臺灣博碩士論文加值系統

抗生素治療包氏不動桿菌的療效難以確立，其原因包括：受到原有疾病因子的干擾、未校正感染嚴重度之差異、以及過去研究對象常摻雜了非包氏的其他不動桿菌菌株感染之病患。包氏不動桿菌與非包氏的不動桿菌其臨床重要性並不相同，以不動桿菌最常造成的臨床感染—肺炎—為例，包氏不動桿菌與非包氏的不動桿菌中最常見的菌種Acinetobacter nosocomialis相比，前者所造成之肺炎嚴重度較高，抗藥性比例較高，病患接受不適當抗生素治療的機會也較多。本回溯性研究不但利用分子生物學方法確定菌株菌種為包氏不動桿菌，排除多重菌種感染的病患，並根據APACHE II分數高低，將包氏不動桿菌菌血症病患病情嚴重度分級。結果發現，適當的抗生素治療可降低死亡率，而且其效應受到APACHE II分數的影響，嚴重度分群分析結果顯示，適當的抗生素治療降低死亡率的程度，在APACHE II分數高的族群更為顯著。進一步分析曾接受適當的抗生素治療的病患，其致病菌株不論是否對carbapenem具抗藥性，帶有ISAba1-blaOXA51-like基因結構即為死亡的獨立危險因子，為了探究此現象可能原因，我們繼續進行了以下的研究。在一位具有中央靜脈導管及腦室腹腔分流管的病人身上發現八株carbapenem heteroresistant之包氏不動桿菌(AbSK-11至-18)。其中一株(AbSK-17)在原先之敏感性實驗顯示對carbapenem 具感受性, 但使用meropenem 及amikacin治療感染結果卻失敗。這八株包氏不動桿菌族群中抗藥的細胞在所有細胞所佔的比例從1.85 ± 1.28 ×10-3 至5.59 ± 0.68 ×10-4 不等。在各種抗生素，包括β-lactam類抗生素的處理下，抗藥細胞的族群會增加。在這株包氏不動桿菌的質體上(pAbSK-OXA-82)有一blaOXA-82基因(屬於blaOXA-51-like家族)，此blaOXA-82基因的上游有一ISAba1 (ISAba1-blaOXA-82)。不等成度抗藥性之原因乃pAbSK-OXA-82在細胞子代中不穩定的傳遞，造成有些子代有攜帶抗藥性的質體，而有些則無。獲得pAbSK-OXA-82的子代(AbSK-17R)其carbapenem的最低抑菌濃度為32 μg/ml；而不帶pAbSK-OXA-82的子代(AbSK-17S)其carbapenem的最低抑菌濃度則為2 μg/ml。在沒有抗生素的篩選下，AbSK-17R族群中抗藥的細胞比例會逐漸減少。然而，在有meropenem、sulbactam 及ciprofloxacin的培養環境下，可在不抗藥的AbSK-17S 中重新篩選出抗藥的突變株(AbSK-17SrevR)。此研究顯示包氏不動桿菌可以利用微調pAbSK-OXA-82的有無來應對環境中抗生素的有無。這也說明了即使phenotype對carbapenem為敏感，具有ISAba1-blaOXA-51-like的細菌仍可能在抗生素的存在下變成抗carbapenem，導致病患的不良預後。

The efficacy of antimicrobial therapy for Acinetobacter baumannii bacteremia has been difficult to establish because of confounding by underlying diseases, severity of infection and differences in the pathogenicity of Acinetobacter species. There are differences in clinical significance between A. baumannii and other Acinetobacter species, among which Acinetobacter nosocomialis is the most common isolated species in clinical settings. Compared with patients with A. nosocomialis pneumonia, patients with A. baumannii pneumonia were significantly more likely to have more severe illness as determined by APACHE II score, and a greater frequency of antimicrobial resistance and inappropriate use of antimicrobials. This retrospective study was conducted to evaluate the effect of appropriate antimicrobial therapy on 14-day mortality after adjustment for multiple risk factors. The population consisted of 252 patients with monomicrobial A. baumannii bacteremia admitted to a large teaching hospital in Taiwan. The isolates were identified to species level using reference molecular methods. Predictors of 14-day mortality were determined by logistic regression analysis. The influence of severity of infection, determined by Acute Physiology and Chronic Health Evaluation (APACHE) II score, on the impact of appropriate use of antimicrobials on 14-day mortality was assessed by including an interaction term. The overall 14-day mortality was 75/252 (29.8%). The unadjusted mortality for appropriate antimicrobial therapy was 12/91 (13.2%). Appropriate therapy was independently associated with reduced mortality (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.01-0.50; P < .001), and the effect was influenced by APACHE II score (OR for interaction term, 0.90; 95% CI, 0.82-0.98; P = .02). Subgroup analysis revealed that the benefit of appropriate therapy limited to patients with high APACHE II scores (for scores > 25 and ≤ 35, OR, 0.16; 95% CI, 0.07-0.37 and for scores >35, OR, 0.06; 95% CI, 0.01-0.25). Appropriate antimicrobial therapy significantly reduced 14-day mortality for A. baumannii bacteremia in severely ill patients. In addition, carriage of the genetic structure ISAba1-blaOXA-82 in A. baumannii is an independent risk factor for 14-day mortality, regardless of carbapenem resistance or not. Therefore, the following study was performed to elucidate the possible mechanism of this phenomenon.
We have identified 8 carbapenem heteroresistant A. baumannii isolates (AbSK-11 to -18) belonging to the same strain from a patient with a central venous catheter and ventriculoperitoneal shunt related infection. One of the isolates (AbSK-17) was initially misidentified as susceptible to carbapenem by the agar dilution test, but the patient failed to response to combination therapy with meropenem and amikacin. Among the eight different isolates, the proportion of resistant cells in mid-log phase growth ranged from 1.85 ± 1.28 ×10-3 to 5.59 ± 0.68 ×10-4. The resistant subpopulation could be increased by treatment with several antibiotics, including non β-lactam antibiotics. In this strain, a blaOXA-51 -like, blaOXA-82 with ISAba1 upstream (ISAba1-blaOXA-82) was found on a plasmid (pAbSK-OXA-82). The reason for heteroresistance was found to be unstable propagation of pAbSK-OXA-82 in cells. The MICs of carbapenem in cells with or without pAbSK-OXA-82 was 32 μg/ml (AbSK-17R) and 2 μg/ml (AbSK-17S), respectively. The resistant subpopulation of AbSK-17R decreased in the absence of antibiotic selection. However, resistant revertants (AbSK-17SrevR) carrying pAbSK-OXA-82 could be re-isolated from AbSK-17S in the presence of meropenem, sulbactam and unexpectedly, ciprofloxacin. This bacterium might respond to selection pressure through the presence or absence of antibiotics by a fine-tuning of the mechanism for propagating pAbSK-OXA-82. It indicated that even though A. baumannii carrying plasmid borne ISAba1-blaOXA-82 were susceptible to carbapenems, they may become resistant to carbapenems in the presence of antibiotics and thereby contributed to a poor prognosis.

Abstract
In English ………………………………………………………………4
In Chinese ………………………………………………………………7
Introduction …………………………………………………………………9
Materials and Methods ……………………………………………………16
Results ………………………………………………………………………37
Discussion …………. ………………………………………………………83
References …………………………………………………………………90
Appendix ……………………………………………………………………105

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