簡歷 現任

2005/5 - 社團法人中華民國防癆協會第一胸腔病防治所所長 2006/1- 行政院衛生署傳染病防治諮詢委員會結核病防治組召集人 2002- 中華民國職業病醫學會理事 1994- 台灣結核病醫學會理事

曾任 2002/7 – 2005/3 行政院衛生署桃園醫院內科師一級主治醫師 2002/2 – 2002/7 行政院衛生署胸腔病院代理院長 2001/8 – 2002/1 行政院衛生署慢性病防治局代理局長 1999/7 – 2001/8 行政院衛生署慢性病防治局副局長 1997/1 – 1999/6 台北縣慢性病防治所醫師 1989/3 – 1997/1 台灣省慢性病防治局技正兼主任 1984/4 – 1989/3 台灣省防癆局技正兼主任 1983/7 – 1984/4 台灣省防癆局主治醫師 1979/7 – 1983/7 台灣省防癆局住院醫師及總住院醫師

索任

1979 台灣大學醫學院醫學系

內科專科醫師職業醫學專科醫師胸腔暨重症醫學專科醫師結核病專科醫師

Tuberculosis and diseases caused by nontuberculosis mycobacteri

a in Taiwan: Clinical aspect

社團法人中華民國防癆協會第一胸腔病防治所索 任 醫 師solo@tstb.org

台北市民權西路 104 號 2樓

http://www.tb.org.tw

The Genus Mycobacterium

Gram-positive, acid-fast, non-spore-forming, straight or slightly curved rods (0.2~0.6 1.0~10m) coccobacillary, filamentous, branched

Pigment in dark or after exposure to light Aerobic or microaerophilic Subdivision: rapid growers, slow growers Large amounts of lipid in cell walls: mycolic acid

s Typical species: Mycobacterium tuberculosis

Classification of mycobacterial species commonly cause human disease

Mycobacterium tuberculosis complexM. lepraeSlowly growing mycobacteria

Photochromogens (Runyon group I) Scotochromogens (Runyon group II) Nonchromogens (Runyon group III)

Rapidly growing mycobacteria (Runyon group IV)

Mycobacterium tuberculosis complex

M. tuberculosis M. bovis M. africanum M. microti M. canetti

M. kansasii

M. tb

結核病 –被遺忘了的瘟疫

1992

Tuberculosis

傳染源

Latent infection vs. disease

感染 發病

感染：會呼吸的人都是結核病的易感宿主發病：新近感染及免疫力減弱為主要危險因子

如何檢查結核菌感染

結核菌素測驗 ( 不夠精準的檢查 ) 結核菌素 tuberculin (Koch,1890) Mantoux test (1907) 干擾 –

宿主的抵抗力 , 卡介苗或其他非結核分枝桿菌 (NTM) 感染 , 測驗技術和判讀經驗

怎樣檢查肺結核病？

驗痰胸部Ｘ光檢查

父 39-10-15 M

75-4-7 “5” M+C+

HS 抗藥

76-10 完治

大女兒 69-4-3 F

82-3-13 “5” M+C+

ST N/A

82-12 完治小女兒 71-3-19 F

88-6-28 “3” M+C+

HS 抗藥

89-4 完治

大兒子 67-11-11 M

95-2-23 “5” M+

TB TB 何時了 潛伏感染 發病

81-3-27

83-4-11

Infectious

Latent TB Infection

Class IIDisease

Class III

Exposure

Class I

結核病

Non Infectious

Death

TB TB 何時了 – 診斷延遲

93/10/12 94/11/30

TB TB 何時了 – 診斷延遲

94/02/23 95/01/12

TB TB 何時了 – 不規則治療

910529 940909

結核病防治

結核潛伏感染

傳染性結核病

非傳染性結核病

Prophylactictreatment

預防性治療

化學治療

卡介苗接種

病人延誤

醫師延誤

傳染 transmission

死亡接觸

Source: Interventions for Tuberculosis Control and Elimination, IUATLD 2002

Preventive therapy

Doctor’s delay

Patient’s delay

Infectious TB

Non-Infectious TB

Subclinical infection

Exposure

BCG vaccination

Death

Chemotherapy

結核病的傳染期 = 病人延遲 + 醫師延遲 + 病人治療管理不當

結核病防治

三個基本動作盡早找出結核病人盡速治癒每個找出來的病人不讓結核菌產生抗藥性

結核菌持續挑釁

衛生體系重組 (Health reform)抗藥性結核菌HIV/AIDS貧窮

Mycobacteria other than M. tuberculosis and M. leprae

Nontuberculous mycobacteria (NTM)Mycobacteria other than tuberculosis (MO

TT)Environmental mycobacteriaOpportunistic mycobacteriaAtypical mycobacteriaAnonymous mycobacteriaUnclassified mycobacteria

NTM of Clinical Significance

Runyon classification and major species

I. Photochromogens M. kansasii, M. marinum, M. simiae, M. asiaticum

II. Scotochromogens M. gordonae, M. scrofulaceum, M. szulgai, M. flavescens

III. Nonchromogens MAC (M. avium, M. intracellulare), M. terrae complex, M. ulcera

ns, M. xenopi, M. malmoense, M. haemophilum, M. genavense, M. gastri, M. celatum

IV. Rapid growers M. fortuitum, M. chelonae, M. abscessus, M. phlei, M. vaccae

I. Photochromogen

M. marimun

M. kansasii

M. szulgai

II. Scotochromogen

M. gordonae

M. scrofulaceum

M. avium

M. intracellulare

III. NonchromogenM. xenopi

M. abscessus

M. chelonae

IV. Rapid grower

M. fortuitum

Historical Perspective and Epidemiology of the NTM (I)

Organism First human Source (s) Animal case reservoir (s)

Rapid growers 1930s Soil, water Cats, cattle, dogs…MAC 1943 Soil, water Birds, cats, swine

dogs, horsesM. ulcerans 1948 Unknown CatsM. marinum 1951 Salt, fresh water FishM. scrofulaceum 1950s Lake, river water Cattle, swineM. kansasii 1953 Water Cattle, deer, swineM. xenopi 1965 Hot water tank, taps Cats, cattle, swineM. simiae 1965 Water (rare) Monkeys

Emerging Infections I, 1998

Geographic Distribution

Organism Distribution

M. malmoense, M. xenopi Coal-mining regions, northern Europe

M. shimoidei Japan, AustraliaM. simiae Southwestern US, Isra

el,Cuba

M. ulcerans Africa, Australia, southeast Asia

M. kansasii Southern, central USM. haemophilum New York City

Epidemiology of NTM Environmental Sources

Most NTM have been recovered from water and soil

Mycobacteria Sources of infection

MAC, M. kansasii Tap water; airborne

M. marinum Salt, fresh water, fish tanks, swimming pool

M. xenopi Hot water; hospital heating tank (43-45oC)

M. simiae Tap water

M. genavense Dogs, pet bird (psittacine birds)

Rapid growers Tap or distilled water, dialysate; nosocomial

Environmental sources of infection are likely: M. ulcerans, M. haemophilum, M. szulgai, M. celatum, M. genavense, M. conspi

cumm

The most important nontuberculous mycobacteria

-1

Harrisons principles of internal medicine, 15th ed.

The most important nontuberculous mycobacteria

-2

Harrisons principles of internal medicine, 15th ed.

Principal Types of Mycobacterial Disease in Man and the Causative Agents (1)Disease Usual Uncommon

Tuberculosis M. tuberculosis M. bovis

M. africanum

Leprosy M. leprae

Lymphadenopathy M. avium complex

M. scrofulaceum

Many other species

Post-traumatic abscesses

M. Chelonae

M. fortuitum

M. terrae

M. flavescense

Swimming pool granuloma

M. marinum

Buruli ulcer M. ulcerans

Other skin lesions M. haemophilum

M. kansasii

M. shinshuenses

Principal Types of Mycobacterial Disease in Man and the Causative Agents (2)Disease Usual Uncommon

Opportunistic pulmonary

disease

M. avium complex

M. kansasii

M. xenopi

M. malmoenses

M. scrofulaceum

M. asiaticum

M. celatum

M. gordonae

M. simiae

M. Szulgai

M. chelonae

M. fortuitum

Disseminated Disease

HIV-associated M. avium complex M. genavense

Non-HIV-associated M. avium complex

M. chelonae

Diseases Caused by Nontuberculous Mycobacteria

Most disease: in immunosuppressed patients Source of infection: environment Person-to-person transmission: not proved Culture contamination: environmental saprophyt

es Colonization without producing overt disease Assessing clinical significance of isolates Clinical syndromes

NTM infection of the lung in HIV- patients

often occur in the context of preexisting lung disease, especially:

chronic obstructive pulmonary disease (COPD), bronchiectasis, pneumoconiosis, cystic fibrosis, and previous tuberculosis

AJRCCM 1997; 156:S1-S19.

Diagnosis of NTM pulmonary diseaseClinical criteria

Compatible signs/symptoms (cough, fatigue most common; fever, weight loss, hemoptysis, dyspnea) with documented deterioration in clinical status of underlying disease,

and Reasonable exclusion of other diseases (eg. TB,

cancer, histoplasmosis) or adequate treatment of other conditions with deterioration in clinical signs/symptoms

AJRCCM 1997; 156:S1-S19.

Diagnosis of NTM pulmonary diseaseRadiographic Criteria

Chest X-ray Evidence of progression if baseline film > 1 year old Infiltrates with or without nodules (persistent 2 months

or progressive) Cavitation Multiple nodules as a solitary finding

HRCT Multiple small nodules Multifocal bronchiectasis with or without small lung nodu

les

AJRCCM 1997; 156:S1-S19.

Diagnosis of NTM pulmonary diseaseBacteriologic Criteria At least 3 sputum/bronchial wash speciemens within previous year

Three positive cultures with negative AFB smears, or Two positive cultures and one positive AFB smear,

OR Single available bronchial wash and inability to obtain sputum sampl

e Positive culture with 2+, 3+, or 4+ growth, or Positive culture with 2+, 3+, or 4+ AFB smear

OR Tissue biopsy, any of following

Any growth from bronchopulmonary tissue biopsy Granuloma and/or AFB on lung biopsy with at least one positive

cultures from sputum or bronchial wash Any growth from usually sterile extrapulmonary

AJRCCM 1997; 156:S1-S19.

Diagnosis of NTM pulmonary disease

To conclusively diagnose NTM pulmonary disease, all three criteria – clinical, radiographic, and bacteriologic – must be satisfied

Culture positive with 1+ growth is sufficient if HIV-positive with CD4<200 (excluding MAC) and in patients with general severe immune suppression, leukemia, lymphoma, organ transplantation, or other immunosuppressive therapy

AJRCCM 1997; 156:S1-S19.

Diagnosis of NTM pulmonary disease Comment

The criteria fit best with M. avium complex M. abscessus M. kansasii

At least three respiratory samples should be evaluated

Other reasonable causes should be excluded

Expert consultation

AJRCCM 1997; 156:S1-S19.

M. kansasii pneumonia

Chest radiographs of a patient with severe emphysema and bilateral upper lobe disease caused by Mycobacterium kansasii. (a) Before treatment. (b) After 9 months of antimycobacterial treatment. (c) 2 months after the end of treatment.

a b c

M. avium complex pneumonia

54 year-old woman

Fever, cough, weight loss, neck LAP

VATS-AFB (+)

Blood, pleural fluid (+) for M. avium complex

MAC pneumonia(MACxIII, sputum)

MAC pneumonia

46/M, AML, M2, post C/T; Pulmonary M. avium Infection Plus PCP; (CIP+EMB+RIF+Baktar)

8/03/200218/03/2002(4017766)

AIDS, MAC

(3300118)

28/F, cystic bronchiectasis

M. abscessusM. abscessus

64 year-old womanDestructive lungM. chelonaeClarithromycin + ciprofloxacinPersistent infection

M. Chelonae

Disseminated MAC infection

75/M, CRI, herbFever, right hand lesion for 2 weeksWBC, 6300; CRP, 1.33

TenosynovitisEMB+CIP+CLA

MAC tenosynovitis

45 year-old femaleProductive cough for 3 weeksNeck LAPP. marneffei pneumoniaMAC lymphadenitis

MAC lymphadenitis

M. marinum infection (Fish-tank granuloma)

A red-violet, verrucous plaque on the dorsum of the thumb of a fish-tank hobbyist arose at the site of an abrasion.

Harrisons principles of internal medicine, 15th ed.

M. Marinum infection

M. ulcerans infection(Buruli ulcer)

A huge ulcer with a clean base and undermined margins extends into the adipose tissue of a Ugandian child.

Harrisons principles of internal medicine, 15th ed.

NTM skin infectionM. flavescens

M. marinum

M. kansasii skin infection

38 year-old female, SLERecurrent

M. chelonae infection

Edema, erythematous nodules, scars on the lower legs of an 83-year-old female, who was taking oral glucocoricoids chronically for asthma.

Harrisons principles of internal medicine, 15th ed.

NTM skin infectionM. chelonae

M. kansasii

M. absxessus

Clinically Significant NTM DiseaseNTUH, 1992-1996

Infection No. Etiologies

Pulmonary 10 MAC (3), M. fortuitum (2), M. abscessus (1)M. chelonae (1), M. gordonae (1)

Soft tissue & 16 M. abscessus (4), M. fortuitum (2), M. marinum (2)osteomyelitis M. chelonae (1), M. gordonae (1),

M. haemophilum (1), M. kansasii (1)

Disseminated 5 MAC (3), M. chelonae (1), M. scrofulaceum (1)

Keratitis & 7 M. abscessus (2), M. fortuitum (2), M. chelonaeconjunctivitis (2), M. xenopi (1)

Peritonitis 1 MAC (1)

Shih JY et al J Formos Med Assoc 1997

Thanks for attention

M. kansasii pneumonia 30 F

NTM infection of the lung in HIV- patients

Cavitary disease in the upper lung zones, similar to pulmonary tuberculosis, is seen in approximately 90 percent of patients with M. kansasii infection and perhaps 50 percent of those with Mycobacterium avium complex (MAC) infection.

The cavities caused by these organisms tend to have thinner walls and less surrounding parenchymal opacity than those caused by M. tuberculosis

Approximately 50 percent of patients with MAC lung disease have radiographic abnormalities characterized by nodules associated with bronchiectasis or nodular/bronchiectatic disease.

The nodules and bronchiectasis are usually present within the same lobe and occur most frequently in the right middle lobe and lingula

NTM DiseaseTreatment Regimen Recommendations

Mycobacteria Established Suggested

M. scrofulaceum M. malmoense, M. simiae (lung) RIF, ETH, INH, STM (AMIK) CLAR (AZI), CIP, CLOFMAC (disseminated) CLAR (AZI), ETH CLOF, RIFB, RIF, CIP, AMKM. kansasii, M. szulgai RIF, INH, ETH STM, CIP, CLARM. xenopi RIF, INH, ETH STMM. marinum ETH, RIF, DOX, TMP-SMX STM, CIPM. haemophilum – RIF, CFOX, DOX, TMP-SMXM. fortuitum AMIK, CIP, SULF CLOF, CLAR, CFOX, DOX,

IPMM. abscessus AMIK CLOF, CLAR, CLOXM. chelonae TOB (AMIK) CLOF, CLAR, DOX

Manual of Clinical Microbiology 1999

MAC Pulmonary DiseasesTreatment

Clarithromycin (500 mg bid) or azithromycin (250 mg gd)

Rifampin (600 mg qd) or rifabutin (300 mg qd)

Ethambutol (25 mg/kg for 2 m, then 15 mg/kg)

Streptomycin (2-3 times/week for first 8 weeks)

Duration: culture (-) on therapy for one year

Disseminated M. avium Complex Disease

Treatment

1. Clarithromycin (500 mg bid) or azithromycin (250-500 mg gd)

2. Ethambutol (25 mg/kg for 2 m, then 15 mg/kg)

3. Rifabutin (300 mg qd) or rifampin (600 mg qd)

(Clofazimine, ciprofloxacin, amikacin, streptomycin)

Duration: 1+2+3 life long

M. kansasii Pulmonary DiseaseTreatment

Isoniazid (300 mg qd)

Rifampin (600 mg qd)

Ethambutol (25 mg/kg for 2 m, then 15 mg/kg)

Clarithromycin or rifabutin (substituted for rifampin) in AIDS patients with protease inhibitors

Duration: 18 months with > 12 month culture (-)

Antibiotic TreatmentRapidly Growing Mycobacteria

Bacteria Parenteral Oral

M. abscessus Amikacin, Imipenem Clarithromycin, Quinolone

s, Sulfonamides

M. chelonae Amikacin (tobramycin), ClarithromycinImipenem

M. fortuitum Amikacin, Cefoxitin ClarithromycinM. smegmatis Amikacin, Imipenem Doxycycline,

Quinolones,

Sulfonamides

Guay DRP Ann Pharmacother 1996

Antibiotic TreatmentRapidly Growing Mycobacteria (III)

Pulmonary disease

Organism Treatment

M. fortuitum Cefoxitin + amikacin (4-8 weeks) sulfamethoxazole + doxyc

ycline + ciprofloxacin (ofloxacin)

M. abscessus Cefoxitin + amikacin + macrolides (4-6 weeks) surgical excision

macrolides (6-12 months)

Clinical Syndromes of NTM Disease Chronic pulmonary disease Lymphadenitis Localized skin, soft tissue, and skeletal infection Infection of bursae, joints, tendon sheaths, and b

ones Disseminated disease in patients without AIDS Disseminated disease in patients with AIDS Other infections

Harrisons principles of internal medicine, 15th ed.

NTM Pulmonary DiseaseImmune Suppression

LocalAlcoholismBronchiectasisCyanotic heart diseaseCystic fibrosisPrior mycobacterial disea

sePulmonary fibrosisSmoking/COPDNone

General

Leukemia

Lymphoma

Organ transplantation

Immunosuppressive

therapy

HIV (+), CD4 count <200