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  • 1. Management of Tuberculosis Dr. Uttam Kumar Dasgupta MBBS (Cal) MD (Cal, Chest)
  • 2. Introduction
    • Commonest cause of death due to a single inf. agent.
    • 1882 – Discovery of TB bacilli.
    • 1944 – First Anti – TB drug, Streptomycin
    • discovered.
    • 1963 – Efficacy of domiciliary treatment established.
    • 1993 – WHO declares TB a global emergency.
  • 3. Statistics
    • Total no. of pts. infected with TB = 2 bi. (0.3 bi.)
    • Total no. of active TB pts. = 20 mi. (12 mi.)
    • Total no. of pts. dying of TB / year = 3 mi. (5 lakhs)
    • Total no. of NSSP pts. / year = 8 mi. (1.5 mi.)
  • 4. Principle of standard short course therapy
    • Mycobacterial population divided into 4 groups
    • (Mitchison’s Theory)
    • Grp. A – EC Bacilli in liq. caseous material (H, R)
    • Grp. B – Slow growing in macrophage (Z)
    • Grp. C – Small no. of EC Bacilli in solid caseations exhibiting brief spurts of metabolism ( R)
    • Grp. D – Dormant bacilli (nil)
  • 5. Aims of treatment
    • To cure pts. with least interference to their lives.
    • To prevent death from active TB or its effects.
    • To avoid relapse / recurrence.
    • To prevent development of drug resistance.
    • To decrease transmission to others.
  • 6. Protocol of treatment with dose
    • 2 RHEZ / 4 RH
    • 2 SRHEZ / 1 RHEZ / 5 RH
    • 2RHZ / 4 RH
    • R = 10 mg / kg H = 5 mg / kg
    • E = 25 mg / kg 15 mg / kg Z = 25 – 35 mg / kg
    • S = 15 mg / kg
  • 7. Side effect profile
    • Rifampicin
    • Common
      • GI toxicity (nausea, anorexia, abd. pain).
    • Uncommon
      • Cut. reactions (flushing, itchiness, rash).
      • Hepatitis.
      • Reduced effectiveness of oral contraceptives.
      • Pseudomembranous colitis, gynaecomastia.
      • ARF, thrombocytopenia, flu syndrome, shock, haemolytic anaemia.
  • 8. Contd…
    • INH
    • Peripheral neuropathy.
    • Hepatitis.
    • Rarely, giddiness, convulsion, optic neuritis, psychosis.
  • 9. Contd…
    • Ethambutol
    • Progressive loss of vision due to retrobulbar neuritis.
    • Rarely peripheral neuropathy, joint pain, skin rash.
  • 10. Contd…
    • Pyrazinamide
    • Hepatitis (Bilirubin, SGPT x3 – stop)
    • Arthralgia – mild but common. Gout.
    • Rarely – GI symptoms, rash, sideroblastic anemia.
  • 11. Contd…
    • Streptomycin
    • Auditory & vestibular nerve damage.
    • Renal damage.
    • Rarely skin rash & anaphylaxis.
  • 12. Adverse effects with management
    • Pyridoxine
    • Change to Cm
    • Amitryptiline
    Cs, H AG, FQ, Eto, Pto Peripheral neuropathy
    • Suspend Tt.
    • Anticonvulsant
    • Pyridoxine
    Cs H, FQ Seizures Management Drugs responsible Adverse effect
  • 13. Contd… 1. Antipsychotics Cs FQ, H, Eto, Pto Depression
    • Stop drugs – 1 to 4 weeks
    • Antipsychotics
    • Reduced dosage / stop
    Cs, H FQ, Eto, Pto Psychotic reactions Management Drugs responsible Adverse effects
  • 14. Contd… PPI / Antiemetics Eto, Pto, PAS R Gastritis Thyroxine PAS, Eto, Pto Hypothyroidsm Change to Cm AG Clr Hearing loss Management Drugs responsible Adverse effects
  • 15. Contd… Stop E Optic neuritis NSAID Dose / Stop Z Arthralgia Replace Cm AG Electrolyte disturbances (K, Mg ) Use Cm Give bi / tri wkly. AG Renal toxicity Management Drugs responsible Adverse effects
  • 16. Revised National Tuberculosis Control Programme (RNTCP)
    • 1963 – Launching of NTP.
    • 1993 – NTP declared a failure.
    • 1993 – 1996 – Pilot Programme
    • 1997 – Formal Launching Of RNTCP
    • 2007 – 632 districts – 1114 million people covered
  • 17. Setup
  • 18. Categorization of TB pts. for registration on diagnosis
    • New – Never ATD / < 1 month
    • Relapse – Declared Cured / TC, again Sp. +ve
    • Failure – Failed with previous treatment now Sp. +ve, also initially Sp. –ve now +ve
    • TAD – ATD > 1 month anywhere, then defaulted, now Sp. +ve
    • Chronic – Sp. +ve after completing rett. Regime.
    • Others – Not in the above categories
  • 19. Standardized treatment protocol
    • Cat I – [2 (RHEZ) 3 / 4 (RH) 3 ]
    • Cat II – [2 (SRHEZ) 3 / 1 (RHEZ) 3 / 5 (RHE) 3 ]
    • Cat III – [2 (RHZ) 3 / 4 (RH) 3 ]
    • Cat IV - Individualised
  • 20. DOTS
    • Aim
      • Cure at least 85% of NSSP pts.
      • Detect 70% of NSSP pts.
  • 21. Contd…
    • 2. Components:
      • Political & Administrative commitment.
      • Good quality diagnosis.
      • Good quality drugs.
      • Short course chemotherapy under direct supervision.
      • Systemic monitoring & accountability.
  • 22. Sputum Categorization 100 - NEG Nil 200 No / 200 Scanty 1 – 9 AFB / 100 OIF 100 1+ POS 10 – 99 AFB / 100 OIF 50 2+ POS 1 – 10 AFB / OIF 20 3+ POS >10 AFB / OIF No. of fields Grading Results If slide has
  • 23. Outcome
    • Cured
    • TC
    • Died
    • Failure
    • Defaulter
    • Transferred Out
  • 24. Debates
    • Cat II
    • Cat III
    • Is it only Cat I & Cat IV
  • 25. TB & Diabetes Mellitus
    • Fact Sheet:
    • TB is 2 to 7 times more common in diabetics.
    • 30% of DM have TB which is the commonest complicating illness (5.9%).
    • Management of TB in DM is no different than in non DM patients.
    • Complication of TB in DM as in non – DM but MDR TB & mortality is more.
  • 26. Points to remember in TB + DM
    • Prompt initiation of Pharmacotherapy.
    • Adequate diet prescription.
    • Possible failure of sulphonylureas with Rifampicin co-administration.
    • Augmentation of hepatotoxicity of ATT (esp. with Thiazolidindiones but less with biguanides).
    • Insulin is always a good option.
  • 27. TB & HIV ( The Deadly Duo )
    • Estimates in 2000:
    • Globally no. of people with TB + HIV = 11.4 mi. (2 mi.).
    • 8.3 million new cases of TB (3.7 mi. is Sp. +ve). Most live in SSA, WP & S.E. Asia where 34 mi. (85%) of estimated 40 mi. people with HIV also live.
    • 9% of 8.3 mi. new TB cases were due to HIV.
  • 28. Contd…
    • 4. 12% of 1.84 mi. deaths due to TB were due to HIV.
    • 5. 11 % of all adult AIDS deaths were due to TB.
    • 6. HIV infected pts. has a five time risk of developing TB than non – HIV pts.
    • 7. TB & HIV interaction is bi-directional.
  • 29. Issues in HAART – ATD
    • When to start HAART
    • ‘ Virologic, immunologic & clinical responses to HAART of HIV – 1 TB patients treated concurrently with antitubercular therapy & HAART was similar to those of non TB patients’
    • Hung C. C. et. al AIDS 2003; 17: 2615 - 2622
  • 30. Contd…
    • Proposal:
    • CD 4 < 100 / µ L or in advanced AIDS – concurrent HAART as early as possible.
    • CD 4 100 – 200 / µL – Start HAART 4 – 8 weeks after ATD initiation.
    • CD 4 > 200 / µ L – initiation of HAART based on
      • Further AIDS defining condition.
      • CD 4 counts & rate of decline.
      • Drug toxicity & interactions.
  • 31. Contd…
    • 2. Optimal duration of therapy
    • 6 months but prolonged to 9 months in delayed clinical (sym.) / microbiologic response (culture +ve at 2 months)
    • Treatment failure & relapse is related to:
      • Advanced immuno deficiency.
      • Acquired Rifamycin resistance (common in intt. ATD).
    • So daily ATD.
  • 32. Overlapping adverse event profile - ZDV CTMX Valganciclovir Bone marrow dysplasia RBT, R Pancytopenia - d4T, ddl & ddc - - H & E Peripheral neuropathy + in pts. With chr. Viral hepatitis NVP, all PI CTMX - ZRH, RBT Hepatitis - Ddl - - E, RBT Ocular Effects + Pancreatitis or Intra – abd. Adenitis ZDV, r, IDV - Do - Other opp infections - Do - Nausea Vomiting - NVP, EVP, ABC CTMX Folliculitis ZRH, RBT Skin Rash IRS ARV drugs Medication other than ARV HIV ATT Possible Causes Adverse Effects
  • 33. Drug – drug interaction
    • R reduces PI & NNRTI by increasing CYP3A which metabolises PI & NNRTI. So R never with PI & NNRTI.
    • RBT also increases CYP3A but less so, so can be used with PI.
    • PI & NNRTI alters R level by increasing or decreasing CYP3A. PI can increase levels of RBT & it’s metabolites.
    • So when using NNRTI with RBT, increase dose of RBT & while using PI reduce dose of RBT
    • H inhibits CYP3A thus increasing levels of PI & NNRTI.
  • 34. IRS
    • Definition : Restoration of immunity by ARV therapy leading to increased inflammation in TB resulting in significant worsening of S / S (Paradoxical reactions)
    • Onset – Within days of ARV therapy or months after ARV initiation.
    • Symptoms : Fever, adenopathy, increased pulmonary infiltrates, serositis. Less common features are worsening of meningitis, increased CNS tuberculomas, soft tissue & bone abscess & diffuse skin lesions.
    • Diagnosis : Difficult.
  • 35. BCG & HIV
    • Role of BCG in preventing TB in HIV +ve pts. is not known.
    • Conversion to +ve MT after BCG is less frequent but significant
    • BCG is safe in HIV
    • WHO recommendation:
    • In high prevalence – BCG except in children with S / S of HIV / AIDS
    • In low prevalence – no BCG
  • 36. MDR TB
    • Definition : Resistance to H + R + / - other drugs.
    • Causes :
    • Inadequate & inappropiate previous treatment with ATD.
    • Patients with extensive cavitary disease.
    • Addition syndrome
    • Ineffectual & irrational drug schedule.
    • Contact with a known MDR patient.
  • 37. Basic principles of Tt. Of MDR TB
    • Tt. should be in a specialised centre with C / S facilities.
    • Careful analysis of past drug history.
    • Never to add a single to a failing regimen.
    • Never combine two drugs of the same group or a drug with known cross resistance. (eg. Thioamides / TZN, Km or Am / Sm, R / RBT)
    • Intt. therapy is not effective in MDR TB
  • 38. Contd…
    • Regimen should contain >= 4 drugs with certain (or nearly so) effectiveness.
    • No drug should be kept in reserve & the most powerful bactericidal drugs should be used initially in maximum combination.
    • Tt. should be under direct observation throughout or at least till sputum conversion.
    • Surgical treatment may be an adjunct.
    • Injectable drugs for a min. of 6 months. Total duration 18 – 24 months after smear conversion or 12 months after culture becomes negative. Z throughout.
  • 39. Drugs used in MDR TB
    • Group 1 – 1 st line oral ATD
    • Group 2 – Injectable ATD (Cm in cross resistance)
    • Group 3 – Fluoroquinolones (Mx = Gx > Lx > Ox > Cx)
    • Group 4 - Oral bacteriostatic drug
      • Eto / Pto – start with small dose.
      • PAS – Combine if imperative.
      • Cs
      • Cs + (Eto / Pto or PAS)
    • Group 5 – Cfz, Amx / Clv, Clr, Lzd
    • Regimen
    • Group 2 + 3 + two to three Group 4 + / - Group 5 + Z
  • 40. Doses 10 – 12 g. 10 g. 8 g. 150 m/K PAS 750-1000 mg. 750 mg. 500 mg. 15-20m/K Cs 750-1000 mg. 750 mg. 500 mg. 15-20m/K Eto / Pto 400 mg. 400 mg. 400 mg. 7.5–10m/k Mfx / Gfx 750-1000 mg. 750 mg. 750 mg. 7.5–10m/k Lfx 800-1000 mg. 800 mg. 800 mg. 15–20m/k Ofx - - - 15–20m/k AG > 70 Kg. 51-70 Kg. 33–50 Kg. < 33 Kg. Drugs
  • 41. Case 1
    • 42 year old male, in whom Cat I / Cat II has failed. DST done. Non diabetic. HIV –ve.
    • Resistant to – S R H
    • Sensitive to – E Km Ofx Eto Cs PAS
    • On RHE since DST has been sent. Sensitivity to Z was not possible.
    • What would you give?
  • 42.
    • KM
    • Ofx
    • Eto
    • Cs
    • + / - PAS
  • 43. Case 2
    • 36 year old female in whom Cat I / Cat II has failed. Non diabetic. HIV –ve. DST sent for.
    • Resistant to – S R H E Z Km
    • Sensitive to – Cm Ofx Pto Cs PAS
    • Not on any drugs since DST was sent.
    • What would you give?
  • 44.
    • Option 1 – Cm Ofx Pto Cs
    • Option 2 – Cm Ofx Pto Cs + / - PAS
  • 45. Case 3
    • 35 year old male on Km Ofx Eto Z remains sputum +ve after eight months of treatment. DST done four months ago.
    • Resistant to – R H E Z Eto
    • Sensitive to – Km Cm Ofx Cs PAS
    • What would you give?
  • 46.
    • Cm
    • Ofx
    • Cs
    • PAS
    • one of Group 5 drugs
  • 47. Management of contacts of MDR TB patients
    • Identify & Evaluate
    • If contact Sp. +ve / CXR +ve – DST
    • If DST NA – Protocol of the index case.
    • If contact Sp. –ve (but symptomatic) & CXR –ve
    • Antibiotics
    • If symptoms persist
    • FOB / CT
    • If all NA – rpt. work-up monthly if patients remains symptomatic.
    • Chemoprophylaxis – 2 nd line not recommended – close FU.
  • 48. XDR TB (Extensively drug resistant TB)
    • Defintion : MDR TB + resistance to any FQ + resistance to at least one of three injectables ( Cm Am Km.) 1 to 2 % of MDR TB in India are XDR TB. This figure is 4% in the US, 19% in Latavia.
    • Causes :
    • Incorrect drug prescription by doctors.
    • Poor quality drugs.
    • Erratic supply of drugs.
    • Patient non – adherence.
  • 49. Actions to prevent XDR TB
    • Strengthen basic TB care to prevent emergence of drug resistance.
    • Ensure prompt diag. & Tt. of DR TB to cure existing cases & prevent further transmission.
    • Increase HIV TB control programme collaboration.
    • Increase investment in lab. infrastrutures to enable better detection & management.
  • 50. DOTS PLUS & Green Light Committee
    • DOTS PLUS is a comprehensive management strategy that includes five tenets of DOTS strategy. It considers specific issues (eg. use of reserve drugs) that needs to be addressed in high MDR TB areas.
    • Green Light Committee is a working group that has made arrangement with the pharmaceutical industry to provide concessionally - priced 2 nd line anti TB drugs to DOTS PLUS pilot projects for management of MDR TB.
  • 51. TB & Pregnancy
    • Avoid.
    • No adverse effect of pregnancy on TB & vice – versa.
    • Effect of maternal TB on baby. Examine placenta.
    • Treatment is the same (avoid Sm Eto Pto).
    • Management of new born
      • Don’t separate (unless mother is desperately ill)
      • If mother Sp. –ve give BCG
      • If mother is / was Sp. +ve during pregnancy / delivery
        • If baby ill & TB suspected – full ATD
        • If baby well - give INH 5 mg. / Kg. X2 months. Then MT done. If MT –ve – stop INH. Give BCG. If MT +ve – give INH upto 6 months.
    • If mother MDR – start Tt. in 2 nd trimester with 3 – 4 oral drugs (except Am, Eto, Pto)
  • 52. Management of latent TB – Indications of Tt. Silicosis / DN / malignancy Chr. immunosupression Lab personnel Prior TB (fiibrosis) Residents & employees of high risk setup. Recent contact No risk persons Immigration HIV +ve 15 mm. induration 10 mm. induration 5 mm. induration
  • 53. Treatment of latent TB
    • HIV –ve – INH 9 months
    • HIV +ve
      • MT +ve – INH 9 months.
      • MT –ve – no INH
    • Shorter alternatives
      • RZ x2 months – not given
      • RH x3 months – not given
      • R x4months – exclude active TB 1 st
  • 54. Toxicity with Tt. of latent TB
    • HIV -ve – Low risk. Hepatitis (fatal), PN (use B 6 )
    • HIV +ve – Toxicity > that of HIV –ve pts.
  • 55. Problems with treatment of latent TB
    • Low rate of Tt. inititation.
    • Low Tt. completion rates.
    • Monitoring for toxicity is a must.
    • Logistic difficulties.
    • Future protocol
    • RPT + INH x3 months
    • Mx
    • Special situations
    • Pregnant / breast feeding females – INH
    • Children – INH
    • Contacts with MDR – Z + E / Z + FQ x6 – 12 months
  • 56. Newer drugs in TB
    • Why is it required?
    • To improve current Tt. Of active TB by
      • Shortening duration of treatment
      • Providing more widely spaced intt. therapy.
    • To improve MDR TB Tt.
    • To provide more effective Tt. of latent TB.
  • 57. The Drugs
    • Rifabutine
      • First used in MAC prophylaxis.
      • Now, used as a substitute for R & for patients who can’t be given R for drug drug interaction.
      • Given twice weekly, it increases acquired drug resistance.
    • Rifalazin
      • Acts by reducing enzyme induction.
      • Reduces drug drug interaction
      • Flu like syndrome
  • 58.
    • Rifapentine
      • It is not indicated in advanced TB & HIV infection (acquired Rifamycin resistance)
      • It’s chief indication is LTBI where it is combined with H.
      • Dose is 900 mg. / day.
    • Moxifloxacin
      • It’s bactericidal activity is better than R but = H
  • 59. Contd…
    • 5. Diarylquinoline (R 207910)
      • Effective against drug sensitive bacilli & strains resistant to SRHEZFQ.
      • It is effective against other myco bacteria. It may be combined with any standard ATD (RHZ).
      • It’s ability to shorten duration is under trial.
    • Pyrrole (LL 3858) – It’s a good steriliser.
    • Dihydroimidazo – oxazoles (OPC – 67683)
      • No cross resistance or antagonistic action against other ATD.
      • Better than the first line drugs.
  • 60. Contd…
    • Nitroimidazopyrans (PA – 824)
      • Effective against sensitive & resistant TB.
      • It is highly selective.
      • Active against non replicating bacilli (cf ‘H’).
      • Active against MDR TB.
      • Does not demonstrate mutagenicity.
      • Min. effective dose is 12.5 mg. / day.
      • It is not genotoxic.
    • SQ 109 – Active against MDR TB
  • 61. Contd…
    • Oxazolidinones
      • It is very active against MDR TB
      • May rarely cause peripheral & optic neuropathy.
  • 62.
    • Where youth grows pale, and spectre-thin, and dies;         Where but to think is to be full of sorrow                 And leaden-eyed despairs,     Where Beauty cannot keep her lustrous eyes,         Or new Love pine at them beyond to-morrow.
    • - John Keats (Ode To A Nightingale)
  • 63. Thank You!

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