1、常用抗菌藥物在 MRSA HAP的臨床應(yīng)用,汕頭大學(xué)醫(yī)學(xué)院第一附屬醫(yī)院 呼吸內(nèi)科 吳潔文,HAP的流行病學(xué),HAP發(fā)病率為0.5%1.0%， 居院內(nèi)感染第二位，占所有院內(nèi)感染的15%20%。在ICU，HAP發(fā)病率高達(dá)18%60%。,Chest,2002,122:2115-2121.,肺炎患病危險(xiǎn)每日增加1%,在美國(guó)，HAP病死率達(dá)30%50%，入住ICU者HAP病死率超過(guò)50%（有報(bào)道達(dá)70%），為院內(nèi)感染首要的死亡原因。,不同人群HAP發(fā)病率,88篇論文總計(jì)8705例HAP的meta分析,VAP的病原體: NNIS database,86% 的醫(yī)院內(nèi)肺炎和機(jī)械通氣相關(guān) 革蘭陽(yáng)性金黃色葡萄球菌

2、非常常見(jiàn),Richards et al. Crit Care Med 1999;27:887892,5,引起ICU內(nèi)HAP的病原體NNIS（19862003年）,Clinical Infectious Diseases 2005; 41:84854,MRSA引起的感染（2004-2005 美國(guó)）,JAMA. 2007;298(15):1763-1771,ICU內(nèi)耐藥菌的增加 (NNIS, 2002 vs 19972001),Resistance (%),0,10,20,30,40,50,60,70,80,90,萬(wàn)古霉素/腸球菌 甲氧西林/金葡菌 甲氧西林/CNS 3rd Ceph/E. col

3、i 3rd Ceph/K. pneumoniae Imipenem/P. aeruginosa Quinolone/P. aeruginosa 3rd Ceph/P. aeruginosa 3rd Ceph/Enterobacter spp.,+11 +13 +1 +14 2 +32 +27 +22 5,Change in resistance (%),JanDec 2002,19972001 ( sd),Ceph = cephalosporin;NNIS = National Nosocomial Infections Surveillance System; CNS = coagulase

4、-negative staphylococci,NNIS. Am J Infect Control 2003;31:48198,ICU病人與MRSA,CDC. Available at: /ncidod/hip/ARESIST/ICU_RESTrend1995-2004.pdf. Accessed August 30, 2005. Lowy FD. J Clin Invest. 2003;111:1265-1273.,63%,MRSA 在中國(guó),不同時(shí)期甲氧西林耐藥葡萄球菌的檢出率,檢出率（%）,中國(guó)CHINET（2006）,Prevalence of MRSA

5、 in China,798 isolates, 2005, 12 Cities, China,%,Wang H et al. Int J Antimicrob Agents 2008; (online),S.aureus Pathogenic Mechanisms,Cell wall Peptidoglycan Teichoic acids Protein A Enzymes Catalase Coagulase Clumping factor,Toxins -toxin -toxin/-toxin/-toxin Leukocidin Super antigens Toxic Shock Sy

6、ndrome Enterotoxins Exfoliative,HA-MRSA 主要感染住院病人，幾乎都是通過(guò)接觸傳播，通常感染年紀(jì)大、病情較嚴(yán)重、皮膚有傷口（例如褥瘡）或有導(dǎo)管（如導(dǎo)尿管）的人，健康人很少會(huì)感染 CA-MRSA 能夠感染健康人 擁擠的監(jiān)獄中頗為流行 近年在美國(guó)各地的城鎮(zhèn)社區(qū)（包括洛杉磯、舊金山、紐約、波士頓、邁阿密等大城市）也出現(xiàn)了多次小規(guī)模爆發(fā),CA-MRSA：現(xiàn)狀,美國(guó)弗吉尼亞州貝德福德一名17歲高中生就因感染MRSA而死亡，21所學(xué)校停課 美國(guó)每年有逾9萬(wàn)人感染MRSA；每年致死人數(shù)可能超過(guò)艾滋病,阿什頓邦茲，07年10月4日感到身體一側(cè)疼痛，就到當(dāng)?shù)匾患裔t(yī)院就診。 1

7、0月17日死亡。,Zeller JL, et al. JAMA patient page. MRSA infections JAMA. 2007 Oct 17;298(15):1826.,CA-MRSA,CA-MRSA,全球范圍內(nèi)社區(qū)獲得性MRSA的發(fā)病率呈上升趨勢(shì) 社區(qū)獲得性MRSA可從以下情況中隱匿獲得 醫(yī)療保健 日常生活 過(guò)去一年中住院超過(guò)5天 社區(qū)獲得性MRSA，表達(dá)Panton-Valentine leukocidin (p-v)潘頓-瓦倫丁殺白細(xì)胞素,JAC 2004; 53: 4749. Infect Control Hosp Epidemiol 2003; 24: 40914.

8、 Emerg Infect Dis 2003; 9: 97884.,Emerg Infect Dis 2003; 9: 97884 Infect Control Hosp Epidemiol 2003; 24: 4515 Clin Infect Dis 2003; 36: 1319.,PVL Positive S.aureusCommunity-acquired PneumoniaGillet et al, Clin Infect Disease,2007,50 cases over 9 years from 39 hospitals in 9 countries Selection bias

9、 Only 12% MRSA cases Influenza-like illness 67%,confirmed in 4/9 24% concomitant skin infections Pleural effusion 53%, multilobar infil 79% Mech vent 78%, ARDS 51% Mortality 56%, all due to pneumonia,Community-acquired MRSA Pneumonia,Survey of IDSA Emerging Infection Network After 06-07 influenza se

10、ason 30% reported a case of hospitalized S.aureus CAP Characteristics 440 adults,117 children 72% MRSA 49% mechanical ventilation 13% mortality 43% bacteremia Influenza suspected 26%,CA-MRSA Pneumonia,CA-MRSA CAP will be an increasing problem May correlate more with skin colonization than nasal PVL

11、is necessary but not sufficient to define high risk pathogen Cavitary/necrotizing pneumonia +/- effusion Combination with influenza appears to be particularly lethal, even if MSSA Massive hemoptysis, neutropenia Toxin suppression appears to be an important component of effective treatmeant,HAP的病原體構(gòu)成

12、主要影響因素,住院的時(shí)間 早發(fā) 晚發(fā) 肺炎本身的嚴(yán)重程度：重癥 非重癥 基礎(chǔ)疾病 先前的治療（抗生素、免疫抑制）,住院時(shí)間與HAP致病菌的關(guān)系,早發(fā)性HAP和晚發(fā)性HAP的病原菌,Infect Control Hosp Epidemiol 2007; 28:825-831,Etiology of HAP In Asian Countries,* Philippines: VAP data,Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.,Adapted from Kollef MH et al. Chest. 1999;1

13、15:462-474. ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.,“selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.” ATS/IDSA Guidelines,A Study by Kollef

14、 and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality,不充分的抗生素治療 (n=169),充分的抗生素治療 (n=486),0,10,20,30,40,50,60,總死亡率,感染相關(guān)死亡率,24,42*,18,住院死亡率 (%),52*,*P.001,充分起始抗生素治療降低ICU內(nèi)肺炎死亡率,1. Ibrahim EH, et al. Chest. 2000;118:146-155. 2. Valles J, et al. Chest. 2003;123:1615-1624.

15、 3. Khatib R, et al. Eur J Clin Microbiol Infect Dis. 2006;25:181-185. 4. Teixeira PJZ, et al. J Hosp Infect. 2007;65:361-367. 5. The American Thoracic Society and the Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416.,0,10,20,30,40,50,60,70,80,菌血癥,社區(qū)獲得性-,菌血癥,金葡菌,菌血

16、癥,呼吸機(jī)相關(guān),肺炎,病死率(患者% ),正確的抗菌治療,不恰當(dāng)?shù)目咕委?P, .001,1a,3,P, .05,P,= .02,2,4a,P =,.02,不充分的初始經(jīng)驗(yàn)性抗菌治療的影響,不充分初始治療使死亡率上升 研究顯示， 不充分治療是病死率高的 重要獨(dú)立危險(xiǎn)因素1-4,不充分初始治療定義為： 分離到的病原菌對(duì) 所使用的藥物不敏感5,選擇初始適當(dāng)治療應(yīng)考慮的因素*,患者 有無(wú)危險(xiǎn)因素 嚴(yán)重程度 HAP或VAP發(fā)生時(shí)間（住院時(shí)間） 既往抗生素使用 區(qū)域微生物學(xué)和細(xì)菌耐藥模式 藥物代動(dòng)力學(xué)和藥效學(xué)* 正確的抗生素劑量和療程 獲取最佳療效的給藥間隔 應(yīng)用可穿透感染部位的制劑 聯(lián)合治療的必要性

17、 預(yù)期的臨床轉(zhuǎn)歸,* Karam, George H, et al. Crit Care Med 2003; 31（2）:648650 * Schentag JJ, et al. Clin Infect Dis 1998, 26:1204-1214. Young RJ, et al. J Antimicrob Chemother 1997, 40:269-273,懷疑HAP、VAP或HCAP,晚發(fā)(5 days)HAP 或 MDR病原體的危險(xiǎn)因素,否,是,窄譜抗菌藥物,廣譜抗菌藥物針對(duì)MDR病原體,HAP初始經(jīng)驗(yàn)性抗菌藥物治療的流程圖,ATS. Am J Respir Crit Care Me

18、d 2005;171:388-416,Risk Factors for Multidrug-Resistant Pathogens (MDRP)HAP, VAP, HCAP,Antimicrobial therapy in preceding 90 days Current hospitalization of 5 days or more High frequency of antibiotic resistance in the community or in the specific hospital unit Presence of risk factor for HCAP Hospi

19、talization for 2 days or more in preceding 90 days Residence in a nursing home or extended care facility Home infusion therapy (including antibiotics) Chronic dialysis within 30 days Home wound care Family member with MDRP Immunosuppressive disease and/or therapy,Bonten MJ et al. Am J Respir Crit Ca

20、re Med 2005;171:388-416.,經(jīng)驗(yàn)性治療: 晚期發(fā)病或存在MDR病原菌感染,2006年亞洲HAP工作組 抗生素選擇策略特殊耐藥菌感染的抗生素方案,Jae-Hoon Song, and the Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.,金葡肺炎：女，26歲，宮腔術(shù)后,金葡菌,Nosocomial Pneumonia due to MRSA,Sputum and blood: MRSA,Better 1st-line Anti-MRSA Agents, Glycopeptide or Linezol

21、id ?,萬(wàn)古霉素、利奈唑胺和替考拉寧分子結(jié)構(gòu)比較,萬(wàn)古霉素是微生物發(fā)酵產(chǎn)生的天然抗生素,屬糖肽類抗生素 利奈唑胺是人工合成的抗菌藥,屬于噁唑烷酮類抗菌藥物 替考拉寧是微生物發(fā)酵產(chǎn)生的抗生素,屬于糖肽類抗生素,萬(wàn)古霉素、利奈唑胺和替考拉寧 抗菌譜比較,萬(wàn)古霉素、替考拉寧和利奈唑胺的抗菌譜相似，都是窄譜抗生素，治療革蘭陽(yáng)性菌感染 金葡菌，包括MRSA 肺炎鏈球菌，包括PRSP 凝固酶陰性葡萄球菌，包括MRCNS 腸球菌，有少數(shù)耐藥菌株,萬(wàn)古霉素、利奈唑胺和替考拉寧 適應(yīng)證的比較,35、穩(wěn)可信、他格適和斯沃產(chǎn)品說(shuō)明書(shū),萬(wàn)古霉素抗菌素作用機(jī)制,萬(wàn)古霉素屬快效殺菌劑 具有三重作用機(jī)制 1.抑制細(xì)菌細(xì)胞

22、壁的合成 抑制細(xì)菌細(xì)胞壁粘肽鏈合成的第二步 與五肽末端氨基酸分子結(jié)合，阻斷轉(zhuǎn)肽交叉連接 轉(zhuǎn)糖作用發(fā)生障礙 2. 影響細(xì)菌細(xì)胞膜的通透性 3. 抑制細(xì)菌孢漿中RNA的合成,糖肽類,糖肽類抗菌機(jī)制,Vancomycin,It is not obsolete It works mostly Resistance is rare It is cheap,It is obsolete Tissue concentration Protein binding Need high trough concentrations MIC creep Poor target attainment when MICs

23、1 VISA and hVISA hVanco,S. aureus with reduced vancomycin susceptibility,2000 (n=945),2001 (n=1026),2002 (n=1317),2003 (n=1297),2004 (n=1418),萬(wàn)古霉素對(duì)金葡菌的MIC值呈逐年上升趨勢(shì),Wang G et al. J Clin Microbiol. 2006;44:3883-3886,*一項(xiàng)自2000年1月至2004年12月UCLA醫(yī)學(xué)中心對(duì)6003例臨床分離金黃色葡萄球菌菌株進(jìn)行的分析監(jiān)測(cè)結(jié)果,近年來(lái)，萬(wàn)古霉素對(duì)70%金黃色葡萄球菌的MIC值1g/mL*

24、,分離菌株的百分比(%),Implications of decreasing susceptibility to vancomycin,Gradual reductions in vancomycin susceptibility in S aureus1,2 Vancomycin-intermediate S aureus (VISA) strains have emerged Treatment failure in MRSA bacteremia may occur within the susceptible vancomycin MIC range2,1. Wang G, et a

25、l. J Clin Microbiol. 2006;44:3883-3886. 2. Sakoulas G, et al. J Clin Microbiol. 2004;42:2398-2402.,CLSI MIC breakpoints: 2 mg/mLSusceptible 4-8 mg/mLIntermediate 16 mg/mL Resistant,CLSI = Clinical and Laboratory Standards Institute.,萬(wàn)古霉素PK與PD,PK/PD分類：兼具時(shí)間依賴性與濃度依賴性雙重特征 萬(wàn)古霉素血藥濃度要求 峰濃20-40ug/ml 谷濃10-15

26、ug/ml 最佳殺菌效應(yīng)應(yīng)為MIC3-5倍 單次給藥間隔TMIC或T3MIC以上時(shí)間應(yīng)40%,萬(wàn)古霉素PK與PD,以t1/2 6hr 1g 滴注 1hr 滴注結(jié)束，即刻峰濃60ug/ml ；2hr后峰濃 25ug/ml計(jì),用藥劑量：1.0g q12h,萬(wàn)古霉素PK與PD,以t1/2 6hr 0.5g 滴注 30分滴注,結(jié)束即刻峰濃33ug/ml; 6hr后峰濃 2.8ug/ml計(jì),用藥劑量： 0.5g q8h,萬(wàn)古霉素小鼠 S. aureus 腿感染PK/PD(AUC24/MIC、Cmax/MIC、TMIC ),R2=90%,-4,-2,0,2,-4,-2,0,2,10,100,1000,10

27、,100,1000,1,-4,-2,0,2,40,100,120,0,20,60,80,R2=56%,R2=75%,Free drug AUC24/MIC,Free drug Cmax/MIC,Free drug %TMIC,CFU change in Lg10/thign,CID 2006,42(suppl 1):S35,萬(wàn)古霉素療效與 AUICs,Outcome Parameters Satisfactory Unsatisfactory Indeterminate MIC 1.0 g/ml 1 4a 0 MIC 125 (76) 71 2 3 Total Patients (84) 75

28、 6 3,a p 0.001 b p 0.005,Hyatt et al, Clinical Pharmacokinetics 1995, 28: 143,萬(wàn)古霉素MIC與MRSA敗血癥/肺炎感染治療,Wilhelm KL. 2008 ICAAC abstract A-1905,萬(wàn)古霉素MIC與MRSA 敗血癥療效,Kaur I. 2008 ICAAC abstract K-564,國(guó)內(nèi)葡萄球菌對(duì)萬(wàn)古霉素始終保持100%敏感率,1998-2006全國(guó)細(xì)菌耐藥監(jiān)測(cè)結(jié)果,1、李家泰, Allan J Weinstein, 楊敏等. 中國(guó)細(xì)菌耐藥監(jiān)測(cè)研究. 中華醫(yī)學(xué)雜志 2001;81(1):8-1

29、6 2-7. 國(guó)家細(xì)菌耐藥性監(jiān)測(cè)中心監(jiān)測(cè)數(shù)據(jù)總結(jié),RESIST研究中3100株耐甲氧西林葡萄球菌對(duì)12種抗生素的耐藥率,RESIST研究中207株甲氧西林敏感葡萄球菌對(duì)12種抗生素的耐藥率,RESIST研究的結(jié)論,3307株葡萄球菌中： 除一株MRCNS，所有菌株對(duì)萬(wàn)古霉素保持100%敏感 無(wú)論對(duì)甲氧西林耐藥還是對(duì)甲氧西林敏感的葡萄球菌對(duì)替考拉寧存在不同程度耐藥，尤其是凝固酶陰性葡萄球菌 MRCNS對(duì)替考拉寧的耐藥性高，其中耐甲氧西林溶血性葡萄球菌(MRSH)對(duì)替考拉寧的耐藥率高達(dá)48.2% 對(duì)甲氧西林敏感的溶血性葡萄球菌(MSSH)對(duì)替考拉寧的耐藥率達(dá)38.5%,2009年CLSI最新指南：

30、,葡萄球菌：,萬(wàn)古霉素與同為糖肽類替考拉寧相比： 萬(wàn)古霉素對(duì)葡萄球菌和腸球菌的MIC值比較中，萬(wàn)古霉素仍然有明顯的優(yōu)勢(shì),腸球菌：,萬(wàn)古霉素在肺組織的濃度,在一項(xiàng)30例行肺葉次全切除術(shù)的患者研究中，靜脈給予萬(wàn)古霉素1 g 之后，組織藥物濃度范圍為0-12.2 mg/kg，平均組織濃度為2.8 mg/kg，組織穿透率為41%,Penetration of vancomycin into human lung tissue M. Cruciani, G. Gattr*, L. Lazzarini, G. Furlan, G. Broccali, M. Malena, C. Franchini and

31、 Ercole Concia,萬(wàn)古霉素的肺組織濃度,健康志愿者給予萬(wàn)古霉素1 g q12h 給藥后，12 h肺組織濃度為2.4 mg/kg ， 總體穿透率為52% 。,Program and abstracts of the 14th European Congress of Clinical Microbiology and Infectious Diseases (Prague). Basel: European Society of Clinical Microbiology and Infectious Diseases, 2004:44 31 MichaelJ.Rybak The P

32、harmacokinetic and Pharmacodynamic Properties of Vancomycin. Clinical Infectious Diseases 2006; 42(Suppl 1):S35S39,不同時(shí)間血漿和肺組織中萬(wàn)古霉素的濃度1,萬(wàn)古霉素治療金葡菌菌血癥和心內(nèi)膜炎的臨床療效,9 Ann Int Med 115:674 10 JAMA 238:1756 11 J Antimicrob Chemo 14:Suppl D:73 12 J Infect Dis 147:137 13 NEJM 262:49-55 14 Ann Int Med 97:330-338

33、 15 Antimicro Agents and Chemo 23:36 16 Ann Int Med 97:344,替考拉寧治療重癥感染的療效,17 J Infect Dis 1987;155(2):187-91 18 Int J Antimicrob Agents 1994;4(Suppl 1):S1-S30 19 Clin Drug Invest 1996;12:80-7,替考拉寧治療金葡菌心內(nèi)膜炎的療效,20 J Antimicro Chemo 27(Suppl B):43 21 Antimicrob Agents S1 24 ICC 1993, Abstract 1223,萬(wàn)古霉素和

34、替考拉寧的療效比較,同屬于糖肽類抗生素，具有相似的化學(xué)結(jié)構(gòu)和抗菌譜 金葡菌和凝固酶陰性葡萄球菌對(duì)替考拉寧易產(chǎn)生耐藥 替考拉寧較高的蛋白結(jié)合率（90-97%) ,使感染部位無(wú)法達(dá)到有效 的藥物濃度，導(dǎo)致對(duì)嚴(yán)重感染療效不確切，需加大劑量 替考拉寧常規(guī)劑量臨床療效不理想（尤其在心內(nèi)膜炎），加大劑 量往往導(dǎo)致副反應(yīng)增加 研究表明，穩(wěn)可信與替考拉寧在引起皮疹，腎功能障礙等副反應(yīng) 方面無(wú)統(tǒng)計(jì)學(xué)差異；但替考拉寧引起的血小板減少癥的發(fā)生率顯 著高于穩(wěn)可信,利奈唑胺抗菌機(jī)制,利奈唑胺抗菌譜,Gram-positive microorganisms: 屎腸球菌(包括VRE) 金黃色葡萄球菌(包括MRSA) 肺炎鏈

35、球菌(包括PRSP) 無(wú)乳鏈球菌 化膿性鏈球菌 糞腸球菌(包括VRE) 表皮葡萄球菌(包括MRSE) 溶血葡萄球菌 草綠色鏈球菌 Some anaerobic bacteria:,萬(wàn)古霉素和利奈唑胺治療院內(nèi)肺炎療效相當(dāng),在利奈唑胺提交給FDA的臨床報(bào)告中,治療醫(yī)院內(nèi)肺炎的臨床研究.用萬(wàn)古霉素和利奈唑胺進(jìn)行對(duì)照,顯示萬(wàn)古霉素可評(píng)價(jià)臨床療效為60%,利奈唑胺可評(píng)價(jià)臨床療效57%,0,10,20,30,40,50,60,利奈唑胺,萬(wàn)古霉素,利奈唑胺,25 ZYVOX 產(chǎn)品說(shuō)明書(shū)信息 Distributed by Pfizer Pharmacia I2=0%; N=853); ME RR=1.10(C

36、I 0.97, 1.23; p=0.11; I2=0%; N=597); and MRSA population RR=1.14(CI 0.82, 1.58; p=0.44; I2=47%; N=191). If linezolid is compared to vancomycin only, the CC RR remains 1.01 (CI 0,73, 1.47), respectively. The risk of thrombocytopenia(RR=1.92CI 1.29, 2.86; p=0.001) and GI event (RR=1.90CI 1.04, 3.48; p

37、=0.03) were significantly higher with linezolid, but no differences were seen for renal dysfunction (RR=0.82CI 0.52, 1.27; p=0.37, or all cause deaths(RR=0.95CI 0.76, 1.18; P=0.63).,2008 ICAAC K-533,Conclusions: Meta-analysis did not detect clinical superiority of linezolid vs. glycopeptides for tre

38、atment of NP. Compared to linezolid, Vancomycin was not associated with more renal dysfunction. Linezolid shows a significant increase in the risk of thrombocytopenia an GI events. Available data dose not support the claim that linezolid is superior to vancomycin for the treatment of NP.,利奈唑胺耐藥性,抗菌機(jī)

39、制:50S亞基中23S rRNA V區(qū)結(jié)合 耐藥機(jī)制: 23S rRNA V區(qū)點(diǎn)突變, G2576T 疊加性: 5-6個(gè)23S rRNA 基因逐步變異 交叉耐藥:氯霉素,鏈陽(yáng)霉素,林可霉素 Enterocccus, Staphylococcus 臨床菌株已有報(bào)道 實(shí)驗(yàn)室篩選,萬(wàn)古霉素和替考拉寧安全性的比較,26、a p = 0.007, Fishers test 27、Source: Wilson, Grunberg, Neu, Int. J. Antimicrob Agents, Suppl 1:S1 (1994),萬(wàn)古霉素和利奈唑胺安全性比較,由于萬(wàn)古霉素制劑的純度顯著提高，目前臨床大量應(yīng)

40、用萬(wàn)古霉素，證實(shí)其腎毒性很少見(jiàn),包括調(diào)整劑量后用于腎功能受損的病人，同時(shí)萬(wàn)古霉素的腎毒性具有可逆性28。而有數(shù)據(jù)表明，利奈唑胺引起的嚴(yán)重不良反應(yīng)血小板減少的病例高達(dá)35%,在腎功能損傷的病人應(yīng)用利奈唑胺引起的血小板減少達(dá)到65%,29。,高純度的萬(wàn)古霉素具有良好的安全性,28 Wakefield DS, Pfaller M, Massanari RM, Hammons GT. Variation in methicillin-resistant Staphylococcus aureus occurrence by geographic location and hospital characteristics. Infect Control. 1987;8(4):151-7 29 Yen-Hung Lin, Vin-Cent Wu High frequency of linezolid-associated thrombocytopenia Among patients with renal insufficiency. International Journal of Antimicrobial Agent 28(2006)345-351,Antibiotic re