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Transcript
Treatment of TuberculosisNot 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 • 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 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 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 semidormant 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 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 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 Give all meds together as a single dose unless: •Profound nausea, vomiting •Swallowing issues 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 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 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 11 Usual dose 10 mg/kg max 600mg 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% 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 Isoniazid 14 Usual dose 300 mg daily (5 mg/kg) Inhibits mycolic acid synthesis Profound early bactericidal activity against rapidly dividing cells 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 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 INH Drug Interactions INH inhibits cytochrome P450 system Increase concentrations of: • carbamazepine, phenytoin, cycloserine, theophylline, warfarin • These effects are offset with rifampin • Check levels 17 Also weak inhibitor of monoamine oxidase Pyrazinamide Active against dormant and semidormant 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 Pyrazinamide side 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 19 • Seen in up to 40% of patients on daily Z 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 Ethambutol side 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 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 Duration of therapy = number of doses Planned duration Doses of 2/7 INH/Rif in continuation Total Doses 3/7 intensive Total Doses 5/7 intensive 6 9 12 months months months 36 62 86 68 94 118 80 106 130 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 Adverse Effects 26 Rifampin Isoniazid • flushing, rash • increase in LFTs, hepatitis • flu-like syndrome • hematologic • body fluid discoloration • increase in LFTs, hepatitis • peripheral neuropathy Pyrazinamide • hepatitis • increased serum uric acid Ethambutol • optic neuritis Common problems during therapy Nausea and vomiting Abnormal LFTs Drowsiness Rash/puritis Missed doses SYMPTOM MANAGEMENT: 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) 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 Nausea, vomiting, abdominal pain seen in 50-75% of patients with hepatotoxicity Fever 10%, rash in 5% Jaundice is a late finding 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 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 Missed doses Manitoba Communicable Disease Control – Tuberculosis Protocol 2009 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 Mgmt of Paradoxical Reactions: Rule out drug resistant TB Aspiration of lymph nodes, effusions Corticosteroids • Unproven benefit NSAIDS Treatment of patients in special populations Hepatic Disease Renal insufficiency/ESRD HIV infection Pregnancy/breastfeeding Treatment in patients with preexisting 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 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 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 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 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 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 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 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 MDR =failure of public health Second Line* Fluoroquinolones • Ciprofloxacin • Levofloxacin • Moxifloxacin Aminoglycosides • Amikacin • Streptomycin • Capreomycin • Kanamycin Rifamycins • Rifabutin • Rifapentine** Ethionamide Cycloserine Para-aminosalicyclic acid (PAS) Clofazimine **not commercially available 46 Third Line Amoxicillin/clavulanate Imipenem/cilastatin Linezolid Clarithromycin Thiacetazone 47 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? 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 Surgery in MDR TB-it’s back Objectives: • 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 Take home points Duration of tx depends on results of 2 month cultures and the inclusion of PZA Treatment completion depends on the number of doses taken not duration of tx Many side effects do not require discontinuation of tx Beware of drug-drug interactions Hepatotoxicity is the most common serious side effect requiring discontinuation of drug • Introduce Rif then INH once LFTs return to normal Questions or Comments? References: Manitoba Health(Dec 2009)Tuberculosis Protocol Public Health Agency of Canada (2007) Canadian TB Standards 6th Edn p.117 – p.119, p.122 – p.128, p.130, p.161 – p.163, p.206 – p.209 MMWR June 20, 2003 WHO guidelines 2009 Saukkonen et al. Am J Resp Crit Care Med 2006 56