微生物感染性角膜潰瘍在台大醫院的現況

Microbial keratitis at National Taiwan University Hospital

馮介凡(Chien-Fan Fong)

指導教授 ： 胡芳蓉

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.01000

摘要

微生物感染性角膜潰瘍致病機轉通常由感染造成。細菌感染是最常見的， 但黴菌、 寄生蟲和病毒感染也是可能發生。這些病源感染最常發生在角膜中央， 但也可能發生在角膜邊緣處。中央角膜感染是會威脅到視覺和眼睛的完整構造; 這是一個真正的眼科急症。微生物感染性角膜潰瘍是造成視力不良的一個主要因素，近代醫學在感染症上的付出研究與實際治療上的進步，讓我們在角膜潰瘍的病因學、臨床表現、實驗室檢查、以及治療上都比以往更了解，治療效果更好。感染症的特殊性，是其病源與發生的地區有密切的相關；也就是說各國都在致力於研究本身感染症的地域性特徵，了解本身環境的致病源，才能進一步去控制與預防。
根據文獻回顧，微生物感染性角膜潰瘍使用抗生素的效果與敏感性因地區，因時間而異。每個地區的微生物感染性角膜潰瘍好發菌種不同，使用的抗生素不同，醫師的用藥習慣也不同，因此抗生素的效果與敏感性的情況也因地而異。台灣地區這一方面的報告闕如，因此建立本地的資料是應即時進行的工作。
特定的微生物感染性角膜潰瘍致病源常有其特殊治療方式，有些以藥物治療為主，其中又對某些特定的藥物反應較佳；這些關係常和時間的演進而有變化。也有些病源菌以手術治療為主，這反應出現代藥物對此病源反應不佳，是需要進一步研究改進的地方。建立本地區的致病源抗生素藥物反應結果，有助於本地角膜潰瘍的治療結果，對全世界角膜潰瘍藥物反應的監控，也有很大的幫助。
本研究的目的：
1 分析在國立臺灣大學醫學院附設醫院在此之前的12 年間，微生物感染性角膜潰瘍的臨床和微生物學致病細菌種類的特徵。
2 在12 年期間，分析最常見微生物感染性角膜潰瘍的致病細菌種類的體外抗生素感受性，建立改變的趨式和嘗試找出最合適的首選藥物或藥物組合。
研究方法：
從1992 年1月到2003 年12月，國立臺灣大學醫學院附設醫院在此12 年間，有角膜炎（keratitis）臨床診斷的住院治療病人；有角膜炎作為出院診斷的所有住院病人。病歷中紀錄的患者特徵均被詳細紀錄分析。
統計分析上，以Stata 軟體程式分析，而分組方式原則上以病患住院日區分，以前六年和後六年分開，分析病源和臨床指標的關係。四種常見的細菌病原生物，測試了特別抗生素，比較抗藥性是否因時間的不同而增加。並依抗生素敏感性試驗結果，與臨床表現及治療結果做相關性研究。為統計結論的目的， P值等於0.05 或較少時，統計地被認為有意義。

結果：
本研究自西元1992年1月起至西元2003年12月止共12年，有547位病人之573隻眼睛納入本研究中。男女與左右眼分佈均無明顯變化，平均年齡是40.8±22.2歳，最近6年間平均年齡下降，16-30歲的人數比例在近6年是統計學上有意義的增加。最常見的因素是隱形眼鏡的配戴（45.4﹪），其次是眼外傷（22.6﹪），慢性眼睛和全身性疾病（17.1﹪）與最近眼科手術術後（15﹪）。隱形眼鏡的配戴所佔比例上升，眼外傷所佔比例下降。。
本研究中角膜潰瘍抹片染色陽性率是49.3﹪，其中包含48.9﹪格蘭氏陰性菌，24.4﹪格蘭氏陽性菌，16.7﹪黴菌，8.5﹪是耐酸菌（acid-fact），阿米巴氏原蟲有1.5﹪。從角膜潰瘍的標本中做微生物培養，陽性率是48.9﹪，綠膿桿菌是最常見的病原菌，佔全體之38.1﹪，其次是黴菌，佔13.4﹪，接下來是非典型分枝桿菌，佔8.4﹪；葡萄球菌屬佔7.7﹪，鏈球菌屬佔7.4﹪，阿米巴氏原蟲有4.3﹪。非典型分枝桿菌佔率顯著下降，綠膿桿菌佔率上升至41.2﹪（p=0.171），這是唯一大幅增加的菌種。綠膿桿菌的感染與隱形眼鏡的配戴誘發因素之勝算比有4.26；非典型分枝桿菌的感染與最近接受眼科手術誘發因素之勝算比有5.84；鏈球菌的感染與隱形眼鏡的配戴誘發因素之勝算比有0.12；黴菌的感染與眼外傷誘發因素之勝算比有5.84。共有421（73.5﹪）隻眼睛僅僅接受藥物治療即痊癒，有152（26.5﹪）隻眼睛要再加上手術治療。最近6年間，藥物治療所佔的比例上升，接受全層角膜移植手術的比例下降。
在綠膿桿菌、非典型分支桿菌，葡萄球菌，鏈球菌的藥物敏感性實驗中，均無藥物抗藥性增加的現象。以格蘭氏陰性菌種分析， cefazolin加上gentamicin有79.4﹪皆為藥物敏感菌種。ciprofloxacin有98.5﹪皆為藥物敏感菌種，藥物敏感性兩者有統計上的差異（p＜0.001）。以所有細菌作母群體， cefazolin加上gentamicin為抗生素分析，有79.7﹪的所有菌種皆為藥物敏感菌種。cefazolin加上ciprofloxacin做抗生素敏感性分析，有89.3﹪的所有菌種皆為藥物敏感菌種，cephalosporin加上ciprofloxacin此組合在體外抗生素敏感性試驗中效果明顯較cephalosporin加上gentamicin效果較佳（p＝0.008）。
分析不同菌種與臨床指標之間的關係。綠膿桿菌方面，發現自症狀起始至確定治療的期間較短，勝算比是0.9（0.85-0.96）；潰瘍的上皮糜爛面積較大，勝算比是1.03（1.01-1.05）；僅以藥物治療為主，勝算比是0.31（0.15-0.65）。非典型分支桿菌方面，發現自症狀起始至確定治療的期間較長，勝算比是1.04（1.01-1.06）；加上手術治療為主，勝算比是29.61（5.44-161.1）。葡萄球菌方面，發現年齡較大，勝算比是1.03（1.01-1.06），僅以藥物治療為主，勝算比是0.07（0.01-0.61）。黴菌方面，發現年齡較大，勝算比是1.03（1.01-1.05）；加上手術治療為主，勝算比是2.65（1.18-5.96）。阿米巴氏原蟲方面，發現自症狀起始至確定治療的期間較長，勝算比是1.02（1.00-1.04）。
分析需輔以手術治療的角膜潰瘍，其臨床表徵有何特殊性。我們發現其年齡較大，勝算比是1.04（1.02-1.05）；自症狀起始至確定治療的期間也較長，勝算比是1.02（1.01-1.04）。性別與潰瘍的上皮糜爛面積均無統計學上相關。誘發危險因子方面，隱形眼鏡的配戴相對於其他危險因子的病例較不會接受手術治療，勝算比是0.25（0.10-0.59）。眼外傷、慢性眼睛和全身性疾病與最近眼科手術術後因素皆無統計學上相關。以不同微生物作分析，發現非典型分支桿菌相對於其他菌種較傾向於接受手術治療，勝算比是16.5（4.45-61.28）；黴菌相對於其他菌種也較傾向於接受手術治療，勝算比是3.48（1.57-7.71）。綠膿桿菌相對於其他菌種較不需要接受手術治療，勝算比是0.47（0.23-0.94）。葡萄球菌、鏈球菌、和阿米巴氏原蟲並無特殊傾向。

結論：
綠膿桿菌（Pseudomonas）是最常見的病原（37.9﹪），其次是黴菌（13.4﹪），非典型分支桿菌（8.4﹪），葡萄球菌（7.7﹪），鏈球菌（7.4﹪）和阿米巴原蟲（1.5﹪）。非典型分支桿菌有顯著減少的趨勢；綠膿桿菌有增加的趨勢，但無顯著的差異。誘發危險因素以隱形眼鏡的配戴最多（45.4﹪），其次是眼外傷（22.6﹪），，慢性眼睛和全身性疾病（17.1﹪）和最近眼科手術術後（15﹪）。其中隱形眼鏡的配戴有顯著增加的趨勢，而外傷有顯著減少的趨勢。綠膿桿菌的感染與隱形眼鏡的配戴誘發因素有密切相關，非典型分枝桿菌的感染與最近接受眼科手術誘發因素有密切相關，黴菌的感染與眼外傷誘發因素有密切相關。
73.5﹪可以藥物點眼治療，有26.5﹪要輔以手術治療。細菌性角膜潰瘍大多以藥物治癒，而黴菌和非典型分支桿菌角膜潰瘍大多要以手術治療。黴菌角膜潰瘍中，71.1﹪都需要以手術治療，22.6﹪最終失明無視力。阿米巴原蟲角膜潰瘍中，50﹪都需要以手術治療，無人最終失明。非典型分支桿菌角膜潰瘍中，88﹪都需要以手術治療，16﹪最終失明。
在綠膿桿菌、非典型分支桿菌，葡萄球菌，鏈球菌的藥物敏感性實驗中，均無藥物抗藥性增加的現象。以格蘭氏陰性菌分析，ciprofloxacin在體外抗生素敏感性試驗中效果明顯較cephalosporin加上gentamicin效果較佳。以所有細菌分析，cephalosporin加上ciprofloxacin組合在體外抗生素敏感性試驗中效果明顯較cephalosporin加上gentamicin效果較佳。分析治療方式和臨床指標的關係，綠膿桿菌感染大多是和隱形眼鏡的配戴危險因子有關，發現自症狀起始至確定治療的期間較短，潰瘍的上皮糜爛面積較大，大部分僅以藥物治療即可。非典型分支桿菌長和眼科手術術後有關，自症狀起始至確定治療的期間較長，大多受要輔以手術治療。黴菌和眼外傷較相關，而且病人年齡較大。手術治療組的年紀較大，手術治療組的自症狀起始至確定治療的期間也較長，隱形眼鏡的配戴較不必接受手術治療。

關鍵字

微生物感染性角膜潰瘍 ； 眼睛感染 ； 角膜潰瘍 ； 危險因子 ； 隱形眼鏡 ； 流行病學 ； 微生物學 ； 綠膿桿菌 ； 藥物治療 ； 抗生素感受性 ； 回顧型研究

並列摘要

Background
Corneal infection is a leading cause of ocular morbidity and blindness worldwide. Effective topical therapy, using fortified antimicrobials selected based on the results of diagnostic corneal smears and cultures, is essential for management of patients with microbial keratitis. The spectrum of micro-organisms responsible for microbial keratitis varies in different geographical locations. Variations such as these probably occur worldwide, however, relatively little is known about the situation in Taiwan, where the climate is subtropical. Understanding the spectrum of microorganisms and clinical characters of microbial keratitis in our environment is the key for successful treatment.
The antibiotic drug susceptibility changes with different locations and different time according to literature reviews. The spectrum of microorganisms and drugs available differ with different countries. There was no such report in Taiwan, and it is necessary for us to establish the work.
Some pathogens have special treatment modality. Some pathogens are susceptible to special antibiotics, and the relationship may vary with time. Some pathogens have poor response to medical treatment, and surgery is inevitable. These pathogens reflect the weak side of our modern pharmacology. It is necessary to establish the spectrum of microorganism of microbial keratitis and the drug susceptibility in Taiwan. The work will improve the prognosis of microbial keratitis in this local area and will be helpful in the drug susceptible monitoring in the world.

Study aims:

1. To analyze the clinical characters and spectrums of microorganisms of microbial keratitis in national Taiwan university hospital in proceeding 12 years.
2. To analyze the antibiotics susceptibility of bacterial keratitis in national Taiwan university hospital in proceeding 12 years and try to find the best regiment for bacterial keratitis.

Materials and Methods:
Medical records were reviewed for patients with clinical diagnosis of keratitis who were hospitalized at the National Taiwan University Hospital (NTUH), one of the largest tertiary medical centers in northern Taiwan, from January 1992 to December 2003. These patients were identified through a computerized diagnostic code search for all inpatients that had keratitis as the discharging diagnosis. Medial records were carefully examined and patients with diagnosis of microbial keratitis were included.
All data were typed in Microsoft Excel software and were transported to STATA software. P value <0.05 was considered statistically significant. For the purpose of comparison, the patients were divided into two groups stratified according to diagnosis during the six-year periods, January 1992 to December 1997, and, January 1997 to December 2003.

Results and Discussions
Five hundred seventy-three eyes in 547 patients were included in the final evaluation. Patients included 272 males (49.7%) and 275 females (50.3%), aged from seven months to 96 years (mean age 40.8±22.2). The mean age of microbial keratitis in recent 6 years was younger than in previous 6 years（39.1 vs. 43.8, p=0.013）. The patients in 16-30 years group increased significantly in recent 6 years（30.3% vs. 45.8%, p<0.001）.
The most common predisposing factor for microbial keratitis was contact-lens wear (45.4%), followed by ocular trauma (22.6%), chronic ocular and systemic disorders （17.1%） and recent ocular surgery （15%）.
Identification of pathogens from the smears of corneal scrapings was achieved for 270 eyes (49.3%), and included Gram-negative (48.9%) and Gram-positive organisms (24.4%), fungi (16.7%), acid-fast bacilli (8.5%), and Acanthamoeba species (1.5%). Cultures of corneal scrapings were available for 550 eyes, with pathogens recovered for 260 (positive culture rate 48.9%). Pseudomonas species were the most commonly isolated organisms (38.17%), followed by fungi (13.4%), staphylococcus species (8.4%), nontuberculous mycobacteria (7.7%), Streptococcus species (7.4%), and Acanthamoeba species (4.3%). The prevalence of atypical mycobacterial keratitis decreased significantly from 12.8% and 5.5% during the second half of this study (1997-2001, p=0.026).
Contact lens wear was highly related to Pseudomonas infection （odds ratio=4.26, p=0.007） as compared with referent other predisposing factors . Recent ocular surgery predisposing factor was related to atypical microbacterial infection （odds ratio=5.84, p=0.008）. Contact lens wear was reversely related to Streptococcus infection （odds ratio=0.12, p=0.01） . Ocular trauma was related to fungal infection （odds ratio=5.94, p=0.009） .
Medical treatment was successful for 421 eyes (73.5%), while 152 eyes (26.5%) required additional surgical treatment, including lamellar keratectomy (n=35), penetrating keratoplasty (n=93), enucleation (n=11), and evisceration (n=13). The percentage of medical treatment increased significantly in recent 6 years（64.7% vs. 79.6%, p<0.001）. The percentage of patient receiving penetrating keratoplasty decreased significantly in recent 6 years（23.8% vs. 10.9%, p<0.001）.
There was no antibiotic susceptibility change in Staphylococcus, Streptococcus, Pseudomonas and atypical mycobacterium in recent 6 years. In Gram-negative organisms the susceptibility of fortified antibiotics, cefazolin and gentamicin combination, was 79.4% during 1994 to 2003. The susceptibility of ciprofloxacin was 98.5%. Ciprofloxacin was better in dealing with Gram-negative organisms（p<0.001）. In all bacterial pathogens the susceptibility of cefazolin and gentamicin combination was 79.7%. The susceptibility of cefazolin and ciprofloxacin combination was 89.3%（p=0.008）.
In the relationship between special pathogen and clinical characters, we found that Pseudomonas was related to a large corneal erosion（OR=1.03）, shorter time between symptom onset to definite treatment（OR=0.9）, and medical treatment only（OR=0.31） as compared with referent other pathogens. Atypical mycobacterium was related to longer time between symptom onset to definite treatment（OR=1.04）and surgical treatment indicated（OR=29.61）. Fungal keratitis was related to old age（OR=1.03）and surgical treatment indicated（OR=2.65）.
In surgically treated microbial keratitis we found that the patients were older（OR=1.04）, have longer time between symptom onset to definite treatment（OR=1.02）. In predisposing factors contact lens wear was reversely related to surgical treatment（OR=0.25）as compared with other predisposing factors. In spectrum of microorganism atypical mycobacterium was highly related to surgical treatment（OR=16.5） as compared with other micro-organisms. Fungal infection was also related to surgery（OR=3.48）. But pseudomonal infection was reversely related to surgical treatment（OR=0.47）.

Conclusions:
Pseudomonas（37.9%） was the most common pathogens, followed by fungus（13.4%）, atypical mycobacterium（8.4%）, Staphylococcus（7.7%）, Streptococcus（7.4%）and Acanthamoeba（1.5%）. Atypical mycobacterial infection decreased significantly. Contact lens wear（45.4%） was the most common predisposing factors, followed by ocular trauma（22.6%）, chronic ocular and systemic disorder（17.1%）and ocular surgery（15%）. The contact lens wear increased and ocular trauma decreased significantly. Contact lens wear was highly related to pseudomonal infection. Recent ocular surgery was related to atypical mycobacterium infection. Ocular trauma was related to fungal infection.
73.5% of microbial keratitis was treated medically, and 26.5% needed surgical treatment. Bacterial keratitis was treated medically and surgery was inevitable in atypical mycobacterium and fungal keratitis. Fungal keratitis was the most common in cases treated by enucleation or evisceration.
There was no increase in drug resistance in Pseudomonas, atypical mycobacterium, Staphylococcus and Streptococcus. Ciprofloxacin was better than cefazolin and gentamicin combination in drug susceptibility test in Gram-negative bacteria during 1994 to 2003. Cefazolin and ciprofloxacin combination regiment was better than cefazolin and gentamicin combination in drug susceptibility test in all bacteria. Pseudomonal keratitis was related to contact lens wear, short interval between symptom onset to definite treatment, large corneal erosion size, and medical treatment only. Atypical mycobacterial keratitis was related to ocular surgery factor, long interval between symptom onset to definite treatment, and additional surgical treatment. Fungal keratitis was related to old age and ocular trauma factor. Patients who were old and had longer time between symptom onset to definite treatment were prone to receive additional surgical treatment.

並列關鍵字

Microbial keratitis ； Eye infection ； Corneal ulcer ； Risk factors ； Contact lens ； Epidemiology ； Microbiology ； pseudomonas ； Drug therapy ； Antibiotic susceptibility ； Retrosepctive studies

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