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In Vitro and in Vivo Confirmation of Amphenicol Synergism and Its Clinical Evaluation as a New Drug Combination against Amphenicol-Resistant Bacteria
|關鍵字:||畜牧獸醫類;應用研究;Amphenicols;Synergism;Antibiotic-resistant bacteria;New drug;Clinical evaluation||摘要:||
隨著抗藥性菌的快速發展及近年來逐漸趨緩的新藥開發腳步，臨床醫師經常依賴藥物併用來對抗細菌感染。寄望藉由可能的協同效果，擴大抗菌範圍及殺菌效力。但藥物併用也可能導致毒性、副作用及增加殘留的可能。本實驗室在研究Amphenicols 熱穩定性的過程中意外發現，Florfenicol (FF)顯著降解後，其抗葡萄球菌及大腸桿菌的最小抑菌濃度(MIC)卻未顯著改變，究其因，發現FF 降解後可生成Thiamphenicol (TAP)且彼此間可能具有協同作用。進一步實驗顯示，當以不到原MIC 1/20 濃度的FF 與1/2 MIC 的TAP混合時，可達到與原MIC濃度一樣的抗菌效果，此一現象也發生在Chloramphenicol (CAP)與FF 混合時，而且對具Amphenicol 抗藥基因(FloR 或CmlA)的野外分離大腸桿菌株同樣有效。基於此一重要發現，本計畫希望再進一步確認Amphenicol 類抗生素組合的協同效果及抗菌範圍，並找出最佳的組合模式及劑量，以開發新藥為目標進行動物實驗及臨床評估。此一組合乃在顯著減量情況下合用，因此有別於前述藥物併用，不但可降低成本，更預期能降低毒性、副作用、殘留以及縮短停藥期。計畫第一年首先找出最佳組合並建立組合藥物的完整抗菌範圍及體外效力評估，第二年進行最佳組合的雞隻保護及治療效力實驗，並配合病理初步評估其毒性。第三年則進行在雞之完整藥物動力學及組織清除試驗，據以評估合適的劑量，給藥間隔及停藥期。最後，利用微陣列技術對於藥物抗菌之作用機制進行基因層面的探討。有鑑於本計畫並未牽涉新化學成分，若能證實組合在藥理及微生物學上的優勢，未來應極具產業開發潛力。基於前置實驗結果，本組合已進行專利申請。
Challenged by rapid emergence of drug-resistant pathogens and limited supply of newantibiotics, clinicians increasingly rely on multidrug treatments to combat infections. Whendrugs are applied together, the interactions between drugs may be additive, synergistic, orantagonistic depending on whether their combined effect on bacterial growth is equal to,greater than, or less than expected based on the inhibitory abilities of the individual drugs.Reasons for combination of antimicrobial therapy include prevention of bacterial resistanceand synergy; other reasons for use of antimicrobial combinations include expansion ofantimicrobial spectrum, minimization of drug toxicity, minimization of antimicrobialresistance, and to reduce drug residues and cost. Preliminary but promising results in ourlaboratory derived from studies of heat stability of amphenicols revealed that this group ofantimicrobials showed synergisms against Staphylococcus aureus and Escherichia colistrains at amphenicol concentrations below 1/10 of their original MICs. Specifically, theflorfenicol (FF) could be reduced to less than 1/20 when combined with 1/2 ofthiamphenicol (TAP) to exert the same inhibitory effect to the said bacteria as the originalconcentration of each drug does. In addition, TAP could be reduced to 1/8 andchloramphenicol (CAP) be reduced to 1/16 when combined with 1/2 of FF and still inhibitsbacterial growth at micro dilution test. In addition, the inhibitory spectrum extends to knownfield isolates of amphenicol-resistant bacteria that contain either FloR or CmlA genes. Thisinitial discovery has been partially released as an invited speech session in the 2ndinternational conference of drug discovery and therapeutics (ICDDT, 2010), and is nowunder patent application. Build upon this exciting discovery and potentiality to develop anew-drug combinations to combat bacteria infections at lower cost, lower toxicity and lowerresidue concerns, we intend to further characterize the synergisms of amphenicols both invitro and in vivo, follows by a clinical evaluation of the combinations on chicken as a newdrug. In the first year the spectrum of synergism against various genera of bacteria especiallyon those presented with antibiotic resistance will be established. The best synergisticcombination(s) will be identified to be used in the second year in which in vivo assessmentsof the protective/therapeutic effects of the best synergistic combinations on chicken will beconducted along with pathological evaluations. In year 3 the complete pharmacokinetic andtissue depletion study will be performed to shed light on the appropriate dosage, dosingregiment and recommended withdrawal time. Initial assessment of the underlyingmechanism(s) of action will also be investigated employing microarray analyses focusing onknown gene profiles responsive to antibiotic treatment. The current proposal whencompleted successfully, should give a comprehensive characterization and validation tosupport a possible industrial development of a new drug (by definition in veterinaryregulation, combination of approved drugs is considered a new drug). The potentialadvantages in reducing drug dosage and associated cost, toxicity and residues, and likely anexpanded antimicrobial spectrum to resistant strains, make this proposal an attractive andworthy investment with patent indications.
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