結核病常見醫療處方疑義案例處理之藝術與醫藥倫理 (ii) - cdc · 2013-08-16 ·...

結核病常見醫療處方疑義案例處理之藝術與醫藥倫理 (II)

主講者: 李欣蓉醫師

高雄榮民總醫院感染科

時間：102年7月27日(星期六)4:00-4:50

地點：高雄市聯合醫院美術館院區4樓大禮堂

102年「結核病醫療處方研習會」課程表

演講大綱

(一) 抗結核藥物治療時程和常見副作用案例前兩個月(intensive phase)– 第一週– 第二至四週– 第二個月第三至六個月(continuation phase)

(二) 結核病/愛滋病共同感染藥物交互作用抗愛滋藥物使用時機IRIS (Immune reconstitution inflammatory

syndrome)

行政院衛生署疾病管制局結核病診治指引第五版第五章治療期間之監測與副作用之處理

Anti-TB drugs use & Monitoring Baseline:– HBsAg, anti-HCV Ab, HIV,– GOT, GPT, T.Bil, Cr, CBC, Glu, HbA1c

Follow-up: at least 2, 4, 8 weeks– GOT, GPT, T.Bil, Cr, CBC, UA– Underlying chronic hepatitis B or C, LFT impaired

(cirrhosis, alcoholism), IDU, HIV-infected: Follow GOT, GPT, T.bil monthly or more frequent

– Color discrimination test (EMB)– Hearing test (Streptomycin, kanamycin)– Symptoms: blurred vision, numbness, pruritis, skin

rash, nausea/vomiting, arthralgia

Taiwan Guidelines for TB Diagnosis & Treatment 2013, 5th edition衛生福利部疾管屬結核病診治指引第五版

案例(一): 第一週 nausea/vomiting

55 y/o woman B.W.: 57kgDM+ Cr 0.8 mg/dLDx: Pulmonary TB, smear+Tx: Rifater 5# + EMB 3# qdDay 2: severe nausea/vomiting

註一: Rifater (RFT) = INH 80mg + RIF 120mg + PZA 250mgRFT 5# = INH 400mg /RIF 600mg /PZA 1250mg

INH4# + RIF 2# + PZA 2.5#註二: EMB: Ethambutol 3# = 1200mg

案例(一): 第一週 nausea/vomiting

GOT 25, GPT 13, T.Bil 0.8嘗試飯後服用

分開服用，同種藥品同時使用

– 早餐: RIF600mg– 中餐: EMB 1200mg– 晚餐: INH 300mg + PZA 1500mg觀察嘔吐症狀時間，主要為中午 (EMB)處置: 停用EMB，HRZ 治療六個月

案例(一): 第一週 nausea/vomitingNausea/vomiting

Mild,tolerable Severe, intolerable

1. Primperan2. pc dosing 3.Separate drugsnot dosing4. Observation

1. Separate drugs to different timing to determine AE drug 2. Discontinue drug causing AE3. Adjust optimal remaining regimen

Check liver function (GOT,GPT, Tbil)

案例(一): 第一週嘔吐處理

Step 1: check GOT/GPT normalStep 2: if symptoms mild separate drugs not dosesStep 3: if symptoms severe separate drugs, determine drug causing AE, discontinue drug & adjust regimen as appropriate

案例(二): 第一週 pruritis

65 y/o man B.W.: 60kgHTN, BPH Cr 1.2 mg/dLDx: Pulmonary TB, smear+Tx: Rifater 5# + EMB 3# qdDay 5: pruritis



案例(二): 第一週 pruritis

P.E. No skin rashMx: add antihistamines, observation for tolerance and progressionP: continue RFT/EMB

案例(二): 第一週 pruritisPruritis

P.E. for skin rash

No skin rash Skin rash present

AntihistaminesObservation

Evaluate as skin rash protocol

案例(三): 第二週 skin rash

68 y/o man B.W.: 75 kgHTN, DM, old CVA Cr 1.1 mg/dLDx: Pulmonary TB, smear+Tx: Rifater 5# + EMB 3# qdDay 12: pruritis with skin rash



案例(三): 第二週 skin rash

No diarrheaP.E. no oral mucositisSevere diffuse skin rash trunk & limbsMx: Discontinue all anti-TB drugsF/U in 1-2 weeksRechallenge

Protocol for Rechallenge after skin rash


1) INH ok RIF okHRE 9M (not +PZA)2) INH x RIF ok PZA okRZE 6-9M3) INH ok RIF x PZA okHZE 18M

INH (100mg) 0.5#INH (100mg) 1#INH (100mg) 3#RIF (300mg) 1#RIF (450mg) 1#RIF (300mg) 2#EMB (400mg) 0.5#EMB (400mg) 1#EMB (400mg) 3#PZA (500mg) 0.5#PZA (500mg) 1#PZA (500mg) 3#

抗藥病人副作用病人：傳統藥敏結果還不知道

副作用病人：已知傳統藥敏結果

INH RMP + PZA + EMB ±INH 6-9個月，或INH + RMP + PZA + EMB 2個月／INH + RMP + EMB 7個月

RMP + PZA + EMB 9個月

RMP + PZA + EMB 6-9個月

RMP INH + PZA + EMB 18個月

INH + PZA + EMB + SM 至少2個月且痰陰轉／INH + PZA + EMB 到痰培養陰轉滿18個月

INH + PZA + EMB 18個月

EMB INH + RMP + PZA 2個月／INH + RMP 4個月

INH + RMP + PZA 6個月

INH + RMP + PZA 2個月／INH + RMP 4個月

PZA INH + RMP 9個月 INH + RMP + EMB 9個月

INH + RMP 9個月

行政院衛生署疾病管制局結核病診治指引第五版

案例(三): 第二週 skin rashSkin rash

P.E. oral mucosa

Mild skin rash Severe/progressiveskin rash

AntihistaminesObservation

Discontinue until improved

Steven-Johnsonsyndrome

Discontinue

2nd line anti-TBdrugs

Rechallenge

案例(四): 第2-4週hepatitis

45 y/o woman B.W.: 53 kgDenied past illnesses Cr 1.06 mg/dLDx: TB lymphadenitis, Rt, culture+Tx: HERZ 2013/6/25Baseline GOT/GPT (6/3): 19/18, Tbil 0.4At 2 weeks (7/9): 31/24At 4 weeks (7/23): - /57, mild fatigue

PLAN: F/U in 1 week

案例(五): 第2-4週hepatitis58 y/o man B.W.: 57 kgCough 6M, BW loss Cr 1.06 mg/dLDenied past illnessesDx: Pulmonary TB, culture+, All susceptibleTx: RFT/EMB 2013/6/11Baseline GPT (6/12): 1335 (6/19, D8)- 82 (6/30,D18)-106 (7/3, D21)-79(7/5, D23) -73(7/10, D29)-100(7/19, D38) DC HRZMx: switch Moxi/EMB 7/19, apply 2nd lineLevofloxacin/EMB/cycloserine 7/23F/U liver enzymesRechallenge when

案例(五): 第2‐4週hepatitisHepatitisGPT= 5 x 正常值或T.bil>3不論有無症狀

治療前肝功能不正常者GPT>= 2 x 正常值

Taiwan Guidelines for TB Diagnosis & Treatment 2013, 5th edition衛生福利部疾管屬結核病診治指引第五版

Protocol for Rechallenge for hepatitis


Day 1: INH 1#Day 2: INH 2#Day 3-7: INH 3#F/U liver function on day 3 & 7

Day 1: RIF(300mg) 1#Day 2: RIF (450mg) 1#Day 3-7: RIF(300mg)2#F/U liver function on day 3 & 7

Day 1: PZA 1#Day 2: PZA 2#Day 3-7: PZA 3#F/U liver function on day 3 & 7

案例(六): 第2-4週hepatitis36 y/o woman B.W.: 50 kgHepatitis B carrier Cr 1.06 mg/dLDx: TB lymphadenitis, Rt, TB, culture+, All susceptibleTx: RFT/EMB 2013/4/17Baseline GPT (4/17): 28GPT 32(4/30) -31(5/14) -44(5/28) -63(6/11) –121 (6/24,>2M), T.Bil 0.6, fatigue, DC all, GPT 46(7/9)Mx: 1) Refer GI, check HBV viral load (pending)

2) Rechallenge H/E (7/9)- GPT 37(7/12), 26 (7/16)HE + R (7/16) GPT 26 (7/19), 21 (7/23)

3) PLAN: HR x total 6M (do NOT rechallenge PZA)

案例(七): 第2月69 y/o man B.W. 45kg, Cr: 4.0 mgl/dLReferred from CM service due to myalgia/poor appetite & rechallenge difficultiesESRD on HD, severe MR s/p CABG, MVADx: TB pleurisy, Rt, all susceptibleTx: HERZ 停用RIF(全身痠痛) HEZ(視力模糊) 停用EMB +HZ/RFB (持續視力模糊) 全部停用改二線藥Levo/CS/TBN (視力模糊 DC)Levo/CS/SM(頭暈) L/C/PAS(腸胃不適)L/C/RFB(視力模糊) L/C/PZA + clofazimine(視力模糊)Final regimen: PZA/Levo/Cycloserine 18M

Leiboid JE. The ocular toxicity of ethambutol and its relation to dose. Ann NY Acad Sci 1966;135:904-9.

Dose related: 15mg/kg: Risk < 1%25mg/kg: Risk 5%30mg/kg: Risk 18%

Dose-related Ocular toxicity of EMB

Ophthalmic toxicity (Retrobulbar neuritis)

Ethambutol is the most common– Dose related: Risk < 1%, 15mg/kg– 25mg/kg: Risk 5%– 30mg/kg: Risk 18%

Isoniazid (INH), Ethionamide (TBN), rifabutin, clofazimine, linezolid are rare causes of optic neuritisSymptoms: blurred vision, central scotoma, green-red color blindnessPotentially reversible if discontinue drug immediately

Ethambutol is toxic to retinal ganglion cell via an excitotoxic pathway

Visual loss with may be mediated through an excitotoxic pathwayEthambutol perturbs mitochodrial function ,decreased ATPase activity and mitochondrial energy homeostasisGanglion cells sensitive to normally tolerated levels of extracellular glutamateGluctamate antagonists may be useful in limiting side effect of ethambutolEthambutol toxicity is more pronounced in depressed serum zinc levels

(Invest Ophthahnol Vis Sci. 1999;40:190-196)

Optic neuritis

Blurred vision

Dyschromatopsia

Refer to Ophthalmologist to test for optic neuritis

Discontinue immediately

Not favored: Re‐evaluate if EMB is necessaryAdjust regimen

Monthly testingRed‐Green colorDiscrimination test

Optic neuritis likely: EMB contraindicated HRZ2/HR4 or HRZ6

案例(八)

66 y/o man B.W.: 48 kg, Cr 3.2 mg/dLReferred from CM service due to numbness of both lower legs up to kneeDx: Pulmonary TB, all-susceptibleTx: HERZ with EMB 3# qd

DC EMB, add pyridoxine

案例(九)

70 y/o woman B.W.: 48 kg, Cr 1.1 mg/dLDx: TB pericarditis, culture+, all susceptibleWBC drop to 2100 DC RifampinHEZ 18M

Agranulocytosis & hemolytic anemia

Rifabutin and Rifampin Rarely, INHHemolytic anemia: EMB & PZAMx: discontinue if severe, and rechallenge after recovery (INH EMB PZA)

案例(十)22 y/o man, MSMAdmitted for fever, cough, BW lossDx: 1) pulmonary TB, smear +2) Just diagnosed with HIV/AIDS (CD4: 98)PLAN: Start HERZ

Important issues:1) Timing of ART?2) Choice of ART (drug-drug interactions)3) Choice of anti-TB drugs and duration of tx4) IRIS

(1) When to start ARV?Treat TB first (AI)ART is recommended in all HIV-infected persons with TB (AI). For ART-naive patients, ART should be started within 2 weeks when the CD4 count is

CAMELIA study: Earlier Start of ART in HIV/TB coinfected patients (n=661)

Blanc FX. NEJM 2011 Oct 20; 365: 1471-1481. CAMELIA study.

Optimal Timing of ART in HIV/TB co-infection

SAPIT trial (South Africa): 642 adults, CD4

TB/HIV co-infection: Treatment

Sequential treatment of TB followed by HIV is not recommendedCo-treatment of TB/HIV is complex due to adherence demands, drug-drug interactions, overlapping side effects and IRIS, but improves survival

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 2013/7/8

(2) What ARV to start with?The preferred co-treatment regimen for HIV-related TB disease is rifampin-based TB therapy with an ARV regimen of efavirenz plus two nucleoside(tide) analogues (AII). For patients who have HIV strains resistant to NNRTIs or are unable to tolerate efavirenz and nevirapine, the preferred co-treatment regimen is rifabutin-based TB therapy with an ARV regimen that includes a ritonavir-boosted protease inhibitor (PI) (BIII). Pending additional data, we recommend a dosage of 150 mg of rifabutin daily (at least during the first 2 months of TB treatment) for patients who are on a PI-containing ARV regimen (BIII). Given the excellent treatment outcomes of co-treatment with standard-dose efavirenz 600-mg daily dose is recommended (BII).


TB/HIV: Drug-drug interactions

Rifampin Effect on ARV Recommendations

PI ↓ all PI AUC around 75% contraindicated

EFV AUC ↓ 26% EFV 600mg/day; may 800mg/day if BW >80kg

NVP AUC ↓ >50% Do not co-administer

Rifampin: strong CYP inducer

Rifabutin: usual dose 300mg qd; metabolite active; CYP3A substrate and inducer; neutropenia or uveitis ↑ when dose ↑

PI: CYP450 inhibitor RFB 2-4x increase

Rifabutin Effect on rifabutin Recommendations

PI AUC (incl. metabolite) ↑ around 4 times

Rifabutin 150mg qod or 3 times/wk, rifamycin resistance reported

EFV AUC ↓ 38% Rifabutin 450mg qd or 600mg 3 times/wk

NVP AUC ↓ >50% Do not co-administer

CID 2009;48:1752‐9 CID 2009;49:1305‐11

Choice of ARV

2NNRTI: TFV/3TC, ABC/3TC(Kivexa), or AZT/3TC (Combivir) + EFV 600mg QN+ NVP (RIF dec NVP conc 40-50%)?Monitor HIV viral load at 1M (< 1 log reduction)

& 6M (undetectable)2NNRTI: + boosted PI switch RIF to rifabutin

台灣結核診治指引第五版

TB/HIV: Treatment regimen

Treatment of suspected TB in HIV-infected individuals is the same as for those who are HIV uninfected and should include an initial four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (AI).An expanded initial regimen—including at least moxifloxacin or levofloxacin and an aminoglycoside or capreomycin—should be used if there is a significant concern about resistance to rifampin, with or without resistance to other drugs (BIII).


TB/HIV: Treatment Duration

Pending the outcome of further studies, 6 months of therapy for most patients with HIV-related, drug susceptible TB disease is recommended (BII). Extension of therapy to 9 months is recommended for those with a positive 2-month sputum culture (BII). Extension of therapy to 9 to 12 months is also recommended – for patients with CNS involvement (BII).

Treatment for 6 to 9 months is recommended for – patients with bone and joint TB (BII).


Steroid use in HIV/TB co-infectionAdjunctive corticosteroid therapy increases survival for patients with HIV-related TB involving the CNS and pericardium (AI). No trials to date have compared different doses and treatment durations of adjunctive corticosteroids. Dexamethasone was used in trials of adjunctive corticosteroids for CNS disease – 0.3–0.4 mg/kg/day for 2–4 weeks, – then taper 0.1 mg/kg per week until dose of 0.1 mg/kg, – then 4 mg per day and – taper by 1 mg/week; total duration of 12 weeks);

prednisone or prednisolone was used in trials of pericardial disease (60 g/day and taper 10 mg per week; total duration of 6 weeks).


案例(十)

22 y/o man, MSMAdmitted for fever, cough, BW lossDx: 1) pulmonary TB, smear +2) Just diagnosed with HIV/AIDS (CD4: 98)PLAN: Start HERZ 4 wks+ Combivir/EFV x 2wksIncreasing dyspnea, then fever

Paradoxical TB-IRISRisk factors for paradoxical TB-IRIS are– low CD4 cell count at start of ART (especially CD4 cell counts

Paradoxical TB-IRISParadoxical TB-IRIS (8%–43%) ,– Incidence of IRIS of 15.7%– A case fatality rate of 3.2%.– Onset typically occurs 1 to 4 weeks after ART

is initiated, – the syndrome lasts for 2 to 3 month, but

some patients have symptoms for months and,– in rare cases, local manifestations may persist

or recur more than a year after onset.

Muller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. Apr 2010;10(4):251-261.

Management of IRISClinicians should initiate symptomatic treatment and supportive care for patients with IRIS. In severe cases, clinicians should consider prescribing prednisone 1-2 mg/kg or equivalent for 1-2 weeks, followed by a taper. (AIII)Clinicians should closely monitor patients receiving corticosteroids for the development of opportunistic infections, including CMV retinitis and TB disease. (AIII) Except in severe cases, ARV therapy should not be interrupted in patients with IRIS. (AIII)

案例(十)

22 y/o man, MSMAdmitted for fever, cough, BW lossDx: 1) pulmonary TB, smear +2) Just diagnosed with HIV/AIDS (CD4: 98)PLAN: Start HERZ 4 wks+ Combivir/EFV x 2wksIncreasing dyspnea, then fever Add hydrocortisone 100mg iva q6h, tapering over 2 weeks.

行政院衛生署疾病管制局結核病診治指引第五版http://www.cdc.gov.tw/professional/info.aspx?treeid=BEAC9C103DF952C4&nowtreeid=6744C19C09435458&tid=E36C

98D85972C6AA

Protease-inhibitor regimensRIFAMPIN RIFABUTIN

Dose change HAART Rifampin HAART RifabutinSingle PIRitonavir (RTV) None None None 300mg qod/tiwAtazanavir Do not use with RIF None 300mg qod/tiwIndinavir Do not use with RIF 1000mg q8h 150mg qdNelfinavir Do not use with RIF 1000mg q8h orAmprenavir Do not use with RIF None 300mg tiwFos-amprenavir Do not use with RIF NoneSaquinavir (SQV) Do not use with RIF Do not use with rifabutinDouble PIKaletra* Do not use with RIF 300mg qod/tiw

RTV dose NoneSQV/RTV400mg/400mg bid None 300mg qod/tiw

DHHS guideline 2012

* Kaletra = Lopinavir/Ritonavir

NNRTIs-containing regimensRIFAMPIN RIFABUTIN

Dose change HAART Rifampin HAART Rifabutin

Efavirenz 800/600mg/day None None 450mg qd orNone 600mg tiw

Nevirapine 200mg bid None None 300mg qd or tiw

Delaviridine Do not use with RIF Do not use with rifabutin

Updated Guidelines for the Use of Rifamycins for the Treatment of Tuberculosis Among HIV-Infected Patients Taking PIs or NRTIs. (www.cdc.gov)Updated January 20, 2004

NNRTIs: non-nucleoside reverse transcriptase inhibitorDaily rifampicin should not used with nevirapine (BHIVA treatment guideline 2005)

案例(七)69 y/o man B.W. 45kgReferred from CM due to blurred visionESRD on HD, severe MR s/p CABG, MVATB pleurisy, Rt, s/p HERZ 2011/7/26

2011/7/26 HERZ2011/9/6 (6wks) 因為myalgia, poor appetite自行停用2011/9/6 Rechallenge +INH 2011/9/15 H+RIF 因為全身酸痛和poor appetite自行停用 RIF2011/9/20 H+EMB2011/10/4 +PZA(10/4-10/25, 21days)2011/10/25 HZE 2012/1/5 雙腳麻2012/1/13 blurred vision (EMB) 停用所有藥物五天2012/1/18 H/Z2012/2/22 H/Z + Rifabutin2012/2/29 blurred vision (RFB) 停用所有藥物五天2012/4/18 PZA/Levo2012/4/25 PZA/Levo + TBN2012/5/16 blurred vision progression DC TBN, PZA/Levo/CS + SM/PAS2012/5/23 GI upset DC PAS, hearing loss DC SM2012/7/3 blurred vision progression DC clofazimine 2012/5/30 PZA/ Levofloxacin/cycloserine Treat 18M until 2013/11/30

結核病常見醫療處方疑義案例 處理之藝術與醫藥倫理 (ii) - cdc · 2013-08-16 ·...

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結核病常見醫療處方疑義案例處理之藝術與醫藥倫理 (ii) - cdc · 2013-08-16 ·...