Tuberculosis medical therapy

Tuberculosis Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Tuberculosis from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Children
HIV Coinfection
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Special Conditions
Drug-resistant
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Tuberculosis medical therapy On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Tuberculosis medical therapy All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Tuberculosis medical therapy
CDC on Tuberculosis medical therapy
Tuberculosis medical therapy in the news
Blogs on Tuberculosis medical therapy
Directions to Hospitals Treating Tuberculosis
Risk calculators and risk factors for Tuberculosis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]; Ahmed Zaghw, M.D. [3]; Ammu Susheela, M.D. [4]; Sara Mehrsefat, M.D. [5]

Overview

The treatment of tuberculosis with anti-tubercular drugs is conducted in 2 phases namely initiation phase and maintenance phase. If their is a high probability of infection, presumptively treat the patient even if the stain is negative, while waiting for the culture results. The patient should be brought back in few weeks. Patients usually feel better a few weeks post-treatment. Patients must be monitored for adverse effects and treatment failure. In the U.S., all TB is tested for drug resistance.

Deciding To Initiate Treatment

• The decision to initiate combination anti-tuberculous therapy should be based on following:

• Epidemiological information
• Clinical evidence
• Pathological
• Radiographic findings
• Microscopic examination of acid-fast bacilli (AFB)--stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria
• Positive PPD-tuberculin skin test

Factors to be considered in deciding to initiate treatment empirically for active tuberculosis (TB) ( prior to microbiologic confirmation)

Drugs Used in the Treatment of Tuberculosis

Groups	Drugs
Group 1: First-line oral drugs	Isoniazid Rifampicin Pyrazinamide Ethambutol Rifabutin
Group 2: Injectable drugs	Kanamycin Amikacin Capreomycin Streptomycin
Group 3: Fluoroquinolones	Levofloxacin Moxifloxacin Ofloxacin
Group 4: Oral bacteriostatic second-line drugs	Para-aminosalicylic acid Cycloserine Terizidone Ethionamide Protionamide
Group 5: Agents with unclear role in treatment of drug resistant-TB	Clofazimine Linezolid Amoxicillin/clavulanate Thioacetazone Imipenem/cilastatin High-dose isoniazid Clarithromycin Pretomanid
Adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.

Standard Treatment Regimens

Empirical Anti-Tuberculosis Therapy

• In developing countries where TB is endemic and in cases with high clinical suspicion of tuberculous pericarditis, starting with empiric antituberculous therapy is appropriate before establishing a definitive diagnosis. In the clinical settings where the diagnosis cannot be established based on bacteriology, histology, or pericardial fluid analysis, clinical response to antituberculous therapy serves as support for a diagnosis of tuberculous pericarditis. In developed countries where TB is not endemic, antituberculous therapy should generally not be initiated empirically in the absence of definitive diagnosis.

Standard Regimens for New Patients

Adults   ▸  Preferred regimen   ▸  Alternate regimen 1   ▸  Alternate regimen 2 Children   ▸  Preferred regimen

Preferred Regimen - Adults Intensive phase (Administer each drug daily for 8 weeks) ▸ Isoniazid 300 mg PO (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg PO (10 mg/kg/day) PLUS ▸ Pyrazinamide 2 g PO (25 mg/kg/day) PLUS ▸ Ethambutol 1.6 g PO (15 mg/kg/day) Continuation phase (Administer each drug for 18 weeks) ▸ Isoniazid 300 mg daily PO (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg daily PO (10 mg/kg/day) OR ▸ Isoniazid 300 mg PO twice weekly (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day) Alternate Regimen 1 - Adults Intensive phase ▸ Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day) PLUS ▸ Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day) PLUS ▸ Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day) FOLLOWED BY ▸ Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day) PLUS ▸ Pyrazinamide 2 g/day PO twice weekly for 6 weeks PLUS ▸Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day) Continuation phase ▸ Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day) Alternate Regimen 2 - Adults 'Intensive phase ▸ Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day P.O thrice weekly for 8 weeks (10 mg/kg/day) PLUS ▸ Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day) PLUS ▸ Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day) Continuation phase ▸ Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day) PLUS ▸ Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day) Preferred Regimen-Children Intensive phase (Administer each drug daily for 8 weeks) ▸ Isoniazid 10 mg/kg PO (Max: 300 mg/day) PLUS ▸ Rifampicin 15 mg/kg PO (Max: 600 mg/day) PLUS ▸ Pyrazinamide 35 mg/kg PO (Max: 2 g/day) PLUS ▸ Ethambutol 20 mg/kg PO (Max: 1.6 g/day) Continuation phase (Administer each drug daily for 18 weeks) ▸ Isoniazid 10 mg/kg PO (Max: 300 mg/day) PLUS ▸ Rifampicin 15 mg/kg PO (Max: 600 mg/day ) Table adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.

Standard Regimens for Previously Treated Patients

The previously treated patients should receive the 8-months regimen with first-line drugs.

Standard regimens for previously treated patients Rapid molecular-based method ▸ Drug Susceptibility Testing (DST) results available in 1–2 days confirm or exclude MDR to guide the choice of regimen Conventional method ▸ High likelihood of MDR: Empirical MDR regimen ▸ Low likelihood of MDR: 2HRZES / HRZE / 5HRE (H = isoniazid, R= rifampicin, Z = pyrazinamide, E = ethambutol, S = streptomycin)† †Regimen should be modified once DST results are available up to 2–3 months after the start of treatment.

Extrapulmonary Tuberculosis Treatment

The principles underlying the treatment of pulmonary tuberculosis also apply to extrapulmonary disease. Increasing evidence, including randomized controlled trials, suggests that 6–9 month isoniazid and rifampicin containing regimens are effective for the majority of extrapulmonary sites of disease.

Type of Extrapulmonary Tuberculosis	Treatment
Lymph Node Tuberculosis	6 month regimen is adequate for initial treatment Therapeutic lymph node excision is not indicated Incision and drainage techniques applied to cervical lymphadenitis (associated with prolonged wound discharge and scarring) Aspiration has been reported to be beneficial (for large lymph nodes that are fluctuant and appear to be about to drain spontaneously)
Bone, Joint, and Spinal Tuberculosis	6 to 9 month regimens containing rifampicin are at least as effective as 18-month regimens that do not contain rifampicin Surgery can be considered in Poor response to chemotherapy with evidence of ongoing infection or ongoing deterioration Relief of cord compression in patients with persistence or recurrence of neurologic deficits Instability of the spine No additional benefit of surgical debridement in combination with chemotherapy compared with chemotherapy alone for spinal tuberculosis Adjunctive corticosteroids is considered in the case of spinal tuberculosis with evidence of tuberculous meningitis
Pericardial Tuberculosis	A 6-month regimen is adequate Adjunctive corticosteroids therapy is no longer recommended. However, selective use of glucocorticoids in patients who are at the highest risk for inflammatory complications might be appropriate which include: Large pericardial effusions, Patients with high levels of inflammatory cells or marker
Pleural Tuberculosis	A standard 6-month regimen No evidence to support the routine use of adjunctive corticosteroids Tuberculous empyema (occurs when a cavity ruptures into the pleural space), treatment include: Drainage (often requiring a surgical procedure) Antituberculous chemotherapy The optimum duration of treatment has not been established
Tuberculous Meningitis	Adult INH, RIF, PZA, and EMB in an initial 2-month phase. INH and RIF continued for an additional 7–10 months Children Initial 4-drug regimen of INH, RIF, PZA, and ethionamide or an aminoglycoside for 2 month, followed by 7–10 months of INH and RIF Optimal duration of chemotherapy is not defined Lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell in the course of therapy Adjunctive corticosteroids with dexamethasone or prednisolone tapered over 6–8 weeks
Disseminated Tuberculosis (miliary tuberculosis)	Standard daily 6-month regimen is adequate The role of adjunct corticosteroid treatment in patients with miliary tuberculosis remains unclear
Genitourinary Tuberculosis	Standard daily 6-month regimen is adequate In cases of Ureteral obstruction Procedures to relieve the obstruction are indicated. In cases of hydronephrosis and renal insufficiency due to obstruction Renal drainage by stenting or nephrostomy is advised In cases of nonfunctioning or poorly functioning kidney (particularly if hypertension or continuous flank pain is present) Nephrectomy is considered In a cases of large tubo-ovarian abscesses Surgery may be indicated
Abdominal Tuberculosis	Standard daily 6-month regimen is adequate Adjunctive corticosteroids therapy is not recommended

Monitoring during treatment

Directly observed treatment, short-course (DOTS) strategy

5 components of DOTS strategy
Government committed to sustained TB control and activities
Case detection by sputum smear microscopy among symptomatic patients self reporting to health services
Standardized treatment, with supervision and patient support
An effective drug supply and management system
Monitoring and evaluation system, and impact measurement

Monitoring the Patients and Baseline Evaluations

• Patients suspected of having tuberculosis should have the following:

• Appropriate sputum specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances.
• Drug susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drug-resistant tuberculosis, who have demonstrated resistance to rifampin or to other first-line drugs, or who have positive cultures after more than 3 months of treatment.
• Counseling and testing for HIV infection; for patients with HIV infection, a CD4+ lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses.
• Baseline measurements of serum amino transferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be routinely obtained.
• Visual acuity and red-green color discrimination should be obtained when EMB is to be used.

• Patients during and after pulmonary tuberculosis treatment, the following should be done:

• A sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture.
• AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness.
• For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved.
• At least monthly clinical evaluation to identify possible adverse effects of the antituberculosis medications and to assess adherence.
• Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur.
• Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse).
• Patients with the following conditions can receive the usual TB regimens provided that there is no clinical evidence of chronic liver disease: hepatitis virus carriage, a past history of acute hepatitis, current excessive alcohol consumption. However, hepatotoxic reactions to anti-TB drugs may be more common among these patients, therefore close follow up is highly recommended.

Assessment of Treatment Response in New and Previously Treated Pulmonary TB

Definition of Treatment Response^₳

Outcome	Definition
Cure	A patient whose positive sputum smear/positive culture at the beginning of the treatment convert into smear-negative/culture-negative in the last month of treatment and on at least one previous occasion.
Treatment completed	A patient who completed treatment but who does not have a negative sputum smear or culture result in the last month of treatment and on at least one previous occasionb ( Two consecutive negative specimens )
Treatment failure	A patient whose sputum smear or culture is positive at 5 months or later during treatment or has a multidrug-resistant (MDR) strain at any point of time during the treatment, whether they are smear-negative or smear-positive.
Died	A patient who dies for any reason during the course of treatment.
Default	A patient whose treatment was interrupted for ≥ 2 months.
Transfer out	A patient who has been transferred to another recording and reporting unit and whose treatment outcome is unknown.
Treatment success	A sum of cured and completed treatmentc
₳:These definitions apply to pulmonary smear-positive and smear-negative patients, and to patients with extrapulmonary disease. b:The sputum examination may not have been done or the results may not be available. c: For smear- or culture-positive patients only.

Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse

• Approximately 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause.
• The risk factors for high adverse outcomes (treatment failure, relapse) are:

• The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase.
• Nonadherence to medications (especially for patients not receiving DOT)
• Extensive cavitary disease at the time of diagnosis
• Drug resistance (especially for patients receiving DOT)
• Malabsorption of drugs
• Laboratory error
• Biological variation in response

Prevention of Adverse Effects of Drugs

Isoniazid-induced peripheral neuropathy manifests as:

• Numbness
• Tingling or burning sensation of the hands or feet
• More commonly in pregnant women and in people with the following conditions: HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease, renal failure.

• Preventive treatment is recommended with Pyridoxine, 10 mg/day with anti-TB drugs. Other guidelines recommend 25 mg/day.

Symptom-Based Approach for Side-Effects of Anti-tuberculous Drugs

The Role of Drug-Susceptibility Testing (DST)

• Initial Phase:

• Ideally, DST is done for all patients at the start of treatment, so that the most appropriate therapy for each individual can be determined. However, the goal of universal access to DST has not yet been realized for most of the world’s TB patients. While countries are expanding laboratory capacity and implementing new rapid tests, WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be obtained from the following patient groups at the start of treatment:

• All previously treated patients . The highest levels of MDR are found in patients whose prior course of therapy has failed .
• All persons living with HIV who are diagnosed with active TB, especially if they live in areas of moderate or high MDR prevalence. It is essential to detect MDR as soon as possible in persons living with HIV, given their high risk of mortality.

• Continuation Phase:

• In settings where rapid molecular-based DST is available, the results of MDR can be confirmed or excluded within 1-2 days, it should guide the choice of regimen.
• In cases if DST is not available, the first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available
• Remark: When DST results become available, regimens should be adjusted appropriately.
• The Global Plan to Stop TB 2006–2015 sets a target for open accessibility to DST for all previously treated patients at the beginning of treatment by 2015.

Recommendations For New Patients

• In new patients, if the specimen obtained at the end of the intensive phase 2^nd month is smear-positive, sputum smear microscopy should be obtained at the end of the third month (Strong/High grade of evidence).
• In new patients, if the specimen obtained at the end of 3^rd month is smear-positive, sputum culture and drug susceptibility testing (DST) should be performed (Strong/High grade of evidence)
• For smear-positive pulmonary TB patients treated with first-line drugs, sputum smear microscopy may be performed at completion of the intensive phase of treatment (Conditional/High or moderate grade of evidence).
• Sputum should be collected after the 1^st dose of the intensive phase treatment. The end of the intensive phase is defined as the end of the 2^nd month in new patients and the end of the 3^rd month in previously treated patients receiving the 8-month regimen of first-line agents. This recommendation also applies to smear-negative patients.
• Sputum specimens should be collected for smear examination at each follow-up sputum check. They should be collected without interrupting treatment and transported to the laboratory as soon as possible.
• Smear status at the end of the intensive phase is a poor predictor of which new patients will relapse. However, detection of a positive sputum smear remains important as a trigger for the patient assessment.
• The proportion of sputum smear positive patients converted to negative at the end of the intensive phase is an indicator of TB program performance.

Management of Treatment Interruption

Time Point of Interruption	Details of Interruption	Approach
During intensive phase	*Lapse is <14 d in duration	Lapse is <14 d in duration Continue treatment to complete planned total number of doses (as long as all doses are completed within 3 mo)
	Lapse is ≥14 d in duration	*Restart treatment from the beginning
During continuation phase	Received ≥80% of doses and sputum was AFB smear negative on initial testing	Further therapy may not be necessary
	*Received ≥80% of doses and sputum was AFB smear positive on initial testing	Continue therapy until all doses are completed
	Received <80% of doses and accumulative lapse is <3 mo in duration	Continue therapy until all doses are completed (full course), unless consecutive lapse is >2 mo If treatment cannot be completed within recommended time frame for regimen, restart therapy from the beginning (ie, restart intensive phase, to be followed by continuation phase
	*Received <80% of doses and lapse is ≥3 mo in duration	Restart therapy from the beginning, new intensive and continuation phases (ie, restart intensive phase, to be followed by continuation phase)

Managing Side-Effects of Anti-TB Drugs

Side-Effects Causative Drugs Management Severe Side-Effects Skin Rash With Or Without Itching Streptomycin, Isoniazid, Rifampicin, Pyrazinamide Stop anti-TB drugs Deafness (no wax on otoscopy) Streptomycin Stop anti-TB drugs Dizziness (vertigo and nystagmus) Streptomycin Stop anti-TB drugs Jaundice (other causes excluded), hepatitis Isoniazid, Rifampicin, Pyrazinamide Stop anti-TB drugs Confusion/jaundice (drug-induced acute liver failure) Most anti-TB drugs Stop anti-TB drugs Visual impairment (other causes excluded) Ethambutol Stop anti-TB drugs Shock, purpura, acute renal failure Rifampicin Stop anti-TB drugs Decreased Urine Output Streptomycin Stop anti-TB drugs Minor Side-Effects Anorexia, nausea, abdominal pain Isoniazid, Rifampicin, Pyrazinamide Give drugs with small meals or before bedtime, swallow pills slowly with small sips of water. If symptoms persist or worsen, or there is protracted vomiting or any sign of bleeding, consider the side-effect to be major and refer to clinician urgently. Joint pains Pyrazinamide Aspirin or non-steroidal anti-inflammatory drug, or paracetamol Burning, numbness or tingling sensation in the hands or feet Isoniazid Pyridoxine 50–75 mg daily Drowsiness Isoniazid Reassurance. Give drugs before bedtime Orange/red urine Rifampicin Reassurance, Patients should be told when starting treatment that this may happen and is normal Flu-like syndrome † Intermittent dosing of Rifampicin Change from intermittent to daily Rifampicin † Fever, chills, malaise, headache, bone pain

Treatment Failure

• Failure to response to anti-TB drugs means;

• Smear or culture-positivity at the fifth month or later.
• Detection of MDR-TB at any point of therapy.

• Treatment failure necessitate to step-wise approach to identify the causes of failure which could be due to any of the following features

• Poor supervision of the initial phase
• Poor patient adherence
• Poor quality of anti-TB drugs
• Inappropriate doses of anti-TB drugs (below than recommended range)
• Slow resolution due to extensive cavitation and a heavy initial bacillary load
• Co-morbid conditions that interfere either with adherence or with response
• MDR M. tuberculosis with no response to the first-line treatment
• Non-viable bacteria remain visible by microscopy

Treatment Regimen

• 1. Standard regimens for new patients

• 1.1. Adult

• 1.1.1. Initial phase

• Preferred regimen: Isoniazid 300 mg PO (5 mg/kg/day) qd for 8 weeks AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 8 weeks AND Pyrazinamide 2 g PO (25 mg/kg/day) qd for 8 weeks AND Ethambutol 1.6 g PO (15 mg/kg/day) qd for 8 weeks
• Alternative regimen (1): Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day) AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day), followed by Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO twice weekly for 6 weeks AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
• Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 8 weeks (10 mg/kg/day) AND Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day) AND Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day)

• 1.1.2 Continuation phase

• Preferred regimen (1): Isoniazid 300 mg PO (5 mg/kg/day) qd AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 18 weeks
• Preferred regimen (2): Isoniazid 300 mg PO twice weekly (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day) for 18 weeks
• Alternative regimen (1): Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day)
• Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day)

• 1.2 Pediatric

• 1.2.1 Initial phase

• Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day) AND Pyrazinamide 35 mg/kg PO (Maximum, 2 g/day) AND Ethambutol 20 mg/kg PO (Maximum, 1.6 g/day), each for 8 weeks

• 1.2.2 Continuation phase

• Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day), each drug daily for 18 weeks

• 2. RR-TB or MDR-TB Tuberculosis

• 2.1 Adult

• Preferred regimen: At least 5 agents combination

• Agent 1: Pyrazinamide 20–30 mg/kg
• Agent 2: Levofloxacin 500-1000 mg OR Moxifloxacin 400 mg OR Gatifloxacin 400mg
• Agent 3: Amikacin 7.5-10 mg/kg OR Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Streptomycin 12–18 mg/kg
• Agent 4: [Ethionamide]] 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 mg/kg OR Clofazimine 100mg
• Agent 5: Bedaquiline 200-400mg OR Delamanid
• Agent 6: Para-aminosalicylic acid 150 mg/kg/day q8-12h OR Imipenem/Cilastatin 250mg/250mg-750mg/750mg {{or} Meropenem 20-40mg/kg OR Amoxicillin clavulanate 500mg-125mg OR Thioacetazone 150mg
• Note: Pyrazinamide and four core second-line TB medicines (one chosen from Group A, one from Group B, and at least two from Group C2)
• Note: If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five

• 2.2 Pediatric

• Preferred regimen: At least 5 agents combination

• Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg)
• Agent 2 (Group A): Levofloxacin 7.5-10mg/kg OR Moxifloxacin 7.5-10mg/kg OR Gatifloxacin 10 mg/kg (maximum 600 mg)
• Agent 3 (Group B): Amikacin 7.5-10 mg/kg OR Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Streptomycin 12–18 mg/kg
• Agent 4 (Group C): [Ethionamide]] 15-20 mg/kg/day q12h (Maximum: 1000 mg)OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg Maximum: 1000 mg) OR Clofazimine 100mg
• Agent 5: (Group D3): Para-aminosalicylic acid 150 mg/kg/day q8-12h(Maximum: 12,000 mg) OR Imipenem/Cilastatin 250mg/250mg-750mg/750mg {{or} Meropenem 20-40mg/kg OR Amoxicillin clavulanate 500mg-125mg OR Thioacetazone 50mg
• Note: Pyrazinamide and four core second-line TB medicines (one chosen from Group A, one from Group B, and at least two from Group C2)
• Note: If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five

• 3. XDR Tuberculosis

• 3.1 Adult

• Preferred regimen: 3 agents combination

• Agent 1: Pyrazinamide 20–30 mg/kg OR Ethambutol 15–25 mg/kg OR Rifabutin 5 mg/kg
• Agent 2: Ethionamide 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 kg/mg OR Para-aminosalicylic acid 8-12 g/day q8-12h
• Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate 500 mg/125 mg q12h OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg

• 3.2 Pediatric

• Preferred regimen: 3 agents combination

• Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg) OR Ethambutol 15 mg/kg OR Rifabutin 5 mg/kg
• Agent 2: Ethionamide 15-20 mg/kg (Maximum: 1000 mg) OR Protionamide 15-20 mg/kg (Maximum: 1000 mg) OR Cycloserine 10-20 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg (Maximum: 1000 mg) OR Para-aminosalicylic acid 150 mg/kg/day q8-12h
• Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg

Ocular tuberculosis

• 1. Pathogen-directed antimicrobial therapy

• 1. Adult patients

• 1.1 Intensive phase

• Preferred regimen: Isoniazid 5 mg/kg (max: 300 mg) PO qd for 2 months AND Rifampin 10 mg/kg (max: 600 mg) PO qd for 2 months AND Pyrazinamide 15–30 mg/kg (max: 2 g) PO qd for 2 months AND Ethambutol 15-20 mg/kg (max: 1 g) PO qd for 2 months

• 1.2 Continuation phase

• Preferred regimen: Isoniazid 5 mg/kg (max: 300 mg) PO qd for 4 months AND Rifampin 10 mg/kg (max: 600 mg) PO qd for 4 months

• 2. Pediatric patients

• 2.1 Intensive phase

• Preferred regimen: Isoniazid 10-15 mg/kg (max: 300 mg) PO qd for 2 months AND Rifampin 10-20 mg/kg (max: 600 mg) PO qd for 2 months AND Pyrazinamide 15-30 mg/kg (max: 2 g) PO qd for 2 months AND Ethambutol

• 2.2 Continuation phase

• Preferred regimen: Isoniazid 10–15 mg/kg (max: 300 mg) PO qd for 4 months AND Rifampin 10–20 mg/kg (max: 600 mg) PO qd for 4 months

• Note (1): Ethambutol may be administered at a dose of 15-20 mg/kg (max: 1 g) PO qd for 2 months but is generally avoided because of potential ocular toxicity.
• Note (2): A short course of systemic corticosteroids may be necessary initially if there is sight-threatening inflammation.

Contraindicated medications

Active tuberculosis is considered an absolute contraindication to the use of the following medications:

• BCG vaccine