Treatment algorithm

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 – treatment for latent TB infection

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INITIAL
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latent TB infection: nonpregnant
1st line – 

treatment for latent TB infection

People who have had significant exposure to an active infectious TB case in the previous 1 to 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 to 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.[9][64]

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.[44][64][65]​​[71] Three months of weekly isoniazid plus rifapentine given as directly observed therapy (DOT) or self-administered therapy (SAT) is recommended for adults and children ages >2 years, including those who have HIV infection where antiretroviral therapy (ART) drug interactions are acceptable.[44][64][65]​​[71][72][73][74][75] 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.[64][71] 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., ART).

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 DOT.[44][64][71] The shorter course rifamycin-based regimens are preferred to isoniazid monotherapy, as they are more likely to be completed (risks of drug-induced hepatitis and treatment discontinuation are low). 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 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][70][64]

Ideally, all medications within a given regimen should be administered at the same time of day if possible. 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.[9]

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 consult should be sought.[64][65][70]​​​[78] For patients exposed to isoniazid-resistant TB, 4 months of daily rifampin may be an option.[65][70]​​​ ​US guidelines recommend that patients with multidrug-resistant (MDR) TB are treated with 6 to 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.[78] 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.[70]

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

More

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

OR

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

OR

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

More

and

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

More

OR

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

More

latent TB infection: pregnant

1st line – specialty consultation

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INITIAL
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latent TB infection: pregnant
1st line – 

specialty consultation

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 HIV-negative nonpregnant: no hepatic dysfunction

1st line – intensive phase therapy

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ACUTE
|
active TB HIV-negative nonpregnant: no hepatic dysfunction
|
drug resistance not suspected
1st line – 

intensive phase therapy

Depending on the regimen, treatment for drug-susceptible active TB is given for a total duration of 4, 6, or 9 months.

The initial intensive phase for the standard 6- and 9-month regimens includes the preferred drugs of isoniazid, rifampin, pyrazinamide, and ethambutol, and lasts 8 weeks (2 months). Ethambutol may be discontinued immediately if the Mycobacterium tuberculosis isolate is sensitive to isoniazid and rifampin.[9] Pyrazinamide is used during the initial phase only and allows the treatment course to be shortened from 9 months to 6 months. It is not recommended for patients with acute gouty arthritis (but can be used in patients with past history of gout) because of little information about the safety data.

Children ages between 3 months and 16 years with nonsevere TB (defined as TB confined to one lobe with no cavities or isolated intrathoracic adenopathy, no signs of miliary TB, no complex pleural effusion, and no clinically significant airway obstruction) may receive a 4-month version of this regimen (with daily administration of isoniazid, rifampin, and pyrazinamide, with or without ethambutol, for 2 months in the intensive phase).[79]

Therapy may be DOT or SAT. DOT remains the standard of practice in the majority of TB programs in the US and Europe, and is suggested by US guidelines for routine treatment.[9] If SAT is selected, drugs should be given daily, 7 days per week for 8 weeks. If DOT is selected, daily dosing is preferred with DOT occurring on weekdays.[9] Drugs may be given three times weekly for 8 weeks if the patient is HIV-negative, without cavitary disease, and smear negative. Twice-weekly dosing is no longer recommended but may be considered in HIV-negative patients with noncavitary and smear-negative disease after an initial 2 weeks of daily treatment when the likelihood of adherence to treatment is high. The recommended dose will depend on the dosing frequency chosen. Ideally, all medications within a given regimen should be administered at the same time of day if possible. 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. After week 8, the continuation phase should be initiated.

The American Thoracic Society, Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America produce a joint guideline which details the recommended 6- and 9-month dosing regimens.[9]

Another 4-month regimen is available for those ages 12 years and over (with severe or nonsevere pulmonary TB). The intensive phase of this 4-month regimen includes daily administration of isoniazid, rifapentine, moxifloxacin, and pyrazinamide and also lasts 8 weeks.[80][81]​​​​ Interim guidance from the CDC recommends that the drugs are given once daily, 7 days per week, and that at least 5 of 7 weekly doses should be administered under direct observation.[80]

Pyridoxine should be administered with isoniazid to help prevent isoniazid-associated neuropathy, and is recommended in all cases of active TB.

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

Expert consultation should be sought in patients with impaired renal function (a creatinine clearance of <30 mL/minute).

Primary options

4-, 6- or 9-month regimen

isoniazid: children <40 kg body weight: 10-15 mg/kg orally/intramuscularly once daily (maximum 300 mg/dose), or 20-30 mg/kg orally/intramuscularly twice weekly (maximum 900 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), or 15 mg/kg orally/intramuscularly twice or three times weekly (maximum 900 mg/dose)

More

and

rifampin: children <40 kg body weight: 10-20 mg/kg orally/intravenously once daily (maximum 600 mg/dose), or 10-20 mg/kg orally/intravenously twice weekly (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), or 10 mg/kg orally/intravenously twice or three times weekly (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)

OR

4-month regimen

isoniazid: children ≥12 years of age and ≥40 kg body weight and adults: 300 mg orally once daily

More

and

rifapentine: children ≥12 years of age and ≥40 kg body weight and adults: 1200 mg orally once daily

and

moxifloxacin: children ≥12 years of age and ≥40 kg body weight and adults: 400 mg orally once daily

and

pyrazinamide: children ≥12 years of age and ≥40 kg body weight and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

Plus – continuation phase therapy

Back
ACUTE
|
active TB HIV-negative nonpregnant: no hepatic dysfunction
|
drug resistance not suspected
Plus – 

continuation phase therapy

Treatment recommended for ALL patients in selected patient group

Patients completing the initial intensive regimen of isoniazid, rifampin, pyrazinamide, and ethambutol continue to receive isoniazid and rifampin in the continuation phase for 18 weeks (a total of 6 months [26 weeks] treatment) or 31 weeks (total of 9 months [39 weeks] treatment). Patients who should receive a total of 9 months treatment include those who did not receive pyrazinamide during intensive phase, those with pyrazinamide resistant TB, or those who have cavitary disease on chest x-ray and have positive sputum culture at 2 months into treatment. Extension of the continuation phase (to 9 months total) may also be considered in patients with either cavitary disease on chest x-ray or positive sputum culture at 2 months into treatment and who also: are HIV-positive; are underweight; have extensive disease on chest x-ray; have diabetes; or are active smokers.[9]

Ideally, all medications within a given regimen should be administered at the same time of day if possible. 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. Daily therapy is preferred throughout the continuation phase. However, if intermittent dosing is chosen, then three times weekly is strongly preferred to twice-weekly treatment.[9]

Children with nonsevere TB receiving the 4-month version of the isoniazid, rifampin, pyrazinamide, and ethambutol regimen should receive isoniazid and rifampin for 2 months in the continuation phase.[79]

In the continuation phase of the isoniazid, rifapentine, moxifloxacin, and pyrazinamide 4-month regimen, isoniazid, rifapentine, and moxifloxacin are given for 9 weeks (total of 17 weeks [4 months]).​[81]​​ Interim guidance from the CDC recommends that the drugs are given once daily, 7 days per week, and that at least 5 of 7 weekly doses should be administered under direct observation.[80]

The recommended treatment duration is independent of any cavitation on baseline chest radiograph and there are no explicit recommendations on conditions under which treatment should be continued beyond 17 weeks in total. Patients with M tuberculosis positive cultures beyond 2 months of therapy, with or without ongoing symptoms, should be evaluated for causes of delayed response including drug susceptibility testing.[80]

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

Pyridoxine should be administered with isoniazid to help prevent isoniazid-associated neuropathy, and is recommended in all cases of active TB.

Primary options

4-, 6- or 9-month regimen

isoniazid: children <40 kg body weight: 10-15 mg/kg orally/intramuscularly once daily (maximum 300 mg/dose), or 20-30 mg/kg orally/intramuscularly twice weekly (maximum 900 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), or 15 mg/kg orally/intramuscularly twice or three times weekly (maximum 900 mg/dose)

More

and

rifampin: children <40 kg body weight: 10-20 mg/kg orally/intravenously once daily (maximum 600 mg/dose), or 10-20 mg/kg orally/intravenously twice weekly (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), or 10 mg/kg orally/intravenously twice or three times weekly (maximum 600 mg/dose)

OR

4-month regimen

isoniazid: children ≥12 years of age and ≥40 kg body weight and adults: 300 mg orally once daily

More

and

rifapentine: children ≥12 years of age and ≥40 kg body weight and adults: 1200 mg orally once daily

and

moxifloxacin: children ≥12 years of age and ≥40 kg body weight and adults: 400 mg orally once daily

1st line – antituberculosis treatment

Back
ACUTE
|
active TB HIV-negative nonpregnant: no hepatic dysfunction
|
isoniazid resistance
1st line – 

antituberculosis treatment

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 TB, US and WHO guidelines recommend treatment with rifampin, ethambutol, pyrazinamide, and a later generation fluoroquinolone (i.e., levofloxacin or moxifloxacin; WHO recommends levofloxacin) for a duration of 6 months.[78][96]​ If a fluoroquinolone cannot be used (because of toxicity or resistance) WHO recommends that the patient is treated with rifampin, ethambutol, and pyrazinamide for 6 months.[96]

As pyrazinamide may be a common cause of adverse effects, the US guidelines suggest that when pyrazinamide toxicity is experienced or anticipated, or when the bacillary burden is low (e.g., noncavitary disease), pyrazinamide may be discontinued after 2 months of therapy.

 Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

WHO guidelines state that resistance to rifampin must be excluded before starting the regimen, and preferably, resistance to fluoroquinolones and pyrazinamide would also be excluded. If isoniazid resistance is identified after a patient has started a regimen for drug-susceptible TB, rapid molecular testing for rifampin resistance should be done, and if rifampin resistance is excluded, the patient should begin a full 6-month course of rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (i.e., levofloxacin or moxifloxacin). If rifampin resistance is detected, the patient should begin an appropriate treatment regimen for MDR TB.[96]

In contrast to regimens for drug-susceptible and MDR TB, the WHO recommended treatment regimen for isoniazid-resistant TB does not have initial intensive and continuation phases.

Consult specialist for guidance on doses.

Primary options

rifampin

-- AND --

ethambutol

-- AND --

pyrazinamide

-- AND --

levofloxacin

or

moxifloxacin

Secondary options

rifampin

and

ethambutol

and

pyrazinamide

1st line – specialty consultation

Back
ACUTE
|
active TB HIV-negative nonpregnant: no hepatic dysfunction
|
multidrug resistance
1st line – 

specialty consultation

Drug resistance may be suspected on the basis of historical or epidemiologic information.

Management requires expert consultation.

The final regimen should be based on the results of drug susceptibility testing.

Management of patients with additional comorbidities is complex, and will require specialist advice.

US guidelines now recommend that at least five drugs are used in the intensive phase of treatment, and four drugs in the continuation phase.[78] 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.[78]

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 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).[96] 

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.

Pretomanid has been approved for the treatment of XDR, treatment-intolerant, or nonresponsive MDR pulmonary TB, when used in combination with bedaquiline and linezolid (the BPaL regimen).[98] The CDC now recommends that BPaL may be used in the treatment of adults with pulmonary XDR or pre-XDR (resistant to isoniazid, rifampin, and at least one fluoroquinolone or injectable medication [i.e., amikacin, kanamycin, capreomycin]) or treatment-intolerant/nonresponsive MDR TB when a safe and effective treatment regimen cannot otherwise be provided.[99]

The WHO 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.[96] The short-course regimens 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.[78]

Consult specialist for guidance on appropriate combinations of agents and doses.

active TB HIV-positive nonpregnant: no hepatic dysfunction

1st line – intensive phase therapy

Back
ACUTE
|
active TB HIV-positive nonpregnant: no hepatic dysfunction
|
drug resistance not suspected
1st line – 

intensive phase therapy

Treatment of HIV-positive patients is similar to that of non-HIV-positive patients. Depending on the regimen, treatment for drug-susceptible active TB is given for a total duration of 4, 6, or 9 months.

The initial intensive phase for the 6- and 9-month regimens includes the preferred drugs of isoniazid, rifampin, pyrazinamide, and ethambutol, and lasts 8 weeks (2 months). Ethambutol may be discontinued immediately if the Mycobacterium tuberculosis isolate is sensitive to isoniazid and rifampin.[9] Pyrazinamide is used during the initial phase only and allows the treatment course to be shortened from 9 months to 6 months. It is not recommended for patients with acute gouty arthritis (but can be used in patients with past history of gout) because of little information about the safety data.

If the patient is on ART, there are some additional considerations including the potential for drug interactions, especially between rifampin and non-nucleoside reverse-transcriptase inhibitors or protease-inhibitors. For this reason, rifabutin may be considered as an alternative to rifampin. Specialist consultation is recommended when considering use of rifabutin.

Therapy may be DOT or SAT. DOT remains the standard of practice in the majority of TB programs in the US and Europe, and is suggested by US guidelines for routine treatment.[9] If SAT is selected, drugs should be given daily, 7 days per week for 8 weeks. If DOT is selected, drugs are also given daily (observed on weekdays). The recommended dose will depend on the dosing frequency chosen. Ideally, all medications within a given regimen should be administered at the same time of day if possible. 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. After week 8, the continuation phase should be initiated.

The American Thoracic Society, CDC, and Infectious Diseases Society of America produce a joint guideline which details the recommended 6- and 9-month dosing regimens.[9]

The intensive phase of the 4-month regimen, which is recommended for those ages 12 years and over, includes daily administration of isoniazid, rifapentine, moxifloxacin, and pyrazinamide and also lasts 8 weeks.[80][81]​​​​​ The regimen can be used in patients with HIV infection who have CD4 counts ≥100 cells/microliter and whose ART regimen will include efavirenz (in the absence of any other known drug-drug interactions between antituberculosis and antiretroviral medications). Guidelines for the prevention and treatment of opportunistic infections in those with HIV recommend this regimen as an alternative option.[64]​ Interim guidance from the CDC recommends that the drugs are given once daily, 7 days per week, and that at least 5 of 7 weekly doses should be administered under direct observation.[80]

Pyridoxine should be administered with isoniazid to help prevent isoniazid-associated neuropathy, and is recommended in all cases of active TB.

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

Expert consultation should be sought in patients with impaired renal function (a creatinine clearance of <30 mL/minute).

Primary options

6- or 9-month regimen

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)

More

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)

Secondary options

4-month regimen

isoniazid: children ≥12 years of age and ≥40 kg body weight and adults: 300 mg orally once daily

More

and

rifapentine: children ≥12 years of age and ≥40 kg body weight and adults: 1200 mg orally once daily

and

moxifloxacin: children ≥12 years of age and ≥40 kg body weight and adults: 400 mg orally once daily

and

pyrazinamide: children ≥12 years of age and ≥40 kg body weight and adults: consult specialist for guidance on dose (dose is based on lean body weight and available tablet formulation)

OR

6- or 9-month regimen

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)

More

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)

More

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
ACUTE
|
active TB HIV-positive nonpregnant: no hepatic dysfunction
|
drug resistance not suspected
Plus – 

continuation phase therapy

Treatment recommended for ALL patients in selected patient group

Treatment of HIV-positive patients is similar to that of non-HIV-positive patients. Therapy may be DOT or SAT, although HIV-positive status is an indication for DOT.

Patients completing the initial intensive regimen of isoniazid, rifampin (or rifabutin), pyrazinamide, and ethambutol continue to receive isoniazid and rifampin (or rifabutin) in the continuation phase for 18 weeks (a total of 6 months [26 weeks] treatment) or 31 weeks (total of 9 months [39 weeks] treatment). Patients who should receive a total of 9 months treatment include those who did not receive pyrazinamide during intensive phase, those with pyrazinamide resistant TB, or those who have cavitary disease on chest x-ray and have positive sputum culture at 2 months into treatment. Extension of the continuation phase (to 9 months total) may also be considered in patients with either cavitary disease on chest x-ray or positive sputum culture at 2 months into treatment and who also: are HIV-positive; are underweight; have extensive disease on chest x-ray; have diabetes; or are active smokers.[9]

If the patient is on ART, rifabutin may be considered as an alternative to rifampin due to the potential for drug interactions, especially with non-nucleoside reverse-transcriptase inhibitors or protease-inhibitors. Specialist consultation is recommended when considering use of rifabutin.

Ideally, all medications within a given regimen should be administered at the same time of day if possible. 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. Daily dosing is recommended throughout treatment for patients with HIV; consult guidelines for details.[9][64][88]

In the continuation phase of the 4-month regimen, isoniazid, rifapentine, and moxifloxacin are given for 9 weeks (total of 17 weeks [4 months]).​[81]​​ Interim guidance from the CDC recommends that the drugs are given once daily, 7 days per week, and that at least 5 of 7 weekly doses should be administered under direct observation.[80] The recommended treatment duration is independent of any cavitation on baseline chest radiograph and there are no explicit recommendations on conditions under which treatment should be continued beyond 17 weeks in total. Patients with M tuberculosis positive cultures beyond 2 months of therapy, with or without ongoing symptoms, should be evaluated for causes of delayed response including drug susceptibility testing.[80] The regimen can be used in patients with HIV infection who have CD4 counts ≥100 cells/microliter and whose ART regimen will include efavirenz (in the absence of any other known drug-drug interactions between antituberculosis and antiretroviral medications).

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

Pyridoxine should be administered with isoniazid to help prevent isoniazid-associated neuropathy, and is recommended in all cases of active TB.

Primary options

6- or 9-month regimen

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)

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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)

OR

4-month regimen

isoniazid: children ≥12 years of age and ≥40 kg body weight and adults: 300 mg orally once daily

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and

rifapentine: children ≥12 years of age and ≥40 kg body weight and adults: 1200 mg orally once daily

and

moxifloxacin: children ≥12 years of age and ≥40 kg body weight and adults: 400 mg orally once daily

Secondary options

6- or 9-month regimen

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)

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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)

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1st line – antituberculosis treatment

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ACUTE
|
active TB HIV-positive nonpregnant: no hepatic dysfunction
|
isoniazid resistance
1st line – 

antituberculosis treatment

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 TB, the US and WHO guidelines recommend treatment with rifampin, ethambutol, pyrazinamide, and a later generation fluoroquinolone (i.e., levofloxacin or moxifloxacin; WHO recommends levofloxacin) for a duration of 6 months.[78][96]​ If a fluoroquinolone cannot be used (because of toxicity or resistance) WHO recommends that the patient is treated with rifampin, ethambutol, and pyrazinamide for 6 months.[96] 

As pyrazinamide may be a common cause of adverse effects, the US guidelines suggest that when pyrazinamide toxicity is experienced or anticipated, or when the bacillary burden is low (e.g., non-cavitary disease), pyrazinamide may be discontinued after 2 months of therapy.

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[100] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.​

WHO guidelines state that resistance to rifampin must be excluded before starting the regimen, and preferably, resistance to fluoroquinolones and pyrazinamide would also be excluded. If isoniazid resistance is identified after a patient has started a regimen for drug-susceptible TB, rapid molecular testing for rifampin resistance should be done, and if rifampin resistance is excluded, the patient should begin a full 6-month course of rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (i.e., levofloxacin or moxifloxacin). If rifampin resistance is detected, the patient should begin an appropriate treatment regimen for MDR TB.[96]

In contrast to regimens for drug-susceptible and MDR TB, the WHO recommended treatment regimen for isoniazid-resistant TB does not have initial intensive and continuation phases.

Consult specialist for guidance on doses.

Primary options

rifampin

-- AND --

ethambutol

-- AND --

pyrazinamide

-- AND --

levofloxacin

or

moxifloxacin

Secondary options

rifampin

and

ethambutol

and

pyrazinamide

1st line – specialty consultation

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ACUTE
|
active TB HIV-positive nonpregnant: no hepatic dysfunction
|
multidrug resistance
1st line – 

specialty consultation

Drug resistance may be suspected on the basis of historical or epidemiologic information.

Management requires expert consultation.

The final regimen should be based on the results of drug susceptibility testing.

Management of patients with additional comorbidities is complex, and will require specialist advice.

US guidelines now recommend that at least five drugs are used in the intensive phase of treatment, and four drugs in the continuation phase.[78] 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 TB.[78]

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 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).[96] 

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.

Pretomanid has been approved for the treatment of XDR, treatment-intolerant or nonresponsive MDR pulmonary TB, when used in combination with bedaquiline and linezolid (the BPaL regimen).[98] The CDC now recommends that BPaL may be used in the treatment of adults with pulmonary XDR or pre-XDR (resistant to isoniazid, rifampin, and at least one fluoroquinolone or injectable medications [i.e., amikacin, kanamycin, capreomycin]) or treatment-intolerant /nonresponsive MDR TB when a safe and effective treatment regimen cannot otherwise be provided.[99] Guidelines for the prevention and treatment of opportunistic infections in those with HIV also now recommend BPaLM, which is a regimen consisting of bedaquiline, pretomanid, linezolid, and moxifloxacin, as the preferred option for rifampin-resistant pulmonary TB in people with HIV.[64]

The WHO 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.[96] The short-course regimens 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.[78]

Consult specialist for guidance on appropriate combinations of agents and doses.

active TB pregnant

1st line – specialty consultation

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ACUTE
|
active TB pregnant
1st line – 

specialty consultation

Specialist consultation is recommended in the treatment of TB in pregnancy.

active TB non-pregnant: pre-existing or drug-induced hepatic dysfunction

1st line – specialty consultation

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ACUTE
|
active TB non-pregnant: pre-existing or drug-induced hepatic dysfunction
1st line – 

specialty consultation

Specialist consultation is recommended in the setting of drug-induced hepatic dysfunction for less hepatotoxic treatment options.

ONGOING

recurrent TB

1st line – specialty consultation

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ONGOING
|
recurrent TB
1st line – 

specialty consultation

Treatment failure is defined as a positive sputum smear or culture at 5 months or later during treatment.[59] When either the sputum smear or culture remains positive beyond 2-3 months into treatment, adherence with medications must be verified; emerging drug-resistant TB strains and gastrointestinal malabsorption of TB medications should also be evaluated.

Recurrence occurs in a case considered to have completed successful treatment. Recurrent cases include relapses due to the same Mycobacterium tuberculosis strain as that responsible for the previous episode, as well as new episodes of TB due to re-exposure resulting in reinfection. In the US, recurrence is generally a result of relapse with the original organism, whereas in TB-endemic countries, it may be the result of exogenous reinfection. Relapse usually occurs in the first 6-12 months following completion of treatment and occurs in 2% to 5% of appropriately treated patients.[101]

If the patient initially had drug-susceptible isolates and treatment was directly observed, recurrence will likely result from the same susceptible organisms and prior therapy can be used. If the patient initially received SAT, there is a greater possibility of the development of a drug-resistant organism. In this situation, or if drug susceptibility has not previously been tested, an expanded MDR regimen with addition of at least two drugs not previously used should be considered.[9]

If exogenous reinfection is suspected, treatment should be based on the drug susceptibility profile of the index case, if known.

Consult specialist for guidance on appropriate combinations of agents and doses.

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