TB Intensive San Antonio, Texas November 11 14, 2014

Transcription

1 TB Intensive San Antonio, Texas November 11 14, 2014 TB Drugs Part 1 & 2 Vanessa Meyer, PharmD November 12, 2014 Vanessa Meyer, PharmD has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1

2 Anti-Tuberculosis Medications Vanessa Meyer, PharmD Objectives First-line anti-tuberculosis medications Second-line anti-tuberculosis medications Management of adverse drug reactions Special considerations New and investigational drugs 2

3 Isoniazid Rifampin Rifabutin* Pyrazinamide Ethambutol FIRST-LINE ANTI-TUBERCULOSIS MEDICATIONS * Not FDA approved for TB Isoniazid Accounts for majority of early bactericidal activity of multidrug TB regimens Absorption: Rapid and complete Distribution: All body tissues and fluids Including CSF Crosses placenta Enters breast milk Metabolism: Hepatic w/ decay rate determined genetically by acetylation phenotype 3

4 Dose Adults Isoniazid 5 mg/kg/day 15 mg/kg two to three times weekly Children mg/kg/day mg/kg/dose two to three times weekly Administration Isoniazid Take 1 hour before or 2 hours after meals May take with small snack if needed Take 1 hour before or 2 hours after antacids Supplement with pyridoxine if needed Avoid alcohol Avoid tyramine-containing foods Aged cheese, tap/draft beers, sauerkraut, soy sauce 4

5 Isoniazid Toxicity Peripheral neuropathy Pyridoxine deficiency Central nervous system effects Irritability, seizures, dysphoria, inability to concentrate Epigastric discomfort Cramping with INH solution Lupus-like syndrome 20% develop antinuclear antibodies <1% develop clinical lupus erythematosis Hypersensitivity reactions Fever, rash, Stevens-Johnson syndrome Hepatotoxicity Isoniazid Toxicity Asymptomatic elevation of aminotransferases Clinical hepatitis: 0.6% of patients Mechanism unknown Occurs after weeks to months Risk factors: Age, alcohol consumption, pregnant and postpartum women, active hepatitis B, other hepatotoxic drugs 5

6 Isoniazid Hepatotoxicity Interventions: Hold INH if: ALT >3x ULN when jaundice and or hepatitis symptoms reported ALT >5x ULN in the absence of symptoms A rapid increase in ALT may be an indication for more frequent monitoring Consider rechallenge (many caveats) Isoniazid Toxicity Peripheral Neuropathy Dose related Uncommon (<0.2%) at conventional doses Increased risk Malnutrition, diabetes, HIV, renal failure, alcohol, pregnant and breastfeeding Supplement with pyridoxine 25 mg/kg 6

7 Isoniazid Toxicity Monitoring The critical element for INH toxicity monitoring is CLINICAL MONITORING Absolutely necessary to do! Absolutely necessary to do well! Absolutely necessary to document well! Drug Interactions Drug interactions CYP450 are the major enzymes involved in drug metabolism Most drugs undergo deactivation by CYPs (some activation) Many drugs may increase or decrease the activity of various CYP450 enzymes Increase activity (inducers) Rifampin > rifapentine > rifabutin Isoniazid: inducer/inhibitor Major concern: reduction in serum concentrations of common drugs to ineffective levels Bidirectional interactions between rifamycins and antiretroviral agents 7

8 Isoniazid Drug Interactions Interaction characteristics CYP2C19 inhibitor, moderate CYP3A4 inhibitor, weak CYP2E1 inducer, major lowers seizure threshold serotonergic effects, weak Clopidogrel CYP2C19: thiol metabolite (active) Carbamazepine CYP3A4 CYP2C19 Citalopram Diazepam Lansoprazole Omeprazole INH levels of these Pantoprazole drugs Phenytoin CYP2E1 Acetaminophen Ethanol How supplied Isoniazid Injection, solution: 100 mg/ml Solution, oral: 50 mg/5 ml in sorbitol Tablet, oral: 100 mg, 300 mg Causes diarrhea Images courtesy: and dailymed.nlm.nih.gov/dailymed 8

9 Rifampin Bactericidal Highest sterilizing activity Cornerstone of short course therapy Absorption: well absorbed Distribution: highly lipophilic Crosses blood brain barrier well Metabolism: Hepatic; undergoes enterohepatic recirculation Rifampin Dose Adults: 10 mg/kg/dose up to 600 mg daily, twice weekly or three times weekly Children: mg/kg/dose up to 600 mg daily or twice weekly Administration Take 1 hour before or 2 hours after meals Take 1 hour before antacids Avoid alcohol May mix the contents of capsule with applesauce or jelly 9

10 Rifampin Toxicity Reddish-orange body fluids Will stain contact lenses Nausea/anorexia/abdominal pain Rash & pruritis Flu-like syndrome <1% of patients on intermittent therapy Hepatotoxicity Severe immunologic reactions Thrombocytopenia, hemolytic anemia, acute renal failure, and thrombotic thrombocytopenic purpura Rifampin Drug Interactions Substrates (CYP3A) Inhibitors Inducers Alprazolam/clonazepam Amiodarone Carbamazepine Atorvastatin Cimetidine Gluccocorticoids Buspirone Clarithromycin Phenobarbital Calcium channel blockers Erythromycin Phenytoin Carbamazepine Fluconazole Decrease Primidone level of Cilostazol Rifampin will Fluoxetine rifabutin in blood Rifampin Citalopram decrease levels Fluvoxamine Clindamycin of these meds Increase Grapefruit juice level Clindamycin in blood of Indinavir rifabutin in Dapsone blood Itraconazole Estrogens Ketoconazole Protease inhibitors Metronidazole Losartan Miconazole Ondansetron Nefazodone Prednisone Nelfinavir Sertraline Ritonavir Simvastatin Saquinavir Warfarin Sertraline 10

11 Rifampin Percentage Reduction in AUC of PI s and NNRTI s by Rifampin Indinavir 89% Ritonavir 35% Nelfinavir 82% Atazanavir 72% Fosamprenavir 82% Saquinavir 84% Delavirdine 96% Nevirapine 20-58% Efavirenz 25% Bacuewucz Am J Med Sci 2008; 335:126 How supplied Rifampin Oral capsule: 150 mg, 300 mg Injection, powder for reconstitution: 600 mg Suspension available through compounding pharmacy Images courtesy: 11

12 Rifabutin Substitute for rifampin Less severe CYP450 enzyme induction Absorption: Readily, 53% Distribution: to body tissues Lungs, liver, spleen, eyes and kidneys Metabolism: to 5 metabolites; predominately: 25-O-desacytel-rifabutin (serum AUC 10% of parent drug) 31-hydroxy-rifabutin (serum AUC 7% of parent drug) Dose Rifabutin Adults: 5 mg/kg (300 mg daily, 2-3x/week) Dose adjustment necessary with NNRTIs/Pis Administration May be taken with or without food 12

13 Rifabutin Toxicity Reddish-orange body fluids Rashes and skin discoloration Bronzing or pseudojaundice Arthralgias GI symptoms Hepatotoxicity, flu-like syndrome Hematologic toxicity Leukopenia/neutropenia Anterior uveitis and other eye toxicities How supplied Rifabutin Capsule, oral: 150 mg Suspension available through compounding pharmacy Images courtesy: 13

14 Rifapentine Long-acting rifamycin that can be used once weekly (600mg) with INH in the continuation phase of treatment for TB HIV seronegative Non-cavitary Drug-susceptible Negative sputum smears at completion of initiation phase Absorption: High-fat meals increase AUC and C max by 43% and 44% respectively Metabolism: Hepatic; to active metabolite 25- desacetyl-rifapentine Dose Rifapentine Adults: 10 mg/kg (600 mg) once weekly Children: Not approved for use in children Studies underway Evaluate higher doses with more frequent administration Alternative dosing schedules Agent for treatment of LTBI (TBTC trials) 14

15 Rifapentine Adverse effects similar to rifampin Body fluid discoloration Flu-like symptoms not as common as with rifampin Drug interactions essentially identical to rifampin Resistance associated with mutations in rpob gene (as with rifampin) How supplied Tablet, oral: 150 mg Rifapentine 15

16 Pyrazinamide Bacteriostatic/sterilizing agent Greatest activity against dormant or semidormant organisms Necessary for 6 months treatment regimen Absorption: well absorbed Distribution: widely into body tissues and fluids: Liver, lung, CSF Metabolism: hepatic Pyrazinamide Dose Adult: mg/kg/daily (2 g) 50 mg/kg (4 g) twice weekly Weight (kg)* Daily Therapy Thrice Weekly DOT Children: mg/kg/daily (2 g) 50 mg/kg (2 g) twice weekly Twice Weekly DOT mg 1500 mg 2000 mg mg 2500 mg 3000 mg mg 3000 mg 4000 mg *Based on lean body weight Maximum dose regardless of weight 16

17 Pyrazinamide Toxicity Non-gouty polyarthralgias Up to 40% of patients Rash/dermatitis Gastrointestinal upset Asymptomatic hyperuricemia: expected Acute gouty arthritis **Contraindicated in patients with severe gout** Hepatotoxicity Unusual at 25 mg/kg Hepatotoxicity of Pyrazinamide > 3,000 patients with TB in Hong Kong in 2001: Compared continuation-phase regimens with or without PZA Hepatotoxicity (ALT > 3x ULN) 12 or more weeks after starting therapy (continuation phase of therapy) in 1.6% of patients Hepatotoxicity risk 2.6% in regimens with PZA vs. 0.8% without PZA Chang et al, AJRCCM 2008, 177;

18 How supplied Pyrazinamide Tablet, oral: 500 mg Suspension available through compounding pharmacy Images courtesy: and dailymed.nlm.nih.gov/dailymed Ethambutol Absorption: ~80% Distribution: Widely throughout body Kidneys, lungs, saliva, and RBCs Metabolism: Hepatic (20%) to inactive metabolites 18

19 Ethambutol Dose Adult: mg/kg/day 50 mg/kg twice weekly Weight (kg)* Daily Therapy Three/Week DOT Twice Weekly DOT mg 1200 mg 2000 mg mg 2000 mg 2800 mg mg 2400 mg 4000 mg Children mg/kg/day 50 mg/kg twice weekly Administration May be taken with or without food *Based on lean body weight Maximum dose regardless of weight Ethambutol Toxicity Retrobulbar neuritis Decreased visual acuity or red-green color discrimination Dose related Unusual at 15 mg/kg Safe at higher doses given intermittently Increased risk with renal insufficiency Peripheral neuritis Cutaneous reactions 19

20 Ethambutol Toxicity: Monitoring Baseline visual acuity and testing of color vision discrimination Snellen chart and Ishihara tests Monthly symptom check Monthly testing: High doses Treatment longer than 2 months Renal insufficiency Ophthalmology evaluation: no single diagnostic test for ethambutol ocular toxicity How supplied Ethambutol Tablet, oral, as hydrochloride: 100 mg, 400 mg Suspension available through compounding pharmacy Images courtesy: and dailymed.nlm.nih.gov/dailymed 20

21 Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB 430 patients treated for TB in Canada Major side effect: Any adverse reaction resulting in discontinuation of one or more drugs, and or resulting in hospitalization Almost all patients received isoniazid, rifampin, pyrazinamide (75% ethambutol) Yee, AJRCCM 2003; 167: 1472 Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB 37 patients had major side-effects 9 had a second major adverse event (46 total events) Rash/drug fever 21 Hepatitis 12 Severe GI upset 11 Visual Toxicity 1 Arthralgia 1 Increased risk Female sex, age >60, birthplace in Asia, HIV status Yee, AJRCCM 2003; 167:

22 Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB Drug Dose (mg/kg) Rash Hepatitis GI INH (5.2) RIFAMPIN (10.2) PZA (24.2) EMB (16.8) Yee, AJRCCM 2003; 167: 1472 Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB PZA: 1.48/100 person-months of exposure INH: 0.49/100 person-months RIF: 0.43/100 person-months EMB: 0.07/100 person-months The drug most likely responsible for the occurrence of hepatitis or rash during therapy for active TB is PZA Yee, AJRCCM 2003; 167:

23 Cycloserine Ethionamide Levofloxacin* Moxifloxacin* Paser Streptomycin Amikacin* Capreomycin Linezolid SECOND-LINE ANTI-TUBERCULOSIS MEDICATIONS * Not FDA approved for TB Cycloserine Bacteriostatic agent Rapid, nearly complete GI absorption Widely distributed in most body fluids and tissues including CSF and breast milk Excretion is primarily renal, half-life is longer in renally impaired patients Not recommended for patients with ESRD 23

24 Cycloserine Dose Adults: mg/kg/day divided every 12 hours Children: mg/kg/day divided every 12 hours Titrate dose as tolerated Drug levels are necessary Peak levels mcg/ml Administration Take on an empty stomach Supplement with pyridoxine Avoid alcohol Cycloserine 250 mg BID 250 mg qam & 500 mg qhs 250 mg daily Dose titration should be completed within 2 weeks 24

25 CNS effects: Cycloserine Toxicity Behavioral changes, seizure, depression, psychosis, suicidal ideation Supplement with pyridoxine mg/day Caution: alcoholics, patients with history of mental illness or seizures Peripheral neuropathy Rash How supplied Cycloserine Capsule, oral: 250 mg Images courtesy: 25

26 Ethionamide Widely distributed throughout body tissues and fluids Metabolized almost exclusively in the liver, no dosage adjustment necessary for renal insufficiency Ethionamide Dose Adults:15-20 mg/kg/day mg/day in single or divided dose Children: mg/kg/day divided in 2-3 doses Titrate dose as tolerated Administration Take with or after meals Supplement with pyridoxine Avoid alcohol 26

27 Ethionamide 250 mg BID 250 mg qam & 500 mg qhs 250 mg daily Dose titration should be completed within 2 weeks Ethionamide Toxicity GI upset/anorexia Metallic taste Neurotoxicity Peripheral neuritis, optic neuritis, depression, psychosis Endocrine effects: Hypothyroidism, acne, alopecia, gynecomastia, menorrhagia, impotence Hepatotoxicity 27

28 How supplied Oral, tablet: 250 mg Ethionamide Fluoroquinolones Preferred oral agents for treating drug resistant TB that is susceptible to this class of drugs or for patients intolerant of first-line drugs Activity against MTB: gati > moxi > levo >>>>>>>>>>>> oflox/cipro Cross resistance? 28

29 Fluoroquinolones Levofloxacin Dose Adult: mg/day No data to support intermittent dosing Moxifloxacin Dose Adults: 400 mg daily No data to support intermittent dosing Administration Take 2 hours before or after aluminum, magnesium, or calcium-containing antacids, iron, vitamins, sucralfate, and/or milk-containing products Promote adequate hydration Fluoroquinolone Hepatotoxicity Reversible transaminase elevation among fluoroquinolones in 2-3% of cases Moxifloxacin: transaminase elevation >1.5x ULN in 0.9% of cases Levofloxacin: severe hepatotoxicity- RARE 29

30 Fluoroquinolone Musculoskeletal Toxicity Tendonitis/tendon rupture Tendon inflammation MILD: Rest the joint/nsaids Reduce dose of FQ if possible If symptoms progress, stop the FQ Tendon inflammation MODERATE/SEVERE Stop the FQ Rest the joint/nsaids Risk/benefit evaluation of FQ continuation Tendon rupture Usually Achilles RARE Fluoroquinolone Toxicity GI disturbance Neurologic effects Dizziness, insomnia, tremulousness, headache Neuropathy Cutaneous reactions Rash, pruritis, photosensitivity Arrythmias: QT prolongation Arthralgias levo> moxi 30

31 Fluoroquinolone Caveats and Controversies Concerns for developing resistance Use for community acquired pneumonia Multiple courses of fluoroquinolone Prolonged courses of fluoroquinolone Rifampin effect on fluoroquinolone levels hepatic metabolism Fluoroquinolone Caveats and Controversies widespread use of the fluoroquinolones for TB treatment is likely to hasten the development of problematic drug resistance in other pathogens for which the drug class plays a key role in treatment. 31

32 How supplied Levofloxacin Tablets, oral: 250 mg, 500 mg, 750 mg Injection, solution: 25 mg/ml Solution, oral: 25 mg/ml Infusion, premixed with D 5 W: 250 mg, 500 mg, 750mg Images courtesy: How supplied Moxifloxacin Tablets: 400 mg Solution for IV: 400 mg/250 ml Images courtesy: and dailymed.nlm.nih.gov/dailymed 32

33 P-aminosalicylic acid Dose Adults: 8-12 grams per day divided 2-3 times daily Children: mg/kg/day divided 2-4 times daily Administration Keep in the refrigerator Take with or immediately following meals Do not chew granules Sprinkle on applesauce or yogurt; swirl in acidic juices P-aminosalicylic acid Bacteriostatic AUC increased by co-administration with food 80% of drug excreted in urine Contraindicated for patients with serious renal disease Toxic metabolites 33

34 P-aminosalicylic acid 4 gm BID 2 gm BID 2 gm qam & 4 gm qhs Dose titration should be completed within 2 weeks P-aminosalicylic acid Toxicity GI upset Malabsorption syndrome Hypothyroidism Rash, lymphadenopathy, leukocytosis, arthralgia Hepatotoxicity 34

35 How supplied P-aminosalicylic acid Oral, granules: 4 gram packet Dose Amikacin Capreomycin Streptomycin Adults 15mg/kg/day, 5-7 days per week mg/kg/dose 2-3 days per week after initial dosing *after culture conversion* Children mg/kg/day, 5-7 days per week mg/kg/day, 2-3 days per week after initial dosing 35

36 Streptomycin Amikacin Capreomycin Ototoxicity Vestibular and hearing disturbances risk: age, loop diuretics, dose and cumulative dose Hearing disturbances, < vestibular dysfunction that streptomycin 722 pts: 11% subclinical auditory loss; 3% clinically apparent hearing loss Neurotoxicity Perioral parasthesias Nephrotoxicity 2% pts, < common than with amikacin & capreomycin Electrolyte Disturbances Rash % of pts risk: pre-existing renal disease, higher doses, other nephrotoxic drugs Hypokalemia, hypomagnesemia (cardiac dysrhythmias) 722 pts: 36% elevated BUN > 20 mg/100 ml; 10% > 30 mg/100 ml Hypokalemia, hypomagasemia, (cardiac dysrhytmias) Monitoring Baseline audiogram, vestibular testing, Romberg testing and creatinine Renal function and questions about auditory and vestibular symptoms monthly Repeat audiogram or vestibular testing if symptoms develop 36

37 How supplied Amikacin Capreomycin Streptomycin Amikacin: Injection, solution: 250 mg/ml (2ml, 4ml) Capreomycin: Injection, powder for reconstitution: 1 g Streptomycin: Injection, powder for reconstitution: 1 g Image courtesy Linezolid Dose Adults: 600 mg daily Children: 10 mg/kg/dose every 8 hours Administration May be taken with or without food Supplement with pyridoxine Avoid tyramine containing food/drinks Aged cheeses, dried meats, sauerkraut, soy sauce, tap beers, red wines Do not use with drugs that increase concentrations of serotonin in the body 37

38 Linezolid Excellent penetration into bronchial mucosa and bronchioalveolar fluid Does not require dosage adjustment with renal insufficiency Optimal dose unknown Does not induce nor is significantly metabolized by cytochrome P450 enzymes Linezolid Toxicity Diarrhea/nausea Rash Optic neuritis Peripheral neuropathy Myelosuppression 38

39 Linezolid Drug Interaction Monoamine oxidase inhibitor risk of serotonin syndrome Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of linezolid treatment. Exception: fluoxetine May be resumed 24 hours after the last dose of linezolid Psychiatric Medications with Serotonergic Activity Selective Serotonin Reuptake Inhibitors Paroxetine Fluvoxamine Fluoxetine Sertraline Citalopram Escitalopram Serotonin-Norepinephrine Reuptake Inhibitors Venlafaxine Desvenlafaxine Duloxetine Tricyclic Antidepressants Amitriptyline Desipramine Clomipramine Imipramine Nortriptyline Protriptyline Doxepin Trimipramine Monoamine Oxidase Inhibitors Phenelzine Selegiline Other Psychiatric Medications Nefazodone Trazodone Bupropion Buspirone Vilazodone Mirtazapine 39

40 Linezolid for treatment of chronic extensively drug-resistant tuberculosis 41 patients with XDR-TB unresponsive to therapy in the previous 6 months Linezolid 600 mg/day initially then after 4 months or sputum smear conversion either 600 mg/day or 300 mg/day 87% pts with neg sputum cultures at 6 mos 13 pts completed therapy without relapse Acquired linezolid resistance in 4 pts (3 who received 300 mg/day) Myungsun et al NEJM 2012, 367; 1508 Linezolid for treatment of chronic extensively drug-resistant tuberculosis 82% clinically significant adverse events (AEs) possibly or probably linezolid related 7 episodes of myelosuppression (anemia and neutropenia) 7 episodes of optic neuropathy 21 episodes of peripheral neuropathy 1 episode rhabdomyolyis Only 3 patients permanently discontinued linezolid owing to drug toxicity 1 anemia, 2 optic neuropathy Myungsun et al NEJM 2012, 367;

41 How supplied Linezolid Infusion, premixed: 200mg; 600mg Powder for suspension, oral: 100mg/5ml Oral, tablet: 600 mg Images courtesy: Immune Reactions Neurotoxicity Nephrotoxicity QT interval prolongation Food Effects MANAGEMENT OF ADVERSE DRUG REACTIONS 41

42 Immune Reactions Urticaria/Hives Hold medications until reaction resolves If no evidence of anaphylaxis, angioedema, airway compromise, may elect to attempt drug re-challenge or desensitization under controlled conditions Severe Drug Reactions Generalized rashes associated with fever, other systemic symptoms, mucous membrane involvement are characteristics of Stevens-Johnson Syndrome DO NOT attempt to rechallenge or desensitize patient to the drugs Petechial rash Rifampin hypersensitivity reaction and thrombocytopenia Oral Desensitization to Rifampin and Ethambutol in Mycobacterial Disease Patients with hypersensitivity reaction to either rifampin or ethambutol Exclusion Hepatitis, hemolytic anemia, purpura, nephritis, ocular toxicity, anaphylaxis, hypotension, bronchospasm, laryngeal angioedema INH: Chest, 1990; 98: 1518 Matz, AJRCCM, 1994; 149:815 42

43 Desensitization Protocol Time from Start (hr:min) Rifampin (mg) Ethambutol (mg) : : : : : : : : : : : Next day 06:30 a.m. 300 twice a day 400 three times a day Neurotoxicity Peripheral Neuropathy Drugs: INH, ethionamide, cycloserine, linezolid Increase risk Diabetes Alcoholism HIV infection Hypothyroidism Pregnancy Inadequate dietary intake of pyridoxine Usually symmetrical 43

44 Neurotoxicity Peripheral neuropathy (cont) Initial symptoms: tingling, prickling, burning in balls of feet/tips of toes May progress to sensory loss, loss of reflexes, unsteady gait May also involve hands and fingers Pyridoxine prophylaxis Nephrotoxicity Drugs: aminoglycosides, capreomycin Baseline serum creatinine 24-hour creatinine clearance if baseline serum creatinine abnormal Lower initial dose in patients > 59 yo 10 mg/kg; max 750 mg If baseline creatinine clearance < 70 ml/min, consider intermittent dosing initially Monitor peak and trough serum drug levels and adjust dose accordingly 44

45 Hepatotoxicity If hepatocellular enzymes <3X ULN with no evidence jaundice Manage nausea/vomiting Monitor closely Stop hepatotoxic medications when transaminase levels: 3x ULN with symptoms 5x ULN without symptoms When transaminase levels <2x ULN and symptom improvement Re-start first line medications (sequentially) Consider liver friendly regimen (EMB, fluoroquinolone, rifamycin) based on severity of TB, length of therapy interruption, pending medication rechallenge Hepatotoxicity Drug Effect on Liver Isoniazid Most likely to cause hepatitis Usually reversible in pts with normal hepatic function Hepatotoxicity increased with rifampin use May be used in pts with stable hepatic disease Rifampin Cholestatic jaundice Can potentiate hepatocyte damage from INH Pyrazinamide Severe and prolonged, and worsen even after stopping therapy Most severe liver injury Ethionamide Implicated in hepatotoxic drug reactions PAS Fluoroquinolones Cipro and moxi: associated with occasional cases of liver damage Levofloxacin Not commonly associated with liver dsyfunction Ethambutol Aminoglycosides Cycloserine 45

46 QT Interval Prolongation Fluoroquinolones Moxi > levo > ofloxacin > cipro Bedaquiline Monitor ECG 2, 12, 24 weeks Optimal screening and monitoring unknown Food Effects Empty Stomach Rifampin Absoprtion 26% Isoniazid Absorption 57% Avoid food with abundant glucose/lactose Avoid food with tyramine or ETOH Cycloserine Cmax 30%, Tmax 3x Orange juice Cmax 15% Administer with water and between meals Fluoroquinolones Avoid Al and Mg antacids With food Rifapentine Fatty food enhances absorption PAS Fatty food enhances absorption Orange juice and antacids minor effects Acidic drinks/yogurt prevent release in stomach, reducing the incidence of nausea Clofazimine Fatty food increases Cmax 46

47 Renal Disease Liver Disease Pregnancy TB Meningitis SPECIAL CONSIDERATIONS Renal Disease dosing interval vs. decreasing dose Insufficient data to guide dosing for CrCl > 30 ml/min Use standard dosing Consider serum concentrations to avoid toxicity Peritoneal dialysis not the same as hemodialysis, requires serum concentration measurements 47

48 Renal Dosing Drug Change in frequency Cl CR <30 ml/min or Hemodialysis Isoniazid No change 300 mg once daily, or 900 mg TIW post-hd Rifampin No change 600 mg once daily, or 600 mg TIW post-hd Dialyzable (50-100%) Notes Poorly dialyzed: no dosage adjustment necessary (intermittent hemodialysis, peritoneal dialysis, or continuous renal replacement therapy) Rifabutin No change Pyrazinamide Yes mg/kg/dose TIW (not daily), post-hd Ethambutol Yes mg/kg per dose TIW (not daily), post-hd Metabolites excreted in the urine and may accumulate in renal insufficiency Risk of hyperuricemia caused by PZA is increased in patients with renal insufficiency 80% cleared by kidney Slightly dialyzable (5-20%) Serum concentrations useful Well documented ocular toxicity monitoring Drug Change in frequency Cl CR <30 ml/min Hemodialysis Notes Levofloxacin Yes mg/dose 3x per week (not daily) Cleared more extensively by kidney than moxifloxacin Cycloserine Yes 250 mg once daily, or 500 mg/dose TIW Ethionamide No change mg/dose daily P- aminosalicylic acid Renal Dosing (cont) Excreted primarily by kidney Cleared by HD (63%) Peak serum conc. (2h postdose) ~20-35mcg/ml No change 4 g/dose, twice daily Modestly cleared by HD (6.3%) Inactive metabolite acetyl-pas eliminated renally Streptomycin Yes mg/kg/dose 2-3x per week (not daily) Cleared almost entirely by kidney; only 40% of dose Capreomycin Yes mg/kg/dose 2-3x per week (not daily) removed by dialysis Monitor closely for ototoxicity (hearing & vestibular) Amikacin Yes mg/kg/dose 2-3x per week (not daily) Serum drug conc. can be used Moxifloxacin No change 400 mg daily Linezolid No change 600 mg daily 48

49 Renal Disease Strongly consider monitoring serum drug concentrations in persons with renal insufficiency who are taking cycloserine, ethambutol, or any of the injectable agents to minimize doserelated toxicity, while providing effective doses Liver Disease Drug Considerations Isoniazid Possible risk of drug accumulation and drug-induced hepatitis May be used in patients with stable liver disease lab and clinical monitoring Rifampin Clearance may be impaired, resulting in serum levels Critical importance in short-course regimen lab and clinical monitoring Rifabutin lab and clinical monitoring Dose reduction might be necessary in patients with severe liver dysfunction Pyrazinamide May cause severe and prolonged liver injury lab and clinical monitoring Ethionamide PAS Use with caution Implicated in hepatotoxic drug reactions Fluoroquinolones Drug levels are not affected by hepatic disease Cycloserine Cycloserine: Caution for patients with alcohol-related hepatitis in whom there is an risk of seizures Levofloxacin Ethambutol Aminoglycosides Generally thought to be liver sparing EMB can be used safely in patients with hepatic disease 49

50 Pregnancy Isoniazid Considered safe in pregnancy Risk of hepatitis increased in peripartum period Supplement with pyridoxine Rifampin Considered safe in pregnancy Ethambutol Considered safe in pregnancy Pyrazinamide Controversial (FDA vs WHO and IUATLD, ATS) Rifabutin Use with caution Cycloserine para-aminosalicylic acid Ethinoamide Amikacin Streptomycin Kanamycin Capreomycin Quinolones Contraindicated Rifapentine Best avoided in 1 st trimester Not sufficient info to recommend use in pregnant women TB Meningitis Drug CSF penetration CSF concentrations Isoniazid Excellent CSF penetration Similar to serum conc. in inflamed meninges 20% of serum conc. in non-inflamed meninges Pyrazinamide Excellent CSF penetration Relative diffusion from blood into CSF: Adeuqate with or without inflammation (exceeds usual MICs) Rifampin Highly lipophilic; cross BBB well Increased with inflammation, adequate for efficacy Similar to serum conc. CSF:blood level ratio: inflamed meninges: 100% CSF:blood level ratio: inflamed meninges: 25% Ethambutol Penetrates inflamed meninges CSF:blood level ratio: -normal meninges: 0% -inflamed meninges: 25% Ethionamide Excellent CSF penetration Similar to serum conc. Streptomycin Poorly distributed into CSF Slight penetration of inflamed meninges Cycloserine Readily penetrates CSF % serum conc. Capreomycin Does NOT penetrate inflamed CSF PAS Marginal efficacy 10-50% serum conc. in CSF with inflamed meninges Levofloxacin CSF conc. ~15% of serum levels Linezolid Good CSF concentration 50

51 Bedaquiline (Sirturo ) Clofazimine NEW DRUG AND INVESTIGATIONAL Bedaquiline FDA indicated for multi-drug resistant pulmonary TB in adults 18 years old Only used when effective treatment regimen cannot otherwise be provided Not used for: Latent TB Drug-sensitive TB Extra-pulmonary TB Should be used with at least 3 other susceptible drugs 51

52 The Diarylquinoline TMC207 for Multidrug Resistant Tuberculosis 47 newly diagnosed MDR-TB patients randomly assigned to placebo (24) or TMC207 (23) 400 mg/day for 2 weeks, then 200 mg TIW for 6 weeks in addition to standard therapy TMC207 vs placebo: Reduced time to sputum conversion Increased proportion of patients with conversion of sputum culture (48% vs 9%) Only nausea occurred significantly more with TMC207 than placebo Diacon et al NEJM 2009, 360; 2397 Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance 2 year F/U results of 47 MDR-TB patients treated with bedaquiline (TMC207) or placebo Bedaquiline (TMC207) vs placebo: Significantly reduced the time to sputum conversion over 24 weeks 26% of patients had nausea with bedaquiline Significantly less acquired drug resistance with bedaquiline (0% vs 22% for ofloxacin) Diacon et al Antimicrob Agents Chemother 2012, 56;

53 Bedaquiline Dose Adults Weeks 1-2: 400 mg once daily, then Weeks 3-24: 200 mg three times per week (with at least 48 hours between doses) Administration Give with food Swallow tablets whole with water Avoid alcohol Common side effects Nausea Arthralgia Headache Elevated AST/ALT Bedaquiline Serious adverse reactions QT prolongation Hepatotoxicity Increase in mortality 53

54 Bedaquiline Restricted use in the United States How supplied Oral, tablet: 100 mg Image courtesy Dose Clofazimine Adults: 100 to 200 mg daily Children: limited data, but doses of 1 mg/kg/day have been given Administration Take with food 54

55 Clofazimine Common side effects Pink or red discoloration Skin, conjunctiva, cornea and body fluids GI upset Rash/pruritis Dry skin Serious adverse reactions Gastrointestinal bleeding Bowel obstruction Clofazimine Not commercially available in the United States How supplied: Oral, capsule: 50 mg 55

56 References 1. Francis J. Curry National Tuberculosis Center and California Department of Public Health, 2008: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Second Edition. 2. Dana WJ, Fuller MA, Goldman MP, et al. Drug Information Handbook, 20th ed. Hudson, Ohio, Lexi-Comp, Inc.; 2011: Micromedex 2.0, Drugdex Evaluations, Greenwood Village, CO: Truven Health Analytics, Inc. (Accessibility verified on September 15, 2014) 4. Dailymed. Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, (Accessibility verified on September 20, 2014) 5. Epocrates Rx Online [database on the Internet]. San Francisco, CA: Epocrates, Inc Retrieved at Web-based; continuous content updates. (Accessibility verified on September 15, 2014) 6. Bedaquiline [package insert]. Titusville, NJ: Janssen Therapeutics; Centers for Disease Control and Prevention (CDC). Treatment of Tuberculosis: American Thoracic Society, CDC, and Infectious Diseases Society of America, MMWR Morb Mortal Wkly Rep. 2003;52(RR-11): Capastat Sulfate [package insert]. Lake Forest, IL: Akron, Inc.; Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy. 2006; 26: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. Philidelphia, PA, Lippincott Williams & Wilkins; DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiological Approach. New York, NY, McGraw-Hill Education;