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Indiana State Department of Health

Tuberculosis Home > Information for Health Professionals > Treatment of Active Tuberculosis in Adults TB Medical Advisory Board Statement on the Treatment of Active Tuberculosis in Adults

1. Recommended Treatment Regimens

Unless there are contraindications, patients with active tuberculosis should be treated initially with four drugs: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Four drugs are recommended because (1) EMB helps to prevent the emergence of RIF-resistant organisms when primary resistance to INH may be present; (2) INH resistance continues to occur in our state, (3) foreign-borne persons from countries with high rates of drug resistance make up a growing number of TB cases in Indiana, and (4) six-month treatment regimens are not possible without the use of PZA.

2. Drug Administration

The preferred regimen in our state is the 'Denver Regimen.' In this regimen, the patient is treated with daily medication for the first two weeks, followed by twice-weekly dosing until a total of 26 weeks of therapy are completed. This regimen must be given using directly observed therapy (DOT), meaning that a public health worker delivers medication to the patient and observes the patient ingest the medication. Completion of treatment is defined by the total number of doses ingested as well as the duration of treatment. Note: twice-weekly therapy is contraindicated for HIV-infected patients with CD4+ lymphocyte counts < 100 cells/µl. An overview of the 'Denver Regimen' is provided in Table 2 as "Option 1." Doses for anti-tuberculosis medications are as follows:

Table 1

Drugs Daily Dose of Anti-tuberculosis Medications

mg / kg

(Maximum Dose)
Twice Weekly Dose of Anti-tuberculosis Medications

mg / kg

(Maximum Dose)
Adults Children Adults Children
INH 5

(300 mg)
10-15

(300 mg)
15

(900 mg)
20-30

(900 mg)
RIF 10

(600 mg)
10-20

(600 mg)
10

(600 mg)
10-20

(600 mg)
PZA See table 4 15-30

(2 g)
See table 4 50

(4 g)
EMB See table 4 15-20

(1.0 g)
See table 4 50

(4.0 g)





















Table 2

Initial Phase Continuation Phase
Drugs Interval and Duration

(Total Number of Doses)
Drugs Interval and Duration

(Total Number of Doses)
Option 1

(preferred)

INH

RIF

PZA

EMB
Daily DOT for 2 weeks (14 doses), and then twice weekly DOT for six weeks (12 doses) INH

RIF
Twice weekly DOT for 18 weeks (36 doses)

(62 total doses over 26 weeks)
Option 2

INH

RIF

PZA

EMB
3 times weekly DOT for 8 weeks (24 doses) INH

RIF
3 times weekly DOT for 18 weeks

(54 doses)

(78 total doses over 26 weeks)
Option 3

INH

RIF

PZA

EMB
Daily for 8 weeks (56 doses)

(DOT should be used for the entire treatment period.)

INH

RIF
Daily for 18 weeks

(126 doses: 182 total over 26 weeks)



































Daily dosing for 5 rather than 7 days per week is an option for the daily portion of treatment options 1 and 2, but should only be used if dosing 7 days per week is not feasible. DOT must be used with this option.

INH, rifampin and pyrazinamide should be continued for the entire first two months. Ethambutol may be discontinued after the drug susceptibility test shows that the patient's organism is susceptible to both INH and RIF.

3. Major Adverse Effects

All patients should be counseled to watch for symptoms of hepatotoxicity.  If hepatotoxicity develops (ALT or AST greater than five times the upper limit of normal, elevated bilirubin, or symptoms of hepatotoxicity), all drugs should be discontinued, and ISDH should be consulted immediately. The ISDH TB Medical Advisory Board has published guidelines on the management of hepatotoxicity. Other significant adverse reactions are listed in the table below:

Table 3

Drug

Major Adverse Effects

Isoniazid

Hepatitis, peripheral neuropathy

Rifampin

Drug interactions, hepatitis

Pyrazinamide

Hepatitis, GI upset, hyperuricemia

Ethambutol

Optic neuritis








4. Drug Dosages and Toxicity

The ISDH TB Medical Advisory Board does not recommend prescribing anything other than standard therapeutic doses (Table 1). Prior to treatment, measure CBC with platelets, liver enzymes, uric acid, visual acuity, and perform color vision screening. Then, assess monthly for side effects and order laboratory tests as indicated.

5. Use of Drugs Other Than INH, RIF, PZA, or EMB

There are no substitutes for any of the first-line agents. Before rifampin was available, TB patients had to take medication for 18-24 months. The combination of INH and rifampin allowed completion of therapy within 9 months. Routine addition of PZA during the first two months has shortened duration of therapy to 6 months for most cases. Ethambutol is known as a 'companion drug,' and has bacteriostatic activity. Its primary purpose is to suppress the further development of resistance in situations where INH resistance is already present at diagnosis. Ethambutol can be discontinued as soon as the organism is known to be susceptible to both INH and RIF.

The drugs are not interchangeable. Second-line agents must be used when patients cannot take first-line drugs because of resistance or intolerance. These second-line agents are substantially less active, and not without risks of toxicity. Patients taking second-line drugs in lieu of both INH and RIF require treatment durations of up to 2 years with frequent monitoring for side effects.

6. Drug Resistance

Contact ISDH immediately. The preferred regimen for INH-resistant tuberculosis is rifampin, pyrazinamide and ethambutol for at least six months. Intermittent therapy should not be used.  For treatment of multi-drug resistant cases, or cases resistant only to RIF, ISDH can arrange for expert consultation.

7. Avoid Divided Medication Doses

Patients are sometimes given split-dose medications for the first few days as a last resort to improve their tolerance if they are experiencing adverse effects. Otherwise, there is no rationale for treatment with divided doses. Therapeutic levels of these drugs are based on single doses. The use of divided doses can markedly reduce adherence to the medication regimen because this practice is not compatible with directly observed therapy.

8. Culture-negative Pulmonary TB

If the patient has a clinical picture consistent with tuberculosis, and has responded to therapy, the patient may have smear-negative, culture-negative tuberculosis. Tuberculosis documented with at least three negative smears and cultures may be treated for four months (17 weeks), provided that the patient does not have HIV infection. Contact ISDH, your local health department, or a TB Medical Advisory Board member for details.

9. Complete Diagnostic Evaluation

It is important to try to make a culture-confirmed diagnosis whenever TB is suspected. Your local health department can collect three sputum specimens on pulmonary TB suspects, and the ISDH laboratory will perform AFB smears, cultures, and drug susceptibility tests at no charge.

10. Length of Treatment

Patients with pulmonary TB, no radiographic evidence of cavitation or cavitary lesions, and who are HIV-negative, can generally be treated successfully in 6 months (26 weeks). Revised treatment guidelines issued by the American Thoracic society recommend extending the continuation phase from 4 to 7 months for (1) patients with cavitary disease and whose sputum specimens collected at the end of the 8-week initial phase are still culture-positive; (2) patients with non-cavitary disease, who are HIV-positive, but whose sputum specimens collected at the end of the 8-week initial phase are still culture-positive, and (3) patients who did not receive PZA during the initial phase.

To further reduce the risk of relapse, ISDH recommends that the continuation phase be extended to 7 months (39 weeks minimum total treatment) for patients with either cavitary disease or who are culture-positive after the initial treatment phase.

Most forms of extrapulmonary TB can be treated in 6-9 months as long as the regimen contained both INH and RIF. Meningeal TB should be treated for 9-12 months.  Many experts recommend 12 months of treatment for bone and joint TB.

11. HIV Infection

Since co-infection with TB and HIV is becoming increasingly more common, all patients diagnosed with TB should be evaluated for HIV infection as well, preferably with serologic studies.

RIF is a potent inducer of cytochrome P450 isoenzymes (CYP450) and can cause serious reductions in the therapeutic levels of most non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).  Some NNRTIs and PIs inhibit CYP450, resulting in serum levels of RIF that are too high.  For these reasons it is often necessary to use rifabutin in place of rifampin.  In addition, HIV-infected TB patients whose CD4+ lymphocyte counts are < 100 cells/µl should not receive their TB drugs with twice-weekly intermittent therapy.

Management of AIDS patients with TB is complicated and should be done by physicians who are experts in this field.

Table 4.     Suggested Pyrazinamide and Ethambutol Doses, Using Whole Tablets,For Adults Weighing 40-90 Kg

Pyrazinamide Doses Weight (Kg)
  40-55

56-75

76-90

Daily 1000 mg 1500 mg 2000 mg
(mg/kg) (18.2-25.0)

(20.0-26.8)

(22.2-26.3)

Thrice Weekly 1500 mg 2500 mg 3000
(mg/kg) (27.3-37.5) (33.3-44.6) (33.3-39.5)
Twice Weekly 2000 mg 3000 mg 4000
(mg/kg) (36.4-50.0) (40.0-53.6) (44.4-52.6)
 
Ethambutol Doses Weight (Kg)
  40-55 56-75 76-90
Daily 800 mg 1200 mg 1600 mg
(mg/kg) (14.5-20.0) (16.0-21.4) (17.8-21.1)
Thrice Weekly 1200 mg 2000 mg 2400
(mg/kg) (21.8-30.0) (26.7-35.7) (26.7-31.6)
Twice Weekly 2000 mg 2800 mg 4000
(mg/kg) (36.4-50.0) (37.3-50.0) (44.4-52.6)
























Based on estimated lean body weight.
Maximum dose regardless of weight.