Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Tuberculosis John H. McClement To cite this article: John H. McClement (1975) Tuberculosis, Postgraduate Medicine, 58:3, 97-101, DOI: 10.1080/00325481.1975.11714143 To link to this article: http://dx.doi.org/10.1080/00325481.1975.11714143

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co sder • What is the most important element in treatment and prophylaxis of tuberculosis? • What are the principal drugs used for treating active tuberculosis? • What is the routine for observing patients taking isoniazid?

JOHN H. McCLEMENT, MD

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New York University School of Medicine New York

Tuberculosis CHEMOPROPHYLAXIS AND TREATMENT Dr. McCiement presents a concise review of the current drug therapy of both pulmonary and extrapulmonary manifestations of tuberculosis. The availability of new agents, such as rifampin, has significantly changed the outlook for the patient with tuberculosis. An excellent table lists 11 antituberculosis drugs with their usual dosage, toxicity, and means of patient follow-up to anticipate possible development of toxicity.-HCN

Tuberculosis, once a highly lethal disease, can now be prevented in most individuals who have been infected but do not have overt disease and can be cured in nearly ali patients who have active disease in any organ. The treatment of tuberculosis may be subdivided info chemoprophylaxis (ie, the preventive treatment of individuals who are infected but do not have identifiable active disease) and treatment of those who have active, clinically apparent disease. An estimated 7% of the US population have been infected with the tubercle bacillus as indicated by skin reactivity to tuberculin, thus producing a group of more than 14 million people who might be considered for chemoprophylaxis. In recent years in the United States, more than 20,000 new cases of active tuberculosis have been reported annually to health authorities and have required treatment. Careful diagnostic studies must always precede

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treatment. If chemoprophylaxis is to be instituted on the basis of significant tuberculin skin reactivity, it is important that the skin test be accurately administered, recorded, and interpreted. Tuberculin reactivity should be judged to be significant only if induration of 10 mm or more is present 48 to 72 hours after intradermal administration of 5 tuberculin units of purified protein derivative. In patients with active disease, sputum or other secretions must be cultured for tubercle bacilli before therapy is started, not only to determine the drug susceptibility of the organism but also to document that infection is caused by Mycobacterium tuberculosis, rather than sorne other mycobacterial species. Antituberculosis Drugs

At !east 11 antituberculosis drugs are available (table 1). Sorne are highly effective, relatively nontoxic, and widely used in the initial treatment of tuberculosis caused by drug-susceptible organisms. Others are Jess effective, have troublesome toxicity, and are used only infrequently and for treatment of disease caused by organisms resistant to the more commonly used drugs. Isoniazid (INH) is the only drug used for chemoprophylaxis. Isoniazid, rifampin, streptomycin, and ethambutol are the principal drugs used in the initial treatment of tuberculosis caused by drug-susceptible tubercle bacilli. Para-aminosalicylic acid (PAS) was once widely used in initial treatment regimens but has now largely

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TABLE 1. COMPARATIVE FEATURES OF AVAILABLE ANTITUBERCULOSIS DRUGS

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Drug

Dose (adult)

Toxicity

Surveillance

Remartts

lsoniazid (INH)

300-400 mg once daily orally

Hepatic Neurologie (rare with 400-mg dose) Hypersensitivity (fever, skin rash)

Pretherapy evaluation of liver function; monthly inquiry for symptoms of hepatitis, with liver function tests if present

Highly effective, inexpensive, nontoxic, most widely used

Rifampin

600 mg once daily orally

Hepatic Hematologie (agranulocytopenia, thrombocytopenia) Hypersensitivity (flu-like syndrome, shock)

Pretherapy evaluation of liver function; monthly inquiry for symptoms of hepatitis, with liver function tests if present

Highly effective, nontoxic, expensive

Streptomycin

1.0 gm once daily lM, 0.75 gm if under 125 lb

Vestibular Auditory Renal (rare unless preexisting renal disease) Hypersensitivity (fever, rash)

Pretherapy and monthly audiograms

Moderately effective; poor patient acceptance because of daily injections

Ethambutol

25 mg/ kg/ day first 60 days, 15 mg/ kg/ day thereafter

Retrobulbar neuritis

Pretherapy ophthalmologic Limited effectiveness; evaluation; monthly good companion drug in evaluation of visual acuity combined therapy and red-green color discrimination; ophthalmologic reevaluation if change is noted

Para-aminosal icyl ic acid (PAS)

12-14 gm/day in 3-4 divided doses orally

Gastrointestinal (common and troublesome) Hypersensitivity (fever, rash, jaundice)

Pyrazinamide

1.5-3.0 gm/day in 3 divided doses

Hepatic (common and severe)

Liver function tests every two weeks

Highly effective; serious hepatic toxicity requires careful surveillance

Ethionamide

0.5-1.0 gm/day in 3 divided doses

Gastrointestinal (common and troublesome) Hepatic

Liver function tests monthly

Moderately effective; poor patient acceptance because of gastrointestinal symptoms

Viomycin

1.0 gm once daily lM

Vestibular Auditory Renal

Monthly audiograms; monthly blood urea nitrogen and creatinine

Similar to streptomycin but less effective and more toxic

Kanamycin

1.0 gm once daily lM

Vestibular Auditory Renal

Monthly audiograms; monthly blood urea nitrogen and creatinine

Similar to streptomycin but less effective and more toxic

Capreomycin

1.0 gm once daily lM

Vestibular Auditory Renal

Monthly audiograms; monthly blood urea nitrogen and creatinine

Similar to streptomycin but less effective and more toxic

Cycloserine

0.5-1.0 gm daily in 2-4 divided doses

Central nervous system (convulsions, psychosis)

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Limited effectiveness; very poor patient acceptance because of gastrointestinal symptoms

Limited effectiveness; toxicity makes it a seldom-used drug

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been replaced by ethambutol. PAS, pyrazinamide, ethionamide, viomycin, kanamycin, capreomycin, and cycloserine are only used for re-treatment of patients with drug-resistant bacteria. Ali of these drugs have unique toxicity characteristics, and sorne require specifie surveillance routines. Knowledge of these characteristics and routines is essential to proper use of these drugs. Chemoprophylaxis Numerous epidemiologie studies have shown that most new active cases of tuberculosis come from individuals already infected as indicated by reactivity to tuberculin, rather than from the large majority of the population who do not react to tuberculin. Other studies indicate that chemoprophylaxis can prevent most of these progressions from clinically inapparent disease to clinically active disease. However, because the risk of development of active disease varies greatly among infected individuals and because the risk from therapy also varies, it is important to identify those infected persons who can be treated with the greatest benefit and the !east risk. Among reactors to tuberculin, the following groups are at special risk of development of tuberculosis and should be offered preventive treatment: (1) patients in whom a diagnosis of tuberculosis was made in the past, who never received adequate chemotherapy, and who now have clinically inactive disease, (2) individuals with abnormal chest x-ray findings compatible with previous inflammatory disease, (3) those with recent (within five years) documented conversion of the tuberculin skin reaction from negative to positive, (4) those with diseases known to predispose to tuberculosis, eg, diabetes mellitus, silicosis, and diseases requiring corticosteroid administration, ( 5) household contacts of persons with recently diagnosed active disease, and (6) children and young adults. Because the risk of development of tuberculosis decreases as the time of primary infection becomes more remote and because it has recently been shown that risk of troublesome liver toxicity to isoniazid increases with age, it has been suggested that chemoprophylaxis should not be given to tuberculin reactors over 35 years old for whom the duration of reaction is unknown unless another risk factor is identified. Chemoprophylaxis should consist of oral administration of 300 mg of isoniazid once daily for 12 months. In those patients who have apparently inactive tuberculosis and who were never treated with adequate chemotherapy, it may be prudent to institute treatment for active tuberculosis (as described later) until it is firmly established by appropriate cultures that their disease is inactive.

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Because hepatic toxicity does occur in sorne patients, a routine for surveillance is required. Elevation of serum transaminase levels is common in the first few weeks of isoniazid administration. lt is usually transient, is not accompanied by other clinical or laboratory evidence of liver disease, and disappears even though the drug is continued. More serious hepatic toxicity has a low incidence ( 1% to 2%) and is manifested by hyperbilirubinemia, marked elevation of serum transaminase levels, and clinical evidence of hepatic disease. Death is uncommon but has been reported. Severe hepatic toxicity is more common in older patients and in heavy consumers of alcohol. The liver status of patients who are to receive isoniazid should be evaluated clinically and by liver function tests before starting treatment. During isoniazid treatment, patients should be interviewed at !east once a month, and any symptoms suggestive of hepatic toxicity (eg, anorexia, nausea, or malaise) should be evaluated by liver function tests. If the only abnormality is moderate elevation of the transaminases to levels not exceeding 200 Karmen units/ml, the isoniazid may be continued with at !east weekly reevaluation. If the transaminase levels exceed 200 Karmen units/ml or if the bilirubin exceeds 2 mg/100 ml, the drug should be discontinued. If the test results return to normal quickly, a second trial of isoniazid may be justified but must be carefully monitored. If hepatic toxicity is severe or prolonged, isoniazid therapy should be abandoned and the patient should be carefully observed. If clinical evidence of tuberculosis develops, treatment with a nonisoniazid-containing regimen should be administered. Treatment of Active Tuberculosis Tuberculosis treatment requires administration of at !east two effective antituberculosis drugs when a large or actively multiplying bacterial population may be present. If a single drug is used in such cases, a resistant bacterial population is likely to apJ>ear. Triple-drug regimens for initial treatment are sometimes recommended, both because they are believed to be more effective and because primary drug resistance to one of the agents used in a double-drug regimen might be present and not recognized when treatment is started. Chemotherapy should be continued without interruption for at !east 18 months. Preliminary reports of short-course chemotherapy (6 to 12 months) are encouraging, but until data from the short-course srudies are more complete, a longterm regimen remains the preferred treatment. A variety of combinations of antituberculosis drugs have been subjected to clinical trials. These vary in effectiveness, cost, toxicity, and patient ac-

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JOHN H. McCLEMENT

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Dr. McCiement is professer of medicine, New York University School of Medicine, and director of the chest service, Bellevue Hospital, New York.

ceptance. The following are sorne of the more commonly used regimens. lsoniazid, streptomycin, ethambutol-The combination of isoniazid (300 mg/day), streptomycin (1 gm/day), and ethambutol (15 to 25 mg/kg/ day) is probably the most powerful non-rifampincontaining regimen available and is suitable for the initial treatment of advanced active tuberculosis if the use of rifampin is undesirable. After maximal bacterial suppression has been obtained (usually three to six months), as judged by disappearance of tubercle bacilli from the sputum, and after it has been demonstrated that the tubercle bacilli were initially susceptible to these drugs, the streptomycin may be discontinued and treatment continued with the simpler, more pleasant isoniazid -ethambutol regimen. lsoniazid, rifampin, ethambutol-The combinadon of isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15 to 25 mg/kg/day) is probably the most effective antituberculosis regimen presently available. lt produces earlier disappearance of tubercle bacilli from the sputum than do regimens without rifampin, and preliminary data suggest that fewer relapses occur. The inclusion of ethambutol has not been shown to add to the effectiveness, but ethambutol does provide more adequate treatment if unrecognized primary drug resistance to isoniazid or rifampin should be present. A major disadvantage of this regimen is the high cost of rifampin. When bacterial suppression has been achieved (usually three to six months) and bacterial sensitivity demonstrated, rifampin may be discontinued and prolonged therapy with isoniazid and ethambutol continued. lsoniazid and rifampin-Isoniazid (300 mg/ day) and rifampin (600 mg/day) probably comprise as effective a regimen as the preceding one if the infecting organisms are susceptible to isoniazid and rifampin. lt is a satisfactory regimen in those places where epidemiologie studies indicate that primary isoniazid resistance is uncommon, or in patients who cannot talee ethambutol. After initial treatment has achieved bacterial suppres-

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sion, the more economical isoniazid-ethambutol regimen may be substituted. lsoniazid and streptomycin-The combination of isoniazid (300 mg/day) and streptomycin (1 gm/day) is a powerful but less effective regimen than those containing rifampin. lt is useful in patients who are unable to talee rifampin or ethambutol. lsoniazid and ethambutol-Isoniazid (300 mg/ day) and ethambutol (15 to 25 mg/kg/day) comprise a commonly used, highly effective regimen, but in advanced disease it is probably not as effective as the preceding regimens in producing early conversion of sputum cultures or insuring against relapse. lt is probably satisfactory in patients with limited disease or as a continuation regimen for prolonged treatment after bacterial suppression has been achieved by one of the more powerful combinations. lsoniazid-Except for chemoprophylaxis, isoniazid (300 mg/day) should probably not be used alone. Sorne have suggested, however, that it be used for prolonged treatment, after complete, wellestablished bacterial suppression has been achieved by a combined regimen. Treatment of Tuberculosis Caused by Drug-Resistant Tubercle Bacilli

Most patients in whom tubercle bacilli have demonstrable in vitro resistance to sorne of the antituberculosis drugs have had improper, interrupted, or inadequate previous treatment that has produced a resistant bacterial population. A few patients have primary resistance to sorne of the · antituberculosis drugs. While the principles that govern treatment are similar for patients with drug-resistant and with drug-susceptible organisms, treatment of the former group is difficult and requires good laboratory support and experience with the less frequently used drugs. lt is important that at least two (and usually more) drugs be given and that these be drugs to which the tubercle bacilli are susceptible. Because the drugs for treatment of this group of patients have troublesome toxicity, they must not be combined with drugs having similar toxic manifestations, eg, ethionamide and PAS (both gastrointestinal irritants) or viomycin and streptomycin (both toxic to the eighth nerve). As for initial treatment, it is important that treatment be prolonged (at least 18 months) and uninterrupted. Extrapulmonary Tuberculosis

Tuberculosis of lymph nodes, pleura, genitourinary tract, bone, and other extrapulmonary sites requires generally the same type of chemotherapeutic program as pulmonary tuberculosis. Treatment should be prolonged and uninterrupted. After such treatment, results are excellent and

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relapse is rare. In renal tuberculosis, where nephrectomy was once commonly used it is now rarely needed; and in vertebral tuberculosis, spinal fusion can be omitted. Other Considerations Resection-Resection for tuberculous residues was once an important part of treatment; it is now almost never needed. A rare patient with drugresistant disease or a patient with troublesome continued and life-threatening hemoptysis may need resection. H ospitalization-The prolonged hospitalization and isolation of tuberculous patients, until quite recently standard practice, is now rarely needed. Most patients can receive all of their treatment as outpatients with little or no interruption of their normal activity. Brief hospitalization may be required for patients with advanced symptomatic disease and for those with other complicating illnesses. With the initiation of effective therapy, there is usually a rapid suppression of symptoms, an early and marked decrease in the number of tubercle bacilli in sputum and other secretions, and a reversai of infectiousness. Patient management-The successful treatment of tuberculosis requires the patient to take antituberculosis drugs for long periods of time and without interruption. The principal reason for failure is the patient's inability to participate in such a program. Therefore, the physician who undertakes to treat a patient with tuberculosis must be prepared to educate, convince, and supervise the patient to see that this lengthy program is completed. At the outset, sorne patients can be identified as unable to complete an unsupervised

program of prolonged medication. Such patients may require prolonged inpatient treatment or referrai to a facility that can arrange for supe.tvised outpatient treatment. Programs that employ supervised drug administration two or three times weekly after a two- to three-month period of more intensive drug therapy have been shown to be effective. Summary Treatment of tuberculosis falls into two categories: (1) chemoprophylaxis for patients infected with tubercle bacillus who do not have identifiable active disease and (2) prolonged, uninterrupted administration of a combination of antituberculosis drugs to patients with active, clinically apparent disease. Chemoprophylaxis consists of daily administration of isoniazid for 12 months. This preventive regimen is recommended for those groups of tuberculin-positive individuals at highest risk of having active disease develop. Treatment of active tuberculosis requires a combination of at least two antituberculosis drugs to minimize the likelihood of a resistant bacterial population emerging. Chemotherapy should be continued without interruption for at least 18 months. Address reprint requests to John H. McClement, MD, Chest Service, Bellevue Hospital, 462 First Ave, New York, NY 10016. For ReadySource on infection control, see page 225. Summary self-test on infection control begins on page 217.

BIBUOGRAPHY British Thoracic and Tuberculosis Association: Short course chemotherapy in pulmonary tuberculosis. Lancet 1:119, 1975 Byrd RB, Kaplan PD, Gracey DR: Treatment of pulmonary tuberculosis. Chest 66:560, 1974 Johnston RF, Wildrick KH: "State of the -art" review. Am Rev Respir Dis 109:636, 1974

Newman R, Doster BE, Murray FJ, et al: Rifampin in initial treatment of pulmonary tuberculosis. Am Rev Respir Dis 109:216, 1974 Second East African/British Medical Research Council Study: Controlled clinical trial of four short-course (6-month) regimèns of chemotherapy for treatment of pulmonary tuberculosis. Lancet 2 : 1100, 197 4

Findings in a patient that wou Id indicate that isoniazid alone, 300 mg/ day, should be administered include a. A positive tuberculin reaction in a patient under 35 b. A positive tuberculin reaction in a patient over 35 who also hasan abnormal chest x-ray film c. One of the diseases that predisposes to tuberculosis (eg, diabetes, silicosis, disorders requiring corticosteroid therapy) d. Ali of the above

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Tuberculosis. Chemoprophylaxis and treatment.

Postgraduate Medicine ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20 Tuberculosis John H. McClem...
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