Recent evidence suggests that multidrug-resistant tuberculosis can be controlled through shorter-term regimens and directly observed therapy.
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, a small, rod-shaped, aerobic, non-spore-forming bacillus. The resurgence of TB outbreaks, although not as severe now as during the period between 1985 and 1992, is nonetheless a cause for concern. Globally, TB is still a leading cause of morbidity and mortality. A crucial strategy for the successful elimination of TB involves prompt, appropriate, and complete treatment of all active cases. Delays or interruptions in therapy may compromise care, cause drug resistance, and sustain infection in the community. A single unchecked case can foster a mini-epidemic.1
Trends in Prevalence
Prevalence rates for TB are available through 1997. Worldwide, about one third of the general population is infected with M. tuberculosis.2,3 From this pool, approximately 8 to 10 million new active cases emerge each year.2 According to World Health Organization estimates, about half of these cases are communicable forms of pulmonary disease.3 The infection and the disease are particularly prevalent in the Pacific Rim region (excluding Japan), Southeast Asia, the Indian subcontinent, sub-Saharan Africa, and Latin America. Globally, about 2 to 3 million people die per year of TB, often as a result of delayed, inadequate, or unavailable therapy.3
In the United States, there is a considerably lower prevalence of TB than in other parts of the world. According to the Centers for Disease Control and Prevention (CDC), about 4% to 6% of US residents (or, roughly, 10 to 15 million individuals) harbor latent infections.3 Case rates in the United States had fallen consistently from 1953 to 1984; however, there was a substantial upsurge in cases from 1985 to 1992.2,3 This increase has been attributed to several factors, including HIV infection, increased immigration, and deterioration of the public-health infrastructure in larger cities.
In response to the upsurge in cases, treatment programs were fortified and measures were taken to reduce nosocomial transmission. As a result, from 1992 to 1997, case rates dropped substantially, with an all-time low of 19,851 cases (representing a case rate of 7.4 per 100,000 persons) in 1997.3 In 1997, six states (California, New York, Texas, Florida, Illinois, and New Jersey) contributed 57% of the national case load.3
TB may be manifested clinically as pulmonary disease and/or extrathoracic disease because the primary pulmonary infection may result in bacillemic dissemination. As a general rule, hosts with more competent immune systems tend to have disease limited to their lungs or other single sites, whereas those with less competent defenses may experience multifocal disease.
Classic symptoms include cough, hemoptysis, fever, sweating, malaise, weight loss, and dyspnea. Patients with advanced disease may exhibit wasting (once known as consumption). Signs may be limited until the disease reaches its advanced stages. The chest radiograph is an important component of the diagnostic workup. Chest radiographs often reveal fibronodular shadowing in one or both lung apices. As the lesions advance, they enlarge, cavitate, and produce an intense local inflammatory reaction that may result in tissue necrosis and sloughing. Even when clinical TB is present, the tuberculin skin test (TST) will be falsely negative in up to 25% of cases. Acid-fast bacilli may be found, however, in respiratory secretions.
Extrapulmonary TB may affect the lymphatic, genitourinary, skeletal, and gastrointestinal systems, as well as the pleura, pericardium, peritoneum, and central nervous system. Diagnosis may be difficult due to the relative paucity of bacilli. Histopathology of involved tissues typically shows giant-cell granulomas with caseating necrosis. Analysis of tuberculous effusions of the pleura, pericardium, and peritoneum may reveal a predominance of polymorphonuclear leukocytes in patients with early-stage disease, or a lymphocyte-rich exudate with low concentrations of glucose in those with advanced disease.
TB in Patients with HIV
In the early stages of disease, the clinical manifestations of TB in people infected by HIV may be indistinguishable from those in patients with competent immune systems. As the T-lymphocyte population declines in HIV-infected individuals, however, TB follows a predictable and devastating course. Extrapulmonary involvement occurs in the majority of HIV-infected individuals, and it may take on an exotic form such as diffuse lymphadenitis or cutaneous disease. Chest radiographs may reveal changing patterns of disease, evolving from classic upper-zone, fibronodular, cavitary changes to lower-zone, nondescript, pneumonic patterns; infrequent cavity formation; prominent hilar adenopathy; and substantial pleural effusions.
Current Treatment Perspectives
Perhaps the single most important aspect of treatment is the public-health mandate that individuals with communicable TB be either treated or quarantined. In the past, patients with communicable TB were often quarantined in asylums or sanitaria. Today, pharmacotherapy has become a chemical quarantine. Hence, noncompliance with drug therapy may be considered a breach of quarantine. Because the consequences of inadequate or incomplete treatment can be devastating, directly observed therapy (DOT) to prevent noncompliance is becoming increasingly common.
Because it usually takes several weeks to culture and identify M. tuberculosis, treatment is often initiated before a definitive diagnosis is established. Generally, treatment involves a combination of drugs. The rationale for combination therapy is two-fold: to prevent the emergence of drug-resistant strains and to accelerate clearance of the microorganism. In addition to combating drug resistance, multiple-drug regimens can shorten the required duration of treatment. For example, a regimen of isoniazid and ethambutol takes 18 months to cure the typical case of pulmonary TB; adding rifampin to isoniazid reduces the duration of treatment to 9 months; and when an initial 2-month phase of pyrazinamide is added to isoniazid and rifampin, therapys duration may be shortened to 6 months.3
|Isoniazid plus rifampin daily for 6 months; Pyrazinamide plus streptomycin or ethambutol daily for 2 months.||6 months||Add streptomycin or ethambutol in areas/patients at risk for initial drug resistance. Stop pyrazinamide, ethambutol, or streptomycin after 2 months if strain is susceptible; continue or modify regimen if resistance is present.|
|Isoniazid, rifampin, pyrazinamide, and streptomycin daily for 2 weeks, then twice weekly for 6 weeks. Following with isoniazid plus rifampin twice weekly||6 months||Stop pyrazinamide and streptomycin at 8 weeks if strain is susceptible; continue through 6 months if there is initial isoniazid resistance. May substitute ethambutol for streptomycin. 24 weeks of twice-weekly therapy facilitates DOT.|
|Isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol thrice weekly for 6 months (may stop pyrazinamide, streptomycin, or ethambutol after 2 months.)||6 months||All intermittent. If strain is susceptible, may stop pyrazinamide and streptomycin or ethambutol after 2 months. If there is isoniazid resistance, stop isoniazid and add the fourth drug (ethambutol or streptomycin).|
|Isoniazid plus rifampin daily for 1 month; then isoniazid plus rifampin twice weekly for 8 months.||9 months||This regimen should be employed only in populations with a very low prevalence of drug resistance. Initial therapy probably should include a third drug until drug susceptibility is reported.|
|Table 1. Drug regimens for the treatment of tuberculosis3,4; DOT=directly observed therapy.|
Because of concerns about drug resistance, the CDC recommends a four-drug regimen for most cases of known or suspected TB (Table 1).4 Isoniazid and rifampin are key agents in any regimen because of their superior bactericidal activity and relatively low toxicity. Pyrazinamide is useful for promoting rapid, early reduction in bacillary burden. Ethambutol is useful primarily to protect against the emergence of drug resistance in cases with unknown initial susceptibility patterns. The role of streptomycin is diminishing in modern therapy due to problems with regularly administering intramuscular injections (the agent must be given parenterally); however, in patients with extensive TB, streptomycin may accelerate initial bactericidal activity.3,4
Factors that might influence the initial choice of drugs are shown in Table 2. In patients with AIDS and TB, an important concern is to ensure adequate absorption of the anti-TB medications. Such patients may not achieve adequate serum concentrations of drug due to AIDS-associated enteropathy. Attainment of adequate drug levels may be confirmed by direct measurement of serum drug concentrations. If this is not feasible, then very close monitoring of responses to treatment and use of high-range drug dosing may be appropriate.
|Certain groups within the infected population are at greater risk than others, and should receive high priority for preventive therapy. In the United States, persons with any of the following six risk factors should be considered candidates for preventive therapy, regardless of age, if they have not previously been treated.
|In addition, in the absence of any of the above risk factors, persons younger than 35 years of age in the following high-incidence groups are appropriate candidates for preventive therapy if their reaction to a tuberculin skin test is >10 mm:
|In addition to these groups, public health officials should be alert for other high-risk populations in their communities. For example, through a review of cases reported in the community over several years, health officials may use geographic or sociodemographic factors to identify groups that should be targeted for intervention. Screening and preventive therapy programs should be initiated and promoted within these populations based on an analysis of cases and infection in the community. To the extent possible, members of high-risk groups and their health care providers should be involved in the design, implementation, and evaluation of these programs. Staff and facilities in which an individual with disease would pose a risk to large numbers of susceptible persons (eg, correctional institutions, nursing homes, mental institutions, other health care facilities, schools, and child-care facilities) may also be considered for preventive therapy if their tuberculin reaction is >10 mm induration.|
|Table 2. Candidates for initial preventive therapy because of high tuberculosis risk.5|
Currently, the Advisory Council for the Elimination of Tuberculosis of the CDC advocates initial four-drug therapy for cases in communities with a background prevalence of initial drug resistance of 4% or more. If susceptibility has been demonstrated or if resistance is deemed very unlikely, initial three-drug regimens may be used.
Certain groups within the infected population are at greater risk than others and should receive high priority for preventive therapy. In the United States, individuals with any of the following six risk factors should be considered candidates for preventive therapy, regardless of age, if they have not previously been treated.
The first group consists of individuals with HIV infection and individuals with risk factors for HIV infection whose infection status is unknown, but who are suspected of having HIV infection.
Close contacts of individuals with newly diagnosed infectious tuberculosis constitute the second group. In addition, TST-negative children and adolescents who have been close contacts of infectious individuals within the previous 3 months are candidates for preventive therapy until a repeat TST is done 12 weeks after contact with the infectious source.
The third group is formed of recent converters, as indicated by TST (>10 mm increase within a 2-year period for those less than 35 years old; >15 mm increase for those 35 or more years old). Individuals with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis are the fourth group.
The fifth group is composed of intravenous drug users known to be HIV-seronegative. Individuals with medical conditions that have been reported to increase the risk of tuberculosis make up the sixth group. In addition, in the absence of any of the above risk factors, individuals younger than 35 years of age in three high-incidence groups are appropriate candidates for preventive therapy if their TST-site reactions measure >10 mm:
individuals born in high-prevalence countries;
medically underserved, low-income populations, including high-risk racial or ethnic minority populations (particularly African Americans, people of Hispanic heritage, and Native Americans); and
residents of facilities for long-term care (correctional institutions, nursing homes, and mental institutions).
In addition, public health officials should be alert for other high-risk populations in their communities. For example, through a review of cases reported in the community over several years, health officials may use geographic or sociodemographic factors to identify groups that should be targeted for intervention. Screening and preventive therapy programs should be initiated and promoted within these populations based on an analysis of cases and infection in the community. To the extent possible, members of high-risk groups and their health-care providers should be involved in the design, implementation, and evaluation of these programs. Staff in facilities in which an individual with disease would pose a risk to large numbers of susceptible individuals (correctional institutions, nursing homes, mental institutions, other health care facilities, schools, and child-care facilities) may also be considered for preventive therapy if their TST-reaction indurations are >10 mm.
Because of problems with compliance, hepatotoxicity, and increasing resistance associated with 6- to 12-month isoniazid programs, alternative short-course TB preventive regimens have been evaluated. Recently, a CDC study group6 reported results of an international, randomized, 7-year trial that compared the effectiveness of two regimens in preventing TB in individuals with HIV infection. The two regimens were a 2-month regimen of daily rifampin plus pyrazinamide and a 12-month regimen of daily isoniazid.
The studys enrolled subjects were 1,583 HIV-positive individuals 13 or more years old. All subjects had a positive TST. Subjects were randomized to one of two study arms: isoniazid at 300 mg per day with pyridoxine hydrochloride for 12 months or rifampin at 600 mg per day plus pyrazinamide at 20 mg/kg per day for 2 months.
Of patients assigned to rifampin plus pyrazinamide, 80% completed the regimen, compared with 69% assigned to isoniazid (P<.001). After a mean follow-up period of 37 months, 19 patients (2.4%) assigned to rifampin plus pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed TB at rates of 0.8 and 1.1 per 100 person-years, respectively. In multivariate analysis, there were no significant differences in rates for confirmed or probable TB (P=.83), HIV progression and/or death (P=.09), or overall adverse events (P=.27), although drug discontinuation was slightly more prevalent in the group receiving rifampin plus pyrazinamide (P=.01). Neither regimen appeared to lead to the development of drug-resistant TB. The investigators concluded that a 2-month regimen of rifampin plus pyrazinamide and a 12-month regimen of isoniazid were similar in safety and efficacy, and suggested that the shorten regimen might offer practical advantages to both patients and TB-control programs.
TB is a serious, highly communicable disease that poses special health concerns for individuals with an immunocompromised status. Although prevalence rates for TB have been in decline since 1992, there is still concern regarding the potential for serious pulmonary and extrathoracic disease. Multidrug treatment regimens have been developed with the intention of achieving bacillary eradication and preventing drug resistance. Recent evidence suggests that, in immunocompromised patients, shorter-term regimens are as effective as longer-term regimens and may offer practical advantages. DOT is becoming more common in order to ensure compliance with therapy.
John D. Zoidis, MD, is a contributing writer for RT Magazine.
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6. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons. An international randomized trial. JAMA. 2000;283:1445-1450.