Approach
The main goals are to cure the patient and to prevent further transmission of TB to others. The treating physician acts in a public health role as well and thus is responsible for ensuring that the patient successfully adheres to and completes treatment.
Treatment is initiated when TB is confirmed or strongly suspected and consists of an initial intensive phase and a subsequent continuation phase.
While infectious, patients should remain isolated (at home or in an appropriate room in the hospital). The treating physician should discuss the case with the local public health department to learn specific local requirements and to initiate a contact investigation in a timely fashion. Refer to guidelines for latest recommendations.
Latent TB infection
People who have had significant exposure in the previous 1-2 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.[9]
For patients with LTBI that is presumed to be susceptible to isoniazid or rifampicin, World Health Organization (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).[66] One month of daily rifapentine plus isoniazid (age 13 years and over) or 4 months of daily rifampicin (all ages) are alternative regimens.[66] Isoniazid and rifampicin are options for use in pregnant women with or without HIV who are eligible for preventive treatment.[66] 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 for those in whom neuropathy is common (e.g., diabetes, uraemia, alcoholism, malnutrition, HIV infection), for pregnant women, or for 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.[66][67][68][69] For patients exposed to isoniazid-resistant TB, 4 months of daily rifampicin may be an option.[66][68] US guidelines recommend that patients with multidrug-resistant (MDR) TB are treated with 6-12 months of a fluoroquinolone (e.g., levofloxacin or moxifloxacin) alone or in combination with a second agent based on susceptibility testing of the source isolate.[69] WHO guidelines recommend that, in selected high-risk household contacts of patients with MDR TB, preventative treatment may be considered based on individualised risk assessment and a sound clinical justification.[66]
Active TB: intensive phase therapy (drug resistance not suspected)
WHO guidelines for the treatment of drug-susceptible active pulmonary TB include regimens that are given for a total duration of 4 or 6 months.[70]
The standard 6-month regimen is recommended by the WHO for new patients with pulmonary TB. The initial intensive phase treatment for the standard 6-month regimen includes the preferred drugs of isoniazid, rifampicin, pyrazinamide, and ethambutol, and lasts 2 months.[70] Patients aged between 3 months and 16 years with non-severe TB (defined as 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.[30][70] Ethambutol should be included in areas of high prevalence of HIV or isoniazid resistance.[30][70] Children and adolescents who do not meet the criteria for non-severe TB should receive the standard 6-month treatment regimen (including ethambutol).[30][70]
Patients aged 12 years and over may receive a 4-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide. The intensive phase of this regimen includes daily administration of isoniazid, rifapentine, moxifloxacin, and pyrazinamide and also lasts 2 months.[70][71] This regimen is not currently recommended for young children, persons who are pregnant, and patients with HIV infection and CD4 count of <100 cells/microlitre.[70]
Pyridoxine should be administered with isoniazid to help prevent isoniazid-associated neuropathy.
It is unlikely that adjunctive corticosteroid treatment provides major benefits for people with pulmonary TB, and thus its routine use is not recommended.[72]
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Active TB: continuation phase therapy (drug resistance not suspected)
WHO guidelines recommend that patients completing the initial intensive standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol continue to receive isoniazid and rifampicin in the continuation phase for 4 months (a total of 6 months treatment). Children aged 3 months to 16 years with non-severe pulmonary TB should receive 2 months of continuation phase therapy (4 months total). Those with severe TB, and also children aged less than 3 months, should receive the standard 6-month treatment regimen.[30][70]
In the continuation phase of the 4-month isoniazid, rifapentine, moxifloxacin, and pyrazinamide regimen, isoniazid, rifapentine, and moxifloxacin are given for another 2 months (total of 4 months).[70][71]
Mode of administration: active TB
To reduce non-adherence rates, therapy can be given by a healthcare professional in conjunction with a local public health authority as DOT. DOT can be given 5 days per week or 3 times weekly, depending on the regimen and phase of treatment. Although one systematic review has concluded that DOT does not provide a solution to poor adherence in TB treatment, the US and WHO guidelines recommend its use for all patients, especially in certain populations, such as drug-resistant disease; HIV co-infection; substance abuse; psychiatric illness; children and adolescents; and others who, in the physician's opinion, might not adhere to SAT.[9][70][73][74]
[ ]
[Evidence B] Video DOT (vDOT) is the use of video calls to view patients ingesting their medicines remotely. The Centers for Disease Control and Prevention recommends the use of vDOT as equivalent to in-person DOT for patients undergoing TB treatment.[75] In the 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 medicine in real time, including via video.[76] Intermittent therapy should be supervised. Non-supervised therapy (SAT) should be daily, 7 days a week. Other regimens may be used; consult guidelines for details.[9]
Interruptions in treatment: 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.[9]
Patients with HIV co-infection
Treatment of HIV-positive patients is similar to that of non-HIV-positive patients.[70] Therapy may be DOT or SAT, although DOT is highly recommended for HIV-positive patients.[9] Treatment should be administered daily.[68]
Patients with HIV can be maintained on standard therapy, but rifabutin may be considered in place of rifampicin, depending on the ART regimen the patient is on.
Rifabutin has less effect on the serum concentrations of protease inhibitors than rifampicin. Patients on protease-inhibitor-based ART regimens should receive rifabutin instead of rifampicin in their TB-treatment regimen. Specialist consultation is recommended when considering use of rifabutin while the patient is on a protease-inhibitor.
WHO guidelines recommend initiation of ART as soon as possible within 2 weeks after starting treatment for TB, regardless of CD4 count.[70] Survival is improved in co-infected individuals with CD4+ counts of <50 cells/microliter if ART is initiated within 2 weeks of starting TB treatment.[77][78][79] Management of patients with additional comorbidities is complex, and will require consultant advice.
Impaired renal function
Patients who have reduced renal function but have a creatinine clearance >30 mL/minute should receive medications in the standard doses. However, monitoring serum drug levels should be considered.[9] In patients with a creatinine clearance of <30 mL/minute, ethambutol and pyrazinamide are given three times a week (dose given after haemodialysis if the patient is on dialysis; expert consultation recommended).[9]
Drug-induced hepatitis or pre-existing liver disease
Tests for hepatitis A, B, and C should be ordered if the patient has no pre-existing liver disease but has abnormal liver function test results. Patients should be asked about other hepatotoxins, including alcohol use. Liver function (aminotransferases, bilirubin, alkaline phosphatase) should be checked at baseline. Monthly liver function tests (LFTs) should be obtained in patients with abnormal baseline liver function, underlying liver disease, HIV co-infection, and other risk factors for hepatitis.
Isoniazid, rifampicin, and pyrazinamide can all cause or exacerbate liver disease. The decision about whether it is safe to continue one, two, or all three of these drugs depends on severity of liver disease. An asymptomatic increase in alanine aminotransferase (ALT) occurs in 20% of patients treated with regimens containing these drugs. If this is under five times upper limit of normal (ULN) with no symptoms, or less than three times ULN with symptoms, first-line regimens can be continued, but LFTs and symptoms should be monitored.
Where ALT increase is more than five times ULN, or more than three times ULN with symptoms, hepatotoxic drugs should be stopped and treatment initiated with at least three drugs without hepatotoxic effects (e.g., ethambutol, fluoroquinolone, and linezolid) especially if the burden of TB is more than minimal. It may be possible to continue with one or two of the more effective drugs, isoniazid and/or rifampicin, with careful monitoring of liver function, especially when ALT becomes less than two times ULN. These can be serially re-introduced, one by one, waiting 4-7 days before adding the next drug. Before introducing each new drug, LFTs should be checked. If an increase in ALT occurs, the most recently introduced drug is likely responsible for the hepatitis.[9][80]
Although rifabutin may cause hepatic injury (mainly a cholestatic pattern like rifampicin), it has been found to be less hepatotoxic compared with rifampicin and may be substituted for rifampicin in order to achieve short-course TB regimen. For example, if liver injury recurs with the re-introduction of rifampicin, rifabutin may be considered as a replacement.
Management of patients with additional comorbidities is complex, and will require consultant advice.
Pregnancy and breastfeeding
Pregnant women who are suspected of having active TB should be treated as there is a risk of TB transmission to the fetus. Initial treatment is normally with isoniazid, rifampicin, and ethambutol. Pyrazinamide is probably safe and can be considered in addition to triple therapy, especially for patients with HIV infection or high bacillary burden. The minimum total duration of treatment is 9 months for women who did not receive pyrazinamide as part of the initial regimen.[9]
Women taking antituberculosis treatment can breastfeed because only low levels of drugs are passed into the milk. However, levels are not high enough to provide effective treatment for the baby.[9]
Management of patients with additional comorbidities is complex, and will require consultant advice.
Isoniazid-resistant TB
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 TB, WHO recommends treatment with rifampicin, ethambutol, pyrazinamide, and levofloxacin for a duration of 6 months.[81] If levofloxacin cannot be used (because of toxicity or resistance) WHO recommends that the patient is treated with rifampicin, ethambutol, and pyrazinamide for 6 months.[81]
Resistance to rifampicin must be excluded before starting the regimen, and preferably, resistance to fluoroquinolones and pyrazinamide should also be excluded. If isoniazid resistance is identified after a patient has started a regimen for drug-susceptible TB, rapid molecular testing for rifampicin resistance should be done, and if rifampicin resistance is excluded, the patient should begin a full 6-month course of rifampicin, ethambutol, pyrazinamide, and levofloxacin. If rifampicin resistance is detected, the patient should begin an appropriate treatment regimen for MDR TB.[81]
In contrast to regimens for drug-susceptible and MDR TB, the recommended treatment regimens for isoniazid-resistant TB do not have initial intensive and continuation phases.
Multidrug-resistant TB
MDR TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs. Extensively drug-resistant TB is defined as resistance to at least isoniazid and rifampicin, as well as any fluoroquinolone, and either bedaquiline or linezolid (or both).[82] Pre-XDR-TB is resistance to isoniazid, rifampicin, and any fluoroquinolone.
Drug resistance may be suspected on the basis of historical or epidemiological information. Management requires expert consultation.
Patients with rifampicin-resistant (RR) TB are also eligible for treatment with MDR TB regimens.[81] 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.[81] 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).[81][83][84] The WHO suggests that this regimen is used where appropriate rather than the 9-month or longer MDR/RR-TB regimens.[81] The WHO advises that if the patient has documented resistance to fluoroquinolones, then the regimen should continue without moxifloxacin (BPaL); although initiation of BPaLM should not be delayed while waiting for results of drug susceptibility testing. The WHO recommends the use of this 6-month regimen for adults and adolescents aged 14 and over, regardless of HIV status, who have less than 1 month exposure to bedaquiline, linezolid, pretomanid, or delamanid.[81]
The 9-month all-oral regimen is recommended by the WHO 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.[81] 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 TB disease, regardless of HIV status, and who have less than 1 month exposure to bedaquiline, fluoroquinolones, ethionamide, linezolid, and clofazimine.[81]
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.[81] This longer term regimen is recommended for all patients who do not fulfil the criteria for the shorter term regimens.[81] 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.[81]
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.
Specific regimens should be selected by a specialist in the treatment of MDR TB.[81] The total number of TB medicines to include in the regimen needs to balance expected benefit with risk of side effects and non-adherence when the pill burden is high.
In patients with RR TB or MDR TB, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR TB regimen.[81]
Management of patients with additional comorbidities is complex, and requires specialist advice.
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.[85]
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.
Treatment failure and TB recurrence
WHO defines treatment failure as a positive sputum smear or culture at 5 months or later during TB treatment.[60] When either the sputum smear or culture remains positive beyond 2-3 months into TB treatment, adherence with TB medications must be verified. Emerging drug-resistant TB during treatment and gastrointestinal malabsorption of TB medications should also be evaluated.
Recurrence of TB occurs in a case previously considered to have been successfully treated for TB. Recurrent cases include relapses due to the same M 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 recrudescence of the original organism (i.e., relapse), whereas in TB-endemic countries, it may be the result of exogenous reinfection. Most relapse events occur in the first 6-12 months following completion of treatment and occur in 2% to 5% of appropriately treated patients.[86]
If the patient initially had drug-susceptible isolates and treatment was directly observed, recurrence will likely be the result of the same susceptible organisms and prior therapy can be used. However, 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 TB regimen with addition of at least two new drugs not previously used should be considered.
If exogenous reinfection is suspected, TB treatment should be based on the drug susceptibility profile of the index case, if known.[9]
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