Treatment of Tuberculosis - Tuberculosis

General principles

Drug treatment is the cornerstone of Tuberculosis management. A minimum of two drugs, and generally three or four drugs, must be used simultaneously.
Drug treatment is continued for at least 6 months and up to 2 to 3 years for some cases of multidrug-resistant Tuberculosis (MDR-Tuberculosis).
Measures to assure adherence, such as directly observed therapy (DOT), are important.

Pharmacologic treatment

Latent Infection

Chemoprophylaxis should be initiated in patients to reduce the risk of progression to active disease.
Isoniazid, 300 mg daily in adults, is the primary treatment for latent Tuberculosis in the United States, generally given for 9 months.
Individuals likely to be noncompliant may be treated with a regimen of 15 mg/kg (to a maximum of 900 mg) twice weekly with observation.
If the individual has been exposed to a patient with Isoniazid-resistant M. tuberculosis or a patient who has failed chemotherapy, chemoprophylaxis with rifampin (for 4 months) should be initiated.
Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine, 10 to 50 mg daily, to reduce the incidence of central nervous system (central nervous system) effects or peripheral neuropathies.

Treating Active Disease

Appropriate samples should be sent for culture and susceptibility testing prior to initiating therapy. Drug susceptibility testing should be done on the initial isolate for all patients with active Tuberculosis, and this data should guide the initial drug selection for the new patient. If the source case cannot be identified, the drug resistance pattern in the area where the patient likely acquired Tuberculosis should be used.
If the patient is being evaluated for the retreatment of Tuberculosis, it is imperative to know what drugs were used previously and for how long.
Patients must complete 6 months or more of treatment. HIV-positive patients should be treated for an additional 3 months and at least 6 months from the time that they convert to smear and culture negativity. When isoniazid and rifampin cannot be used, treatment duration becomes 2 years or more, regardless of immune status.

TABLE. Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection

Drug	Interval and Duration	Comments	Rating^a (Evidence)^b
Drug	Interval and Duration	Comments	HIV ^–	HIV ⁺
Isoniazid	Daily for 9 months^c^,d	In human immunodeficiency virus (HIV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (Nonnucleoside Reverse Transcriptase Inhibitors), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs)	A (II)	A (II)
	Twice weekly for 9 months^c^,d	Directly observed therapy (DOT) must be used with twice-weekly dosing	B (II)	B (II)
Isoniazid	Daily for 6 months^d	Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children	B (I)	C (I)
	Twice weekly for 6 months^d	DOT must be used with twice-weekly dosing	B (II)	C (I)
Rifampin	Daily for 4 months	For persons who cannot tolerate pyrazinamide For persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible Tuberculosis who cannot tolerate pyrazinamide	B (II)	B (III)
^aStrength of recommendation: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given. ^bQuality of evidence: I, randomized clinical trial data; II, data from clinical trials that are not randomized or were conducted in other populations; III, expert opinion. ^cRecommended regimen for children younger than 18 yr of age. ^dRecommended regimens for pregnant women. Some experts would use rifampin and pyrazinamide for 2 months as an alternative regimen in HIV-infected pregnant women, although pyrazinamide should be avoided during the first trimester.

TABLE. Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

Initial Phase			Continuation Phase			Range of Total Doses (Minimal Duration)	Rating^a (Evidence)^b
*Regimen*	*Drugs*	Interval and Doses^c (Minimal Duration)	*Regimen*	*Drugs*	Interval and Doses^c^,d	Range of Total Doses (Minimal Duration)	*HIV*^–	*HIV*⁺
1	Isoniazid rifampin PZA	7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)^c	1a	Isoniazid/rifampin	7 days/wk for 126 doses (18 wk) or 5 days/wk for 90 doses (18 wk)^c	182-130 (26 wk)	A (I)	A (II)
	EMB		1b	Isoniazid/rifampin	Twice weekly for 36 doses (18 wk)	92-76 (26 wk)	A (I)	A (II)^g
	EMB		1c^f	Isoniazid/RPT	Once weekly for 18 doses (18 wk)	74-58 (26 wk)	B (I)	E (I)
2	Isoniazid	7 days/wk for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 days/wk for 10 doses (2 wk)^e then twice weekly for 12 doses (6 wk)	2a	Isoniazid/rifampin	Twice weekly for 36 doses (18 wk)	62-58 (26 wk)	A (II)	B (II)^g
	rifampin		2b^f	Isoniazid/RPT	Once weekly for 18 doses (18 wk)	44-40 (26 wk)	B (I)	E (I)
	PZA
	EMB
3	Isoniazid rifampin PZA EMB	3 times weekly for 24 doses (8 wk)	3a	Isoniazid/rifampin	3 times weekly for 54 doses (18 wk)	78 (26 wk)	B (I)	B (II)
4	Isoniazid rifampin	7 days/wk for 56 doses (8 wk) or 5 days/wk for 40 doses (8 wk)^c	4a	Isoniazid/rifampin	7 days/wk for 217 doses (31 wk) or 5 days/wk for 155 doses (31 wk)^e	273-195 (39 wk)	C (I)	C (II)
	EMB		4b	Isoniazid/rifampin	Twice weekly for 62 doses (31 wk)	118-102 (39 wk)	C (I)	C (II)
Definition of abbreviations: EMB, Ethambutol; Isoniazid, isoniazid; PZA, pyrazinamide; rifampin, rifampin; RPT, rifapentine. ^aDefinitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given. ^bDefinition of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. ^cWhen DOT is used, drugs may be given 5 days/wk and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. ^dPatients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 wk; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. ^eFive-day-a-week administration is always given by DOT. Rating for 5 day/wk regimens is AIII. ^fOptions 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months. ^gNot recommended for HIV-Infected patients with CD4⁺ cell counts <100 cellsВµL. ^g Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.

TABLE. Doses^a of Antituberculosis Drugs for Adults and Children^b

Drug	Preparation	Adults/Children	Doses
Drug	Preparation	Adults/Children	*Daily*	*11x/wk*	*2x/wk*	*3x/wk*
First-Line Drugs
Isoniazid	Tablets (50 mg, 100 mg, 300 mg); elixir (50 mg/5 ml); aqueous solution (100 mg/mL) for intravenous or intramuscular injection	Adults (max.) Children (max.)	5 mg/kg (300 mg) 10-15 mg/kg (300 mg)	15 mg/kg (900 mg) –	15 mg/kg (900 mg) 20-30 mg/kg (900 mg)	15 mg/kg (900 mg) –
Rifampin	Capsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection	Adults^c (max.) Children (max.)	10 mg/kg (600 mg) 10-20 mg/kg (600 mg)	– –	10 mg/kg (600 mg) 10-20 mg/kg (600 mg)	10 mg/kg (600 mg) –
Rifabutin	Capsule (150 mg)	Adults^c (max.)	5 mg/kg (300 mg)	–	5 mg/kg (300 mg)	5 mg/kg (300 mg)
		Children	Appropriate dosing for children is unknown	Appropriate dosing for children is unknown	Appropriate dosing for children is unknown	Appropriate dosing for children is unknown
Rifapentine	Tablet (150 mg, film coated)	Adults	–	10 mg/kg (continuation phase) (600 mg)	–	–
		Children	The drug is not approved for use in children	The drug is not approved for use in children	The drug is not approved for use in children	The drug is not approved for use in children
Pyrazinamide	Tablet (500 mg, scored)	Adults	1000 mg (40-55 kg)	–	2000 mg (40-55 kg)	1500 mg (40-55 kg)
			1500 mg (56-75 kg)	–	3000 mg (56-75 kg)	2500 mg (56-75 kg)
			2000 mg (76-90 kg)^d	–	4000 mg (76-90 kg)^d	3000 mg (76-90 kg)^d
		Children (max.)	15-30 mg/kg (2 g)	–	50 mg/kg (2 g)	–
Ethambutol	Tablet (100 mg, 400 mg)	Adults	800 mg (40-55 kg)	–	2000 mg (40-55 kg)	1200 mg (40-55 kg)
			1200 mg (56-75 kg)	–	2800 mg (56-75 kg)	2000 mg (56-75 kg)
			1600 mg (76-90 kg)^d	–	4000 mg (76-90 kg)^d	2400 mg (76-90 kg)^d
		Children^e (max.)	15-20 mg/kg daily (1 g)	–	50 mg/kg (2.5 g)	–
Second-Line Drugs
Cycloserine	Capsule (250 mg)	Adults (max.)	10-15 mg/kg/day (1 g in two doses), usually 500-750 mg/d in two doses^f	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
		Children (max.)	10-15 mg/kg/day (1 g/day)	–	–	–
Ethionamide	Tablet (250 mg)	Adults^g (max.)	15-20 mg/kg/day (1 g/day), usually 500-750 mg/day in a single daily dose or two divided doses^g	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
		Children (max.)	15-20 mg/kg/day (1 g/day)	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
Streptomycin	Aqueous solution (1-g vials) for intravenous or intramuscular administration	Adults (max.) Children (max.)	h 20-40 mg/kg/day (1 g)	h –	h 20 mg/kg	h –
Amikacin/ kanamycin	Aqueous solution (500-mg and 1-g vials) for intravenous or intramuscular administration	Adults (max.) Children (max.)	h 15-30 mg/kg/day (1 g) intravenous or intramuscular as a single daily dose	h –	h 15-30 mg/kg	h –
Capreomycin	Aqueous solution (1-g vials) for intravenous or intramuscular administration	Adults (max.) Children (max.)	h 15-30 mg/kg/day (1 g) as a single daily dose	h –	h 15-30 mg/kg	h –
p-Aminosalicylic acid (PAS)	Granules (4-g packets) can be mixed with food; tablets	Adults	8-12 g/day in 2-3 doses	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
	(500 mg) are still available in some countries, but not in the United States; a solution for intravenous administration is available in Europe
		Children	200-300 mg/kg/day in 2-4 divided doses (10 g)	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
Levofloxacin	Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500-mg vials) for intravenous injection	Adults	500-1000 mg daily	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
		Children	i	i	i	i
Moxifloxacin	Tablets (400 mg); aqueous solution (400 mg/250 mL) for intravenous injection	Adults	400 mg daily	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
		Children	j	j	j	j
Gatifloxacin	Tablets (400 mg); aqueous solution (200 mg/20 mL; 400 mg/40 mL) for intravenous injection	Adults	400 mg daily	There are no data to support intermittent administration	There are no data to support intermittent administration	There are no data to support intermittent administration
		Children	k	k	k	k
^aDose per weight is based on ideal body weight. Children weighing more than 40 kg should be dosed as adults.
^bFor purposes of this document adult dosing begins at age 15 yr. ^cDose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. ^dMaximum dose regardless of weight. ^eThe drug can likely be used safely in older children but should be used with caution in children less than 5 yr of age, in whom visual acuity cannot be monitored. In younger children EMB at the dose of 15 mg/kg/day can be used if there is suspected or proven resistance to Isoniazid or rifampin. ^fIt should be noted that, although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for patients to be able to tolerate this amount. Serum concentration measurements are often useful in determining the optimal dose for a given patient. ^gThe single daily dose can be given at bedtime or with the main meal. ^hDose: 15 mg/kg/day (1 g), and 10 mg/kg in persons more than 59 yr of age (750 mg). Usual dose: 750-1000 mg administered intramuscularly or intravenously, given as a single dose 5-7 days/wk and reduced to 2 or 3 times/wk after the first 2-4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen. ⁱThe long-term (more than several weeks) use of levofloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with tuberculosis caused by organisms resistant to both Isoniazid and rifampin. The optimal dose is not known. ^jThe long-term (more than several weeks) use of moxifloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. The optimal dose is not known. ^kThe long-term (more than several weeks) use of gatifloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. The optimal dose is not known.

If the organism is drug resistant, the aim is to introduce two or more active agents that the patient has not received previously. With MDR-Tuberculosis, no standard regimen can be proposed. It is critical to avoid monotherapy or adding only a single drug to a failing regimen.

Drug Resistance

Drug resistance should be suspected in the following situations:

Patients who have received prior therapy for Tuberculosis
Patients from geographic areas with a high prevalence of resistance (New York City, Mexico, Southeast Asia, and the former Soviet states)
Patients who are homeless, institutionalized, intravenous drug abusers, and/or infected with HIV
Patients who still have acid-fast bacilli (AFB)-positive sputum smears after 2 months of therapy
Patients who still have positive cultures after 3 to 4 months of therapy
Patients who require retreatment

Special Populations

Tuberculous meningitis and Extrapulmonary disease

In general, isoniazid, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid readily. Patients with central nervous system tuberculosis are often treated for longer periods (9 to 12 months). Extrapulmonary Tuberculosis of the soft tissues can be treated with conventional regimens. Tuberculosis of the bone is typically treated for 9 months, occasionally with surgical debridement.

Children

Tuberculosis in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months.

Pregnant women

The usual treatment of pregnant women is isoniazid, rifampin, and ethambutol for 9 months.
Women with Tuberculosis should be cautioned against becoming pregnant, as the disease poses a risk to the fetus as well as to the mother. Isoniazid or ethambutol are relatively safe when used during pregnancy. Supplementation with B vitamins is particularly important during pregnancy. Rifampin has been rarely associated with birth defects, but those seen are occasionally severe, including limb reduction and central nervous system lesions. Pyrazinamide has not been studied in a large number of pregnant women, but anecdotal information suggests that it may be safe. Ethionamide may be associated with premature delivery, congenital deformities, and Down’s syndrome when used during pregnancy. Streptomycin has been associated with hearing impairment in the newborn, including complete deafness.

HIV-infected patients

AIDS patients and other immunocompromised hosts may be managed with chemotherapeutic regimens similar to those used in immunocompetent individuals, although treatment is often extended to 9 months.

Renal failure

In nearly all patients, isoniazid and rifampin do not require dose modifications in renal failure. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly (Table Dosing Recommendations for Adults Patients with Reduced Renal Function and for Adult Patients Receiving Hemodialysis).

TABLE. Dosing Recommendations for Adults Patients with Reduced Renal Function and for Adult Patients Receiving Hemodialysis

Drug	Change in Frequency?	Recommended Dose and Frequency for Patients with Creatinine Clearance <30 mL/min or for Patients Receiving Hemodialysis
Isoniazid	No change	300 mg once daily, or 900 mg 3 times/wk
Rifampin	No change	600 mg once daily, or 600 mg 3 times/wk
Pyrazinamide	Yes	25-35 mg/kg per dose 3 times/wk (not daily)
Ethambutol	Yes	15-25 mg/kg per dose 3 times/wk (not daily)
Levofloxacin	Yes	750-1000 mg per dose 3 times/wk (not daily)
Cycloserine	Yes	250 mg once daily, or 500 mg/dose 3 times/week^a
Ethionamide	No change	250-500 mg per dose daily
p-Aminosalicylic acid	No change	4 g per dose, twice daily
Streptomycin	Yes	12-15 mg/kg per dose 2 or 3 times/wk (not daily)
Capreomycin	Yes	12-15 mg/kg per dose 2 or 3 times/wk (not daily)
Kanamycin	Yes	12-15 mg/kg per dose 2 or 3 times/wk (not daily)
Amikacin	Yes	12-15 mg/kg per dose two or 3 times/wk (not daily)
Note: Standard doses are given unless there is intolerance. The medications should be given after hemodialysis on the day of hemodialysis. Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation, and to assist in avoiding toxicity. Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving hemodialysis and verify adequacy of dosing, using serum concentration monitoring. ^aThe appropriateness of 250-mg daily doses has not been established. There should be careful monitoring for evidence of neurotoxicity.