A number of microorganisms have evolved mechanisms to overcome the inhibitory actions of the p-lactam antibiotics. There are four major mechanisms of resistance: inactivation of the p-lactam ring, alteration of PBPs, reduction of antibiotic access to PBPs, and elaboration of antibiotic efflux mechanisms. Bacterial resistance may arise from one or more than one of these mechanisms.
The most important mechanism of resistance is hydrolysis of the p-lactam ring by p-lactamases (penicilli-nases and cephalosporinases). Many bacteria (Staphylococcus aureus, Moraxella [Branhamella] catarrhalis, Neisseria gonorrhoeae, Enterobacteriaceae, Haemophilus influenzae, and Bacteroides spp.) possess p-lactamases that hydrolyze penicillins and cephalosporins. The p-lactamases evolved from PBPs and acquired the capacity to bind p-lactam antibiotics, form an acyl enzyme molecule, then deacylate and hydrolyze the p-lactam ring. Some bacteria have chromosomal (inducible) genes for p-lactamases. Other bacteria acquire p-lactamase genes via plasmids or transposons. Transfer of p-lactamase genes between bacterial species has contributed to the proliferation of resistant organisms resulting in the appearance of clinically important adverse consequences.
Efforts to overcome the actions of the p-lactamases have led to the development of such p-lactamase inhibitors as clavulanic acid, sulbactam, and tazobactam. They are called suicide inhibitors because they permanently bind when they inactivate p-lactamases. Among the p-lactamase inhibitors, only clavulanic acid is available for oral use. Chemical inhibition of p-lactamases, however, is not a permanent solution to antibiotic resistance, since some p-lactamases are resistant to clavulanic acid, tazobactam, or sulbactam. Enzymes resistant to clavulanic acid include the cephalosporinases produced by Citrobacter spp., Enterobacter spp., and Pseudomonas aeruginosa.
An additional mechanism of antibiotic resistance involves an alteration of PBPs. Resistant bacteria, usually gram-positive organisms, produce PBPs with low affinity for p-lactam antibiotics. The development of mutations of bacterial PBPs is involved in the mechanism for p-lactam resistance in Streptococcus pneumoniae, Enterococcus faecium, and methicillin-resistant S. au-reus (MRSA).
Some gram-negative bacteria employ a third mechanism of resistance, namely, one that reduces antibiotic access to PBPs. Gram-positive organisms have an exposed peptidoglycan layer easily accessible to p-lactam antibiotics (Fig. 45.2). In contrast, gram-negative organisms have an outer membrane surrounding the peptido-glycan layer. The gram-negative outer membrane hinders ingress of large molecules and helps bacteria resist the actions of antibiotics. In susceptible gram-negative
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