Mdr , xdr,dots strategy

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Mdr , xdr,dots strategy

  1. 1. Multidrug resistant tuberculosis,Extended - Drug resistanttuberculosis, DOTS
  2. 2.  A Global Emergency Kills 5,000 people per day 2.3 million people die each year Highly prevalent in Pakistan-the estimated incidence is around 2,50,000 per year Ranks 6th among the 22 high burden countries of TB in the world.
  3. 3.  The 22 countries most affected by tuberculosis are Afghanistan, Bangladesh, Brazil, Cambodia, China, the Democratic Republic of Congo, Ethiopia, India, Indonesia, Kenya, Myanmar, Nigeria, Pakistan, Peru, the Philippines, Russia, South Africa, Thailand, Tanzania, Uganda, Vietnam and Zimbabwe
  4. 4.  Emergence of multi-drug resistant (MDR-TB), extremely drug resistant tuberculosis (XDR- TB) and latent TB have been the major constraints in the eradication of TB.
  5. 5.  Data from the latest 12 month period the highest ever number of infectious patients – 2.3 million people – were cured with the launch of DOTS 87% of treated patients being cured 85% global target was exceeded
  6. 6.  estimated half a million MDR-TB cases occur per year almost 30 000 were officially reported 6000 known to be treated but almost 29 ,000 people are expected to be treated in 2010.
  7. 7.  Eradicating M. tuberculosis infection Preventing development of drug resistance Preventing relapse of infection
  8. 8.  Occur in a patient who has never received antituberculosis therapy
  9. 9.  The development of resistance during or following chemotherapy in patients who previously had drug-susceptible tuberculosis. Main cause of primary drug resistance due to transmission of resistant strains.
  10. 10.  Cases of tuberculosis caused by an isolate of Mycobacterium tuberculosis that is resistant to one of the first-line antituberculosis drugs: INH, RMP, PZA, EMB, or streptomycin
  11. 11. A.Genetic mutations occur spontaneously- confer resistance to Anti-Tuberculous drugs  are present in Wild type M tuberculosis isolates  occur by chance alone  do not depend upon prior drug exposure  not linked  occur in frequency specific for each drug 1 in 107 for INH 1 in 108 for STM and INH 1 in 1010 for RMP 1 in 1014 for INH & RMP
  12. 12. Wild TB Strain Spontaneous mutationStrains with genetic drug resistance Selection: Inadequate treatment Acquired drug resistance Primary Drug Resistance
  13. 13. B. Treatment with a Single TB drug- Due to natrural occurrence of spontaneous mutations, treatment with one drug (or one efective drug) leads to development of resistance . - drug susceptible bacteria will be killed - drug resistant bacteria will survive
  14. 14. )) 1950s-1970s: Mycobacterium tuberculosis resistant to INH, streptomycin and / or PAS 1980s-curreny: TB that is resistant at least to INH and RMP Isolates that are multiply-resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB
  15. 15.  While community based information is lacking, laboratory data suggests an increasing frequency of MDR from 14% in 1999 to 28% in 2004[6] and 47% in 2006[8]. (referemces: 6. utt T, Ahmad RN, Kazmi SY, Rafi N. Multi-drug resistant tuberculosis in Northern Pakistan. J Pak Med Assoc. 2004;54:469–472(PUBMED) 8. rfan S, Hassan Q, Hasan R. Assessment of resistance in multi drug resistant tuberculosis patients. J Pak Med Assoc. 2006;56:397–400. [PubMed]
  16. 16.  MDR Bacilli-resistant to at least INH and RM. Are the consequence of human error in any of the following: prescription of chemotherapy management of drug supply case management process of drug delivery to the patient
  17. 17.  MDR-TB plus - resistance to one of the fluroquinolones  Ofloxacin  Levofloxacin  Moxifloxacin AND -resistance to one of the second line injectables  Amikacin  Kanamycin  Capreomycin
  18. 18.  XDR plus cycloserine, PAS, all injectables 15 TDR isolates identified in IRAN
  19. 19.  Resistance to all major anti-TB drugs Treatable but requires extensive chemotherapy upto 2 yrs of treatment. Expensive Drugs are toxic to the patient
  20. 20.  Previous treatment especially if prolonged Contact with drug resistant patient Country of origin East Europe Former USSR Middle East South and SE Asia Latin America Africa Age (In MDR area, commoner in children) HIV (Where MDR common) Substance abuse and homelessness
  21. 21. Drug GeneRifampicin rpoB Streptomycin rps Isoniazid No: base pairs katG inhA
  22. 22. Programmatic Drugs: Patients: Inadequate Inadequate drug Supply/Quantity intakeAbsence of guidance Non-availability of Poor adherence (oror certain drugs (stock outs poor DOT) – lack ofInappropriate or delivery disruptions) Informationguidelines Poor quality non-availability ofNon-compliance with Poor storage conditions free drugs guidelines Wrong dosages or Adverse drugInadequate training of combination reactionshealth staff Social andNo monitoring of economic barriers treatment MalabsorptionPoorly organized or Substance abusefunded TB control disordersprogrammes
  23. 23.  Treat with adequate number of drugs to prevent emergence of further resistance - use more drugs if susceptibility tests pending (often start with 5-6 drugs) DRUG SELECTION - at least 3 new drugs not previously not used - those with proven or suspected susceptibility - as many bactericidal drugs as possible -Any first line drugs with proven susceptibility Limit toxicity a much as possible
  24. 24. Step 1 Use any One of available plus plus One of these these Begin Injectable agentswith a 1st line 1st line drugs Fluroquinolones Amikacin agents to PZA & EBM Levofloxacin Capreomycinwhich the isolateIs susceptible Moxifloxacin StreptomycinAdd a fluroquinolones and an injectable drug KanamycinBased on susceptibllity Add2 line drugs nd Strep 2 Oral 2nd line drugsUntil u have4-6 drugs to which Cycloserineisolate is susceptible Ethionamide PAS if there are not 4-6 drugs 3rd line drugsAvailable, consider 3rd line Imepenemin consult with MDRTB Step 3experts Macrolides Linezolid Amoxicillin/Clavulante
  25. 25.  Treat at least 18-24 months after conversion of the culture to the negative Continue injectables to at least 6-12 months after conversion of the culture to the negative Shorter therapy for limited, primary or early disease
  26. 26.  Primarily available for INH & rifampin gene probe for rpoB ( for Rifampicin)is available in some countries & this serves as a useful marker for MDR-TB If a gene probe (rpoB) test - positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine
  27. 27.  Careful history taking for previous treatment regimens. Compliance of the drugs in the previous regime Determine the status of sputum smears at all junctures (in terms of positivity ,conversions and sensitivities – if available). Confirmed/ Strongly suspect MDR TB Counsel the Patient and family members Send Tissue / sputum for culture and sensitivity testing (if available) Start MDR Regimen
  28. 28.  Depends on a number of factors: How many drugs the organism is resistant to (the fewer the better), How many drugs the patient is given (Patients treated with five or more drugs do better), Whether an injectable drug is given or not (it should be given for the first three months at least),
  29. 29.  The expertise & experience of the physician responsible How co-operative the patient is with treatment (treatment is long, requires persistence & determination on the part of the patient), HIV positive or not (HIV co-infection is associated with an increased mortality
  30. 30.  Hurdles in the success of the treatment Lack of awareness/misconceptions about the disease Late / improper diagnosis Limited accessibility to diagnostic facilities Incorrect treatment by doctors Patients’ non-compliance to treatment Socio-economic factors
  31. 31. Dates and chemotherapy Smear Culture Susceptibility Radiolog Clinical results results results ical results resultsa)Date of diagnosis: ..................b ) Date of starting first course of chemotherapy: Drugs taken (dose, frequency, duration) i..e.: H300, 7/7, 6 Months R450, 7/7, 6 Months S1g, 7/7, 2 Monthsc) Date of completing or stopping first course of chemotherapyd) Date of starting second course of chemotherapy:……………....................... Drugs taken (dose, frequency, duration) ......., .........., ........ ......., .........., ........e) Date of completing second course ofchemotherapy: ..........................f) Date of starting third course ofchemotherapy: ........................(to be continued ...)
  32. 32. Resistance Suggested Length Comments- regimenIsoniazid Amik, 9 months to Anticipateand PZI RIF,E,Mox a year good responseIsoniazid Amik,RIF, 9-12/12and E PZI,Mox.Isoniazid Amik,PZI, At least Considerand RIF E,Mox. 18/12 surgery
  33. 33. Resistance Suggested Length Comments regimenINH,RIF, Amik,E, 18-24/12 ConsiderPZI Mox,Eth,Cy After cul-ve surgeryINH,RIF, Amik,Mox. As above As abovePZI,E Eth,Cy,Clar
  34. 34. The top priority is not themanagement but theprevention of MDRTuberculosis
  35. 35.  In new cases Best prevention - give each new case of sputum positive pulmonary tuberculosis an effective regimen of short course chemotherapy with four drugs at least for 4 months, given under direct observation
  36. 36.  In the group of TB patients previously treated with one or several courses of chemotherapy & who remain sputum positive (by smear and/or culture), 3 subpopulations can be observed: • patients excreting bacilli still susceptible to all antituberculosis drugs • patients excreting bacilli resistant to at least isoniazid, but still susceptible to rifampicin; • patients excreting bacilli resistant to at least isoniazid and rifampicin
  37. 37.  In patients who have failure after the 1st course of chemotherapy ( WHO recommended or any other)– WHO Tx regimen of 8 months ( using 5 drugs for the 1st 2 months, 4 drugs in the 3rd month and 3 drugs for the remaining 5 months ( 2 SHRZE/1HRZE/5HRE), given under direct observation
  38. 38. Rank Drugs Average daily Type of antimycobacterial dosage activity1 Aminoglycosides 15 mg/kg Bactericidal against actively a. Streptomycin multiplying organisms b. Kanamycin/Amikacin c. Capreomycin2 Thioamides 10-20 mg/kg Bactericidal (Ethionamide / rothionamide)3 Pyrazinamide 20-30 mg/kg Bactericidal at acid pH 7.5-104 Ofloxacin 7.5-15 mg/kg Bactericidal5 Ethambutol 15-20 mg/kg Bacteriostatic6 Cycloserine 10-20 mg/kg Bacteriostatic7 PAS acid 10-12 g Bacteriostatic
  39. 39. Aminoglycosides Kanamycin, Amikacin, Capreomycin ( useful in cases with tubercle bacilli resistant to streptomycin, amikacin and kanamycin)Thiamides- Ethionamides Prothionamides
  40. 40. Fluroquinolones Ofloxacin Ciprofloxacin (Complete cross resistance within the group) Sparfloxacin – should be avoided due to severe cutaneous side effects ( photo sensitisation) Norfloxacin should not be used as it does not give adequate serum level
  41. 41. Cycloserine ( or terizidone)- bactriostatic agent no cross reaction with other ATT limited use due to the high toxicityPara-aminosalicyclic acid-valuable for preventing resistance to INH-& Streptomycin
  42. 42.  Treat for 6 months or observe without treatmnet * use drugs source case is sensitive to * Choose 2: EMB, FQN, PZA Follow for 2 years regardless of treatment * Chest X-ray and clinical evaluation
  43. 43.  1970’s Tanzania Dr Karel Styblo strategy 1991 WHO TB a global problem In 1992 The WHO Global Tuberculosis Program developed a new strategy-DOTS ( brand name of the WHO Recommended TB Control Strtegy) 1993 WHO promoted Styblo’s strategy (DOTS) Implemented in 200+ countries
  44. 44.  That the highest ever number of infectious patients – 2.3 million people – were cured. With 87% of treated patients being cured, the 85% global target was exceeded for the first time since it was established in 1991 A total of 53 countries surpassed this treatment milestone
  45. 45.  Directly Observed Treatment Short-course
  46. 46.  To achieve universal access to high-quality diagnosis and patient-centered treatment To reduce suffering and socio-economic burden associated with TB To protect the poor and vulnerable populations from TB, TB/HIV and MDR-TB To support development of new tools and enable their timely and effective use
  47. 47.  National TB Control Program adopted DOTS strategy first in 1995
  48. 48.  Political commitment with increased and sustained financing Case detection through quality assured bacteriology Standardized treatment with supervision and patient support An effective drug supply and management system Monitoring and evaluation system, and impact m measurement
  49. 49. DIRECTLY OBSERVED DIRECTLY OBSERVED TB SHORT COURSE TREATMENT Comprehensive TB  A part of the DOTS management strategy strategy Consists of 5 elements  Direct supervision of Now expanded Stop individual patients to TB Strategy ensure treatment adherence
  50. 50.  Health inspectors  Wife of medical officers Pharmacists  Mid-wife Malaria field workers  Self help group volunteers Workplace supervisors  Senior dressers Railwayschool teachers  Multi purpose health Cured patients workers
  51. 51.  Prompt sputum conversion, cessation of transmission Halts generation of resistant (MDR- TB) strains Lessening of relapse rates Early recognition of drug toxicity
  52. 52.  Treatment with properly implemented DOTS has a success rate exceeding 95% prevents the emergence of further multi-drug resistant strains of tuberculosis The WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called "DOTS- Plus").
  53. 53. Country population 163,902,000Established no. of new TB cases 297,108Established TB incidence(all cases per one lakh 181population)DOTS population coverage (%) 99Rate of new SS+c ases(per 100.000 population) 81DOTS caes detection rate 67(new SS+ cases) (%)DOTS treatment success rate,2006 88(new SS+ cases) (%)New Multidrug resistant TB cases(%) 3.2
  54. 54.  New MDR-TB cases rose from 2.0 percent in 2003 to 3.2 percent in 2007. Pakistan accounts for 57 percent of the MDR-TB burden within WHO’s Eastern Mediterranean Region. Extensively drug-resistant TB has not been reported in the country.
  55. 55. New developments ineradicating tuberculosis
  56. 56.  May 2009- a new antibiotic Moxifloxacin has completed phase II trial and is expected to reduce the drug regimen by several months
  57. 57.  Standard TB drugs are dissolved into/adsorbed to fine, particulate carriers (simple and economical) Can be given orally (as well as IV), in distinction to liposomes Taken up by RES, mononuclear cells and solid organs Extremely long half-lives (give every 2 weeks?) More effective sterilizing than std. drug forms
  58. 58.  A new compound exhibiting a completely new mode of action (inhibition of ATP synthase) against mycobacteria The compound is being developed in phase IIa trials for the treatment of active tuberculosis as TMC207
  59. 59.  Cytokines IL-2 Gamma-interferon Immunomodulators Mycobacterium vaccae
  60. 60. Development of affordable newdrugs, diagnostics and vaccines
  61. 61.  BCG vaccine (for TB) currently administered against infection only reduces the risk of TB in infants but offers no protection against pulmonary TB and infection in adolescence or adulthood. A new TB vaccine, developed at the Oxford University called MVA85A/AERAS-485 holds promise. It has entered Phase II b trial in April 2009 and is being carried out in South Africa.
  62. 62.  New challenges addressed by new Stop TB Strategy Strengthen TB control Prevent drug resistance Treat 50 million TB cases Saves 14 million lives

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