認識Cephalosporin

觀念剖析:
認識Cephalosporin

< 觀念剖析 >
  Cephalosporin頭孢類藥物是一種殺菌藥(bactericidal),正確名稱為Cephem類,抗菌機轉與青黴素類相同(have the same mode of action as other beta-lactam antibiotics),它能與細菌細胞膜上的penicillin-binding proteins(PBPs)結合,阻止細菌細胞壁mucopeptide的合成,導致滲透不穩定的細胞壁(disrupt the synthesis of the peptidoglycan layer of bacterial cell walls)。

【註】 PBPs bind to the D-Ala-D-Ala at the end of mucopeptide to crosslink the peptidoglycan. β-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan

  Cephalosporin類依其結構可區分為cephalosporin、cephamycin 兩類。此外,此類藥物可再依其抗菌範圍,區分第一代~第四代Cephalosporins,甚至第五代。

< 藥品分類 >
   Cephalosporin 可分為如下:
第一代 Cephalosporin Cefacetrile、Cefadroxil (Duricef), Cephalexin (Keflex),, Cefaloridine, Cefalotin (Keflin), Cefapirin (Cefadryl), Cefazolin (Ancef, Kefzol), Cefradine (Velosef), Cefroxadine
第二代 Cephalosporin Cefaclor (Ceclor , Keflor, Raniclor), Cefonicid (Monocid), Cefprozil (cefproxil; Cefzil), Cefuroxime (Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym, Xorimax), Cefuzonam. 
‧cephalosporins with antianaerobe activity: Cefmetazole, Cefotetan, Cefoxitin
第三代 Cephalosporin Cefdinir (Zinir, Omnicef, Kefnir), Cefixime (Zifi, Suprax), Cefotaxime (Claforan), Cefovecin (Convenia),Cefpodoxime (Vantin, PECEF), Ceftibuten (Cedax), Ceftizoxime (Cefizox), Ceftriaxone (Rocephin).
‧cephalosporins with antipseudomonal activity: Cefoperazone (Cefobid), Ceftazidime (Fortum, Fortaz)
第四代 Cephalosporin Cefclidine, Cefepime (Maxipime), Cefluprenam, Cefoselis, Cefozopran, Cefpirome (Cefrom), Cefquinome, flomoxef
第五代 Cephalosporin Ceftobiprole, Ceftaroline

< 抗菌範圍 >
1、第一代Cephalosporin:
  (1) 對G(+)菌的抗菌作用較第二代、第三代強。主要包括對MSSA及Streptococcus。對大部分簡單的G(-)細菌也有一點效果,但效果差,包括E. coli、Klebsiella、Proteus等。
  (2) 能被細菌產生的β-內(β-lactamase)破壞,所以第一代cephalosporin對MRSA及Enterococcus 無效(No activity against methicillin-resistant staphylococci or enterococci)。
  (3) 主要用於治療敏感菌所導致的URI及UTI、皮膚軟組織感染等。
Gram-positive: Activity against penicillinase- producing, methicillin-susceptible staphylococci and streptococci . No activity against methicillin-resistant staphylococci or enterococci 
Gram-negative: Activity against Proteus mirabilis, some E. coli, and Klebsiella pneumoniae ("PEcK"), but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia.
2、第二代Cephalosporin:
  (1) 對G(+)菌的抗菌作用較第一代差,但對G(-)細菌的抗菌活性增加,包括對Proteus、E. coli、Klebsiella的效力比一代為佳,對H. influenzae也有效,對厭氧菌也有一定作 用,如Cefmetazole, Cefotetan, Cefoxitin;但對銅綠假單孢菌(Pseudomonas) 無效
  (2) 對多種細菌產生的β-內比較穩定。
  (3) 主要用於治療敏感菌所導致Pneumonia、膽道感染、UTI、菌血症。
Gram-positive: Less than first-generation.
Gram-negative: Greater than first-generation: HEN (Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + Proteus mirabilis, some E. coli, and Klebsiella pneumoniae
3、第三代Cephalosporin:
  (1) 具有更強對抗G(-)細菌的活性,包括對腸桿菌、厭氧菌等具有一定作用,對H. influenzae 也具有效力,但對MRSA及Enterococcus無效,對Streptococcus則仍有效力。第三代中的Ceftazidime具有抗pseudomonas的效果,而其它第三代cephalosporin 則無效
  (2) 對β-內有較高的穩定性。
  (3) 主要用於治療危及生命的敗血症、腦膜炎(meningitis)、肺炎、骨髓炎、嚴重的UTI。
Gram-positive: Some members of this group (in particular, those available in an oral formulation, and those with anti-pseudomonal activity) have decreased activity against Gram-positive organisms.
Gram-negative: a broad spectrum of activity and further increased activity against Gram-negative organisms. They may be particularly useful in treating hospital-acquired infections. They are also able to penetrate the CNS, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae. Since 2007, ceftriaxone or cefixime have been the only recommended treatment for gonorrhea in the United States
4、第四代Cephalosporin:
  (1) 第四代對G(+)、G(-)菌均有效,它除了具有第三代的抗菌活性外,對MSSA也具有抗菌活性,對Pseudomonas也有效,但對MRSA及Enterococcus 仍無效。
Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins.
Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria. They also have a greater resistance to beta-lactamases than the third-generation cephalosporins. Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa.
5、第五代Cephalosporin:(這樣的分類還未被廣泛接受)
  對抗Pseudomonas強效
Ceftobiprole has been described as "fifth-generation" cephalosporin. though acceptance for this terminology is not universal. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance.

< 代謝途徑 >
  口服吸收良好,但吸收會受食物的干擾而延遲。靜脈注射的吸收不錯,血中尖峰藥物濃度通常為30min~60 min。大多數cephalosporin由腎臟排泄。當腎臟衰竭時,cephalosporin的排除半衰期會延長,對於腎功能不全的患者需調整劑量。

< 副作用>
  口服偶有胃腸道方面反應,如食慾不振、噁心、腹痛、腹瀉、消化不良。靜脈給藥可發生靜脈炎。過敏反應包括皮疹、蕁麻疹、發燒,過敏性休克罕見,對青黴素過敏者約10%對cephalosporin過敏。血液學方面有嗜中性白血球↓,白血球↓,血小板↓。其它尚有頭痛、頭暈等CNS中毒反應、感覺異常等。另外,第一代cephalosporin大量使用時,可損害近曲小管而出現腎臟毒性。第四代cephalosporin幾乎無腎臟毒性。

(Common ADRs(1% of patients) associated with the cephalosporin therapy include: diarrhea、nausea、rash、electrolyte disturbances、pain and inflammation at injection site。Infrequent ADRs (0.1~ 1% of patients) include: vomiting、headache、dizziness、oral and vaginal candidiasis、eosinophilia、 pseudomembranous colitis、superinfection、fever。The commonly quoted figure of 10% of patients with allergic hypersensitivity to penicillins。

(Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol。This is thought to be due to the N-methylthiotetrazole (NMTT) side-chain of these cephalosporins, which blocks the enzyme vitamin K epoxide reductase (likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance)。

 曾經醫師考試有考過這樣題組
1. 一位60歲男性病患於一週前因退化性關節炎接受左髖部人工髖關節全置換手術治療(total hip replacement),術後連續五天注射止痛劑和cephalosporin治療,病人於術後第7天開始發生持續性腹瀉、腹痛、且帶有少許血便,發燒及白血球增多,但並無腹膜炎現象,此時除了stool culture之外,該先如何處理?<100-1-10>
  A. 給予buscopan,並重新使用cephalosporin治療
  B. 作stool cytotoxin assay,保守性治療,並安排大腸鏡檢查
  C. 安排barium enema檢查
  D. 安排緊急全大腸切除術治療

2. 承上題,若stool culture長出何種細菌,則會被認為是
 antibiotic-associated colitis?<100-1-11>
  A. Clostridium difficile
  B. Staphylococcus aureus
  C. E. coli
  D. Streptococcus bovis

3.承上題,此時會選擇何種藥物治療?<100-1-12>
  A. 注射clindamycin
  B. 口服asacol
  C. 注射ampicillin
  D. 口服metronidazole或vancomycin
【註】 萬古黴素(vancomycin)
抗菌機制:抑制細胞壁合成
抗菌譜:G+球菌
不良反應:紅人綜合症(瘙癢、皮疹、頭部及軀幹上部紅斑)、靜脈炎、腎毒炎(輕微的、不常見)、耳毒性、白細胞減少、皮疹、過敏反應。

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