ISTC TB Training Modules 2009

ISTC TB Training Modules 2009
Drug-Resistant Tuberculosis Instructor’s Guide and Teaching Notes Module: Drug-resistant Tuberculosis ISTC Standards covered: Standard 11 Module Time: Approximately 60 minutes Alternate slides: Resource list for web-based materials, Template slides to list local diagnostic testing resources and contact information, 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: Management of Drug-resistant Tuberculosis, Microbiologic Diagnosis of 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: Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency Update World Health Organization. Drug-resistant tuberculosis: A survival guide for clinicians, 2nd edition. Francis J. Curry National Tuberculosis Center, The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health [Image Credit: World Lung Foundation/ Pierre Virot] Your name Institution/organization Meeting Date International Standard 11

Drug-Resistant Tuberculosis
ISTC TB Training Modules 2009 Objectives: At the end of this presentation, participants will be able to: Define the areas with the highest global burden of MDR. Understand the microbiological basis for the development of drug resistance. Recognize the clinical errors and programmatic factors that can lead to the development of drug resistance. Recognize the risk factors for MDR/XDR and the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment. It is intended that after completion of this module the student will be aware of the clinical and microbiological factors that predispose to drug resistance, and to identify persons who should be evaluated for possible drug-resistant TB. [Review content of slide]

ISTC TB Training Modules 2009 Overview: Definitions Global burden and individual impact Pathogenesis and clinical/programmatic contributors to development Early identification and risk factors Recommendations for diagnosis Drug-Resistant Tuberculosis Overview: [Review content of slide] [Image Credit: Francis J. Curry National Tuberculosis Center / Lisa Chen] Lecture/module includes International Standard for Tuberculosis Care 11 International Standard 11

ISTC TB Training Modules 2009 MDR-TB is a manmade problem… It is costly, deadly, debilitating and is a major threat to our current control strategies. While many of the general concepts regarding drug-resistant TB will be covered here, a significant amount of the material will focus on multidrug-resistant TB (MDR-TB). Understanding how MDR-TB develops and how to prevent MDR-TB is of the utmost importance because: [Read content of slide]. The development of MDR-TB (and XDR-TB) is largely man-made and therefore preventable. Often it is a consequence of suboptimal regimens and treatment interruptions. Clinical misjudgments, co-morbid conditions, and programmatic shortcomings may all contribute to the emergence of drug-resistance. The impact of MDR/XDR-TB is significant, both to the individual and to the healthcare system. [Interactive option: Ask participants how many of them care for MDR cases on a regular basis. Ask approximately what proportion of their TB population has drug resistance and compare to the relative impact these cases have on their program resources.] [Image Credit: World Lung Foundation/ Pierre Virot]

Standard 11: Drug-Resistant TB
ISTC Training Modules 2008 ISTC TB Training Modules 2009 (1 of 3) An assessment of the likelihood of drug resistance, based on history of prior treatment, exposure to a possible source case having drug-resistant organisms, and the community prevalence of drug resistance, should be obtained for all patients. The assessment for possible drug resistance is addressed in the ISTC Standard 11 as follows: [Read Standard] 5 5

ISTC Training Modules 2008 ISTC TB Training Modules 2009 (2 of 3) Drug susceptibility testing should be performed at the start of therapy for all previously treated patients Patients who remain sputum smear-positive at completion of 3 months of treatment and patients who have failed, defaulted from, or relapsed following one of more courses of treatment should always be assessed for drug resistance [Read Standard] 6 6

ISTC Training Modules 2008 ISTC TB Training Modules 2009 (3 of 3) For patients in whom drug resistance is considered to be likely, culture and testing for susceptibility/resistance to at least isoniazid and rifampicin should be performed promptly Patient counseling and education should begin immediately to minimize the potential for transmission Infection control measures appropriate to the setting should be applied [Read Standard] 7 7

Drug-Resistant TB: Definitions
ISTC TB Training Modules 2009 Mono-resistant: Resistance to a single drug Poly-resistant: Resistance to more than one drug, but not the combination of isoniazid and rifampicin Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin) Begin with the definitions for drug resistance: Mono-resistant: The most common single drug-resistance pattern is mono-resistance to isoniazid. In general, this pattern of resistance is not usually associated with a worse outcome and does not require modification of the treatment regimen (as long as there are 4 drugs in the initial phase and rifampicin is included throughout the full duration of treatment). Rifampicin mono-resistance occurs, but is uncommon and is seen mainly in patients with HIV infection. The reasons for this association are not known. Poly-resistant: A general term used when the organism is resistant to more than one drug, but not the combination of isoniazid and rifampicin. MDR-TB: Resistance to at least isoniazid and rifampicin (the two most effective anti-tuberculosis drugs). MDR has a major adverse effect on the outcome of treatment. Patients with TB caused by MDR organisms generally require treatment with second line drug regimens. XDR-TB: MDR-TB plus resistance to the 2 most important classes of 2nd-line agents used in MDR-TB treatment: the fluoroquinolones and at least 1 of 3 injectable agents (amikacin, kanamycin, capreomycin). In addition to meeting the defining criteria, XDR-TB cases are often resistant to all four 1st-line agents. Consequently, patients with XDR-TB are significantly more difficult to treat and require specialized care. [Note: Material also covered (duplicate slide) in Management of Drug-Resistant TB module.]

Drug-Resistant TB: Definitions
ISTC TB Training Modules 2009 Primary drug-resistance: “New Cases” Drug resistance in a patient who has never been treated for tuberculosis or received less than one month of therapy Secondary (acquired) drug-resistance: “Previously Treated Cases” Drug resistance in a patient who has received at least one month of anti-TB therapy Cases of drug-resistant TB may also be further defined (particularly for reporting purposes) as being a New Case or a Previously Treated Case. A drug-resistant “New Case” is defined as one in which the patient has not received prior TB treatment for any significant time. This situation then infers a primary drug resistance, i.e. the patient became infected with a strain from a drug resistant source case. A “Previously-treated case” with drug resistance has received prior TB treatment for at least one month. In these cases, the concern is that the patient has developed a secondary (acquired) drug resistance due to the past treatment. [Note: Material also covered (duplicate slide) in Management of Drug-Resistant TB module.]

Estimated Global MDR Cases
ISTC TB Training Modules 2009 Estimated global incidence and proportion of MDR among TB cases, 2006 2006 TB cases MDR cases % New Cases* 9,123,922 285,718 3.8 Previously treated cases* 1,052,145 203,230 19.3 Total cases** 10,192,986 489,139 4.8 Data published in 2008 from WHO (for 2006) estimates the number of MDR cases globally, based on a number of assumptions, using data reported from 175 countries (185 countries reporting for total estimates). [Review content of slide] It is notable that the estimated percentage of MDR-TB among previously treated TB cases is about 5 times greater than the estimated percentage of MDR-TB among new (previously untreated) cases. This finding highlights the increase risk for MDR-TB among individuals previously treated. The total case estimates indicate that 4.8% of all cases of TB beginning treatment in 2006 had MDR organisms. [Reference: WHO Anti-tuberculosis drug resistance in the world, Fourth global report,2008; *175 countries reporting; **185 countries reporting WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008

Estimated Global MDR Cases
ISTC TB Training Modules 2009 Estimated global prevalence of MDR (based on 2-3 year duration as an active case): 1,000,000 –1,500,000 cases Estimated 42% of global MDR cases have had prior treatment China and India carry 50% of the global MDR burden, with the Russian Federation carrying a further 7% Prevalence Estimates: Because MDR-TB is not cured as rapidly as drug-susceptible disease the estimated duration as an active case is 2-3 years. If this is generally true, at any point in 2006 there were an estimated 1,000,000-1,500,000 MDR cases in the world. Impact of Prior Treatment: It is important to note that, although there are many fewer cases of MDR-TB who have been treated in the past compared to the numbers of new cases (previously untreated) with MDR-TB, the previously treated groups contribute a disproportionate number of drug-resistant cases. This is likely a consequence of acquired drug resistance caused by poor compliance or poor treatment management in the past. Countries with highest burden MDR: Three countries, China and India (because of the total numbers of cases) and the Russian Federation (because of a disproportionate number of MDR cases) contribute an estimated 57% of the world’s MDR cases in 2006. [Reference: WHO Anti-tuberculosis drug resistance in the world, Fourth global report,2008; WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008

Distribution of MDR: No Prior Treatment
ISTC TB Training Modules 2009 Using 2004 data to look at the geographic distribution (proportion) of MDR cases among cases without previous treatment (previously untreated): The areas with the highest estimated proportion of MDR cases among previously untreated cases (more than 6%) depicted in green include much of Eastern Europe, particularly the Russian Federation and countries of the former Soviet Union. The light blue areas indicate countries with a proportion of MDR of 3-6% of all new cases. This includes China, the most populous country in the world. [Reference: Zignol M, et al. Global Incidence of Multidrug-Resistant Tuberculosis. JID 2006; 194: ] Distribution of MDR rates among new cases (previously untreated) Zignol M, et al. JID 2006; 194:

Distribution of MDR: Prior Treatment
ISTC TB Training Modules 2009 This map shows the distribution (proportion) of MDR cases among previously-treated cases of TB. The areas with the greatest proportion of MDR among previously-treated cases (red) have proportions of greater than 40%. Notice the similarities between the two distribution maps in regards to areas with the highest rates in both categories. [Reference: Zignol M, et al. Global Incidence of Multidrug-Resistant Tuberculosis. JID 2006; 194: ] Distribution of MDR rates among previously treated cases Zignol M, et al. JID 2006; 194:

Individual Impact of MDR
ISTC TB Training Modules 2009 Average direct medical costs per case in the US: $27,752 [Burgos, et al. CID 2005; 40: ] Long treatment duration (18-24 mos.), often difficult and toxic Long periods of isolation may be necessary Depression is common Disease may be incurable (chronic) Higher rate of death The cost of MDR is astounding. In the US the average direct medical costs per MDR case are far higher than for treatment of drug-susceptible TB. This is due to the costs of hospitalization, which is much more likely to be necessary for patients with MDR, and the much longer duration of treatment with costlier drugs. The costs to the patients are also profound. Treatment is more toxic than with standard 1st-line agents and duration is always at least 18 months. There may be longer periods of isolation for these patients because of lower effectiveness of 2nd-line agents, which may result in a longer time before sputum smears convert to negative. Because of the ongoing effects of having a chronic illness, depression is common and may interfere with adherence to treatment. The patient may face an incurable status, and mortality rates are higher with MDR-TB. [Reference: Burgos, et al. Treatment of Multidrug-resistant tuberculosis in San Francisco: An outpatient-based approach. CID 2005; 40: ]

Impact of Resistance on Outcome
ISTC TB Training Modules 2009 % of cases with failure or death, standard 4-drug regimen Resistance pattern New Cases (%) Retreatment (%) Pan-susceptible 4 10 Any Resistance 5 21 MDR 30 45 INH (not MDR) 6 23 RIF (not MDR) 13 29 Other 15 This table describes the outcome of treatment using a standard first line regimen in patients with various patterns of drug resistance. Investigators conducted a retrospective cohort study of patients with TB in the Dominican Republic, Hong Kong, Italy, Ivanovo Oblast (Russian Federation), the Republic of Korea, and Peru. The outcome was determined for new (previously untreated) and retreatment TB cases who received short-course chemotherapy with isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin between 1994 and Treatment outcome was defined according to WHO criteria. In this table, death during treatment and treatment failure were combined to provide a measure of unfavorable outcome. As the table shows, both MDR and rifampicin resistance were associated with a greater percentage of unfavorable outcomes than any of the other categories. Retreatment cases in all categories did less well than new cases. Again MDR cases had the highest percentage of unfavorable outcomes. The success rate of retreated cases drops substantially in all categories. Successful treatment outcomes for both new and retreated cases are significantly lower for RIF-resistant and MDR cases. [Reference: Espinal MA, et al. Standard Short-course Chemotherapy for Drug-Resistant Tuberculosis: Treatment Outcomes in 6 Countries. JAMA. 2000;283(19): ] Espinal MA, et al. JAMA. 2000;283(19):

Estimated Global XDR 2007 Global TB estimates: XDR and MDR 2007
ISTC TB Training Modules 2009 Global TB estimates: XDR and MDR 2007 2007 Estimated number of cases Estimated number of deaths All forms of TB 9.2 million (139 per 100,000) 1.77 million (27 per 100,000) MDR 511,000 ~150,000 XDR ~50,000 ~30,000 Extensively drug-resistant TB (XDR) was first described in 2006 and has been rapidly recognized as a serious emerging threat to global public health. Recent estimates of the global burden of XDR with the higher associated mortality rate as compared to estimates of MDR cases in 2007 are shown here. [Review content of slide] [Reference: Adapted from Paul Nunn, MDR, XDR TB and HIV: global data, approaches and operational research issues; (lecture), Cape Town, July 19, StopTB/WHO 2009] Adapted from Paul Nunn, StopTB/WHO 2009

Distribution of XDR ISTC TB Training Modules 2009 Reports have noted the presence of XDR-TB in all regions of the world. [Reference: Adapted from Paul Nunn, MDR, XDR TB and HIV: global data, approaches and operational research issues; (lecture), Cape Town, July 19, StopTB/WHO 2009] Countries that had reported at least one XDR-TB case by end of April 2009 WHO 2009

Pathogenesis of Drug Resistance The next few slides will review how MDR-TB develops [Scanning Electron Micrograph of Mycobacterium tuberculosis] [Image Credit: Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, NIH]

Frequency of Resistance Mutations
ISTC TB Training Modules 2009 INH = 1 in 106 RIF = 1 in 108 EMB = 1 in 106 Strep = 1 in 106 INH + RIF = 1 in 1014 In any given population of TB bacilli, naturally occurring resistant organisms occur at the rates as shown. [Review above] The greater the burden of disease, the larger the bacillary population and the greater the risk for harboring drug-resistant mutants and acquiring drug resistance. [Note: Year drug was discovered is listed under each drug.] [Image Credit: CDC/Dr. Ray Butler; Janice Carr. Illustration Credit: National Institute of Allergy and Infectious Diseases (NIAID). Illustrator: Krista Townsend]

Development of Drug Resistance
ISTC TB Training Modules 2009 Multiple Drugs vs. Monotherapy 1 2 In the culture plate depicted on the left (1) there is a mixture of susceptible and resistant organisms. If four anti-TB drugs are used to treat this population of TB organisms, they are all killed as indicated by the empty culture plate (2). However, if only isoniazid is used, the susceptible organisms are killed, but the isoniazid resistant organisms proliferate and a population of organisms emerges that is resistant to isoniazid (3). [One might question why the use of isoniazid alone as treatment for latent TB infection (LTBI) doesn’t cause resistance to emerge. Presumably this doesn’t happen because in LTBI the bacillary population is very small and thus contains very few, if any, drug-resistant mutants.] 3 I = INH resistant, R = RIF resistant, P = PZA resistant, E = EMB resistant

ISTC TB Training Modules 2009 Further acquired resistance after single drug added As the population of INH-resistant organisms continues to grow, additional mutations will occur resulting in a few bacilli resistant not only to INH, but also to PZA, RIF, and other anti-TB drugs. If RIF is added as a single drug at this point to the INH regimen, the RIF will kill off the organisms resistant to any anti-TB drug except for those that are resistant to RIF. I = INH resistant, R = RIF resistant, P = PZA resistant

ISTC TB Training Modules 2009 Mixed population (susceptible and resistant) INH-resistant bacilli Emergence of INH-resistant strain because of ineffective treatment (INH monotherapy) Here in graph format, one can see the selective growth of an isoniazid-resistant strain (blue line) if monotherapy is used on a large, mixed population of susceptible and isoniazid resistant organisms. Effective multi-drug treatment can rapidly reduce the bacillary population such that within 2 weeks of beginning appropriate chemotherapy the number of organisms in sputum is decreased from approximately 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. [Note: Material also covered (duplicate slide) in Treatment of TB module] Effective multi-drug therapy 2 4 6 8 1 1 2 1 4 1 6 1 8 2 2 2 2 4 Weeks

Resistance: Unintended Monotherapy
ISTC TB Training Modules 2009 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 (treating provider was unaware). 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 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 in March, 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 an important concept in the management of TB. Stop to ask if any questions or clarifications are needed.] [Note: Same slide is covered in Treatment of TB module] * Results not known to clinician

Resistance: Unintended Acquired
ISTC TB Training Modules 2009 Months of Rx 2 4 8 INH/RIF/EMB/PZA Capreo/Moxi Smear + - Culture Susceptibility INH R* R RIF S* EMB Here is another hypothetical example of a patient with a strain that is not MDR to begin with, but is resistant to multiple drugs. In this situation, transformation into an MDR strain can take place very quickly. The baseline tests show resistance to INH and EMB (treating provider was unaware). Although the standard WHO recommended 4-drug regimen is used, rifampicin resistance occurs at 2 months because the only effective drugs in the regimen at the beginning of treatment are rifampicin and PZA. Unfortunately, PZA does not prevent drug resistance like other companion drugs and rifampicin resistance occurs. In this case, Capreomycin and a fluoroquinolone (moxifloxacin) were added and by 8 months smear and culture conversion occurred. * Results not known to clinician

Factors that Lead to Drug Resistance
ISTC TB Training Modules 2009 Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors As we have seen from a microbiological perspective, resistance is caused by genetic mutations that make drugs ineffective against the mutant bacilli. An inadequate or poorly administered treatment regimen allows a drug-resistant strain to become the dominant strain in a patient infected with TB. Causes of inadequate treatment can be due to: Patient-related factors Healthcare provider-related factors Healthcare system-related factors [Reference: Guidelines for the programmatic management of drug-resistant tuberculosis. World Health Organization,

ISTC TB Training Modules 2009 Patient-related factors: Non-adherence, default Malabsorption of drugs Adverse drug reactions Lack of information, transportation, money Social barriers to treatment adherence Substance dependency disorders Common causes of patient-related factors include: Non-adherence to treatment (patient self-selecting which drugs they will take) or default (treatment interruption of two consecutive months or greater). Malabsorption or adverse drug reactions may prohibit adequate drug uptake or effect. Lack of information or appropriate education about TB disease may impede adequate treatment. Factors such as lack of transportation or money to purchase drugs (if free treatment not an option) are also barriers to care. Social barriers or substance dependency disorders must also be taken into consideration as reasons for poor patient compliance. [Reference: Guidelines for the programmatic management of drug-resistant tuberculosis. World Health Organization,

ISTC TB Training Modules 2009 Healthcare provider-related factors: Inadequate initial treatment regimen: Wrong combination or doses, guideline noncompliance Treatment “in the dark” for retreatment cases: no drug susceptibility testing available, or results delayed Clinical errors: Adding a single drug to a failing regimen Lack of proper monitoring Lack of proper provider awareness Healthcare provider-related factors may include: Inadequate regimen - this could happen if an inadequate regimen is prescribed (wrong combination or doses). The provider may not be aware of a drug-resistance pattern particularly if drug-susceptibility testing is not available or results are pending. Understanding and recognizing the risk factors that should raise suspicion for drug resistance is critical. Well-crafted local or national guidelines should be followed to optimize results. Poor case management and physician errors such as adding a single drug to a failing regimen may select for drug-resistant mutants. Lack of proper monitoring can delay appropriate interventions, allowing complications to go undetected and progress. A lack of knowledge regarding the complexities of TB treatment can lead to mismanagement and the development of drug resistance.

ISTC TB Training Modules 2009 Healthcare program-related factors: Inconsistent access to care Unavailability of drugs (stock-outs or delivery disruptions) Poor drug quality, poor storage conditions Poorly organized or under-funded TB-control programs Inappropriate or no guidelines Lack of appropriate or timely laboratory testing Some healthcare system-related factors that can contribute to suboptimal treatment and development of drug resistance: Poor access to care may be a significant factor. Centralized care may not reach isolated regions of catchment area. Consistent drug availability and quality is a problematic issue for many areas of the world. Not all areas have a strong or adequately funded TB-control program to offer public health oversight, nor are up to date guidelines available for all localities. Due to resource limitations, optimal high-quality laboratory testing with timely results is not available in all areas. Lack of optimal testing does not directly cause the development of drug resistance, but can constrain the ability to appropriately recognize and treat complex drug-resistant cases.

Strategies to Prevent Drug Resistance
ISTC TB Training Modules 2009 Common Causes Interventions Nonadherence, default Patient-centered DOT, education, support, incentives Management errors, lack of expertise Consultation with experts, vigilant patient monitoring for treatment failure, provider training Inadequate regimen in presence of drug resistance Improved access to drugs and susceptibility testing A few examples of interventions to counter some of the common clinical/programmatic causes that contribute to the development of drug resistance: [Review content from slide] [Interactive option: Have participants share interventions that have worked in their practice that address some of contributing factors for the development of drug resistance.]

Diagnosis of MDR-TB We now shift from how drug resistance develops to the diagnosis of MDR-TB. [Image Credit: World Lung Foundation/Jad Davenport]

Diagnosis of MDR ISTC TB Training Modules 2009 Appropriate diagnosis and timely treatment intervention for MDR-TB is facilitated by: Recognition of risk factors for MDR-TB Early recognition of treatment failure Drug-susceptibility testing (if available) To identify patients with potential drug resistance and begin appropriate treatment in a timely manner, clinicians should focus on: Recognizing and evaluating risk factors for MDR-TB Recognizing and properly monitoring for evidence of treatment failure Developing the appropriate clinical suspicion for drug-resistance is the essential first step. Treatment can then be adjusted based on local guidelines, and case management and monitoring also adjusted accordingly. If laboratory resources are available, timely use of drug-susceptibility testing can confirm the presence of drug resistance and allow the informed tailoring of treatment drugs. If MDR-TB is strongly suspected, consultation with an expert is suggested.

Clinical Suspicion for MDR
ISTC TB Training Modules 2009 Recognition of risk factors: History of prior therapy (most powerful predictor) Failure of a retreatment regimen Failure of the initial treatment regimen Relapse after apparently successful treatment Return after default without recent treatment failure Clinical and epidemiologic risk factors for MDR, as noted in Standard 11, that should be assessed include: History of prior treatment - the most powerful predictor for MDR: A history of prior treatment may be difficult to obtain. Patients may not know that they were treated for TB or may willfully deny prior therapy. In the patient who cannot describe what he/she was treated for, clues can be obtained by asking the duration of treatment (few lung diseases other than TB will be treated for 6 or more months with antibiotics), the number and color of pills or use of injections (possible streptomycin), or orange-discoloration of urine (rifampicin). It is important to attempt to determine if the patient was adherent to treatment by asking directly and indirectly. If there has been prior treatment, the source of the treatment should be ascertained. Patients who are still sputum smear-positive at the end of a retreatment regimen have perhaps the highest MDR-TB rates of any group, often exceeding 80%. Patients who fail to become sputum smear-negative while on initial treatment are likely to have drug-resistant organisms. However, the likelihood depends on a number of factors, including whither rifampicin was used in the continuation phase and whether DOT was used throughout treatment . Thus, a detailed history of drugs used is essential. This is especially true for patients treated by private providers, often with non-standard regimens. In clinical trials most patients who relapse have fully susceptible organisms. However, under clinical program conditions, an apparent relapse, especially an early relapse, may be an unrecognized treatment failure and thus have a higher likelihood of drug resistance. The likelihood of MDR-TB in those who default can vary substantially, depending in part on the amount of treatment taken and the degree of adherence before default.

ISTC TB Training Modules 2009 Recognition of risk factors: Close contact to known or suspected MDR-TB case (“incurable” TB or TB requiring multiple treatment courses) Residence in an MDR-endemic area Exposure in institutions that have drug-resistance outbreaks or high prevelance HIV infection (in some settings) Clinical and epidemiologic risk factors for MDR (continued): Exposure to possible drug-resistant sources: Commonly, patients do not know if there has been exposure to a drug-resistant source case. The provider should ask if anyone in the house has had tuberculosis or any lung disease for which they have been treated for many months repeatedly, or if their treatment for TB was deemed “incurable”. Most studies have shown the tuberculosis occurring in close contacts of MDR-TB cases to have high rates of MDR-TB. Community prevalence of drug resistance: In most situations this is not known. In general one should not assume that a previously untreated patient has drug-resistance based on an assumed prevalence of drug resistance. Exceptions would include certain specific situations in which a high prevalence of drug resistance has been documented such as some refugee-camp settings or documented outbreaks. In areas with high rates of drug-resistance, use of routine DST in all new cases may be justified. Exposure in institutions: Patients who frequently stay in homeless shelters, prisoners in many countries, and healthcare workers in clinics, laboratories and hospitals can have high rates of drug-resistant TB. HIV infection: In some areas of the world, HIV infection is a risk factor for MDR. HIV is also associated with acquiring rifamycin resistance. Hence, HIV-infected TB patients deserve special attention. Assessment of the response to treatment in patients with HIV infection is often complicated by the likelihood of other opportunistic lung diseases. Adherence should be assured and intermittent treatment regimens should be avoided if CD-4 counts are low.

ISTC TB Training Modules 2009 Early recognition of treatment failure: Cough should improve within the first two weeks of effective treatment Signs of failure: lack of sputum conversion, persistent or recurrent cough, continued fever, night sweats and failure to gain weight Early recognition of signs and symptoms for treatment failure in patients currently on TB treatment should also raise clinical suspicion for possible drug-resistant disease. Clinical evidence of failure can include persistence or recurrence of symptoms. A significant proportion of patients with cough improve over the initial few weeks of treatment. An unchanged or worsening cough may be an early clue for treatment failure. Suspicion of treatment failure should prompt further microbiologic evaluation. The official WHO definition for treatment failure is a positive sputum smear at month 5 of treatment. A high percentage of patients usually become smear negative by month 3. If a smear is still positive at month three, guidelines (and Standard 11) now suggest a culture and DST be sent. If treatment failure is suspected, the patient should also be assessed for other factors that may contribute to inadequate treatment (non-adherence, malabsorption, etc) and DOT instituted if not already in use.

Laboratory Diagnosis of MDR
ISTC TB Training Modules 2009 Drug-susceptibility testing, if available, should be ordered when: Risk factors for MDR are present There is evidence of treatment failure Results can both: Confirm diagnosis of drug resistance Guide treatment choices If drug resistance is suspected based on the assessment of clinical or epidemiologic risk factors and/or evidence of treatment failure, drug-susceptibility testing (DST) should be obtained to both confirm the diagnosis and pattern of drug resistance and guide treatment choices.

Drug-Susceptibility Results: Problems
ISTC TB Training Modules 2009 Identification of MDR may take 4 – 8 weeks, and second-line drug testing 6 – 12 weeks for results: 2 – 4 weeks for initial culture to become positive Additional 2 – 4 weeks to get 1st-line DST Additional 2 – 4 weeks to get 2nd-line DST  In view of this inherent delay, don’t wait to treat with an augmented regimen if MDR suspicion is high and resistance pattern can be predicted. One must realize that current available DST methods are slow. With standard culture and DST methods, 4-12 weeks are usually needed to get results (liquid broth methods are faster) from the time of initial sputum collection to the completion of both first- and second-line DST tests. Because results take a long time to return, one should NOT wait to treat a patient who is suspected of having MDR with an augmented regimen that includes a fluoroquinolone and injectable agent. The only reason not to treat an MDR suspect while waiting for test results is when the disease burden is minimal or if prior MDR treatment was given and it remains unpredictable which drugs will work.

Rapid Drug-Susceptibility Tests
ISTC TB Training Modules 2009 Line-probe assays Identifies M.tb and genetic mutations associated with INH and RIF resistance Can be used directly on sputum specimens, results within 1-2 days With the rising rates of MDR and XDR, the need for rapid and accurate identification of drug resistance is significant. While other tests may currently be in use or under investigation include, the line probe assays have been endorsed (WHO 2008) for use as a rapid means of detecting drug-resistance for INH and RIF on both direct smear-positive and culture specimens. [Additional material may be found in the Microbiologic Diagnosis module.] Line probe assays: DNA from M.tb directly from sputum samples can be amplified and identified. Probes can both identify M.tb and test for drug resistance based on the presence of genetic mutations associated with specific drug resistance (isoniazid and rifampicin). Has a high sensitivity (>=97%) and specificity (>=99%) for rifampicin resistance. Overall accuracy for detection of MDR equally high at 99%, and retained when rifampicin resistance alone was used as a marker for MDR. The WHO has endorsed their use for both direct smear-positive sputum and culture specimens. - Image shows examples of GenoType MTDBRplus strips (Hain Lifescience, Nehren, Germany). [Resource: WHO Policy Statement, Molecular line probe assays for rapid screening of patients at risk of multi-drug resistant tuberculosis (MDR-TB), 2008] [Image credit: Rapid Molecular Screening for Multidrug-Resistant Tuberculosis in a High-Volume, Barnard et al. Am. J. Respir. Crit. Care Med 2008; 177: ] *GenoType MTDBRplus strips (Hain Lifescience) Endorsed for use on either direct smear positive sputum or culture specimens

Drug-Susceptibility Results: Problems
ISTC TB Training Modules 2009 Drug-susceptibility testing requires training and experience Quality assurance is difficult Testing is unreliable for some drugs, especially ethambutol and pyrazinamide Results will sometimes differ in different laboratories In addition to the current methods being slow, there are other common problems with drug susceptibility testing. Substantially more training and experience is required for susceptibility testing than for culture alone. Having a quality assurance program in place is essential, yet few labs are qualified to provide the assessments. Testing is unreliable for both ethambutol and pyrazinamide. This may lead to conflicting results in different laboratories.

Predicting Patterns of Resistance
ISTC TB Training Modules 2009 Examine prior treatment regimen: Consider all drugs used previously as potentially ineffective Example: A symptomatic patient with 2 prior treatment courses using red capsules, white pills and shots Predict: Resistance to INH, RIF, and streptomycin In MDR-TB suspects, predicting the pattern of resistance is important in determining what drugs you use while waiting for DST results. One should attempt to utilize all available information to make treatment decisions. Carefully obtaining a good history of prior TB treatment from the patient is essential. Example: A 62 yr-old woman with diabetes presents with classic symptoms of TB, cavitary lesions, and 2 prior treatment episodes using red capsules, white pills and shots. She likely has taken rifampicin, isoniazid and streptomycin, consequently resistance to these drugs should be presumed. Predict: Resistance to INH, RIF, and streptomycin

Predicting Risk for MDR
ISTC TB Training Modules 2009 If there has been contact to a known MDR case, use pattern of drug resistance in index case Use epidemiologic information determined from surveys to identify patterns and rates of resistance Presence of RIF resistance predicts MDR If contact to a known MDR case, use pattern of drug resistance from index case. If drug resistance surveys have been performed in the region the results might be used to infer the likelihood and pattern of resistance in an individual patient. If rifampicin resistance is known, there is a high likelihood that the case is also INH-resistant (MDR). Non-MDR rifampicin resistance is relatively rare (<1% in majority of reporting countries, WHO 2006).

Predicting Risk for XDR
ISTC TB Training Modules 2009 Two strongest risk factors for XDR are: Failure of a TB treatment which contains second-line drugs including an injectable agent and a fluoroquinolone Close contact with an individual with documented XDR or for whom treatment with second-line drugs is failing or has failed A heightened suspicion for risk of XDR exists in patients known to have failed prior treatment with second-line drugs that included an injectable agent and a fluoroquinolone. Diagnosis of XDR is dependant on access to second-line drug sensitivity testing. There are well-documented cases of XDR transmission (within healthcare facilities) and close contact with a known or suspected case of XDR should also predict risk.

ISTC TB Training Modules 2009 Summary: Early suspicion, diagnosis and appropriate treatment is critical in preventing further progression and transmission of drug-resistant disease Prior treatment is the most significant predictor for drug resistance, but learn to recognize all risk factors To conclude: [Review content of slide]

ISTC TB Training Modules 2009 Summary (cont.): Recognize when your patient is failing standard treatment Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR To conclude: [Review content of slide]

Summary: ISTC Standard Covered*
ISTC TB Training Modules 2009 Standard 11: Assessment for drug resistance should be obtained based on a history of: Prior treatment Exposure to a possible drug-resistant source High community prevalence Drug-susceptibility testing should be performed at the start of therapy for all patients previously treated, or smear+ at three months of treatment, or if failed/defaulted/relapsed If drug-resistance likely, do culture and DST for at least isoniazid and rifampicin Patient counseling/education should begin immediately to minimize potential for transmission Infection control measures should be applied And in summary, the International Standard reviewed with this material: (abbreviated) [Review above] [End] *[Abbreviated version]

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

Resources ISTC TB Training Modules 2009 WHO: Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update Drug-Resistant Tuberculosis, A Survival Guide for Clinicians 2nd edition, The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 46

Resource Availability
ISTC TB Training Modules 2009 The following tests are available at _________: Smear microscopy Direct smear / light microscopy Fluorescence microscopy Concentration/chemical processing Culture Solid media Liquid media Drug susceptibility testing Other [Optional slide: Use this slide to add specific information on where and what type of testing (those listed above or others) is available to the course participants.] [Interactive option – ask participants what resources have they utilized, share views on how to optimize the proper use of the diagnostic tests available.]

Resource Contact Information ISTC TB Training Modules 2009 Laboratory testing: Microscopy/culture/DST [Name, addresses, , etc.] Specimen transport: [Optional slide: Use this slide to add in specific information who and how to contact local/regional/reference laboratory resources for questions].

Purpose of ISTC ISTC Training Modules 2008 ISTC TB Training Modules 2009 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: World Lung Foundation/Jad Davenport ] 49

ISTC: Key Points ISTC TB Training Modules 2009 21 Standards (revised/renumbered in 2009) 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 21 evidence-based standards. The original 17 standards from 2006 were revised and renumbered in 2009. 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: Key Points ISTC TB Training Modules 2009 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.

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

Drug-resistant Tuberculosis
ISTC TB Training Modules 2009 1. A 68 year-old man presents with cough and weight loss for 2 months. He recalls treatment for TB eight years ago, but believes it only lasted a few months. A chest film reveals a cavitary infiltrate in the right apex of the lung. Factors that predict or are associated with a risk for the development of drug-resistance would include all of the following except: Prior inadequate TB treatment Development of chronic diarrhea with possible malabsorption of drugs New diagnosis of diabetes Persistent cough and weight loss after two months of standard therapy Correct Answer: C

ISTC TB Training Modules 2009 2. Extensively-drug resistant (XDR) TB is defined as TB that is resistant to: At least six anti-tuberculosis drugs At least isoniazid and rifampicin Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, and a fluoroquinolone Isoniazid, rifampicin, a fluoroquinolone, and at least one of these three injectable agents (amikacin, kanamycin, capreomycin) Correct Answer: D

ISTC TB Training Modules 2009 3. Which of the following statements regarding the microbiologic pathogenesis of drug-resistant tuberculosis is most correct? Patients with cavitary tuberculosis have a low bacillary load and therefore are unlikely to harbor any naturally occurring drug-resistant organisms Mono-therapy with a single anti-tuberculosis drug can lead to selective proliferation of naturally occurring drug-resistant organisms Acquired resistance to anti-tuberculosis drugs only occurs for isoniazid and rifampicin In a patient on a standard initial four-drug treatment regimen with evidence for clinical failure in whom there is a high suspicion for drug resistance, the addition of a fluoroquinolone alone will reduce the risk for further development of drug resistance Correct Answer: B

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