背景
菌血症為造成院內死亡主要原因之一，但其嚴重程度與病人感染來源及菌種差異明顯不同。目前僅腦膜炎、心內膜炎及導管相關之血液感染於美國感染科學會(IDSA)指引中有明確治療建議。其他次發性菌血症臨床多採14天療程，除社區型肺炎合併菌血症之外，其他無建議何時可轉換為口服抗生素。現有菌血症及早轉換為口服抗生素研究，探討疾病發生後7天內轉換為口服之安全性，但此轉換時機不明確，注射治療長度較長。國外機構包含英國國民健保署 (NHS)發布口服抗生素轉換建議，依據病人臨床狀況及口服吸收能力，評估是否適合轉換為口服治療。NHS轉換建議中未排除菌血症，但缺乏足夠證據支持其能否應用於菌血症病人。

目的
證明由Nottingham大學醫院修訂NHS發布的口服抗生素轉換建議，是否能應用於腸內菌科菌血症病人，及早轉換為口服是否不差於長時間注射治療，並了解目前菌血症治療模式。

方法
本研究為單中心回溯性世代研究，以病歷回顧方式納入2013.3.1-2016.1.31於成大醫院急診採檢為腸內菌科菌血症之病人。排除癌症、多重菌株感染及需長時間注射治療等病人，且只納入最早一次符合之菌血症事件。當病人的臨床表現及口服吸收情況符合Nottingham大學醫院口服轉換建議時，依據48小時內轉換口服與否分為及早轉換或對照組。主要評估指標為治療成功，為一綜合性結果，包含急診採檢後30天任何檢體培養結果同菌血症之菌種、死亡或出院後因相同感染症狀再入院。其他次要指標包含口服治療失敗、住院天數及醫療花費，並以10%範圍檢測及早轉換為口服抗生素是否符合Non-inferiority。另外以Propensity score (傾向分數)配對增加兩組可比較性，或排除不同條件進行敏感性分析，檢測結果之一致性。 

結果
共納入616位病人，及早轉換組及較對照組分別為276人、340人，兩組特性不同，及早轉換組顯著較年輕、較少使用管灌飲食、共病較少及有效口服抗生素選擇較多等。及早轉換組及對照組治療成功率分為為96.4%及90.9%，成功率差異為0.055 (95% CI 0.006-0.104) p值<0.05，符合10% Non-inferiority假設，且及早轉換組治療成功率顯著較對照組高。由羅吉斯多因子迴歸分析中，菌血症嚴重程度 (Pitt Bacteremia Score)顯著減少治療成功率，而Escherichia coli菌血症和及早轉換為口服治療並不是危險因子。校正可能的干擾因素後，OR為2.13 (95% CI 1.058-4.280)。由於原始兩組收案病人顯著不同，以傾向分數配對後兩組各為232人，與結果相關之變項皆以平衡，治療成功率為及早轉換組96.1% 對照組91.4%，成功率差異 95% CI-0.006-0.101，仍符合10% Non-inferiority假設，且及早轉換組治療成功率顯著較高。僅納入達穩定狀態時培養報告已發布或有效抗生素已使用3天等情況作為敏感性分析，結果無論原始資料或傾向分數配對後之結果皆一致。適當抗生素療程兩組皆為14天，住院天數包含急診，及早轉換組及對照組分別為7天、10天 (p<0.0001)，總醫療花費減少12,260,174元新臺幣 (p<0.0001)。抗生素選擇以Cephalosporin為主，急診及轉換為口服前的注射抗生素兩組顯著不同，注射轉換為口服抗生素及早轉換組採降階模式較多，達統計差異。

結論
非院內感染且無惡性腫瘤、免疫低下、多重菌株菌血症或其他需長時間注射治療的腸內菌科菌血症病人，當臨床狀況及口服吸收符合Nottingham大學轉換口服建議時，則48小時內及早轉換為口服抗生素，不差於較長時間注射治療的效果。菌血症療程多採14天，及早轉換為口服抗生素能顯著縮短住院天數，減少醫療花費。未來須考量更多評估臨床穩定因素，以使此轉換建議可信度及應用性增加。

SUMMARY

Although guidelines for infection treatment are available, there were limited information when infection accompanied with bacteremia. Except for community-acquired pneumonia, there were no advice on the timing for antibiotic oral switch in secondary bacteremia. Some switch criteria suggested by international institutes including National Health Service (NHS) that evaluate clinical stability and oral tolerance to determine oral switch timing. Due to lack of the information of switch timing, the aims of this study were to assess non-inferiority of oral antibiotic early switch for Enterobacteriaceae bacteremia based on NHS Grampian staff guidance on Indications for IV to oral antibiotic switch therapy modified by Nottingham hospital, and to investigate treatment duration and antibiotic pattern as well. Thus we conducted a retrospective cohort study by using chart review and selected 10% as non-inferior margin. From March 2013 to January 2016, 616 patients with community-onset Enterobacteriaceae bacteremia were included from Emergency Service (ER) in National Cheng Kung University Hospital (NCKUH). Early switch wasn’t a risk factor associated with treatment success in multivariate analysis. In Non-inferiority test, treatment success was 96.4% and 90.9% in early and control group, respectively. Risk difference of treatment success was compatible with 10% non-inferiority (95% CI 0.006-0.104). After matching with propensity score or conducting sensitivity analysis, consistent results were obtained. The result of the study, early switch isn’t inferior to longer intravenous therapy as patients’ status met oral switch criteria of NHS modified by Nottingham hospital.

INTRODUCTION

Bacteremia can be life-threatening while extent of risk varies with bacteremia acquisition and pathogens. Although standard treatment protocols for primary bacteremia including infectious endocarditis and catheter-related bloodstream infection are provided in IDSA guidelines, there are limited information suggested for other infection with bacteremia. Secondary bacteremia usually takes 14 days for antibiotic therapy. Except for community-acquired pneumonia, there were no advice on oral antibiotic switch timing for secondary bacteremia in guidelines. Prolonged intravenous antibiotics may not benefit treatment outcome but increase intravenous related adverse effect, length of hospitalization and cost. In current study for early switch in bacteremia, oral switch within 7 days of treatment is appropriate. However, it remains uncertain to implement. Recently, there are antibiotic stewardship program about switch criteria which based on patients’ clinical stability and oral tolerance. For example, NHS has suggested switch criteria and modified by hospitals like Nottingham hospital. Bacteremia are not excluded in the switch criteria, but there is lack of evidence to support whether it should be indicated in bacteremia.

MATERIALS AND METHODS

This was a single-centered retrospective cohort study by using chart review. We included patients with Enterobacteriaceae bacteremia from ER in NCKUH since March 2013 to January 2016. Patients with malignancy carcinoma, immunosuppression, polymicrobial bacteremia, high risk or deep infection were excluded. Only first event was counted. Patients were grouped as ‘early switch’ if they had oral antibiotic treatment within 48 hours when met with switch criteria of NHS modified by Nottingham hospital, and the other patients were grouped as ‘control’. A non-inferiority margin of 0.1 was selected to detect difference in the primary outcome. We set composition treatment success as primary one and microbiologic eradication, readmission, switch failure, length of hospitalization and cost were secondary outcome. We performed matching with propensity score and sensitivity analysis in different groups to test robustness.

 
RESULTS

There were 616 patients included in the study. Patients in early switch group were younger, fewer enteral feeding, less comorbidity, more available oral antibiotics and etc. Treatment success rate were 96.4% and 90.9% in early switch and control group, respectively. Risk difference of treatment success was 0.055 (95% CI 0.006-0.104) which met 10% non-inferiority margin. In stepwise multivariate analysis, early switch was not a risk factor and adjusted OR with age, Charlson comorbidity score, source of bacteremia, Pittsburgh score and Escherichia coli bacteremia was 2.13 (95% CI 1.058-4.280). After matching with propensity score, there remained 232 cases per group. Treatment success in matching cohort was 96.1% and 91.4% in early switch and control group. 95% CI of non-inferiority test was -0.006-0.101 that was compatible with non-inferior hypothesis. We test result robustness by excluding patients without further blood culture, unknown to culture result as index date or appropriate antibiotic treatment shorter then 3 days and other condition. All results were consistent in non-inferiority of early switch treatment. Antibiotic treatment durations were 14 days in both groups. Included ER stay, length of hospitalization were 7 days and 10 days in early switch or control group (-3 days, p<0.001) and cost were 12,649,463 TWD and 24,909,637 TWD (-12,260,174 TWD, p<0.001), respectively. Antibiotic patterns were similar in two groups, while more attenuation therapy from intravenous to oral form were observed in early switch group significantly.

CONCLUSION

Early switch to oral antibiotic within 48 hours is non-inferior to longer intravenous therapy in patients with community-onset Enterobacteriaceae bacteremia, who meet with condition in NHS switch criteria modified by Nottingham hospital. Furthermore, early switch to oral antibiotic may reduce length of hospital stay and medical cost in the designated patients.

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