TB Grand Rounds. MDR-TB: Management of Adverse Drug Reactions. Reynard J. McDonald, M.D. September 18, Patient History

Transcription

1 TB Grand Rounds MDR-TB: Management of Adverse Drug Reactions Reynard J. McDonald, M.D. September 18, 2007 Patient History This 30 y/o H/M was born in Ecuador and immigrated to the US in 2001 On he was admitted to a local hospital with complaints of night sweats, a 6-week history of productive cough, 10 lb. weight loss, fatigue, and hemoptysis 1

2 Past Medical History Approximately 8 years prior to admission, the patient s father was diagnosed and treated for TB in Ecuador The patient s TST was negative then and on repeat testing on 11/26/05 was also read as negative (0 mm) The patient had no other significant past medical history Social History The patient is employed as a construction worker He lives with his girlfriend (20 y/o) and her two children (ages 1 and 3) and his two cousins (ages 38 and 41) He denies tobacco use and is a social user of alcohol 2

3 Hospital Course HIV serology was negative 12/21/05 CXR revealed bilateral upper lobe reticular nodular infiltrates greater on the left with a 3 cm cavity Sputum specimens (x3) were positive for AFB on smear and were identified as M. tb on PCR testing He was diagnosed with pulmonary tuberculosis and started on DOT with RIPE and was discharged on 12/19/05 Initial Management Initial treatment of patient: DOT with RIF, INH, PZA, & EMB Cultures subsequently grew M. tb Awaiting results of drug susceptibility testing 3

4 Hospital Course Approximately 1 week after starting RIPE, INH was discontinued because hepatic transaminases were elevated Hepatic transaminases serum levels: AST (0-40 u/l) ALT (0-35 u/l) Treatment started RIPE INH stopped; RIF, PZA & EMB continued Hepatotoxicity of Anti-TB Therapy Drug induced hepatitis is defined as a serum AST level >3x the upper limits of normal (ULN) in the presence of symptoms or >5x ULN in the absence of symptoms Mild toxicity AST level <5x ULN Moderate toxicity AST level 5 10x ULN Severe toxicity AST level >10x ULN ATS, CDC, & IDSA. Treatment of Tuberculosis. MMWR 2003;52(No. RR-11):

5 Hepatotoxicity of Anti-TB Therapy An increase in ALT is more specific for hepatocellular injury than an increase in AST An increase in AST may also signify an abnormality in muscle, heart or kidney ATS. Amer J Respir Crit Care Med. 2006; 174: Steps in RECHALLENGE STOP III Restart RIF + EMB or RIF alone V Restart INH Repeat ALT I IV VI ALT II Normal <2x ULN Abnormal 3-7 days Repeat ALT If symptoms recur or ALT increases stop last drug added 5

6 Drug Susceptibility (Commercial Lab) Specimen collected: 11/24/05 ID: M. tb Sensitive Pyrazinamide (100 mcg/ml) Ethambutol (2.5 mcg/ml) Resistant Isoniazid (0.1 mcg/ml) Rifampin (2.0 mcg/ml) Streptomycin (2.0 mcg/ml) Drug Susceptibility (National Reference Laboratory) Specimen collected: 12/27/05 Sensitive EMB (7.5 mcg/ml) ETA (10 mcg/ml) CM (10 mcg/ml) KM (6 mcg/ml) AK (6 mcg/ml) CS (60 mcg/ml) PAS (8 mcg/ml) LFX (2 mcg/ml) MFX (0.5 mcg/ml) GFX (0.5 mcg/ml) Clarithromycin (4 mcg/ml) Linezolid (4 mcg/ml) ID: M. tb Resistant INH (0.2mcg/ml, 1.0 mcg/ml) RIF (1.0 mcg/ml) SM (2.0 mcg/ml, 4.0 mcg/ml) 6

7 Treatment Course On : Stopped: RIF 600 mg/d PO Continued: PZA 1500 mg/d PO EMB 1200 mg/d PO Vit B mg/d PO Added: MFX 400 mg/d PO CS 1000 mg/d PO CM 1 gm 5 x/wk PAS 12gm (4gm AM, 8 gm PM) Monthly MD visits Routine Monitoring Monitoring of sputum smears and cultures for M.tb Radiographic imaging Monitor for general toxicities and drug-specific toxicities 7

8 Laboratory Monitoring The patient was monitored for hepatic toxicity, serum uric acid levels, TSH and renal functions TSH ( uu/ml) Uric Acid ( mg/dl) Visual acuity and color vision were also monitored Cyclic polypeptide Capreomycin (CM) Bactericidal and has no cross-resistance with the aminoglycosides Dose Adults: 15mg/kg/d, 5-7 days/wk (max 1 gram) Elderly: 15mg/kg/d, 5-7 days/wk (max 750 mg) Renal failure/dialysis: 12-15mg/kg/dose, 2-3x/wk (not daily) Can be administered IV or IM 8

9 Capreomycin Cont d Adverse reactions are similar to the aminoglycosides Nephrotoxicity Ototoxicity occurs more often in elderly and those with preexisting renal impairment; vestibular toxicity Local pain with IM injections Electrolyte abnormalities Liver function test abnormalities when used with other TB drugs Monitoring Baseline and monthly auditory and renal function as well as serum K+ and Mg++ levels Clinical Course on CM Patient had high frequency hearing loss prior to starting treatment with CM Monthly audiometry while receiving CM revealed no signs of worsening Audiometry High frequency hearing loss but stable The patient refused placement of a PICC line or Mediport for CM administration and opted for IM injections After approximately 4 months, he increasingly complained of pain and swelling at the injection sites 9

10 Treatment Course On : Stopped: CM 1 gm 5 x/wk IM Continued: PZA 1500 mg/d PO EMB 1200 mg/d PO MFX 400 mg/d PO CS 500 mg/d PO PAS 8gm/d PO Vit B mg/d PO Bacteriostatic Cycloserine (CS) Dose Adult: mg/kg/d; usually 250 mg PO 2x/day or can increase to mg QD or divided BID Vitamin B6: All patients should receive vitamin B6 ( mg/d) while taking CS Renal failure/dialysis: 500 mg/dose 3x/wk 10

11 Cycloserine Cont d Adverse reactions CNS toxicity, including inability to concentrate and lethargy More serious CNS side effects, including seizure, depression, psychosis, and suicidal ideation, usually occur at peak levels >35 mcg/ml, but may be seen in the normal therapeutic range Monitoring Peak levels within first 1-2 wks of therapy and serially during therapy Neuropsychiatric status assessed monthly Note: anti-depressants may alleviate depression symptoms Clinical Course on CS Serum CS levels were monitored CS (8-20 mcg/ml) The patient experienced mild depression while taking CS CS was first reduced to 500 mg/d with serum level of 20.6 mcg/ml ( mcg/ml) before stopping the drug completely 11

12 Treatment Course On : Stopped: CS 500 mg/d PO Continued: PZA 1500 mg/d PO EMB 1200 mg/d PO MFX 400 mg/d PO PAS 8 gm/d PO Para-Aminosalicylate (PAS) Bacteriostatic Dose Adults: 8-12 gm/d in 2-3 doses Renal failure/dialysis: no change Adverse reactions Gastrointestinal distress (less with Paser formulation than with older preparations) Rare hepatotoxicity and coagulopathy Reversible hypothyroidism treat with thyroid replacement Monitoring TSH, electrolytes, blood counts, and liver function tests 12

13 Clinical Course on PAS Patient experienced significant nausea/vomiting and abdominal discomfort and diarrhea and improved with treatment with antacids and antidiarrheal medications initially Eventually, the dose was lowered from 12gm/d to 8gm/d before stopping the PAS after approximately 16 months of treatment Fluoroquinolone Moxifloxacin (MFX) Bactericidal; cross resistance with other fluoroquinolones Dose Adults: 400 mg daily Renal failure/dialysis: no dose adjustment required Can be administered PO or IV 13

14 Moxifloxacin (MFX) Adverse reactions Nausea and diarrhea Headache and dizziness Rare tendon rupture; arthralgias Rare hepatotoxicity Monitoring Symptomatic monitoring Bacteriology Date Smear Culture M.tb M.tb Neg. Neg. M.tb Neg. Neg. Drug Susceptibility Test S:PZA,EMB;R:RIF,INH,SM S:PZA,EMB;R:RIF,INH,SM Patient has remained smear and culture negative for M.tb since

15 Chest X-Rays 7/3/06 7/9/07 Drug-O-Gram 15

16 Step 1 Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities Use any available First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin Kanamycin Step 1 Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities Use any available First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS 16

17 Step 1 Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities Use any available First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Adapted from Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, available from Francis J. Curry National Tuberculosis Center Step 3 If there are not 4-6 drugs available consider 3 rd line in consult with MDRTB experts Consider use of these Third line drugs Imipenem Linezolid Macrolides Amoxicillin/Clavulanate Management of Contacts Adult contacts of MDR-TB: Immunocompromised contacts: PZA + EMB or PZA + FQN for 6-12 months Immunocompetent contacts: Observed w/o treatment or treat for at least 6 months Child contacts of MDR-TB: EMB + PZA for 9-12 months Long-term use of fluoroquinolones should be avoided in children All persons with suspected MDR LTBI should be monitored for 2 yrs regardless of treatment regimen Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection MMWR 2000; 49 (No. RR-6) 17

18 Evaluation of Contacts Assess the risk of the contacts Administer tuberculin skin test for contacts Adults: TST positive Children: TST negative x2 Chest x-rays Negative for all contacts Treatment Adults: observed Children: INH x12 weeks; discontinued when repeat TST remained negative Questions? 18