MYCOBACTERIAL INFECTIONS
Mycobacterium tuberculosis infects one-third of the world’s population and tuberculosis (TB) remains one of the most common infectious diseases among humans. Each year, more than 8 million new cases and 3 million deaths are reported worldwide, 95% of them in the developing world. TB may be one of the most common human immunodeficiency virus (HIV)-related opportunistic infections in the world. The annual number of new TB cases in the United States exhibited a steady decline for decades, until 1985 when the number of TB cases reached a plateau. By the late 1980s, incident TB cases began to increase steadily and peaked in 1992 with more than 26,000 cases reported that year. Since 1992, there has been more than a 30% decline in cases reported annually. Of the 18,361 cases of TB reported in the United States in 1997, 2,000 cases (11%) occurred in New York State, of which almost 80% were reported in New York City. Factors that contributed to the resurgence of TB in the United States included homelessness, nosocomial transmission resulting from poor infection control programs in hospitals, and inadequate support of both the public health infrastructure and TB control programs. Arguably, however, the most important factor responsible for the increased rates of TB has been the epidemic of HIV infection. HIV has had a profound impact on the epidemiology, natural history, and clinical presentation of TB. HIV infection increases a person’s susceptibility to both primary progressive tuberculosis and reactivation of latent infection. The risk of primary progressive TB in HIV-infected persons is as high as 40% compared with approximately 5% in non-HIV-infected populations. HIV-infected individuals with latent infection have a 5%-10% annual risk of developing active disease, a risk that approximates the lifetime risk in non-HIV-infected persons with latent TB. In addition, exogenous TB reinfection has been documented among patients with advanced AIDS, but it remains unclear how often this occurs. Although initial concerns existed that HIV-infected patients with TB might be more infectious than nonHIV-infected patients, a considerable body of data suggests that both groups are similarly infectious. The AIDS epidemic has also led to a much greater understanding and appreciation of the pathogenic potential of mycobacteria other than M. tuberculosis, especially the Mycobacterium avium complex (MAC). MAC, composed of the two closely related species M. avium and M. intracellulare, was one of the most common systemic bacterial infections in AIDS, affecting 20-40% of patients. Highly active antiretroviral therapy (HAART) has had a significant impact on the incidence and clinical presentation of this infection. In addition, advances in the therapy and prevention of MAC infection have been considerable. The most important risk factor for the development of disseminated MAC infection remains severe immunosuppression, generally seen in individuals with CD4 cell counts <50 cell/mm3. Numerous other mycobacteria have been associated with HIV infection. Many of the more unusual nontuberculous mycobacteria are more commonly isolated as laboratory contaminants or colonizers rather than true pathogens. However, in the setting of severe immunosuppression, isolation of these organisms may represent true infection. Among the mycobacterial organisms that have been associated with infection are M. kansasii, M. haemophilum, M. genavense, M. gordonae, and M. xenopi.
A.
Presentation of TB in HIV-infected patients RECOMMENDATIONS:
Practitioners should consider pulmonary tuberculosis in the differential diagnosis of any HIV-infected patient with unexplained fever and cough. Practitioners should consider tuberculosis, both pulmonary and extrapulmonary, in the differential diagnosis of any HIV-infected patient with fever, weight loss, and/or any signs and symptoms of systemic or localized infection.
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The clinical, radiographic, and laboratory features of TB in HIV-infected persons vary, depending on the patient’s degree of immunosuppression. TB often develops early during the course of, and may be the initial manifestation of, HIV infection. Persons with relatively intact cellular immune function, as evidenced by higher CD4 cell counts, positive response to PPD (purified protein derivative) antigen skin testing, and no prior AIDS-associated illness, present with signs and symptoms of reactivation TB comparable with those observed in non-HIV-infected patients. Disease generally remains localized to the lungs. Fever, productive cough, night sweats, weight loss, and malaise are common. Chest x-rays frequently reveal typical apical infiltrates and cavitary disease; sputum smears generally demonstrate acid-fast bacilli (AFB). With advanced HIV infection, TB often has an atypical presentation, with extrapulmonary disease being a prominent feature. In extrapulmonary TB, symptoms may not appear localized in a particular organ or site. Patients present with constitutional symptoms; alternatively, symptoms may relate more to the site of extrapulmonary involvement. In atypical pulmonary TB, chest x-rays may reveal adenopathy (hilar, mediastinal, or paratracheal), atypical infiltrates, pleural effusions, or miliary disease. Alternatively, they may reveal no abnormality at all.
B.
Diagnosis of TB disease RECOMMENDATION:
Practitioners should require that all HIV-infected patients suspected of having tuberculosis have appropriate specimens sent to a microbiology laboratory for AFB staining and mycobacterial cultures. Results of AFB sputum smears should be available within 24 hours of obtaining a specimen. In addition to sending specimens to the microbiology laboratory, practitioners should send, when available, other tissue specimens (e.g., bone marrow, lymph node, liver) to the anatomic pathology laboratory for histopathology and special staining (i.e., AFB stains).
1.
Culture
The definitive diagnosis of TB requires isolation of M. tuberculosis by culture from a specimen. Given the high rate of pulmonary disease in TB, sputum is often the most appropriate initial specimen to send for AFB staining and culture. For patients with pulmonary disease who are unable to produce sputum, induction or even bronchoscopy can be helpful in obtaining suitable specimens for culture. However, because TB can occur in almost any anatomic site, and it is much more likely to be isolated from an extrapulmonary site in an HIV-infected patient compared with an HIV-uninfected patient, clinical specimens other than sputum (e.g., urine, blood, cerebrospinal fluid, pleural and pericardial fluid, biopsy specimens) should be submitted for examination when extrapulmonary TB is suspected.
2.
Staining
The detection of AFB on stained smears varies widely, with sensitivities ranging from 22% to 78%. Although not accurately quantified, the sensitivity depends on factors such as specimen type, number of specimens examined, observer experience, clinical conditions, and number of AFB present. In general, HIV-infected patients have lower frequencies of positive sputum smears, due, at least in part, to a lower incidence of cavitary disease. The fluorochrome stain is generally more sensitive than the traditional Kinyoun or Ziehl-Neelsen stains, but any of these methods is acceptable. Stained smears, however, are not useful for species identification. Moreover, because even non-viable bacilli will stain, a positive smear does not necessarily indicate the presence of live organisms.
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3.
Nucleic acid amplification tests
Newer diagnostic tests that rely on gene amplification, such as polymerase chain reaction (PCR) and the Mycobacterium tuberculosis Direct (MTD) tests have been extensively evaluated on clinical specimens. These technologies hold great promise for supplementing the obvious limitations of currently available microbiologic methods. Two such situations in which standard microbiologic methods are often of limited value are in the diagnosis of tuberculosis in patients who have negative smears but have a high clinical probability of pulmonary TB and, generally, in the diagnosis of suspected extrapulmonary disease with low numbers of organisms. In New York State, the use of the MTD test (RNA-based direct test on sputum) has been invaluable in obtaining earlier identification of AFB in smear positive patients. The FDA recently approved this test for smear-negative specimens as well. These assays are now part of the management of specimens submitted from smear-positive patients in New York State. However, cost and required technical skill make these technologies largely unavailable to much of the developing world and to many institutions in more developed countries.
C.
Treatment of TB in HIV-infected patients RECOMMENDATIONS:
Practitioners with a clinical suspicion of TB when AFB are seen in clinical specimens should institute antituberculous chemotherapy for HIV-infected persons, even if the results of definitive cultures are not yet available. If hospitalized, patients with suspected or proven pulmonary laryngeal tuberculosis should be placed in respiratory isolation until appropriate therapy has been instituted and the patient has had a clinical and bacteriologic response to therapy (three consecutive negative AFB sputum smears) or disease due to Mycobacterium tuberculosis has been ruled out. In addition to ordering AFB smears and cultures, practitioners should order susceptibility testing to the five first-line antituberculosis agents (isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin) once M. tuberculosis is identified. Current initial recommendations for the treatment of tuberculosis are detailed in Table 1.
Table 1. Tuberculosis Treatment Dosage Recommendations
Daily Dose
(should be given as single daily dose, if possible)
Intermittent Dosing
(directly observed therapy only)
Medication Isoniazid1 Rifampin2,3 Pyrazinamide
Adults (Usual) 300 mg PO or IM 600 mg PO or IV 2.0 g (51-74 kg) 2.5 g ( ≥ 75 kg) 15-25 mg/kg PO Max 2.5 g 15 mg/kg IM
Two Times per Week 15 mg/kg Max. 900 mg 600 mg 2.5 g (<50 kg) 3.0 g (51-74 kg) 3.5 g ( ≥75 kg) 50 mg/kg 25-30 mg/kg
Three Times per Week 15 mg/kg Max. 900 mg 600 mg 2.0 g (<50 kg) 2.5 g (51-74 kg) 3.0 g ( ≥75 kg) 30 mg/kg 25 mg/kg
Ethambutol Streptomycin
1. Patients should receive oral pyridoxine therapy 50 mg per day when receiving INH. 2. Rifampin has interactions with numerous medications including protease inhibitors, antifungal azoles, and oral contraceptives (see Table 3). 3. Rifampin interacts with methadone by enhancing its metabolism. To avoid precipitating drug withdrawal, increase methadone dosage. Increments of methadone 5-10 mg are advisable at the first signs of narcotic withdrawal symptoms following initiation of rifampin therapy, on a daily or every-other-day basis, until the symptoms of withdrawal and craving are eliminated. When rifampin is discontinued, the methadone dosage should be lowered to avoid over-sedation.
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Patients who reside in a community where resistance to isoniazid is greater than 4% should be started on a daily 4-drug regimen: isoniazid 300 mg/day; rifampin 600 mg/day; pyrazinamide 25 mg/kg/day; and ethambutol 15-25 mg/kg/day. If audiogram testing is available, streptomycin given intramuscularly at 15/mg/day can be used instead of ethambutol. Once the strain is known to be susceptible to isoniazid and rifampin, ethambutol can be discontinued. Pyrazinamide should be discontinued after 2 months or when sputum smears become negative for AFB, whichever is later. Drugs for the treatment of tuberculosis are available free of charge through the NYSDOH, the NYCDOH, or local health departments. In general, good data on the efficacy of nonstandard antituberculosis regimens are not currently available.
1.
Length of treatment RECOMMENDATION:
For patients with drug-susceptible TB, treatment should continue for a minimum of 6 months. In patients with a delayed response (persistent symptoms or failure to convert to sterile cultures after 2 months of appropriate TB therapy), treatment should be prolonged to 9 months. The length of treatment for drug-susceptible TB remains somewhat controversial. Many clinicians treat drug-susceptible TB with a 6-month course of therapy. Two randomized studies have compared various durations of treatment utilizing rifampincontaining regimens for HIV-related pulmonary TB. In one study conducted in Zaire, HIV-infected patients with pulmonary TB who completed 6 months of therapy were randomized to receive either placebo or 6 more months of biweekly isoniazid and rifampin. The relapse rate was significantly higher among HIV-infected patients who received only 6 months of therapy (9.9%) compared with those who received 12 months of therapy biweekly (1.9%). An NIH-funded randomized study compared 6- and 9month courses of therapy. The failure/relapse rate in both groups was less than 5%. Three non-randomized prospective studies also evaluated short-course rifampin-containing regimens among HIV-infected persons. One study conducted in Haiti was an intermittent, supervised regimen, and the other two, one in Tanzania and the other in the Ivory Coast, evaluated daily therapy. These three 6-month short-course therapy trials demonstrated relapse rates of between 0% and 5.4%.
2.
Directly observed therapy RECOMMENDATION:
Practitioners should enroll all patients in a directly observed therapy (DOT) program for tuberculosis. For those who refuse DOT, practitioners should carefully monitor their therapy. Directly observed therapy (DOT), the practice of observing patients as they take each dose of their antituberculous medication, has become the standard form of care in New York State and in many other parts of the United States. The impetus for broad-based DOT was twofold: rates of TB and multidrug-resistant TB (MDRTB) were rising rapidly because, in part, of the failure of patients to complete a course of therapy and because certain cities had shown that DOT was an effective intervention for maximizing completion of treatment rates. In a well established program in Denver, Colorado, fewer than 10% of patients were lost to treatment. More dramatically, Weis and colleagues documented a relapse rate of 5.5% for the 581 patients on DOT compared with a relapse rate of 21% for the 407 patients on unsupervised therapy. No patient who relapsed on DOT had MDRTB compared with 6% of those not on DOT. Most patients will adhere to therapy when adequate social services and either home- or field-based DOT are provided. However, in the event that these measures have failed,
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New York State Law empowers local public health authorities to issue any order that protects the public health, such as a DOT order, an isolation order, or, in rare instances, a long-term detention order.
3.
Multidrug-resistant TB RECOMMENDATIONS:
Practitioners should consider the possibility of drug-resistant TB, including MDRTB, in all patients being treated for TB if they have a previous history of treatment for TB, have been exposed to an individual with resistant TB, or fail to exhibit the expected clinical or mycobacteriologic response to a standard 4-drug antituberculosis regimen. Practitioners should prescribe a regimen of three or more drugs to which the strain is susceptible, if possible. Practitioners should add at least two new drugs to a treatment regimen that is failing, such as if the patient is not improving clinically or the smears and cultures are positive after 4 months of therapy. For patients with TB resistant only to isoniazid, practitioners should prescribe a three-drug regimen on rifampin, ethambutol, and pyrazinamide given for 6 -9 months or given 6 months after culture conversion, whichever is longer. Aminoglycosides or capreomycin can supplement this regimen if disease is extensive or response not optimal. For patients with rifampin resistance, isoniazid, pyrazinamide, and streptomycin given for 9 months is a reasonable regimen. For patients with a delayed response to treatment, the treatment should be prolonged to 12 months. For HIV-infected patients, TB strains resistant to at least isoniazid and rifampin, i.e., MDRTB, require a minimum of 24 months of treatment after culture conversion. Aminoglycosides (streptomycin, kanamycin and amikacin) or capreomycin should be used for at least 6 months after culture conversion unless ototoxicity, nephrotoxicity, or other severe toxicity develops. The continuation of these parenteral agents for longer than 6 months after culture conversion is reasonable if sputum conversion is slow or disease is extensive. The above guidelines should be considered only as suggested regimens. Opinions vary about both the optimal drug regimens and the necessary duration of therapy. When any doubt about optimal therapy is present, expert consultation is advised. Decisions about initial therapy for suspected MDRTB must take into account both individual and institutional factors. While awaiting susceptibility data for both first- and second-line antituberculosis agents at institutions where outbreaks are ongoing, it is prudent to initiate empiric therapy that optimizes treatment for the outbreak strain, using six- or seven-drug regimens until susceptibility data are available. At institutions where no known outbreaks have occurred but where drug resistance has been encountered, the recommended four-drug regimen is appropriate. Individual patient characteristics also play a role in deciding whether to initiate empiric treatment. Details of a previous history of TB, including prior susceptibility data and treatment; contact with persons who have documented TB and their susceptibility data, if available; exposure to MDRTB at an institution (e.g., hospital, prison, or shelter); and immigration from a country where MDRTB is endemic must all be considered in optimizing empiric treatment. For such individuals deemed to be at high risk for MDRTB, a drug regimen might include more than the four currently recommended drugs,
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including at least two drugs not included in prior regimens. Table 2 presents as a guide a reasonable medication list by order of efficacy for empiric therapy. In general, the optimal drugs for treating MDRTB should include the other first-line anti-TB drugs and the quinolones when susceptibility tests indicate no resistance to the drugs. Among the fluoroquinolones, levofloxacin (the optically active L-isomer of ofloxacin) is the preferred agent for TB. Although sparfloxacin appears to have excellent TB activity, the side effects of phototoxicity and torsades de pointes limit its use for patients with MDRTB.
Table 2. Recommended Drugs by Order of Efficacy Activity Against Mycobacterium tuberculosis
Medication
Rifampin Rifabutin Isoniazid Pyrazinamide Ethambutol Streptomycin (amikacin kanamycin) or Capreomycin Levofloxacin or *Sparfloxacin Ethionamide
Usual Dosage
600 mg PO qd 300 mg PO qd 300 mg PO qd 25 mg/kg/d PO 25 mg/kg/d PO - 15 mg/kg/d IM/IV - 15 mg/kg/d IM/IV - 15 mg/kg/d IM/IV 15 mg/kg/d IM/IV 1,000 mg PO qd 400 mg PO qd 0.5 -1.0 g/d PO Give 250 mg PO bid to qid (or 500 mg bid, if tolerated) 0.5 -1 g/d PO Give 250 mg PO bid to qid (or 500 mg qd to bid, if tolerated) 4 g packet tid
Cycloserine
PAS
* See text below for potential contraindications.
RECOMMENDATION:
In HIV-infected patients with clinically suspected but not proven TB and negative smears and negative cultures, a 6-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol is recommended. Among patients who have signs and symptoms that are suggestive of TB but in whom repeated smears and cultures remain negative and other causes have been excluded, physicians are often unsure whether to start anti-TB chemotherapy. In such situations, when therapy is initiated, a course of four drugs for the entire length of treatment is justified because of the possibility of drug resistance.
4.
Patient follow-up RECOMMENDATIONS:
Patients receiving antituberculous chemotherapy should be monitored monthly for response to treatment, adherence to treatment, and evaluation of medication toxicity. Expectorated or induced sputum should also be ordered monthly for both AFB smear and culture for patients who have had pulmonary TB. Repeat susceptibility testing should be obtained if cultures remain positive after
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4 months of treatment, or earlier, if patients are worsening on an apparently adequate regimen. A careful history and physical examination should be performed each month while the patient is receiving antituberculous chemotherapy for tuberculosis. The practitioner should pay particular attention to the specific side effects of certain anti-TB medications during these evaluations. For example, visual acuity and color vision should be checked during treatment with ethambutol. An expectorated or induced sputum should also be ordered monthly for both an AFB smear and a culture for those who have had pulmonary TB. Repeat susceptibility testing should be obtained if cultures remain positive after 4 months of treatment or earlier if patient is worsening on an apparently adequate regimen. Liver function tests (LFTs) should be repeated if one of the following situations applies: 1) if baseline LFTs were elevated, 2) if the patient has symptoms suggestive of hepatitis, or 3) if other risk factors for hepatitis exist (such as older age [≥65 years], use of other potentially hepatotoxic drugs, alcoholism, or viral hepatitis). For patients with normal liver function tests, treatment with potentially hepatotoxic drugs can be continued unless transaminase levels exceed fivefold the upper limit of the normal range. Other laboratory data should be obtained as required, based on clinical symptoms. Potential medication toxicities, such as renal toxicity as a result of aminoglycoside therapy, should likewise be considered. Table 3 is a listing of side effects associated with antituberculosis therapies.
Table 3. Toxicities of Antituberculosis Medications
Isoniazid Rash Hepatic enzyme elevation Hepatitis Peripheral neuropathy Mild CNS effects Rifampin/Rifabutin Rash Hepatitis Fever Thrombocytopenia Flu-like symptoms Orange-colored body fluids Pyrazinamide Gastrointestinal upset Hepatitis Rash Arthralgias Hyperuricemia Gout (rare) Ethambutol Optic neuritis (decreased redgreen color discrimination) Decreased visual acuity Rash Streptomycin Ototoxicity (hearing loss or vestibular function) Nephrotoxicity Hypokalemia Hypomagnesemia Levofloxacin Abdominal cramps GI upset Insomnia Headache Photosensitivity Sparfloxacin Similar to levofloxacin Photosensitivity QT Prolongation Cycloserine Psychosis Seizures Headache Depression Other CNS effects Rash Ethionamide GI upset Bloating Hepatotoxicity Metallic taste Hypothyroidism (esp. with PAS) Kanamycin/Amikacin Auditory and renal toxicity Vestibular toxicity (rare) Hypokalemia Hypomagnesemia Capreomycin Auditory, vestibular and renal toxicity Eosinophilia Hypokalemia Hypomagnesemia Para-aminosalicylic Acid (PAs) GI disturbance Hypersensitivity Hepatotoxicity Hypothyroidism
5.
Protease inhibitors and TB treatment RECOMMENDATIONS:
Nucleoside reverse transcripase inhibitors (zidvudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir) are not contraindicated and do not require dose adjustment when used with rifamycins.
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Protease inhibitors complicate TB therapy because of their significant interaction with rifamycins, especially rifampin. For patients with HIV infection and relatively intact immune function, practitioners should consider delaying treatment with a protease inhibitor until a minimum of 6 months of a standard rifampin-containing regimen is completed. If additional TB treatment is required, the remainder can be with a non-rifamycin containing regimen. When protease inhibitor therapy cannot be delayed, practitioners may substitute rifabutin for rifampin, coadministered with indinavir or nelfinavir. The rifabutin dose should be reduced to 150 mg for daily regimens or 300 mg for twice or thrice weekly regimens. Some authorities recommend increasing the dose of indinavir and nelfinavir when they are given with rifabutin, although the optimal dose remains unclear. When rifampin is used, neither saquinavir alone, nor indinavir, nelfinavir, or amprenavir should be coadministered. Coadministration of ritonavir (with or without saquinavir hard- or soft-gel capsules) and rifampin or rifabutin is possible based on CDC recommendations although pharmacokinetic data and clinical experience are limited. If rifampin is utilized with ritonavir (+/- saquinavir) then the dose recommended is unchanged (600 mg daily or two to three times per week depending on the regimen prescribed). If rifabutin is utilized, a substantial reduction of rifabutin to 150 mg two or three times per week is recommended. For patients who require complex combinations of protease inhibitors or NNRTIs, practitioners may adopt an acceptable non-rifamycin containing regimen for TB consisting of isoniazid, pyrazinamide and streptomycin thrice weekly for 9 months. Delavirdine should not be used with rifamycins. Efavirenz exposure is not significantly affected by rifabutin. Based on limited data, rifabutin dosage may be increased from the usual dose of 300 mg to a daily dosage of 450-600 mg or a twice or thrice weekly dose of 600 mg when used with efavirenz. Protease inhibitors complicate TB therapy because of their significant interactions with rifamycins, especially rifampin. Protease inhibitors are metabolized in the liver by the cytochrome p450 enzyme system. All protease inhibitors inhibit p450 to a variable extent. Rifampin is a very potent inducer of the cytochrome p450 system; rifabutin induces it to a lesser extent. In addition, protease inhibitors increase serum levels of rifampin, thus increasing the toxicity of this drug. Consequently, previous CDC guidelines suggested that rifampin be contraindicated with all protease inhibitors. More recent data, and updated CDC guidelines, suggest that coadministration of rifampin with ritonavir, either as a single protease inhibitor or in combination with saquinavir, is a possibility, though pharmacokinetic data and clinical experience are limited. Rifabutin is probably equivalent in efficacy to rifampin in the treatment for TB. The interaction of rifabutin with indinavir and nelfinavir is the best studied and seem to be the least problematic. If rifabutin is to be used with these protease inhibitors, it should be used at a dose of 150 mg/day, which is one-half the usual dose, or 300 mg two or three times per week. While the optimal dose of protease inhibitors remains unclear when concurrent rifabutin is being used, many clinicians are increasing indinavir to 1,000 mg every 8 hours and nelfinavir to 1,000 mg every 8 hours. Updated CDC guidelines also suggest that coadministration of rifabutin with ritonavir may be possible, though pharmacokinetic data and clinical experience are even more limited. If these two drugs are coadministered, the dose of rifabutin is substantially reduced to 150 mg two or three times per week. Rifampin also increases metabolism of methadone, frequently necessitating upward adjustment of methadone dose. 8
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D. TB infection RECOMMENDATIONS:
For HIV-infected patients without a history of tuberculosis or a positive PPD, practitioners should order a 5-tuberculin unit (TU) PPD at the time of the initial evaluation and annually thereafter. Induration of >5 mm is considered a positive test and an indication of TB infection. For all HIV-infected patients with a new positive PPD, practitioners should obtain a detailed history, perform physical examination, and order chest x-rays. Anergy testing is not routinely recommended at the time of tuberculin skin testing. HIV-infected persons with a positive PPD but without active disease should receive isoniazid for 9 months, 300 mg daily (or 900 mg twice weekly if directly observed) and pyridoxine, 25 mg per day or 50 mg twice weekly to prevent peripheral neuropathy. An alternative regimen for chemoprophylaxis is pyrazinamide and rifampin daily for 2 months. Directly observed preventive therapy (DOPT) should be offered to patients when it is locally available. HIV-infected individuals have consistently shown lower rates of reactivity to PPD skin testing when compared with demographically similar HIV-seronegative individuals. This phenomenon is due primarily to the failure of the delayed-type hypersensitivity (DTH) response in patients with advanced HIV infection. While induration of ≥10 mm in response to an intradermal injection of 5 TU in HIV-seronegative persons defines a positive skin test and is, thus, considered an infection, tuberculin positivity in HIV-positive persons requires only a 5 mm response to 5 TU to be considered an infection. This lower cut-off for HIV-infected persons exists for two reasons: the high incidence of TB in HIV-infected persons and the elevated risk of TB for HIV-infected persons with advanced disease (i.e., ≤200 CD4 cells/mm3) with induration of 5-9 mm following PPD testing. Cutaneous anergy is more common among HIV-infected persons, and the prevalence of anergy increases relative to the degree of immunosuppression. Cutaneous anergy as a functional measure of cellular immunity has been used to determine if negative tuberculin skin tests are valid in the presence of HIV immunosuppression. Anergy testing is no longer routinely recommended because skin test anergy has been found to be both an unstable finding and difficult to standardize and reproduce. In addition, two large prospective trials, one conducted in Uganda by Whalen et al. and one in the United States by Gordin et al., found low rates of active TB among anergic HIV-infected individuals regardless of whether or not they received isoniazid chemoprophylaxis. Isoniazid has repeatedly been shown to be effective in preventing the development of TB in those infected with M. tuberculosis. In addition, chemoprophylaxis should be given to those who have radiographic evidence of old TB or have had a close exposure to a known case of TB. In the latter situaiton, regimens should be based on the susceptibility of the isolate from the index patient. A recently completed prospective trial has documented the equivalency of a 2-month regimen of rifampin and pyrazinamide compared with 12 months of isoniazid. HIV-infected patients who have been exposed to a patient with isoniazid-resistant TB should undergo a 2-month course of rifampin and pyrazinamide. Several additional unproven options are available for those exposed to MDRTB. For example, pyrazinamide with ethambutol, and pyrazinamide with levofloxacin are two preventive regimens, which have yet to be studied. When the infecting strain is partially susceptible to either isoniazid or rifampin, these drugs should be used in combination with other oral agents. Therapy should last a minimum of 12 months.
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E.
Issues in infection control RECOMMENDATIONS:
Practitioners should place any individual admitted to a hospital and suspected of having AFB smear-positive pulmonary or laryngeal tuberculosis in a code-compliant AFB isolation room. Practitioners should use appropriate precautions and specialized rooms in situations that are of high-risk for TB transmission, including sputum induction, bronchoscopy and use of aerosol pentamidine for prophylaxis of PCP . Practitioners may transfer patients receiving therapy for pulmonary TB to a nonisolation room if they have resolution of signs and symptoms, especially cough and they have three consecutive negative AFB sputum smears. Staff who enter the rooms of, or who have contact with smear-positive patients with TB, should wear properly fitted disposable particulate respirators capable of filtering small (1-5 microns) aerosolized particles. Common surgical masks are not effective. Practitioners may discharge patients with smear-positive pulmonary TB from the hospital if they meet the following criteria: their symptoms and signs, especially the cough, are resolved or near resolution; they are receiving therapy to which the strain is known to be, or very likely to be, susceptible; they are highly likely to adhere to the prescribed course of anti-TB therapy (e.g. they are on DOT); and they are not being discharged to congregate living environments or households where immunocompromised or very young children live. The principles of infection-control to limit intrainstitutional transmission of TB in the United States apply to both the HIV-infected and the non-HIV-infected populations who are infected with drug-resistant or drug-susceptible strains of TB. Nevertheless, transmission to HIV-infected patients and employees is of particular concern because of the high likelihood of developing active TB if they become infected with M. tuberculosis. These straightforward principles include effective isolation of suspected or known cases of TB until they are no longer infectious, rapid confirmation of diagnosis, and implementation of appropriate antituberculous chemotherapy medications. The advances in isolation procedures have improved the prevention of hospital-acquired infection, contributing substantially to the decrease in the total number of cases of both drug-susceptible and drug-resistant TB. Failure to adhere to effective isolation and control programs has resulted in a large number of institutional outbreaks and cases of nosocomial TB that have affected both patients and employees. The isolation of suspected or known cases of TB in an institutional setting is a labor-intensive process and has met with varying degrees of success. Placement of patients into rooms with negative pressure and a minimum of 6 air-exchanges per hour is currently recommended. Other supplemental environmental interventions include the use of masking devices and high-efficiency filtration systems. Given the difficulty in adhering to rigorous respiratory isolation algorithms and procedures, however, some have advocated widespread use of ultraviolet irradiation as an adjunctive measure. At present, no controlled studies exist to support widespread use of this intervention.
F.
Mycobacterium avium (MAC) infections 1. Description
Disseminated MAC infection is usually a late complication of HIV infection. It occurs in patients who are severely immunosuppressed, with CD4 cell counts generally <50
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cells/mm3. In contrast to MAC disease in immunocompetent hosts, in whom it is rare and usually limited to the lungs, in patients with AIDS, bacteremia is by far the most common syndrome. Frequently, widespread dissemination occurs involving the liver, spleen, bone marrow, and lymph nodes. Patients generally complain of fever, anorexia, night sweats, and weight loss. Abdominal pain and diarrhea are also frequent. Anemia and pancytopenia are common as a result of bone marrow infiltration. Elevated serum alkaline phosphatase levels are a common consequence of liver infiltration. More recently, localized disease from MAC has been documented and appears to be more common following immune reconstitution soon after the initiation of HAART.
2.
Diagnosis RECOMMENDATIONS:
Practitioners should consider a diagnosis of disseminated MAC infection in any severely immunosuppressed patient with AIDS who presents with persistent fever, sweats, and weight loss. Practitioners should choose blood culture, which is the test of choice, to diagnose disseminated MAC infection. Sputum and stool cultures are generally not diagnostic of disease. In patients suspected of having disseminated MAC, a blood specimen should be obtained for mycobacterial culture. When symptoms are moderate or severe, mycobacteremia is continuous, and, therefore, one blood culture is usually sufficient for diagnosis. However, because transient mycobacteremia also occurs, additional cultures are warranted when symptoms persist with a negative culture. Cultures become positive in 5 days to 3 weeks, varying with the culture system used and the severity of the mycobacteremia. Because patients with disseminated MAC usually manifest deep-tissue involvement before developing continuous bacteremia, culture of a biopsy specimen from a normally sterile site (e.g., bone marrow, liver, or lymph node) may facilitate an earlier diagnosis in individuals with negative blood cultures. However, tissue biopsy is rarely needed to make the diagnosis. Respiratory and stool specimens are not recommended to diagnose disseminated disease because many people are colonized with MAC. The presence of the organism in these specimens, therefore, is not diagnostic of disseminated MAC.
3.
Treatment RECOMMENDATIONS:
Practitioners should treat all patients with disseminated MAC infections. Treatment regimens should include at least two drugs to increase efficacy and prevent the emergence of resistance. Every treatment regimen should include a macrolide antibiotic, either clarithromycin or azithromycin, and ethambutol. Pending results of ongoing clinical trials, treatment should continue for life. MAC bacteremia has been independently associated with an increased risk of death, and antimycobacterial therapy has been associated with prolonged survival. The macrolides, clarithromycin and azithromycin, demonstrate excellent clinical and microbiologic activity in a number of single-drug and combination-drug studies. Because treatment of MAC with clarithromycin with the high dose of 1,000 mg twice a day is associated with decreased survival compared with the 500 mg twice daily, the lower dose should be used. Ethambutol is the most commonly recommended second drug. Although clinical trials
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have not substantiated the benefits of adding additional drugs to the initial regimen, many clinicians continue to use three- or four-drug combinations. Other antibiotics with activity against MAC include the rifamycins (rifampin and rifabutin), quinolones (especially ciprofloxacin), and amikacin. Table 4 lists the agents used for MAC prophylaxis and treatment, and their potentially significant interactions with other drugs.
4.
Prevention RECOMMENDATIONS:
Practitioners should administer chemoprophylaxis against disseminated MAC to adults and adolescents who have HIV infection with CD4 cell counts of <50 cells/mm3. Regimens of clarithromycin 500 mg b.i.d. or azithromycin 1,200 mg each week are the recommended treatment options for primary prevention of disseminated MAC. If neither clarithromycin nor azithromycin can be tolerated, rifabutin (300 mg each day) is an alternative agent for primary prevention.
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Before initiating prophylaxis, practitioners should rule out disseminated MAC disease by clinical evaluation, which may include obtaining a blood culture. Because of the morbidity and mortality associated with disseminated MAC, prevention strategies have been studied. Prevention of exposure to these ubiquitous organisms is highly impractical. Consequently, numerous chemoprophylaxis trials have been completed. Three agents that have been well studied, both singly and in combination, are rifabutin, clarithromycin, and azithromycin. In two large placebo-controlled trials, rifabutin prophylaxis decreased the incidence of MAC bacteremia by approximately 50%, from 17.5% in placebo to 8.5% in the rifabutin-treated group. Follow-up of these groups found a survival advantage in the rifabutin-treated groups. Similarly, in clarithromycin versus placebo studies, clarithromycin was shown to be advantageous in decreasing the rate of MAC bacteremia and mortality. In a three-arm study, clarithromycin was compared with rifabutin and to their combination. Clarithromycin was more effective than rifabutin at preventing MAC; the combination was similar to clarithromycin alone. However, both groups who received clarithromycin had breakthrough bacteremia with a resistant isolate; those on rifabutin with MAC bacteremia still had susceptible isolates. In a subsequent three-arm study comparing the relative effectiveness of weekly azithromycin, daily rifabutin, and the combination of both drugs, the combination approach provided the most effective prevention, followed by azithromycin alone and finally rifabutin alone. However, the combination regimen resulted in significantly higher toxicity and conferred no survival advantage compared with azithromycin alone. Based on the current USPHS/IDSA guidelines, discontinuation of primary prophylaxis can be considered for patients who have a sustained rise in CD4 count to >100 mm3 with a suppressed viral load for 3-6 months, whereas there are insufficient data to recommend discontinuation of secondary prophylaxis/maintenance.
G. Mycobacteria other than TB and MAC
Mycobacteria other than TB (MOTT) are a diverse group of organisms that are differentiated on the basis of a variety of morphologic, physiologic, and biochemical characteristics. Unlike M. tuberculosis disease, in which the isolation of a single colony is always clinically significant, the isolation of MOTT and subsequent discrimination among contamination, colonization, and disease is often difficult. MOTT species are ubiquitous in soil, water, dust, and foodstuffs and may colonize secretions or body surfaces for prolonged periods without causing disease. In addition, MOTT may contaminate clinical specimens. Drug susceptibilities vary considerably among MOTT, and treatments for some of these organisms are not standardized. When these organisms are isolated and implicated in infection, the practitioner should seek the advice of an experienced clinician to aid in the management of these difficult and unusual cases. Other mycobacteria that cause localized and/or disseminated infections include M. gordonae, M. fortuitum, M. chelonae, M. haemophilum, M. xenopi, and M. marinum. Mycobacterium kansasii is the second most frequently reported MOTT to cause disease. The clinical presentation of M. kansasii is often similar to that of TB, but the organism, in general, is less virulent. Pulmonary parenchymal disease and disseminated disease are the most common clinical presentations. Treatment is often complex. Higher doses of isoniazid may be required, and pyrazinamide is ineffective. In addition, increasing rates of rifampin resistance have been reported. Most HIV-infected patients with M. kansasii infection have treatable disease, although a small proportion of these patients appear to have rapidly progressing and fatal disease.
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References Alland D, Kalkut GE, Moss AR, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994;330:1710-16. American Thoracic Society and the Centers for Disease Control and Prevention. Authors: Bass JB Jr, Farer LS, Hopewell PC, et al. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 1991;144;745-9. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49:185-9. Centers for Disease Control and Prevention. Management of persons exposed to multidrugresistant tuberculosis. MMWR 1992;41(RR-11):61-71. Centers for Disease Control and Prevention. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. USPHS/IDSA Prevention of Opportunistic Infections Working Group. MMWR 1997;46(RR-12):1-46. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;47(RR-20):1-58. Frieden TR, Sterling T, Pablos-Mendez A, et al, The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993;328:521-6. Horsburgh CR Jr, Havlik JA, Ellis DA, et al. Survival of patients with acquired immune deficiency syndrome and disseminated Mycobacterium avium complex infection with and without antomycobacterial chemotherapy. Am Rev Respir Dis 1991;144:557-9. New York City Department of Health, Bureau of Tuberculosis Control. Clinical Policies and Protocols. 3rd ed. New York: New York City Department of Health, 1999. Turett GS, Telzak EE, Torian LV et al. Improved outcomes for patients with multidrug-resistant , tuberculosis. Clin Infect Dis 1995;21:1238-44. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179-84. Witzig RS, Fazal BA, Mera RM, et al. Clinical manifestations and implications of coinfection with Mycobacterium kansasii and human immunodeficiency virus type I. Clin Infect Dis 1995;21:77-85.
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