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Treatment of Tuberculosis-Not just another pill

Treatment of Tuberculosis-Not just another pill. Karen Fitzmaurice, RN Martha Ainslie, MD Alfred Gin, PharmD. Objectives:. By attending the session, the attendee will be able to: Become familiar with the first and second line anti-tuberculosis antibiotics and the standard treatment regimes

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Treatment of Tuberculosis-Not just another pill

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  1. Treatment of Tuberculosis-Not just another pill Karen Fitzmaurice, RN Martha Ainslie, MD Alfred Gin, PharmD

  2. Objectives: • By attending the session, the attendee will be able to: • Become familiar with the first and second line anti-tuberculosis antibiotics and the standard treatment regimes • Identify the common adverse effects and drug interactions associated with these antibiotics • Describe problem-solving techniques that are used to help identify and manage common adverse effects

  3. Outline • Review the first line agents • Discuss duration of therapy • Review common side effects and management • Review treatment of TB in special populations • Briefly talk about drug resistance and second line agents

  4. The scope of the problem • A 2 cm cavity contains 108 organisms • A patient with active TB will have organisms that are rapidly dividing as well as semi-dormant and dormant organisms • There are naturally occurring mutations to all our TB drugs • Use of monotherapy allows the selective growth of the resistant organisms and gives rise to drug resistance • A prolonged course of antibiotics is required to kill the semi-dormant and dormant organisms

  5. In order to treat TB you must • Take into consideration: • Known or suspected drug resistance • Hx of prior TB treatment • Country of origin • Location of disease • Standard tx is 6 months • TB meningitis: 9-12 months • Likelihood of adherence and/or adverse reactions • Co morbidities and host immune status

  6. Standard treatment regime: • Intensive phase • Goal is to quickly kill the rapidly dividing organism to control disease and render patient non-infectious and prevent emergence of drug resistance • Continuation phase • Sterilize the lungs by killing dormant and semi-dormant organisms to prevent relapse • DOT allows for intermittent therapy

  7. Give all meds together as a single dose unless: Profound nausea, vomiting Swallowing issues

  8. Standard treatment Regime: • Intensive phase (first 8 weeks) • 4 drugs X 8 weeks in the intensive phase • INH/RMP/PZA/EMB daily X 14 doses • If in hospital – daily until smear negative • 5/7 X 6 weeks (30 doses) WRHA • 3/7 X 6 weeks (18 doses) FNIH, unless drug resistance suspected, then 5/7 • Ethambutol can be dropped if organism pansensitive • Continuation phase • Twice weekly INH and rifampin DOT

  9. 2HREZ/4HR2 • In intensive phase • H,R: kill rapidly dividing TB • Z: works to kill semi dormant TB in the acidic environment of the cavity or in macrophages • E: used to prevent the emergence of RIF resistance when primary resistance to INH may be present • In continuation phase • H,R: kill any remaining rapidly dividing cells as well as sterilizing fibrotic areas

  10. Rifampin • Inhibits RNA polymerase • The most important drug we use • Bactericidal against rapidly dividing agents, and penetrates into fibrotic areas to kill semidormant organisms • Without rifampin treatment course is 12-18 months • Usual dose 10 mg/kg max 600mg 11

  11. Rifampin side effects • Change in colour of urine, sweat • Puritis with or without rash: 6% • Hepatotoxicity • Significant transaminase elevation: rare • Can be seen as part of hypersensitivity rx • Dose dependent interference with bilirubin uptake causing unconjugated hyperbilirubinemia or jaundice without LFT abnormalities • Thrombocytopenia • Hypersensitivity rx in 0.07-0.3%

  12. Rifampin Drug Interactions • Potent inducer of cytochrome P450 enzyme system • Rifampin decreases drug concentration of: • alfentanil, amiodarone, anticoagulants (oral), atovaquone, barbiturates, beta-blockers, buspirone, calcium channel blockers, clarithromycin, oral contraceptives, corticosteroids, cyclosporine, dapsone, digoxin, disopyramide, HMG-CoA reductase inhibitors, azole antifungals, lamotrigine, losarten, macrolides, methadone, morphine, NNRTIs, odansetron, phenytoin, propafenone, protease inhibitors, quinidine, sirolimus, sulfonylureas, tacrolimus, theophylline, tricyclic antidepressants • Rifampin concentration decreased by: • protease inhibitors eCPS accessed 4/2/12 13

  13. Isoniazid • Usual dose 300 mg daily (5 mg/kg) • Inhibits mycolic acid synthesis • Profound early bactericidal activity against rapidly dividing cells 14

  14. Isoniazid side effects • Peripheral neuropathy • Dose related side effect • Vit B6 supplements to prevent • Rare: seizures • +ANA antibodies in 20%, less than 1% develop lupus * 15

  15. INH Hepatotoxicity • Hepatitis • Incidence increases with age • Generally occurs within weeks to months rather than days • Takes weeks to regress, recovery is complete in most following drug cessation

  16. INH Drug Interactions • INH inhibits cytochrome P450 system • Increase concentrations of: • carbamazepine, phenytoin, cycloserine, theophylline, warfarin • These effects are offset with rifampin • Check levels • Also weak inhibitor of monoamine oxidase 17

  17. Pyrazinamide • Active against dormant and semi-dormant TB within macrophages or in acidic environments • No proven benefit extending PZA beyond 2 months in pts with pansensitive TB • No PZA → minimum of 9 months of tx • Dose is 25 mg/kg, requires renal dosing 18

  18. Pyrazinamideside effects • Hepatotoxicity • Actual incidence hard to predict as PZA always used with other TB meds, in one study hepatotoxicity attributed to PZA in 1% • In the RZ studies for LTBI incidence os severe liver injury 5% • Rash • Non gouty arthralgias • Seen in up to 40% of patients on daily Z 19

  19. Ethambutol Inhibits arabinosyl transferase (synthesis of TB cell wall component) Less bactericidal compared to INH or RIF Dose: 15 mg/kg Requires renal dosing 20

  20. Ethambutolside effects • retrobulbar neuritis • Manifests as decreased visual acuity or decreased red-green colour discrimination in one or both eyes • Risk higher in pts with renal failure • Rarely used in children due to an inability to monitor for symptoms 21

  21. Duration of therapy in patients with pansensitive strain of TB • Depends on location of TB • CNS involvement • Osteomyelitis • Was PZA used in first 2 months • No→9 months of tx • What were the culture results at 2 months? • positive→9 months of tx

  22. Duration of therapy = number of doses

  23. Monitoring for side effects during therapy • Clinical • Screen for common side effects • Microbiological response • Sputum at 2 months • Sputum at completion of therapy • Laboratory response • First 2 weeks: twice weekly • At 1 month then monthly • Check: AST, ALT, Bilirubin, CBC

  24. Adverse Effects 26

  25. Common problems during therapy • Nausea and vomiting • Abnormal LFTs • Drowsiness • Rash/puritis • Missed doses

  26. Drowsiness: HS dosing Nausea: Have light food 30 – 60 minutes prior to DOT Antiemetic 30 minutes prior to DOT Stronger antiemetic/ranitidine/PPI Rash/Itch: Minor itch continue meds with antihistamine (usually RMP) Major rash drug challenge after rest RMP/INH/EMB/PZA (usually PZA) SYMPTOM MANAGEMENT:

  27. Hepatotoxicity • Asymptomatic increases in LFTs occur in 20% of pts on tx for TB • Most common serious side effect • Defined as AST >5xULN or >3xULN with symptoms • Incidence depends on • Age • Pre-existing liver disease • ETOH: appears to more than double risk of INH hepatotoxiticity • INH more hepatotoxic than rifampin

  28. Nausea, vomiting, abdominal pain seen in 50-75% of patients with hepatotoxicity • Fever 10%, rash in 5% • Jaundice is a late finding

  29. What to do if a patient develops abnormal LFTs on therapy? • AST/ALT 5X ULN asymptomatic or • AST/ALT 3X ULN symptomatic or • Jaundice • → HOLD TB Meds • Once ALT returns to <2x ULN then • Restart rifampin alone or with ethambutol, repeat ALT on day 3 • IF ALT <2x ULN then add in INH and repeat ALT in 3 days • Rechallenge with PZA may be hazardous and consider D/C and extending tx to 9 months

  30. Rash • If minor, consisting of mainly puritis or affecting limited area • → trial antihistamines • Petechial rash • Check platelet count • Generalized rash especially with fever or involving mucocutaneous areas • → hold all TB meds • Once rash subsides: restart drugs one by one • Rif → INH→ethambutol or PZA. If no rash with 3rd drug then assume it is the 4th drug that is the cause

  31. Missed doses Manitoba Communicable Disease Control – Tuberculosis Protocol 2009

  32. Paradoxical Reactions: • Worsening of TB adenitis with development of new lymph nodes, increasing lymph node size or sinus drainage • Seen in up to 20% of patients • Median time to onset: 1.5 months • Can present with new pleural effusions during trt for Pulm TB

  33. Mgmt of Paradoxical Reactions: • Rule out drug resistant TB • Aspiration of lymph nodes, effusions • Corticosteroids • Unproven benefit • NSAIDS

  34. Treatment of patients in special populations • Hepatic Disease • Renal insufficiency/ESRD • HIV infection • Pregnancy/breastfeeding

  35. Treatment in patients with pre-existing liver disease • Remember ↑ AST/ALT may be secondary to TB • If ALT more than 3xULN not related to TB • Avoid PZA • IF patient has cirrhosis • Rifampin + ethambutol + fluoroquinolone • Severe liver disease with encephalopathy • Ethambutol, fluoroquinolone, aminoglycoside (or capreomycin), cycloserine

  36. Renal insufficiency/ESRD: • Dose adjust Z and E if CrCl<30ml/min or on PD or HD • Intensive: • INH/RMP OD post HD • PZA/EMB 3X per week post HD • Continuation • INH/RMP 3X per week post HD • No data on peritoneal dialysis

  37. HIV infection: • CD4 count <200 • OD 7/7 X 2 months for intensive phase • 3X per week for continuation phase • Protease inhibitor interaction with Rifampin Rifabutin in consultation with HIV pharmacist • Starting of ART (on new HIV DX) • Dependent on CD4 count

  38. TB and HIV Drug Interactions • Rifampin and Protease inhibitors (PI) • Effect: Decreased PI serum levels • Substitute Rifampin with Rifabutin 150 mg po thrice weekly (may need to increase to 300 mg thrice weekly or 150 mg po daily) • Rifampin and Efavirenz • Effect: Decreased efavirenz levels • Increase efavirenz dose to 800 mg po daily (usual 600 mg daily) • Rifampin and Raltegravir • Effect: Decreased raltegravir levels • Increase raltegravir to 800 mg po BID (usual dose 400 mg po BID and continue higher dose for at least 2 weeks post completion of Rifampin) 40

  39. Pregnancy: • TB not an indication for pregnancy termination • First line drugs safe in pregnancy (H,R,E) • PZA: limited data with respect to teratogenic effects. Recommended by WHO and IUATLD • Fluoroquinolones and aminoglycosides contraindicated while pregnant

  40. Breastfeeding Moms: • 1st line drugs • Very small concentrations in breast milk • Encourage breast feeding • Have not shown to produce toxic effects in newborn • Mum should be on pyridoxine supplements • Drugs level in breast milk not sufficiently high to be considered effective tx for infant • Certain 2nd line drugs not recommended - data unknown

  41. Concerns re poor absorption: • Consider if significant malnutrition, diabetic gastroparesis, HIV, underlying GI disease, treatment failure • INH/RMP serum levels: • Usually 2 hours (+/- 6 hours) post oral drug admin • Special lab handling • Done in Mayo Clinic (Rif) and in Ontario Lab (INH) results take ~ 2-3 weeks • Available IV drugs include INH, RIF, fluoroquinolones, aminoglycocides • Recommendations-Parental route (delays discharge) • Only select drugs via Home Care/Mount Carmel Clinic/Lions Place in WRHA

  42. Drug resistance • Primary versus acquired • PZA resistance: treat for 9 months • INH monoresistance • 6 month R,Z,E • 12 months of 2RZE/10RE • MDR= resistance to INH and RIF

  43. MDR =failure of public health

  44. Second Line* **not commercially available • Fluoroquinolones • Ciprofloxacin • Levofloxacin • Moxifloxacin • Aminoglycosides • Amikacin • Streptomycin • Capreomycin • Kanamycin • Rifamycins • Rifabutin • Rifapentine** • Ethionamide • Cycloserine • Para-amino-salicyclic acid (PAS) • Clofazimine 46

  45. Third Line Amoxicillin/clavulanate Imipenem/cilastatin Linezolid Clarithromycin Thiacetazone 47

  46. Management of MDR-TB Individual regimes guided by DST Ask yourself: could the DST pattern have changed due to tx during the interval from sputum collection to obtaining DST?

  47. Management of MDR-TB Injectable: used daily for first 2-6 months then can be stepped down to 3x/week, ideally for >6 months Must have daily directly observed therapy for the duration of therapy Duration: 18-24 months after sputum conversion

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