DR-TB

1. DR-TB Dr. Magdy Fawzy NTP, EGYPT PAL Coordinator

2. Causes of drug-resistant tuberculosis: • From a microbiological perspective, resistance is caused by a genetic mutation. • An inadequate or poorly administered treatment regimen allows a drug-resistant strain to become the dominant strain drug-resistant; hence, TB is essentially a man-made phenomenon.

4. Factors That May Lead To Developing Resistance

5. Factors may include: • HEALTH-CARE PROVIDERS through - INADEQUATE REGIMENS: - Inappropriate, Absence of or Noncompliance with guidelines - Poor training - No monitoring of treatment.

6. 2- PATIENTS through INADEQUATE DRUG INTAKE (patient incompliance): - Poor adherence - Lack of information, poor health education - Adverse effects. - Social barriers.

7. 3- DRUGS through: • Poor quality • Stock-outs or delivery disruptions. • Wrong dose. • Poor storage conditions

8. Short-course chemotherapy for patients infected with drug-resistant strains may create even more resistance to the drugs in use. • This has been termed the “amplifier effect” of short-course chemotherapy.

9. Different resistance patterns

10. Mono-resistance, colonies are resistant to only one of the first-line anti-TB drugs. • Poly-resistance, colonies are resistant to more than one of the first line anti-TB drugs but do not combine resistance to both Isoniazid and Rifampicin. Examples of poly-resistance may include Streptomycin, Isoniazid and Ethambutol or Streptomycin, Rifampicin and Ethambutol.

11. Multiple drug resistant, colonies combine resistance to at least Isoniazid and Rifampicin. • Extensively Drug Resistant TB (XDR-TB): Colonies are resistant to: • 1st Line drugs , at least Rifampicin and Isoniazid, (MDR-TB) • A fluoroquinolone • One or more of the following injectable drugs: • kanamycin • Amikacin • Capreomycin

12. Primary resistance and acquired resistance: • “Primary resistance” means that the patient was infected with already resistant bacilli while , • “Acquired resistance” means that patient was initially infected with sensitive bacilli but developed resistance of any pattern during the course of treatment because of any or a combination of the previously mentioned causes

13. Treatment of DR-TB

14. Anti-TB drugs are classified into 5 classes

15. Class 1 – First-line oral anti-tuberculosis • First-line oral anti-tuberculosis drugs should be used where there is laboratory evidence or clinical history to suggest their efficacy. • Patient who is resistance to low levels of Isoniazid but are susceptible to higher concentrations may benefit from high dose of the drug but should not be included as one of the four core drugs.

16. Class 2 – injectable agents • A Group 2 injectable agent should be given to all patients in whom susceptibility is documented. • streptomycin is the usual injectable agent of choice • Kanamycin or amikacin is the logical second choice given the low cost of these drugs and good experience of their use. • If an isolate is resistant to both streptomycin and kanamycin, capreomycin should be used. • Duration of injectable agent (intensive phase) is guided by smear and culture conversion. • At least 6 months and at least 4 months after the patient first becomes and remains sputum smear- or culture-negative.

17. Intermittent therapy (3-5 times weekly after an initial period of 2–3 months of daily therapy) can be considered for patients in whom the injectable agent has been used for a prolonged period and when the risk of toxicity increases.

18. Class 3 – Fluoroquinolones • Should be used whenever the strain is susceptible. • The most potent according to in vitro studies in descending orders are:- • Moxifloxacin = Gatifloxacin • Levofloxacin • Ofloxacin = Ciprofloxacin • Long-term safety of the newer-generation Fluoroquinolones has not yet been fully evaluated.

19. Class 4 – Oral bacteriostatic second-line anti-tuberculosis drugs • If only one is needed, ethionamide/protionamide is often added because of its proven efficacy and low cost. • If cost is not a constraint, PAS may be added first. • If two agents are needed, Cycloserine is commonly used in conjunction with ethionamide/protionamide or PAS. • Combination of ethionamide/protionamide and PAS has a high incidence of gastrointestinal adverse effects,

20. Class 4 – Oral bacteriostatic second-line anti-tuberculosis drugs, (cont.) • Ethionamide/protionamide should be started at a low dose (250 mg) for a few days and then gradually increased every 3–5 days. • The use of thioacetazone is limited by the development of rashes that are more prevalent in HIV-positive individuals and can result in Stevens-Johnson syndrome and death. • In addition, thioacetazone has cross-resistance with the thioamides (ethionamide and protionamide) and is considered a relatively weak antituberculosis agent.

21. Class 5. • Not recommended by WHO for routine use in DR-TB treatment because their contribution to the efficacy of multi-drug regimens is unclear. • can be used in cases where adequate regimens are impossible to form with the medicines from Groups 1–4.

25. Treatment regimens for DR-TB in Egypt

27. Suggested treatment regimens for mono &poly-resistance patterns

29. initial pretreatment clinical investigation includes: • A thorough medical history and physical examination. • Direct smear examination • DST for first and second line anti-TB drugs. • Liver functions: • Total serum Bilirubin • SGPT & SGOT • Total serum albumin, total serum protein and A/G ratio.

30. Serum Creatinine, blood urea, complete urine analysis with estimation of total urine protein content • Serum uric acid. • Fasting and PP blood sugar. • Serum Sodium and Potassium. • HIV • Pregnancy test. • Initial chest x-ray

31. Monitoring during DR-TB treatment

34. Monitoring of side effects should also include base line and check of: • Full blood count. • In highly risk patients (over 50 years, renal insufficiency, DM, HIV, underweight), creatinine should be evaluated every week or every other week for at least the first month of treatment.

35. Creatinine clearance may be needed for high risk group patients. • Audiometry or hearing evaluation. • Visual acuity and color vision evaluation. • If Serum potassium is low, check the Magnesium and Calcium levels

36. Special attention should be paid for: • Liver toxicity • Vestibular and hearing toxicity with injectable drugs • Psychiatric disorders with Cycloserine • Allergic reactions • Hematological changes .

37. Summary of important adverse reactions

38. Summary of important adverse reactions, (cont.)

39. Adverse effects, suspected agents & management strategies

45. Ancillary drugs

47. Side effects, general considerations • All anti-tuberculosis drugs are associated with side effects. • Adverse effects are not a contraindication to appropriate treatment. • Poorly managed side effects may lead to non-adherence or inappropriate therapy. • Minor side effects are common during initial months of treatment. • Serious reactions are rare but require attention.

48. Side effects, general considerations, (cont.) • Timely diagnosis and early management are crucial. • Changing treatment regimen is rarely indicated • Ambulatory management of side effects is usually adequate.

49. THANK YOU