Anti-mycobacterial Agents

Ethambutol	Isoniazid
Pyrazinamide	rifabutin (Mycobutin ®)
Rifamate ®	Rifampin
Rifapentine (Priftin®)	Rifater®
Measuring Induration (TB Test)

Ethambutol

CLINICAL PHARMACOLOGY
Ethambutol hydrochloride tablets following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of ethambutol hydrochloride falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intercellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours.

During the 24-hour period following oral administration of ethambutol hydrochloride tablets approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency.

Ethambutol hydrochloride diffuses into actively growing Mycobacterium cells such as tubercle bacilli. Ethambutol hydrochloride tablets appear to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated.

Ethambutol hydrochloride tablets have been shown to be effective against strains of Mycobacterium tuberculosis but do not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to ethambutol hydrochloride have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When ethambutol hydrochloride tablets have been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to ethambutol hydrochloride by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between ethambutol hydrochloride tablets and other antituberculous drugs has been reported. Ethambutol hydrochloride tablets have reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently. An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of ethambutol hydrochloride in serum and urines

INDICATIONS AND USAGE
Ethambutol hydrochloride tablets are indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety and appropriate in vitro susceptibility studies. In patients who have not received previous antituberculous therapy, i.e., initial treatment, the most freguently used regimens have been the following:

Ethambutol Hydrochloride Tablets plus isoniazid
Ethambutol Hydrochloride Tablets plus isoniazid plus streptomycin.
In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, ethambutol hydrochloride tablets should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been indicated by appropriate in vitro studies. Antituberculous drugs used with ethambutol hydrochloride tablets have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized.

CONTRAINDICATIONS
Ethambutol hydrochloride tablets are contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. Ethambutol hydrochloride tablets are contraindicated in patients who are unable to appreciate and report visual side ettects or changes in vision (e.g., young children, unconscious patients).

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Dosing:
Oral:
Treatment of tuberculosis: Note: Used as part of a multidrug regimen. Treatment regimens consist of an initial 2 month phase, followed by a continuation phase of 4 or 7 additional months; frequency of dosing may differ depending on phase of therapy.

Children:
Daily therapy: 15-20 mg/kg/day (maximum: 1 g/day).
Twice weekly directly observed therapy (DOT): 50 mg/kg (maximum: 4 g/dose) .

Adults (suggested doses by lean body weight):
Daily therapy: 15-25 mg/kg
40-55 kg: 800 mg
56-75 kg: 1200 mg
76-90 kg: 1600 mg (maximum dose regardless of weight)

Twice weekly directly observed therapy (DOT): 50 mg/kg
40-55 kg: 2000 mg
56-75 kg: 2800 mg
76-90 kg: 4000 mg (maximum dose regardless of weight)

Three times/week DOT: 25-30 mg/kg (maximum: 2.5 g)
40-55 kg: 1200 mg
56-75 kg: 2000 mg
76-90 kg: 2400 mg (maximum dose regardless of weight)

Disseminated Mycobacterium avium complex (MAC) in patients with advanced HIV infection: 15 mg/kg ethambutol in combination with azithromycin 600 mg daily
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Dosing interval in renal impairment:
Clcr 10-50 mL/minute: Administer every 24-36 hours
Clcr<10 mL/minute: Administer every 48 hours
Hemodialysis: Slightly dialyzable (5% to 20%); Administer dose postdialysis
Peritoneal dialysis: Dose for Clcr<10 mL/minute
Continuous arteriovenous or venovenous hemofiltration: Administer every 24-36 hours

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Monitoring
Baseline and periodic (monthly) visual testing (each eye individually, as well as both eyes tested together) in patients receiving >15 mg/kg/day; baseline and periodic renal, hepatic, and hematopoietic tests

Supplied:
Tablet, as hydrochloride: 100 mg, 400 mg

Isoniazid

Mechanism of Action:
Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms.

Isoniazid resistant Mycobacterium tuberculosis bacilli develop rapidly when isoniazid monotherapy is administered.

INDICATIONS AND USAGE:
Isoniazid is recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant antituberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid, or any other medication, is inadequate therapy.

Isoniazid is recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parenthesis):

1. Persons with human immunodeficiency virus (HIV) infection (

5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection.

Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy.

2. Close contacts of persons with newly diagnosed infectious tuberculosis (

5 mm). In addition, tuberculin-negative (< 5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (> 5 mm), therapy should be continued.

3. Recent converters, as indicated by a tuberculin skin test (

10 mm increase within a 2-year period for those < 35 years old;

15 mm increase for those

35 years of age). All infants and children younger than 4 years of age with a > 10 mm skin test are included in this category.

4. Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (

5 mm). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly.

5. Intravenous drug users known to be HIVseronegative ( > 10 mm).

6. Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (

10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin’s disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state (with or without weight loss), chronic peptic ulcer disease, chronic malabsorption syndromes, and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly.

Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups:

1. Foreign-born persons from high-prevalence countries who never received BCG vaccine.

2. Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics, and Native Americans.

3. Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions).

Children who are less than 4 years old are candidates for isoniazid preventive therapy if they have > 10 mm induration from a PPD Mantoux tuberculin skin test.

Finally, persons under the age of 35 who a) have none of the above risk factors (1-6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy.

The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of isoniazid is recommended for those with the additional risk factors listed above (1-6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected.

CONTRAINDICATIONS:
Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology

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Dosing:
Recommendations often change due to resistant strains and newly-developed information; consult MMWR for current CDC recommendations:
Oral (injectable is available for patients who are unable to either take or absorb oral therapy):

Infants and Children:
Treatment of latent TB infection (LTBI): 10-20 mg/kg/day in 1-2 divided doses (maximum: 300 mg/day) or 20-40 mg/kg (maximum: 900 mg/dose) twice weekly for 9 months

Treatment of active TB infection:
Daily therapy: 10-15 mg/kg/day in 1-2 divided doses (maximum: 300 mg/day).
Twice weekly directly observed therapy (DOT): 20-30 mg/kg (maximum: 900 mg).

Adults:
Treatment of latent tuberculosis infection (LTBI): 300 mg/day or 900 mg twice weekly for 6-9 months in patients who do not have HIV infection (9 months is optimal, 6 months may be considered to reduce costs of therapy) and 9 months in patients who have HIV infection. Extend to 12 months of therapy if interruptions in treatment occur.

Treatment of active TB infection (drug susceptible):
Daily therapy: 5 mg/kg/day given daily (usual dose: 300 mg/day); 10 mg/kg/day in 1-2 divided doses in patients with disseminated disease

Twice weekly directly observed therapy (DOT): 15 mg/kg (maximum: 900 mg); 3 times/week therapy: 15 mg/kg (maximum: 900 mg)

Note: Treatment may be defined by the number of doses administered (eg, "six-month" therapy involves 192 doses of INH and rifampin, and 56 doses of pyrazinamide). Six months is the shortest interval of time over which these doses may be administered, assuming no interruption of therapy.

Note: Concomitant administration of 6-50 mg/day pyridoxine is recommended in malnourished patients or those prone to neuropathy (eg, alcoholics, diabetics)
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Dosing adjustment in renal impairment:
Clcr<10 mL/minute: Administer 50% of normal dose
Hemodialysis: Dialyzable (50% to 100%)
Administer dose post dialysis

Peritoneal dialysis, continuous r venovenous hemofiltration: Dose for Clcr<10 mL/minute

Dosing adjustment in hepatic impairment:
Dose should be reduced in severe hepatic disease
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Supplied:
Syrup: 50 mg/5 mL (473 mL)
Tablet: 100 mg, 300 mg

Pyrazinamide

Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.

INDICATIONS AND USAGE:
Pyrazinamide is indicated for the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents. (The current recommendation of the CDC for drugsusceptible disease is to use a six-month regimen for initial treatment of active tuberculosis, consisting of isoniazid, rifampin and pyrazinamide given for 2 months, followed by isoniazid and rifampin for 4 months.*4)

(Patients with drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy.)

(In patients with concomitant HIV infection, the physician should be aware of current recommendation of CDC. It is possible these patients may require a longer course of treatment)

It is also indicated after treatment failure with other primary drugs in any form of active tuberculosis.

Pyrazinamide should only be used in conjunction with other effective antituberculous agents.

*See recommendations of Center for Disease Control (CDC) and American Thoracic Society for complete regimen and dosage recommendations.

CONTRAINDICATIONS:
Pyrazinamide is contraindicated in persons:

with severe hepatic damage.
who have shown hypersensitivity to it.
with acute gout.

WARNINGS:
Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Those patients with preexisting liver disease or those at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely.

Pyrazinamide should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear

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Dosage
Oral: Treatment of tuberculosis:
Note: Used as part of a multidrug regimen. Treatment regimens consist of an initial 2-month phase, followed by a continuation phase of 4 or 7 additional months; frequency of dosing may differ depending on phase of therapy.

Children:
Daily therapy: 15-30 mg/kg/day (maximum: 2 g/day)

Twice weekly directly observed therapy (DOT): 50 mg/kg/dose (maximum: 4 g/dose)

Adults (dosing is based on lean body weight):

Daily therapy: 15-30 mg/kg/day
40-55 kg: 1000 mg
56-75 kg: 1500 mg
76-90 kg: 2000 mg (maximum dose regardless of weight)

Twice weekly directly observed therapy (DOT): 50 mg/kg
40-55 kg: 2000 mg
56-75 kg: 3000 mg
76-90 kg: 4000 mg (maximum dose regardless of weight)

Three times/week DOT: 25-30 mg/kg (maximum: 2.5 g)
40-55 kg: 1500 mg
56-75 kg: 2500 mg
76-90 kg: 3000 mg (maximum dose regardless of weight)

Elderly: Start with a lower daily dose (15 mg/kg) and increase as tolerated.

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Dosing adjustment in renal impairment: Clcr<50 mL/minute: Avoid use or reduce dose to 12-20 mg/kg/day

Avoid use in hemo- and peritoneal dialysis as well as continuous arteriovenous or venovenous hemofiltration.

Dosing adjustment in hepatic impairment: Reduce dose
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Supplied:
Tablet: 500 mg

rifabutin (Mycobutin):

Mechanism of Action
Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli, rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC).

INDICATIONS AND USAGE
MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

CONTRAINDICATIONS
MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.

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Dosing:
Oral:
Children >1 year:
Prophylaxis: 5 mg/kg daily; higher dosages have been used in limited trials

Treatment (unlabeled use): Patients not receiving NNRTIs or protease inhibitors:

Initial phase (2 weeks to 2 months): 10-20 mg/kg daily (maximum: 300 mg).
Second phase: 10-20 mg/kg daily (maximum: 300 mg) or twice weekly

Adults:
Prophylaxis: 300 mg once daily (alone or in combination with azithromycin)

Treatment (unlabeled use):
Patients not receiving NNRTIs or protease inhibitors:
Initial phase: 5 mg/kg daily (maximum: 300 mg)
Second phase: 5 mg/kg daily or twice weekly

Patients receiving nelfinavir, amprenavir, indinavir: Reduce dose to 150 mg/day; no change in dose if administered twice weekly

Dosage adjustment in renal impairment: Clcr<30 mL/minute: Reduce dose by 50%

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Supplied:
Capsule: 150 mg

Rifamate (INH 150mg + rifampin 300mg):

[Management of active tuberculosis.]

Dosing (Adults): 2 capsules orally once daily.

Supplied:
Capsule: Rifampin 300 mg and isoniazid 150 mg

Rifampin

Microbiology
Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Rifampin at therapeutic levels has demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms.

Organisms resistant to rifampin are likely to be resistant to other rifamycins.

Rifampin has bactericidal activity against slow and intermittently growing M tuberculosis organisms. It also has significant activity against Neisseria meningitidis isolates.
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Dosing:
Oral (I.V. infusion dose is the same as for the oral route):
Tuberculosis therapy (drug susceptible): Note: A four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) is preferred for the initial, empiric treatment of TB. When the drug susceptibility results are available, the regimen should be altered as appropriate.

Infants and Children <12 years:
Daily therapy: 10-20 mg/kg/day usually as a single dose (maximum: 600 mg/day)

Twice weekly directly observed therapy (DOT): 10-20 mg/kg (maximum: 600 mg)

Adults:
Daily therapy: 10 mg/kg/day (maximum: 600 mg/day)

Twice weekly directly observed therapy (DOT): 10 mg/kg (maximum: 600 mg); 3 times/week: 10 mg/kg (maximum: 600 mg)

Latent tuberculosis infection (LTBI): As an alternative to isoniazid:

Children: 10-20 mg/kg/day (maximum: 600 mg/day) for 6 months

Adults: 10 mg/kg/day (maximum: 600 mg/day) for 4 months. Note: Combination with pyrazinamide should not generally be offered ( MMWR , Aug 8, 2003).

H. influenzae prophylaxis (unlabeled use):

Infants and Children: 20 mg/kg/day every 24 hours for 4 days, not to exceed 600 mg/dose

Adults: 600 mg every 24 hours for 4 days

Meningococcal meningitis prophylaxis:
Adults: 600 mg every 12 hours for 2 days

Nasal carriers of Staphylococcus aureus (unlabeled use):
Children: 15 mg/kg/day divided every 12 hours for 5-10 days in combination with other antibiotics

Adults: 600 mg/day for 5-10 days in combination with other antibiotics

Synergy for Staphylococcus aureus infections (unlabeled use): Adults: 300-600 mg twice daily with other antibiotics
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Dosing adjustment in hepatic impairment: Dose reductions may be necessary to reduce hepatotoxicity

Hemodialysis or peritoneal dialysis: Plasma rifampin concentrations are not significantly affected by hemodialysis or peritoneal dialysis.
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Supplied:
Capsule (Rifadin®): 150 mg, 300 mg
Injection, powder for reconstitution (Rifadin®): 600 mg

Rifapentine (Priftin):

Mechanism of Action

Rifapentine, a cyclopentyl rifamycin, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but not in mammalian cells. At therapeutic levels, rifapentine exhibits bactericidal activity against both intracellular and extracellular M. tuberculosis organisms. Both rifapentine and the 25-desacetyl metabolite accumulate in human monocyte-derived macrophages with intracellular/extracellular ratios of approximately 24:1 and 7:1, respectively.

In Vitro Activity

Rifapentine and its 25-desacetyl metabolite have demonstrated in vitro activity against rifamycin-susceptible strains of Mycobacterium tuberculosis including cidal activity against phagocytized M. tuberculosis organisms grown in activated human macrophages.

The correlation between rifapentine MICs and clinical cure has not been established. Interpretive criteria/breakpoints to determine whether clinical isolates of M. tuberculosis are susceptible or resistant to rifapentine have not been established.

In Vivo Activity

In mouse infection studies a therapeutic effect, in terms of enhanced survival time or reduction of organ bioburden, has been observed in M. tuberculosis-infected animals treated with various intermittent rifapentine containing regimens. Animal studies have shown that the activity of rifapentine is influenced by dose and frequency of administration

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Dosing:
Adults: Rifapentine should not be used alone ; initial phase should include a 3- to 4-drug regimen

Intensive phase (initial 2 months) of short-term therapy: 600 mg (four 150 mg tablets) given twice weekly (with an interval of not less than 72 hours between doses); following the intensive phase, treatment should continue with rifapentine 600 mg once weekly for 4 months in combination with INH or appropriate agent for susceptible organisms
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Supplied:
Tablet [film coated]: 150 mg

Rifater (INH 50mg+ rifampin 120mg +pyr 300mg):

Management of active tuberculosis:
Dosing:
Adults: Oral: Patients weighing:
</= 44 kg: 4 tablets

45-54 kg: 5 tablets

>/= 55 kg: 6 tablets

Doses should be administered in a single daily dose.
Administer dose either 1 hour before or 2 hours after a meal with a full glass of water.
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Supplied:
Tablet: Rifampin 120 mg, isoniazid 50 mg, and pyrazinamide 300 mg

Measuring Induration (TB Test)

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