Centers for Disease Control and Prevention (CDC)-recommended treatment regimens for adults and children include an initial phase treatment with isoniazid, rifampin, pyrazinamide, and ethambutol, and then continuation-phase treatment based on chest x-ray and sputum culture results (Table 54-3). In children whose visual acuity cannot be monitored, ethambutol is rarely recommended unless there is an increased likelihood of disease caused by isoniazid-resistant organisms or when the child has “adult-type” (upper lobe infiltration, cavity formation) TB. Extrapulmonary TB requires 6 months of therapy, except bone and joint disease requires 6–9 months, and neurotuberculosis requires 9–12 months. Corticosteroids are generally not recommended but are strongly recommended in cases of TB pericarditis and neurotuberculosis.
Table 54-3.Treatment regimens for patients with culture-positive pulmonary tuberculosis caused by drug-susceptible organisms (CDC guidelines). ||Download (.pdf) Table 54-3.Treatment regimens for patients with culture-positive pulmonary tuberculosis caused by drug-susceptible organisms (CDC guidelines).
|Initiation Phase ||Continuation Phase || |
|Agents ||Dosage and Minimal Duration ||Agents ||Dosage and Minimal Duration ||Length of Therapy (Total Doses) ||Notes |
|Isoniazid (INH), rifampin (RIF), pyrazinamide, ethambutol ||Once daily for 8 weeks (56 doses) or 5 times per week for 8 weeks (40 doses DOT) ||Isoniazid and rifampin ||Once daily for 18 weeks (126 doses) or 5 times per week for 18 weeks (90 doses DOT) ||26 weeks (130–182) || |
Directly observed therapy (DOT) required for <7 times a week dosing.
Daily regimen is required if HIV- positive.
When susceptibility testing shows sensitivity to INH and RIF, then ethambutol may be discontinued.
If sputum is smear-positive at 2 months, repeat smear at 3 months.
| || ||Isoniazid and rifampin ||Twice weekly for 18 weeks (36 doses DOT) ||26 weeks (76–92) ||Intermittent dosing not recommended for HIV- positive patients. |
| || ||Isoniazid and rifampin ||Once weekly for 18 weeks (18 doses DOT) ||26 weeks (58–74) ||Only for HIV-negative patients with no cavity on CXR and negatove sputum at 2 months. |
| || ||Isoniazid and rifampin ||Daily for 31 weeks (217 doses, 155 DOT) ||39 weeks (195–273) ||If cavity on CXR and sputum positive at 2 months, maintain continuation phase for 31 weeks. |
| || ||Isoniazid and rifampin || |
Twice weekly for 31 weeks
(62 doses DOT)
|39 weeks (102–118) || |
|Isoniazid, rifampin, pyrazinamide, ethambutol ||Once daily for 2 weeks, then twice weekly for 6 weeks (26 doses DOT) or 5 times per week for 2 weeks, then twice weekly for 6 weeks (22 doses DOT) ||Isoniazid and rifampin ||Twice weekly for 18 weeks (36 doses DOT) ||26 weeks (58–62) ||Intermittent dosing not recommended for HIV-positive patients |
| || ||Isoniazid and rifapentine ||Once weekly for 18 weeks (18 doses DOT) ||26 weeks (40–44) ||Only for HIV-negative patients with no cavity on CXR and negative sputum at 2 months. |
|Isoniazid, rifampin, pyrazinamide, ethambutol ||3 times per week for 8 weeks (24 doses DOT) ||Isoniazid and rifampin ||3 times per week for 18 weeks (54 doses DOT) ||26 weeks (78) || |
|Isoniazid, rifampin, ethambutol ||Once daily for 8 weeks (56 doses) or 5 times per week for 8 weeks (40 doses DOT) ||Isoniazid and rifampin ||Once daily for 31 weeks (217 doses) or 5 times per week for 31 weeks (155 doses DOT) ||39 weeks (195–273) ||May withhold pyrazinamide if pregnant, severe liver disease, or gout with extended continuation phase. |
| || ||Isoniazid and rifampin ||Twice weekly for 31 weeks (62 doses DOT) ||39 weeks (102–118) || |
Initial empiric therapy usually includes four drugs daily for 2 months:
Isoniazid orally (PO), intravenously (IV), or intramuscularly (IM) 5 mg/kg daily (maximum 300 mg/day), 10–15 mg/kg daily in children (max 300); weekly adult dose 15 mg/kg (max 900 mg), twice weekly adult dose 15 mg/kg (max 900), children 20–30 mg/kg (max 900).
Rifampin PO or IV, adult 10 mg/kg daily (maximum 600 mg/day, children 10–20 mg/kg per day (max 600).
Pyrazinamide orally 25 mg/kg per day (maximum 2 g/day), 15–30 mg/kg daily in children.
Ethambutol orally 15 mg/kg per day (maximum 1.6 g/day), 20 mg/kg per day in children.
Streptomycin 15 mg/kg per day may be an additional drug or substituted for ethambutol in some patients.
Regardless of initial regimen, continuation phase typically is 4 months with isoniazid and rifampin.
The CDC-recommended number of doses to complete therapy is defined by completion of the recommended total number of doses, not necessarily the expected duration of therapy. If the specified number of doses cannot be administered in the expected timeframe, the initial phase can be extended to 3 months and doses for an 18-week continuation phase can be extended for 6 months If the longer timeframe is not feasible, consider as interrupted therapy. A 5-day/wk treatment with directly observed therapy (DOT) is considered equivalent to a 7-day/wk.
The WHO recommendations for dosing frequency in treatment of pulmonary TB in adults include DOT as the preferred initial management, and all patients receiving drugs <7 days a week must receive DOT. New patients with pulmonary TB may receive a daily intensive phase followed by 3 times weekly continuation phase if each dose is directly observed. New patients with pulmonary TB may receive 3 times weekly dosing throughout therapy, provided that every dose is directly observed therapy and the patient is not HIV-positive or living in an HIV-prevalent setting.
The standard regimen for new patients with TB is isoniazid, rifampin, pyrazinamide, and ethambutol orally daily for 2 months, followed by isoniazid and rifampin for 4 months. In countries with high levels of isoniazid resistance, in new patients, and where isoniazid drug susceptibility testing results are unavailable before the continuation phase begins, add ethambutol to 4-month isoniazid, rifampin continuation phase (recommendation based on expert opinion not evidence).
The WHO recommendations for treatment of TB in children (note higher dose of pyrazinamide compared to CDC) are as follows:
A. Treatment of Active TB in Patients with HIV
Initiation of antiretroviral therapy (ART) during antituberculosis therapy is associated with not only increased survival but also an increase in the risk of immune reconstitution inflammatory syndrome (IRIS). This paradoxical response as the patient is responding to the antiretroviral treatment is attributed to the stronger immune response to TB and includes fever, worsening pulmonary infiltrates, and lymphadenopathy and rarely, death.
The United States Department of Health and Human Services (DHHS) recommendations for timing of ART in patients with HIV and Mycobacterium tuberculosis (TB) coinfection [DHHS Guidelines on Use of Antiretroviral Agents in Adolescents and Adults with HIV-1 Infection (available at AIDSinfo2013Feb12PDF)] are as follows:
Recommended initial treatment is four drugs for 2 months, consisting of INH plus rifampicin (or rifampin) plus pyrazinamide plus ethambutol; rifabutin is substituted for rifampin in patients taking protease inhibitors or maraviroc. The preferred continuation therapy is INH plus rifampicin for 4 months, given once daily or 2–3 times weekly (but not twice weekly if CD4 counts <100 cells/μL). Duration of therapy is 6 months, except 9 months for patients with cavitary lung disease, delayed response to therapy, or extrapulmonary TB. Extending treatment from 6 months to 12 months in HIV-positive patients with pulmonary TB may reduce relapse rates. Long-term isoniazid plus sulfadoxine-pyrimethamine may reduce recurrence and sick days after recovery from pulmonary TB in patients with HIV infection.
Trimethoprim-sulfamethoxazole (cotrimoxazole) reduces mortality in HIV-positive patients treated for pulmonary TB. Add corticosteroids when treating central nervous system (CNS) and pericardial disease. Adjunctive prednisolone therapy may reduce mortality in patients with tuberculous pericarditis. Recommended daily doses are dexamethasone 0.3–0.4 mg/kg tapered over 6–8 weeks or prednisone 1 mg/kg for 3 weeks and then tapered for 3–5 weeks.
The World Health Organization (WHO) proposes the following approach that is useful in limited resource environments for the diagnosis and treatment of TB in HIV prevalent settings. For ambulatory patients with cough for 2–3 weeks and no danger signs [ie, respiratory rate >30/minute, fever >39°C (102.2°F), pulse rate > 120/minute, inability to walk unaided], obtain an acid-fast bacilli (AFB) and an HIV test at the first visit. Treat patients who are HIV-positive or whose status remains unknown as follows:
If AFB-positive–treat for TB, cotrimoxazole, HIV assessment.
If AFB-negative–chest x-ray, sputum AFB and culture, clinical assessment (all at same time wherever possible to decrease visits and time to diagnosis).
If TB likely–treat for TB, cotrimoxazole, HIV assessment
If TB unlikely–HIV assessment and one of following: (1) treat for bacterial infection plus cotrimoxazole; (2) treat for Pneumocystis carinii pneumonia, especially if hypoxic; (3) if there is a response, advise to return if symptoms recur; (4) if there is no or only partial response, reassess for TB.
The WHO recommendations for dosing regimens in HIV-positive and HIV-negative children are as follows:
Four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 4 months followed by isoniazid and rifampin regimen for 4 months should be given in any of following cases:
Children with extensive pulmonary disease.
Children living in places with high isoniazid resistance or high HIV prevalence (≥ 1% in adult pregnant women or ≥ 5% in patients with TB) who have suspected/confirmed either
Three-drug regimen (isoniazid, rifampin, pyrazinamide) for 2 months followed by a two-drug regimen of isoniazid and rifampin for 4 months can be given to children without HIV infection living in places with low HIV prevalence and isoniazid who have suspected/confirmed either
Avoid intermittent (2 times weekly or 3 times weekly) dosing regimens in children with HIV infection or in any children living in high-HIV-prevalence areas with suspected/confirmed pulmonary TB or tuberculous peripheral lymphadenitis.
During continuation phase, consider 3 times weekly regimens for HIV-negative children in settings with well-established DOT.
Treat children with suspected or confirmed tuberculous meningitis or osteoarticular TB with standard four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by standard two-drug regimen of isoniazid and rifampin for 10 months, for a total duration of treatment of 12 months.
The WHO recommendations for dosing frequency in HIV-positive patients are as follows:
B. Treatment of Multidrug-Resistant Tuberculosis (MDR-TB)
Never add only one new drug to an ineffective regimen. When starting or changing treatment, use at least three previously unused drugs that have demonstrated in vitro susceptibility and include one injectable agent in the regimen (two simultaneous injectable agents not recommended). Use more than three agents if other previously unused drugs likely to be active are available. In patients with multidrug-resistant TB resistant to isoniazid, rifampin, and other first-line agent regimens, consider regimens with four to six medications and institute hospital-based or home-based DOT for oral medications; intermittent therapy for injectable agents after 2–4 months of daily therapy is also an option.
Drug resistance patterns are as follows:
Rifampin resistance usually associated with cross-resistance to rifabutin and rifapentine; avoid rifabutin unless in vitro susceptibility is demonstrated.
No cross-resistance between streptomycin and other injectable agents amikacin, kanamycin, and capreomycin.
Cross-resistance between amikacin and kanamycin is universal.
If mono-resistance to pyrazinamide is demonstrated without resistance to other first-line drugs, evaluate for infection with Mycobacterium bovis.
For INH-resistant M. tuberculosis, use rifampin, pyrazinamide, and ethambutol for 6 months and add a fluoroquinolone as a fourth agent in extensive disease.
For RIF-resistant M. tuberculosis, use isoniazid, pyrazinamide, ethambutol either daily or 3 times weekly for 12 months. If extensive disease, consider adding a fluoroquinolone. If there is extensive disease, or to shorten duration of treatment, consider adding an injectable agent (streptomycin, amikacin, kanamycin, or capreomycin) during initial 2 months of therapy. Isoniazid, pyrazinamide, and streptomycin for 9 months has demonstrated efficacy, although an injectable agent for 9 months may not be feasible.
For INH- and RIF-resistant M. tuberculosis, use fluoroquinolone, pyrazinamide, ethambutol and injectable streptomycin, amikacin, kanamycin, or capreomycin for 18–24 months. If there is extensive disease, consider adding one of following for 18–24 months: ethionamide, cycloserine, p-aminosalicylic acid, clarithromycin, amoxicillin/clavulanate, or linezolid. Resectional surgery may be appropriate.
For INH and RIF plus either ethambutol- or pyrazinamide-resistant M. tuberculosis, use fluoroquinolone (either ethambutol or pyrazinamide if susceptibility demonstrated on testing), and an injectable agent (streptomycin, amikacin, kanamycin, or capreomycin) for 24 months. If there is extensive disease, consider adding two of the following for 24 months: ethionamide, cycloserine, p-aminosalicylic acid, clarithromycin, amoxicillin/clavulanate, or linezolid. Surgery may be appropriate since drug treatment may be very difficult.
2. WHO principles of treatment
WHO (WHO 2007 PDF, National Guideline Clearinghouse 2010 March 1: 13595) recommends using at least four drugs known to be effective. It recommends againsst using drugs that may have cross-resistance or are not safe, and recommends including drugs from groups 1 to 5 in a hierarchical order based on potency:
Group 1: first-line oral agents–use any or all of the following drugs if clinical or laboratory suggest susceptibility:
Group 2: injectable agents– use one of the following in the drug regimen if laboratory susceptibility is documented or suspected:
Group 3: fluoroquinolones–use one of the following if laboratory susceptibility is documented or is deemed efficacious:
Group 4: oral bacteriostatic second-line agents–use two or three of the following to obtain a regimen of at least four drugs:
Group 5: agents with unclear role in treatment of drug-resistant TB–use any two of the following in the drug regimen if unable to complete a four-drug regimen from selections in groups 1 to 4:
Children with proven or suspected multidrug-resistant pulmonary TB or tuberculous meningitis can be treated with a fluoroquinolone in the context of a well-functioning multidrug-resistant TB control program and within an appropriate multidrug-resistant TB regimen.
In populations with known or suspected high levels of isoniazid resistance, WHO recommends that new TB patients receive isoniazid, rifampin, and ethambutol as therapy in continuation phase as an acceptable alternative to isoniazid and rifampin. Daily dosing during initial intensive phase may also prevent acquired drug resistance in patients with suspected isoniazid resistance.
C. Options for Drug Intolerance
The CDC recommendations for drug intolerance are as follows:
For patients intolerant of isoniazid [Am J Respir Crit Care Med. 2003;167(4):603]:
For patients intolerant of rifampin:
Use isoniazid, pyrazinamide, and ethambutol for ≥2 months, followed by continuation of isoniazid and ethambutol to complete 12–18 months’ treatment.
Fluoroquinolones may be useful, but optimal length of therapy has not been defined.
Rifabutin has been substituted for rifampin in standard regimens if necessary to avoid drug interactions, generally with antiretroviral drugs.
For patients intolerant of pyrazinamide in initial therapy, use 7 months of isoniazid and rifampin for continuation therapy.