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Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 14.

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Presentation on theme: "Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 14."— Presentation transcript:

1 Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 14

2 ISTC Training Modules 2008 Drug-Resistant Tuberculosis 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 and the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment.

3 Drug-Resistant Tuberculosis Overview: Definitions Global burden and individual impact Pathogenesis and clinical/programmatic contributors to development Early identification and risk factors Recommendations for diagnosis International Standard 14

4 ISTC Training Modules 2008 Drug-Resistant Tuberculosis MDR-TB is a manmade problem… It is costly, deadly, debilitating and is a major threat to our current control strategies.

5 ISTC Training Modules 2008 Standard 14: Drug-Resistant TB 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. Patients who fail treatment and chronic cases should always be assessed for possible drug resistance. For patients in whom drug resistance is considered to be likely, culture and drug-susceptibility testing for isoniazid, rifampicin, and ethambutol should be performed promptly.

6 ISTC Training Modules 2008 Drug-Resistant TB: Definitions 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)

7 ISTC Training Modules 2008 Drug-Resistant TB: Definitions 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

8 ISTC Training Modules 2008 WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008 Estimated global incidence and proportion of MDR among TB cases, 2006 Estimated Global MDR Cases 2006TB casesMDR cases% New Cases*9,123,922285, Previously treated cases* 1,052,145203, Total cases**10,192,986489, *175 countries reporting; **185 countries reporting

9 WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008 Estimated Global MDR Cases 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%

10 ISTC Training Modules 2008 Distribution of MDR: No prior treatment Zignol M, et al. JID 2006; 194: Distribution of MDR rates among new cases (previously untreated)

11 ISTC Training Modules 2008 Zignol M, et al. JID 2006; 194: Distribution of MDR: Prior Treatment Distribution of MDR rates among previously treated cases

12 ISTC Training Modules 2008 Individual Impact of MDR 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

13 ISTC Training Modules 2008 Impact of Resistance on Outcome Resistance patternNew Cases (%)Retreatment (%) Pan-susceptible410 Any Resistance521 MDR3045 INH (not MDR)623 RIF (not MDR)1329 Other415 % of cases with failure or death, standard 4-drug regimen Espinal MA, et al. JAMA. 2000;283(19):

14 ISTC Training Modules 2008 Pathogenesis of Drug Resistance

15 ISTC Training Modules 2008 INH = 1 in 10 6 RIF = 1 in 10 8 EMB = 1 in 10 6 Strep = 1 in 10 6 INH + RIF = 1 in Frequency of Resistance Mutations

16 ISTC Training Modules 2008 Development of Drug Resistance 12 3 Multiple Drugs vs. Monotherapy I = INH resistant, R = RIF resistant, P = PZA resistant, E = EMB resistant

17 ISTC Training Modules 2008 Development of Drug Resistance I = INH resistant, R = RIF resistant, P = PZA resistant Further acquired resistance after single drug added

18 ISTC Training Modules 2008 Mixed population (susceptible and resistant) INH-resistant bacilli Emergence of INH-resistant strain because of ineffective treatment (INH monotherapy ) Effective multi-drug therapy Development of Drug Resistance Weeks

19 ISTC Training Modules 2008 Months of Rx0579 INH RIF EMB Smear++++ Culture++++ Susceptibility INHR*RRR RIFS*RRR EMBS*SSR * Results not known to clinician Resistance: Unintended Monotherapy

20 ISTC Training Modules 2008 Resistance: Unintended Acquired Months of Rx0248 INH/RIF/EMB/PZA Capreo/Moxi Smear+++- Culture+++- Susceptibility INHR*RRR RIFS*RRR EMBR*RRR * Results not known to clinician

21 ISTC Training Modules 2008 Factors that Lead to Drug Resistance Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors

22 ISTC Training Modules 2008 Factors that Lead to Drug Resistance 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

23 ISTC Training Modules 2008 Factors that Lead to Drug Resistance 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

24 ISTC Training Modules 2008 Factors that Lead to Drug Resistance 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

25 ISTC Training Modules 2008 Common CausesInterventions 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 Strategies to Prevent MDR

26 ISTC Training Modules 2008 Diagnosis of MDR-TB

27 ISTC Training Modules 2008 Diagnosis of MDR-TB 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)

28 ISTC Training Modules 2008 Recognition of risk factors: History of prior therapy (most powerful predictor) History of non-adherence, default Residence in an MDR-endemic area Exposure to known or suspected MDR-TB case (incurable TB or TB requiring multiple treatment courses) HIV infection (in some settings) Clinical Suspicion for MDR-TB

29 ISTC Training Modules 2008 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 Clinical Suspicion for MDR-TB

30 ISTC Training Modules 2008 Laboratory Diagnosis of MDR 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

31 ISTC Training Modules 2008 Drug-Susceptibility Results: Problems 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, dont wait to treat with an augmented regimen if MDR suspicion is high and resistance pattern can be predicted.

32 ISTC Training Modules 2008 Drug-Susceptibility Results: Problems 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

33 ISTC Training Modules 2008 Predicting Patterns of Resistance 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

34 ISTC Training Modules 2008 Predicting Patterns of Resistance 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

35 ISTC Training Modules 2008 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 Drug-Resistant Tuberculosis

36 ISTC Training Modules 2008 Summary (cont.): Recognize when your patient is failing standard treatment Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR Drug-Resistant Tuberculosis

37 ISTC Training Modules 2008 Summary: ISTC Standard Covered* Standard 14: Assessment for drug resistance should be obtained based on a history of: Prior treatment Exposure to a possible drug-resistant source High community prevalence Treatment failure or chronic disease If suspicion for drug-resistance, obtain culture and drug-susceptibility testing promptly. *[Abbreviated version]

38 ISTC Training Modules 2008 Alternate Slides

39 ISTC Training Modules 2008 Resources WHO: Guidelines for the programmatic management of drug-resistant tuberculosis Drug-Resistant Tuberculosis, A Survival Guide for Clinicians The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health

40 ISTC Training Modules 2008 Purpose of ISTC

41 ISTC Training Modules 2008 ISTC: Key Points 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

42 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 ISTC: Key Points

43 ISTC Training Modules 2008 Questions

44 ISTC Training Modules 2008 Drug-resistant Tuberculosis 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: A.Prior inadequate TB treatment B.Development of chronic diarrhea with possible malabsorption of drugs C.New diagnosis of diabetes D.Persistent cough and weight loss after two months of standard therapy

45 ISTC Training Modules 2008 Drug-resistant Tuberculosis 2. Extensively-drug resistant (XDR) TB is defined as TB that is resistant to: A.At least six anti-tuberculosis drugs B.At least isoniazid and rifampicin C.Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, and a fluoroquinolone D.Isoniazid, rifampicin, a fluoroquinolone, and at least one of these three injectable agents (amikacin, kanamycin, capreomycin)

46 ISTC Training Modules 2008 Drug-resistant Tuberculosis 3. Which of the following statements regarding the microbiologic pathogenesis of drug-resistant tuberculosis is most correct? A.Patients with cavitary tuberculosis have a low bacillary load and therefore are unlikely to harbor any naturally occurring drug- resistant organisms B.Mono-therapy with a single anti-tuberculosis drug can lead to selective proliferation of naturally occurring drug-resistant organisms C.Acquired resistance to anti-tuberculosis drugs only occurs for isoniazid and rifampicin D.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


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