Current medical treatment for tuberculosis

Sources and selection criteria

We performed a Medline search of the past 10 years using the key words “tuberculosis and treatment or drug therapy” to find pertinent literature. We also searched bibliographies from review articles on the treatment of tuberculosis for relevant references.

Principles of chemotherapy and rationale for multidrug regimen

Treatment using more than one drug is based on two principles: preventing acquired drug resistance and enhancing efficacy. Tubercle bacilli undergo random chromosomal mutations that have made them resistant to every drug used to treat tuberculosis. Fortunately, these mutations are infrequent.5 Because they are unlinked (in terms of chromosomal location or function) and specific to a drug or drug class, spontaneous generation of an organism with multiresistance is extremely improbable. Acquired drug resistance for tuberculosis is almost always caused by inadequate treatment. This can include failure of the patient to take the prescribed drugs, failure of the physician to prescribe appropriately, failure of the healthcare system to ensure that drugs are available, or—rarely—malabsorption of the drug(s) due to dysfunction of the digestive system or substandard bioavailability of the preparation.

Treatment that uses a combination of drugs (table 1) has been shown to accelerate the response of the disease to treatment and to shorten the length of treatment required to cure.6 Rifampicin and isoniazid are the main drugs used today, rifampicin being the more important agent in terms of reducing the duration of treatment and assuring favourable outcomes.6 Nine month regimens using rifampicin and isoniazid, together with an introductory phase of streptomycin or ethambutol, or both, have been predicted to cure 95% or more patients.7 Studies from the UK's Medical Research Council showed that, if pyrazinamide is included in the treatment for the first two months, the length of treatment could be reduced to six months and still retain cure rates of 95% or more.8

A regimen of rifampicin, isoniazid, and pyrazinamide given to patients who have strains of the bacilli resistant to isoniazid—the most common type of resistance—is thought to result in treatment failure and acquired resistance to rifampicin. Therefore, the American Thoracic Society and US Centers for Disease Control and Prevention recommended in 1994 that a fourth drug, ethambutol, should initially be included in the treatment for patients in whom the bacilli might be susceptible to resistance.9 Such individuals may be immigrants from regions known to have a high prevalence of resistance, people from urban areas, or individuals with a medical history that might predispose them to resistance; arbitrarily, the fourth drug was to be included in areas in which the level of resistance was known to be 4% or more. In 1998, the British Thoracic Society embraced regimens that use four drugs for the initial phase of treatment as standard practice.

It is recommended that all patients with tuberculosis undergo a test for HIV. Supplements of pyridoxine (vitamin B6)—not to exceed a daily dose of 50 mg—are suggested for patients taking isoniazid to prevent peripheral neuritis. Particular attention should be given to patients at risk of neuropathy, including patients who are malnourished or pregnant. Baseline liver function tests and periodic and regular monitoring are advocated in view of the potential hepatotoxicity of isoniazid, rifampicin, and pyrazinamide. The risk of major liver damage is less than 1%, but mild asymptomatic increases in transaminase blood concentrations are seen in up to 20% of patients. Doses of ethambutol should be carefully adjusted in patients with renal impairment. In addition, patients taking ethambutol should have their visual acuity checked initially and monitored monthly (Snellen acuity and Ishihara colour). They should be instructed to report promptly any perceived disturbances in their vision.

Hospital admission is not routinely indicated for patients with tuberculosis unless the clinical illness merits such care, extenuating psychosocial circumstances exist, or patients have prognostic factors associated with poor short term outcome (respiratory failure or death) such as lymphopenia, advanced age, or alcoholism.10 To prevent nosocomial transmission, patients with tuberculosis (and suspected cases) should be placed in rooms of negative pressure and frequent air changes and, ideally, the means to filter out or lethally irradiate the tubercle bacilli with ultraviolet γ radiation.

The first line agents and their common drug toxicities are listed in table 2. A low and unavoidable risk of relapse is present after treatment. For the regimens described in table 1, the probability of relapse is less than 5%.11 Most recurrences occur within six months and the disease usually has the same drug susceptibility profile as before treatment.11 Current guidelines do not state the need for surveillance after treatment, especially when drugs have been given under supervision. Rather, patients should be instructed to return to their clinic or physician after treatment when their clinical status changes; in these instances,suitable tests, including examination of sputum samples and chest radiographs, should be carried out.

Non-adherence to treatment and directly observed therapy (DOT)

Some patients with tuberculosis, as in virtually all chronic disorders, will fail to take their drugs.12 Unique public health philosophies and practices have evolved, however, which have helped to tackle this problem. For example, the public in industrialised nations has come to expect the air to be free of tuberculosis, in the same way that the water is free of such potentially lethal pathogens as typhoid and cholera. This has led to mandated treatment, quarantine, or even short term incarceration of patients in the United States or other countries.13

DOT programmes use a nurse or surrogate to deliver and observe patients taking all the doses of their drugs, rather than relying on patients to take them on their own. To facilitate DOT, intermittent (less frequently than daily) regimens have been used. Two popular intermittent regimens are represented in table 1; these six month regimens have been shown to be comparable in efficacy to daily treatment of equal length. The patients may either come to a health facility (clinic based DOT)14 (fig 1) or be seen elsewhere—for example, at home, work, or shelter (community based DOT).15 Preparations using drug combinations—for example, isoniazid and rifampicin (Rifamate; Hoechst Marion Roussel) and isoniazid, rifampicin, and pyrazinamide (Rifater; Hoechst Marion Roussel)—are also available, and may improve adherence. Whether such drug combinations prove to be more beneficial, given their increased cost and the reduced ability to discriminate which drug is responsible for toxicity or intolerance, has yet to be shown.

Fig 1

Directly observed therapy in Rangoon, Burma. The two Buddhist nuns are receiving antituberculosis drugs at a public health facility that is also a poultry market

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DOT is highly effective at promoting successful treatment. A comparison of self treatment versus various forms of DOT has shown that completion of treatment is significantly higher when the treatment is supervised (fig 2).16 Some observers have argued that DOT is an infringement of individual liberty,17 but well designed DOT programmes can be regarded as enhancing the health service and as a manifestation of community care.15 Successful DOT programmes provide a variety of incentives and enablers (practices that facilitate the treatment programme) to make them “consumer friendly.” Incentives may include rewards for making oneself available for treatment—for example, provision of social services, food stamps, assistance with housing or, in some cases, cash payments for the inconvenience. Some enablers facilitate treatment by being open during convenient hours, being in accessible locations, and providing help with transport, child care in clinics, or comprehensive services at a single site—for example, radiology, blood drawing, and sputum induction services.

Fig 2

Rate of completion of treatment for various directly observed therapy (DOT) regimens versus non-supervised therapy.¹⁶ Enhanced DOT standard=DOT plus incentives and enablers; modified DOT= supervision for only part of the treatment, typically during initial hospitalisation, followed by self supervision; non-supervised therapy= self administered therapy. Figure adapted from Chaulk and Kazandjian16

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Concern exists that governments cannot afford to provide DOT, but recent analyses show that, by assuring prompt cure, preventing relapses, and lessening acquired drug resistance, DOT programmes result in net savings to the community. 18 19 The impact of DOT programmes may be seen in the reduction in the number of cases of tuberculosis in the 1990s in the United States, together with an increase in the proportion of patients receiving DOT in 1990 from 4% to over 70% by 2000.20 From 1995 to 2000, the rate of tuberculosis in the United States fell by an average of 7.8% per year. Although the broad implementation of DOT was not the only intervention during this period (improved measures to limit nosocomial transmission were also introduced), we believe it was the major factor driving these improved rates.

Treatment of different groups

Future directions

The immediate challenges for the control of tuberculosis include developing curative regimens that are shorter or that require patients to take drugs less frequently. Ideally, future regimens would have both features—that is, a once weekly regimen requiring that patients be treated for only four months. Such regimens would greatly facilitate monitoring compliance.36 The more compelling long term issue is the development of an improved vaccine that would have an epidemiological impact. BCG does reduce morbidity and mortality in infants but has little effect on adult pulmonary disease, which is the primary cause of death and virtually the only source of transmission. Unfortunately, because the reservoir of currently infected people is so huge, the benefits of an improved vaccine would not have substantive impact for decades. Finally, it is crucial that new, affordable and non-toxic drugs be developed to replace those lost to drug resistance.