Tuberculosis in the 1990s*

Transcription

1 Tuberculosis in the 1990s* Epidemiology and Therapeutic Challenge John A. Sbarbaro, MD, MPH, FCCP I (CHEST 1995; 108:58S-62S) n 1984, with the number of tuberculosis cases in the United States at an all time low, the Director of the Centers for Disease Control and Prevention (CDC) challenged the nation's health community to eliminate tuberculosis from within the borders of the United States. 1 One year later, after 30 years of a progressive decline of 5% per year, the United States began to experience a remarkable and unexpected increase in the number and seriousness of active cases of tuberculosis. Of epidemiologic significance, many of the cases were clearly occurring among newly infected individuals rather than arising, as in earlier decades, from the larger pool of previously infected individuals-ie, reactivation of dormant infection. As confirmation that transmission of new infection was occurring within the community, the case rate of tuberculosis among children younger than 4 years rose from 3.7/100,000 in 1988 to a rate of 5.5/100,000 in 1992-a 33% increase in just 4 years. 2 Of much more serious concern was the finding in 1991 that 3.1% of the new active cases of tuberculosis cases were multidrug resistant; ie, resistant to both isoniazid and rifampin. More than 14% of the cases were caused by bacilli resistant to at least one antituberculous drug. 2 During the earlier decade years of 1982 through 1986, only 0.5% of the new active cases were multidrug resistant. Multidrug resistance raises the deadly specter of tuberculosis in the years prior to the discovery of chemotherapy when more than 50% of patients with active tuberculosis died within 5 years of the onset of their disease. What went wrong? What are the epidemiologic implications? And how does this unexpected event impact on our concepts of treatment? EPIDEMIOLOGY There is no question that the emergence of AIDS with its suppressive impact on the human immune system played a major role in this sudden resurgence of a disease that was diminishing in the United States. Additionally, 25% of the new cases in the past 5 years came from refugees and new immigrants migrating to the United States from countries still experiencing high rates of tuberculosis. 2 Indeed it would be most com- *From the University of Colorado Health Science Center, Denver. 58S forting to attribute the entire tuberculosis problem to AIDS and the foreign-hom but to do so would be a tragic mistake. Four other significant factors contributed to this unprecedented rise in the US rate of tuberculosis: a failure of political leadership, a failure of public health leadership, a failure of physician leadership, and as a result, a failure of administration of an adequate and appropriate course of treatment to many patients. Failure of Political and Public Health Leadership With the advent of chemotherapy in 1952, the care of patients with tuberculosis began to shift away from sanitoriums and specialized physicians to general hospitals and private physicians. As this transfer of patient care grew in magnitude, tuberculosis experts recognized that to be successful, definite requirements would have to be made. 3 First, there had to be a strong commitment of official public health agencies to continue to fulfill their responsibility to maintain tuberculosis control programs, to establish adequate outpatient facilities through which to assure that all patients completed their treatment, and to ensure that appropriate isolation and containment practices were continued. Second, there had to be a commitment by publicly elected officials to sustain the funding for these programs even as the public became less fearful of this diminishing disease. Neither requirement was met. Despite the existence of communicable disease laws in all 50 states, elected officials at the state and municipal levels progressively reduced their support for tuberculosis control. Instead of committing state and local tax dollars, they relied on temporary federal funds that had been designed to assist the states in transition from locally controlled sanatorium taxing districts to general tax support. As these federal funds diminished, they were not replaced and tuberculosis control efforts languished and in many areas essentially disappeared. 2 Even during the past 5 years with tuberculosis on the increase, 4% of the country's major metropolitan health departments reduced funding of their own tuberculosis control programs by 50%; 23% reduced their programs by 26 to 50% over the past 8 years with an additional 30% reducing their control programs by 11 to 25% during that same period. 4 Even the CDC was not immune from this process. In 1961, the CDC had begun to conduct periodic na-

2 tional surveys of primary drug resistance but discontinued the practice in 1986, partly due to the evidence of stable or declining proportions of patients with drug resistance but also due to competing priorities for CDC resources. 2 A snapshot of the situation in New York City perhaps best depicts the condition to which tuberculosis control programs had declined. In 1992, 4 years after rising tuberculosis rates had been widely publicized in the New York newspapers, a survey of 20 hospitals in New York City revealed that only 50% of hospitalized patients with tuberculosis were in rooms with negative pressure and 33% were in rooms with no environmental controls. Only 50% of these hospitals were able to provide acid-fast bacteria smear results in less than 34 h. 5 Interestingly, this had been predicted two decades previously by Aaron Chaves, Medical officer of Health for the New York City Department of Health in In describing the situation in New York in 1970, he stated "... most patients who now receive the major part of their treatment on an outpatient basis, are on a self-administered drug regimen." He added that: ". :. a sizable proportion of tuberculosis patients being treated in the city's chest clinics are not taking their drugs regularly" and predicted"... the development of a reservoir ofpersistently infectious patients who harbor strains of tubercle bacilli which could be resistant to the commonly used drugs." Nationwide, 27% of US hospitals still had no rooms within which patients with tuberculosis could be safely isolated. 6 Failure of Physician Leadership Physicians were even less prepared to care for patients with tuberculosis. A 1988 report by Koponoff et af revealed that of 129 compliant recurrent tuberculosis cases supervised by health departments, only 53% had had an adequate regimen prescribed; of 54 patients supervised by hospitals, only 33% received an adequate regimen; and that of 34 patients receiving their care from a private physician, only 29% had been prescribed an adequate treatment regimen! Mahmoudi and Iseman 8 reviewed the records of patients with pulmonary tuberculosis admitted to the National Jewish Center from 1989 to 1990 and compared CDC/ ATS/ ACCP recommended standards of practice with the care the patients had actually received. They found an average of 3.93 physician treatment decision errors per patient. 8 In the United States, many tuberculosis cases are still first diagnosed at autopsy and up to 50% of these patients had been hospitalized for 2 or more weeks before their death! 9 It appears clear that the decline of tuberculosis control leadership at the state and local government level was followed by a cascade of adverse events-a decline in professional interest, followed by a decline in professional expertise, followed by a decline in professional training, resulting in a further decline of professional interest, expertise, and leadership. Similarly, the absence of research funding has led to a loss of academic interest in tuberculosis throughout our nation's medical schools adding further to the decline of our nation's ability to respond with new diagnostic and treatment techniques. THE THERAPEUTIC CHALLENGE Forty-five years of chemotherapeutic experience has given us the knowledge and the tools to effectively treat and prevent tuberculosis. We know, for example, that the bacillus Mycobacterium tuberculosis is an obligate aerobe that multiplies slowly (every 20 to 30 h) and generates, at a predictable rate, mutants resistant to each drug and combination of drugs. Therefore, large populations of bacilli, such as occur with active disease, contain many of these mutants. Treatment with a single drug will kill bacilli susceptible to that drug, leaving unchecked the resistant organisms to flourish and continue the active disease process. However, we have also learned that treatment with three drugs to which the organism is susceptible can eliminate these mutants and successfully cure the disease process. We know that if the drugs are effective, most of the actively growing bacilli will be eliminated during the first 1 to 2 months of treatment (the "initial phase" of the treatment regimen) and that once this large bacterial population is reduced, two effective drugs can control the remaining bacteria (the "continuation phase" of the treatment regimen). Theoretically, the "initial phase" of treatment is directed at a large extracellular bacillary population growing in a relatively unchecked manner and harboring the potential for the existence of many drug-resistant mutants. The "continuation" phase of treatment is directed at a smaller bacillary population contained within macrophages. Once these macrophages are "activated" by the patient's immune response system, they have the ability to contain bacillary growth, theoretically limiting tuberculosis bacilli to intermittent spurts of metabolism. If these metabolic growth spurts occur while an effective drug is present, the bacillus is destroyed. Preventive therapy is, in essence, the "continuation phase" of treatment without the need for an "initial phase" of multiple medications. Similar to other antibiotics, antituberculous medications impact directly on the metabolic functions of the bacillus-for example, rifampin is effective because of its inhibition of DNA-dependent RNA polymerase.l0 The effectiveness of antituberculous medications can be predicted from published minimum inhibitory concentration (MIC) and pharmacokinetic data. The greater the ratio of the maximum serum level over the MIC, the greater the area under the serum CHEST I 1 08 I 2 I AUGUST, 1995 I Supplement 59S

3 Table!-Drug-Sensitive Active T u b e r c ~ l o s i s * Month of Success Rate, Regimen Line Drugs % 6 Two first-line drugs plus 98 2 mo ofpza 6 Two first-line drugs plus mo of a second-line drug 6 Two first-line drugs 90 9 Two first -line drugs plus 98 2 mo of a second-line drug 12 One first-line drug plus a second-line drug 18 One first-line drug plus a second-line drug *Note: when used as a component of the "initial phase" of therapy, ethambutol should be used in the bactericidal dosage of 25 mglkg. After 2 months or less of treatment, the dosage should be reduced to 15 mglkg to avoid optic toxic reactions. concentration curve; and the greater the time serum concentration remains above the MIC, the more potent the drug.l Clinical studies support this pharmacologic model. The antituberculous medications can be ranked as follows: first line-rifampin and isoniazid; and second line-streptomycin, ethambutol, and probably the fluoroquinolones; third line-kanamycin, amikacin, capreomycin, ethionamide, cycloserine, clofazemine, and para-aminosalicylic acid. Pyrazinamide (PZA) is a unique antituberculous drug. It must be converted into pyrazinoic acid to have significant antituberculous action. It has been long believed that because of this property, PZA is effective against intracellular bacilli presumably dwelling in the acid media of the macrophage. However, neither clinical trials nor studies in the human macrophage support this hypothesis. 11 In clinical trials conducted by the British Medical Research Council, PZA contributed significantly to the "initial phase" of treatment but offered no benefit when combined with rifampin in the continuation phase of treatment. It is far more likely that PZA's major action is against extracellular bacilli dwelling in the outer layers of acidified caseous material. However, it should be noted that PZA has enhanced the "continuation phase" effectiveness of isoniazid and streptomycin (when rifampin was not present in the regimen) and therefore should be considered for such retreatment regimens. 12 A summary of treatment regimens is shown in Table 1. Theoretically, with the availability of this wide array of regimen options, there should be no barrier to effective treatment. Unfortunately, three confounding factors have made the treatment and control of tuberculosis a true therapeutic challenge. (1) On the average, 35% of patients do not adhere/ comply with their treatment regimen. 13 (2) Physicians are unable to predict or determine which patients are not adherent/compliant with their therapeutic regimen. ( 3) Drug resistance is now present and increasing in the United States. Whenever there is the possibility of drug resistance, clinicians are now advised to initiate treatment with four drugs-rifampin, isoniazid, PZA, and streptomycin or ethambutol.l 4.l 5 If through clinical history the physician can identify potential specific drug resistance, the regimen can be tailored with additional drugs added or the original regimen restarted while awaiting sensitivity results. Far rrwre challenging is the responsibility to ensure a full course of treatment. Because both the patient and society as a whole are affected by the degree to which antituberculous therapy succeeds, a physician treating a patient with tuberculosis must be certain that adequate treatment is being taken by the patient. Unfortunately, the many years of decline in the incidence of tuberculosis has resulted in most physicians being poorly trained in the diagnosis and care of patients with tuberculosis. Supported by grant funds from the Division of Tuberculosis Elimination of the CDC, four model tuberculosis centers along with many professional organizations are now focusing on physician education. However, while many physicians will be involved in considering tuberculosis among the diagnostic possibilities afflicting their patients, only a relatively few physicians will actually become involved in the treatment of a clinically diseased patient. Therefore, it is to the benefit of all involved to support only those regimens that minimize the potential for either patient or physician error-such as programs of directly administered treatment that involve cooperation between the physician and a health department. Fortunately, because of its slow metabolic growth rate, M tuberculosis is ideally suited for either low dosages of medications given once daily or higher dosages of the same medications administered intermittently only twice a week. Intermittent regimens involving as few as 62 doses directly administered over a 6-month period have cure rates equal to the best of daily treatment regimens. 16 Because directly administered regimens involve the presence of another individual, they deny the patient an opportunity to selectively take medications, thereby minimizing the risk of developing resistant disease. Should the patient prematurely discontinue treatment, the physician can immediately be made aware of the situation. Of equal importance, if relapse subsequently occurs, the organisms will most likely be susceptible to the same medications. A directly administered regimen is unquestionably the therapy of choice and should 60S

4 become the standard of care for every patient with clinically active tuberculosis. Ensuring that every patient is placed on a directly administered regimen is the true therapeutic challenge facing the United StatesP Another benefit of direct administration programs is prevention of drug resistance. Particularly important is the protection of rifampin (or any of the other rifamycins that might be used). Without rifampin, 6-monthduration short -course chemotherapy is very difficult to achieve and in resource-poor developing countries the control of tuberculosis becomes almost impossible. The best manner to protect drugs is by the use of directly observed chemotherapy and by the use of reputably manufactured fixed combination tablets. When the direct administration of medication is not possible, the preferable choice is a combination tablet containing at first three and subsequently two antituberculous medications. This approach again prevents patients from omitting one or more essential medications at the risk of developing resistance to the drug that is actually taken 18 and, in addition, reduces the opportunity for physician error. ELIMINATION OF TUBERCULOSIS OR OF TUBERCULOSIS CoNTROL Fortunately because of the high level social and economic living conditions throughout the United States, 25,000 cases of tuberculosis do not represent a significant threat to the overall population of the United States. From 1985 through 1992, although there was a 75% increase in reported tuberculosis cases among Hispanics, a 46% increase among Asian/Pacific Islanders, and a 27% increase among US born African Americans, the number of counties reporting no tuberculosis cases continued to increase, indicating that tuberculosis is becoming increasingly focal in its geographic distribution within the United States.' 9 Unquestionably, tuberculosis has become a definitive threat to other specific populations such as hospital workers and corrections personnel where unique institutional/environmental circumstances exist. But these populations can be protected with effective environmental controls. Mter analyzing the recent miniepidemics in such institutions, the Office of Technology Assessment concluded that, "Delayed or inadequate infection control measures, premature discontinuation of patient isolation, delayed reporting of drug resistance and lack of isolation facilities were major factors in the spread of MDR-TB in these institutions."2 The infectious threat of multidrug-resistant tuberculosis will extend to the general public only if we do not contain it now. Following the publicity and public concern over the reemergence of tuberculosis, the federal government markedly increased funding for tuberculosis surveillance and containment. As a result, the numbers of tuberculosis cases should again begin to fall. However as noted by Reichman, 20 the success of a public program often leads to a diminishment in public support and attention to that program. The result is a resurgence of the original problem recreating public concern and public funding-followed again by success and renewed program abandonment. Hopefully we can avoid this "U -shaped curve of concern" and maintain a sloping curve of achievement. Tuberculosis control is indeed an "exercise in vigilance." 2 CONCLUSIONS The incidence of tuberculosis is again on the rise, a problem exacerbated by both the immunosuppressive effect of AIDS and the influx of immigrants/refugees from countries with a high prevalence of tuberculosis. However, as demonstrated by the emergence of miniepidemics of multidrug-resistant tuberculosis, the real underlying causes are a failure of physician and political leadership resulting in inadequate treatment of patients. Four drug regimens are now required where there is a probability of drug resistance. The weaker the initial phase of the treatment regimen, the longer treatment must be continued. Direct administration of all medication or the use of combination tablets is essential. REFERENCES 1 US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention. A strategic plan for the elimination of tuberculosis in the United States. MMWR 1989; 38(S-3): US Congress, Office of Technology Assessment. The continuing challenge of tuberculosis. OTA-H-574. Washington, DC: US Government Printing Office, September Reagan WP. Treatment of tuberculosis in the general hospital. ATS Clin Notes Respir Dis 1973; 11: Leff DR, Leff AR. Tuberculosis control policies in major metropolitan health departments: V. Standards of practice Am Rev Respir Dis 1993; 148: Department of Health State of New York!IPRO Survey, Rudnick JR, KrocK, Mamagan L, et al. Are US hospitals prepared to control nosocomial transmission of tuberculosis [abstract]? Program and abstracts of the Epidemic Intelligence Service 42nd Annual Conference, Atlanta. 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