Management of Drug-Resistant Tuberculosis

1. Management of Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 15

2. 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. 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 International Standards 15

4. Standard 15: Management of Drug-Resistant TB • Patients with tuberculosis 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, and treatment should be given for at least 18 months. • Patient-centered measures are required to ensure adherence. • Consultation with a provider experienced in treatment of patients with MDR-tuberculosis should be obtained.

5. 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)

6. 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

7. 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 INH, rifampicin, ethambutol, (and streptomycin). Recognizing Predictors of Drug-resistant TB

8. Empiric Regimens for Drug-resistant TB Note: PZA does not prevent acquired resistance to companion drugs.

9. Multidrug-Resistant TB “I have been treated several times over the past five years and I’m still coughing and can’t gain weight!”

10. MDR/XDR Treatment Strategies: WHO Three approaches to treatment: • Standardized regimens • Empiric regimens • Individualized treatment regimens (Ideal, but resources must be considered) The choiceamong 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

11. Categories of Antituberculosis Drugs: WHO • Group 1 – First-line drugs: isoniazid, rifampicin, ethambutol, pyrazinamide • Group 2 - Injectable agents: streptomycin, kanamycin, amikacin, capreomycin, (viomycin) • Group 3 - Fluoroquinolones: ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, (gatifloxacin) • Group 4 - Oral bacteriostatic agents: ethionamide, cycloserine, para-aminosalicylic acid (prothionamide, thioacetazone, terizadone) • Group 5 - Unproven agents: clofazamine, amoxicillin/clavulanate, clarithromycin, linezolid Drugs in parentheses = varies by country availability

12. 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.

13. Additional Important Principles: WHO • Use direct observation of treatment (DOT) • Use daily, not intermittent, administration • Treatment duration of a minimum of 18-24 months • When possible, continue injectable for at least six months post-culture conversion • Continue at least three oral drugs for full treatment duration

14. 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.

15. 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

16. 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)

17. 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

18. Empiric Regimens for MDR-TB

19. Building a Regimen for MDR-TB PLUS PLUS 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

20. 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) Pick one or more of these

21. Building a Regimen for MDR-TB STEP 3 If there are not four to six drugs available in the above categories, consider third-line drugs in consultation with an expert. Consider use of these

22. Building a Regimen for XDR-TB PLUS PLUS 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

23. Building a Regimen for XDR-TB STEP 2 Pick one or more of these 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)

24. Building a Regimen for XDR-TB STEP 3 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

25. Initiating Treatment: WHO • 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.

26. MDR/XDR-TB: Management Principles Isolate until three consecutive sputum AFB smears 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.

27. MDR/XDR-TB: Management Principles 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 and nutritional status.

28. 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)

29. MDR/XDR-TB: Laboratory Testing • 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.

30. 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

31. Directly Observed Treatment Effect on Resistance and Relapse * P < 0.001 Weis SE, et al. NEJM 1994; 330(17): 1179-84

32. Common Adverse Effects

33. Common Adverse Effects

34. Common Adverse Effects

35. 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.

36. 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.

37. 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.

38. Summary: ISTC Standard Covered* Standard 15: • 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). *[Abbreviated version]

39. Summary: ISTC Standard Covered* Standard 15 (cont.): • Patient-centered measures are required to ensure adherence. • Consultation with a provider experienced in treatment of patients with MDR-TB should be obtained. *[Abbreviated version]

40. Alternate Slides

41. Resources • WHO: Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis www.who.int/tb • Drug-Resistant Tuberculosis, A Survival Guide for Clinicians www.nationaltbcenter.edu • The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org

42. Purpose of ISTC

43. 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

44. ISTC: Key Points • 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

45. Questions

46. 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: Begin empiric treatment with at least four drugs that the mother’s organism is known to be susceptible to Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide with the addition of a fluoroquinolone Begin empiric treatment with the standard initial regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide Treat first for a potential community-acquired pneumonia with a fluoroquinolone

47. 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: Always start by choosing any available first-line drug that the isolate remains susceptible to 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) 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 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

48. 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:  Daily patient-centered directly observed treatment (DOT) throughout the entire treatment course Diligent recording of drugs given, bacteriological results, chest film findings and any occurrence of medication toxicity Periodic sputum specimens for smear and culture, both to document culture conversion and monitor for signs of treatment failure Monthly sputum for drug-sensitivity testing throughout the entire course of treatment