Sandbox TB

Empirical Anti-Tuberculosis Therapy

It should be considered that 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 TB patients (with presumed, or known, to have drug-susceptible TB)

Statandard Regimens For New TB Patients With Drug-Susceptible TB Intensive Initial Phase ▸ Initial Phase: 2 months of HRZE † Continuation phase ▸ Continuation Phase: 4 months of HR

† WHO no longer recommends omission of ethambutol during the intensive phase of treatment for patients with non-cavitary, smear-negative PTB or EPEPTB who are known to be HIV-negative.

Standard regimens for new TB patients (with known or suspected high levels of Isoniazid resistance TB)^∞

Statandard regimens for new TB patients with isoniazid resistance TB Intensive Initial Phase ▸ Initial Phase: 2 months of HRZE Continuation phase ▸ Continuation Phase: 4 months of HRE

^∞ Applies also in the countries with high levels of isoniazid resistance in new TB patients, and where isoniazid drug susceptibility testing in new patients is not done (or results are unavailable) before the continuation phase begins

Dosing Frequency for New TB Adult Patients with Active Tuberculosis caused by Drug-Susceptible Organisms

Dosing Frequency for New TB Adult Patients with Active Tuberculosis caused by Drug-Susceptible Organisms Optimal first line ▸ Initial Phase: Daily ▸ Continuation Phase: Daily Alternative line in DOT ▸ Initial Phase: Daily ▸ Continuation Phase: Three times a week Alternative line accepted in limited situations † ▸ Initial Phase: Three times a week ▸ Continuation Phase: Three times a week

DOT; Direct Observed Therapy

† if patient is getting DOT and not living with HIV infected patient or HIV prevalent setting

Level Of Evidence in Dosing Frequency

The level of evidence of the dosage frequency came from the systematic review showed that equivalent efficacy of daily intensive-phase dosing followed by two times weekly continuation phase, however twice weekly dosing is not recommended on operational grounds. Also showed that the daily (rather than three times weekly) intensive-phase dosing may also help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. The systematic review found that patients with isoniazid resistance treated with a three times weekly intensive phase had significantly higher risks of failure and acquired drug resistance than those treated with daily dosing during the intensive phase.

Standard Regimens for Previously Treated Patients

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

Standard regimens for previously treated patients Rapid molecular-based method ▸ 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 / 5HRERE† Regimen should be modified once DST results are available up to 2–3 months after the start of treatment.

† 2HRZES/1HRZE/5HRE is given if country-specific data show low or medium levels of MDR in these patients or if such data are not available

Assessment of Treatment Response

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
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.

Monitoring the Response to MDR-TB Treatment

• The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment

Rapid drug susceptibility testing for Early start of Appropriate Treatment

Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources

The role of DST in Management

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 (see below), 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 (17, 21, 22). The highest levels of MDR are found in patients whose prior course of therapy has failed (6). • 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 at the end of the intensive phase is at 2^nd month in new patients and 3^rd month in previously treated patients receiving the 8-month regimen of first-line drugs. 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.1 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.

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:

• 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.

Drugs Groups for Treatment of MDR-TB

• Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
• All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
• All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
• The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).

Drugs Groups for MDR-TB Group 1: First-line oral agents ▸ pyrazinamide (Z) ▸Ethambutol (E) ▸ Rifabutin (Rfb) Group 2: Injectable Agents ▸ Kanamycin (Km) ▸ Amikacin (Am) ▸ Capreomycin (Cm) ▸ Streptomycin (S) Group 3: Fluoroquinolones ▸ Levofloxacin (Lfx) ▸ Moxifloxacin(Mfx) ▸ Ofloxacin (Ofx) Group 4: Oral Bacteriostatic Second-Line Agents ▸ Para-amino salicylic acid (PAS) ▸Cycloserine (Cs) ▸ Terizidone (Trd) ▸ Ethionamide (Eto) ▸ Protionamide (Pto) Group 5: Agents with Unclear Role in Treatment of Drug Resistant-TB ▸ Clofazimine (Cfz) ▸ Linezolid (Lzd ▸ Amoxicillin/clavulanate (Amx/Clv) ▸ Thioacetazone (Thz) ▸ Imipenem/cilastatin (Ipm/Cln) ▸ high-dose Isoniazid (high-dose H) ‡ ▸ Clarithromycin (Clr)

Guidelines for second-line Anti-TB Regimens for MDR

• In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
• In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
• In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
• In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
• In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).

Major changes in recommendation for second-line Anti-TB Regimens for MDR:

• Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
• No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
• Ethambutol may be used but is not included among the drugs making up the standard regimen.
• Group 5 drugs may be used but are not included among the drugs making up the standard regimen.

General principles for Designing MDR-TB Treatment Regimens

General principles for Designing MDR -TB Treatment Regimens Principle 1: Use At Least 4 Drugs Certain To Be Effective The more factors are present, the more likely the drug to be effective ▸ Resistance to these drugs is known from surveys to be rare in similar patients. ▸ DST results show susceptibility to drugs for which there is good laboratory reliability: Injectable agents and Fluoroquinolones. ▸ The drug is not commonly used in the area. ▸ No prior history of treatment failure with the drug. ▸ No known close contacts with resistance to the drug. Principle 2: Do Not Use Drugs For Which There Is The Possibility Of Cross-Resistance ▸ Many antituberculosis agents exhibit cross-resistance both within and across drug classes Principle 3: Eliminate Drugs That Are Not Safe ▸ Quality of the drug is unknown. ▸ Known severe allergy or unmanageable intolerance; high risk of severe adverse drug effects such as renal failure, deafness, hepatitis, depression and/or psychosis.) Principle 4: Include Drugs Groups 1–5 In a Herarchical Order Based On Potency ▸ Use any of the first-line oral agents (Group 1) that are likely to be effective. ▸ Use an effective aminoglycoside or polypeptide by injection (Group 2) ▸ Use a fluoroquinolone (Group 3). ▸ Use the remaining Group 4 drugs to complete a regimen of at least four effective drugs. ▸ For regimens with fewer than four effective drugs, consider adding two (Group 5) drugs. The total number of drugs will depend on the degree of uncertainty, and regimens often contain five to seven.

Prevention of Adverse Effects of Drugs

• Isoniazid-induced peripheral neuropathy: Numbness or a tingling or burning sensation of the hands or feet and occurs 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 with Pyridoxine, 10 mg/day with anti-TB drugs. Other guidelines recommend 25 mg/day.

Managing Side-Effects of Anti-TB Drugs

Side-Effects	Causative Drugs	Management
Major Side Effects	Possible Drug	Stop and Refer Urgently to Clinician
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	Possible Drug	Continue and Check the drug dosage
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 syndrome †	Intermittent dosing of Rifampicin	Change from intermittent to daily Rifampicin administration (3)

† (fever, chills, malaise, headache, bone pain)

Hepatitis and Anti-TB medications

The management of Anti-TB induced hepatitis depends on:

• Phase of the therapy (intensive or continuation phase)
• Severity of the liver disease
• Severity of the TB
• Capacity to manage the side-effects of TB drugs

• If TB treatment has been stopped, Wait for liver function tests to normalize and resolution of the clinical symptoms (nausea, abdominal pain) before reintroducing the anti-TB drugs.
• If the liver function tests is not available, it is advisable to wait for extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment.

• If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18-24 months.

• Reintroducing one drug at a time is the optimal approach, especially if the patient’s hepatitis was severe.
• Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. But if symptoms recur or liver function tests become abnormal again as the drugs are reintroduced, the last drug added should be stopped.

• Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent . After 3–7 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.

Alternative regimens in Anti-TB induced Hepatitis

It depends on which drug is implicated as the cause of the hepatitis.

• If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of Isoniazid, Ethambutol and Streptomycin followed by 10 months of Isoniazid and Ethambutol.
• If Isoniazid cannot be used, 6-9 months of Rifampicin, Pyrazinamide and Ethambutol can be considered.
• If Pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months.
• If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of Streptomycin, ethambutol and a fluoroquinolone should be continued for a total of 18-24 months.
• Hepatitis during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by Rifampicin and Isoniazid for the 6-month continuation phase.
• Hepatitis during the continuation phase: once hepatitis has resolved, restart Isoniazid and Rifampicin to complete the 4-month continuationphase of therapy.

HIV and Tuberculosis

Screening for TB in HIV infected patients

Intensified case finding recommendation according to WHO recommendations, lately updated in 2011.

1. Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence)
2. Adults and adolescents living with HIV and screened for TB with a clinical algorithm and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)

Detecting Latent TB Infection in Resources Limited Situations

Tuberculin Skin Test (TST) as screening tool for latent TB

1. TST is not a requirement for initiating IPT in people living with HIV. People living with HIV who have a positive TST benefit more from IPT;(Strong recommendation, moderate quality of evidence)
2. TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)

Interferon-gamma release assays (IGRA) as screening tool for latent TB

• IGRA has two types; Quantiferon Gold in tube test assay and T-Spot assay.
• Studies showed the ability of IGRA to predict development of TB over time, and reported its sensitivity in children and adults already infected with TB.
• Most of studied showed a significant higher rates of indeterminate test results (non-conclusive results) with Quantiferon Gold in tube test assay in persons with HIV in comparison with non HIV persons. The sensitivity was also markedly reduced among HIV patients with low CD4 counts in comparison with HIV patients with high CD4.
• However, most of studies found no impact of low CD4 cell count on the sensitivity of T-Spot assay.
• Based on the best available evidence considering the fact that IGRA cannot distinguish between active TB disease and latent infection and most of studies were done in low TB prevalence settings, WHO do not recommended IGRA to screen people living with HIV for eligibility to receive IPT.

Regimen's Efficacy and Duration in Prevention of TB in HIV Patients

1. Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 6 months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
2. Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least 36 months of IPT. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence)

IPT and Drug -Resistant TB

1. Providing IPT to people living with HIV does not increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)

Prevention of TB in HIV Patients

HIV is the strongest risk factor for tuberculosis (TB) disease in those with latent or new Mycobacterium tuberculosis infection. The risk of developing TB is about 20-37 times more in people infected with HIV than people non infected HIV. TB is responsible for more than a 25% of deaths in HIV infected people. In response to the dual epidemics of HIV and TB, the World Health Organization (WHO) recommends 12 collaborative TB/HIV activities as part of core HIV and TB prevention, care and treatment services.

1. Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence1)
2. Adults and adolescents living with HIV and screened with a clinical algorithm for TB, and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
3. Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
4. Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 36 months of IPT². IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence3)
5. TST is not a requirement for initiating IPT in people living with HIV.(Strong recommendation, moderate quality of evidence)
6. People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
7. Providing IPT to people living with HIV does not increase the risk of developing isoniazid (INH)-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
8. Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB.(Strong recommendation, low quality of evidence)
9. Children living with HIV who have any one of the following symptoms – poor weight gain, fever, current cough or contact history with a TB case – may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, such children should be offered IPT regardless of their age.(Strong recommendation, low quality of evidence)
10. Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services.(Strong recommendation, moderate quality of evidence)
11. In children living with HIV who are less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease.(Strong recommendation, low quality of evidence)
12. All children living with HIV who have successfully completed treatment for TB disease should receive INH for an additional six months.(Conditional recommendation, low quality of evidence)

Drug regimens for active tuberculosis in adults caused by drug-susceptible organisms Initial phase Regimen 1 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLUS ▸ EMB ???? mg/kg Regimen 2 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg ▸ RIF ???? mg/kg ▸ PZA ??? mg/kg ▸ EMB ???? mg/kg Regimen 3 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLSU ▸ EMB ???? mg/kg Regimen 4 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLSU ▸ EMB ???? mg/kg

Drug regimens for active tuberculosis in adults caused by drug-susceptible organisms Continuation phase Regimen 1 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† 1.a ▸ INH ??? mg/kg  :▸ RIF ???? mg/kg OR 1.b ▸ INH ??? mg/kg  :▸ RIF ???? mg/kg OR 1.c ▸ INH ??? mg/kg ▸ RPT ???? mg/kg PLSU ▸ EMB ???? mg/kg Regimen 2 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLSU ▸ EMB ???? mg/kg Regimen 3 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLSU ▸ EMB ???? mg/kg Regimen 4 ▸ Seven days per week for 56 doses (8 wk) or ▸ 5 d/wk for 40 doses (8 wk)† ▸ INH ??? mg/kg PLUS ▸ RIF ???? mg/kg PLUS ▸ PZA ??? mg/kg PLSU ▸ EMB ???? mg/kg

† Five-day-a-week administration is always given by DOT.