泌尿道感染之抗生素不當使用與抗藥性腸內菌屬感染之分子流行病學研究

Inappropriate Antimicrobial Usage in Urinary Tract Infection and the Study of Molecular Epidemiology on Antimicrobial Resistance of Enterobactericeae

林秀真(Hsiu-Chen Lin)

指導教授 ： 薛玉梅

共同指導教授 ： 陳豪勇(Hour-Young Chen)

臺北醫學大學/公共衛生暨營養學院/公共衛生學系暨研究所/博士(2014年)

摘要

細菌對抗生素產生抗藥性已經是全球公共衛生上的主要課題，例如methicillin resistant Staphylococcus aureus、產生超廣譜型乙內醯胺酶(extended spectrum beta-lactamase, ESBL)的腸內菌屬細菌等，會讓感染症的治療更形困難。細菌產生抗藥性主要來自抗生素的濫用，包含過度使用和錯誤使用，都稱為不適當的抗生素使用。在因感染症而到門診求診的病人中，以上呼吸道感染為最常見，泌尿道感染是占第二位的。而上呼吸道感染的病人大多不需使用抗生素，實際上，泌尿道感染是最需使用抗生素治療的病人。泌尿道感染的病原菌以大腸桿菌、克雷白氏肺炎菌、奇異變形桿菌等腸內菌屬細菌佔最大的比例，根據國家衛生研究院台灣抗生素抗藥性監測計畫的報告顯示，台灣目前此三種病原菌的抗藥性正快速增加。這些細菌產生抗藥性種類以ESBL為主，而ESBL的構成基因是以CTX-M基因型為主。因為ESBL的治療多以如carbapenem類的後線抗生素為主。但不同的CTX-M基因型ESBL對第三代頭孢菌素的水解能力不同，例如 CTX-M-14(屬於群組9)對ceftazidime的感受性較CTX-M-15型(屬於群組1)的感受性更好，而CTX-M-15型對所有的第三代頭孢菌素都具有高抗藥性。也就是在遇到群組9這類的ESBL抗藥性細菌時，不一定要直接使用最後一線且廣效性的carbapenem類，而可以選擇先使用對此基因型仍有效的第三代頭孢菌素ceftazidime來治療。
所以，臨床醫師在門診治療泌尿道感染時選用正確抗生素，或在特殊病房單位正確辨識出病人的危險因子而選擇正確的抗生素種類治療，都可以減少臨床醫師的不適當使用抗生素，減少抗藥性產生的機會。另外，若能提供台灣全國腸內菌屬細菌的主要抗藥性的基因型別，更可以讓醫師在治療常見的腸內菌屬細菌感染時，能清楚的分辨有效殺菌的抗生素種類，減少使用後線抗生素，更能減少抗藥性產生的機會。所以本論文第一個目的是藉由探討門診單純泌尿道感染(急性膀胱炎)的抗生素不適當的使用及其治療成果，第二個研究目的為針對國內的一種特殊專門病房(呼吸照護病房)的住院病人，因泌尿道感染產生超廣譜型乙內醯胺酶的抗藥性腸內菌屬細菌的危險因子進行探討，找出台灣此種特殊照護病房的感染抗藥性的細菌之危險因子，是否與其他種照護單位的危險因子有所不同。藉由避免危險因子的產生，不但可降低感染抗藥性腸內菌屬細菌的機率，亦經由辨識出病人感染的危險性，可以正確選擇抗生素的使用。第三個研究目的是藉由國內北中南東各區所收集的全國近500株細菌，包括大腸桿菌、克雷白氏肺炎菌、奇異變形桿菌等，探討其ESBL基因群組的分子流行學研究，提供國內主要流行的ESBL基因型別，作為醫師治療這些細菌感染時正確抗生素的處方參考。
本論文的研究方法是先由全民健康保險研究資料庫100萬人承保抽樣歸人檔 LHID 2005 (Longitudinal Health Insurance Database)中找出門診急性膀胱炎就醫病人，依照衛生福利部公告，由台灣感染症醫學會所提供的抗微生物製劑使用準則，將抗生素用藥分為「遵從處方準則」與「未遵從處方準則」兩群，統計分析其28天內膀胱炎相關疾病的復發率。收集國內北部二家呼吸照護病房的240筆尿液培養的菌株結果，比對臨床資料，分析呼吸照護病房內住院病人尿道感染ESBL抗藥性細菌的危險因子。另由全國20家醫院收集477株ESBL抗藥性大腸桿菌、克雷白氏肺炎菌、奇異變形桿菌，以聚合酶連鎖反應實驗來分析其基因型別的分子流行病學研究。
本論文的結果是當急性膀胱炎的病人若接受不適當的抗生素治療（不遵守治療準則處方）時，相對於遵守準則組的病人，會有較高的復發危險性，縱然是在經過多種危險因子的校正後也呈現相同的結果。表示當醫師在治療急性膀胱炎時應遵守專業的抗生素治療準則，避免病人復發的機率，得到較好的治療效果。所以，教育醫師瞭解治療急性膀胱炎的抗生素準則，應可降低細菌抗藥性並增進病人治療品質。本研究指出，台灣的此類特殊病房-呼吸照護病房病人的尿道感染ESBL細菌的危險因子只有兩種。(1)感染前三個月內曾使用過兩種以上抗生素。(2)病人本身具有兩種以上的慢性病。也就是說當醫師診斷病人有疑似尿道感染時，不需使用與其他特殊病房一樣，若判斷錯誤反而會濫用carbapenem類抗生素。在全台灣的20家醫院代表菌株中，研究結果發現台灣地區的此三類細菌的ESBL抗藥性仍以CTX-M型為最多，尤其是奇異變形桿菌和大腸桿菌。基因型別群組以CTX-M-9最多，CTX-M-1次之，而CTX-M-25雖然所佔比率最少，卻是第一次在台灣被發現。而北美和歐洲存在的CTX-M-8和CTX-M-2目前在台灣仍未發現。所以，在臨床上遇到ESBL抗藥性細菌時，不一定要直接使用最後一線且廣效性的carbapenem類，而可以選擇先使用對CTX-M-9基因型仍有效的第三代孢子素ceftazidime來治療。
減緩細菌抗藥性的產生需要從多方面著手，本論文結果提出醫師在門診治療急性膀胱炎時應遵守抗生素治療準則，可確保治療效果的實證證據。並提供醫師在治療呼吸照護病房病人泌尿道感染時，可以參考與其他種類照護單位不同的感染危險因子。同時指出台灣地區超廣譜型乙內醯胺酶抗藥性的分子流行病學與其他國家不同的基因型別分佈，可選擇的抗生素會有不同。以上結論，都是為降低台灣地區不適當使用抗生素的努力。

關鍵字

泌尿道感染 ； 抗藥性 ； 腸內菌屬 ； 超廣譜型乙內醯胺酶

並列摘要

Antimicrobial resistance of the pathogenic bacteria is a major concern of public health worldwide now. In the other word, Methicillin resistant Staphylococcus aureus, extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae may lead to the treatment more difficult than before. The major mechanism of antimicrobial resistance in bacteria is the inappropriate antimicrobial usage including the overuse and underuse. Upper respiratory tract infection is the major infectious disease of ambulatory patients. However, urinary tract infection (UTI) is the second infectious disease of those patients and is the major reason needed the antimcrobial prescription. The commonest pathogens of the UTI are the E. coli, K. pneumoniae, and P. mirabilis. According to the surveillance study by National Health Research Institute, the antimicrobial resistances of the three pathogens are increasing rapidly. The major resistance of these pathogens is from the production of ESBL. Nevertheless, the CTX-M is the major genotype of ESBL in the world. Clinically, the empirical antimicrobial treatment of the ESBL-producing bacteria infection is carbapenems. However, the hydrolysis ability to third generation cephalosporins is different from various kinds of CTX-M genotypes. For example, the CTX-M-14 (belong to CTX-M-9 group) is more susceptible to ceftazidime than CTX-M-15 (belong to CTX-M-1 group). But the CTX-M-15 type is resistant to all of the third generation cephalosporins. In other words, the physicians may choose the ceftazidime while the patients are infected with CTX-M-9 group ESBL-producing pathogen. They can avoid prescribing the broadest spectrum antimicrobials, such as carbapenem, for the UTI patients initially.
However, the physicians could choose the appropriate antimicrobials for the ambulatory patients with UTI and recognize the risk factors in the special care ward. It can result in the reduction of inappropriate antimicrobial prescription and decrease the antimicrobial resistance of bacteria. In addition, the surveillance study could provide the genotype of ESBL resistance of Enterobacteriaceae, and provide various susceptibility patterns for Enterobacteriaceae. Then, physicians could prescribe the appropriate antimicrobials for Enterobacteriaceae infection.
The first purpose of the present study is to investigate the treatment outcome of ambulatory patients with acute cystitis with inappropriate antimicrobials. Second, we explore the risk factors of patients acquiring the UTI with ESBL-producing Enterobacteriaceae in the respiratory care wards. The third purpose is to determine the molecular epidemiology of ESBL genotypes in Taiwan. It could demonstrate various antimicrobial susceptibility of ESBL resistance as a reference for treatment in clinics.
The longitudinal observational study was conducted using clinical records sampled from the National Health Insurance Research Database in Taiwan. It included one million persons. The ambulatory patients with acute cystitis were enrolled. These patients were classified into "adherence group" and "non-adherence group" according to the guideline established by Infectious Diseases Society Taiwan. Then, the outcome of UTI was defined recurrence of UTI-associated infections within 28 days. Furthermore, 240 isolates of urine culture from two respiratory wards (RCW) at Northern Taiwan. The demographic, clinical, and microbiologic data were analyzed to obtain the risk factors for acquiring the UTI of ESBL-producing Enterobacteriaceae. In addition, 477 isolates of ESBL-producing E. coli, K. pneumoniae, and P. mirabilis were collected from 20 hospitals distributed in Taiwan. PCR was performed in order to clarify the molecular epidemiology of genotypes of ESBL resistance.
In conclusion, physicians who adhered to recommend guidelines for the treatment of bacterial infections, had better therapeutic outcomes in their patients with acute cystitis, regardless of whether they had multiple chronic comorbidities. Thus, intensive implementation by physicians in all health care disciplines of patients with lower UTIs is necessary to ensure a discreet antibiotic policy that will decrease recurrence rates, and thus improve patient care. On the other hand, geriatric patients with recent exposure to two or more antibiotics and two or more numbers of comorbidities were at risk for ESBL-producing organism infection. Our results suggest that infection control procedures in RCW should be concerned with reducing antimicrobial prescriptions and patient comorbidities. In our study, we found the most prevalent genotype of CTX-M of ESBL in Taiwan is CTX-M-9 group; the second is the CTX-M-1 group. The study is the first report about isolated CTX-M-25 group, but the genotypes of CTX-M-8 and CTX-M-2 groups existed in Europe and America are not found in Taiwan untill now.
In conclusion, carbapenem may not be the first choice to treat ESBL-producing bacteria infection in Taiwan. We could use ceftazidime which is still effective to treat the CTX-M-9 group ESBL-producing Enterobacteriaceae.
Reducing the bacterial resistance should be approached from various manipulations. Our study found that patients would have a good clinical outcome and low recurrence rate if physicians would adhere to guidelines and prescribe appropriate antimicrobials for acute cystitis. We also indicated previous antibiotics prescribed to a geriatric patient with multiple chronic diseases in RCW should be carefully evaluated the risk factors of ESBL-producing organisms. These risk factors are different from other intensive care units. Moreover, the distribution of genotypes of CTX-M of ESBL resistance in Taiwan is different from other countries; it suggests different antimicrobial susceptibility of ESBL should be considered in Taiwan. All of above effort were done in order to attain the reduction of inappropriate antimicrobial usage.

並列關鍵字

Urinary tract infection ； Antimicrobial resistance ； Enterobacteriaceae ； Extended-spectrum beta-lactamase

參考文獻

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