Initial Treatment of Tuberculosis

Initial Treatment of Tuberculosis
ISTC Training Modules 2008 Initial Treatment of Tuberculosis Instructor’s Guide Module: Initial Treatment of Tuberculosis ISTC Standards covered: 7, 8, 10, 11, and 17 Module Time: Approximately 60 minutes Alternate slides: Introductory ISTC slides Interactive options: Ideas for interactive discussions are offered on many of the slides in this module. Participant discussion can enhance active learning, but will add more time to the lecture and must be planned for. Additional Material: Slides containing related material may be found in the following modules: Treatment and co-management of TB and HIV, Management of Drug-resistant Tuberculosis. Test Questions: May be attached or inserted within presentation for discussion purposes, or alternatively, combined with questions from other modules to produce evaluation tool. The full text of the ISTC and all supporting references are available at Other useful Resources/References: Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. World Health Organization, ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4): Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Freiden TR ed., World Health Organization, Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): [Image Credit: Lung Health Image Library/Gary Hampton] Your name Institution/organization Meeting Date International Standards 7, 8, 10, 11, 17

ISTC Training Modules 2008 Objectives: At the end of this presentation, participants will have an understanding of: Drug regimens used in the initial treatment of both pulmonary and extrapulmonary tuberculosis The basis for the public health benefits of treating tuberculosis The clinical and microbiological effects of treatment The rationale for patient monitoring and reporting The main adverse effects of antituberculosis drugs It is intended that after completion of this module the student will be able to describe the approach to and rationale for the initial treatment of tuberculosis. These objectives represent the key points in the presentation. [Review objectives from slide] ISTC Training Modules 2008

ISTC Training Modules 2008 Overview: Effect of appropriate treatment on public health First-line treatment recommendations Treatment of extrapulmonary tuberculosis Monitoring of treatment Adverse reactions Recording and reporting Initial Treatment of Tuberculosis Overview: [Review content of slide] Lecture/module includes International Standards for Tuberculosis Care 7, 8, 10, 11, and 17. [Standard 9, “Developing a Patient-centered approach to treatment” is presented in a separate module.] [Image credits: Lung Health Image Library/Gary Hampton (top); Erlina Burhan, MD, Persahabatan Hospital (bottom)] International Standards 7, 8, 10, 11, and 17 ISTC Training Modules 2008

Standards for Treatment
ISTC Training Modules 2008 This slide emphasizes the fact that treatment for TB is both a matter of individual health and public health and that adherence to treatment must be assured to have confidence that the patient will be cured. Assessing adherence and addressing poor adherence may (likely will) require collaboration between the provider and a program or facility that is capable of ensuring adherence. The main interventions to prevent the spread of TB in the community are the detection of patients with infectious TB and providing them with effective treatment to ensure a rapid and lasting cure. Consequently, treatment for TB is not only a matter of individual health, it is also a matter of public health. [Image Credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

ISTC Training Modules 2008 Initial Treatment of Tuberculosis Standards 7 & 8 Standards 7 and 8 relate to treatment of the new, previously untreated case of TB. The information relates to both pulmonary and extrapulmonary TB, although most of the public health issues relate to pulmonary TB. Differences in the treatment of extrapulmonary TB are presented at the end of the discussion. The photos include a chest radiograph showing extensive bilateral upper lobe opacities consistent with TB and a patient with lymph node TB (swelling and erythema of an anterior cervical node together with a sinus tract from spontaneous rupture of a supraclavicular node). [Image credits: Francis J. Curry National Tuberculosis Center, University of California, San Francisco (top); Austin Brewin, MD (bottom).] ISTC Training Modules 2008

Standard 7: Public Health Effects of Treatment
ISTC Training Modules 2008 Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility. To fulfill this responsibility, the practitioner must not only prescribe an appropriate regimen, but also be capable of assessing the adherence of the patient to the regimen and addressing poor adherence when it occurs. By so doing, the provider will be able to ensure adherence to the regimen until treatment is completed. [Read Standard] Standard 7 emphasizes that treatment for TB is both a matter of individual health and public health and that it is the responsibility of the provider to both prescribe the correct regimen and to ensure adherence to the regimen. Assessing adherence and addressing poor adherence may (likely will) require collaboration between the provider and a program or facility that is capable of ensuring adherence. ISTC Training Modules 2008

Effect of Treatment on Public Health
ISTC Training Modules 2008 Why is TB Treatment a Public Health Measure? Effective treatment rapidly kills organisms, reducing the bacillary population in respiratory secretions, thus reducing the potential for transmission. Effective multiple-drug treatment greatly reduces the risk of resistant organisms emerging. Effective treatment decreases the duration and severity of illness and reduces the risk of death. The main interventions to prevent the spread of TB in the community are the detection of patients with infectious TB and providing them with effective treatment to ensure a rapid and lasting cure. Consequently, treatment for TB is not only a matter of individual health, such as is provided by, for example, treatment of hypertension or diabetes mellitus, it is also a matter of public health. All providers, public and private, who undertake to treat a patient with TB, must have the knowledge to prescribe a standard treatment regimen and the means to ensure adherence to the regimen until treatment is completed. National or local TB programs commonly possess mechanisms and tools to ensure adherence with treatment and, when properly organized, can offer these to non-program providers. Failure of a provider to ensure adherence could be equated with, for example, failure to ensure that a child receives the full set of immunizations. Communities and patients deserve to be assured that providers treating TB are doing so in accordance with this principle and are, thereby, meeting this standard. ISTC Training Modules 2008

Effect of Treatment on Public Health
ISTC Training Modules 2008 Effects of Treatment on the Incidence of Tuberculosis in Peru 220 DOTS 1990 200 case finding 180 Pulmonary TB cases/100,000 160 This slide shows the effect of an effective drug regimen that was closely supervised to ensure adherence. Peru began a DOTS program in late Because of the increased coverage of the program, more cases were found and, initially, case rates increased. However with the continued effectiveness of the program case rates began falling at the rate of approximately 6% per year. Because of the decrease in case rates, Peru “graduated” from the list of 22 high-burden TB countries. [The module “Fostering and Assessing Adherence to Treatment” describes approaches to enhance patient adherence and treatment supervision.] 140 120 PTB falling at 6%/yr 100 1980 1985 1990 1995 2000 ISTC Training Modules 2008

Standard 8: Initial Phase of Treatment
ISTC Training Modules 2008 (1 of 4) All patients (including those with HIV infection) who have not been treated previously should receive an internationally accepted first- line treatment regimen using drugs of known bioavailability. The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide and ethambutol. Because Standard 8 is lengthy and contains several concepts, it has been divided into 4 parts. [Read Standard] This part describes the most widely-used and effective initial phase of the initial drug regimen. There are 3 major points to be made with this slide: An accurate history is critical. Patients who have been treated previously have a greater risk of drug resistance and are assessed as described in Standard 14 [Drug-resistant Tuberculosis module]. The drugs used must be quality assured. Poor quality drugs are common and lead to poor outcomes. For maximum efficacy, 4 drugs should be given in the initial phase, although there are exceptions to this rule described subsequently. A large number of well-designed clinical trials have provided the evidence base for this standard and several sets of treatment recommendations based on these studies have been written in the past few years. All these data indicate that a rifampicin-containing regimen is the backbone of antituberculosis chemotherapy and is highly effective in treating TB caused by drug-susceptible M. tuberculosis. It is also clear from these studies that the minimum duration of treatment for smear and/or culture-positive TB is six months. For the six-month treatment duration to be maximally effective, the regimen must include pyrazinamide during the initial two-month phase and rifampicin must be included throughout the full six months. There are several variations in the frequency of drug administration that have been shown to produce acceptable results. [Image credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

Effect of Treatment on Bacillary Population
ISTC Training Modules 2008 Mixed population (susceptible and resistant) INH resistant bacilli Emergence of INH resistant strain because of ineffective treatment (INH monotherapy) Log cfu Effective multi-drug treatment rapidly reduces the bacillary population. Within 2 weeks of beginning appropriate chemotherapy the number of organisms in sputum is decreased from ~107 (107 would be a typical number of bacilli to find in the sputum of a person with cavitary pulmonary TB) to 104 (104 is the approximate threshold for detecting acid fast organisms by sputum smear microscopy). This greatly decreases (but does not completely eliminate) the potential for transmission. Further treatment beyond the initial period is intended to kill the remaining organisms that persist through the initial period. In all populations of M. tb there is a small number of organisms that are resistant to each of the drugs used. If treatment does not contain at least two drugs to which the organisms are susceptible, a bacillary population that is resistant to one or more of the first line drugs emerges. Effective multi-drug therapy Weeks ISTC Training Modules 2008

Unintended Monotherapy and Resistance
ISTC Training Modules 2008 Months of Rx 5 7 9 INH RIF EMB Smear + Culture Susceptibility R* R S* S In this hypothetical example a patient is begun on treatment with an initial 2 drug regimen, a clear mistake. The organisms were initially resistant to isoniazid, although the treating provider was unaware of this. After 5 months of treatment, the smear was still positive and the organisms had become resistant to rifampicin because the resistance to isoniazid prevented the eradication of the few organisms that were rifampicin resistant and the rifampicin resistant strain proliferated. Again the provider was not aware of the resistance that had occurred. Because the smear was still positive, the provider added ethambutol. This is also a clear mistake. A single drug should never be added to a failing regimen. A sputum specimen, after 9 months of treatment, was still positive. In effect the patient had been treated with ethambutol alone for the last 4 months of the regimen and the organisms that were resistant to ethambutol proliferated. This result would have been prevented if a regimen of isoniazid, rifampicin, ethambutol and pyrazinamide had been used in the initial 2 months of treatment. [Interactive option: This is a very important concept in the management of TB treatment. Stop to ask if there are any questions or clarifications needed.] * Results not known to clinician ISTC Training Modules 2008

Treatment Goals Microbiological Goals of Antituberculosis Chemotherapy
ISTC Training Modules 2008 Microbiological Goals of Antituberculosis Chemotherapy Kill tubercle bacilli rapidly (early bactericidal effect) Prevent the emergence of drug resistance Eliminate persistent bacilli to prevent relapse (sterilizing effect) The previous slides presented the individual and public health goals of treatment for TB. This slide defines the microbiological goals of treatment. [Review content of slide] Antituberculosis drugs operate in a complimentary way to accomplish these goals as shown in the next slide. ISTC Training Modules 2008

Activities of Antituberculosis Drugs
ISTC Training Modules 2008 Drug Early bactericidal activity Preventing drug resistance Sterilizing activity Isoniazid ++++ +++ ++ Rifampicin Pyrazinamide + Streptomycin Ethambutol This table shows the relative activities of the first line antituberculosis drugs. Isoniazid has the most potent early bactericidal effect and is also effective in preventing resistance, but has less sterilizing effect. Rifampicin has a weaker early effect but is more potent than isoniazid in its sterilizing activity. Pyrazinamide is only effective as a sterilizing agent. [Note: relatively poor agent for prevention of drug resistance] Streptomycin has an intermediate effect in all three activities as does ethambutol. Highest High Intermediate Low + ISTC Training Modules 2008

Standard 8: Continuation Phase of Treatment
ISTC Training Modules 2008 (2 of 4) The preferred continuation phase consists of isoniazid and rifampicin given for four months. Isoniazid and ethambutol given for six months is an acceptable continuation phase regimen that may be used when adherence cannot be assured, but is associated with a higher rate of failure and relapse, especially in patients with HIV infection. Standard 8 continued: [Read Standard] This slide describes the continuation phase regimens. The major points from the slide are that it is preferable to use rifampicin throughout the continuation phase, although isoniazid and ethambutol may be used in some circumstances. The reason for this alternative continuation phase regimen is to reduce the likelihood of resistance to rifampicin developing when treatment cannot be supervised effectively. A review of the outcomes of treatment of TB in patients with HIV infection clearly shows that TB relapse is minimized by the use of a regimen containing rifampicin throughout a six-month course. Thus, the 6 month regimen containing rifampicin throughout the entire course is preferable in patients with HIV infection to minimize the risk of relapse; however, the patient’s HIV stage, the need for, and availability of, antiretroviral drugs, and the quality of treatment supervision/support must be considered in choosing an appropriate continuation phase of therapy. Second, the shortest total duration of treatment is 6 months. Although regimens of less than 6 months have been evaluated in clinical trials, a Cochrane systematic review on this topic, and a more recent review found that regimens <6 months have an unacceptably high rate of relapse. The current international standard, therefore, is a regimen administered for a minimum duration of 6 months. [Gelband H., et al. Regimens of less than six months for treating tuberculosis. Cochrane Database Syst Rev 2000(2):CD001362; and Santha T, et al. What is the optimum duration of treatment? In: Friedan TR, ed. Toman’s tuberculosis. Case detection, treatment and monitoring, 2nd Edition. Geneva: WHO,2004] ISTC Training Modules 2008

Standard 8: Continuation Phase of Treatment
ISTC Training Modules 2008 (3 of 4) Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, who do not have extensive pulmonary tuberculosis or severe forms of extrapulmonary disease, and who are known to be HIV negative. Standard 8 continued: [Read Standard] In the situations noted in the slide, the bacillary population is small and thus there is a lower likelihood of resistant organisms being present, thus 3 drugs may be used in the initial phase. ISTC Training Modules 2008

Treatment Recommendations
ISTC Training Modules 2008 Ranking Initial Phase (2 mos.) Continuation Phase Preferred INH, RIF, PZA, EMB1,2 daily INH, RIF daily, 4 mos. INH, RIF, PZA, EMB1,2 3x/wk. INH, RIF 3x/wk, 4 mos. Optional3 INH, RIF, PZA, EMB daily INH, EMB daily, 6 mos. Treatment recommendations for persons not previously treated. This slide presents in tabular form the information contained in Standard 8 and also indicates that streptomycin can be substituted for EMB per current WHO recommendations (note: this recommendation may change). Note: All patients with TB and HIV infection should be evaluated to determine if antiretroviral therapy is indicated during the course of treatment for TB. [Additional information on this topic can be found in TB and HIV Infection: Introduction and Diagnosis module.] [Interactive option: Ask participants about what their standard practice is locally for the initiation and continuation phases of treatment.] [World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. Geneva: World Health Organization, 2003.] 1. Streptomycin may be substituted for EMB 2. Ethambutol may be omitted for adults and children who have negative sputum smears, do not have extensive pulmonary tuberculosis or severe forms of extra-pulmonary disease and who are HIV negative 3. Associated with higher rate of treatment failure and relapse; should generally not be used in patients with HIV infection. ISTC Training Modules 2008

Standard 8: Drug Formulations and Doses
ISTC Training Modules 2008 (4 of 4) The doses of antituberculosis drugs used should conform to international recommendations. Fixed-dose combinations of two (INH and RIF), three (INH, RIF and PZA), and four (INH, RIF, PZA, and EMB) drugs are highly recommended, especially when medication ingestion cannot be observed. Standard 8 continued: [Read Standard] Although there is no evidence that fixed dose combinations (FDCs) are superior to individual drugs, expert opinion suggests that they may reduce inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors. FDCs also reduce the number of tablets to be consumed and may thereby increase adherence to recommended treatment regimens. ISTC Training Modules 2008

Dose Recommendations mg/kg (range) Drug Daily 3x Week INH
ISTC Training Modules 2008 mg/kg (range) Drug Daily 3x Week INH 5 (4-6), max 300/d 10 RIF 10 (8-12), max 600/d 10 (8-12) max 600/ d PZA 25 (20-30) 35 (30-40) EMB children: 20 (15-25)* adults: 15 (15-20)* 30 (25-35) Streptomycin 15 (12-18) The evidence base for currently recommended anti-TB drug dosages derives from human clinical trials, animal models, pharmacokinetic and toxicity studies. The evidence on drug dosages and safety and the biological basis for dosage recommendations have been extensively reviewed in publications by the WHO, The Union, the ATS, the CDC, and IDSA. Intermittent administration of anti-TB drugs enables supervision to be provided more efficiently and economically with no reduction in efficacy. The evidence on effectiveness of intermittent regimens was reviewed recently. These reviews, based on several trials, suggest that anti-TB treatment may be given intermittently 3 times a week throughout or twice weekly in the continuation phase without apparent loss of effectiveness. However, the WHO and The Union do not recommend the use of twice-weekly intermittent regimens because of the potentially greater consequences of missing 1 of the 2 doses. Treatment of TB in special clinical situations such the presence of liver disease, renal disease, pregnancy, and HIV infection may require modification of the standard regimen or alterations in dosage or frequency of drug administration. [For further guidance in these situations: World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, Third Edition. Geneva: World Health Organization, 2003; ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4): ] *The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15mg/kg), because the pharmacokinetics are different (peak serum ethambutol concentrations are lower in children than in adults receiving the same mg/kg dose) ISTC Training Modules 2008

Treatment of Extrapulmonary TB
ISTC Training Modules 2008 Treatment of Extrapulmonary TB This slide introduces the topic of extrapulmonary TB. Three extrapulmonary sites are shown: CT scan of the head showing 2 enhancing lesions consistent with intracranial tuberculomas. Cervical lymphadenopathy with a large swollen node in the anterior cervical chain and spontaneously draining supraclavicular nodes Involvement of the lumbar spine with destruction of part of the body of a lower lumbar vertebra and soft tissue swelling anterior to the vertebra. The disc spaces are also narrowed. [Image credits: Francis J. Curry National Tuberculosis Center (top); Austin Brewin, MD (center); Francis J. Curry National Tuberculosis Center (bottom).] ISTC Training Modules 2008

ISTC Training Modules 2008 In general, extrapulmonary tuberculosis is treated the same as pulmonary tuberculosis Some experts recommend extending the duration of therapy in patients with: Meningeal tuberculosis Bone/joint tuberculosis Corticosteroids may be useful adjunctive treatment in some forms of extrapulmonary tuberculosis [Review content of slide] The emphasis in this slide is that there are minimal differences between the treatment of pulmonary and extrapulmonary sites of TB. Whereas with pulmonary TB there is extensive published evidence on the most effective treatment regimens, there is not much information for treatment of extrapulmonary sites, thus there is generally more controversy. [Recommended adult steroid dosing: Prednisone 60 mg/day for 4 weeks, then reduce to 30 mg/day for 4 weeks, then 15 mg/day for 2 weeks, then 5 mg/day for one week. ATS/CDC/IDSA Statement: Treatment of Tuberculosis. Am J Respir Crit Care Med 2003; 167(4): ] ISTC Training Modules 2008

ISTC Training Modules 2008 Treatment Duration and Use of Steroids Site Length of Rx (mos.) Corticosteroids Lymph node 6 No Bone/Joint 6-9 Pleural Pericarditis Yes CNS 9-12 Disseminated Genitourinary Abd/Peritoneal Other than for bone and joint and CNS tuberculosis, the duration of treatment is the same as for pulmonary TB. There are data that support the use of corticosteroids in treating tuberculous pericarditis and CNS tuberculosis. ISTC Training Modules 2008

Monitoring Treatment for TB and Public Health Reporting
ISTC Training Modules 2008 Monitoring Treatment for TB and Public Health Reporting Standards 10, 11, & 17 Patient monitoring is necessary for both initial treatment and re-treatment. Adequate monitoring involves both patent evaluations and recording of the relevant clinical and microbiological data. [Image credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

Standard 10: Monitoring Treatment
ISTC Training Modules 2008 (1 of 2) All patients should be monitored for response to therapy, best judged in patients with pulmonary tuberculosis by follow-up sputum smear microscopy (2 specimens) at least at the time of completion of the initial phase of treatment (2 months), at 5 months, and at the end of treatment. Patients who have positive smears during the 5th month of treatment should be considered as treatment failures and have therapy modified appropriately. [Read Standard] Patient monitoring and treatment supervision are two separate functions. (1) Patient monitoring is necessary to evaluate the response of the disease to treatment and to identify adverse drug reactions. For the latter function, contact between the patient and a provider is necessary. (2) To judge response of pulmonary TB to treatment, the most expeditious method is sputum smear microscopy. Ideally, where quality-assured laboratories are available, sputum cultures, as well as smears, should be performed for monitoring. Having a positive sputum smear at completion of five months of treatment defines treatment failure, indicating the need for determination of drug susceptibility and initiation of a re-treatment regimen*. [*As described in Standards 14 and 15, details covered in Drug-resistant TB and Managing Drug-resistant TB modules.] ISTC Training Modules 2008

ISTC Training Modules 2008 (2 of 2) In patients with extrapulmonary tuberculosis and in children, the response to treatment is best assessed clinically. Follow-up radiographic examinations are usually unnecessary and may be misleading Standard 10 continued: [Read Standard] Radiographic assessment, although used commonly, have been shown to be unreliable for evaluating response to treatment. Similarly, clinical assessment can be unreliable and misleading in the monitoring of patients with pulmonary TB. In patients with extra-pulmonary TB and in children, clinical evaluations may be the only available means of assessing the response to treatment. [Image credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

Monitoring: Timing of Sputum Specimens
ISTC Training Modules 2008 Initial Phase Continuation Phase Isoniazid Rifampicin Pyrazinamide Ethambutol Sputum specimens are to be obtained at the time of the diagnostic evaluation, at completion of the initial phase of treatment, at 5 months to assess for treatment failure, and at the end of the continuation phase (6 months) to confirm that treatment has been successful. By WHO criteria, having a positive sputum at 5 months defines treatment failure, indicating the need to assess for drug resistance*. A person who completes 6 months of treatment and has negative sputum smears at the time of completion is defined as cured. If sputum is not examined at the end of treatment, the patient is defined as having completed treatment. For purposes of defining outcome, those who are cured and those who have completed treatment are considered to have been successfully treated. *[Standard 14 – see Drug-resistant TB module.] months Diagnostic Assessment for failure End of intensive phase Completion ISTC Training Modules 2008

Treatment Outcomes for Pulmonary TB
ISTC Training Modules 2008 1.2% 50% 10% 98% 64% Dead Sputum negative 32% Sputum positive 20% Appropriate chemotherapy is highly successful in the initial treatment of pulmonary TB, whereas poor chemotherapy not only has a substantially lower rate of success and higher death rates but serves to create chronic sputum positive patients, likely with drug-resistant organisms. Analysis of cohorts of patients enables programs, institutions, and individual practitioners to determine the level of success of treatment in their setting and to identify weaknesses in treatment. This can only be accomplished when there is systematic monitoring of patients and recording of treatment results. [Reference: Grzybowski S et al. Results in pulmonary tuberculosis patients under various treatment program conditions. Bull Int Union Tuberc 1978; (53)2: 70-5] 18% 0.8% No Chemotherapy Poor Chemotherapy Good Chemotherapy Grzybowski S et al, Bull Int Union Tuberc 1978; (53)2: 70-5 ISTC Training Modules 2008

Monitoring: Adverse Reactions
ISTC Training Modules 2008 Adverse Reaction Drugs Rash PZA, INH, RIF, EMB Gastrointestinal intolerance PZA, RIF Liver toxicity PZA, INH, RIF Peripheral neuropathy INH, (EMB) Optic neuritis EMB Gout PZA These are the most common adverse drug reactions that occur in patients being treated for TB. [Review content of slide] All drugs can cause skin rash which, rarely, can be severe. Gastrointestinal upset can usually be managed with alterations in dosing schedules and symptomatic measures. Liver toxicity is the most common severe reaction. Each of the three agents listed can cause liver toxicity. In a large review clinical hepatitis occurred in 0.6% of patients taking INH alone, 1.6% of patients taking INH and other drugs but not RIF, 2.7% of patients taking INH and RIF and 1.1% of patients taking RIF plus other drugs but not INH. In addition studies of RIF/PZA with no other drugs for treatment of latent TB infection showed an unacceptable rate of hepatitis. This combination is no longer recommended. [For a more complete review of the adverse effects of antituberculosis drugs see: ATS/CDC/IDSA Statement: Treatment of Tuberculosis. American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America, Am J Respir Crit Care Med 2003; 167(4): ] Drugs are listed in order of relative likelihood of causing adverse reaction. INH/RIF and RIF/PZA appear to have synergistic effects in causing hepatitis ISTC Training Modules 2008

Adverse Reactions: Rash
ISTC Training Modules 2008 Classic drug-related rash Severe skin rash from thioacetazone The rash due to anti-TB drugs is similar to that seen with other drug-related rashes (example here actually due to amoxicillin) with a erythematous, maculopapular appearance. Although skin rashes are generally mild, they may be severe, including Stevens Johnson Syndrome which may be fatal. In the bottom example, the skin reaction was from thioacetazone, a drug which is not commonly used because of the frequency of severe skin reactions especially in persons with HIV infection. [Image credits: Catalog of Clinical Images/ Charlie Goldberg, MD, (top); Lung Health Image Library/Paul Nunn (bottom)] ISTC Training Modules 2008

Drug-induced Hepatotoxicity
ISTC Training Modules 2008 Hepatotoxic reactions: Transaminase elevation age-dependent with INH Transaminase elevation dose-dependent with PZA Cholestasis (increase in bilirubin and alkaline phosphatase) with RIF Symptoms imply significant hepatotoxicity (Mild transaminase elevation may not be clinically significant) Because drug-induced hepatitis is the most common severe adverse effect, providers should be aware of the patterns of abnormalities and the general approach to management. INH, RIF, and PZA may all cause transaminase elevation. In addition, the reactions to specific first-line drugs can show the following: [Review content of slide] Overall, how adverse reactions are handled will depend on the severity of symptoms and the available facilities for evaluation and management. [Mild transaminase elevations may not be treatment limiting. One recommended strategy suggests that elevated liver enzymes of 5x upper limit of normal without symptoms or 3x upper limit of normal with symptoms serve as the thresholds for holding and re-evaluating TB treatment due to possible drug-related hepatotoxicity.] [For detailed information: Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): ] ISTC Training Modules 2008

Managing Hepatotoxicity
ISTC Training Modules 2008 Management Hold all medications and follow liver enzymes for significant hepatotoxicity Re-challenge depends on circumstances and severity of liver dysfunction In general, patients should be restarted with EMB (the least hepatotoxic drug) and RIF, usually followed in several days by INH if there is no worsening of liver function Once a significant hepatotoxic reaction is suspected, all medications should be held and liver enzymes monitored for signs of recovery. Alternate causes should be excluded (ex. viral hepatitis). If a re-challenge is deemed safe: The combination of EMB and RIF is least likely to be hepatotoxic and may be re-introduced first. If there is no worsening of liver function, INH can then be added with close observation. If there is no worsening of liver function after adding the INH, it can be assumed that PZA alone or in combination caused the adverse reaction and PZA should not be restarted. Without PZA the minimum duration of treatment is 9 months. [For detailed information: Saukkonen JJ, et al. An official ATS statement: Hepatotoxicity of antituberculosis drugs. Am J Resp Crit Care Med 2006; 174(8): ] ISTC Training Modules 2008

ISTC Training Modules 2008 A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients [Read Standard] There is a sound rationale and clear benefits of a record keeping system. The recording and reporting system enables targeted, individualized follow-up to identify patients who are failing therapy. It also helps in facilitating continuity of care, particularly in settings (e.g. large hospitals) where the same practitioner might not see the patient every visit. A good record of medications given, results of investigations such as smears, cultures, and CXR, and progress notes on clinical improvement, adverse events, and adherence will provide for more uniform monitoring and ensure a high standard of care. Records are important to provide continuity when patients move from one care provider to another and enable tracing of patients who miss appointments. In patients who default and then return for treatment, and patients who relapse after treatment completion, it is critical to review previous records in order to assess the likelihood of drug resistance. Lastly, management of complicated cases (e.g., MDR-TB) is not possible without an adequate record of previous treatment, adverse events, and drug susceptibility results. It should be noted that, wherever patient records are concerned, care must be taken to insure confidentiality of the information. [Image credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

Standard 17: Reporting Cases
ISTC Training Modules 2008 All providers must report both new and retreatment tuberculosis cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policies. [Read Standard] An additional record keeping step is the appropriate reporting of both new and retreatment cases to the local public health authorities. Reporting TB cases to the local TB control program is an essential public health function, and in many countries is legally mandated. An effective reporting system enables a determination of the overall effectiveness of TB control programs, of resource needs, and of the true distribution and dynamics of the disease within the population as a whole. A system of recording and reporting information on TB cases and their treatment outcomes is also one of the key elements of the DOTS strategy Finally, a system of recording and reporting ensures accountability. [Image credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008 ISTC Training Modules 2008

ISTC Training Modules 2008 Summary: Appropriate treatment and assessment of adherence to treatment is an important public health issue. The use of internationally accepted first-line treatment regimens is associated with a high cure rate and a low risk of acquired drug resistance. [Review content of slide] ISTC Training Modules 2008

ISTC Training Modules 2008 Summary (cont.): Pulmonary and extrapulmonary TB are generally treated with the same regimens. (Exception: extended duration in meningeal and bone/joint disease.) Monitoring for both response to treatment and for potential adverse events is essential. [Review content of slide] ISTC Training Modules 2008

Summary: ISTC Standards Covered*
ISTC Training Modules 2008 Standard 7: Practitioners assume an important public health responsibility in ensuring both appropriate treatment regimens and assessment of treatment adherence for their patients. Standard 8: All patients who have not been previously treated should receive an internationally accepted treatment regimen: Initial phase: 2 months INH, RIF, PZA, and EMB Continuation phase: 4 months INH and RIF, or 6 months of INH and EMB (higher failure in HIV) And in summary, the International Standards reviewed: [Review content of slide] * Abbreviated versions ISTC Training Modules 2008

ISTC Training Modules 2008 Standard 8: (continued) EMB may be omitted in the initial phase for non-HIV smear-negative cases without severe disease. The doses of anti-TB drugs used should conform to international recommendations. Fixed-dose combinations are highly recommended. Standard 10: All patients should be monitored for response to therapy, best judged in patients with pulmonary TB by follow-up sputum smear microscopy (at 2 and 5 months and end of treatment). [Review content of slide] * Abbreviated versions ISTC Training Modules 2008

ISTC Training Modules 2008 Standard 10: (continued) Positive smears during the 5th month of treatment are considered treatment failures and treatment should be modified appropriately. Response to treatment in extrapulmonary TB is best assessed clinically. Follow-up radiographs are usually unnecessary and may be misleading. [Review content of slide] * Abbreviated versions ISTC Training Modules 2008

ISTC Training Modules 2008 Standard 11: A written record of all medications given, bacteriologic responses, and adverse reactions should be maintained for all patients. Standard 17: All providers must report both new and retreatment TB cases and their treatment outcomes to local public health authorities [Review content of slide] [End] * Abbreviated versions ISTC Training Modules 2008

ISTC Training Modules 2008 Alternate Slides Alternate Slides: Offer additional options that may be added or substituted into module. See Facilitator’s Guide for further information. ISTC Training Modules 2008

Purpose of ISTC ISTC Training Modules 2008 The International Standards for Tuberculosis Care (ISTC): Are intended to unite public and private sectors in providing a uniformly accepted level of care for all patients with, or suspected of having, TB. Describes the essential elements of TB care that should be available everywhere. Provides a vehicle for mobilizing professional societies globally in support of TB programs. Serves as a powerful advocacy tool to ensure that the essential elements are available. [Image Credit: Lung Health Image Library/Gary Hampton] ISTC Training Modules 2008

ISTC: Key Points 17 Standards
ISTC Training Modules 2008 17 Standards Differ from existing guidelines: standards present what should be done, whereas, guidelines describe how the action is to be accomplished Evidence-based, living document Developed in tandem with Patients’ Charter for Tuberculosis Care Handbook for using the International Standards for Tuberculosis Care The ISTC consist of 17 evidence-based standards. Standards differ from existing guidelines in that standards present what should be done, whereas, guidelines describe how the action is to be accomplished. To meet the requirements of the Standards, approaches and strategies, determined by local circumstances and practices and developed in collaboration with local and national public health authorities, will be necessary. There are many situations in which the level of care can, and should, go beyond what is specified in the Standards. The Standards should be viewed as a living document that will be revised as technology, resources, and circumstances change. Revisions to the original document released December 2005 are currently underway. Funded (Oct 1, 2004) by USAID via TBCTA, development was supervised by an international steering committee (28 members / 14 countries) chosen to represent perspectives relevant to tuberculosis care and control. The Standards are also intended to serve as a companion to and support for the Patients’ Charter for Tuberculosis Care developed in tandem with the Standards. A Handbook for using the International Standards for Tuberculosis Care is also available (2007). The Handbook presents suggestions and guidance, based mainly on country-level experiences, for using the ISTC as a tool to foster and guide the delivery of high-quality care by all practitioners providing TB care. [Resource: ISTC Training Modules 2008

ISTC: Key Points ISTC Training Modules 2008 Audience: all health care practitioners, public and private Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs The Standards are addressed to all healthcare providers, private and public, who care for persons with proven tuberculosis or with symptoms and signs suggestive of TB. Three categories of activities are addressed by the Standards: diagnosis, treatment, and public health responsibilities of all providers. The ISTC are intended to be complementary to local and national TB control policies that are consistent with the World Health Organization (WHO) recommendations. In many parts of the world there is great variability in the quality of tuberculosis care, and poor quality care continues to plague global tuberculosis control efforts. Effective engagement of all providers in providing high quality care in collaboration with TB control programs is key to the promotion of sound tuberculosis control. ISTC Training Modules 2008

ISTC Training Modules 2008 Questions Questions: May be used for interactive discussion, course evaluation, or continuing medical education purposes. See Facilitator Guide for further information. ISTC Training Modules 2008

ISTC Training Modules 2008 1. A 28 year-old woman taking standard four-drug treatment for TB for five weeks now complains of nausea, vomiting, and right upper-quadrant discomfort. When seen in clinic she is noted to have scleral icterus and right upper-quadrant tenderness. Her urine is dark colored. What is the appropriate action to take at this time? Stop all drugs Stop isoniazid Give pyridoxine (vitamin B6) Replace pyrazinamide with streptomycin Correct Answer: A ISTC Training Modules 2008

ISTC Training Modules 2008 2. A 68 year-old woman with smear-positive TB needs to start treatment. She lives too far to be given directly-observed treatment (DOT) by your office. Which treatment regimen is preferred for this patient? Isoniazid and ethambutol for twelve months Isoniazid/rifampicin/ethambutol for the first two months, followed by isoniazid/rifampicin for an additional four months Fixed-dose combination of isoniazid/rifampicin/pyrazinamide for nine months Fixed-dose combinations of isoniazid/rifampicin/ethambutol/pyrazinamide for the first two months, followed by isoniazid/rifampicin for an additional four months Correct Answer: D ISTC Training Modules 2008

ISTC Training Modules 2008 3. In considering treatment for extrapulmonary disease, all of the following statements are correct except: Extrapulmonary disease is a sign of disseminated disease, and therefore always requires a longer duration of treatment Most presentations of extrapulmonary TB can be treated with the same standard six month regimens used for pulmonary TB Extending the duration of therapy is recommended by many experts for central nervous system (CNS) and bone/joint extrapulmonary TB Corticosteroids are sometimes recommended for pericardial and central nervous system (CNS) extrapulmonary TB Correct Answer: A ISTC Training Modules 2008

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