1. Management of Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 12

2. ISTC TB Training Modules 2009 Management of Drug-Resistant TB Objectives: At the end of this presentation, participants will be able to: Describe the principles upon which treatment of drug-resistant TB is based Understand the essential features of MDR-TB case management Recognize the importance of patient-centered DOT in MDR-TB treatment Become familiar with common side effects of drugs used in the treatment of MDR-TB

3. International Standards 12 Management of Drug-Resistant TB Overview: Definitions and predictors of drug resistance Treatment principles Case-management principles Patient-centered directly observed therapy Common side effects of MDR-TB treatment

4. ISTC TB Training Modules 2009 Standard 12: Management of Drug-Resistant TB Patients with or highly likely to have tuberculosis caused by drug-resistant (especially MDR/XDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs The regimen chosen may be standardized or based on suspected or confirmed drug susceptibility patterns At least four drugs to which the organisms are known or presumed to be susceptible, including an injectable agent, should be used, and treatment should be given for at least 18–24 months beyond culture conversion (1 of 2)

5. ISTC TB Training Modules 2009 Standard 12: Management of Drug-Resistant TB Patient-centered measures, including observation of treatment, are required to ensure adherence Consultation with a provider experienced in treatment of patients with MDR/XDR tuberculosis should be obtained (2 of 2)

6. 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)

7. 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

8. ISTC TB Training Modules 2009 Recognizing Predictors of Drug-resistant TB Assess drug resistance in any patient being started on treatment for tuberculosis Nonadherence, default History of prior treatment Exposure to possible drug-resistant source case Community prevalence of drug resistance If drug resistance is suspected based on any of the above factors, culture and susceptibility testing should be performed for at least INH and rifampicin

9. ISTC TB Training Modules 2009 Note: PZA does not prevent acquired resistance to companion drugs. Predicted Resistance Pattern Empiric Regimen (minimum duration) INHRIF, EMB, PZA (6-9 mo) INH, EMB RIF, PZA, Fluoroquinolone + Injectable (9-12 mo) RIFINH, EMB + PZA (18 mo minimum) RIF, EMB INH, Fluoroquinolone, PZA + Injectable (18-month minimum) INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide Empiric Regimens for Drug-resistant TB

10. ISTC TB Training Modules 2009 Multidrug-Resistant TB I have been treated several times over the past five years and Im still coughing and cant gain weight!

11. ISTC TB Training Modules 2009 MDR/XDR Treatment Strategies: WHO Three approaches to treatment: Standardized regimens Empiric regimens Individualized treatment regimens (based on DST results) The choice among these should be based on: Availability of second-line drugs Local drug-resistance patterns, and the history of use of second-line drugs Drug susceptibility testing of first- and second-line drugs

12. ISTC TB Training Modules 2009 Categories of Antituberculosis Drugs: WHO Group 1 – First-line drugs: Isoniazid, rifampicin, ethambutol, pyrazinamide Group 2 - Injectable agents: Kanamycin, amikacin, capreomycin, streptomycin Group 3 - Fluoroquinolones: Levofloxacin, moxifloxacin, ofloxacin Group 4 - Oral bacteriostatic agents: Ethionamide, cycloserine, para-aminosalicylic acid (PAS), prothionamide, terizadone Group 5 – Unclear role: Clofazamine, linezolid, amoxicillin/clavulanate, Imipenem/cilastatin, thioacetazone, high-dose isoniazid, clarithromycin,

13. ISTC TB Training Modules 2009 Designing an MDR/XDR Treatment Regimen General Principles, WHO Use of at least four drugs highly likely to be effective Do not use drugs for which there is cross-resistance Eliminate drugs that are unsafe for the patient. Include drugs from groups 1-5 in a hierarchical order based on potency Be prepared to prevent, monitor and manage adverse effects from the drugs selected

14. ISTC TB Training Modules 2009 Additional Important Principles: WHO Use direct observation of treatment (DOT) with a patient-centered approach to care Use daily, not intermittent, administration Treatment duration of a minimum of 18-24 months after culture conversion When possible, continue injectable for minimum six months (at least 4 months post-culture conversion) Continue at least three oral drugs for full treatment duration

15. ISTC TB Training Modules 2009 Potential Effectiveness: WHO Effectiveness is supported by a number of factors: Demonstrated susceptibility No history of treatment failure with the drug No contacts with resistance to the drug Resistance rare in similar patients (surveys) Drug is not commonly used in the area If at least four drugs are not certain to be effective, use five to seven drugs, depending on specific drugs and degree of certainty.

16. ISTC TB Training Modules 2009 Cross-Resistance: WHO All rifamycins: high level cross-resistance Fluoroquinolones: variable, but probably should be assumed to be cross-resistant Amikacin and kanamycin: generally highly cross-resistant, but both should be tested Capreomycin and aminoglycosides: occasional cross-resistance, susceptibilities should be tested

17. ISTC TB Training Modules 2009 Drug Contraindications: WHO Known severe drug allergy Unmanageable drug intolerance Risk of severe toxicity, with symptoms such as renal failure, hepatitis, hearing loss, depression, and psychosis Drugs of unknown quality (lack of quality assurance exposes patient to risks with unknown benefits)

18. ISTC TB Training Modules 2009 Determining Drugs to Use: WHO Use any first-line drug likely to be effective (Group1) Include aminoglycoside or capreomycin (Group 2) A fluoroquinolone should always be used if deemed likely to be effective (Group 3) Use remaining Group 4 drugs to make a regimen of at least four effective agents Use Group 5 drugs as needed to make a regimen of at least four effective agents

19. ISTC TB Training Modules 2009 Predicted Resistance Pattern Empiric Regimen INH, RIF Fluoroquinolone, PZA, EMB, Injectable INH, RIF, EMB Fluoroquinolone, PZA, Injectable, CS, + PAS or ETH INH, RIF, PZA Fluoroquinolone, EMB, Injectable, CS, + PAS or ETH INH, RIF, PZA, EMB Fluoroquinolone, Injectable, CS, PAS or ETH, + one more drug INH = Isoniazid, RIF = Rifampicin, EMB = Ethambutol, PZA = Pyrazinamide CS = Cycloserine, PAS = P-aminosalicylic acid, ETH = Ethionamide Empiric Regimens for MDR-TB

20. ISTC TB Training Modules 2009 Use any available One of these One of these First-line drugs Fluoroquinolones Injectable agents Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Ofloxacin Amikacin Capreomycin Streptomycin Kanamycin Building a Regimen for MDR-TB STEP 1 Begin with any first-line agents to which the isolate is susceptible Add a fluoroquinolone and an injectable drug based on susceptibilities PLUS

21. ISTC TB Training Modules 2009 Pick one or more of these Oral second-line drugs Cycloserine Ethionamide PAS Building a Regimen for MDR-TB STEP 2 If 4 drugs are not identified in Step 1: Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)

22. ISTC TB Training Modules 2009 Consider use of these Third-line drugs Clofazimine Linezolid Amoxicillin/ Clavulanate Imipenem Clarithromycin STEP 3 Building a Regimen for MDR-TB If there are not four to six drugs available in the above categories, consider third-line drugs in consultation with an expert.

23. ISTC TB Training Modules 2009 Building a Regimen for XDR-TB STEP 1 Begin with any first-line agents to which the isolate is susceptible Add a fluoroquinolone and an injectable drug based on susceptibilities Use any available One of these One of these First-line drugs Fluoroquinolones Injectable agents Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Ofloxacin Amikacin ? Capreomycin ? Streptomycin ? Kanamycin ? Commonly not susceptible By definition there is fluoroquinolone resistance Select agent based on history and susceptibility testing PLUS

24. ISTC TB Training Modules 2009 STEP 2 Building a Regimen for XDR-TB Add second- line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously) Pick one or more of these Oral second-line drugs Cycloserine Ethionamide PAS With XDR-TB, often all three of these agents are necessary

25. ISTC TB Training Modules 2009 STEP 3 Building a Regimen for XDR-TB If there are not four–six drugs available in the above categories, consider third- line drugs in consultation with an expert. Consider use of these Third-line drugs Clofazimine Linezolid Amoxicillin/ Clavulanate Imipenem Clarithromycin

26. ISTC TB Training Modules 2009 Ensure laboratory services for hematology, biochemistry and audiometry are available Establish a clinical and laboratory baseline before starting the regimen Initiate treatment gradually when using drugs that cause gastro-intestinal intolerance Ensure availability of ancillary drugs to manage adverse effects Use DOT for all doses Initiating Treatment: WHO

27. ISTC TB Training Modules 2009 Isolate until three consecutive sputum AFB smears (or documented culture conversion) are negative and there has been a good clinical response to treatment Initiate MDR-TB treatment under close supervision to provide patient education and monitoring and to treat drug toxicity Tailor toxicity monitoring to specific drugs employed Seek consultation with an expert as soon as drug resistance is known MDR/XDR-TB: Management Principles

28. ISTC TB Training Modules 2009 Use daily patient-centered DOT throughout entire treatment course Record drugs given, bacteriological results, chest radiographic findings, and the occurrence of toxicities Optimize management of underlying medical conditions (example: diabetes) and nutritional status MDR/XDR-TB: Management Principles

29. ISTC TB Training Modules 2009 MDR/XDR-TB: Monitoring Collect sputum specimens for smear and culture periodically during treatment once culture negative Obtain end-of-treatment sputum specimen for smear and culture Perform chest radiograph periodically during treatment and at end of treatment Resources permitting, monitor minimum of two years following treatment (quarterly during first year, every six months during second year)

30. ISTC TB Training Modules 2009 As soon as rifampicin resistance is known, order second-line drug susceptibility testing Repeat susceptibility testing on cultures that remain positive after two–three months of treatment MDR/XDR-TB: Laboratory Testing

31. ISTC TB Training Modules 2009 More Than Watching Patients Swallow Their Pills DOT is a support system that enables the completion of the long, difficult course of MDR-TB treatment A patient requires respect and dignity regardless of social class, educational level or unhealthy behaviors The whole patient, lifestyle and support system are assessed and routinely addressed in the delivery of care Goal: Inspire and empower patient via a relationship of trust and support Patient-centered DOT

32. ISTC TB Training Modules 2009 Weis SE, et al. NEJM 1994; 330(17): 1179-84* P < 0.001 Self-RX N=407 (pre 1987) DOT N=581 (1987 +) Primary R13.0%6.7% Secondary R10.3%1.4% Relapse20.9%5.5% MDR relapse6.1%0.9% Directly Observed Treatment Effect on Resistance and Relapse

33. ISTC TB Training Modules 2009 Common Adverse Effects G.I. complaints Ethionamide Cycloserine PAS Fluoroquinolones Clofazimine Rifabutin Hepatotoxicity (early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice) INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones

34. ISTC TB Training Modules 2009 Common Adverse Effects Peripheral neuropathy INH Ethionamide Cycloserine Linezolid Ethambutol Rash All Headache Fluoroquinolones Isoniazid Cycloserine Ethionamide Ethambutol Seizures Cycloserine

35. ISTC TB Training Modules 2009 Common Adverse Effects Hypothyroidism Ethionamide, PAS Hearing loss, Vestibular toxicity Aminoglycosides, Capreomycin Behavioral changes Cycloserine, Ethionamide, Isoniazid, Fluoroquinolones Visual changes Ethambutol, Rifabutin, Isoniazid, Linezolid Renal failure Hypokalemia, Hypomagnesemia Aminoglycosides, Capreomycin

36. ISTC TB Training Modules 2009 Management of Drug-Resistant TB Summary: Treatment of MDR-TB is complex and costly. It is much easier to prevent than to treat. XDR-TB is even more difficult! Expert consultation should be obtained whenever possible when MDR- or XDR- TB is suspected.

37. ISTC TB Training Modules 2009 Management of Drug-Resistant TB Summary (cont.): Patients can be treated with a standardized or an empiric regimen. Ideally the regimen should be guided by drug-susceptibility tests. There are sound principles that can be used to guide the design of a treatment regimen.

38. ISTC TB Training Modules 2009 Management of Drug-Resistant TB Summary (cont.): Considerable attention must be paid to treatment supervision and support. A patient-centered approach to DOT is an important element of successful care. Adverse effects of second-line drugs are common and may be severe. Monitoring for these effects is essential.

39. ISTC TB Training Modules 2009 Standard 12: Patients with TB caused by drug-resistant (especially MDR) organisms should be treated with specialized regimens containing second-line antituberculosis drugs. At least four drugs to which the organisms are known or presumed to be susceptible should be used (treatment for at least 18 months). Summary: ISTC Standard Covered* *[Abbreviated version]

40. ISTC TB Training Modules 2009 Standard 12 (cont.): Patient-centered measures are required to ensure adherence. Consultation with a provider experienced in treatment of patients with MDR-TB should be obtained. Summary: ISTC Standard Covered* *[Abbreviated version]

41. ISTC TB Training Modules 2009 Alternate Slides

42. ISTC TB Training Modules 2009 Resources WHO: Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis, Emergency Update 2008 www.who.int/tb Drug-Resistant Tuberculosis, A Survival Guide for Clinicians, 2 nd edition 2008 www.nationaltbcenter.ucsf.edu The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org

43. ISTC TB Training Modules 2009 Purpose of ISTC

44. 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

45. 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

46. ISTC TB Training Modules 2009 Questions

47. ISTC TB Training Modules 2009 Management of Drug-Resistant TB 1. The 5 year-old son of a woman you are currently treating for known isoniazid and rifampicin resistant tuberculosis presents with cough and malaise for three weeks and an abnormal chest film. Of the following available regimens, choose the one best option: A.Begin empiric treatment with at least four drugs that the mothers organism is known to be susceptible to B.Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide with the addition of a fluoroquinolone C.Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide D.Treat first for a potential community-acquired pneumonia with a fluoroquinolone

48. ISTC TB Training Modules 2009 Management of Drug-Resistant TB 2. Reasonable steps for building a regimen for multidrug-resistant tuberculosis after drug- sensitivities results are known include all of the following except: A.Always start by choosing any available first-line drug that the isolate remains susceptible to B.Aim for a total of four to six drugs that the isolate is known to be sensitive to (preferably not drugs used previously by the patient) C.Second-line agents (like cycloserine, ethionimide, and PAS) would be preferred over injectable agents to minimize healthcare resources used in association with injections and improve patient comfort D.If there are not four to six drugs available among the first- and second-line agents, third-line agents could be considered, preferably in consultation with an expert

49. ISTC TB Training Modules 2009 Management of Drug-Resistant TB 3. Clinical management and monitoring plans for the care of MDR/XDR-TB should include (as resources permit) all of the following except: A.Daily patient-centered directly observed treatment (DOT) throughout the entire treatment course B.Diligent recording of drugs given, bacteriological results, chest film findings and any occurrence of medication toxicity C.Periodic sputum specimens for smear and culture, both to document culture conversion and monitor for signs of treatment failure D.Monthly sputum for drug-sensitivity testing throughout the entire course of treatment