Tuberculosis medical therapy

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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]

Overview

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.

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
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 Initial 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 Initial 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 Initial 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 Initial 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.

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 (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 . 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

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.

Contraindicated medications

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

• BCG vaccine