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Resistance to and Immunomodulation Effects of Cephalosporin Antibiotics

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Summary

In order to be effective, cephalosporins must penetrate the outer membrane of bacteria to reach the β-lactam target enzymes, avoid hydrolysis by β-lactamases and bind to the bacterial penicillin-binding proteins (PBPs) corresponding to the peptidases responsible for catalysing the cross-linking of peptidoglycan. Resistance to cephalosporins can arise if the targets are modified, or if they are protected by other cell products (β-lactamases) or structures (permeability barriers). Target modification can involve either reduced affinity of an existing PBP or the acquisition of supplementary β-lactam-resistant PBPs. β-Lactamases are produced universally by bacteria and may be chromosomally or plasmid-mediated. Although generally species specific, chromosomal enzymes from Gram-negative bacteria can be divided into 4 main categories: chromosomal cephalosporinases (not inhibited by clavulanic acid), cefuroximases, broad spectrum β-lactamases, and β-lactamases of anaerobic species. Plasmid-mediated enzymes include 3 categories: penicillinases from Staphylococcus aureus, broad spectrum β-lactamases (e.g. TEM-1, -2; SHV-1) and extended broad spectrum β-lactamases (TEM-3, -5; SHV-2 to SHV-5). The degree of β-lactamase-mediated resistance is related to the amount of enzyme produced, the location of the enzyme and the kinetics of the enzyme’s activity. β-Lactamases of Gram-positive organisms are usually extracellular, while those of Gram-negative bacteria are retained within the cell periplasm. While synthesis of β-lactamases by streptococci is of little or no clinical importance, these enzymes play a major role in the resistance of staphylococci. The outer membrane of Gram-negative organisms constitutes a substantial permeability barrier retarding the entry of β-lactams into the cell. Nevertheless, specialised outer membrane proteins called ‘porins’ create pores in this membrane, enabling the diffusion of small aqueous solutes, such as cephalosporins. Shielding by permeability barriers is minimal in Gram-positive bacteria, as the PBPs of such organisms are located on the outer aspect of the cytoplasmic membrane.

The ever-increasing problem of bacterial resistance to antibiotics combined with the increased number of immunocompromised patients explains the upsurge of interest in the interplay between host defences and antibacterial agents. A number of difficulties and controversies are associated with the analysis of immunomodulation by antimicrobial agents. Many of these problems are a consequence of using in vitro data, which do not accurately reflect the dynamic interactions occurring in vivo. Extrapolation of data derived from experimental animal models of infection to human therapy should also be viewed with much caution. The possible occurrence of neutropenia in patients administered some β-lactam antibiotics appears to be related either to an immune-mediated process involving peripheral leucocytes or to a direct toxic effect of the drug on bonemarrow precursors. Several studies have now investigated the oxidant scavenging properties of cephalosporins. Interestingly, inhibition of neutrophil myeloperoxidase activity has been observed with cefdinir, in contrast to the significant enhancement of this activity observed with cefaclor.

Subinhibitory concentrations of some antibacterial agents can influence bacterial morphology and physiology. While few β-lactams directly interfere with the phagocyte oxidative burst, indirect enhancement by β-lactam-modified bacteria may account for the inflammatory response that may be observed during therapy with these agents. Potentiation of the oxidative burst may also be accompanied by increased bacterial susceptibility to phagocytic killing and is referred to as postantibiotic leucocyte enhancement.

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Labro, M.T. Resistance to and Immunomodulation Effects of Cephalosporin Antibiotics. Clin. Drug Invest. 9 (Suppl 3), 31–44 (1995). https://doi.org/10.2165/00044011-199500093-00006

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