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]

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 epidemiological information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)--stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPD-tuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis.

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.

Medical Therapy

Drug	Category	Comment
Carfilzomib MLN 9708 ONX 0912 NPI-0052	Proteosome Inhibitors	Inhibitors of the immunoproteasome should have a favorable therapeutic index owing to the selective expression of immunoproteasome subunits in malignant, but not in normall blood cells. Second-generation inhibitors of the ubiquitin–proteasome cascade are now in preclinical and clinical studies. Inhibitos of de ubiquitinating enzymes of proteosomes, such as the USP-7 inhibitor and P5091, have own activity against various types of myeloma. Simultanous inhibition of both the proteosomes and histone deacetylase inhibitors leads to the accumualation of polyubiquinated protiens followed by the activation of apoptotic signaling cascade and cytotoxicity.|} Essential anti-TB drugs First-Line Drugs: Isoniazid Rifampin Rifabutin Rifapentine Pyrazinamide Ethambutol Fixed-dose combination preparations: Two combined preparations, INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®). Second-Line Drugs: Group 2: Injectable Agents Streptomycin Amikacin kanamycin Group 3: Fluoroquinolones Levofloxacin Moxifloxacin Ofloxacin Group 4: Oral Bacteriostatic Second-Line Agents Cycloserine Ethionamide Terizidone Protionamide Capreomycin p-Aminosalicylic acid 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. Dosing Frequency and the Level Of Evidence 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 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 New Patients Standard regimens for new TB patients (with presumed, or known, to have drug-susceptible TB) Preferred regimen Alternative regimen Alternative regimen Initial phase    Daily INH,RIF,PZA and EMB for 56 doses(8 weeks) Initial phase    Daily INH, RIF, PZA, and EMB* for 14 doses (2 weeks), then twice weekly for 12 doses (6 weeks) Initial phase    Thrice-weekly INH, RIF, PZA, and EMB* for 24 doses (8 weeks) Continuation Phase    Daily INH and RIF for 126 doses (18 weeks) or Twice-weekly INH and RIF for 36 doses (18 weeks) Continuation Phase    Twice-weekly INH and RIF for 36 doses (18 weeks) Continuation Phase    Thrice-weekly INH and RIF for 54 doses (18 weeks) Isoniazid (INH) rifampin (RIF) ethambutol (EMB) pyrazinamide (PZA) 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 (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 2nd 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 3rd 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 1st dose of the intensive phase treatment at the end of the intensive phase is at2nd month in new patients and 3rd 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. Treatment of Drug-Resistant Tuberculosis WHO has recommended the following for the susceptibility and response monitoring of MDR-TB 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 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 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. 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) WHO 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. Treatment in Special Situations HIV Co-infection Recommendations for the treatment of tuberculosis in HIV-infected adults: The recommended treatment of TB disease in HIV-infected adults (when the disease is caused by organisms that are known or presumed to be susceptible to first-line drugs) is a 6-month regimen consisting of: For the first 2 months: An initial phase of isoniazid (INH), a rifamycin, pyrazinamide (PZA), and ethambutol (EMB). For the last 4 months: A continuation phase of INH and a rifamycin. Patients with advanced HIV (CD4 counts < 100/µl) should be treated with daily or three-times-weekly therapy in both the initial and the continuation phases. Twice weekly therapy may be considered in patients with less-advanced immunosuppression (CD4 counts ≥ 100/µl). Once-weekly INH/rifapentine in the continuation phase should not be used in any HIV-infected patient. Recommendations for the treatment of tuberculosis in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults. The INH--rifapentine once weekly continuation phase is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin- or rifabutin-based regimens. Consequently, patients with CD4+ cell counts <100/µl should receive daily or three times weekly treatment. DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis. Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified. On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic findings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinflammatory agents may be useful for symptomatic relief. For severe paradoxical reactions, prednisone (1--2 mg/kg per day for 1--2 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach. Further information: HIV coinfection with tuberculosis Children Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop "adult-type" tuberculosis with upper lobe infiltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15--20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary. Most studies of treatment in children have used 6 months of INH and RIF supplemented during the first 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Most treatment studies of intermittent dosing in children have used daily drug administration for the first 2 weeks to 2 months. DOT should always be used in treating children. Because it is difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 9--12 months of treatment is recommended. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation. Extrapulmonary Tuberculosis According to the 4th edition of WHO recommendations; Pulmonary and extrapulmonary disease should be treated with the same regimens. Continuation phase for 6-9 months regimens that include INH and RIF are highly recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis. In tuberculous meningitis, ethambutol should be replaced by streptomycin. Statandard Regimens For New TB Patients With Drug-Susceptible TB Intensive Initial Phase ▸ Initial Phase: 2 months of HRZS † Continuation phase ▸ Continuation Phase: 6-9 months ‡ of HR ‡ In this group decisions to prolong the continuation phase should be made on an individual basis. Tuberculous Pericarditis With the use of antituberculosis chemotherapy, survival rate in tuberculous pericarditis has improved dramatically. Mortality rate in preantibiotic era was 80-90%. At present it is 8-17% and 17-34% if associated with HIV. A 2 months course of isoniazid, pyrazinamide, rifampicin, and ethambutol followed by 4 months course of isoniazid and rifampicin is shown to be effective. Short course chemotherapy is beneficial in HIV infected patients. American Thoracic Society, CDC, and Infectious Diseases Society of America recommends use of corticosteroids (prednisone) as adjunctive therapy for tuberculous pericarditis during the first 11 weeks of antituberculosis therapy. Following are the dosage recommendations: Adults: Prednisone 60 mg/day (or the equivalent dose of prednisolone) given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and finally 5 mg/day for week 11 (the final week) Children: Doses should be proportionate to their weight, beginning with about 1 mg/kg body weight and decreasing the dose as described for adults. Further information: Tuberculous pericarditis Culture-Negative Pulmonary Tuberculosis and Radiographic Evidence of Prior Pulmonary Tuberculosis Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months. Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely). Renal Insufficiency and End-Stage Renal Disease For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs. Liver Disease INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation. In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury. Pregnancy and Breastfeeding Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount. Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis. The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs. TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems. The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015. To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin. The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field. The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS", the acronym for "Directly Observed Therapy, Short course", in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, 3) a standardized treatment regimen of 6-8 months for at least all confirmed sputum smear-positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall. A Number of Other Differences Exist as Well The WHO and the IUATLD recommend diagnosis and classification of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities. Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIV-negative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue. Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly. New Advances in Pharmacotherapy A new drug, called Bedalaquine, was recently approved by the FDA in December 2012, to treat multi-drug resistant tuberculosis. About 12 million people worldwide had tuberculosis in 2011, and about 630,000 had multidrug-resistant forms of tuberculosis. Bedaquiline affects theproton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase . It was formally approved for use by the U.S. Food and Drug Administration (FDA) for use intuberculosis (TB) treatment- but it is to be used normally only in cases of multi-drug-resistant tuberculosis, and in an even more resistant category, extensively drug resistant tuberculosis. Multi-drug resistant tuberculosis is defined as tuberculosis cases that do not respond to at least two of the four primary (first-line) antibiotics, developed mostly in the 1950s and 1960s, that are used to treat tuberculosis. The drug has been given a black-box warning for arrhythmias which may cause cardiac arrest . In addition, a novel, 3-drug, anti-TB regimen (PaMZ) consisting of the chemical entity, nitroimidazooxazine, PA-824 (Pa), the fluoroquinolone, moxifloxacin (M), and the first-line TB drug, pyrazinamide (Z), has shown recent promise in the treatment of tuberculosis. The results of a recent phase II clinical trial published in the Lancet, showed that the three drug regimen killed more than 99% of TB bacteria within 2 weeks of treatment. A Research Agenda for Tuberculosis Treatment New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data. New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection. A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of protective cytokines such as interferon-g and interleukin-2, and nutritional supplements, especially vitamin A and zinc. Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT. References