Extrapulmonary tuberculosis

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

The goals of TB treatment are to cure the patient clinically, minimize the chance of relapse, and prevent further transmission of TB to others.

The treating physician acts in a public health role and is responsible for ensuring that the patient successfully completes treatment. Therefore, many physicians share that responsibility with a local public health department.

Empiric treatment may be initiated before confirmatory tests and drug-susceptibility results are available when TB is strongly suspected and after appropriate specimens are collected.

The following treatment recommendations are for practice in the US and are based on US guidelines. For management in areas with different epidemiology, resistance patterns, and resources, please see local guidelines and World Health Organization resources.[94]

Latent TB infection

People who have had significant exposure in the previous 2 years should be evaluated for active TB disease and latent TB infection (LTBI) (also sometimes referred to as TB infection). 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 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 (ART) drug interactions are acceptable.[88][89][95][97][98][99][100] Safety of this regimen during pregnancy is not known, and is not recommended in pregnant women or those expecting to become pregnant during treatment. Four months of daily rifampin is recommended for adults and children of all ages and those with HIV infection where drug interactions allow; 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] Four months of daily rifampin was found to be noninferior in preventing TB, compared with 9 months of isoniazid in two randomized controlled trials, and was superior in safety and treatment completion.[101][102]Three months of daily isoniazid plus rifampin is an option for adults and children of all ages and those with HIV infection where drug interactions allow.[95] Note that rifampin and rifapentine are not interchangeable between these regimens.

Regimens of daily or intermittent isoniazid for 6 or 9 months are alternative options for adults and children of all ages, including those with HIV infection. 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 there are 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]

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] 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]

Active TB: intensive phase therapy (drug resistance not suspected)

Microbiologic confirmation of EPTB can take several weeks and this delay in treatment initiation may increase mortality in some forms (central nervous system [CNS], disseminated, peritoneal). Therefore, antituberculous therapy is initiated based on clinical suspicion after optimal diagnostic samplings.

Initial intensive-phase treatment involves the first-line drugs of isoniazid, rifampin, pyrazinamide, and ethambutol, for 2 months with drug-susceptibility testing for those agents.[46] In children with suspected drug-susceptible TB meningitis, ethambutol may be replaced with ethionamide or a fluoroquinolone.[105] Ethionamide has been shown to cross the blood-brain barrier in higher concentrations.[96]

Patients can receive treatment through direct observation of therapy (DOT) whereby the patient is provided with the tablets and is observed swallowing them. This is often done in conjunction with a local public health department. Video DOT (vDOT) is the use of video calls to view patients ingesting their medications remotely. In the US, the Centers for Disease Control and Prevention (CDC) recommend the use of vDOT as equivalent to in-person DOT for patients undergoing tuberculosis treatment.[106] Note that in World Health Organization (WHO) guidelines, the term "directly-observed therapy (DOT)" has been replaced with "treatment support," which refers to any person (not necessarily a healthcare worker) observing the patient taking medication in real time, including via video.[107]

The decision on the use of DOT as opposed to daily self-administered therapy (SAT) depends on the resources available to local public health, collaboration with community partners, and prioritization of cases. [ ] CDC guidelines suggest that the high priority should be given to situations such as treatment failure, drug resistance, relapse, HIV co-infection, current or prior substance abuse, psychiatric illnesses, memory impairment, and cases in children/adolescents.

Active TB: continuation phase therapy (drug resistance not suspected)

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 in 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).

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

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 CNS TB receive 7-10 months of continuation phase therapy (9-12 months total).[46][105]

Duration of therapy may be longer for people living with HIV. For children with HIV and skeletal TB, CNS TB, or disseminated/miliary disease, total therapy should be given for at least 12 months.[96]

Interruptions in treatment of active TB

Interruptions in therapy are common in the treatment of TB. The decision is then whether to restart a complete course of treatment or simply to continue. As a general guide, the earlier in the course of treatment and the greater the length of the lapse, the more likely the need to return to the beginning of the intensive phase of treatment.[46]

Advice on how to manage interruptions to treatment can be found in the American Thoracic Society/US Centers for Disease Control and Prevention/Infectious Diseases Society of America guidelines (ATS/CDC/IDSA), and are summarized below.[46]

Treatment interrupted during the intensive phase:

<14 days in duration - continue treatment as planned (must complete all doses within 3 months)
≥14 days in duration - completely restart treatment

Treatment interrupted during the continuation phase:

Received ≥80% of doses and sputum was acid-fast bacilli (AFB) smear negative on initial testing - then no further therapy may be required
Received ≥80% of doses and sputum was AFB smear positive on initial testing - continue therapy and complete all doses
Received <80% of doses and accumulative lapse is <3 months in duration - continue therapy until all doses are completed, unless the consecutive lapse is >2 months. If treatment cannot be completed within the recommended time frame for the regimen, restart therapy from the beginning (i.e., from the intensive phase)
Received <80% of doses and lapse is ≥3 months in duration - restart therapy from the beginning (i.e., from the intensive phase).

Isoniazid-resistant TB

Drug-resistance may be suspected on the basis of historical 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.[103][108] The WHO guidelines note that this regimen is likely to be effective in patients with EPTB, 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-resistant TB

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. Treatment of MDR-TB and rifampin-resistant (RR) TB/RR-TB meningitis should be guided by knowledge of TB drugs that cross the blood–brain barrier.

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 coformulation 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]

Adjunctive corticosteroids

Adjunctive corticosteroid therapy has been shown to attenuate 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 to 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]

One Cochrane review assessing treatments for tuberculous pericarditis found moderate certainty evidence that corticosteroids probably reduce death from pericarditis in people without HIV infection.[113] Low certainty evidence found that in people living with HIV infection (but not on ART) use of corticosteroids had little or no effect on deaths. [ ] [Evidence C] 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]

Situations in which the use of pyrazinamide is not recommended

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

Liver injury

Several TB medications (e.g., isoniazid, rifampin, and pyrazinamide) 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. A specialist should be consulted for guidance on choice of regimen and appropriate doses.

If drug-induced liver injury (DILI) occurs, potentially hepatotoxic drugs should be stopped and alcohol should be avoided (alcohol should ideally be avoided in all patients who start TB therapy [either latent or active]).

An asymptomatic, mild increase in aspartate aminotransferase (AST) occurs in 20% of patients; if this is <5 times the upper limit of normal (ULN) with no symptoms, or <3 times ULN with symptoms, TB medications can be continued but LFTs and symptoms are monitored closely.[46]

While LFTs are normalizing and symptoms are improving, at least three drugs without hepatotoxic effects may be given, especially if the burden of TB disease is more than minimal. When AST becomes <2 times ULN, first-line drugs are serially reintroduced one by one, waiting 4-7 days before adding next drug. Before introducing each new drug LFTs are checked. If an increase in AST occurs, the most recently introduced drug is likely responsible for hepatitis.[46] Expert opinion should be sought.

Renal insufficiency

Renal insufficiency complicates treatment as some medications and their metabolites (e.g., ethambutol, pyrazinamide, aminoglycosides, capreomycin, levofloxacin) are cleared by the kidneys. Dose adjustments may be required in patients with renal insufficiency or end-stage renal disease.[46] A specialist should be consulted for guidance on choice of regimen and appropriate doses. 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.

HIV infection

Although there are many TB patients co-infected with HIV globally, expert advice should be sought if the clinician is not familiar with management of TB patients co-infected with HIV.

Patients with TB and HIV infection should receive antiretroviral therapy during antituberculosis treatment. For antiretroviral therapy (ART)-naïve patients, ART should be started within 2 weeks for those patients with a CD4 count <50 cells/microliter, except for those with CNS TB, for whom ART should be delayed, regardless of CD4.[46][88] The ATS/CDC/IDSA guidelines recommend that for those with CNS TB, ART should not start before 8 weeks of TB treatment is completed, regardless of CD4 count; however, HIV clinical guidelines note that many experts recommend that ART should be initiated within the first 2 to 8 weeks after starting anti-TB treatment.[46][88]

TB medications should be administered daily. Intermittent twice-weekly administration is not recommended for HIV-infected patients.[114] A three times weekly regimen may be used during the continuation phase of therapy in carefully selected patients with high CD4 counts and paucibacillary TB disease.[46]

A rifamycin (rifampin or rifabutin) should be included in TB regimens for patients receiving antiretroviral therapy; however, consideration should be given to drug interactions when building the regimen.[88] Dosage should be adjusted as necessary.

Safety of fluoroquinolones

Systemic fluoroquinolone antibiotics are a key part of some TB treatment regimens, but it is important to note that they 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.[115]

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.

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