Approach
The goals of TB treatment are to cure the patient clinically, minimise 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.
Empirical treatment may be initiated before confirmatory tests and drug-susceptibility results are available when TB is strongly suspected and after appropriate specimens are collected.
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.[41]
For patients with LTBI that is presumed to be susceptible to isoniazid or rifampicin, WHO guidelines recommend the following regimens regardless of HIV status: 6 or 9 months of daily isoniazid (all ages), 3 months of weekly rifapentine plus isoniazid (age 2 years and over), or 3 months of daily isoniazid plus rifampicin (all ages).[38][90] One month of daily rifapentine plus isoniazid (age 13 years and over) or 4 months of daily rifampicin (all ages) are alternative regimens.[38][90] Isoniazid and rifampicin are options for use in pregnant women with or without HIV who are eligible for preventive treatment.[90] Rifamycins should only be used if there are no significant interactions with other medications (e.g., antiretroviral therapy [ART]).
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, uraemia, alcoholism, malnutrition, HIV infection), pregnant women, or patients with seizure disorders.[33]
For patients with LTBI presumed to be due to contact with an infectious patient with drug-resistant TB, expert consultation should be sought.[91][90][92][93] For patients exposed to isoniazid-resistant TB, 4 months of daily rifampicin may be an option.[90][93] 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.[91] WHO guidelines recommend that, in selected high-risk household contacts of patients with MDR TB, preventive treatment may be considered based on individualised risk assessment and a sound clinical justification.[90]
Active TB: intensive phase therapy (drug resistance not suspected)
Microbiological 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, rifampicin, pyrazinamide, and ethambutol, for 2 months with drug-susceptibility testing for those agents.[48][94]
WHO guidelines for the treatment of drug-susceptible EPTB advise that regimens are given for a total duration of 6 months, except TB of the central nervous system, bone, or joint, for which a longer duration of therapy is recommended.[94]
WHO guidelines recommend that children aged between 3 months and 16 years with non-severe TB (defined as peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease, confined to one lobe of the lungs, and without a miliary pattern) may receive a 4-month version of this regimen. The intensive phase of this regimen includes daily administration of isoniazid, rifampicin, and pyrazinamide, with or without ethambutol, for 2 months.[38][94] Ethambutol should be included in areas of high prevalence of HIV or isoniazid resistance.[38][94] Children and adolescents who do not meet the criteria for non-severe TB should receive the standard 6-month treatment regimen (including ethambutol) or extended treatment regimens for severe forms of extrapulmonary TB.[38][94]
An alternative option for children and adolescents with bacteriologically confirmed or clinically diagnosed TB meningitis is an intensive treatment regimen composed of 6 months of isoniazid, rifampicin, pyrazinamide, and ethionamide. The WHO recommends that this shorter intensive regimen is suitable for children and adolescents who have a low likelihood of drug resistant TB. Due to a lack of data, this shorter intensive regimen should not be used in children and adolescents living with HIV.[38]
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 recommends the use of vDOT as equivalent to in-person DOT for patients undergoing tuberculosis treatment.[95] 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.[96]
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 prioritisation of cases.
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]
Centers for Disease Control and Prevention (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 are discontinued, and isoniazid and rifampicin are given for the continuation phase. 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).
Total therapy for 9 months is considered for patients with extensive skeletal TB, especially when large joints are involved with slow clinical response. Patients with CNS TB receive 7-10 months of continuation phase therapy (9-12 months total).[48][94]
Children aged 3 months to 16 years with non-severe TB (defined as peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease, confined to one lobe of the lungs, and without a miliary pattern) should receive 2 months of continuation phase therapy (4 months total). Those with severe TB, other than TB meningitis or osteoarticular TB, and also children aged less than 3 months, should receive the standard 6-month treatment regimen.[38][94] Children with osteoarticular TB or TB meningitis should receive 10 months of continuation phase therapy (12 months total).[38]
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.[48]
Isoniazid-resistant TB
Drug-resistance may be suspected on the basis of historical or epidemiological information. Isoniazid-resistant TB is defined as resistance to isoniazid and susceptibility to rifampicin that has been confirmed in vitro.
In patients with confirmed rifampicin-susceptible and isoniazid-resistant pulmonary TB, US and World Health Organization (WHO) guidelines recommend treatment with a 6-month regimen of rifampicin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone.[91][97] 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.[97]
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 rifampicin, with or without resistance to other first-line drugs. Extensively drug-resistant (XDR) TB is defined as resistance to at least isoniazid and rifampicin, as well as any fluoroquinolone and either bedaquiline or linezolid (or both).[98] Pre-XDR-TB is resistance to isoniazid, rifampicin, and any fluoroquinolone.
The treatment regimen should be based on the results of drug susceptibility testing. Specific regimens should be selected by a specialist in the treatment of MDR TB.[97] The total number of TB medicines to include in the regimen needs to balance expected benefit with risk of adverse effects and non-adherence when the pill burden is high. Treatment of MDR-TB and rifampicin-resistant (RR) TB/RR-TB meningitis should be guided by knowledge of TB medicines that cross the blood-brain barrier.[97]
Patients with rifampicin-resistant (RR) TB are also eligible for treatment with MDR TB regimens.[97] Short (6 or 9 months) and longer (18 months or more) regimens are included in the WHO guidelines for the treatment of people with drug-resistant TB.[97] The WHO 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, 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 6-month all-oral regimen is composed of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM).[97][99][100] The WHO recommends the use of this 6-month regimen for adults and adolescents aged 14 and over with confirmed pulmonary TB and all forms of extrapulmonary TB (except for TB involving the CNS, osteoarticular and disseminated [miliary] TB), regardless of HIV status, who have less than 1 month exposure to bedaquiline, linezolid, pretomanid, or delamanid. The WHO suggests that this regimen is used where appropriate rather than the 9-month or longer MDR/RR-TB regimens.[97] If the patient has documented resistance to fluoroquinolones, the WHO advises that the regimen should continue without moxifloxacin (BPaL); although initiation of BPaLM should not be delayed while waiting for results of drug susceptibility testing.
The 9-month all-oral regimen is recommended by the WHO for patients who have extrapulmonary TB that is not severe, where severe disease is defined as miliary TB or TB meningitis, or in children aged less than 15 years defined as extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression).[97] It is recommended over the longer MDR/RR-TB regimens (18 months or more) when resistance to fluoroquinolones has been excluded and can be used when patients are not eligible for the 6-month regimen. In the 9-month regimen, bedaquiline is used for 6 months in combination with levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose), pyrazinamide, and clofazimine for 4 months (with the possibility of extending to 6 months if the patient remains sputum smear positive at the end of 4 months), and this is followed by 5 months of treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol, and pyrazinamide.[97] Two months of linezolid may be used in place of the 4 months of ethionamide. The WHO recommends the use of the 9-month regimen for adults and children without extensive pulmonary TB disease, regardless of HIV status, and who have less than 1 month exposure to bedaquiline, fluoroquinolones, ethionamide, linezolid, and clofazimine.[97]
Longer MDR TB regimens last 18 months or more and may be standardised or individualised; regimens are designed to include a minimum number of medicines considered to be effective based on patient history or drug-resistance patterns.[97] This longer -term regimen is recommended for all patients with extrapulmonary TB who do not fulfil the criteria for the shorter-term regimens; however, adjustments may be required, depending on the specific location of the disease.[97] The WHO guidelines recommend that patients with RR TB or MDR TB on longer regimens receive treatment with at least four TB agents likely to be effective, including all three Group A agents and at least one Group B agent, and that at least three agents are included for the rest of treatment if bedaquiline is stopped. If only one or two Group A agents are used, both Group B agents should be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it.[97]
Group A (include all three medicines):
Levofloxacin or moxifloxacin
Bedaquiline
Linezolid
Group B (add one or both medicines):
Clofazimine
Cycloserine or terizidone
Group C (add to complete the regimen and when medicines from Groups A and B cannot be used):
Ethambutol
Delamanid
Pyrazinamide
Imipenem/cilastatin or meropenem
Amikacin or streptomycin
Ethionamide or prothionamide
Aminosalicylic acid
Adjunctive corticosteroids
Adjunctive corticosteroid therapy has been shown to attenuate the inflammatory response in TB meningitis and result in improved survival.[101][102]
[ ]
The American Thoracic Society (ATS)/Centers for Disease Control and Prevention (CDC)/Infectious Diseases Society of America (IDSA) and WHO guidelines recommend initial adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for patients with tuberculous meningitis.[48][94] US 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.[92] One subsequent randomised 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.[103] US guidelines for the prevention and treatment of opportunistic infections in children with HIV recommend considering adjunctive corticosteroid treatment for those with TB meningitis.[93] The British Infection Society recommends that, in children, the initial dose of dexamethasone should be given for 4 weeks, then tapered over 4-8 weeks.[53]
One Cochrane review assessing treatments for tuberculous pericarditis found moderate certainty evidence that corticosteroids probably reduce death from pericarditis in people without HIV infection.[104] 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.[48] 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.[93] The WHO recommends that adjunctive corticosteroid therapy may be used in tuberculous pericarditis.[94]
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.[48] 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 medicines (e.g., isoniazid, rifampicin, and pyrazinamide) are metabolised 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 medicines 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 upper limit of normal (ULN) with no symptoms, or <3 times ULN with symptoms, TB medicines can be continued but liver function tests (LFTs) and symptoms are monitored closely.
While LFTs are normalising and symptoms are improving, at least 3 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.[48] Expert opinion should be sought.
Renal insufficiency
Renal insufficiency complicates treatment as some medicines and their metabolites (e.g., ethambutol, streptomycin, pyrazinamide, aminoglycosides, capreomycin, levofloxacin) are cleared by the kidneys. Dose adjustments may be required in patients with renal insufficiency or end-stage renal disease.[48] 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/colour discrimination and counselling 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. WHO guidelines recommend that ART is started as soon as possible within 2 weeks of starting TB treatment, regardless of CD4 cell count, unless the patient has TB meningitis (when ART is delayed for 4-8 weeks).[94]
TB medications should be administered daily. Intermittent twice-weekly administration is not recommended for HIV-infected patients.[105]
A rifamycin (rifampicin 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.[92] 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; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[106]
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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