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Essential principles of care for persons with active or suspected TB include prompt and accurate diagnosis; the use of a standardized and effective treatment regimen with proper treatment support and supervision; and monitoring treatment response. Patients should be provided with adequate knowledge regarding the disease and the importance of treatment compliance. The optimal duration of treatment for sputum-positive PTB is at least 6 months.
Treatment Goals
The treatment goals are to treat the patient and bring back quality of life and productivity; prevent death and relapse of TB; lower TB transmission; achieve goals with the lowest possible dose and minimal toxic drug effects; and stop the development and transmission of drug resistance. Acquired resistance occurs during therapy when resistance to >1 drug develops in organisms that were initially susceptible to the drugs. The best way to prevent this is to use at least two bactericidal drugs to which the organisms are sensitive and to employ daily intensive-phase dosing, especially in TB patients starting treatment with Isoniazid resistance.
Treatment Phases
The initial or intensive phase is when combination drugs are used to rapidly kill replicating populations of M tuberculosis and the occurrence of drug resistance is prevented. Bactericidal effect leads to fast conversion of bacteriological sputum and improvement in clinical symptoms. The continuation phase is when drugs slowly and intermittently kill replicating populations. The remaining bacteria are eliminated, and a consequent relapse is prevented.
Dosing Frequency
In individuals with drug-susceptible PTB, daily intake of the required medications is recommended, and the thrice-weekly regimen is no longer advisable, both in the intensive and continuation phases, because of an increase in the noncompliance rate. Thrice-weekly dosing is also no longer recommended since studies showed that when a daily regimen was compared to a thrice-weekly regimen throughout the duration of treatment, TB recurrence, failure in therapy, and acquired drug resistance were all higher in the latter. When the daily regimen was compared to the thrice-weekly regimen in the continuation phase, TB recurrence and failure in therapy were seen more in the latter; however, there was no difference when it came to acquired drug resistance. Hence, if the thrice-weekly regimen is to be used in the continuation phase, it is important that the patient be under directly observed therapy (DOT) and that medications be taken without fail. There is a higher risk of failure and acquired drug resistance that was also noted in patients with pre-treatment Isoniazid resistance using the 3x/week dosing during the intensive phase; hence, daily intensive-phase dosing is preferable.
Tuberculosis - Pulmonary_ManagementTreatment Adherence Interventions
Treatment adherence interventions include tracers (home visitation) and/or digital medication monitors (phone calls, messaging), material support (food, transportation fees, monetary allowance, etc), education of staff members, and psychological support. Health education and counseling on the disease and treatment adherence are recommended for all patients on TB treatment. Treatment administration strategies include DOT, non-everyday DOT, video-observed treatment (VOT), and unsupervised therapy.
Directly Observed Therapy (DOT)
Poor compliance with the anti-TB regimen is the most common cause of treatment failure. Directly Observed Therapy (DOT is a part of the patient-centered care adherence plan. This is a helpful way to monitor patient adherence to therapy. This is a process where a treatment supervisor or supporter (eg healthcare worker, patient’s friend, relative, or layperson) watches the patient swallow each dose of the drug to ensure that completion of treatment is achieved. This ideally prevents the emergence of drug resistance when a suitable regimen is given. DOT given at home or in the local municipal area is preferred rather than in a healthcare institution. DOT facilitated by healthcare practitioners or laypeople who underwent training is preferred to those provided by relatives and those that are self-administered.
Video Observed Treatment (VOT)
Compliance is observed even if the patient is far away, more convenient with regard to schedules, less expensive, and can be used as an alternative or as an adjunct to other types of treatment administration.
Decentralized Versus Centralized Model of Care
Decentralized care is recommended for MDR-TB patients, including those who were hospitalized for <1 month for treatment initiation or management of complications. This is centered in the local district area, wherein care is delivered in healthcare centers by general physicians, community-based healthcare workers, and volunteers. This may not be applicable for certain groups of patients, such as those with severe or highly infectious TB, with concomitant medical disorders, or non-compliant patients. Practices of this type of care should not hinder the need for hospitalization.
Centralized care is carried out by hospitals and specialized institutions or clinics particularly allocated for drug-resistant TB patients, facilitated by physicians or other healthcare providers with a specialty in this field. This is implemented during the intensive phase of treatment or until culture or smear conversion.
Treatment Interruption
If a patient misses a treatment, the National Tuberculosis Control Program (NTP) should contact the patient within a day after missing treatment during the initial phase or within a week if during the continuation phase. Culture and DST should be done upon return of the patient who missed two consecutive months of treatment.
Hospitalization
Hospitalization is recommended in severely ill patients and for those with complications of the disease or its treatment that need closer clinical monitoring. This may also be considered in patients during the intensive phase for whom there are no other means of ensuring treatment adherence and support.
Pharmacological therapy
First-Line Anti-TB Agents (Group 1)
First-line anti-TB agents are recommended for patients without previous anti-TB treatment and without risk factors for drug resistance. The initial/intensive phase is a combination of four drugs used for 2 months. The continuation phase is Isoniazid + Rifampicin combination for 4 months.
Isoniazid (H)
Isoniazid is highly bactericidal against replicating tubercle bacilli. This is indicated for all forms of TB caused by organisms that are known or presumed to be susceptible. Clinical monitoring and liver function tests (LFTs) are recommended during treatment of patients with pre-existing liver disease.
Rifampicin (R)
Rifampicin is a semi-synthetic derivative of Rifamycin. This has bactericidal action and a potent sterilizing effect against tubercle bacilli in both cellular and extracellular locations. This is indicated for all forms of tuberculosis caused by organisms that are known or presumed to be susceptible and is also considered to be an essential component of all short-course regimens. Rifampicin should always be administered together with other effective anti-TB drugs because of the high risk for development of resistance. A 6-month regimen is recommended since a 2-month regimen is associated with more relapses and deaths. Clinical monitoring and LFTs are recommended during the treatment of patients with pre-existing liver disease. Rifampicin has a narrow therapeutic index; thus, dosage should not be lower than the recommended dose. In new pulmonary TB patients treated with the regimen containing Rifampicin throughout treatment, extension of the intensive phase is not recommended even if there is a positive sputum smear found at completion of the intensive phase.
Pyrazinamide (Z)
Pyrazinamide is indicated for all forms of tuberculosis caused by organisms that are known or presumed to be susceptible. This is only weakly bactericidal but has potent sterilizing activity, particularly in macrophages and in areas of acute inflammation. Pyrazinamide is highly effective against acute inflammatory changes during the first 2 months of treatment. This has shortened the treatment regimen and reduced the risk of relapse.
Ethambutol (E)
Ethambutol is generally used in combination with other anti-TB agents to prevent or delay the emergence of resistant strains. This is included in the initial treatment regimen primarily to prevent the emergence of Rifampicin resistance when primary resistance to Isoniazid may be present. Ethambutol is added to Isoniazid + Rifampicin continuation phase in patients from populations with known or suspected high levels of Isoniazid resistance and Isoniazid susceptibility testing is not done.
Second-Line Anti-TB Agents
Second-line anti-TB agents should be used in patients with MDR-TB.
Aminoglycosides
Example drugs: Amikacin, Streptomycin
In the revised grouping, aminoglycosides currently belong to group C for use in susceptible MDR-TB and RR-TB patients in longer treatment regimens (refer to the next page for the revised grouping). Amikacin is preferred over Streptomycin. These have been used extensively for the treatment of MDR-TB. Capreomycin and Kanamycin are no longer included in any regimen for MDR-TB due to increased risk of treatment failure, relapse, or death.
Streptomycin (S)
Streptomycin is an aminoglycoside antibiotic derived from Streptomyces griseus that is used for tuberculosis and gram-negative sensitive infections. Streptomycin and Ethambutol are approximately equivalent when used in the initial treatment phase, but Streptomycin use may be limited based on local M tuberculosis resistance patterns. This has high resistance in drug-resistant TB. Streptomycin may be substituted if Ethambutol is contraindicated. Although it is not usually part of the second-line agents in the long-term duration of MDR-TB therapy, it may be used instead if the other three drugs in group B are contraindicated (refer below for the revised grouping). This is not absorbed from the gastrointestinal tract, but after intramuscular administration, it diffuses readily into the extracellular component of most body tissues and attains bactericidal concentrations, particularly in tuberculous cavities.
Bedaquiline
Bedaquiline is a recently approved treatment for adult patients with pulmonary MDR-TB and RR-TB. This is given as part of the combination therapy for extensively drug-resistant TB (XDR-TB) and MDR-TB allergic to >2 drugs. In the revised grouping, it is currently under group A for the longer regimen of MDR-TB and RR-TB treatment (refer below for the revised grouping).
Delamanid
Delamanid is a nitro-dihydro-imidazooxazole that inhibits mycolic acid synthesis and has been recently approved for the treatment of MDR-TB and RR-TB patients aged ≥3 years on longer regimens. This is given as part of the combination therapy for MDR-TB in adult patients who are intolerant or resistant to standard effective treatment regimens. In the revised grouping, it is currently under group C as part of the add-on medications to complete the longer regimen of MDR-TB and RR-TB treatment when group A and B agents cannot be used (refer to the next page for the revised grouping). Delamanid may be useful in patients with increased risk for poor outcomes (eg drug intolerance or contraindication, extensive or advanced disease, resistance to fluoroquinolones and/or injectable drugs, and XDR-TB). This may now be used in patients 6-17 years of age in the longer regimen of MDR-TB and RR-TB therapy.
Fluoroquinolones
Example drugs: Levofloxacin, Moxifloxacin
Fluoroquinolones belong to group A drugs used to treat MDR-TB and RR-TB under the longer treatment regimen (refer below for the revised grouping). Ofloxacin and Ciprofloxacin are removed from the list of medications approved for MDR-TB and RR-TB because of a lack of information regarding their effectiveness.
Oral Bacteriostatic Second-Line Agents
Example drugs include Linezolid, Clofazimine, Cycloserine/Terizidone, and Ethionamide/Prothionamide, in order of preferred use as recommended by the WHO. Agents belonging to group B or C that may be used in MDR-TB and RR-TB longer-term regimens (refer below for the revised grouping). Terizidone may be used to replace Cycloserine, while Prothionamide may be used instead of Ethionamide. Ethionamide is often added to the treatment regimen due to its low cost. Ethionamide or Prothionamide and Para-aminosalicylic acid may be included in the longer regimens for MDR-TB and RR-TB only if Bedaquiline, Linezolid, Clofazimine or Delamanid are not used or when there are no other possible options.
Pretomanid
Pretomanid is a recently approved oral nitroimidazooxazine antimycobacterial given as part of the combination therapy with Bedaquiline and Linezolid for treatment of XDR-TB or treatment-intolerant or non-responsive MDR-TB. This is approved for a limited and specific patient population only since further studies are needed to prove its safety and effectiveness in other patient groups.
Medicines for Longer MDR-TB and RR-TB Treatment Based on Groups
Group A includes Levofloxacin or Moxifloxacin, Bedaquiline and Linezolid. These are highly recommended to be included in all longer MDR-TB regimens and used for all patients with MDR-TB or RR-TB eligible for longer regimens. These has been shown to be highly effective in improving treatment outcomes and decreasing mortality.
Group B includes Clofazimine and Cycloserine or Terizidone.
Group C (in order of preference) includes Ethambutol, Delamanid, Pyrazinamide, Imipenem/cilastatin or Meropenem, Amikacin or Streptomycin, Ethionamide or Prothionamide and Para-aminosalicylic acid. These are less effective drugs.
Fixed-Dose Combinations (FDC)
Fixed-dose combinations are the preferred preparation in managing drug-susceptible TB patients, instead of the individual drugs. Separate medications may be beneficial for certain individuals who have accompanying medical disorders (eg those with kidney or renal disease or drug intolerance) since each drug may need to undergo dose adjustment. Two or more drugs are incorporated in a single tablet that reduces the number of pills that need to be consumed. Fixed-dose combinations may prevent having drug resistance secondary to monotherapy. These are advantageous since prescription errors may be less frequent because of more straightforward dosage recommendations and easier adjustment of dosage based on the patient's weight and may promote the patient's compliance due to a smaller number of tablets to consume. Some trials have shown that FDC and monotherapy are equally effective, but FDC is more acceptable to patients. Fixed-dose combinations do not prevent the need for separate drugs in patients who will develop drug toxicity or intolerance or in patients with contraindications to individual drug components.
Treatment Regimen for New TB Patients
Daily dosing remains as the recommended dosing frequency. Therapy consists of first-line anti-TB agents: Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E). In patients with drug-susceptible PTB, the 6-month Rifampicin-based therapy 2HRZE/4HR is the preferred treatment, while the 4-month fluoroquinolone-containing therapy should be avoided.
For smear-negative with intrathoracic lymph nodes and tuberculous peripheral lymphadenitis (HIV-negative, low drug resistance), an intensive phase of HRZE x 2 months and a continuation phase of HR x 4 months are recommended. For smear-positive, with EPTB (HIV-negative, low drug resistance), intensive phase of HRZE x 2 months; and continuation phase of HR x 4 months. For smear-positive or smear-negative with or without extensive parenchymal involvement, with severe EPTB (high HIV/Isoniazid resistance risk factor), intensive phase of HRZE x 2 months; and continuation phase of HR x 4 months. For EPTB of CNS, bones, and joints, intensive phase of HRZE x 2 months; and continuation phase of HR x 10 months.
The Centers for Disease Control and Prevention (CDC) and WHO recommend a 4-month Rifapentine-Moxifloxacin (Rpt-Mfx) regimen or a regimen of Isoniazid, Rifapentine, Moxifloxacin and Pyrazinamide (2HPMZ/2HPM) for treating drug-susceptible PTB patients aged ≥12 years with body weight ≥40 kg and who have no contraindications to the regimen's intensive phase of HZ-Rpt-Mfx x 8 weeks and continuation phase of H-Rpt-Mfx x 9 weeks. In patients between 3 months and 16 years of age with non-severe TB (without suspicion or evidence of MDR/RR-TB), a 4-month treatment regimen of 2HRZE/2HR should be used.
TB Retreatment
For patients who had treatment interruption or disease recurrence, the treatment regimen will depend upon the patient’s DST result. This is more prone to develop drug resistance compared to new TB patients. If there is no resistance to the initial treatment of 2HRZE/4HR, this same therapy can be given. If resistance to Rifampicin is detected, a WHO-based treatment regimen for MDR-TB is recommended.
Treatment Regimen for Rifampicin-susceptible and Isoniazid-resistant TB Patients
Recommended treatment by the WHO is 6 months (H)REZ and Levofloxacin (6[H]REZ-Lfx). 6(H)REZ may be used in Isoniazid-resistant TB patients with unknown Rifampicin susceptibility and with fluoroquinolone resistance or intolerance to Levofloxacin.
Treatment Regimen for MDR-TB Patients
The treatment regimen depends on drug susceptibility tests. The intensive phase is defined by the duration of treatment with the injectable agents. Injectable agents should be continued for a minimum of 6 months and for at least 4 months after the patient has smear and culture conversion. Therapy should be continued for a minimum of 18 months until after culture conversion. Therapy may be extended for up to 24 months in patients with extensive pulmonary damage.
Individuals diagnosed with MDR-TB or RR-TB who are identified to have an absence of resistance to fluoroquinolones and second-line injectable agents or are regarded as having such resistance improbable and did not have prior second-line drug treatment may have a shorter duration of MDR-TB therapy of 9-12 months. A shorter all-oral Bedaquiline-containing regimen for 9-12 months is recommended by the WHO as the preferred regimen for patients diagnosed with MDR-TB or RR-TB without previous treatment with second-line drugs for >1 month and without resistance to fluoroquinolones, and in patients without extensive TB disease (eg presence of bilateral cavitary disease or extensive parenchymal damage on chest X-ray) or severe EPTB (eg miliary TB or TB meningitis). The WHO also suggests use of a 6-month treatment regimen composed of Bedaquiline, Pretomanid, and Linezolid (BPaL) or Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin (BPaLM) rather than longer regimens (9-18 months). DST for fluoroquinolones is strongly recommended. Moxifloxacin may be excluded from the regimen if resistance is identified. The BPaLM recommendation applies to adolescents aged 14 years and older and adults regardless of HIV status with MDR/RR-TB or with MDR/RR-TB and resistance to fluoroquinolones; confirmed pulmonary tuberculosis and EPTB except TB involving the CNS, osteoarticular, and miliary; and <1 month previous exposure to Bedaquiline, Linezolid, Pretomanid or Delamanid. Shorter MDR-TB therapy is not advisable in patients who received treatment with second-line drugs for >1 month and those with extrapulmonary disease. The following may follow the short-term regimen: Adult and children diagnosed with RR-TB without MDR-TB, even without documented resistance to Isoniazid; patients free from resistance to the medications used in the shorter regimen; and non-pregnant women. Children and patients with HIV can be regarded with the same consideration as adults and people without HIV, respectively, in terms of using the shorter regimen.
A longer treatment regimen is recommended for patients with MDR-TB or RR-TB who are not eligible for shorter all-oral regimens, including patients with resistance to fluoroquinolones. These include all three group A agents and at least one group B agent or, as an alternative, 1-2 group A agents and all group B agents. Group C agents are added to the regimen when group A and B agents cannot be used alone. Clavulanic acid is not recommended for inclusion in the longer regimens for MDR-TB and RR-TB. A fully oral regimen for longer MDR-TB treatment is preferred. A total treatment duration of 18-20 months is suggested for most patients with MDR-TB or RR-TB on longer regimens or 15-17 months after culture conversion. The duration of therapy may be modified according to the patient's response to treatment. In longer regimens for MDR-TB or RR-TB containing Amikacin or Streptomycin, an intensive phase of 6-7 months is suggested, which may be modified based on the patient's response to treatment.
Phẫu thuật
Elective partial lung resection (eg lobectomy, wedge resection), with an appropriate MDR-TB therapy, may be utilized as a treatment approach in patients with MDR-TB or RR-TB. This should be done after at least 2 months of treatment to reduce bacterial infection in the surrounding tissue, but the prognosis is better if performed after culture conversion.
Phòng ngừa
Tuberculosis Preventive Treatment (TPT)
Tuberculosis preventive treatment is recommended for people living with HIV regardless of their antiretroviral treatment (ART) status; persons in contact with TB patients regardless of HIV status (household contacts); persons with immunocompromised conditions at high risk for tuberculosis; and persons on anti-TNF treatment, receiving dialysis, for organ or hematological transplant, or with silicosis. This should be initiated only after active TB disease has been ruled out.
Preventive treatment options regardless of HIV status include the following: Isoniazid daily for 6 or 9 months (6H or 9H) (extrapolated data from randomized trials suggest that 9 months of treatment is optimal for prevention); Isoniazid-Rifapentine combination regimen administered weekly for 3 months (3HP); Isoniazid-Rifampicin combination regimen daily for 3 months (3HR) (preferred for children); Isoniazid-Rifapentine combination regimen daily for 1 month (1HP) as an alternative regimen in individuals ≥13 years old; Rifampicin daily for 4 months (4R) as an alternative regimen; Isoniazid preventive therapy (IPT) daily for 36 months is recommended in settings where there is high TB transmission for adults and adolescents living with HIV who have unknown or positive LTBI tests and are unlikely to have active TB disease; and Levofloxacin daily for 6 months may be used as TPT for contacts of MDR/RR-TB.