Extrapulmonary tuberculosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

latent TB infection: nonpregnant

1st line – antituberculous therapy

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1st line –

antituberculous therapy

People who have had significant exposure to an active infectious TB case in the previous 1-2 years should be evaluated for active TB disease and latent TB infection (LTBI). A repeat test for LTBI (TB skin test or interferon-gamma release assay) is recommended 8-10 weeks after the last exposure, if the initial evaluation was performed prior to this and the initial test result was negative.

The decision whether to treat depends on the duration, proximity, and environment of exposure, as well as the immune status of the exposed contacts.[38][88]

For patients with LTBI that is presumed to be susceptible to isoniazid or rifampin, US guidelines’ preferred regimens are rifamycin-based: 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin.[88][89][95][96]

Three months of weekly isoniazid plus rifapentine given as directly observed therapy (DOT) or self-administered therapy (SAT) is recommended for adults and children aged >2 years, including those who have HIV infection where antiretroviral therapy drug interactions are acceptable.[88][89][95][97][98][99][100] The regimens of 4 months of daily rifampin and 3 months of daily isoniazid plus rifampin are recommended for adults and children of all ages; however, the US guidelines note that there is no evidence available for effectiveness of 4 months of daily rifampin in patients with HIV infection and it may be considered only as an alternative option to the other regimens in patients with HIV.[88][95] Note that rifampin and rifapentine are not interchangeable between these regimens. Rifamycins should only be used if there are no significant interactions with other medications (e.g., antiretroviral therapy).

Regimens of daily or intermittent isoniazid for 6 or 9 months are alternative options for adults and children of all ages. Intermittent regimens (i.e., twice weekly) should be given as directly observed therapy.[88][89][95] The shorter course rifamycin-based regimens are preferred to isoniazid monotherapy, as they are more likely to be completed. Isoniazid may be preferred when it is difficult to manage drug interactions between a patient’s other medications and the rifamycins.

Peripheral neuropathy is a common adverse effect of isoniazid due to pyridoxine antagonism. Pyridoxine supplementation should, therefore, be considered for the prevention of peripheral neuropathy in patients with latent infection taking isoniazid, particularly in those in whom neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition, HIV infection), pregnant women, or patients with seizure disorders.[21][88][104]

Ideally, all medications within a given regimen should be administered at the same time. If the patient cannot tolerate the pill burden, different medications can be administered separately, but the dose of each individual medication should not be split up. Consult guidelines for dosing information.[46]

Patients with complex comorbidity, or for whom treatment is contraindicated, should be managed after expert consultation.

For patients with LTBI presumed to be due to contact with an infectious patient with drug-resistant TB, expert consultation should be sought.[88][96][103][104] For patients exposed to isoniazid-resistant TB, 4 months of daily rifampin may be an option.[96][104]

US guidelines recommend that patients with multidrug-resistant (MDR) TB are treated with 6-12 months of a fluoroquinolone (i.e., levofloxacin or moxifloxacin) alone or in combination with a second agent based on susceptibility testing of the source isolate.[103] Specific regimens are not detailed here. World Health Organization (WHO) guidelines recommend that in selected high-risk household contacts of patients with MDR TB, preventive treatment may be considered based on individualized risk assessment and a sound clinical justification.[104]

Primary options

isoniazid: children 2-11 years of age: 25 mg/kg orally/intramuscularly once weekly for 3 months, maximum 900 mg/dose; children ≥12 years of age and adults: 15 mg/kg orally/intramuscularly once weekly for 3 months, maximum 900 mg/dose

and

rifapentine: children ≥2 years of age and body weight 10-14 kg: 300 mg orally once weekly for 3 months; children ≥2 years of age and body weight 14.1 to 25 kg: 450 mg orally once weekly for 3 months; children ≥2 years of age and body weight 25.1 to 32 kg: 600 mg orally once weekly for 3 months; children ≥2 years of age and adults body weight 32.1 to 49.9 kg: 750 mg orally once weekly for 3 months; children ≥2 years of age and adults body weight ≥50 kg: 900 mg orally once weekly for 3 months

rifampin: children: 15-20 mg/kg orally/intravenously once daily for 4 months, maximum 600 mg/day; adults: 10 mg/kg orally/intravenously once daily for 4 months, maximum 600 mg/dose

isoniazid: children: 10-20 mg/kg orally/intramuscularly once daily for 3 months, maximum 300 mg/dose; adults: 5 mg/kg orally/intramuscularly once daily for 3 months, maximum 300 mg/dose

and

rifampin: children: 15-20 mg/kg orally/intravenously once daily for 3 months, maximum 600 mg/day; adults: 10 mg/kg orally/intravenously once daily for 3 months, maximum 600 mg/dose

Secondary options

isoniazid: children: 10-20 mg/kg orally/intramuscularly once daily for 6 or 9 months, maximum 300 mg/dose; adults: 5 mg/kg orally/intramuscularly once daily for 6 or 9 months, maximum 300 mg/dose

isoniazid: children: 20-40 mg/kg orally/intramuscularly twice weekly for 6 or 9 months, maximum 900 mg/dose; adults: 15 mg/kg orally/intramuscularly twice weekly for 6 or 9 months, maximum 900 mg/dose

latent TB infection: pregnant

1st line – referral to specialist

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1st line –

referral to specialist

Pregnancy has minimal influence on progression of latent TB infection to active disease, and pregnant women should be tested based on the presence of risk factors. If there is a high risk for progression to TB (e.g., recent TB infection, HIV infected), immediate treatment is indicated. Otherwise treatment may be deferred until at least 3 months postpartum because of increased incidence of serious drug-induced hepatitis during peripartum period.

Specialist consultation is recommended in pregnancy.

ACUTE

active TB: nonpregnant, HIV-negative

drug resistance not suspected

1st line – intensive phase therapy

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1st line –

intensive phase therapy

Antituberculous therapy is initiated based on clinical suspicion after optimal diagnostic samplings.

While awaiting that information, an empiric regimen may be used. The final regimen will be based on the results of drug-susceptibility testing.

All medications should be administered together.

Intensive phase should continue for 2 months, with the ultimate duration to be determined on the basis of eventual drug susceptibilities and expert consultation.[46]

In patients with drug-susceptible TB, the initial intensive-phase treatment involves the first-line drugs of isoniazid, rifampin, pyrazinamide, and ethambutol, for 2 months.[46]

In children with suspected drug-susceptible TB meningitis, ethambutol may be replaced with ethionamide or a fluoroquinolone.[96][105] Ethionamide has been shown to cross the blood-brain barrier in higher concentrations.[96]

Pyrazinamide is not recommended for patients experiencing acute gout as it further elevates uric acid levels. Older patients (ages >75 years) may not tolerate pyrazinamide and providers may consider leaving it out of treatment regimens.[46] Patients who do not receive pyrazinamide during the intensive phase should receive 7 months of continuation phase (to give 9 months of total treatment).

Regimens may need to be modified in patients with hepatic injury or renal insufficiency; a specialist should be consulted for guidance on choice of regimen and appropriate doses. Several TB drugs are metabolized by the liver and may potentially cause or exacerbate hepatic injury. Mild hepatitis may require only closer monitoring without changes in the standard regimen. However, severe hepatitis while on TB treatment may make it necessary to hold medications and use an alternate liver-sparing regimen. Dose adjustments may be required in patients with renal insufficiency or end-stage renal disease.[46]

As there is increased risk of retrobulbar neuritis resulting from ethambutol toxicity in patients with renal failure, particular attention to testing of visual acuity/color discrimination and counseling of patients is also required in this population.

Primary options

isoniazid: children <40 kg body weight: 10-15 mg/kg orally/intramuscularly once daily (maximum 300 mg/dose); children ≥15 years of age or ≥40 kg body weight and adults: 5 mg/kg orally/intramuscularly once daily (maximum 300 mg/dose)Pyridoxine (vitamin B6) is given with isoniazid to all people at risk of neuropathy.

and

rifampin: children <40 kg body weight: 10-20 mg/kg orally/intravenously once daily (maximum 600 mg/dose); children ≥15 years of age or ≥40 kg body weight and adults: 10 mg/kg orally/intravenously once daily (maximum 600 mg/dose)

and

pyrazinamide: children and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

and

ethambutol: children and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

Plus – continuation phase therapy

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Plus –

continuation phase therapy

Treatment recommended for ALL patients in selected patient group

Duration of the continuation phase depends on the site of infection and severity of disease. Generally, for EPTB that does not involve CNS or bones and joints, continuation phase therapy is given for 4 months (i.e., 6 months of total treatment). Patients who do not receive pyrazinamide during the intensive phase should receive 7 months of continuation phase (to give 9 months of total treatment).

Total therapy for 9 months is considered for patients with extensive skeletal TB, especially when large joints are involved with slow clinical response.[46] Patients with central nervous system (CNS) TB receive 7-10 months of continuation phase therapy (9-12 months total).[46] For children with HIV and skeletal TB, CNS TB, or disseminated/miliary disease, total therapy should be given for at least 12 months.[96]

In children with peripheral lymph node TB, a continuation phase of 2 months can be considered (4 months total).[105]

Primary options

and

Consider – corticosteroid

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Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

Corticosteroids may be used in limited situations. Adjunctive corticosteroid therapy attenuates the inflammatory response in TB meningitis and results in improved survival.[110][111] [ ]

Limited evidence suggests there may be a mortality benefit for use of corticosteroids in TB pericarditis without HIV infection.[113] Currently, the ATS/CDC/IDSA guideline suggests that adjunctive corticosteroid therapy should not be routinely used in patients with TB pericarditis but may be appropriate for selected patients who are at the highest risk for inflammatory complications, including those with large pericardial effusions, high levels of inflammatory markers, or signs of constriction.[46]

Consult local guidelines for dosing information as dose regimens vary.

Primary options

dexamethasone: children and adults: consult specialist for guidance on dose

prednisone: children and adults: consult specialist for guidance on dose

isoniazid resistance

1st line – antituberculous therapy

Back

1st line –

antituberculous therapy

Drug-resistance may be suspected on the basis of historic or epidemiologic information. Isoniazid-resistant TB is defined as resistance to isoniazid and susceptibility to rifampin that has been confirmed in vitro.

In patients with confirmed rifampin-susceptible and isoniazid-resistant pulmonary TB, US and World Health Organization (WHO) guidelines recommend treatment with a 6-month regimen of rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone.[108][103] The WHO guidelines note that this regimen is likely to be effective in patients with extrapulmonary TB, but that no data are available for patients with exclusive extrapulmonary isoniazid-resistant TB.[108]

Consultation with an appropriate specialist is recommended to determine the most appropriate antituberculous therapy and supportive care.

multidrug resistance

1st line – antituberculous therapy

Back

1st line –

antituberculous therapy

Drug resistance may be suspected on the basis of historic or epidemiologic information. Multidrug-resistant (MDR) TB is defined as resistance to isoniazid and rifampin, with or without resistance to other first-line drugs. Extensively drug-resistant (XDR) TB is defined as resistance to at least isoniazid and rifampin, as well as any fluoroquinolone and either bedaquiline or linezolid (or both).[109]

Pre-XDR-TB is resistance to isoniazid, rifampin, and any fluoroquinolone.

The treatment regimen should be based on the results of drug susceptibility testing. Consultation with an appropriate specialist is recommended to determine the most appropriate antituberculous therapy and supportive care.

US guidelines now recommend that at least five drugs are used in the intensive phase of treatment, and four drugs in the continuation phase.[103] The duration of treatment will vary; however, the intensive phase is 5-7 months after culture conversion, and treatment then continues for a total of 15-21 months (after culture conversion), or 15-24 months for extensively drug-resistant (XDR) TB.[103]

The regimen should include the following oral agents: one later-generation fluoroquinolone (i.e., levofloxacin or moxifloxacin), bedaquiline, linezolid, clofazimine, cycloserine, or terizidone.If the regimen cannot be assembled with five effective oral drugs, the injectable agents amikacin or streptomycin may be used (depending on susceptibility testing). Agents that may be used in place of the injectables include pyrazinamide, ethambutol, and delamanid (note: delamanid was approved for the treatment of multidrug-resistant (MDR)-TB by the European Medicines Agency in 2013 but has not yet received Food and Drug Administration approval; the US guideline writing committee agrees with the WHO consolidated guidelines on drug-resistant tuberculosis treatment that delamanid may be included in the treatment of patients with MDR/rifampin‐resistant-TB ages ≥3 years on longer regimens).[108] If more effective options are not available to assemble a regimen of five drugs, then the following options may be considered: ethionamide or prothionamide; a carbapenem (e.g., imipenem/cilastatin or meropenem) plus clavulanate (note: clavulanate is only available as a co-formulation with amoxicillin; therefore, amoxicillin/clavulanate must be given with the carbapenem when using this regimen); aminosalicylic acid; or high-dose isoniazid.

The World Health Organization guideline on MDR TB includes recommendations for short (6 or 9 months) and longer (18 months or more) regimens for the treatment of people with drug-resistant TB.[108] The short-course regimens (which are only recommended for pulmonary TB and uncomplicated extrapulmonary TB) are a major step forward for low- and middle-income settings where access to second-line drug susceptibility testing may not be available. In places with the ability to check second-line drug sensitivities (as is the case in the US), creation of an appropriate regimen would be based on drug susceptibilities. The short-course regimens may expose patients to drugs that are not indicated. The US guideline makes no recommendation for or against a standardized, shorter-course regimen at this time.[103]

active TB: nonpregnant, HIV-positive

drug resistance not suspected

1st line – intensive phase therapy

Back

1st line –

intensive phase therapy

Treatment of TB in HIV-positive patients follows the same general principles as in other patients with TB. In patients with drug-susceptible TB, the initial intensive-phase treatment involves the first-line drugs of isoniazid, rifampin, pyrazinamide, and ethambutol, for 2 months.[46] However, there are some additional considerations, including the potential for drug interactions, especially between rifampin and antiretrovirals (non-nucleoside reverse-transcriptase inhibitors and protease-inhibitors). For this reason, rifabutin may be considered as an alternative to rifampin.[46] Dosage should be adjusted as necessary.

Patients with TB and HIV infection should receive antiretroviral therapy (ART) during antituberculosis treatment. ART should be started within 2 weeks for those patients with a CD4 count <50 cells/microliter, except for those with central nervous system TB.[46][88]

The antituberculous therapy is given once-daily on 5 days per week by directly observed therapy (DOT) during the intensive phase with the weekend/holiday doses self-administered.[46] All medications are administered together.

Treatment duration for this phase is 8 weeks. After week 8, the continuation phase is started. TB medications should be administered daily; intermittent twice-weekly administration is not recommended for HIV-positive patients. The preferred method for HIV patients is daily DOT.[46]

Primary options

-- AND --

rifabutin: children <40 kg body weight: consult specialist for guidance on dose; children ≥15 years of age or ≥40 kg body weight and adults: 5 mg/kg orally once daily (maximum 300 mg/dose)

-- AND --

pyrazinamide: children and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

-- AND --

ethambutol: children and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

Plus – continuation phase therapy

Back

Plus –

continuation phase therapy

Treatment recommended for ALL patients in selected patient group

Treatment of TB in HIV-positive patients follows the same general principles as in other patients with TB. However, there are some additional considerations, including the potential for drug interactions, especially antiretrovirals. For this reason, rifabutin may be considered as an alternative to rifampin. Dosage should be adjusted as necessary.

Patients with TB and HIV infection should have antiretroviral therapy (ART) during antituberculosis treatment. ART should be started within 2 weeks for those patients with a CD4 count <50 cells/microliter, except for those with central nervous system TB.[46][88]

After 2 months of intensive phase treatment in patients with drug-susceptible EPTB, pyrazinamide and ethambutol (or alternatives) are discontinued, and isoniazid and rifampin are given for the continuation phase.[46] Duration of the continuation phase depends on the site of infection and severity of disease. Generally, for EPTB that does not involve CNS or bones and joints, continuation phase therapy is given for 4 months (i.e. 6 months of total treatment).

Primary options

-- AND --

rifabutin: children <40 kg body weight: consult specialist for guidance on dose; children ≥15 years of age or ≥40 kg body weight and adults: 5 mg/kg orally once daily (maximum 300 mg/dose)

Consider – corticosteroid

Back

Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

Corticosteroids may be used in limited situations. Adjunctive corticosteroid therapy attenuates the inflammatory response in TB meningitis and results in improved survival.[110][111] [ ]

The American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC)/Infectious Diseases Society of America (IDSA) guideline recommends initial adjunctive corticosteroid therapy with dexamethasone or prednisone tapered over 6-8 weeks for patients with tuberculous meningitis.[46] Guidelines for the prevention and treatment of opportunistic infections in those with HIV recommend adjunctive treatment with dexamethasone for adults with TB involving the CNS, though notes that studies involving those with HIV are limited.[88] One subsequent randomized controlled trial in adults with HIV infection and TB meningitis found that adjunctive dexamethasone did not reduce mortality over 12 months (death from any cause) compared with placebo.[112] Guidelines for the prevention and treatment of opportunistic infections in children with HIV recommend considering adjunctive corticosteroid treatment for those with TB meningitis.[96]

Limited evidence suggests there may be a mortality benefit for use of corticosteroids in TB pericarditis.[113] Currently, the ATS/CDC/IDSA guideline suggests that adjunctive corticosteroid therapy should not be routinely used in patients with TB pericarditis but may be appropriate for selected patients who are at the highest risk for inflammatory complications, including those with large pericardial effusions, high levels of inflammatory markers, or signs of constriction.[46] Guidelines for the prevention and treatment of opportunistic infections in those with HIV state that adjunctive corticosteroid therapy is not recommended in the treatment of adults and adolescents with TB pericarditis; however, it may be considered in children.[88][96]

Consult local guidelines for dosing information as dose regimens vary.

Primary options

dexamethasone: children and adults: consult specialist for guidance on dose

prednisone: children and adults: consult specialist for guidance on dose

isoniazid resistance

1st line – antituberculous therapy

Back

1st line –

antituberculous therapy

In patients with confirmed rifampin-susceptible and isoniazid-resistant pulmonary TB, US and World Health Organization (WHO) guidelines recommend treatment with a 6-month regimen of rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone.[103][108] The WHO guidelines note that this regimen is likely to be effective in patients with extrapulmonary TB, but that no data are available for patients with exclusive extrapulmonary isoniazid-resistant TB.[108]

Consultation with an appropriate specialist is recommended to determine the most appropriate antituberculous therapy and supportive care.

multidrug resistance

1st line – antituberculous therapy

Back

1st line –

antituberculous therapy

Drug resistance may be suspected on the basis of historical or epidemiologic information. Multidrug-resistant (MDR) TB is defined as resistance to isoniazid and rifampin, with or without resistance to other first-line drugs. Extensively drug-resistant (XDR) TB is defined as resistance to at least isoniazid and rifampin, as well as any fluoroquinolone and either bedaquiline or linezolid (or both).[109] Pre-XDR-TB is resistance to isoniazid, rifampin, and any fluoroquinolone.

The treatment regimen should be based on the results of drug susceptibility testing.Consultation with an appropriate specialist is recommended to determine the most appropriate antituberculous therapy and supportive care.

The regimen should include the following oral agents: one later generation fluoroquinolone (i.e., levofloxacin or moxifloxacin), bedaquiline, linezolid, clofazimine, cycloserine, or terizidone. If the regimen cannot be assembled with five effective oral drugs, the injectable agents amikacin or streptomycin may be used (depending on susceptibility testing). Agents that may be used in place of the injectables include pyrazinamide, ethambutol, and delamanid (note: delamanid was approved for the treatment of multidrug-resistant (MDR)-TB by the European Medicines Agency in 2013 but has not yet received Food and Drug Administration approval; the US guideline writing committee agrees with the WHO consolidated guidelines on drug-resistant tuberculosis treatment that delamanid may be included in the treatment of patients with MDR/rifampin‐resistant-TB ages ≥3 years on longer regimens).[108] If more effective options are not available to assemble a regimen of five drugs, then the following options may be considered: ethionamide or prothionamide; a carbapenem (e.g., imipenem/cilastatin or meropenem) plus clavulanate (note: clavulanate is only available as a co-formulation with amoxicillin; therefore, amoxicillin/clavulanate must be given with the carbapenem when using this regimen); aminosalicylic acid; or high-dose isoniazid.

active TB: pregnant

1st line – referral to specialist

Back

1st line –

referral to specialist

Expert consultation is obtained. Antituberculous therapy is initiated based on clinical suspicion after optimal diagnostic samplings.

While awaiting that information, an expanded empiric regimen may be used. The final regimen will be based on the results of drug-susceptibility testing.

Use of pyrazinamide in pregnant women is controversial due to lack of detailed teratogenicity data, but it should be considered in patients with EPTB, particularly when HIV co-infection is present. Patients who do not receive pyrazinamide during the intensive phase should receive 7 months of continuation phase (to give 9 months of total treatment).

All medications should be administered together.

Intensive therapy should continue for 2 months, with the ultimate duration to be determined on the basis of eventual drug susceptibilities and expert consultation.[46]

Treatment of drug-resistant TB, especially multidrug-resistant (MDR) TB, should be attempted only with expert advice.

Drug-resistance may be suspected on the basis of historical or epidemiologic information. MDR isolates are resistant to at least both isoniazid and rifampin.[103][108][116]

Consult a specialist for guidance on choice of regimen and doses.

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Extrapulmonary tuberculosis

Treatment algorithm

latent TB infection: nonpregnant

antituberculous therapy

Primary options

Secondary options

latent TB infection: pregnant

referral to specialist

active TB: nonpregnant, HIV-negative

intensive phase therapy

Primary options

continuation phase therapy

Primary options

corticosteroid

Primary options

antituberculous therapy

antituberculous therapy

active TB: nonpregnant, HIV-positive

intensive phase therapy

Primary options

continuation phase therapy

Primary options

corticosteroid

Primary options

antituberculous therapy

antituberculous therapy

active TB: pregnant

referral to specialist