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Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 11.

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Presentation on theme: "Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 11."— Presentation transcript:

1 Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 11

2 ISTC TB Training Modules 2009 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/XDR 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 11

4 ISTC TB Training Modules 2009 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 TB Training Modules 2009 Standard 11: Drug-Resistant TB (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.

6 ISTC TB Training Modules 2009 Standard 11: Drug-Resistant TB 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 (2 of 3)

7 ISTC TB Training Modules 2009 Standard 11: Drug-Resistant TB 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 (3 of 3)

8 ISTC TB Training Modules 2009 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)

9 ISTC TB Training Modules 2009 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

10 ISTC TB Training Modules 2009 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

11 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%

12 ISTC TB Training Modules 2009 Distribution of MDR: No Prior Treatment Zignol M, et al. JID 2006; 194: Distribution of MDR rates among new cases (previously untreated)

13 ISTC TB Training Modules 2009 Zignol M, et al. JID 2006; 194: Distribution of MDR: Prior Treatment Distribution of MDR rates among previously treated cases

14 ISTC TB Training Modules 2009 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

15 ISTC TB Training Modules 2009 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):

16 ISTC TB Training Modules 2009 Adapted from Paul Nunn, StopTB/WHO 2009 Global TB estimates: XDR and MDR 2007 Estimated Global XDR 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

17 ISTC TB Training Modules 2009 WHO 2009 Distribution of XDR Countries that had reported at least one XDR-TB case by end of April 2009

18 ISTC TB Training Modules 2009 Pathogenesis of Drug Resistance

19 ISTC TB Training Modules 2009 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

20 ISTC TB Training Modules 2009 Development of Drug Resistance 12 3 Multiple Drugs vs. Monotherapy I = INH resistant, R = RIF resistant, P = PZA resistant, E = EMB resistant

21 ISTC TB Training Modules 2009 Development of Drug Resistance I = INH resistant, R = RIF resistant, P = PZA resistant Further acquired resistance after single drug added

22 ISTC TB Training Modules 2009 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

23 ISTC TB Training Modules 2009 Months of Rx0579 INH RIF EMB Smear++++ Culture++++ Susceptibility INHR*RRR RIFS*RRR EMBS*SSR * Results not known to clinician Resistance: Unintended Monotherapy

24 ISTC TB Training Modules 2009 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

25 ISTC TB Training Modules 2009 Factors that Lead to Drug Resistance Causes of inadequate treatment: Patient-related factors Healthcare provider-related factors Healthcare system-related factors

26 ISTC TB Training Modules 2009 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

27 ISTC TB Training Modules 2009 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

28 ISTC TB Training Modules 2009 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

29 ISTC TB Training Modules 2009 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 Drug Resistance

30 ISTC TB Training Modules 2009 Diagnosis of MDR-TB

31 ISTC TB Training Modules 2009 Diagnosis of MDR 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)

32 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 Suspicion for MDR

33 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 Suspicion for MDR

34 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 Clinical Suspicion for MDR

35 ISTC TB Training Modules 2009 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

36 ISTC TB Training Modules 2009 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.

37 ISTC TB Training Modules 2009 Rapid Drug-Susceptibility Tests 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 Endorsed for use on either direct smear positive sputum or culture specimens *GenoType MTDBRplus strips (Hain Lifescience)

38 ISTC TB Training Modules 2009 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

39 ISTC TB Training Modules 2009 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

40 ISTC TB Training Modules 2009 Predicting Risk for MDR 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

41 ISTC TB Training Modules 2009 Predicting Risk for XDR 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

42 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 Drug-Resistant Tuberculosis

43 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 Drug-Resistant Tuberculosis

44 ISTC TB Training Modules 2009 Summary: ISTC Standard Covered* 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 *[Abbreviated version]

45 ISTC TB Training Modules 2009 Alternate Slides

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

47 ISTC TB Training Modules 2009 Resource Availability 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

48 ISTC TB Training Modules 2009 Resource Contact Information Laboratory testing: Microscopy/culture/DST [Name, addresses, , etc.] Specimen transport: [Name, addresses, , etc.]

49 ISTC TB Training Modules 2009 Purpose of ISTC

50 ISTC TB Training Modules 2009 ISTC: Key Points 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

51 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 ISTC: Key Points

52 ISTC TB Training Modules 2009 Questions

53 ISTC TB Training Modules 2009 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

54 ISTC TB Training Modules 2009 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)

55 ISTC TB Training Modules 2009 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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