Management of tuberculosis

Choosing an effective regimen and ensuring compliance

CAPT Angeline Lazarus, MC, USN; LCDR John Sanders, MC, USNR

VOL 108 / NO 2 / AUGUST 2000 / POSTGRADUATE MEDICINE

CME learning objectives

• To understand the principles and guidelines of therapy for active tuberculosis
• To recognize treatment failure and the risk factors for multidrug-resistant tuberculosis
• To learn the adverse effects and drug interactions of antituberculous treatment

The authors disclose no financial interests in this article.

This is the third of four articles on tuberculosis

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Preview: With the introduction of effective agents against tuberculosis (TB) and the use of combinations of these agents, significant progress has been made toward shortening the duration of therapy (ie, to 6 months) and reducing the relapse rate (ie, to <4%). In addition, use of directly observed therapy, in which patients receive prescribed medications under direct observation of healthcare personnel, has increased compliance and decreased the emergence of drug resistance. In this article, the authors review the principles and discuss the specifics of choosing, prescribing, and monitoring drug therapy for TB.
Lazarus A, Sanders J. Management of tuberculosis: choosing an effective regimen and ensuring compliance. Postgrad Med 2000;108(2):71-84

Before the advent of effective chemotherapy for tuberculosis (TB), treatment strategies included bed rest, improved nutrition, lung collapse, surgical excision of diseased lung, and isolation. These methods reduced the incidence but not the mortality of TB (1). The first effective drug against TB, para-aminosalicylic acid, was identified in 1944. In the subsequent four decades, additional anti-TB agents were introduced that have become the foundation of therapy: streptomycin sulfate, isoniazid (Laniazid), ethambutol hydrochloride (Myambutol), rifampin (Rifadin, Rimactane), and pyrazinamide. At present, with the emergence of drug resistance, a four-drug initial regimen using directly observed therapy is recommended as standard care (2,3).

Treatment principles

An effective anti-TB regimen must contain multiple drugs to which the organism is susceptible and must be continued for a sufficient period of time. The American Thoracic Society and US Centers for Diseases Control and Prevention have established guidelines for treatment of TB (2,4). The following principles are critical (1):

• Perform drug-susceptibility studies on all isolates of Mycobacterium tuberculosis.
• Select drugs and treatment duration on the basis of results of susceptibility studies.
• Repeat susceptibility testing whenever clinical worsening occurs or new drug resistance is suspected.
• Never add a single drug to a failing regimen.
• Isolate all patients with suspected or proven active TB until the disease is excluded or effective therapy has been initiated.
• Initiate directly observed therapy in all cases of active TB.
• Perform HIV testing in all newly diagnosed cases of active TB.
• Monitor patients for adverse drug effects and drug interactions.
• Consult a specialist early, especially in cases of multidrug-resistant (MDR) TB, pregnancy, and HIV infection.
• Promptly report all cases of confirmed active TB, as well as the patient's HIV status, to the state department of health. Department of health clinics can provide both consultative and ongoing care through a team of physicians, nurses, social workers, and outreach specialists free of charge.

In selecting an effective regimen, physicians should take into account any coexisting conditions (eg, diabetes, renal disease, hepatic disease, seizure disorder, alcoholism, substance abuse) and concurrent medication needs. In a patient with previous episodes of TB, thorough history taking regarding treatment and susceptibility-testing results is critical to the assessment of potential drug resistance. Often, initial treatment is started before findings of drug-susceptibility studies are available. Therefore, all regimens should be reviewed when these results have been obtained (2).

Oral-treatment approaches

Treatment of newly diagnosed active TB is shown in tables 1 and 2. In general, a 6-month regimen with four of the first-line agents is recommended for adults and children (2). The regimen can be divided into an induction and a continuation phase as follows:

• Induction phase: isoniazid + rifampin + pyrazinamide + ethambutol daily for 2 months (or daily for 2 weeks and then two or three times a week for 6 weeks, or two or three times a week for 2 months)
• Continuation phase: isoniazid + rifampin daily or twice a week for 4 months

Unfortunately, at least one study has found that a "substantial proportion" of physicians do not fully adhere to the recommended treatment guidelines (5).

MDR TB
MDR TB refers to M tuberculosis that is resistant to at least two drugs, usually isoniazid and rifampin. Although the incidence of MDR TB in the United States has been declining in the last 5 years, there has been an increase worldwide. In the United States, MDR TB has been noted mainly among immigrants from countries with high MDR-TB rates, HIV-infected patients, the homeless, and injecting drug users. Healthcare workers were found to be at high risk because of delays in diagnosis and inadequate respiratory isolation procedures. The most common cause of emergence of drug resistance is previous inadequate or incomplete treatment (6,7).

The principles of treatment for MDR TB are similar to those listed for susceptible organisms. Treatment regimens should contain multiple bactericidal drugs not previously used and to which the organism is sensitive. Bacteriostatic drugs can also be used (7,8). Susceptibility testing allows determination of effective regimens, including use of second-line agents as listed in table 3.

Duration of treatment for MDR TB depends on the response. In general, treatment with at least three effective drugs should be continued until the culture becomes negative, and then a regimen of at least two drugs should be continued for 12 to 24 months (2,7,8). Consultation with an experienced specialist should be considered for management of all cases of MDR TB.

An earlier report by Goble and associates (9) showed a treatment-failure rate of 44% and a TB-associated mortality rate of 22% among 171 patients with MDR TB between 1973 and 1983. Fortunately, a more recent study by Telzak and colleagues (10) reported better results, with a 96% clinical response rate among 25 HIV-negative patients between 1991 and 1994.

Directly observed therapy
The steady decline in the rate of new cases of active TB and the decreasing incidence of MDR TB in the United States are attributed to successful completion of regimens because of the use of directly observed therapy (11,12). Physicians who choose not to employ directly observed therapy assume responsibility for patient noncompliance and its consequences. Because completion of adequate therapy is critical for management of TB and protection of public health, many health codes permit compulsory action, including directly observed therapy and detention, to ensure compliance (13).

Monitoring for adverse reactions

Adverse effects of commonly used anti-TB drugs are shown in tables 2 and 3. Patients should undergo pretreatment measurement of liver-associated enzyme, serum urea nitrogen, platelet, bilirubin, creatinine, and uric acid levels. These values should be monitored monthly during treatment and whenever symptoms suggesting adverse effects occur. An ophthalmologic evaluation for visual acuity and color vision is recommended at baseline and 3-month intervals in patients receiving ethambutol. Baseline and monthly audiograms are recommended if aminoglycosides are used (2,3). Some experts recommend therapeutic drug monitoring, especially in MDR TB, but this remains controversial (2,8).

Physicians should be familiar with interactions between anti-TB drugs and other medications. Isoniazid increases the level of phenytoin (Dilantin) and carbamazepine (Atretol, Epitol, Tegretol). Aluminum hydroxide reduces the bioavailability of isoniazid. Clinically significant interactions have been reported between rifampin and oral contraceptives, corticosteroids, cyclosporine (Neoral, Sandimmune, SangCya), erythromycin, nifedipine (Adalat, Procardia), phenytoin, imidazole antifungals, several antiretroviral agents, warfarin sodium (Coumadin), propranolol (Betachron E-R, Inderal), and opioids (2,14).

Evaluating response to treatment

The efficacy of a regimen is determined by the rate of bacteriologic conversion during therapy and the rate of relapse during or after completion of therapy. Patients should be closely observed during therapy and for the first 12 to 24 months after its completion (2).

Monitoring should consist of sputum smears and cultures at biweekly or monthly intervals until cultures become negative or therapy is completed. A follow-up chest film is indicated if sputum smears remain positive after 2 months of therapy or if new symptoms develop. Chest films at regular intervals are not necessary if there is bacteriologic improvement, but one should be obtained on completion of therapy.

In treatment of drug-resistant TB, frequent follow-up with sputum studies and chest films is indicated. In the case of MDR TB, sputum smears and cultures should be checked quarterly after conversion, to monitor for relapse.

Treatment failure
A finding on acid-fast smear or culture of the sputum after 5 months of treatment is considered a treatment failure. Failure can result from prescription of an inappropriate dosage or inadequate number of drugs, patient noncompliance, malabsorption, or organism resistance (2).

Relapse
Occasionally, active TB develops within the first 2 years after successful completion of therapy. In such cases of relapse, the organism often has a susceptibility pattern that is similar to that of the initial infection. The possibility of a new infection with M tuberculosis should also be considered (2,15).

Role of surgery in active TB

In general, M tuberculosis thrives best in a high-oxygen-level environment. Surgical techniques in the early 20th century included artificial pneumothorax, plombage (ie, placing lucite balls or paraffin in pleural spaces), and pneumoplasty to collapse the upper lobes and minimize oxygen availability. Advances in thoracic surgery led to lobar resection or pneumonectomy in some cases. With the availability of effective drugs, surgery is rarely used today. However, in carefully selected patients with MDR TB who have a poor response or an unfavorable prognosis with use of medical therapy alone, surgical therapy has had cure rates exceeding 90% (16). Antibiotic activity should be adequate to permit healing of the bronchial stump and prevent development of bronchopleural fistulas.

TB and pregnancy

No increase in morbidity or mortality from TB has been noted during pregnancy if treatment is adequate (2,17). In the United States, pyrazinamide is not recommended for use in pregnant women; however, it has been used outside the United States for MDR TB during pregnancy. The aminoglycosides and all of the second-line anti-TB medications except para-aminosalicylic acid should be avoided during pregnancy (2,17). Breast-feeding is safe during anti-TB therapy. Consultation with a specialist in TB is strongly recommended when initiating treatment in pregnant women, especially those with MDR TB. After initial radiographic imaging, follow-up x-ray monitoring during pregnancy, with proper shielding, is recommended only if no clinical improvement is noted.

Use of corticosteroids in TB

The addition of systemic corticosteroid therapy to TB regimens has been shown to reduce morbidity in patients with high fever, severe paradoxical response, miliary TB, pericarditis, endobronchial TB, central nervous system TB, and occasionally, those with peritonitis or pleuritis. In children, corticosteroids are recommended to decrease long-term sequelae of central nervous system involvement. Close clinical, radiologic, and bacteriologic monitoring should be continued whenever corticosteroids are added to the treatment plan (18).

Paradoxical response

In the first 3 to 12 weeks after initiation of an apparently adequate regimen, old lesions may enlarge or new lesions may develop. The most commonly reported findings are high fever, lymphadenopathy, and worsening pulmonary or extrapulmonary lesions. Recognition of this rare occurrence is important, because lesions regress without change in the initial regimen. Severe reactions can be treated with a short course of oral corticosteroids (4,19).

Extrapulmonary TB

The incidence of extrapulmonary TB is about 10% to 14% of newly diagnosed cases of TB in non-HIV-infected patients and up to 50% in HIV-infected patients. Occurrences most commonly are pleural (26.5%), genitourinary (17.9%), miliary (10.6%), bones or joint (8.8%), central nervous system (4.7%), abdominal (3.8%), or pericardial (0.9%).

The treatment regimen for extrapulmonary TB is similar to that for pulmonary TB. In selected cases (eg, bone or joint TB, tuberculous meningitis, children with miliary TB), the recommended duration of treatment is 12 months. Use of adjunctive methods (eg, addition of corticosteroids in initial management, surgery) has proved to be beneficial in decreasing morbidity and mortality (2,20).

Recent treatment advances

Several established drugs not listed in the tables are being evaluated as possible second-line agents for TB. These include isoniazid given in high doses (16 to 20 mg/kg), clarithromycin (Biaxin), clofazimine (Lamprene), metronidazole (Flagyl, Metric 21, Protostat), and amoxicillin-clavulanate potassium (Augmentin). Use of fluoroquinolones has increased in treatment of MDR TB. Although some fluoroquinolones may be as potent as the first-line drugs, they are still considered second-line agents (2,3,8).

Studies of alternative therapies are under way, including gene therapy and immunotherapy with aerosolized interferon-gamma or Mycobacterium vaccae at initiation of treatment. The benefits of these approaches are not yet established, but such research gives hope for future development of more effective treatment strategies.

Summary

Management of active TB requires a team approach. All patients newly diagnosed with TB should be tested for HIV infection. Currently available anti-TB drug regimens are well tolerated and highly effective. Directly observed therapy has shown improved survival and decline in the rate of new cases of active TB. In suspected or proven drug-resistant TB, the regimen should be individualized in consultation with a specialist experienced in MDR TB. Primary care physicians play a pivotal role in reducing morbidity and emergence of drug resistance through early diagnosis and prompt initiation of an effective regimen under directly observed therapy.

References

1. Styblo K. Recent advances in epidemiologic research in tuberculosis. Adv Tuberc Res 1980;20:1-63
2. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74
3. Bastian I, Colebunders R. Treatment and prevention of multidrug-resistant tuberculosis. Drugs 1999;58(4):633-61
4. 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 Morb Mortal Wkly Rep 1998;47(RR-20):1-58
5. Liu Z, Shilkret KL, Finelli L. Initial drug regimens for the treatment of tuberculosis: evaluation of physician prescribing practices in New Jersey, 1994 to 1995. Chest 1998;113(6):1446-51
6. Bradford WZ, Daley CL. Multiple drug-resistant tuberculosis. Infect Dis Clin North Am 1998;12(1):157-72
7. Moore M, Onorato IM, McCray E, et al. Trends in drug-resistant tuberculosis in the United States, 1993-1996. JAMA 1997;278(10):833-7
8. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993;329(11):784-91
9. Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328(8):527-32
10. Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995;333(14):907-11
11. 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(17):1179-84
12. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998;279(12):943-8
13. Gasner MR, Maw KL, Feldman GE, et al. The use of legal action in New York City to ensure treatment of tuberculosis. N Engl J Med 1999;340(5):359-66
14. Grange JM, Winstanley PA, Davies PD. Clinically significant drug interactions with antituberculosis agents. Drug Saf 1994;11(4):242-51
15. Fine PE, Small PM. Exogenous reinfection in tuberculosis. N Engl J Med 1999;341(16):1226-7
16. Pomerantz M, Brown JM. Surgery in the treatment of multidrug-resistant tuberculosis. Clin Chest Med 1997;18(1):123-30
17. Miller KS, Miller JM Jr. Tuberculosis in pregnancy: interactions, diagnosis, and management. Clin Obstet Gynecol 1996;39(1):120-42
18. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25(4):872-87
19. Smith H. Paradoxical responses during the chemotherapy of tuberculosis. (Editorial) J Infect 1987;15:1-3
20. Dutt AK, Stead WW. Treatment of extrapulmonary tuberculosis. Semin Respir Infect 1989;4(3):225-31

The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Navy, or the naval services at large.

For a helpful guide to electronic and print resources on tuberculosis for physicians and patients, see the Resource Guide in this issue.

Dr Lazarus is chair, department of internal medicine, and Dr Sanders is a staff member, division of infectious diseases, National Naval Medical Center, Bethesda.Correspondence: CAPT Angeline Lazarus, MC, USN, Department of Internal Medicine, National Naval Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889-5600.

Symposium Index

• TUBERCULOSIS: Introduction to a four-article symposium by CAPT Angeline Lazarus, MC, USN
• EPIDEMIOLOGY AND DIAGNOSIS OF TUBERCULOSIS: Recognition of at-risk patients is key to prompt detection by CDR Gregory Martin, MC, USN, CAPT Angeline Lazarus, MC, USN
• TUBERCULOSIS AND HIV INFECTION: How to safely treat both disorders concurrently by Catherine F. Decker, MD, CAPT Angeline Lazarus, MC, USN
• MANAGEMENT OF TUBERCULOSIS: Choosing an effective regimen and ensuring compliance by CAPT Angeline Lazarus, MC, USN, LCDR John Sanders, MC, USNR
• PREVENTION OF TUBERCULOSIS: Vigilance and infection control strategies are mainstays of efforts by LCDR Melissa Means-Markwell, MC, USNR, CDR Kevin M. O'Neil, MC, USN

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