Pharmacology for Anaesthesia and Intensive Care

P1: PSB Printer: Yet To Come
9780521704632c22 CUFX213A/Peck 9780521618168 December 29, 2007 14:51

22 Antimicrobials

inherent antimicrobial activity.) Aminoglycosides have a synergistic effect against

Pseudomonas when combined with this group of drugs. Ticarcillin in high doses

has been shown to prolong bleeding time through platelet dysfunction. Its use in

patients with a bleeding risk should be considered with care.

Cephalosporins

R 1 — C — N

C

—

— O

R 2

—

——

H

O

———

OH

N

O

-lactam ring

S

Cephalosporins possess a similar ring structure to penicillins but the thiazoli-

dine ring is replaced by a six-membered hydrothiazine ring. The cephalosporins are

extended-spectrum antimicrobials that are broadly categorized into successive gen-

erations. With each generation gram-positive cover is maintained but gram-negative

cover is steadily improved. Some of the third-generation cephalosporins also demon-

strate activity against Pseudomonas.

Mechanism of action

Cephalosporins are bactericidal and in common with allβ-lactam antimicrobials

exert their effect by disrupting peptidoglycan cell wall integrity (see above). The

β-lactam ring in cephalosporins is more stable than that in penicillins and is less

susceptible toβ-lactamase, but once cleaved it becomes very unstable and rapidly

decomposes to smaller fragments.

Pharmacokinetics

Cephalosporins distribute widely in the body, readily crossing inflamed membranes

and the placenta. Third-generation agents penetrate CSF well especially if the

meninges are inflamed (10% penetration), however, earlier generation agents pene-

trate less well and hardly at all if not inflamed. Protein-binding is variable (cefurox-

ime, 30%; ceftazidime, 20%) and plasma half-lives are generally short (1–1.5 hours).

This contrasts markedly with ceftriaxone, which is 95% protein bound and has a

prolonged half-life of 5.5–11 hours. Cephradine, cefuroxime and ceftazidime are not

metabolized at all and are excreted unchanged in the urine. Cefotaxime is metabo-

lized by the liver (the activity of the metabolites being 10% that of the parent com-

pound) with only 50% appearing unchanged in the urine. Renal excretion utilizes