Mechanisms Of Bacterial Resistance To The Cephalosporins

Cephalosporin resistance may be related to the inability of the antibiotic to reach its sites of action or to alterations in the PBPs that are their targets. Alterations in two PBPs that decrease their affinity for cephalosporins render pneumococci resistant to third-generation cephalosporins because the other three PBPs have inherently low affinity.

Cephalosporin resistance usually reflects hydrolysis of the ß-lactam ring. The cephalosporins are variably susceptible to ß-lactamase. Of the first-generation agents, cefazolin is more susceptible to hydrolysis by ß-lactamase from S. aureus than is cephalothin. Cefoxitin, cefuroxime, and the third-generation cephalosporins are more resistant to hydrolysis by the ß-lactamases produced by gram-negative bacteria than first-generation cephalosporins. Third-generation cephalosporins are susceptible to hydrolysis by inducible, chromosomally encoded ß-lacta-mases. Induction of ß-lactamases by treatment of infections owing to aerobic gram-negative bacilli with second- or third-generation cephalosporins and/or imipenem may result in resistance to all third-generation cephalosporins. Fourth-generation cephalosporins (e.g., cefepime) are poor inducers of ß-lactamases and are less susceptible to hydrolysis than the third-generation agents.

general features of the cephalosporins Cephalosporins are excreted primarily by the kidney, and dosage should be decreased in patients with renal insufficiency. Cefpi-ramide (not available in U.S.) and cefoperazone are excreted predominantly in the bile. Cefotaxime is deacetylated to a metabolite with less antimicrobial activity than the parent compound and excreted by the kidneys. The other cephalosporins do not undergo appreciable metabolism.

Several cephalosporins (e.g., cefotaxime, ceftriaxone, and cefepime) penetrate into CSF in sufficient concentration to be useful for the treatment of meningitis. Cephalosporins also cross the pla-

Names, Structural Formulas, Dosage, and Dosage Forms of Selected Cephalosporins and Related Compounds

Cephem nucleus

Cephem nucleus

Compound (TRADE NAMES)

Dosage Forms,* Adult Dosage for Severe Infection, and tln

First-generation

Cefazolin (ancef, kefzol, others)

4 Cephalexin (keflex, others)

Cefadroxil (duricef)

Second-generation Cefoxitin1' (mefoxin)

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