Case Discussion <Brief History> This 73-year-old woman is a case of hypertension and ovarian cancer diagnosed in Dec 2004, status post debulking surgery and 5 times of the chemotherapy with chemotherapy (Taxol + Carboplatin). The latest chemotherapy was performed at gynecology ward on April 2, 2005 and she was discharged on April 13. There was no obvious side effect of the chemotherapy before this admission. She denied travel or animal exposure before this admission. However, bilateral leg weakness developed since April 26 2005, followed by fever at night 2 days later. She was brought to ER where a urine examination showed hematuria and pyuria. Her consciousness was lethargy on arrival. Urosepsis was diagnosed and cefotiam was given. Her fever persisted and her conscious level deteriorated since April 29. Neck stiffness was also noted later at ER. For suspected intra-pelvic infection and CNS infection, antibiotic was switched to 3rd generation cephalosporin since April 29. Brain CT without contrast enhancement on April 30 showed no obvious abnormality without space occupying lesion. Lumbar puncture was suggested but the family hesitated. She was then admitted to our ward on May2. <Physical Examination> On physical examinations, the body temperature was 37.0℃, blood pressure 140/60 mmHg, pulse rate 120 /min, and the respiratory rate 22 /min. Her consciousness was E3V2M4. The conjunctivae were not pale and sclerae were not icteric. Light reflex of the pupils was sluggish but symmetric. The neck was stiffness and there was no lymphadenopathy or jugular vein engorgement. The chest was symmetrically expanded with clear breath sound.The heart beats were regular. No heart murmur was audible. The abdomen was flat and soft on palpation. There was no tenderness or rebound tenderness. The extremities were free movable and there was no cyanosis, clubbing or pitting edema. The peripheral pulse was palpable. <Laboratory Data> 1. CBC/DC WBC K/uL RBC M/uL Hb G/dL Hct % MCV fL PLT K/uL 6370 3.0 9.4 27.4 91.3 51 Band % Seg % Eos % Baso % Mono %  Lym % 25 70 0 0 1 3 2. Biochemistry Study BUN mg/dL Cre mg/dL Na mmol/L K mmol/L Ca mmol/L Alb g/dL  TP g/dL 23.1 0.9 123 4.3 2.29 3.06 5.6 T-Bil mg/dL AST U/L ALT U/L ALP U/L GGT U/L NH3 μmmol/L CRP mg/dL 1.50 19 19 273 104 7 22 <Course and Treatment> After a thorough discussion with her family, they agreed CSF study and lumbar puncture was performed on May 2. CSF study revealed white cell count: 300 /μl with differential count: lymphocyte/neutrophil: 45/55, total protein: 344 mg/dL, glucose: 184 mg/dL, and LDH: 1188 IU/L. Her conscious deteriorated to comatose so acyclovir was added for suspected viral encephalitis. Respiratory distress developed though chest roentgenogram showed no opacity. Blood gas did not show respiratory acidosis or hypoxemia. She was then intubated for impending respiratory failure. Gram-positive bacilli was found by Gram stain of CSF culture on May 4. Ampicillin with gentamicin were given and acyclovir was discontinued. Following CSF study on May 4 showed pleocytosis up to 600/μl with persistent high protein level. Seizure attacks and intermittent myoclonus developed. Listeria monocytogenes finally isolated from CSF culture. Ampicillin and gentamicin was instituted for three weeks. Low grade fever and CRP waned gradually. Her consciousness became complete clear 3 weeks later and she was extubated smoothly thereafter. <討論> 本案例為一腫瘤病人，發生腦膜腦炎，因為家屬遲疑腦脊髓液穿刺，起初只用一般治療腦膜炎針對肺炎雙球菌以及格藍氏陰性桿菌之第三代頭包芽素(third-generation cephalosporin)治療，且腦脊髓穿刺結果為主要淋巴球為主之白血球增生，原本只懷疑為病毒，但其腦脊髓液蛋白質又很高，又比較像結核菌，黴菌性腦膜炎或經治療後之細菌性腦膜炎。直到培養出來才知道是對所有頭包芽素沒有效之李斯特菌感染。李斯特菌感染表現主要以腦膜炎，菌血症，以及腸胃炎為主。因為工作因素較常接觸動物者比如獸醫，屠宰業，畜牧業等屬於高危險群。正常人雖也有可能得病，但特別容易患有李斯特菌感染症的情況是孕婦及免疫力不全之病人，例如腫瘤患者、酗酒、使用類固醇者，以及新生兒或老人等。李斯特菌的主要傳染途徑是遭受污染的牛奶，或是牛的排泄物污染水源或食物所致。若牛奶未經徹底消毒，則製成的乳製品便可能會帶有致病菌。冷藏的乳製品及冰品若於製造過程中消毒不完全，就可能會帶有這個細菌。 李斯特菌感染中樞神經系統時，比起一般的細菌性腦膜炎，有以下不同點：病程有時較亞急性，較容易有抽搐發生，頸部比較少僵硬，腦脊髓液的格蘭氏抹片發現細菌之陽性比率較低，而腦脊髓液主要是以淋巴球為主之白血球增生，有時與結核性腦膜炎難區分。要注意的是雖然只有1/3之 Listeria monocytogenes，在腦脊髓液格蘭氏染色中可看到細菌，比起一般的60% 90%少，但格蘭氏染色抹片仍是腦膜炎病人應該執行的檢驗，因為其快速簡便且特異性很高。不管是培養或初步染色，在腦脊髓液中，一但發現格蘭氏陽性桿菌(Gram positive bacilli)，除非是污染菌(diphtheroids)，比如 Bacillus, Lactobacillus ,或Corynebacterium，就應考慮有高致病力的Listeria monocytogenes，要趕緊調整抗生素用藥。 在2004年美國感染症醫學會腦膜炎的經驗療法中建議，大於50歲者，因為考慮S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli等細菌的感染，所以建議Vancomycin加上 ampicillin 以及第三代頭包芽素( third-generation cephalosporin)是作為第一線經驗療法，屬於A-III的建議等級。在台灣的腦膜炎主要是以克雷白氏桿菌以及肺炎雙球菌為最多，李斯特菌比國外略少，但在台灣的腦膜炎菌種分佈研究，也約佔3-10％不等，可見此菌在台灣是的確存在的。因此遇到腦膜炎病人，詢問動物接觸病史，或飲食內容，以及找出免疫差的高危險群病人是很重要的。若確定為Listeria monocytogenes感染，建議使用ampicillin（每天12g）(或penicillin) 加上Gentamicin(每天每公斤5mg)治療3週，有時免疫力差的病人，或是有腦膿瘍的病人治療時間會更久。若有過敏，可考慮用Trimethoprim-sulfamethoxazole或 meropenem 替代。 繼續教育考題 1. (C) 下列何者在社區性腦膜炎中使用第三代頭包芽素( third-generation cephalosporin)抗生素無效？ A 腦膜炎雙球菌 B  肺炎雙球菌 C 李斯特菌 D 克雷白氏桿菌 2. (A) 下列何者非屬於常見李斯特菌感染之表現？ A 肺炎 B 腦膜炎 C 菌血症 D 以上皆是 3. (D) 下列何者在免疫力好的病人少發生，但是T細胞不全者，比如類固醇使用者發生中樞神經感染之常見病原菌？ A  Listeria monocytogenes B Cryptococcus neoforman C Mycobacterium tuberculosis D 以上皆是 4. (D) 下列何者非屬於常見Listeria monocytogenes危險族群？ A 癌症患者 B 飲用生牛奶者 C 孕婦或老人 D 素食者 5. (D) 下列何者非格蘭氏陽性桿菌？ A Bacillus spp. B Corynebacterium spp. C Listeria monocytogenes D Hemophilus influenzae 6. (C) 在一位60kg肺癌人確診為 Listeria monocytogenes腦膜炎之病人，若已經用 Ampicillin合併使用 Gentamicin使用下意識仍未改善，伴隨有抽搐，下列何者非屬於有幫忙的處理？ A 安排腦部核磁共振來排除腦膿瘍之可能。 B 加上phenytoin。 C 加上類固醇。 D 安排腦波並追蹤腦脊髓液穿刺。 7. (D) 在下列各種細菌中腦脊髓液格蘭氏染色最不易陽性者為何？ A S. pneumoniae B N. meningitidis C H. influenzae D L. monocytogenes 8. (A) 治療 Listeria monocytogenes腦膜炎感染之抗生素使用，下列何者不適？ A Ceftriaxone + Vancomycin B Meropenem single use C Penicillin + Gentamicin D Trimethoprim-sulfamethoxazole 9. (D) 下列哪種抗生素對 Listeria monocytogenes細菌最無效 ？ A Penicillin B Meropenem C Trimethoprim-sulfamethoxazole D Ciprofloxacin 10. (B) 下列何者非屬於李斯特菌腦膜炎，比起一般的細菌性腦膜炎之不同點： A 病程有時較亞急性 B 腦脊髓液以中性球為主之白血球增生，有時與結核性腦膜炎難區分 C 腦脊髓液的格蘭氏抹片不易陽性 D 較容易有抽搐發生 答案解說 (C ) 李斯特菌不能用cephalosporin治療。 (A ) 肺炎少見。 (D ) 全部都需考慮。 (D ) 多和肉品，或乳製品沒有消毒有關。 (D ) H.influenza為格蘭氏陰性桿菌。(A)(B)為常見污染菌。 (C ) 類固醇治療只有在肺炎雙球菌感染認為對腦膜炎死亡率有幫忙，在其他細菌 角色未明。 (D ) 李斯特菌約30% Gram stain陽性。 (A ) Vancomycin 不建議用來治療李斯特菌，Cefepime天生沒效。 (D ) 選Ciprofloxacin。 (B ) 比起其他細菌，較多為淋巴球為主之白血球增生。