第四代头孢菌素——头孢派姆
作者：潘启超
单位：(中山医科大学肿瘤研究所，广州 510060)
关键词：头孢派姆；第四代头孢菌素
第四代头孢菌素 摘要 目的：阐明第四代头孢菌素头孢派姆的特性。方法:用常规体内、体外及临床方法评价本药。结果与结论:头孢派姆抗菌力强,抗菌谱广,较少产生耐药性。
CEFEPIME——A CEPHALOSPORINE OF THE FOURTH GENERATION
Pan Qichao
(Cancer Institute, Sun Yat-sen University of Medical Sciences, Guangzhou 510060)
, 百拇医药
ABSTRACT OBJECTIVE：To explain the characteristics of the fourth generation cephalosorine, cefepime. METHODS: The durg is evaluated by usual in vitro, in vivo, and clinical methods. RESULTS AND CONCLUSION: Cefepime is a powerful antibaterial agent with broader antibacterial spectra and fewer bacterial resistance.
KEY WORDS Cefepime; Cephalosporine of the fourth generation
头孢菌素类已出现第一至第三代产品,第二代产品引入了肟基,提高了对β-内酰胺酶的稳定性。第三代头孢类提高了抗绿脓杆菌的活性,延长了半衰期,减轻了对肾的毒性。现在又出现第四代头孢菌素。第四代头孢菌素有头孢派姆(cefepime,CFP)即Maxisime,同类还有头孢克列定(cefaclidine)、头孢派洛姆(cefpirome)及E1077等。
, 百拇医药
1 化学〔1〕
CFP在头孢烯的3位上有一个季铵化的N-甲基吡咯啶基,使化合物成为阴阳双性离子,易于透入G-菌外层细菌膜孔而起抗菌作用。其7位上取代,则基本上与其他第三代头孢菌素类相同,均有肟基,对酶稳定;又有噻唑环增强其抗菌活性。
2 抗菌谱〔2～6〕
对1 757个临床分离菌株的最低抑菌浓度(MIC)研究认为:① 对非β-内酰胺酶产生性细菌,如大肠杆菌、奇异变形杆菌的MIC在0.06～0.12μg/ml。② 对β-内酰胺酶产生菌如弗氏枸橼酸菌、粘质沙雷杆菌、摩根氏摩根菌等MIC为0.03～16μg/ml,均优于多数三代头孢菌素类药。③ 对(副)流感杆菌MIC为0.016～0.16mg/ml。④ 对不动杆菌MIC为0.12～4μg/ml,略低于三代头孢菌素类药。⑤ 抗绿脓杆菌活性与头孢他定相似,MIC为0.5～>128μg/ml,对头孢他定耐药菌仍有效。⑥ 对G-双球菌如脑膜炎或淋病菌MIC为0.004～0.12μg/ml。⑦ G+菌方面,对甲氧苯青霉素敏感的金葡菌(MSSA)的MIC为0.5～16μg/ml,但对该药不敏感菌(MRSA)则仍为耐药。对非肠源链球菌,如A、B、C、G族链球菌及肺炎球菌的MICs为0.016～0.5μg/ml。但对致单核细胞性李斯特菌的MIC为32～128μg/ml。⑧ 对脆弱拟杆菌等厌氧菌无效。
, 百拇医药
在囊性纤维化病人本品抗绿脓杆菌与环丙沙星、托普霉素、单酰胺菌素协同，但与泰宁(Tienem)及多粘菌素B对抗〔7〕。
3 耐药性机理〔1,4,6〕
3.1 G-菌可改变其外层细胞膜孔而改变其药物的透过性。本品透入大肠杆菌、假单孢菌类、阴沟肠杆菌的速率比头孢氨噻肟快。
3.2 青霉素结合性蛋白质(PBPs)在肺炎球菌、流感嗜血杆菌及淋病双球菌中发生变异,是耐药性产生原因之一,而本品对PBPs的亲和力较高。本药对大肠杆菌及绿脓杆菌的PBPs比三代头孢菌素类亲和力更高。
3.3 本品对于肠杆菌属、克雷伯氏细菌属及绿脓杆菌属染色体所介导的头孢菌素酶头孢氨噻肟及头孢他定的亲和力小,亦较稳定。本品对质粒介导的头孢菌素酶亦较稳定。同时,本品无诱导β-内酰胺酶产生的能力是其特性之一。
, 百拇医药
4 药代动力学〔8～14〕
多剂量给药,每次如用双倍递增剂量250、500、1000及2000mg,其峰浓度依次为17.5,31.2,66.9及137mg/L,而其AUC依次为33.9,58.1,137及239 μg*h/ml。表现其随剂量增加而递增,呈线性增加。按正常剂量2g/次计,峰浓度远高于敏感细菌的MIC。达峰时间一般为0.5～1.5h,平均半衰期为2.195(2.09～2.32)h,平均全身清除率为134(124～144)ml/min。如在健康志愿者静滴30min,浓度为250,500,1 000或2 000μg/ml,其峰浓度亦由16.3mg/L递增至133mg/L;AUC由34mg*h/L递增至263mg*h/L。平均半衰期为1.85(1.8～1.9)h;平均清除率为104.8(96～116)ml/min;尿中平均回收率为81.2(78.4～85.6)%,大部分为原形。iv或静滴所达到的峰浓度为im的2～3倍(57.5mg/L),但im的AUC、清除或尿中回收等与静滴相同。本品与血清蛋白的结合率仅16%～19%,稳态分布容积为14～20L。少部分药物在体内代谢变为7位表同分异构体、N-甲基吡咯啶及其N-氧化物。
, 百拇医药
肾功能不良及肌酐清除率为10～30或<10ml/min者峰浓度不会升高,AUC则升高达7倍(由131升到928mg*h/L),表观分布容积不变,半衰期升6倍,且尿中回收率为0。对这样的病人,要由2g/次,q12h,减到1g/次，q16h。而肌酐≤10ml/min者及要求血透析的病人,则1g/次,q24h。每次透析后要补给1g。对于连续腹腔透析病人则静滴1g,q48h。肝功能不良者不再调整剂量。
通过支纤境研究,证明q12h给药2g时,支气管粘膜组织浓度已经足够。本药亦可透入腹腔及胆汁中,在阑尾及前列腺组织亦达相应浓度。患囊性纤维化病患者的药动学变化不大。本品可透入脑脊液中,在金葡菌性新生大鼠慢性脑膜炎,本品与头孢氨噻肟等效,但对克雷伯氏菌、绿脓杆菌或流感嗜血菌所致脑膜炎则较优。
5 不良反应〔3～5,11〕
不良反应少见且不严重,头痛发生率约为2.4%,恶心1.8%,皮疹1.8%,腹泻1.7%。其他还有视物模糊、头轻感、消化不良等。静脉给药者可见静脉炎。血清AST偶见升高,但无临床的肝毒性。在4 400病人应用6g/d仍安全。
, 百拇医药
6 临床应用〔6,15～20〕
6.1 单药治疗 一般q12h给药1～2g,用于G-杆菌所致严重中枢神经系统感染,如脑膜炎等。社会上获得的G-杆菌(非绿脓杆菌)所致的肺炎,囊性纤维化病人的肺炎亦可用。皮肤及软组织感染疗效亦颇满意。骨及关节感染疗效亦好。在兔葡萄球菌性慢性骨髓炎中用本品可使53%动物无菌。在泌尿道感染中代替常用的氨基甙类,除抑菌作用较强、尿中药物浓度高外,无肾脏毒性,故疗效好。
6.2 联合治疗 对腹腔内感染宜加用抗厌氧菌药物如甲硝唑、替硝唑或氯洁霉素。绿脓杆菌所致的医院获得性肺炎,宜与其他抗绿脓杆菌的抗生素如氧哌嗪青霉素、单酰胺菌素、氟喹诺酮类等合用,对头孢他定耐药菌株用本药仍有效。
对免疫力低的病人白细胞减少性发热,亦须与氟喹诺酮类、抗绿脓杆菌的青霉素(如哌嗪青霉素)或头孢菌素(如头孢他定)或与庆大霉素等合用。同时本药常须2g/次,q8h。
, http://www.100md.com
参 考 文 献
1 Naito T,Aburaki S,Kamachi H, et al. Synthesis and structure activity relationships of a new series of cephalosporins BMY 28142 and related compounds. J Antibiotics, 1986, 39(8)∶1092
2 Bosso JA, Saxon BA, Matsen JM. Comparative activity of cefepime alone and in combination against clinical isolates of pseudomonas aeruginosa and pseudomonas cepacia from cystic fibrosis patients. Antimicrob Agents Chemother, 1991,35(4)∶783
, 百拇医药
3 Kessler RE, Fung-Tomc J.Susceptibility of recent bacterial isolates from the cefepime clinical trials in the United States. Am J Med, 1993,95 (Suppl 4A)∶S10
4 Neu HC. Safety of cefepime: A new extended-spectrum cephalosporin antibiotic. Am J Med, 1993, 95 (Suppl 4A)∶S67
5 Okamoto MP,Nakahiro RK,Chin A, et al. Cefepime: A new fourth generation cephalosporin. Am J Hosp Pharm, 1994, 51(4)∶463
, http://www.100md.com 6 Sanders CC. Cefepime: The next generation? Clin Infect Dis, 1993, 17(3)∶369
7 McCabe R, Chirugi V,Farkas SA,et al. Cefepime versus ceftazidime in the treatment of lower respiratory tract infections. Am J Med, 1993, 95 (Suppl 4A)∶S24
8 Barbhaiya RH, Forgue ST, Gleason CR, et al. Pharmacokinetics of cefepime after single and multiple intravenous administrations in health subjects. Antimicrob Agents Chemother, 1992, 36(3)∶552
, http://www.100md.com
9 Barbhaiya RH, Knupp CA, Forgue ST, et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther, 1990, 48(3)∶268
10 Barbhaiya RH, Knupp CA, Pfeffer M, et al. Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother, 1992, 6(7)∶1387
11 Barbhaiya RH, Knupp CA, Pittman KA. Effects of age and gender on pharmacokinetics of ecfepime. Antimicrob Agents Chemother, 1994, 36(6)∶1181
, http://www.100md.com
12 Barbhaiya RH, Knupp CA, Tenney J, et al. Safety, tolerance, and pharmacokinetics of cefepime administered intramuscularly to health subjects. J Clin Pharmacol, 1990, 30(10)∶900
13 Barriere SL. The pharmacokinetic profile of cefepime. Am J Med, 1993, 95 (Suppl 4A)∶S18
14 Kovarik JM, ter Maaten JC, Rademaker CMA, et al. Pharmacokinetics of cefepime in patients with respiratory tract infections. Antimicrob Agents Chemother, 1990, 34(10)∶1885
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15 Ramphal R,Gulcalp R,Rotstein C,et al. Clinical experience with cefepime as empiric therapy for fever and neutropenia. Am J Med, 1993,95(Suppl 4A)∶S48
16 Saez-Llorens X,Castano E,Garcia R,et al. Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children. Antimicrob Agents Chemother, 1995, 39(4)∶937
17 Schwartz R,Young LRD,Ramirez-Ronda C,et al. Intravenenous cefepime versus intravenous ceftazidime for the treatment of serious skin and skin structure infections. Am J Med, 1993, 95(Suppl 4A)∶S55
, 百拇医药
18 Shafiri R, Geckler R,Childs S. A comparative study of cefepime versus ceftazidime in the treatment of urinary tract infections. Am J Med, 1993, 95 (Suppl 4A)∶S55
19 Tauber MG,Hackbarth CJ,Scott KG, et al. New cephalos-porins cefotaxime, cefepimizole, BMY28142, and HR810 in experimental pneumococcal meningitis in rabbits. Antimicrob Agents Chemother, 1985, 27(3)∶340
20 Tsai YH, Bies M, Leitner F,et al. Therapeutic studies of cefepime (BMY 28142) in murine meningitis and pharmacokinetics in neonatal rats. Antimicrob Agents Chemother, 1990, 34(5)∶733
(收稿:1997—01—29 修回:1997—12—01), 百拇医药
单位：(中山医科大学肿瘤研究所，广州 510060)
关键词：头孢派姆；第四代头孢菌素
第四代头孢菌素 摘要 目的：阐明第四代头孢菌素头孢派姆的特性。方法:用常规体内、体外及临床方法评价本药。结果与结论:头孢派姆抗菌力强,抗菌谱广,较少产生耐药性。
CEFEPIME——A CEPHALOSPORINE OF THE FOURTH GENERATION
Pan Qichao
(Cancer Institute, Sun Yat-sen University of Medical Sciences, Guangzhou 510060)
, 百拇医药
ABSTRACT OBJECTIVE：To explain the characteristics of the fourth generation cephalosorine, cefepime. METHODS: The durg is evaluated by usual in vitro, in vivo, and clinical methods. RESULTS AND CONCLUSION: Cefepime is a powerful antibaterial agent with broader antibacterial spectra and fewer bacterial resistance.
KEY WORDS Cefepime; Cephalosporine of the fourth generation
头孢菌素类已出现第一至第三代产品,第二代产品引入了肟基,提高了对β-内酰胺酶的稳定性。第三代头孢类提高了抗绿脓杆菌的活性,延长了半衰期,减轻了对肾的毒性。现在又出现第四代头孢菌素。第四代头孢菌素有头孢派姆(cefepime,CFP)即Maxisime,同类还有头孢克列定(cefaclidine)、头孢派洛姆(cefpirome)及E1077等。
, 百拇医药
1 化学〔1〕
CFP在头孢烯的3位上有一个季铵化的N-甲基吡咯啶基,使化合物成为阴阳双性离子,易于透入G-菌外层细菌膜孔而起抗菌作用。其7位上取代,则基本上与其他第三代头孢菌素类相同,均有肟基,对酶稳定;又有噻唑环增强其抗菌活性。
2 抗菌谱〔2～6〕
对1 757个临床分离菌株的最低抑菌浓度(MIC)研究认为:① 对非β-内酰胺酶产生性细菌,如大肠杆菌、奇异变形杆菌的MIC在0.06～0.12μg/ml。② 对β-内酰胺酶产生菌如弗氏枸橼酸菌、粘质沙雷杆菌、摩根氏摩根菌等MIC为0.03～16μg/ml,均优于多数三代头孢菌素类药。③ 对(副)流感杆菌MIC为0.016～0.16mg/ml。④ 对不动杆菌MIC为0.12～4μg/ml,略低于三代头孢菌素类药。⑤ 抗绿脓杆菌活性与头孢他定相似,MIC为0.5～>128μg/ml,对头孢他定耐药菌仍有效。⑥ 对G-双球菌如脑膜炎或淋病菌MIC为0.004～0.12μg/ml。⑦ G+菌方面,对甲氧苯青霉素敏感的金葡菌(MSSA)的MIC为0.5～16μg/ml,但对该药不敏感菌(MRSA)则仍为耐药。对非肠源链球菌,如A、B、C、G族链球菌及肺炎球菌的MICs为0.016～0.5μg/ml。但对致单核细胞性李斯特菌的MIC为32～128μg/ml。⑧ 对脆弱拟杆菌等厌氧菌无效。
, 百拇医药
在囊性纤维化病人本品抗绿脓杆菌与环丙沙星、托普霉素、单酰胺菌素协同，但与泰宁(Tienem)及多粘菌素B对抗〔7〕。
3 耐药性机理〔1,4,6〕
3.1 G-菌可改变其外层细胞膜孔而改变其药物的透过性。本品透入大肠杆菌、假单孢菌类、阴沟肠杆菌的速率比头孢氨噻肟快。
3.2 青霉素结合性蛋白质(PBPs)在肺炎球菌、流感嗜血杆菌及淋病双球菌中发生变异,是耐药性产生原因之一,而本品对PBPs的亲和力较高。本药对大肠杆菌及绿脓杆菌的PBPs比三代头孢菌素类亲和力更高。
3.3 本品对于肠杆菌属、克雷伯氏细菌属及绿脓杆菌属染色体所介导的头孢菌素酶头孢氨噻肟及头孢他定的亲和力小,亦较稳定。本品对质粒介导的头孢菌素酶亦较稳定。同时,本品无诱导β-内酰胺酶产生的能力是其特性之一。
, 百拇医药
4 药代动力学〔8～14〕
多剂量给药,每次如用双倍递增剂量250、500、1000及2000mg,其峰浓度依次为17.5,31.2,66.9及137mg/L,而其AUC依次为33.9,58.1,137及239 μg*h/ml。表现其随剂量增加而递增,呈线性增加。按正常剂量2g/次计,峰浓度远高于敏感细菌的MIC。达峰时间一般为0.5～1.5h,平均半衰期为2.195(2.09～2.32)h,平均全身清除率为134(124～144)ml/min。如在健康志愿者静滴30min,浓度为250,500,1 000或2 000μg/ml,其峰浓度亦由16.3mg/L递增至133mg/L;AUC由34mg*h/L递增至263mg*h/L。平均半衰期为1.85(1.8～1.9)h;平均清除率为104.8(96～116)ml/min;尿中平均回收率为81.2(78.4～85.6)%,大部分为原形。iv或静滴所达到的峰浓度为im的2～3倍(57.5mg/L),但im的AUC、清除或尿中回收等与静滴相同。本品与血清蛋白的结合率仅16%～19%,稳态分布容积为14～20L。少部分药物在体内代谢变为7位表同分异构体、N-甲基吡咯啶及其N-氧化物。
, 百拇医药
肾功能不良及肌酐清除率为10～30或<10ml/min者峰浓度不会升高,AUC则升高达7倍(由131升到928mg*h/L),表观分布容积不变,半衰期升6倍,且尿中回收率为0。对这样的病人,要由2g/次,q12h,减到1g/次，q16h。而肌酐≤10ml/min者及要求血透析的病人,则1g/次,q24h。每次透析后要补给1g。对于连续腹腔透析病人则静滴1g,q48h。肝功能不良者不再调整剂量。
通过支纤境研究,证明q12h给药2g时,支气管粘膜组织浓度已经足够。本药亦可透入腹腔及胆汁中,在阑尾及前列腺组织亦达相应浓度。患囊性纤维化病患者的药动学变化不大。本品可透入脑脊液中,在金葡菌性新生大鼠慢性脑膜炎,本品与头孢氨噻肟等效,但对克雷伯氏菌、绿脓杆菌或流感嗜血菌所致脑膜炎则较优。
5 不良反应〔3～5,11〕
不良反应少见且不严重,头痛发生率约为2.4%,恶心1.8%,皮疹1.8%,腹泻1.7%。其他还有视物模糊、头轻感、消化不良等。静脉给药者可见静脉炎。血清AST偶见升高,但无临床的肝毒性。在4 400病人应用6g/d仍安全。
, 百拇医药
6 临床应用〔6,15～20〕
6.1 单药治疗 一般q12h给药1～2g,用于G-杆菌所致严重中枢神经系统感染,如脑膜炎等。社会上获得的G-杆菌(非绿脓杆菌)所致的肺炎,囊性纤维化病人的肺炎亦可用。皮肤及软组织感染疗效亦颇满意。骨及关节感染疗效亦好。在兔葡萄球菌性慢性骨髓炎中用本品可使53%动物无菌。在泌尿道感染中代替常用的氨基甙类,除抑菌作用较强、尿中药物浓度高外,无肾脏毒性,故疗效好。
6.2 联合治疗 对腹腔内感染宜加用抗厌氧菌药物如甲硝唑、替硝唑或氯洁霉素。绿脓杆菌所致的医院获得性肺炎,宜与其他抗绿脓杆菌的抗生素如氧哌嗪青霉素、单酰胺菌素、氟喹诺酮类等合用,对头孢他定耐药菌株用本药仍有效。
对免疫力低的病人白细胞减少性发热,亦须与氟喹诺酮类、抗绿脓杆菌的青霉素(如哌嗪青霉素)或头孢菌素(如头孢他定)或与庆大霉素等合用。同时本药常须2g/次,q8h。
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参 考 文 献
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(收稿:1997—01—29 修回:1997—12—01), 百拇医药