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. In the U.S., all TB is tested for drug resistance.

Deciding To Initiate Treatment

The decision to initiate combination antituberculosis chemotherapy should be based on following features

• Epidemiological information;
• Clinical evidence
• Pathological
• Radiographicfindings
• 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.

• If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, treatment can be continued to complete a standard course of therapy. When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPD-tuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tuberculosis. If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered.

• If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months). In low-suspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, one of the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include INH for a total of 9 months, RIF with or without INH for a total of 4 months, or RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIF--PZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this egimen.

Drugs in treatment of Tuberculosis

Groups	Drugs
Group 1: First-line oral drugs	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

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 Patients

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

Preferred regimen Initial phase ▸ Isoniazid 300mg/day P.O for 8 weeks(56doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O for 8 weeks(56 doses)(10mg/kg/day) Plus ▸ Pyrazinamide 2g/day P.O for 8 weeks (56 doses) (25mg/kg/day) Plus ▸ Ethambutol 1.6g P.O for 8 weeks (56 doses)(15mg/kg/day) Continuation phase ▸ Isoniazid 300mg/day P.O for 18 weeks(126doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O for 18 weeks(126 doses)(10mg/kg/day) OR ▸ Isoniazid300mg/day P.O twice weekly for 18 weeks(36doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O twice weekly for 18 weeks(36 doses)(50mg/kg/day) Alternate regimen 1 Initial phase ▸ Isoniazid300mg/day P.O for 2 weeks(14doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O for 2 weeks(14 doses)(10mg/kg/day) Plus ▸ Pyrazinamide 2g/day P.O for 2 weeks (14 doses) (25mg/kg/day) Plus ▸ Ethambutol 1.6g P.O for 2 weeks (14 doses)(15mg/kg/day) FOLLOWED BY ▸ Isoniazid300mg/day P.O twice weekly for 6 weeks(12doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O twice weekly for 6 weeks(12doses)(10mg/kg/day) Plus ▸ Pyrazinamide 2g/day P.O twice weekly for 6 weeks(12doses) Plus ▸Ethambutol 1.6g P.O for 2 weeks (14 doses)(15mg/kg/day) Continuation phase ▸ Isoniazid300mg/day P.O biweekly for 18 weeks(36doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O biweekly for 18 weeks(36 doses)(10mg/kg/day) Alternate regimen 2 Initial phase ▸ Isoniazid300mg/day P.O thrice weekly for 8 weeks(24 doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O thrice weekly for 8 weeks(24 doses)(10mg/kg/day) Plus ▸ Pyrazinamide 2g/day P.O thrice weekly for 8 weeks(24 doses) (25mg/kg/day) Plus ▸ Ethambutol 1.6g P.O thrice weekly for 8 weeks(24 doses)(15mg/kg/day) Continuation phase ▸ Isoniazid300mg/day P.O thrice weekly for 18 weeks(54doses)(5mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O thrice weekly for 18 weeks(54doses)(10mg/kg/day)' Preferred regimen Initial phase ▸ Isoniazid 300mg/day P.O for 8 weeks(56doses)(10mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O for 8 weeks(56 doses)(15mg/kg/day) Plus ▸ Pyrazinamide 2g/day P.O for 8 weeks (56 doses) (35mg/kg/day) Plus ▸ Ethambutol 1.6g P.O for 8 weeks (56 doses)(20mg/kg/day) Continuation phase ▸ Isoniazid 300mg/day P.O for 18 weeks(126doses)(10mg/kg/day) Plus ▸ Rifampicin 600mg/day P.O for 18 weeks(126 doses)(15mg/kg/day)

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

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 ▸ 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.

Monitoring during treatment

Monitoring the Patients and Baseline Evaluations

Patients suspected of having tuberculosis should have the followings:

• 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 isunknown.
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 is manifested 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-Tb Drugs

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 . 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 at the end of the intensive phase is at2^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.

Management of Treatment Interruption

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

† (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

WHO Recommendation for Anti-TB drug induced hepatitis are:

• 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 Streptomycinfollowed 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 afluoroquinolone 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 byRifampicin 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.

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.