Advanced Management of Patients with Tuberculosis Little Rock, Arkansas August 13 14, 2014

Transcription

1 Advanced Management of Patients with Tuberculosis Little Rock, Arkansas August 13 14, 2014 TB Drugs David Griffith, MD August 13, 2014 David Griffith, MD 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 TB Drugs David E. Griffith, M.D. Assistant Medical Director Heartland Regional TB Center Professor of Medicine University of Texas Health Center,Tyler Statements and recommendations consistent with ATS/CDC guidelines. Agents,Tuberculosis 2008; 66: Treatment of Tuberculosis: Am J Respir Crit Care Med, 2003; 167: Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection: Am J Respir Crit Care Med, 2000; 161: S221-S247 Hepatotoxicity of Antituberculosis Therapy: Am J Respir Crit Care Med, 2006; 174: Tuberculosis; Handbook of Antituberculosis Agents:

3 ANTITUBERCULOSIS DRUGS (ATS/CDC/IDSA) First-Line drugs Isoniazid Rifampin Rifapentene Rifabutin* Ethambutol Pyrazinamide *Not FDA approved for TB Second-Line Drugs Cylcoserine Ethionamide Levofloxacin* Moxifloxacin* PAS Streptomycin Amikacin/Kanamycin Capreomycin Linezolid Bedaquiline ISONIAZID (INH) Profound early bacteriacidal activity Accounts for the majority of early bacteriacidal activity of multidrugtb regimens Excellent absorption and tissue penetration Adults: 5mg/kg (300 mg/daily), mg/kg (900 mg) twice or three times weekly Children: mg/kg daily, mg/kg (900 mg) twice weekly 3

4 INH Hepatotoxicity Asymptomatic elevation of aminotransferases: 20% of patients Clinical hepatitis: 0.6% of patients Fulminant hepatitis (hepatic failure): Approximately 4/100,000 persons completing therapy (continued INH with symptoms of hepatitis, prior INH hepatotoxicity, malnutrition). Isoniazid Hepatotoxicity (AJRCCM, 2006; 174: ) Mechanism Unknown Generally occurs after weeks to months (rather than days to weeks) Risk factors: Age, alcohol consumption (> 4X î risk w/daily ETOH), pregnant and postpartum women, active hepatitis B, other hepatotoxic drugs?non-risk factors: Race, gender, quiescent hepatitis B, hepatitis C, HIV 4

5 Isoniazid Hepatotoxicity: Pretreatment Evaluation (AJRCCM, 2006; 174: ) Standardized history form, including risks for hepatotoxicity Physical examination: liver tenderness, hepatosplenomegaly, jaundice, caput medusa, spider angiomata, ascites, edema Screening for viral hepatitis: IV drug users, patients from endemic areas of the world, household and work contacts, undiagnosed liver disease Treatment of LTBI AJRCCM 2006, 174; 935 Limit dispensed dose to 1 month supply Patients should be categorically told to immediately stop medications (INH) for nausea, vomiting, abdominal discomfort,or unexplained fatigue and to contact the clinic for further evaluation Document, document, document 5

6 Isoniazid Hepatotoxicity: Treatment Choice (AJRCCM, 2006; 174: ) For those with ALT elevation more than 2.5 to 3 times the ULN, chronic alcohol consumption, or severe liver disease manifested by low albumin and coagulopathy or encephalopathy, the risks of LTBI may outweigh benefits. If LTBI is undertaken, close monitoring is indicated. The decision to treat LTBI, or more likely defer, should be carefully made on a case-by-case basis, weighing the risk of progression to TB disease against the risk of INH or rifampinrelated DILI. Treatment of LTBI AJRCCM 2006, 174; 935 Factors influencing the decision to treat LTBI in a patient with elevated ALT Degree of baseline ALT elevation Alcohol consumption Age Evidence of active replication of hepatitis virus Evaluate risk of progression from LTBI to active TB 6

7 Isoniazid Hepatotoxicity: Monitoring (AJRCCM, 2006; 174: ) Face-to-face clinical assessments are the cornerstone of clinical monitoring for treatment adherence and adverse events. Baseline and follow-up serum ALT and bilirubin are recommended for patients with a possible liver disorder; those with a history of chronic liver disease patients with chronic alcohol use, those with HIV infection treated with HAART, pregnant women and those who are up to 3 months post partum. Isoniazid Hepatotoxicity: Monitoring (AJRCCM, 2006; 174: ) Consider baseline testing for patients receiving other medications or for those with chronic medical conditions. Some experts recommend biochemical testing for healthy individuals over the age of 35. ALT is preferred (AST less liver specific) 7

8 Isoniazid Hepatotoxicity: Interventions (AJRCCM, 2006; 174: ) Isoniazid should be withheld if ALT is at least three times the ULN when jaundice and/or hepatitis symptoms are reported, or if ALT is at least five times the ULN in the absence of symptoms A rapid increase in ALT may be an indication for more frequent monitoring Consider rechallenge (many caveats) Treatment of LTBI AJRCCM 2006, 174; 935 If treatment is started (in patients with elevated ALT) some experts recommend measuring serum transaminasess and bilirubin every 2 to 4 weeks for the first 2 to 3 months, and as necessary. The INR may also be followed periodically in patients with severe hepatic impairment. 8

9 Treatment of LTBI AJRCCM 2006, 174; 935 For the few patients who begin INH LTBI treatment with a baseline ALT more than 3 times the ULN< some experts recommend that treatment should be discontinued if there is more than 2 to 3-fold increase above baseline or if there is a mental status change, jaundice, or significant increase in bilirubin or INR. Severe INH Liver Injuries Among Persons Being Treated for LTBI, U.S., MMWR 3/5/10/ 59(08); CDC project to monitor SAEs with treatment of LTBI patients with SAEs, all hepatotoxicity 2 children < 15 yrs of age Adults median age 39 Diagnosed between 2 nd and 9 th month One patient HIV seropositive for Hep C, HIV 5/17 liver transplant (one child), 5/17 died (one transplant) 9

10 Severe INH Liver Injuries Among Persons Being Treated for LTBI, U.S., MMWR 3/5/10/ 59(08); patients with CDC on-site investigation All patients had indications for LTBI treatment, were prescribed INH within recommended dosage range, took the medication as prescribed Prescribers followed ATS/CDC guidelines for monthly clinical monitoring Baseline ALT WNL for 5 patients, 2 patients with monthly ALT monitoring Severe INH Liver Injuries Among Persons Being Treated for LTBI, U.S., MMWR 3/5/10/ 59(08); patients with CDC on-site investigation Symptoms 1-7 months after INH started Fatigue, nausea, abdominal pain in 7 patients who waited for jaundice to seek medical attention 3/10 with possible predispositions 7/10 patients diagnosed by provider other than the prescriber of INH 2 patients INH discontinued within 3 days of symptoms, 8 stopped at least one week after symptom onset, all after medical instruction 10

11 Severe INH Liver Injuries Among Persons Being Treated for LTBI, U.S., MMWR 3/5/10/ 59(08); Death and liver transplantation approximately 1/150,000-1/220,000 patients receiving LTBI treatment All patients monitored according to current guidelines SAEs idiosyncratic reaction, independent of dosing, possible anytime during treatment, can occur in children Severe INH Liver Injuries Among Persons Being Treated for LTBI, U.S., MMWR 3/5/10/ 59(08); Medical providers should emphasize to patients that INH treatment should be stopped immediately upon the earliest onset of symptoms (e.g. excess fatigue, nausea, vomiting, abdominal pain, or jaundice), even before a clinical evaluation has been conducted, and that initial symptoms might be subtle and might not include jaundice. 11

12 INH Toxicity Monitoring The critical element for INH toxicity monitoring is CLINICAL MONITORING. Clinical monitoring of patients on INH is absolutely necessary to do, absolutely necessary to do well and absolutely necessary to document well. LTBI Treatment Acceptance and Completion in the U.S. and Canada Horsburgh et al Chest 2010, 137; 401 Employees at health care clinics more likely to decline therapy Risk factors for failing to complete treatment: 9 month INH regimen Residence in a congregate setting Injection drug use Age 15 years Employment at health care facility Overall, fewer than half of the people starting LTBI therapy completed treatment 12

13 INH Peripheral Neurotoxicity Dose Related Uncommon (< 0.2%) at conventional doses Increased risk with other conditions associated with neuropathy: malnutrition, diabetes, HIV, renal failure, alcohol Retrobulbar (optic) neuritis Pyridoxine 25 mg/kg recommended patients with above conditions INH Toxicity Central Nervous System Effects: irritability, seizures, dysphoria, inability to concentrate Lupus-like syndrome: 20% develop antinuclear antibodies, < 1% develop clinical lupus erythematosis Hypersensitivity Reactions: fever, rash GI reactions (nausea, anorexia, abdominal pain) Drug Interactions: levodopa, phenytoin, valproic acid, carbamazepene 13

14 RIFAMPIN (Rif) (Rifamycins: rifampin, rifabutin, rifapentene) Bacteriocidal (highest sterilizing activity). Activity against rapidly dividing and against semi-dormant bacterial populations. Cornerstone of short course therapy Well absorbed, good tissue levels Adults: 10 mg/kg (600 mg) daily, twice weekly or three times weekly (dosing of rifampin being re-evaluated) Children: mg/kg (600 mg) daily or twice weekly Rifampin Toxicity Cutaneous Reactions: 6%, generally selflimited Orange discoloration of body fluids Gastrointestinal symptoms: nausea, anorexia, abdominal pain Flulike symptoms: < 1% of patients on intermittent therapy. Hepatotoxicity: nearly 0% as monotherapy, 2-3% with INH, cholestatic 14

15 Rifampin Toxicity Severe immunologic reactions: thrombocytopenia, hemolytic anemia, acute renal failure and thrombotic thrombocytopenic purpura (each < 0.1% of patients) Drug interactions due to induction of hepatic microsomal enzymes Rifampin Drug Interactions Interactions due to induction of hepatic microsomal enzymes (cytochrome P-450, CYP, enzyme system) that accelerate metabolism of multiple drugs Major concern is reduction in serum concentrations of common drugs (BCP s, warfarin, etc.) to ineffective levels Bidirectional interactions between rifamycins and antiretroviral agents, INH 15

16 Common Rifampin Drug Interactions HMG-CoA reductase inhibitors Oral anticoagulants Oral contraceptives Cyclosporine/Tacrolimus Digoxin Glucocorticoids Itraconazole/ketoconazole Methadone Phenytoin Theophylline Verapamil/diltiazem Amiodarone Midazolam Thyroid hormone Percentage Reduction in AUC of PI s and NNRTI s by Rifampin (Baciewicz Am J Med Sci 2008; 335: 126) Indinavir 89% Ritonavir 35% Nelfinavir 82% Atazanavir 72% Fosamprenavir 82% Saquinavir 84% Delavirdine 96% Nevirapine 20-58% Efavirenz 25% 16

17 Rifampin Drug Interactions When that patient is placed on rifampin. It is imperative to be aware of all medications a patient is taking (Plavix: go figure) Should Rifampin be used in place of INH for treatment of LTBI? Less hepatotoxicity Improved compliance? Comparable efficacy Not so fast, wait for the next slide New Regimens to Prevent TB in Adults with HIV Infection (Martinson et al, NEJM 2011, 365; 79) HIV seropositive adults with (+) TST Randomly assigned to Rpt + INH weekly for 12 weeks Rmp + INH BIW for 12 weeks INH 300 mg/day or continuous INH Rpt + INH not inferior to 6 mos INH No difference in serious AE s except in continuous INH group 17

18 Latent TB Infection (LTBI) Treatment TBTC Study 26 PREVENT TB Study TBTC Study 26 N= 8,053, 10 years; US, Brazil, and Spain 33wk f/u Randomized 9INH versus 3Rifapentine plus INH (weekly) 3Rifapentine plus INH safe and effective TB dis: 7 cases 3RFP/INH (0.19%) vs 15 cases 9INH (0.43%) Completion: 82% 3RFP/INH versus 69% 9INH (p<0.001) AE: 4.9% vs 3.7% (p=0.009), hepatotoxicity: 0.4% vs 2.7% (p<0.001) Applicable to: Countries with low-to-medium TB incidence Treatment given via DOT (directly observed therapy) NEJM 365: 2155, 2011 Rifapentine Long acting rifamycin that can be used once weekly (600 mg) with INH in the continuation phase of treatment for TB Should not be used: HIV seropositive, cavitary disease, positive sputum smears after the initiation phase of therapy Adverse effects similar to rifampin Investigation underway, a) alternative dosing schedules and b) as an agent for treatment of LTBI (TBTC trials) 18

19 Rifapentine Long ½ life, 12 hours, (+) high plasma binding (+) long post-antibiotic effect = weekly dosing ( mg) Studies underway to evaluate higher doses with more frequent administration Resistance associated with mutations in Rpo-beta gene (as with rifampin) Side effects almost identical to Rmp including body fluid discoloration Flu-like symptoms not as common as with Rmp Rifapentine No activity against MDR TB Drug Interactions essentially identical to Rmp Not useful for most HIV seropositive patients receiving HAART therapy 19

20 Rifabutin A substitute for rifampin for patients who are receiving drugs, especially antiretroviral drugs, that have unacceptable interactions with rifampin. Adverse effects: Less severe induction of hepatic microsomal enzymes, therefore, less effect on the metabolism of other drugs Adult dose 5 mg/kg (300 mg daily, 2-3X/week). Adjust dose with some NNRTI s, PI s Rifabutin Toxicity Hematologic toxicity: neutropenia and thrombocytopenia Drug interactions: less severe than rifampin Uveitis: Rare, < 0.01% GI Symptoms Polyarthralgias: 1-2% at standard doses Pseudojaundice Hepatotoxicity, flu-like syndrome 20

21 PYRAZINAMIDE (PZA) Bacteriostatic/sterilizing agent: Greatest activity against dormant or semi-dormant (slowly growing) organisms within macrophages or caseous foci (acidic envirionment). Necessary for 6 months treatment regimen Adults: mg/kg (2.0 g) daily, 50 mg/kg (4.0 g) twice weekly Children: mg/kg (2.0 g) daily, 50 mg/kg (2.0 g) twice weekly Pyrazinamide (PZA) Toxicity Hepatotoxicity: Less at 25 mg/kg than 50 mg/kg Gastrointestinal symptoms: nausea and vomiting mild at standard doses. Nongouty polyarthralgia: Up to 40% of patients: not an indication to stop therapy. Asymptomatic hyperuricemia: Expected Acute gouty arthritis: Unusual except in patients with pre-existing gout. Rash/dermatitis: usually self limited 21

22 Ethambutol (EMB) Included in first-line treatment regimens to prevent the emergence of Rif resistance when INH resistance may be present. Adults: 15 mg/kg daily, 50 mg/kg twice weekly (max dosage based on wt, AJRCCM, 2003; 167: ) Children: mg/kg daily, 50 mg/kg (2.5 g) twice weekly Ethambutol Toxicity Retrobulbar neuritis: decreased visual acuity or red-green color discrimination, dose related, unusual at dose 15 mg/kg. Increased risk with renal insufficiency. Safe at higher doses given intermittently. Peripheral neuritis Cutaneous reactions: < 1% of patients 22

23 Ethambutol Toxicity: Monitoring All patients should have baseline visual acuity (Snellen chart) and testing of color vision discrimination (Ishihara tests). PATIENT EDUCATION Monthly symptom check (blurred vision scotoma) Monthly testing: high doses, treatment longer than 2 months, renal insufficiency Opthalmology evaluation, no single diagnostic test for ethambutol ocular toxicity Incidence of serious side effects from firstline antituberculosis drugs among patients treated for active TB (Yee, AJRCCM 2003; 167: 1472) 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 IRZ (75% E) 23

24 Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB Yee, AJRCCM 2003; 167: 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 Associated with Female sex, age >60, Birthplace in Asia and HIV status Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active TB (Yee, AJRCCM 2003; 167: 1472) Dose (mg/kg) Rash Hepatitis GI INH (5.2) RIFAMPIN (10.2) PZA (24.2) EMB (16.8)

25 Fluoroquinolones Levofloxacin: mg/day, no data to support intermittent dosing (dosing adjustment in renal insufficiency) Moxifloxacin: 400 mg/day, no data to support intermittent dosing (NO dosage adjustment with renal insufficiency). The FQ s exhibit early bacteriacial activity form days 0-2 slightly less than INH but grater extended EBA (days 2-7) compared with INH 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] >Moxifloxacin > levofloxacin > ofloxacin/ciprofloxacin Cross resistance (?) 25

26 Fluoroquinolone Heptotoxicity Moxifloxacin metabolized in part by the liver, levofloxacin excreted unchanged by the kidneys: no dosage adjustment necessary in renal insufficiency. Reversible transaminase elevation among the fluoroquinolones in 2 to 3% of cases Moxifloxacin: transaminase elevation >1.5 times ULN in 0.9% of cases Levofloxacin: severe hepatotoxicity- RARE Fluoroquinolone Toxicity Musculoskeletal Tendonitis/Tendon Rupture (Black box warning) If tendon inflammation is mild: Rest the joint/nsaid s Reduce dose of FQ if possible If symptoms progress, stop the FQ If tendon inflammation is moderate/severe Stop the FQ Rest the joint/nsaid s Risk/benefit evaluation of FQ continuation Tendon rupture (usually Achilles) is rare 26

27 Fluoroquinolone Toxicity Gastrointestinal disturbance: nausea/bloating 0.5-2% Neurologic effects: dizziness, insomnia, tremulousness, headache 0.5% Cutaneous reactions: rash, pruritis, photosensitivity % Arryhthmias: QT prolongation (congenital, medications, MI) Avoid in pregnancy Fluoroquinolones in the Treatment of TB TBTC Moxifloxacin vs Emb in the initiation phase of therapy: no advantage (AJRCCM 2006, 174: 331) TBTC Moxifloxacin vs INH in the initiation phase of therapy: no advantage (AJRCCM 2009, Apr) Peru Moxifloxacin vs INH in the initiation phase of therapy: improved sputum conversion with moxifloxacin (Lancet, 2009, 373; 1183) 27

28 Fluoroquinolone Caveats and Controversies Fluoroquinolone use for community acquired pneumonia and risk for developing fluoroquinolone resistant TB: Multiple courses of fluoroquinolone Prolonged courses of fluoroquinolone Rifampin effect on fluoroquinolone levels TB Disease: Baseline Testing and Monitoring AJRCCM 2006; 174: Baseline transaminases, bilirubin, alkaline phosphatase, creatinine and platelet count for all adults beginning TB therapy Routine measurements during treatment: baseline abnormalities, chronic alcohol consumption, other hepatotoxic drugs, viral hepatitis or history of liver disease, HIV infection, prior DILI Screen for viral hepatitis in at risk patients Assess the patient prior to each DOT dose and monthly, at a minimum, in a face-to-face encounter with the health care provider 28

29 Hepatotoxicity of TB Drugs Hepatotoxic INH Rifampin/Rifabutin PZA Ethionamide PAS (Fluoroquinolones) Nonhepatotoxic Ethambutol Cycloserine Strep/Amikacin Capreomycin (Fluoroquinolones) Interventions for Hepatotoxicity AJRCCM 2006; 174: Transaminase levels either 3X ULN with symptoms or 5X ULN without symptoms: stop hepatotoxic medications. Obtain serologic tests for viral hepatitis; evaluate biliary disease, use of alcohol, other hepatotoxic drugs Consider liver friendly regimen (EMB, fluoroquinolone, injectable) based on severity of TB, length of therapy interruption, pending medication rechallenge 29

30 Interventions for Hepatotoxicity AJRCCM 2006; 174: After ALT <2X ULN: restart RMP ± EMB After 3-7 days: restart INH If symptoms recur: stop last drug added If RMP and INH tolerated: do not restart PZA Advantage: 2 most potent TB drugs Disadvantages: 9 month regimen, still potentially hepatotoxic Interventions for Hepatotoxicity AJRCCM 2006; 174: After ALT <2X ULN: restart RMP ± EMB After 3-7 days: restart PZA If symptoms recur: stop last drug added If RMP and PZA tolerated: do not restart INH Advantage: 6 month regimen Disadvantage: Still potentially hepatotoxic 30

31 Interventions for Hepatotoxicity AJRCCM 2006; 174: If patient cannot tolerate Rifampin: INH, Emb, PZA, FQ ± injectable-12 months If patient cannot tolerate INH or PZA: Rmp, Emb, FQ ± injectable-9-12 months If patient cannot tolerate Rmp, INH or PZA (no hepatotoxic drugs): liver friendly regimen with EMB, FQ, injectable, other 2 nd line agent-24 months Antituberculous Drugs in Renal Disease AJRCCM 2003, 167; Decreasing the dose of selected antituberculosis drugs may not be the best method of treating tuberculosis because, although toxicity may be avoided, the peak serum concentrations may be too low. Therefore, instead of decreasing the dose of the antituberculosis agent, increasing the dosing interval is recommended. 31

32 Antituberculous Drugs in Renal Disease AJRCCM 2003, 167; Administration of drugs that are cleared by the kidneys to patients having a CC < 30 ml/min and those receiving hemodialysis are managed in the same manner, with an increase in dosing interval. Insufficient data to guide dosing for CC > 30 ml/min: use standard dosing, consider serum concentrations to avoid toxicity Peritoneal dialysis not the same as hemodialysis, requires serum concentration measurements Antituberculous Drugs in Renal Disease INH: No dosage adjustment in patients with renal insufficiency and end stage renal disease (900 mg TIW post hemodialysis). Not affected by hemodialysis. Rifampin/Rifabutin: No dosage adjustment in patients with renal insufficiency and end stage renal disease (rifampin, 600 mg TIW post hemodialysis). Not affected by hemodialysis 32

33 Antituberculous Drugs in Renal Disease PZA: Cleared primarily by the liver, but metabolites excreted in urine so that some dosage reduction necessary with renal insufficiency, risk of hyperuricemia also increased with renal impairment mg/kg with cc < 30 ml/min mg/kg TIW post hemodialysis, PZA significantly affected by hemodialysis Antituberculous Drugs in Renal Disease Ethambutol: cleared by the kidneys, significant dose reduction with renal insufficiency and end stage renal disease. Dose or dosing interval should be adjusted with cc < 70 ml/min 15 mg/kg q 48h with cc < 10 ml/min mg/kg TIW post hemodialysis Serum concentrations useful Well documented ocular toxicity monitoring 33

34 Antituberculous Drugs in Renal Disease Streptomycin: Excreted almost exclusively by the kidney, renal impairment increases toxicity risk. Affected by hemodialysis CC < 30 ml/min: mg/kg 2-3X per week Hemodialysis, mg/kg/2-3x per week Antituberculous Drugs in Renal Disease AJRCCM 2003, 167; It is important to monitor serum drug concentreations in persons with renal insufficiency who are taking cycloserine, ethambutol, or any of the injectable agents to minimize doserelated toxicity, while providing effective doses. 34

35 Antituberculosis Drugs in Pregnancy INH: Approved, risk of hepatitis increased in peripartum period. Biochemical monitoring indicated Rifampin: Approved Ethambutol: Approved PZA: Controversial, FDA vs WHO and IUTLD, ATS Antituberculous Drugs in Pregnancy Used with caution: rifabutin, cycloserine, para-aminosalicylic acid Contraindicated: ethionamide, amikacin, streptomycin, kanamycin, capreomycin, quinolones Unknown: rifapentine 35

36 Antituberculosis Drugs for TB Meningitis INH: Excellent CSF penetration, CSF concentrations similar to serum PZA: Excellent CSF penetration, CSF concentrations similar to serum Rif: Concentrations in CSF 10-20% serum concentrations, increased with inflammation, adequate for efficacy Antituberculosis Drugs for TB Meningitis EMB: Penetrates inflamed meninges, role in TB meningitis therapy not established Cycloserine: Excellent CSF penetration, CSF concentrations similar to serum Ethionamide: Excellent CSF penetration, CSF concentrations similar to serum Streptomycin: Slight penetration of inflamed meninges 36

37 Antituberculosis Drugs for TB Meningitis Capreomycin: Does not penetrate inflamed CSF PAS: 10-50% serum concentration in CSF with inflamed meninges, marginal efficacy Levofloxacin: CSF concentrations 16-20% serum concentrations Linezolid: Good CSF concentration Adverse Drug Events Immune Reactions Urticaria/Hives Hold medications until reaction resolves If no evidence of anaphylaxis, angioedema, airway compromise, may elect to attempt a drug rechallenge or desensitization under controlled conditions Severe Drug Reactions Generalized rashes associated with fever, other systemic symptoms, mucous membrane involvement are characteristic of Stevens-Johnson Syndrome Do not attempt to rechallenge or desensitize patient to the drugs Petechial rash May be a sign of a rifampin hypersensitivity reaction and thrombocytopenia 37

38 Oral Desentization to Rif and EMB in Mycobacterial Disease (Matz, AJRCCM, 1994;149:815) Patients with hypersensitivity reaction to either rifampin or ethambutol Not for patients with: hepatitis, hemolytic anemia, purpura, nephiritis, ocular toxicity, anaphylaxis, hypotension, bronchospasm, laryngeal angioedema INH: Chest, 1990; 98:

39 Adverse Drug Events Neurotoxicity Peripheral neuropathy Drugs: INH, EMB, (ethionamide, cycloserine) More common in patients with Diabetes Alcoholism HIV infection Hypothyroidism Pregnancy Inadequate dietary intake of pyridoxine (Vitamin B6) Usually symmetrical 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 Adverse Drug Events Nephrotoxicity Drugs: aminoglycosides, capreomycin Baseline serum creatinine 24-hour creatinine clearance if baseline serum creatinine abnormal Lower initial dose in patients over age 59 yrs. (10 mg. per kg.; max. dose 750 mg.) If baseline creatinine clearance less than 70ml./min., consider use of intermittent dosing initially Monitor peak and trough serum drug levels and adjust dose accordingly 39

40 Adverse Drug Events GI upset: PZA, rifabutin, fluoroquinolones, ethionamide, PAS, (any drug) Central Nervous System: INH, fluoroquinolones, amikacin, ethionamide, cycloserine Musculoskeletal: PZA, fluoroquinolones, rifabutin Drugs best taken on an empty stomach Rifampin: Absorption 26% by food INH: Absorption 57% by food ( esp CHO) Avoid liquids with abundant glucose/lactose Avoid foods with abundant tyramine or ETOH Cycolserine: Food Cmax 30%, Tmax 3X Orange juice Cmax 15% If possible administer with water and between meals Fluoroquinolones: Avoid Al and Mg antacids 40

41 Drugs best taken with food Rifapentine: Fatty meal enhance absorption PAS: Fatty food enhances absorption Orange juice and antacids had minor effects Acidic drinks or yoghurt prevent release in stomach, reducing the incidence of nausea Clofazimine: fatty food increased Cmax QT interval prolongation Flouroquinolones Moxifloxacin>levofloxacin>ofloxacin>cipro floxacin Bedaquiline Degree of risk not determined with recent studies Risk of torsades de pointes unknown (?small) Optimal screening and monitoring unknown 41