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CDHS/CTCA JOINT GUIDELINES

1997 Guidelines for the Treatment of Tuberculosis  

The following guidelines have been developed by the California Department of Health Services, Tuberculosis Control Branch in consultation with the Executive Committee of the California Tuberculosis Controllers Association. These guidelines are official State Recommendations and have been endorsed by the California Tuberculosis Controllers Association.

The treatment of tuberculosis (TB) patients with effective anti-TB chemotherapy is the highest priority in TB control. Not only does treatment benefit the individual patient, it also benefits the public at large as infectious cases are cured and sources of infection are removed from the community. Even though the first effective chemotherapeutic agent for TB was discovered more than 50 years ago, many patients today are still not effectively treated and cured. Treatment with ineffective drug regimens and poor patient adherence to medications are partly responsible for poor treatment outcomes. Therefore, promoting the use of effective chemotherapy and monitoring adherence to treatment are essential for treatment to be successful.

The California Tuberculosis Controllers Association (CTCA) and the California Department of Health Services (CDHS), Tuberculosis Control Branch, have jointly developed the following guidelines for the treatment of TB disease and infection. By providing these official State Recommendations, we hope to provide an additional tool for those involved in the treatment of TB infection and disease. No set of guidelines can cover all individual treatment situations. Therefore, when questions on individual situations not covered by these guidelines do arise, consult with the Local TB Control Program or the California Department of Health Services, TB Control Branch, for further information.

Note: For a description of American Thoracic Society (ATS) TB Classifications, see Suggested Readings, 2.

CONTENTS
Treatment of Tuberculosis Disease in Adults
Treatment of Tuberculosis Disease in Children and Adolescents
Issues in Case Monitoring and Management
Treatment of Tuberculosis Infection in Adults and Children (TB Class II and IV)
DOT
Mycobacteriology

Treatment of Tuberculosis Disease in Adults  

I. Standard Initial Treatment Regimens

A. All TB cases (TB Class III) or suspects (TB Class V) in California should be started on a four drug regimen of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) and ethambutol (EMB), unless otherwise contra-indicated (see Table 1 for proper dosages). The treatment may be given in three ways:

1. Daily treatment regimen: Drugs should be given together; dosages should not be split.

2. Bi-weekly treatment regimen: Four drug therapy, administered daily for 2 weeks and then two times a week for 6 weeks; this is followed by therapy with INH and RIF given two times a week for 16 weeks (if susceptibility to INH and RIF is demonstrated).

3. Thrice weekly treatment regimen: three times weekly from the beginning; all four drugs must be given for 6 months.

B. For I (A.1) above, EMB should be continued until drug susceptibility results are available and resistance to INH and RIF has been excluded. PZA is continued for the first 2 months. RIF and INH are continued for a total of 6 months.

C. Intermittent therapy [I (A.2 and A.3)] should only be given by directly observed therapy (DOT).

D. If cultures remain positive beyond 2 months of treatment, therapy should be prolonged. Ideally, treatment should be continued at least 6 months after the culture converts to negative (see Issues in Case Monitoring and Management, II).

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Table 1. Dosage Recommendation for the Initial Treatment of Tuberculosis in Adults and Children

II. Alternative Treatment Regimens

A. INH and RIF for 9 months. Can be used when disease is caused by a pan-susceptible organism and the patient cannot take PZA. EMB should be added to the regimen at the start of therapy and discontinued when sensitivities to INH and RIF are documented.
B. RIF and EMB for 12 - 18 months. Can be used when disease is caused by an INH-resistant organism or when INH cannot be given.
C. RIF, EMB, and PZA for 6 - 9 months. Also an acceptable regimen when disease is caused by an INH-resistant organism or when INH cannot be given.
D. INH and EMB for 18 - 24 months. Used when RIF cannot be given or if disease is caused by a RIF-resistant organism.
E. For II (B, C, and D) above, the longer duration of therapy should be used when there is extensive disease, delay in sputum conversion, or relapse of disease.


III. Treatment of Drug-Resistant Disease

A. Disease with mono-resistance to INH. The regimens discussed in II (B or C) should be used.
B. Disease with mono-resistance to RIF. The regimen discussed in II (D) should be used.
C. Multi-Drug Resistant (MDR) Disease Defined as resistance to at least INH and RIF. Because of the reduced efficacy and higher toxicity of secondary drugs, the treatment of MDR-TB must be adjusted to the individual case. In order to achieve optimum results one should adhere to some basic principles:

1. Never add one drug at a time to a failing regimen.
2. At least 3 drugs (4 or 5 are better) to which the organism is not resistant should be used. Initially, one drug should be a bactericidal injectable agent.
3. The duration of treatment must be from 18 months to 2 years after cultures become negative.
4. Treatment should be directly observed throughout the entire course of therapy.
5. The treating physician should notify the local TB Control Program as soon as possible to discuss management, follow up and all public health aspects of the case.
6. Consult with TB experts who are familiar with treatment of MDR-TB.

IV. Smear and Culture Negative Tuberculosis

A. For adults with smear- and culture-negative TB, a 4-month regimen of INH and RIF, combined with PZA for the first two months, may be used when drug resistance is unlikely.
B. A more conservative approach would be the use of a 6-month regimen of INH and RIF, combined with PZA for the first two months.

V. Extrapulmonary Tuberculosis

A. Extrapulmonary TB can generally be managed in the same way as pulmonary TB.
B. 12 months of therapy is recommended for miliary TB, and TB involving the central nervous system, bones, and joints.

VI. Treatment of Relapse of Tuberculosis

A. For individuals with relapse of TB following treatment for TB with pan-sensitive organisms, the standard 4-drug regimen (INH, RIF, PZA, and EMB) can be used. However, treatment may be prolonged to 9 months or more.
B. It is critical, however, to perform drug susceptibility testing of the M. tuberculosis organism responsible for the relapse and adjust the treatment regimen if resistance has developed.
C. Directly observed therapy (see Issues in Case Monitoring and Management, I) is strongly recommended.

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VII. Treatment of Tuberculosis in HIV Infected Individuals
Because the optimal strategy for treating tuberculosis in HIV-infected persons is evolving at this time, the following section can only outline some of the current issues. The local TB Controller or experts in the treatment of TB in HIV-infected patients should be consulted for the most recent recommendations.

A. Duration of treatment

1. For patients with TB due to a pan-sensitive organism, 6 months of treatment (using the standard initial regimen) is effective.

2. A more conservative but well-accepted approach is to prolong the treatment to 9 months or until 6 months beyond the last positive culture. Because taking every dose is extremely important in the immunocompromised patients, even minor lapses in therapy would justify prolonging the treatment and a referral for DOT.

B. Use of an intermittent treatment regimen

1. There are recent reports of acquired drug resistance in HIV-infected patients who were adherent to anti-TB treatment; some of these cases occurred in persons using intermittent therapy. Because of this, use of an intermittent regimen should be individualized and patients using these regimens should be closely monitored for treatment response.

2. Among the available intermittent regimens, the bi-weekly regimen has the lowest number of doses, thus it may carry the greatest risk of poor treatment response. Providers should take this into account when considering the use of the bi-weekly regimen.

C. Management of patients using protease inhibitors

1. RIF (and rifabutin to a lesser extent) can substantially reduce the serum level of protease inhibitors. Because of this drug interaction, many HIV care providers have reservations about using RIF to treat TB in those who are (or plan to be) on protease inhibitors. In addition, protease inhibitors can substantially increase the serum level of RIF.

2. The best approach to manage TB in a patient using a protease inhibitor has not been determined. The CDC has outlined the problem in detail and provided some preliminary suggestions (see Suggested Readings, 4). Experts in the management of TB in HIV-infected persons should be consulted when managing a TB patient using or planning to use a protease inhibitor.

3. Regardless of the approach taken, coordination between clinicians managing TB and HIV disease is essential.

VIII. Treatment of Tuberculosis Disease in Pregnant Women
A. The three-drug regimen with INH, RIF, and EMB can be used in pregnant women. Although PZA has not been approved for use in pregnancy due to inadequate data on teratogenicity, it has been used safely throughout the world and recommendations for its use should be individualized.
B. Streptomycin or other aminoglycosides should not be used because of the high incidence of 8th nerve toxicity in the fetus.
C. There is no known harm to the breast-fed infant if the mother is taking anti-TB drugs.

IX. Use of Fixed Combination Drugs
A. Fixed drug combinations are recommended for persons on self-administered daily therapy.
B. Two capsules of Rifamate (INH 150 mg + RIF 300 mg/capsule) are used daily for persons weighing > 60 kg. The number of Rifater (INH 50 mg + RIF 120 mg + PZA 300 mg/tablet) used per day should be adjusted by weight according to the manufacturer=s recommendations.
C. Fixed drug combinations are not recommended for persons on intermittent therapy because it is difficult to adjust the number of pills to the proper dosages.

Treatment of Tuberculosis Disease in Children and Adolescents
The basic principles of treatment of TB in children and adolescents are essentially the same as for adults. These Guidelines apply to adolescents up to the age of 16 - 18. The following information is provided to highlight selected issues in this population.
I. When drug-resistant disease is unlikely, treatment of intrathoracic TB with INH and RIF for 6 months with PZA in the initial 2 months is adequate. Some experts recommend prolonging treatment to 9 months in very young children (< 4 years of age).
II. Because it is difficult to monitor ocular toxicity in children, EMB is less frequently used in young children. If drug-resistant disease is suspected or known, streptomycin and PZA are alternative drugs to use.
III. Extrapulmonary TB can be managed the same way as in adults, with prolonged treatment (to 12 months) when there is disseminated disease, or disease involving the central nervous system, bone, or joint.
IV. Because it is difficult to collect 'good' sputum specimens from children, bacteriologic examinations are less useful in following the response to treatment. Therefore, clinical and radiographic examinations are of relatively greater importance in children. Chest radiographs are recommended for following the resolution of hilar adenopathy.

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Issues in Case Monitoring and Management
I. Directly Observed Therapy

A. Directly Observed Therapy (DOT), the process by which a health care worker observes the patient swallowing anti-TB medications, is being used extensively throughout the United States and the world. The decision to order DOT should be considered based on the potential for non-adherence of the patient. Providers should contact their local health department to coordinate DOT for patients. DOT is indicated for patients with the following characteristics [see CDHS/CTCA "Directly Observed Therapy Program Guidelines," (4/97)]:

1. History of alcohol or drug abuse
2. Adolescents
3. Homeless/shelter resident, or unstably housed persons
4. Non-adherence with TB medications, present or past
5. History of previous TB treatment
6. History of being in correctional facility
7. Major psychiatric disorder/memory or cognitive disorder
8. Poor or nonacceptance of TB diagnosis
9. Poor compliance during initial medical management
10. Slow sputum conversion or slow clinical improvement
11. Clinical deterioration while on TB therapy
12. Adverse reaction to TB medications
13. Too ill to self manage
14. Children needing therapy whose parents are in any of the above categories
15. Drug-resistant TB
16. Persons with relapse of their disease

B. Before weekends or holidays, patients receiving daily therapy in a DOT program may be given a dose appropriate for twice weekly treatment regimen, or provided with packets of drugs for self administration over the weekend or holiday.
C. DOT should be used with incentives and enablers. Each jurisdiction should outline its own DOT protocol.

II. Sputum monitoring

A. Patients with smear-positive pulmonary TB should have sputa collected at least every 2 weeks until 3 consecutive negative sputum smears have been documented. Once sputum smears become negative, or for those patients with smear-negative but culture-positive pulmonary TB, 2 or more sputa should be collected monthly for smears and cultures until persistently negative cultures have been documented.
B. If possible, two further sputum smears and cultures should be performed at the completion of therapy.
C. Patients with MDR-TB should have sputum smears and cultures performed monthly for the entire course of treatment.

III. Treatment failure
A. Patients on treatment for TB but whose sputum specimen(s) either remain bacteriologically positive after 3 months of treatment or become bacteriologically positive after initially converting to negative should be evaluated for treatment failure. Specimens that are either smear-positive for AFB or culture-positive for M. tuberculosis are bacteriologically positive.
B. Evaluation for possible treatment failure include: symptom review, chest radiography, and repeat drug susceptibility testing if sputum specimen is culture-positive.
C. All patients suspected of having treatment failure should be put on DOT.
D. The treating physician should discuss the management of these patients with the local TB Control Program or with other TB experts.
E. If additional anti-TB drugs are added to the treatment regimen, at least 2 new drugs that the patient has not been treated with previously should be used.

IV. Infectiousness of Tuberculosis Patients [see CDHS/CTCA "Guidelines for the Placement or Return of Tuberculosis Patients to High Risk Housing, Work, Correctional, or In-Patient Settings," (4/97)]
Patients with smear-positive pulmonary TB should be considered infectious until they meet all of the following criteria:
A. They have received adequate therapy for 2 weeks
B. They have a favorable clinical response to therapy
C. They have three consecutive negative sputum smears from sputa collected on different days