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The cephalosporins, structurally related to the penicillins, consist of a beta-lactam ring attached to a dihydrothiazoline ring. Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial activities. Type 1 allergic cross-reactions between penicillins and cephalosporins are primarily due to similarities in the molecular structure of the R side chains; for example, penicillin and cefoxitin have similar R side chains; ampicillin and cephalexin share similar side chains. Consequently, a patient with a type 1 reaction to penicillin would be more likely to experience a similar reaction with cefoxitin when compared with cephalexin. In contrast, a patient with an allergic reaction to ampicillin would be more likely to have a reaction to cephalexin than cefoxitin.

The mechanism of action of cephalosporins is analogous to that of the penicillins: (1) binding to specific penicillin-binding proteins, (2) inhibition of cell wall synthesis, and (3) activation of autolytic enzymes in the cell wall. Resistance to cephalosporins may be due to poor permeability of the medication into bacteria, lack of penicillin-binding proteins, or degradation by beta-lactamases.

Cephalosporins have been divided into five major groups or “generations” (see eTable 30–1) based on their antibacterial activity: First-generation cephalosporins have good activity against aerobic gram-positive organisms (but not enterococcus) and some community-acquired gram-negative organisms (P mirabilis, Escherichia coli, Klebsiella species); second-generation medications have a slightly extended spectrum against aerobic gram-negative bacteria, and some are active against gram-negative anaerobes (eg, cefoxitin); and third-generation cephalosporins are active against many aerobic gram-negative bacteria. Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general characterization of the medications in the individual classes; however, the generational classification of cephalosporins is useful for discussion purposes. Cefepime is considered a fourth-generation agent because it is more stable against plasmid-mediated beta-lactamase with little or no beta-lactamase–inducing capacity. Cefepime compares favorably with ceftazidime with respect to its gram-negative activity; however, its stability versus plasmid-mediated beta-lactamase results in improved coverage over ceftazidime against Enterobacter and Citrobacter species.

The gram-positive coverage of cefepime approaches that of cefotaxime or ceftriaxone. None of the currently available agents are active against the enterococcus. A fifth-generation cephalosporin, ceftaroline, is uniquely active against methicillin-resistant S aureus and has comparable gram-negative spectrum activity as ceftriaxone. Two cephalosporin–beta-lactamase inhibitor combinations are available, ceftazidime-avibactam and ceftolozane-tazobactam, each of which is more likely than the cephalosporin alone to be active against resistant Pseudomonas and ESBL-producing E coli.

1. FIRST-GENERATION CEPHALOSPORINS

Antimicrobial Activity

In vitro activity includes coverage of gram-positive cocci, including viridans streptococci, group A hemolytic streptococci, and methicillin-susceptible S aureus. As with all cephalosporins, first-generation cephalosporins are inactive against enterococci and methicillin-resistant staphylococci. Activity against H influenzae is poor, and both intermediately and highly penicillin-resistant streptococci are resistant to first-generation cephalosporins. Among gram-negative bacteria, E coli, Klebsiella pneumoniae, and P mirabilis are the most likely to be susceptible. Anaerobic gram-positive cocci ...

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