIV patients in the U.S. are infected with MAC than with M. tuberculosis; and the incidence of dMAC is increasing as people with H1V infection live longer with the profound degree of inunune system suppression that leaves them susceptible to dMAC. Nurses have a role in identifying symptoms of dMAC, in helping to monitor the many medications required to treat the infection, and in educating patients about the infection and methods of preventing MAC.
Microbiology MAC are slow-growing, aerobic bacilli, which stain acid fast, like the bacteria that cause tuberculosis and JANAC Vol. 6, No. 5, September-October, 1995
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M y c o b a c t e r i u m A v i u m C o m p l e x I n f e c t i o n in A I D S : C l i n i c a l Features, T r e a t m e n t , a n d Prevention
leprosy (so-called acid-fast bacilli or AFB). Mycobacterium avium and Mycobacterium intracellulare are g r o u p e d together as a complex because they are difficult to distinguish using routine laboratory techniques. They cause similar infections and are sensitive to the same antibiotics.
Epidemiology The risk of developing dMAC increases as the CD4+ count decreases. Most cases of dMAC are seen in HIVinfected patients with a CD4+ count of less than 50 cells/mm3; MAC is seldom seen in patients who have a CD4+ count above 100 cells/ram 3. Factors such as age, race, gender, and H W risk factor do not appear to affect the risk of developing dMAC (Benson, 1994a). One year after the CD4+ count drops to less than 100 cells/mm 3, the incidence of d M A C is about 21%. This incidence increases to about 43% two years after the CD4+ count falls to less than 100 cells/mm 3 (Nightingale et al., 1992). HIV-infected children appear to develop dMAC at a similar rate (Lewis et al., 1992). Persons with MAC are more likely to have a newly acquired infection than a reactivation of a past infection. in a recent study, researchers looked at skin test reactions to MAC in healthy persons. They found a low number of positive reactions, which challenged the idea that the high rate of dMAC in HIV-infected patients is mostly the r e s u l t of r e a c t i v a t i o n (von Reyn et al., 1993). Furthermore, another s t u d y has linked d M A C with recent exposure to organisms found in potable hot water (von Reyn, Maslow, Barber, Falkinham, & Arbeit, 1994). MAC organisms are found throughout the world in soil, natural and municipal water sources, and in various animal species. Tile organisms are resistant to chlorine and generally have been found if{ higher numbers in hot w a t e r t h a n in cold w a t e r (du M o u l i n , Stottmeier, Pelletier, Tsang, & Hedley-White, 1988). MAC organisms most likely enter the body through the respiratory or gastrointestinal tract and eventually spread to the liver, spleen, and bloodstream. Scientists think it is possible that the infection results from a relatively commonplace water exposure such as drinking
38
contaminated water or inhaling aerosolized water (e.g., mist from a shower). Researchers have not found evidence of person-to-person transmission, and believe s t a n d a r d universal precautions are sufficient w h e n providers care for someone colonized or infected with MAC. Two or more strains of MAC may infect a person at the same time (polyclonal infection), suggesting that MAC can be acquired from v a r i o u s e n v i r o n m e n t a l sources (Arbeit et al., 1993). Polyclonal infection also may prove to have implications for treatment and prophylaxis. For example, two strains of MAC may have different antibiotic sensitivities, and patients with such dual infection may require different treatment regimens from patients infected with a single strain of MAC. The clinical and epidemiologic significance of polyclonal MAC infection requires further investigation.
Clinical Presentation Disseminated MAC may present insidiously in latestage HIV infection with nonspecific systemic symptoms. Symptoms that are reported most frequently in dMAC are persistent fever, weight loss, night sweats, diarrhea, and fatigue. In most patients symptoms are disabling; in some patients they are severe. Muscle wasting, adenopathy, and hepatomegaly a n d / o r splenomegaly may be present. Providers may observe a m u d d y - g r a y facial pigmentation. Laboratory findings include anemia, elevated liver function tests (especially alkaline phosphatase), and hypoalbuminemia (Chin et al., 1994b). CT or MRI scan m a y demonstrate intra-abdominal lymphadenopathy (Benson & Ellner, 1993). The clinical features of dMAC are summarized in Table 1. The nonspecific systemic features of dMAC may be similar to other conditions of advanced AIDS, so the differential diagnosis may be extensive. The index of suspicion for dMAC should be high when the CD4+ count is less than 50 cells/mm 3 and the patient has symptoms of a systemic illness. Other diseases of late-stage H1V infection w i t h similar, systemic s y m p t o m s include lymphoma, disseminated tuberculosis, cytomegalovirus
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Table 1. Clinical Features of Disseminated MAC C o m m o n Signs and S y m p t o m s (in order of relative frequency)
- Fever (especially >30 days) - Night sweats - Malaise - Weight loss - Abdominal pain - Diarrhea - Hepatosplenomegaly Common Laboratory Features
- CD4 count < 50 c e l l s / m m3 - Anemia - Elevated alkaline phosphatase - Hypoalbuminemia Other Reported Features
- Acalculous cholecystitis - Skin lesions - Pneumonia - Lymphadenitis
(CMV) i n f e c t i o n , a n d i n f e c t i o n d u e to R o c h a l i m e a species. Treatment for d M A C usually is not initiated until a definitive diagnosis is made. Diagnosis
Clinicians m a k e the diagnosis of d M A C w h e n the organism is isolated in blood, bone marrow, or tissue from other sterile sites. Most commonly, MAC is isolated from a peripherally drawn blood culture. Since isolation of MAC requires special blood culture techniques, the provider must specify on the microbiology requisition that the culture is for MAC or for mycobacteria. Three types of blood culture techniques can be used to isolate MAC: the Isolator tube, the Bactec system, and conventional blood culture media. Isolator tube. The Isolator vacutainer tube (Wampole Laboratories, Cranbury, NJ) is inoculated with 7 to 10 cc of blood. The tube contains a detergent that lyses red and white blood cells allowing the predominantly intracellular JANAC
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MAC organisms to be released. The laboratory technician places the Isolator tube in a centrifuge to concentrate o r g a n i s m s for plating on a m y c o b a c t e r i a l m e d i u m . Growth of MAC usually occurs in 21-28 days. Cultures showing no growth after 8 weeks are considered negative. B a c t e c s y s t e m . In t h e B a c t e c s y s t e m ( B e c t o n Dickinson Instrument Systems, Sparks, MD) the technician inoculates 5 cc of blood directly into liquid media containing a radioactive substrate. If MAC is present in the b l o o d , bacterial m e t a b o l i s m releases d e t e c t a b l e radioactive carbon dioxide. A positive result m a y be available in 7-14 days. C o n v e n t i o n a l b l o o d culture. Conventional blood culture m e d i a also m a y be used; however, the p r o v i d e r must specifically ask the laboratory to test for MAC. This m e t h o d takes 21 to 28 d a y s for a p o s i t i v e r e s u l t to become apparent. Blood culture methods first identify the organism as an acid-fast bacillus or mycobacterium, which means the organism could be MAC, M. tuberculosis, or another mycobacterium. Within 1-2 days a technician can do a D N A probe to identify the organism as MAC or another mycobacterium (Woods, 1994). Analysis. A clinician may make a presumptive diagnosis of dMAC when AFB are identified on a stain from bone marrow or sterile tissue from organs such as liver or lymph nodes. The results of the AFB stain may be reported 1-2 days after the biopsy, but definitive identification of MAC requires cul~re, which may take 2- 6 weeks. MAC may be present in bone marrow, liver, a n d / o r l y m p h nodes before bacteremia occurs and blood cultures become positive. Biopsy and AFB staining of these tissues may provide diagnosis earlier than blood culture. Quantitative blood cultures m a y be done, but it is not clear that they are necessary in the medical management of patients. Response to treatment usually can be conf i r m e d by i m p r o v e m e n t in clinical s y m p t o m s . Using q u a n t i t a t i v e b l o o d cultures, H o r s b u r g h et al. (1994) d e m o n s t r a t e d an association between longer survival and lower levels of mycobacteremia (<100 colonies of MAC/ml) at the time of diagnosis. The major limitation of current diagnostic methods is that s y m p t o m s may precede demonstrable bacteremia 39
Mycobacterium Avium Complex Infection in AIDS: Clinical Features, Treatment, and Prevention
by 2-3 months. Infection is present within organ tissue (bone marrow, liver, lymph nodes, GI tract) before disseminating into the blood. When a certain magnitude of infection has developed in the tissues, intermittent bacteremia occurs as bacteria "spill" into the bloodstream. Bacteremia eventually becomes persistent and symptoms of disseminated disease are present continuously. A single positive blood or tissue culture is sufficient for a diagnosis of dMAC and warrants initiation of antiMAC therapy. If the first blood culture for MAC is negative, the clinician should consider repeating the culture, should the symptoms persist. Rarely (2% of cases), MAC bacteremia may be noted before the development of symptoms (Nightingale et al., 1993). The significance of finding MAC in sputum or stool is not completely understood. Asymptomatic colonization of the GI or respiratory tract often precedes disseminated infection. Not everyone who is colonized develops disseminated infection, and the length of time from colonization to dissemination varies. A positive sputum or stool culture alone does not indicate dMAC. About 60% of patients with a positive sputum or stool culture for MAC will develop dMAC with positive blood cultures within 12 months (Chin et al., 1994a).
Treatment Early in the AIDS epidemic many clinicians were reluctant to treat dMAC because its clinical features and consequences were not well recognized. Treatment regimens were difficult to adrrrinister and their effectiveness was not proven. The late stage at which dMAC occurred made treatment seem futile. As a result, diagnostic approaches were not aggressive. Because of recent developments in MAC therapy, clinicians have made aggressive diagnosis and treatment of dMAC a standard of care. Studies of current multidrug treatment regimens have documented microbiologic response, as well as improved survival among people with dMAC. Horsburgh and colleagues (1994) observed a mean survival time after diagnosis of 37 days in patients who were not treated compared to 167 days in
40
those who received antimycobacterial treatment. Chin and peers (1994a) noted a survival of 139 days without therapy versus 263 days for those who received treatment. More importantly, treatment can relieve disabling symptoms that greatly impact quality of life. Researchers have studied several drugs and their combinations and found them to be effective against MAC. These drugs include clarithromycin, azithromycin, rifabutin, rifampin, ethambutol, ciprofloxacin, clofazimine, amikacin, and liposomal encapsulated gentamycin. Benson (1994b) recently reviewed the studies that document the efficacy of various treatment regimens. The greatest advance in the treatment of dMAC has been the introduction of newer macrolide antibiotics, which have rapidly become the foundation of initial multidrug therapy. The drugs shown to have the most activity a g a i n s t MAC are c l a r i t h r o m y c i n and azithromycin. Both drugs are concentrated within cells, where most MAC organisms are found. In a study where patients were given either 1000 mg or 2000 mg BID of clarithromycin (monotherapy), cultures reverted to negative in 75% of patients by 1-2 months (Dautzenberg et al., 1991). Both side effects and bacteriological efficacy were found to be dose related. Higher doses of macrolides, t h o u g h more effective against dMAC, have intolerable side effects (primarily GI related). Thus, the s t a n d a r d adult dose of clarithromycin is 500 mg bid and the standard adult dose of azithromycin is 500mg po qd. Single drugs cannot be used to treat established MAC infection because antimicrobial resistance will develop. The clarithromycin study by Dautzenberg and associates (1991) demonstrated that when clarithromycin was used alone, a high rate of relapse existed. This relapse was the result of an acquired resistance, which developed 2-7 months after patients started therapy. Higher doses of clarithromycin caused a more rapid development of resistance. While the macrolides have been shown to have the best anti-MAC activity, studies demonstrate that the addition of other drugs leads to enhanced bactericidal
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activity. Further, combination therapy may prevent or delay the development of drug resistance. Ethambutol, rifabutin, rifampin, and clofazimine all have been studied in combination with the macrolides. Standard initial therapy for most patients is shown in Table 2 and usually would include three or four of the f o l l o w i n g d r u g s : c l a r i t h r o m y c i n 500 m g p o bid or azithromycin 500 po or IV qd; ethambutol 15 m g / k g / d ; and rifabutin 300 m g / d or rifampin 600 m g / d . Other d r u g s t h a t can be a d d e d or s u b s t i t u t e d i n c l u d e ciprofloxacin 500 mg po bid, clofazimine 100 mg qd or amikacin 10 m g / k g / d IV or IM (Masur, 1993). Effectiveness. If treatment is successful, symptomatic relief may be observed in 1-4 weeks with defervescence, weight gain, and reduction of diarrhea. The authors have o b s e r v e d that m o s t patients on t r e a t m e n t r e p o r t an improved quality of life, with increased energy, appetite, and sense of well-being. Patients need encouragement to comply with the medication regimen because drug side effects may occur before the symptoms of dMAC disappear completely. Within several weeks, the benefits may be dramatic for the patient who has been symptomatic for months. While not essential, a MAC blood culture 4 - 8 weeks into therapy m a y be helpful in confirming the response
Table 2. Recommended Multiple Drug Therapy for Disseminated MAC A. Standard Initial Regimen: 3 or 4 of the following
1. Clarithromycin 500 mg po bid or azithromycin 500 mg PO or IV QD 2. Ethambuto115 mg/kg/d po 3. Rifabutin 300 mg po qd or rifampin 600 mg PO QD 4. Amikacin 10 mg/kg/d IV or IM B. Additional Drugs: These may be added to or substituted for above therapies in the event of treatment failure, relapse, or drug intolerance. 1. Clofazimine 100 mg po qd 2. Ciprofloxach~ 500 mg po qd
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to therapy and providing a baseline for reevaluation if relapse is suspected. Therapy should be continued for life, although some clinicians m a y choose to reduce the regimen from three drugs to two after a few months, if symptoms have resolved. Clinical treatment failure is suspected if the patient has persistent symptoms at 4 - 8 weeks. Blood cultures usually, but not always, revert to negative with standard treatment. P r i m a r y treatment failure m a y occur for a variety of reasons, including resistance to the chosen drugs, poor absorption of drugs from the gastrointestinal tract, or coexisting opportunistic infections or malignancies. If the patient does not respond to standard therapy, the addition of parenteral amikacin, ciprofloxacin, or rifampin may be useful. The value of baseline antimicrobial susceptibility testing is unclear at this time. Methods are not standardized and no evidence exists that antimicrobial susceptibilities are useful in predicting a clinical response. Some patients may experience a relapse of symptoms after several months of effective treatment. Relapse may be associated with a new positive blood culture (after a previous negative culture). Relapse may occur because of the d e v e l o p m e n t of d r u g resistance (which m a y take place even with multidrug regimens) or poor absorption of oral drugs in advanced HIV infection. MAC isolates from patients who relapse on macrolide therapy often demonstrate newly acquired resistance to the macrolide (clarithromycin or azithromycin). Clinicians m u s t evaluate patients presenting with new or relapsing symptoms to rule out new opportunistic infections or malignancies. In the California Treatment C o l l a b o r a t i v e S t u d y ( K e m p e r et al., 1992), 30% of patients on dMAC treatment had fever lasting more than 30 days. Researchers found new opportunistic infections in 7 of 10 patients in this group. Malabsorption of medications and nutrients, a common complication of late-stage HIV infection, may be due to local infiltration of MAC in the gastrointestinal tract, other opportunistic infections, or changes in the gastrointestinal tract from HIV itself. Also, diarrhea m a y impair absorption of drugs and nutrients. Poor absorption of 41
Mycobacterium Avium Complex Infection in AIDS: Clinical Features, Treatment, and Prevention
Table 3. Side Effects and Other C o n s i d e r a t i o n s for D r u g s U s e d in Treatment of M A C Drug
S i d e Effects
Considerations
Manufacturer
9 Clarithromycin (Biaxin)
Nausea, vomiting, diarrhea, headache, bitter taste, elevated LFTs, ototoxicity
Concomitant use of rifabutin may lower serum levels of clarithromycin. Take with food to decrease GI side effects.
Abbott Laboratories, 800/688-9188
9 Azithromycin (Zithromax)
Nausea, vomiting, diarrhea, headache, elevated LFTs, ototoxicity
Take with food to decrease GI side effects.
Pfizer Labs, Division Pfizer Indigent Patient Program, 212/573-3954
9 Ethambutol (Myambutol)
Arthralgias, nausea, vomiting, headache, rash, fever, visual changes
May divide daily dose to reduce side effects.
Lederle Laboratories. Contact local company sales representative
9 Rifabutin
Orange discoloration of body fluids (pseudojaundice), rash, nausea, vomiting, elevated LFTS, neutropenia, thrombocytopenia, myositis, uveitis
Clarithromycin and fluconazole raise rifabutin levels and have been associated with uveitis. May affect hepatic clearance of many drugs (e.g., azoles, dapsone, anticonvulsants, methadone).
Adria Laboratories, Mycobutin Patient Assistance Program, 800 / 795-9759
9 Rifampin (Rifadin)
Orange discoloration of body fluids (pseudojaundice) rash, nausea, vomiting, elevated LFTs, neutropenia, thrombocytopenia, myositis
May affect hepatic clearance of many other drugs (e.g., azoles, anticonvulsants, methadone). May be given IV.
Marion Merril Dow, Indigent Patient Program, 816/966-4000
9 Clofazimine (Lamprene)
Abdominal pain, nausea, vomiting, discoloration of skin, visua~l changes
Take with food to reduce GI side effects.
Ciba-Geigy Pharmaceuticals, Patient Support Program, 800/257-3273
9 Ciprofloxacin (Cipro)
Nausea, vomiting, abdominal pain, rash
Use 500 mg dose if patient has GI side effects.
Miles Labs, 203/937-3273
9 Amikacin (Amikin)
Ototoxicity, nephrotoxicity
Must be given IV or IM.
Elkins-Sinn, 215/688-4400
(Mycobutin)
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drugs may result in inadequate serum levels. Switching to o n e or m o r e i n t r a v e n o u s d r u g s ( a z i t h r o m y c i n , amikacin, ciprofloxacin, or rifampin) m a y be beneficial in this situation. The clinician usually can change parenteral therapy to oral therapy after 4 - 8 weeks, if the patient has responded. Researchers are conducting studies to determine the clinical utility of testing serum levels of antimycobacterial drugs. Gordon and colleagues (1993) studied serum levels of patients on a variety of anti-MAC regimens. P a t i e n t s w i t h HIV w e r e f o u n d to h a v e l o w e r than e x p e c t e d s e r u m levels of a l m o s t all antimicrobials. However, even those individuals with very low serum levels responded to therapy, possibly because: (a) intracellular levels of the drugs were sufficient to treat the infection; (b) local t r e a t m e n t of the intestinal MAC caused some relief; or (c) the synergistic effects of the drugs enhanced efficacy. Thus, serum levels are not routinely recommended at this time, but might be conside r e d in p a t i e n t s with p r i m a r y t r e a t m e n t failure or relapse. Side effects. Many patients on multiple drug treatment for d M A C will d e v e l o p one or more d r u g side effects as summarized in Table 3. Gastrointestinal side effects are the most c o m m o n problems, especially nausea or epigastric pain related to the macrolides or the rifamycins (rifampin, rifabutin). For some patients, it may be prudent to start each of the three standard medications 2-3 days apart to assess the side effects of each one independently. Longer intervals between initiation of single drugs are not recommended, since the developm e n t of r e s i s t a n c e m i g h t be e n c o u r a g e d w i t h this approach. Prevention
Prevention of MAC has become more important as people with HIV infection continue to live longer with very low CD4+ counts. As environmental risk factors for dMAC are identified, it m a y be possible to recommend strategies to limit exposure to MAC bacteria. At present, however, chemoprophylaxis is n o w an estabJANAC
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lished method of prevention. In December 1992, the Food and Drug Administration (FDA) licensed rifabutin for prophylaxis against dMAC in people with H1V infection and CD4+ counts less than 200 cells/mm 3. Rifabutin is a broad spectrum antibiotic with activity similar to rifampin against aerobic bacterial pathogens. The FDA decision was based on two large prospective, placebo-controlled studies, both of which demonstrated a 50% reduction in the incidence of dMAC d u r i n g the s t u d y p e r i o d in s u b j e c t s w h o w e r e o n rifabutin versus placebo (Nightingale et al., 1993). A total of 1,146 patients were enrolled in two studies. Patients (mean CD4+ counts: 50-60 c e l l s / m m 3) were randomized to receive either rifabutin 300 mg per day or placebo. Monthly follow-up visits included evaluation for signs or symptoms of dMAC, blood cultures, and Karnofsky Performance scales. In each of the two studies, the number of patients who developed dMAC while on r i f a b u t i n p r o p h y l a x i s was half the n u m b e r w h o developed dMAC on placebo (8% and 9% versus 17% and 18%, respectively). A l t h o u g h clinical evaluation revealed no difference between the groups in weight loss, diarrhea, night sweats, and abdominal pain, a significant difference in o t h e r clinical p a r a m e t e r s was noted. Fatigue, Karnofsky Performance Scale, and anemia all improved at significant levels in the group that received rifabutin. The researchers observed no survival difference during the study period. A National Institutes of Health study group subsequently recommended starting rifabutin when the CD4+ count is less than 100 cells/mm 3, since the incidence of dMAC is almost zero in people whose counts are greater than 100 cells/mm 3. Rifabutin is administered at the dosage of two 150 mg tablets taken once daily; if a patient has gastrointestinal i n t o l e r a n c e , the d r u g m a y be t a k e n in t w o d i v i d e d doses. Taking rifabutin on a full stomach m a y reduce gastrointestinal side effects. Prophylaxis is a lifelong prevention measure. However, if disease develops while the patient is on prophylaxis, the clinician should initiate standard multidrug therapy. These considerations are summarized in Table 4. 43
Mycobacterium Prevention
Avium
Complex
Infection
in AIDS:
Table 4. Chemoprophylaxis for Disseminated MAC 9 Criteria for Chemoprophylaxis - CD4+ < 100 cells/mm3 - no active tuberculosis - no disseminated MAC (consider routine MAC blood culture if CD4+ < 25 cells/B) - no major drug interactions anticipated 9 Current Recommendation - rifabutin 300mg po qd 9 Future Options - clarithromycin reported to be effective - other prophylactic agents and combinations under investigation i
:
The most c o m m o n side effect of rifabutin is orange discoloration of urine, which occurs in about 30% of patients taking the drug. Side effects were noted in about 50% of participants in the prophylaxis trials, but only a small percentage had to discontinue therapy because of the side effects (16% on d r u g versus 8% on placebo) (Nightingale et al., 1993). Reactions that led to discontinuation of drug included: rash (4%), gastrointestinal distress (3%) and neutropenia (2%). The authors' experience suggests that gastrointestinal side effects may be the most comanon reason patients are tmable to conthme rifabutin. Researchers (Siegal et al., 1990) h a v e r e p o r t e d the o c c u r r e n c e of r e v e r s i b l e polyarthritis/arthralgias and uveitis when patients received higher doses. Although uveitis has been observed primarily when rifabutin is combined with clarithromycin in MAC treatment (clarithromycin increases serum levels of rifabutin), uveitis also has been observed in patients on single-agent prophylaxis. Most of these cases occurred in patients taking fluconazole, which may raise serum rifabutin levels (Frank, Graham, & Wispelway, 1994; Fuller, Stanfield, & Craven, 1994). Clinicians should consider MAC-prevention therapy for their patients at risk. Yet, at this ~-ne, no evidence presents clear proof all H1V-infected persons with CD4+ <100 44
Clinical
Features,
Treatment,
and
should be on rifabutin prophylaxis. One major concern is the possibility that rifabutin prophylaxis will lead to the development of resistant strains of MAC. In the rifabutin prophylaxis studies (Nightingale et al., 1993), no difference e x i s t e d in the s u s c e p t i b i l i t y p a t t e r n s of M A C between those who developed dMAC while on rifabutin and those who received placebo. Clinicians practicing in areas with endemic tuberculosis have expressed the fear that rifabutin prophylaxis against MAC may lead to rifabutin and rifampin resistance a m o n g strains of M. tuberculosis. This c o n c e r n deserves further study. Clearl3r clinicians should evaluate patients carefully for active tuberculosis and dMAC before starting prophylaxis and after beginning treatment. In addition, clinicians should obtain a MAC blood c u l t u r e b e f o r e s t a r t i n g r i f a b u t i n p r o p h y l a x i s in the asymptomatic patient with a very low CD4+ count (e.g., less than 25 cells/mm3). In the rifabutin trials, 2.2% of asymptotnatic subjects had unsuspected disseminated infection identified by a baseline MAC blood culture (Nightingale et al., 1993). Another concern about rifabutin is its effect on serum levels of other medications. Because rifabutin has the capacity to induce cytochrome P450 liver enzymes, clearance of some drugs may be increased, resulting in diminished serum drug levels. An incomplete list of medications that might be affected by this phenomenon include: methadone, zidovudine, dapsone, ketoconazole, itraconazole, anticonvulsants, warfarin, barbiturates, theop h y l l i n e , oral c o n t r a c e p t i v e s , a n d c o r t i c o s t e r o i d s . Clinicians should monitor patients' clinical responses to these drugs when rifabutin is started. Researchers do not have adequate information about rifabutin's effects on maternal-fetal outcomes. The drug should be used only if potential benefits outweigh the u n k n o w n risks. The risk of the p a t i e n t d e v e l o p i n g dMAC, necessitating multidrug therapy with the concomitant risks to the fetus, must be considered. Clinicians should weigh carefully any decision to place a patient on rifabutin. A patient who is not a candidate for this drug should be monitored closely for early JANAC Vol. 6, No. 5, September-October,1995
symptoms of dMAC. Unfortunately, the patient may experience significant clinical deterioration between the time MAC infection starts and when response to treatment begins. Researchers currently are looking at the effectiveness of other drugs and combinations of drugs to prevent the occurrence of dMAC. A recently reported placebo-controlled study demonstrates that clarithromycin prophylaxis at a dose of 500 mg BID reduces MAC bacteremia and mortality (Pierce et al., 1994). However, patients who failed clarithromycin therapy were often infected with strains of MAC resistant to clarithromycin. The impact of widespread clarithromycin prophylaxis on drug resistance patterns deserves further study. Researchers also are studying combinations of clarithromycin/rifabutin and azithromycin/ clofazimine. Patient Education and Nursing Considerations For patients with late-stage HIV infection, the development of an opportunistic infection can be devastating. Patients may interpret the presence of an opportunistic infection as a life-threatening progression of disease. In such situations these patients are reminded of their fears about dependency, suffering, and death. On the other hand, the stress of the new diagnosis may be offset by the relief that comes when the doctor is able to make a definitive diagnosis and treatment is started. The patient may feel renewed hope that treatment might bring symptomatic relief and an improved sense of well-being. At this time, the nurse should do active listening and provide appropriate psychological support so that the patient can start to deal with the new diagnosis. Patient education is essential to the successful management of HIV-infected individuals. For patients with CD4+ counts of less than 100 cells/mm 3, nurses should teach the characteristic symptoms of dMAC: prolonged fever, night sweats, diarrhea, and weight loss. The patients need to report such symptoms to the clinician for prompt evaluation. Individuals being considered for rifabutin prophylaxis need to understand the risks and benefits of such JANAC
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therapy. Explanations about MAC-related bacteremia, rifabutin's effect on drug serum levels, treatment side effects, and symptom recognition are important components of patient education. Additionally, healthcare professionals need to tell patients that prophylaxis is not 100% effective and that current diagnostic techniques can be time consuming Patients being screened for MAC need to know the limitations and delays inherent in current diagnostic techniques. Individuals with confirmed MAC face the medical demands of multidrug therapy and require considerable psychological support. The disabling symptoms of fatigue, diarrhea, and fever may take weeks to improve after the patient starts therapy. Unfortunately, the initiation of this therapy may take place weeks or months after the first occurrence of symptoms. Nurses should insure that assessment of home support systems and referrals to appropriate agencies are done. Maintaining complicated multidrug treatment regimens is a challenge to patients and providers. Patients need to understand the importance of long-term treatment and the need for maintenance therapy, even after symptoms improve. Monitoring for side effects of the medications and possible drug interactions is essential. Adjusting the scheduling of medications may help diminish side effects. Patients experiencing severe gastrointestinal side effects need to have their medications changed to prevent reduced oral intake or diminished absorption. Proper nutrition is extremely important when a person has dMAC. Most patients will have significant weight loss at the time of diagnosis. Early intervention can help minimize this loss. Referrals should be made to a registered dietician so that appropriate nutritional counseling and interventions can be initiated. Choosing a supplement that is easily absorbed and does not contribute to diarrhea is essential. Patients who fatigue easily may need assistance in meal preparation. Medications used in both the prevention and treatment of dMAC are expensive. Most drug manufacturers have free drug distribution programs that can be utilized by a physician for uninsured or underinsured patients. 45
M y c o b a c t e r i u m A v i u m C o m p l e x I n f e c t i o n i n A I D S : C l i n i c a l Features, Treatment, a n d Prevention
(See Table 3.) State A I D S d r u g r e i m b u r s e m e n t p r o g r a m s , financed b y federal Ryan W h i t e f u n d s t h r o u g h state p u b lic health d e p a r t m e n t s , m a y cover the cost of antimicrobials. Eligibility for these p r o g r a m s a n d the m e d i c a t i o n s c o v e r e d varies f r o m state to state.
Summary T h e i n c i d e n c e of d i s s e m i n a t e d M A C is i n c r e a s i n g as p e o p l e w i t h H I V i n f e c t i o n live l o n g e r w i t h p r o f o u n d i m m u n o d e f i c i e n c y . D i s s e m i n a t e d M A C affects i n d i viduals from all demographic and risk categories. S t u d i e s s u g g e s t that d M A C is c a u s e d b y r e c e n t e x p o s u r e to t h e o r g a n i s m r a t h e r t h a n b y r e a c t i v a t i o n . Patients with dMAC experience severe and disabling c o n s t i t u t i o n a l s y m p t o m s . R e s p o n s e r a t e s to t r e a t m e n t for d M A C h a v e i m p r o v e d w i t h c o m b i n a t i o n d r u g therapy, including macrolide antibiotics (clarithromycin and azithromycin). M u l t i d r u g r e g i m e n s i m p r o v e r e s p o n s e rates a n d m a y d e l a y or p r e v e n t the d e v e l o p m e n t of resistance. Rifabutin p r o p h y l a x i s r e s u l t s in a 50% r e d u c t i o n in the d e v e l o p m e n t of d M A C in i n d i v i d u a l s w i t h low CD4+ counts. N u r s i n g i n t e r v e n t i o n s for p e o p l e w i t h late-stage HIV infection include: m o n i t o r i n g for signs a n d s y m p t o m s of d M A C , e d u c a t i n g patients a b o u t the risks a n d benefits of rifabutin, a s s i s t i n g p a t i e n t s w i t h m u l t i d r u g m e d i c a t i o n regimens, m o n i t o r i n g for t r e a t m e n t side effects, a n d providing essential psychosocial assessment and support w i t h a p p r o p r i a t e referrals.
References Arbeit, R., Slutsky, A., Barber, T., Maslow, J., Niemczyk, S., Falkinham, J., O'Connor, G., &von Reyn, C. r Genetic diversity of mycobacterium avium strains causing monoclonal and polyclonal bacteremia in patients with the acquired immunodeficiency syndrome (AIDS).Journal of lnfecthJus Disease, 167, 1384 - 1390. Benson, C. (1994a). Disease due to mycobacterium avium complex in patients with AIDS: Epidemiology and clinical syndromes. Clinical Infectious Disease,18, $218 - $222. Benson, C. (1994b). Treatment of disseminated disease due to the mycobacterium avium complex in patients with AIDS. Clinical hlfectious Disease, 18, $237- $242.
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Benson, C., & Etlner,J. (1993). Mycobacterium avium complex and AIDS: advances in theow and practice. Clinicallnfectious Disease,17, 7 20. Chin, D., Hopewell, P., Yajko, D., Vittinghoff, E., Horsburgh, C., Hadley, W., Stone, E., Nassos, P., Ostroff, S., Jacobsen, M., Matkin, C., & Reingold, A. (1994a). Mycobacterium avium complex in the respiratory or gastTointestinal tract and the risk of M. avium bacteremia in patients with human immunodeficiency virus infection. Journal of Infecthnls Disease, 169, 289 - 295. Chin, D., Reingold, A., Horsburgh, C., Yajko, D., Hadley, W., Elkin, E., Stone, E., Simon, E., Gonzalez, P., Ostroff, S., Jacobsen, M., & Hopewell, P. (I994b). Predict mycobacterium avium complex bacteremia in patients infected with human immunodeficiency virus: A prospectively validated model. Clinical Infectious Disease, 19, 668 - 674. Dautzenberg, B., Tmffot, C., Legris, S., Meyohas, M., Berlie, H., Mercat, A., Chevret, S., & Grosset, J. (1991). Activity of clarithromycin against mycobacterium avium in patients with the acquired immunodeficiency syndrome. American Review of Respiratory Disease, 144, 564 - 569. du Moulin, G, Stuttmier, K., Pelletier, R, Tsang, A., & Hedley-White, J. (1988). Concentration of Mycobacterium avium by hospital hot water systems, lAMA, 260, 1599 1601. Frank, M., Graham, M., & Wispelway, B. (1994). l~ifabutin and uveitis. Ncqo England Journal of Medicine, 330, 868. Fuller, [., Stanfield, L., & Craven, D. (1994). Rifabutin prophylaxis and uveitis. New England Journal of Medicine, 330, 1315 - 1316. Gordon, S., Horsburgh, C., Peloquin, C., Havlik, J., Melchock, B., Heifers, L., McGowan, J., & Thompson, S. (1993) Low serum levels of oral antimycobacterial agents in patients with disseminated mycobacterium avium complex disease. Journal of Infectious Disease, 168, 1559 - 1562. Horsburgh, C. (1991). Mycobacterium avium complex icdection in the acquired immunodeficiency syndrome. New En,gland Journal of Medicine, 324, 1332 - 1338. Horsburgh, C., Metchock, B., Gordon, S., Havlik, J., McGowan, J., Thompson, S., (1994). Predictors of survival in patients with AIDS and disseminated mycobacterium avium complex disease. Journal of Infectious Diseases, 170, 573 - 577. Kemper, C., Meng, T., Nussbaum, J., Chiu, J., Feigat, D., Bartok, A., Leedom, J., Tilles, J., Deresinski, S., McCutchan, J., & the California Collaborative Treatment Group (1992). Treatment of mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen: Rifampin, ethambutol, clofazimine, and ciprofloxacin. Annuals of Internal Medicine, I16, 466 - 472. Lewis, L., Butler, K., Husson, R., Mueller, B., Fowler, C., Steinberg, S., & Pizzo, i~ (1992). Defining the population of human immunodeficiency virus-infected children at risk for mycobacterium aviumintracellulare infection. Journal of Pediatrics, 121,677 - 683. Masur, H. (1993). Recommendations on prophylaxis and therapy for disseminated inycobacterium avium complex disease in patients infected with the human immunodeficiency virus. New England Journal of Medicine, 329, 898 - 904.
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Nightingale, S., Byrd, L., Southern, P., Jockusch, J., Cal, S. Wynne, B. (1992). mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus positive patients. Journal of Infectious Disease, 165, 1082 - 1085. Nightingale, S., Cameron, D., Gordin, F., Sullam, P., Cohn, D., Chaisson, R., Eron, L., Sparti, P., Bihari, B., Kaufman, D., Stern, J., Pearce, D., Weinberg, W., LaMarca, A., & Siegal, E (1993). Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. New England Journal of Medicine, 329, 828 - 833. Pierce, M., Lamarca, A., Jablonowski, H., et al. (1994, October). A
placebo controlled trial of clarithromycin prophylaxis against MAC infection in AIDS patients. Paper presented at the Thirty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL.
Siegal, E, Eilboh, D., Burger, H., Gehan, K., Davidson, B., Kaell, A., & Weiser, B. (1990). Dose-limiting toxicity of rifabutin in AIDS-related complex: Syndrome of arthralgia/arthritis. AIDS, 4, 433 - 441. von Reyn, C., Barber, T., Arbeit, R., Sox, C., O'Connor, G., Brindle, R., Gilks, C., Hakkarainen, K., Ranki, A., Bartholomew, C., Edwards, J., Tosteson, A., & Magnusson, M. (1993). Evidence of previous infection with M. avium among healthy subjects: An international study of dominant mycobacterial skin test reactions. Journal of Infectious Disease, 168, 1553-1558. von Reyn, C., Maslow, J., Barber, T., Falkinham, J., & Arbeit, R. (1994). Persistent M. avium colonization of potable water as a source of infection in patients with AIDS. Lancet, 343, 1137 - 1141. Woods, G. (1994). Disease due to mycobacterium avium complex in patients infected with human immunodeficiency virus: Diagnosis and susceptibility testing. Clinical Infectious Disease, 18, $227 - $232.
Coming in February 1996 ...
ANAC's Core Curriculum for HIV/AIDS Nursing * 500 pages * About $40.00
Edited by:
Kathleen McMahon Casey, MEd, MA, RN Felissa Cohen, PhD, RN, FAAN Anne Hughes, MN, RN
To order call 800-242-6757 or write: Nursecom, Inc. 1211 Locust Street Philadelphia, PA 19107 215-545-7222 215-545-8107 - FAX
Look in future issues of J A N A C for more information.
JANAC
VoL @ No. 5, September-October, 1995
47
Infection with Mycobacterium avium complex (MAC) may cause a serious disseminated
Elizabeth Eccles,MS, RN, and Judy Ptak, MSN, RN, are Infectious DiseaseNurse Clinicians, Dartmouth-Hitchcock Medical Center, Lebanon,Nit.
bacterial infection in up to 40% of patients with advanced HIV infection. Disseminated MAC has a negative impact on quality of life and contributes significantly to morbidity and mortality. Prompt diagnosis and aggressive treatment can diminish those effects. Disseminated disease can be prevented in many patients with the use of rifabutin prophylaxis. Nurses play an important role in evaluating symptoms and educating patients about the prevention and treatment of disseminated MAC. Key w o r d s : AIDS, mycobacterium avium
complex, patient education
T h e term Mycobacteriumavium complex (MAC) refers to a g r o u p of closely related bacteria, i n c l u d i n g Mycobacterium avium and Mycobacterium intracellulare. Researchers first described human disease caused by MAC about 40 years ago. Most reports concerned localized pulmonary infection in adults with chronic lung disease or cervical adenitis in children. Descriptions of disseminated infection were rare, and most of these cases occurred in patients with leukemia or l y m p h o m a (Horsburgh, 1991). The HIV epidemic brought new awareness and interest in MAC infection as it became apparent that disseminated infection with MAC (dMAC) was a common and serious complication of late-stage HIV infection in both adults and children. Disseminated MAC causes a disabling syndrome of fever and wasting and contributes significantly to mortality in persons with HIV/A1DS (Horsburgh, 1991). Nurses in the United States who care for patients with late-stage HIV infection see dMAC infection in up to 40% of these patients (Nightingale et al., 1992). In the United States, dMAC is the most common disseminated bacterial infection seen in patients with AIDS. More HIV patients in the U.S. are infected with MAC than with M. tuberculosis; and the incidence of dMAC is increasing as people with H1V infection live longer with the profound degree of inunune system suppression that leaves them susceptible to dMAC. Nurses have a role in identifying symptoms of dMAC, in helping to monitor the many medications required to treat the infection, and in educating patients about the infection and methods of preventing MAC.
Microbiology MAC are slow-growing, aerobic bacilli, which stain acid fast, like the bacteria that cause tuberculosis and JANAC Vol. 6, No. 5, September-October, 1995
37
M y c o b a c t e r i u m A v i u m C o m p l e x I n f e c t i o n in A I D S : C l i n i c a l Features, T r e a t m e n t , a n d Prevention
leprosy (so-called acid-fast bacilli or AFB). Mycobacterium avium and Mycobacterium intracellulare are g r o u p e d together as a complex because they are difficult to distinguish using routine laboratory techniques. They cause similar infections and are sensitive to the same antibiotics.
Epidemiology The risk of developing dMAC increases as the CD4+ count decreases. Most cases of dMAC are seen in HIVinfected patients with a CD4+ count of less than 50 cells/mm3; MAC is seldom seen in patients who have a CD4+ count above 100 cells/ram 3. Factors such as age, race, gender, and H W risk factor do not appear to affect the risk of developing dMAC (Benson, 1994a). One year after the CD4+ count drops to less than 100 cells/mm 3, the incidence of d M A C is about 21%. This incidence increases to about 43% two years after the CD4+ count falls to less than 100 cells/mm 3 (Nightingale et al., 1992). HIV-infected children appear to develop dMAC at a similar rate (Lewis et al., 1992). Persons with MAC are more likely to have a newly acquired infection than a reactivation of a past infection. in a recent study, researchers looked at skin test reactions to MAC in healthy persons. They found a low number of positive reactions, which challenged the idea that the high rate of dMAC in HIV-infected patients is mostly the r e s u l t of r e a c t i v a t i o n (von Reyn et al., 1993). Furthermore, another s t u d y has linked d M A C with recent exposure to organisms found in potable hot water (von Reyn, Maslow, Barber, Falkinham, & Arbeit, 1994). MAC organisms are found throughout the world in soil, natural and municipal water sources, and in various animal species. Tile organisms are resistant to chlorine and generally have been found if{ higher numbers in hot w a t e r t h a n in cold w a t e r (du M o u l i n , Stottmeier, Pelletier, Tsang, & Hedley-White, 1988). MAC organisms most likely enter the body through the respiratory or gastrointestinal tract and eventually spread to the liver, spleen, and bloodstream. Scientists think it is possible that the infection results from a relatively commonplace water exposure such as drinking
38
contaminated water or inhaling aerosolized water (e.g., mist from a shower). Researchers have not found evidence of person-to-person transmission, and believe s t a n d a r d universal precautions are sufficient w h e n providers care for someone colonized or infected with MAC. Two or more strains of MAC may infect a person at the same time (polyclonal infection), suggesting that MAC can be acquired from v a r i o u s e n v i r o n m e n t a l sources (Arbeit et al., 1993). Polyclonal infection also may prove to have implications for treatment and prophylaxis. For example, two strains of MAC may have different antibiotic sensitivities, and patients with such dual infection may require different treatment regimens from patients infected with a single strain of MAC. The clinical and epidemiologic significance of polyclonal MAC infection requires further investigation.
Clinical Presentation Disseminated MAC may present insidiously in latestage HIV infection with nonspecific systemic symptoms. Symptoms that are reported most frequently in dMAC are persistent fever, weight loss, night sweats, diarrhea, and fatigue. In most patients symptoms are disabling; in some patients they are severe. Muscle wasting, adenopathy, and hepatomegaly a n d / o r splenomegaly may be present. Providers may observe a m u d d y - g r a y facial pigmentation. Laboratory findings include anemia, elevated liver function tests (especially alkaline phosphatase), and hypoalbuminemia (Chin et al., 1994b). CT or MRI scan m a y demonstrate intra-abdominal lymphadenopathy (Benson & Ellner, 1993). The clinical features of dMAC are summarized in Table 1. The nonspecific systemic features of dMAC may be similar to other conditions of advanced AIDS, so the differential diagnosis may be extensive. The index of suspicion for dMAC should be high when the CD4+ count is less than 50 cells/mm 3 and the patient has symptoms of a systemic illness. Other diseases of late-stage H1V infection w i t h similar, systemic s y m p t o m s include lymphoma, disseminated tuberculosis, cytomegalovirus
JANAC Vol.6, No. 5, September-October,1995
Table 1. Clinical Features of Disseminated MAC C o m m o n Signs and S y m p t o m s (in order of relative frequency)
- Fever (especially >30 days) - Night sweats - Malaise - Weight loss - Abdominal pain - Diarrhea - Hepatosplenomegaly Common Laboratory Features
- CD4 count < 50 c e l l s / m m3 - Anemia - Elevated alkaline phosphatase - Hypoalbuminemia Other Reported Features
- Acalculous cholecystitis - Skin lesions - Pneumonia - Lymphadenitis
(CMV) i n f e c t i o n , a n d i n f e c t i o n d u e to R o c h a l i m e a species. Treatment for d M A C usually is not initiated until a definitive diagnosis is made. Diagnosis
Clinicians m a k e the diagnosis of d M A C w h e n the organism is isolated in blood, bone marrow, or tissue from other sterile sites. Most commonly, MAC is isolated from a peripherally drawn blood culture. Since isolation of MAC requires special blood culture techniques, the provider must specify on the microbiology requisition that the culture is for MAC or for mycobacteria. Three types of blood culture techniques can be used to isolate MAC: the Isolator tube, the Bactec system, and conventional blood culture media. Isolator tube. The Isolator vacutainer tube (Wampole Laboratories, Cranbury, NJ) is inoculated with 7 to 10 cc of blood. The tube contains a detergent that lyses red and white blood cells allowing the predominantly intracellular JANAC
Vol. 6, No. 5, September-October, 1995
MAC organisms to be released. The laboratory technician places the Isolator tube in a centrifuge to concentrate o r g a n i s m s for plating on a m y c o b a c t e r i a l m e d i u m . Growth of MAC usually occurs in 21-28 days. Cultures showing no growth after 8 weeks are considered negative. B a c t e c s y s t e m . In t h e B a c t e c s y s t e m ( B e c t o n Dickinson Instrument Systems, Sparks, MD) the technician inoculates 5 cc of blood directly into liquid media containing a radioactive substrate. If MAC is present in the b l o o d , bacterial m e t a b o l i s m releases d e t e c t a b l e radioactive carbon dioxide. A positive result m a y be available in 7-14 days. C o n v e n t i o n a l b l o o d culture. Conventional blood culture m e d i a also m a y be used; however, the p r o v i d e r must specifically ask the laboratory to test for MAC. This m e t h o d takes 21 to 28 d a y s for a p o s i t i v e r e s u l t to become apparent. Blood culture methods first identify the organism as an acid-fast bacillus or mycobacterium, which means the organism could be MAC, M. tuberculosis, or another mycobacterium. Within 1-2 days a technician can do a D N A probe to identify the organism as MAC or another mycobacterium (Woods, 1994). Analysis. A clinician may make a presumptive diagnosis of dMAC when AFB are identified on a stain from bone marrow or sterile tissue from organs such as liver or lymph nodes. The results of the AFB stain may be reported 1-2 days after the biopsy, but definitive identification of MAC requires cul~re, which may take 2- 6 weeks. MAC may be present in bone marrow, liver, a n d / o r l y m p h nodes before bacteremia occurs and blood cultures become positive. Biopsy and AFB staining of these tissues may provide diagnosis earlier than blood culture. Quantitative blood cultures m a y be done, but it is not clear that they are necessary in the medical management of patients. Response to treatment usually can be conf i r m e d by i m p r o v e m e n t in clinical s y m p t o m s . Using q u a n t i t a t i v e b l o o d cultures, H o r s b u r g h et al. (1994) d e m o n s t r a t e d an association between longer survival and lower levels of mycobacteremia (<100 colonies of MAC/ml) at the time of diagnosis. The major limitation of current diagnostic methods is that s y m p t o m s may precede demonstrable bacteremia 39
Mycobacterium Avium Complex Infection in AIDS: Clinical Features, Treatment, and Prevention
by 2-3 months. Infection is present within organ tissue (bone marrow, liver, lymph nodes, GI tract) before disseminating into the blood. When a certain magnitude of infection has developed in the tissues, intermittent bacteremia occurs as bacteria "spill" into the bloodstream. Bacteremia eventually becomes persistent and symptoms of disseminated disease are present continuously. A single positive blood or tissue culture is sufficient for a diagnosis of dMAC and warrants initiation of antiMAC therapy. If the first blood culture for MAC is negative, the clinician should consider repeating the culture, should the symptoms persist. Rarely (2% of cases), MAC bacteremia may be noted before the development of symptoms (Nightingale et al., 1993). The significance of finding MAC in sputum or stool is not completely understood. Asymptomatic colonization of the GI or respiratory tract often precedes disseminated infection. Not everyone who is colonized develops disseminated infection, and the length of time from colonization to dissemination varies. A positive sputum or stool culture alone does not indicate dMAC. About 60% of patients with a positive sputum or stool culture for MAC will develop dMAC with positive blood cultures within 12 months (Chin et al., 1994a).
Treatment Early in the AIDS epidemic many clinicians were reluctant to treat dMAC because its clinical features and consequences were not well recognized. Treatment regimens were difficult to adrrrinister and their effectiveness was not proven. The late stage at which dMAC occurred made treatment seem futile. As a result, diagnostic approaches were not aggressive. Because of recent developments in MAC therapy, clinicians have made aggressive diagnosis and treatment of dMAC a standard of care. Studies of current multidrug treatment regimens have documented microbiologic response, as well as improved survival among people with dMAC. Horsburgh and colleagues (1994) observed a mean survival time after diagnosis of 37 days in patients who were not treated compared to 167 days in
40
those who received antimycobacterial treatment. Chin and peers (1994a) noted a survival of 139 days without therapy versus 263 days for those who received treatment. More importantly, treatment can relieve disabling symptoms that greatly impact quality of life. Researchers have studied several drugs and their combinations and found them to be effective against MAC. These drugs include clarithromycin, azithromycin, rifabutin, rifampin, ethambutol, ciprofloxacin, clofazimine, amikacin, and liposomal encapsulated gentamycin. Benson (1994b) recently reviewed the studies that document the efficacy of various treatment regimens. The greatest advance in the treatment of dMAC has been the introduction of newer macrolide antibiotics, which have rapidly become the foundation of initial multidrug therapy. The drugs shown to have the most activity a g a i n s t MAC are c l a r i t h r o m y c i n and azithromycin. Both drugs are concentrated within cells, where most MAC organisms are found. In a study where patients were given either 1000 mg or 2000 mg BID of clarithromycin (monotherapy), cultures reverted to negative in 75% of patients by 1-2 months (Dautzenberg et al., 1991). Both side effects and bacteriological efficacy were found to be dose related. Higher doses of macrolides, t h o u g h more effective against dMAC, have intolerable side effects (primarily GI related). Thus, the s t a n d a r d adult dose of clarithromycin is 500 mg bid and the standard adult dose of azithromycin is 500mg po qd. Single drugs cannot be used to treat established MAC infection because antimicrobial resistance will develop. The clarithromycin study by Dautzenberg and associates (1991) demonstrated that when clarithromycin was used alone, a high rate of relapse existed. This relapse was the result of an acquired resistance, which developed 2-7 months after patients started therapy. Higher doses of clarithromycin caused a more rapid development of resistance. While the macrolides have been shown to have the best anti-MAC activity, studies demonstrate that the addition of other drugs leads to enhanced bactericidal
JANAC Vol.6, No. 5, September-October,1995
activity. Further, combination therapy may prevent or delay the development of drug resistance. Ethambutol, rifabutin, rifampin, and clofazimine all have been studied in combination with the macrolides. Standard initial therapy for most patients is shown in Table 2 and usually would include three or four of the f o l l o w i n g d r u g s : c l a r i t h r o m y c i n 500 m g p o bid or azithromycin 500 po or IV qd; ethambutol 15 m g / k g / d ; and rifabutin 300 m g / d or rifampin 600 m g / d . Other d r u g s t h a t can be a d d e d or s u b s t i t u t e d i n c l u d e ciprofloxacin 500 mg po bid, clofazimine 100 mg qd or amikacin 10 m g / k g / d IV or IM (Masur, 1993). Effectiveness. If treatment is successful, symptomatic relief may be observed in 1-4 weeks with defervescence, weight gain, and reduction of diarrhea. The authors have o b s e r v e d that m o s t patients on t r e a t m e n t r e p o r t an improved quality of life, with increased energy, appetite, and sense of well-being. Patients need encouragement to comply with the medication regimen because drug side effects may occur before the symptoms of dMAC disappear completely. Within several weeks, the benefits may be dramatic for the patient who has been symptomatic for months. While not essential, a MAC blood culture 4 - 8 weeks into therapy m a y be helpful in confirming the response
Table 2. Recommended Multiple Drug Therapy for Disseminated MAC A. Standard Initial Regimen: 3 or 4 of the following
1. Clarithromycin 500 mg po bid or azithromycin 500 mg PO or IV QD 2. Ethambuto115 mg/kg/d po 3. Rifabutin 300 mg po qd or rifampin 600 mg PO QD 4. Amikacin 10 mg/kg/d IV or IM B. Additional Drugs: These may be added to or substituted for above therapies in the event of treatment failure, relapse, or drug intolerance. 1. Clofazimine 100 mg po qd 2. Ciprofloxach~ 500 mg po qd
JANAC
Vol. 6, No. 5, September-October, 1995
to therapy and providing a baseline for reevaluation if relapse is suspected. Therapy should be continued for life, although some clinicians m a y choose to reduce the regimen from three drugs to two after a few months, if symptoms have resolved. Clinical treatment failure is suspected if the patient has persistent symptoms at 4 - 8 weeks. Blood cultures usually, but not always, revert to negative with standard treatment. P r i m a r y treatment failure m a y occur for a variety of reasons, including resistance to the chosen drugs, poor absorption of drugs from the gastrointestinal tract, or coexisting opportunistic infections or malignancies. If the patient does not respond to standard therapy, the addition of parenteral amikacin, ciprofloxacin, or rifampin may be useful. The value of baseline antimicrobial susceptibility testing is unclear at this time. Methods are not standardized and no evidence exists that antimicrobial susceptibilities are useful in predicting a clinical response. Some patients may experience a relapse of symptoms after several months of effective treatment. Relapse may be associated with a new positive blood culture (after a previous negative culture). Relapse may occur because of the d e v e l o p m e n t of d r u g resistance (which m a y take place even with multidrug regimens) or poor absorption of oral drugs in advanced HIV infection. MAC isolates from patients who relapse on macrolide therapy often demonstrate newly acquired resistance to the macrolide (clarithromycin or azithromycin). Clinicians m u s t evaluate patients presenting with new or relapsing symptoms to rule out new opportunistic infections or malignancies. In the California Treatment C o l l a b o r a t i v e S t u d y ( K e m p e r et al., 1992), 30% of patients on dMAC treatment had fever lasting more than 30 days. Researchers found new opportunistic infections in 7 of 10 patients in this group. Malabsorption of medications and nutrients, a common complication of late-stage HIV infection, may be due to local infiltration of MAC in the gastrointestinal tract, other opportunistic infections, or changes in the gastrointestinal tract from HIV itself. Also, diarrhea m a y impair absorption of drugs and nutrients. Poor absorption of 41
Mycobacterium Avium Complex Infection in AIDS: Clinical Features, Treatment, and Prevention
Table 3. Side Effects and Other C o n s i d e r a t i o n s for D r u g s U s e d in Treatment of M A C Drug
S i d e Effects
Considerations
Manufacturer
9 Clarithromycin (Biaxin)
Nausea, vomiting, diarrhea, headache, bitter taste, elevated LFTs, ototoxicity
Concomitant use of rifabutin may lower serum levels of clarithromycin. Take with food to decrease GI side effects.
Abbott Laboratories, 800/688-9188
9 Azithromycin (Zithromax)
Nausea, vomiting, diarrhea, headache, elevated LFTs, ototoxicity
Take with food to decrease GI side effects.
Pfizer Labs, Division Pfizer Indigent Patient Program, 212/573-3954
9 Ethambutol (Myambutol)
Arthralgias, nausea, vomiting, headache, rash, fever, visual changes
May divide daily dose to reduce side effects.
Lederle Laboratories. Contact local company sales representative
9 Rifabutin
Orange discoloration of body fluids (pseudojaundice), rash, nausea, vomiting, elevated LFTS, neutropenia, thrombocytopenia, myositis, uveitis
Clarithromycin and fluconazole raise rifabutin levels and have been associated with uveitis. May affect hepatic clearance of many drugs (e.g., azoles, dapsone, anticonvulsants, methadone).
Adria Laboratories, Mycobutin Patient Assistance Program, 800 / 795-9759
9 Rifampin (Rifadin)
Orange discoloration of body fluids (pseudojaundice) rash, nausea, vomiting, elevated LFTs, neutropenia, thrombocytopenia, myositis
May affect hepatic clearance of many other drugs (e.g., azoles, anticonvulsants, methadone). May be given IV.
Marion Merril Dow, Indigent Patient Program, 816/966-4000
9 Clofazimine (Lamprene)
Abdominal pain, nausea, vomiting, discoloration of skin, visua~l changes
Take with food to reduce GI side effects.
Ciba-Geigy Pharmaceuticals, Patient Support Program, 800/257-3273
9 Ciprofloxacin (Cipro)
Nausea, vomiting, abdominal pain, rash
Use 500 mg dose if patient has GI side effects.
Miles Labs, 203/937-3273
9 Amikacin (Amikin)
Ototoxicity, nephrotoxicity
Must be given IV or IM.
Elkins-Sinn, 215/688-4400
(Mycobutin)
42
JANAC
Vol. 6, No. 5, September-October, 1995
drugs may result in inadequate serum levels. Switching to o n e or m o r e i n t r a v e n o u s d r u g s ( a z i t h r o m y c i n , amikacin, ciprofloxacin, or rifampin) m a y be beneficial in this situation. The clinician usually can change parenteral therapy to oral therapy after 4 - 8 weeks, if the patient has responded. Researchers are conducting studies to determine the clinical utility of testing serum levels of antimycobacterial drugs. Gordon and colleagues (1993) studied serum levels of patients on a variety of anti-MAC regimens. P a t i e n t s w i t h HIV w e r e f o u n d to h a v e l o w e r than e x p e c t e d s e r u m levels of a l m o s t all antimicrobials. However, even those individuals with very low serum levels responded to therapy, possibly because: (a) intracellular levels of the drugs were sufficient to treat the infection; (b) local t r e a t m e n t of the intestinal MAC caused some relief; or (c) the synergistic effects of the drugs enhanced efficacy. Thus, serum levels are not routinely recommended at this time, but might be conside r e d in p a t i e n t s with p r i m a r y t r e a t m e n t failure or relapse. Side effects. Many patients on multiple drug treatment for d M A C will d e v e l o p one or more d r u g side effects as summarized in Table 3. Gastrointestinal side effects are the most c o m m o n problems, especially nausea or epigastric pain related to the macrolides or the rifamycins (rifampin, rifabutin). For some patients, it may be prudent to start each of the three standard medications 2-3 days apart to assess the side effects of each one independently. Longer intervals between initiation of single drugs are not recommended, since the developm e n t of r e s i s t a n c e m i g h t be e n c o u r a g e d w i t h this approach. Prevention
Prevention of MAC has become more important as people with HIV infection continue to live longer with very low CD4+ counts. As environmental risk factors for dMAC are identified, it m a y be possible to recommend strategies to limit exposure to MAC bacteria. At present, however, chemoprophylaxis is n o w an estabJANAC
Vol. 6, No. 5, September-October, 1995
lished method of prevention. In December 1992, the Food and Drug Administration (FDA) licensed rifabutin for prophylaxis against dMAC in people with H1V infection and CD4+ counts less than 200 cells/mm 3. Rifabutin is a broad spectrum antibiotic with activity similar to rifampin against aerobic bacterial pathogens. The FDA decision was based on two large prospective, placebo-controlled studies, both of which demonstrated a 50% reduction in the incidence of dMAC d u r i n g the s t u d y p e r i o d in s u b j e c t s w h o w e r e o n rifabutin versus placebo (Nightingale et al., 1993). A total of 1,146 patients were enrolled in two studies. Patients (mean CD4+ counts: 50-60 c e l l s / m m 3) were randomized to receive either rifabutin 300 mg per day or placebo. Monthly follow-up visits included evaluation for signs or symptoms of dMAC, blood cultures, and Karnofsky Performance scales. In each of the two studies, the number of patients who developed dMAC while on r i f a b u t i n p r o p h y l a x i s was half the n u m b e r w h o developed dMAC on placebo (8% and 9% versus 17% and 18%, respectively). A l t h o u g h clinical evaluation revealed no difference between the groups in weight loss, diarrhea, night sweats, and abdominal pain, a significant difference in o t h e r clinical p a r a m e t e r s was noted. Fatigue, Karnofsky Performance Scale, and anemia all improved at significant levels in the group that received rifabutin. The researchers observed no survival difference during the study period. A National Institutes of Health study group subsequently recommended starting rifabutin when the CD4+ count is less than 100 cells/mm 3, since the incidence of dMAC is almost zero in people whose counts are greater than 100 cells/mm 3. Rifabutin is administered at the dosage of two 150 mg tablets taken once daily; if a patient has gastrointestinal i n t o l e r a n c e , the d r u g m a y be t a k e n in t w o d i v i d e d doses. Taking rifabutin on a full stomach m a y reduce gastrointestinal side effects. Prophylaxis is a lifelong prevention measure. However, if disease develops while the patient is on prophylaxis, the clinician should initiate standard multidrug therapy. These considerations are summarized in Table 4. 43
Mycobacterium Prevention
Avium
Complex
Infection
in AIDS:
Table 4. Chemoprophylaxis for Disseminated MAC 9 Criteria for Chemoprophylaxis - CD4+ < 100 cells/mm3 - no active tuberculosis - no disseminated MAC (consider routine MAC blood culture if CD4+ < 25 cells/B) - no major drug interactions anticipated 9 Current Recommendation - rifabutin 300mg po qd 9 Future Options - clarithromycin reported to be effective - other prophylactic agents and combinations under investigation i
:
The most c o m m o n side effect of rifabutin is orange discoloration of urine, which occurs in about 30% of patients taking the drug. Side effects were noted in about 50% of participants in the prophylaxis trials, but only a small percentage had to discontinue therapy because of the side effects (16% on d r u g versus 8% on placebo) (Nightingale et al., 1993). Reactions that led to discontinuation of drug included: rash (4%), gastrointestinal distress (3%) and neutropenia (2%). The authors' experience suggests that gastrointestinal side effects may be the most comanon reason patients are tmable to conthme rifabutin. Researchers (Siegal et al., 1990) h a v e r e p o r t e d the o c c u r r e n c e of r e v e r s i b l e polyarthritis/arthralgias and uveitis when patients received higher doses. Although uveitis has been observed primarily when rifabutin is combined with clarithromycin in MAC treatment (clarithromycin increases serum levels of rifabutin), uveitis also has been observed in patients on single-agent prophylaxis. Most of these cases occurred in patients taking fluconazole, which may raise serum rifabutin levels (Frank, Graham, & Wispelway, 1994; Fuller, Stanfield, & Craven, 1994). Clinicians should consider MAC-prevention therapy for their patients at risk. Yet, at this ~-ne, no evidence presents clear proof all H1V-infected persons with CD4+ <100 44
Clinical
Features,
Treatment,
and
should be on rifabutin prophylaxis. One major concern is the possibility that rifabutin prophylaxis will lead to the development of resistant strains of MAC. In the rifabutin prophylaxis studies (Nightingale et al., 1993), no difference e x i s t e d in the s u s c e p t i b i l i t y p a t t e r n s of M A C between those who developed dMAC while on rifabutin and those who received placebo. Clinicians practicing in areas with endemic tuberculosis have expressed the fear that rifabutin prophylaxis against MAC may lead to rifabutin and rifampin resistance a m o n g strains of M. tuberculosis. This c o n c e r n deserves further study. Clearl3r clinicians should evaluate patients carefully for active tuberculosis and dMAC before starting prophylaxis and after beginning treatment. In addition, clinicians should obtain a MAC blood c u l t u r e b e f o r e s t a r t i n g r i f a b u t i n p r o p h y l a x i s in the asymptomatic patient with a very low CD4+ count (e.g., less than 25 cells/mm3). In the rifabutin trials, 2.2% of asymptotnatic subjects had unsuspected disseminated infection identified by a baseline MAC blood culture (Nightingale et al., 1993). Another concern about rifabutin is its effect on serum levels of other medications. Because rifabutin has the capacity to induce cytochrome P450 liver enzymes, clearance of some drugs may be increased, resulting in diminished serum drug levels. An incomplete list of medications that might be affected by this phenomenon include: methadone, zidovudine, dapsone, ketoconazole, itraconazole, anticonvulsants, warfarin, barbiturates, theop h y l l i n e , oral c o n t r a c e p t i v e s , a n d c o r t i c o s t e r o i d s . Clinicians should monitor patients' clinical responses to these drugs when rifabutin is started. Researchers do not have adequate information about rifabutin's effects on maternal-fetal outcomes. The drug should be used only if potential benefits outweigh the u n k n o w n risks. The risk of the p a t i e n t d e v e l o p i n g dMAC, necessitating multidrug therapy with the concomitant risks to the fetus, must be considered. Clinicians should weigh carefully any decision to place a patient on rifabutin. A patient who is not a candidate for this drug should be monitored closely for early JANAC Vol. 6, No. 5, September-October,1995
symptoms of dMAC. Unfortunately, the patient may experience significant clinical deterioration between the time MAC infection starts and when response to treatment begins. Researchers currently are looking at the effectiveness of other drugs and combinations of drugs to prevent the occurrence of dMAC. A recently reported placebo-controlled study demonstrates that clarithromycin prophylaxis at a dose of 500 mg BID reduces MAC bacteremia and mortality (Pierce et al., 1994). However, patients who failed clarithromycin therapy were often infected with strains of MAC resistant to clarithromycin. The impact of widespread clarithromycin prophylaxis on drug resistance patterns deserves further study. Researchers also are studying combinations of clarithromycin/rifabutin and azithromycin/ clofazimine. Patient Education and Nursing Considerations For patients with late-stage HIV infection, the development of an opportunistic infection can be devastating. Patients may interpret the presence of an opportunistic infection as a life-threatening progression of disease. In such situations these patients are reminded of their fears about dependency, suffering, and death. On the other hand, the stress of the new diagnosis may be offset by the relief that comes when the doctor is able to make a definitive diagnosis and treatment is started. The patient may feel renewed hope that treatment might bring symptomatic relief and an improved sense of well-being. At this time, the nurse should do active listening and provide appropriate psychological support so that the patient can start to deal with the new diagnosis. Patient education is essential to the successful management of HIV-infected individuals. For patients with CD4+ counts of less than 100 cells/mm 3, nurses should teach the characteristic symptoms of dMAC: prolonged fever, night sweats, diarrhea, and weight loss. The patients need to report such symptoms to the clinician for prompt evaluation. Individuals being considered for rifabutin prophylaxis need to understand the risks and benefits of such JANAC
Vol. 6, No. 5, September-October, 1995
therapy. Explanations about MAC-related bacteremia, rifabutin's effect on drug serum levels, treatment side effects, and symptom recognition are important components of patient education. Additionally, healthcare professionals need to tell patients that prophylaxis is not 100% effective and that current diagnostic techniques can be time consuming Patients being screened for MAC need to know the limitations and delays inherent in current diagnostic techniques. Individuals with confirmed MAC face the medical demands of multidrug therapy and require considerable psychological support. The disabling symptoms of fatigue, diarrhea, and fever may take weeks to improve after the patient starts therapy. Unfortunately, the initiation of this therapy may take place weeks or months after the first occurrence of symptoms. Nurses should insure that assessment of home support systems and referrals to appropriate agencies are done. Maintaining complicated multidrug treatment regimens is a challenge to patients and providers. Patients need to understand the importance of long-term treatment and the need for maintenance therapy, even after symptoms improve. Monitoring for side effects of the medications and possible drug interactions is essential. Adjusting the scheduling of medications may help diminish side effects. Patients experiencing severe gastrointestinal side effects need to have their medications changed to prevent reduced oral intake or diminished absorption. Proper nutrition is extremely important when a person has dMAC. Most patients will have significant weight loss at the time of diagnosis. Early intervention can help minimize this loss. Referrals should be made to a registered dietician so that appropriate nutritional counseling and interventions can be initiated. Choosing a supplement that is easily absorbed and does not contribute to diarrhea is essential. Patients who fatigue easily may need assistance in meal preparation. Medications used in both the prevention and treatment of dMAC are expensive. Most drug manufacturers have free drug distribution programs that can be utilized by a physician for uninsured or underinsured patients. 45
M y c o b a c t e r i u m A v i u m C o m p l e x I n f e c t i o n i n A I D S : C l i n i c a l Features, Treatment, a n d Prevention
(See Table 3.) State A I D S d r u g r e i m b u r s e m e n t p r o g r a m s , financed b y federal Ryan W h i t e f u n d s t h r o u g h state p u b lic health d e p a r t m e n t s , m a y cover the cost of antimicrobials. Eligibility for these p r o g r a m s a n d the m e d i c a t i o n s c o v e r e d varies f r o m state to state.
Summary T h e i n c i d e n c e of d i s s e m i n a t e d M A C is i n c r e a s i n g as p e o p l e w i t h H I V i n f e c t i o n live l o n g e r w i t h p r o f o u n d i m m u n o d e f i c i e n c y . D i s s e m i n a t e d M A C affects i n d i viduals from all demographic and risk categories. S t u d i e s s u g g e s t that d M A C is c a u s e d b y r e c e n t e x p o s u r e to t h e o r g a n i s m r a t h e r t h a n b y r e a c t i v a t i o n . Patients with dMAC experience severe and disabling c o n s t i t u t i o n a l s y m p t o m s . R e s p o n s e r a t e s to t r e a t m e n t for d M A C h a v e i m p r o v e d w i t h c o m b i n a t i o n d r u g therapy, including macrolide antibiotics (clarithromycin and azithromycin). M u l t i d r u g r e g i m e n s i m p r o v e r e s p o n s e rates a n d m a y d e l a y or p r e v e n t the d e v e l o p m e n t of resistance. Rifabutin p r o p h y l a x i s r e s u l t s in a 50% r e d u c t i o n in the d e v e l o p m e n t of d M A C in i n d i v i d u a l s w i t h low CD4+ counts. N u r s i n g i n t e r v e n t i o n s for p e o p l e w i t h late-stage HIV infection include: m o n i t o r i n g for signs a n d s y m p t o m s of d M A C , e d u c a t i n g patients a b o u t the risks a n d benefits of rifabutin, a s s i s t i n g p a t i e n t s w i t h m u l t i d r u g m e d i c a t i o n regimens, m o n i t o r i n g for t r e a t m e n t side effects, a n d providing essential psychosocial assessment and support w i t h a p p r o p r i a t e referrals.
References Arbeit, R., Slutsky, A., Barber, T., Maslow, J., Niemczyk, S., Falkinham, J., O'Connor, G., &von Reyn, C. r Genetic diversity of mycobacterium avium strains causing monoclonal and polyclonal bacteremia in patients with the acquired immunodeficiency syndrome (AIDS).Journal of lnfecthJus Disease, 167, 1384 - 1390. Benson, C. (1994a). Disease due to mycobacterium avium complex in patients with AIDS: Epidemiology and clinical syndromes. Clinical Infectious Disease,18, $218 - $222. Benson, C. (1994b). Treatment of disseminated disease due to the mycobacterium avium complex in patients with AIDS. Clinical hlfectious Disease, 18, $237- $242.
46
Benson, C., & Etlner,J. (1993). Mycobacterium avium complex and AIDS: advances in theow and practice. Clinicallnfectious Disease,17, 7 20. Chin, D., Hopewell, P., Yajko, D., Vittinghoff, E., Horsburgh, C., Hadley, W., Stone, E., Nassos, P., Ostroff, S., Jacobsen, M., Matkin, C., & Reingold, A. (1994a). Mycobacterium avium complex in the respiratory or gastTointestinal tract and the risk of M. avium bacteremia in patients with human immunodeficiency virus infection. Journal of Infecthnls Disease, 169, 289 - 295. Chin, D., Reingold, A., Horsburgh, C., Yajko, D., Hadley, W., Elkin, E., Stone, E., Simon, E., Gonzalez, P., Ostroff, S., Jacobsen, M., & Hopewell, P. (I994b). Predict mycobacterium avium complex bacteremia in patients infected with human immunodeficiency virus: A prospectively validated model. Clinical Infectious Disease, 19, 668 - 674. Dautzenberg, B., Tmffot, C., Legris, S., Meyohas, M., Berlie, H., Mercat, A., Chevret, S., & Grosset, J. (1991). Activity of clarithromycin against mycobacterium avium in patients with the acquired immunodeficiency syndrome. American Review of Respiratory Disease, 144, 564 - 569. du Moulin, G, Stuttmier, K., Pelletier, R, Tsang, A., & Hedley-White, J. (1988). Concentration of Mycobacterium avium by hospital hot water systems, lAMA, 260, 1599 1601. Frank, M., Graham, M., & Wispelway, B. (1994). l~ifabutin and uveitis. Ncqo England Journal of Medicine, 330, 868. Fuller, [., Stanfield, L., & Craven, D. (1994). Rifabutin prophylaxis and uveitis. New England Journal of Medicine, 330, 1315 - 1316. Gordon, S., Horsburgh, C., Peloquin, C., Havlik, J., Melchock, B., Heifers, L., McGowan, J., & Thompson, S. (1993) Low serum levels of oral antimycobacterial agents in patients with disseminated mycobacterium avium complex disease. Journal of Infectious Disease, 168, 1559 - 1562. Horsburgh, C. (1991). Mycobacterium avium complex icdection in the acquired immunodeficiency syndrome. New En,gland Journal of Medicine, 324, 1332 - 1338. Horsburgh, C., Metchock, B., Gordon, S., Havlik, J., McGowan, J., Thompson, S., (1994). Predictors of survival in patients with AIDS and disseminated mycobacterium avium complex disease. Journal of Infectious Diseases, 170, 573 - 577. Kemper, C., Meng, T., Nussbaum, J., Chiu, J., Feigat, D., Bartok, A., Leedom, J., Tilles, J., Deresinski, S., McCutchan, J., & the California Collaborative Treatment Group (1992). Treatment of mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen: Rifampin, ethambutol, clofazimine, and ciprofloxacin. Annuals of Internal Medicine, I16, 466 - 472. Lewis, L., Butler, K., Husson, R., Mueller, B., Fowler, C., Steinberg, S., & Pizzo, i~ (1992). Defining the population of human immunodeficiency virus-infected children at risk for mycobacterium aviumintracellulare infection. Journal of Pediatrics, 121,677 - 683. Masur, H. (1993). Recommendations on prophylaxis and therapy for disseminated inycobacterium avium complex disease in patients infected with the human immunodeficiency virus. New England Journal of Medicine, 329, 898 - 904.
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Nightingale, S., Byrd, L., Southern, P., Jockusch, J., Cal, S. Wynne, B. (1992). mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus positive patients. Journal of Infectious Disease, 165, 1082 - 1085. Nightingale, S., Cameron, D., Gordin, F., Sullam, P., Cohn, D., Chaisson, R., Eron, L., Sparti, P., Bihari, B., Kaufman, D., Stern, J., Pearce, D., Weinberg, W., LaMarca, A., & Siegal, E (1993). Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. New England Journal of Medicine, 329, 828 - 833. Pierce, M., Lamarca, A., Jablonowski, H., et al. (1994, October). A
placebo controlled trial of clarithromycin prophylaxis against MAC infection in AIDS patients. Paper presented at the Thirty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL.
Siegal, E, Eilboh, D., Burger, H., Gehan, K., Davidson, B., Kaell, A., & Weiser, B. (1990). Dose-limiting toxicity of rifabutin in AIDS-related complex: Syndrome of arthralgia/arthritis. AIDS, 4, 433 - 441. von Reyn, C., Barber, T., Arbeit, R., Sox, C., O'Connor, G., Brindle, R., Gilks, C., Hakkarainen, K., Ranki, A., Bartholomew, C., Edwards, J., Tosteson, A., & Magnusson, M. (1993). Evidence of previous infection with M. avium among healthy subjects: An international study of dominant mycobacterial skin test reactions. Journal of Infectious Disease, 168, 1553-1558. von Reyn, C., Maslow, J., Barber, T., Falkinham, J., & Arbeit, R. (1994). Persistent M. avium colonization of potable water as a source of infection in patients with AIDS. Lancet, 343, 1137 - 1141. Woods, G. (1994). Disease due to mycobacterium avium complex in patients infected with human immunodeficiency virus: Diagnosis and susceptibility testing. Clinical Infectious Disease, 18, $227 - $232.
Coming in February 1996 ...
ANAC's Core Curriculum for HIV/AIDS Nursing * 500 pages * About $40.00
Edited by:
Kathleen McMahon Casey, MEd, MA, RN Felissa Cohen, PhD, RN, FAAN Anne Hughes, MN, RN
To order call 800-242-6757 or write: Nursecom, Inc. 1211 Locust Street Philadelphia, PA 19107 215-545-7222 215-545-8107 - FAX
Look in future issues of J A N A C for more information.
JANAC
VoL @ No. 5, September-October, 1995
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