- 學位論文
抗生素的最小抑制濃度對胃幽門螺旋桿菌之治療組合療效的影響
The impact of antibiotics MIC value on the efficacy of treatment regimens for Helicobacter pylori infection
摘要
研究背景 現今常用於治療胃幽門螺旋桿菌 (Hp)感染的抗生素包括：克拉黴素 (clarithromycin; CLA)、安摩西林 (amoxicillin; AMO)、甲硝唑 (metronidazole; MET)、左氧氟沙星 (levofloxacin; LEV)、四環黴素 (tetracycline; TET)等。已有文獻指出抗生素抗藥性的趨勢與治療成效有重要的相關性，而選擇有效的治療方式也可以減少病菌抗藥性的持續增加。除了服藥順從性以及抗生素抗藥性之外，其餘因子包括年齡、性別、潰瘍診斷、共病症等，皆有可能影響療效。另外，從部分研究結果也可以發現，即使所有Hp菌株觀察到的抗生素最小抑制濃度 (minimal inhibitory concentration; MIC) (單位: μg/mL)皆已超過目前常用的臨界值 (breakpoint)，被認為對此抗生素具有抗藥性，仍能有效治癒，但治癒率隨著菌株MIC值的升高而下降。然而目前少有研究將MIC數值高低納入為變動選項，與治療效果做相關性分析。 研究目的 探討年齡、性別、潰瘍診斷、共病症等，特別加上MIC數值這項因子與不同的治療組合進行治療效果的相關性分析。 研究方法 本研究設計採回溯性世代研究 (retrospective cohort study)，以臺大醫院電子、紙本病歷等相關資料，回溯收集自1994年1月至2018年3月符合所定納入以及排除條件篩選的受試者進行分析。受試者相關資料的收集，包括年齡、性別、診斷、抗生素抗藥性以及MIC數值等。除描述性統計，本研究也進行單因子相關性分析以及羅吉斯複迴歸分析 (multiple logistic regression analysis)來檢定各個變項，對於治療幽門螺旋桿菌療效的影響是否具顯著性，並以勝算比 (odds ratio)以及95%信賴區間 (95% confidence interval)來表示各項危險因子變項對Hp治癒率的影響情形，本研究將以雙邊對立假設p值 (two-sided p value)小於0.05表示具有統計學顯著性。 研究結果 含有clarithromycin之三合一療法中，共納入784位符合分析條件的受試者進行分析。單因子相關性分析以及羅吉斯複迴歸分析的結果顯示，對clarithromycin具有抗藥性或依照不同clarithromycin MIC值進行分組的這兩因子會顯著影響治療效果。而在clarithromycin MIC<1、1≤clarithromycin MIC<4以及4≤clarithromycin MIC各組別的治癒率分別為：91.3%、59.1%以及13.3%。相較於clarithromycin MIC<1這一組別，1≤clarithromycin MIC<4以及4≤clarithromycin MIC兩組治療失敗的風險隨著MIC值的升高而顯著增加，其勝算比 (95%信賴區間)分別為：7.263 (2.971-17.753)以及68.191 (22.964-202.494)。 含有metronidazole之三合一療法以及同時性療法 (同時使用amoxicillin、metronidazole以及clarithromycin三種抗生素)中，分別有170人以及100人進行分析。單因子相關性分析以及羅吉斯複迴歸分析結果皆指出，抗生素抗藥性為最顯著影響療效的因子。在含有metronidazole之三合一療法中，具有metronidazole抗藥性的族群，其治療失敗的風險相較於無抗藥性的族群高。而在同時性療法中，具有clarithromycin或metronidazole抗藥性的族群，其治療失敗的風險相較於無抗藥性的族群高。另外，性別與年齡也會顯著影響含有metronidazole之三合一療法的治療效果。 連續性療法 (治療前五天使用的抗生素為amoxicillin，而後五天所使用的抗生素為metronidazole以及clarithromycin)中，納入了199位符合條件的受試者進行分析。單因子相關性分析以及羅吉斯複迴歸分析結果皆指出，只有依照clarithromycin或metronidazole MIC值分組或抗生素抗藥性為最顯著影響療效的因子。若受試者對clarithromycin以及metronidazole皆具有抗藥性，則治癒率會顯著下降至31.4%。相較於clarithromycin MIC小於1這一組別，clarithromycin MIC大於等於4此組治療失敗的風險會顯著增加，其勝算比 (95%信賴區間)為：20.397 (7.445-55.883)；而相較於metronidazole MIC小於8這一組別，metronidazole MIC大於等於32此組治療失敗的風險會顯著增加，其勝算比 (95%信賴區間)為： 5.605 (2.149-14.617)。若族群對clarithromycin MIC值小於4且metronidazole MIC值小於32，治癒率仍可維持在90%以上，即使MIC值皆已超過現今常用之臨界值，被視為對此兩抗生素具有抗藥性。 結論 含有clarithromycin三合一療法中，治癒率會隨著菌株對clarithromycin MIC值的不同而有所不同。而在連續性療法中，即使菌株的MIC值皆已超過臨床常用的臨界值，已被視為具有抗藥性，但若在clarithromycin MIC<4且metronidazole MIC<32的情況下，治癒率仍可維持在90%以上。由上述結果可得知，目前臨床上常用於判斷菌株是否對抗生素具有抗藥性的臨界值，並未達到最好的分界。換句話說，雖然病患所帶的菌株依照現今臨床上常用之臨界值會被視為對clarithromycin或metronidazole具有抗藥性，但若屬於低抗藥性範圍的族群，仍然可以得到不錯的治療效果。 中文關鍵詞：幽門螺旋桿菌、抗藥性、最小抑制濃度、治療效果
並列摘要
Background Clarithromycin (CLA)、amoxicillin (AMO)、metronidazole (MET)、levofloxacin (LEV) and tetracycline (TET) are commonly used antibiotics for Helicobacter pylori (Hp) therapy. However, the efficacy of treatment for Hp infection has decreased due to increasing resistance to CLA, MET and LEV. Studies have reported that beside antibiotics resistance, other factors such as age, sex, underlying disease, etc. may also affect the treatment efficacy. In some cases, even the MICs (minimal inhibitory concentration, μg/mL) for Hp strains were greater than the breakpoint, Hp strains with lower MICs had better eradication than the ones with higher MIC values. However, few study investigated the relationship between MIC values and treatment outcome. Study objective We aimed to analyze the impact of influencing factors, especially minimal inhibitory concentration (MIC) value, on the efficacy of different treatment regimens. Methods We performed a retrospective study by using electric medical record at National Taiwan University Hospital (NTUH) in Taiwan. Patients who had been diagnosed with H. pylori infection and received H. pylori therapy between 1994 and 2018 were recruited. The demographic and clinical data (age, sex, gastrointestinal diagnosis, antibiotic resistance, MIC value, etc.) from each subject were collected. Univariate and multiple logistic regression analysis was performed to find out factors which significantly affected the treatment efficacy. The impacts of factors on the treatment efficacy were described by odds ratios and 95% CIs. Two-sided P values less than 0.05 were considered statistically significant. Results In clarithromycin-containing triple therapy group, 784 patients were recruited for analysis. In univariate analysis, sex, age and diagnosis did not significantly affect the treatment efficacy. However, resistant to clarithromycin significantly reduced the treatment efficacy (p value<0.001). Eradication rates at different clarithromycin MIC values (MIC<1; 1≤MIC<4; 4≤MIC) were 91.3%, 59.1% and 13.3%, respectively. The multiple logistic regression analysis revealed that group with 1≤CLA MIC<4 and 4≤CLA MIC were independent factors predictive of treatment failure, with odds ratio of 7.263 (95% CI: 2.971-17.753) and 68.191 (95% CI: 22.964-202.494), respectively. In metronidazole-containing triple therapy and concomitant therapy, 170 and 100 patients were recruited for analysis, respectively. In univariate analysis, resistant to clarithromycin or metronidazole significantly reduced the treatment efficacy (p value<0.001). Sex and age also affected the treatment efficacy of metronidazole-containing triple therapy significantly. In sequential therapy, 199 patients were recruited for analysis. In univariate analysis, sex, age and diagnosis did not significantly affect the treatment efficacy. However, resistant to clarithromycin or metronidazole significantly reduced the treatment efficacy (p value<0.001). Eradication rate was only 31.4% in patients with clarithromycin/metronidazole dual resistance. The multiple logistic regression analysis revealed that group with 4≤CLA MIC and 32≤MET MIC were independent factors predictive of treatment failure, with odds ratio of 20.397 (95% CI: 7.445-55.883) and 5.605 (95% CI: 2.149-14.617), respectively. However, eradication rate remained greater than 90% in patients with clarithromycin MIC <4 and metronidazole MIC <32. In multiple logistic regression analysis, the most important impact factor was clarithromycin and metronidazole MIC values. Conclusion In clarithromycin-containing triple therapy, treatment efficacy varied depending on the clarithromycin MIC values. In sequential therapy, eradication rate remained greater than 90% in patients with clarithromycin MIC <4 and metronidazole MIC <32, even the MIC values were higher than the common used breakpoint. Keywords：Helicobacter pylori, resistance, minimal inhibitory concentration, treatment efficacy