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学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

Inactivation by a bacterial enzyme




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Enterobacter, indole-positive Proteus, Serratia, and Citrobacter produce an inducible chromosomal beta-lactamase that may be difficult to detect on initial susceptibility testing but can mediate resistance to all currently available beta-lactams other than carbapenems.

The most common plasmid-mediated beta-lactamases in Gram negative bacteria mediate resistance to penicillins and first- and some second-generation cephalosporins. Extended spectrum plasmid-mediated beta-lactamases can additionally cleave later-generation cephalosporins and aztreonam. These plasmids can transfer to other species and genera.

Inactivation by a bacterial enzyme 

Production of beta-lactamase is a major mechanism of resistance to the beta-lactam antibiotics in clinical isolates. Such bacterial enzymes may cleave predominantly penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases). Their production may be encoded within the bacterial chromosome (and hence be characteristic of an entire species) or the genes may be acquired on a plasmid or transposon (and hence be characteristic of an individual strain rather than the species). Bacteria may synthesize the beta-lactamase constitutively (as for many plasmid-mediated enzymes) or synthesis may be inducible in the presence of antibiotic (as for many chromosomal enzymes). Inducible beta-lactamases may not be reliably detected by initial susceptibility testing, particularly with the newer rapid methods.

Chromosomal beta-lactamases

Although virtually all Gram negative bacilli possess a chromosomal beta-lactamase gene, certain species express insignificant amounts of this enzyme and their susceptibility to beta-lactams is largely determined by plasmid-mediated beta-lactamases and antibiotic permeability. These include E. coli, Proteus mirabilis, Salmonella, Shigella, and H. influenzae. Klebsiella pneumoniae produces a chromosomal beta-lactamase that is primarily a penicillinase; thus, these strains are frequently more susceptible to the cephalosporins. The last group of species within the Enterobacteriaceae, including Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, produce an inducible chromosomal beta-lactamase that may be difficult to detect on initial susceptibility testing but that can mediate resistance to all currently available beta-lactams with the exception of the carbapenems and perhaps cefepime. In addition to inducible production of this chromosomal enzyme, these species may give rise to regulatory mutants that are "derepressed" and produce high levels of this broad-spectrum chromosomal enzyme constitutively.

Plasmid-mediated beta-lactamases

The most common plasmid-mediated beta-lactamases of Gram negative bacteria (such as TEM-1, TEM-2, and SHV-1) mediate resistance to the penicillins and first- and some of the second-generation cephalosporins, but not cefuroxime, cephamycins, third- and fourth-generation cephalosporins, or the novel beta-lactam compounds such as the carbapenems or aztreonam.

More recently, extended-spectrum plasmid-mediated beta-lactamases (derived from the common TEM and SHV enzymes) have arisen, which are capable of cleaving later-generation cephalosporins and aztreonam. Originally described in strains of Klebsiella from Europe, these beta-lactamases have now been found in a variety of Gram negative bacilli in many areas of the United States, and spread between patients in intensive care units has been documented. In addition, a study from Chicago documented that nursing home patients may be an important reservoir for strains of Enterobacteriaceae producing extended-spectrum plasmid-mediated beta-lactamases.In one nursing home, for example, 18 of 39 patients were colonized with such resistant strains, and of the 55 patients in an acute care hospital colonized with resistant E. coli or K. pneumoniae, 35 had been admitted from nursing homes and 31 of them were colonized on admission. Although the strains of resistant E. coli and K. pneumoniae differed, most harbored a common plasmid encoding an extended-spectrum beta-lactamase, suggesting intraspecies and interspecies transfer of the plasmid between strains, rather than transfer of a single strain between patients. All of these strains were resistant to ceftazidime, gentamicin, and tobramycin, and 96 and 41 percent were also resistant to trimethoprim-sulfamethoxazole and ciprofloxacin, respectively.

These enzymes, of which there are many varieties, mediate high-level resistance to the third- and fourth-generation cephalosporins and aztreonam, but not to the cephamycins (cefoxitin and cefotetan) or the carbapenems. However, use of the cephamycins against strains containing these new enzymes is limited by the development of permeability mutants in the porin protein, OmpF. The beta-lactamase inhibitors, clavulanate, sulbactam, and tazobactam have generally retained the ability to inhibit these newer plasmid-mediated beta-lactamases. 

Another plasmid-mediated beta-lactamase has been described in Klebsiella, which is homologous to the AmpC chromosomal beta-lactamase of Enterobacter cloacae. This plasmid-mediated beta-lactamase is capable of cleaving all of the currently available beta-lactams (with the exception of the carbapenems) and its activity is not inhibited by clavulanate, sulbactam, or tazobactam. This plasmid-mediated beta-lactamase confers a broad resistance pattern similar to stably derepressed mutants of Enterobacter.

Over the past several years, carbapenem-hydrolyzing enzymes have been described in Klebsiella pneumoniae and other members of the Enterobacteriaceae. These are encoded on transmissible plasmids, which facilitate their spread. In one report from New York City in 2005, 45 percent of 602 isolates of K. pneumoniae had a plasmid-encoded, extended spectrum beta-lactamase, and of those, 3.3 percent also carried a carbapenem-hydrolyzing beta-lactamase termed KPC-2 (Klebsiella pneumoniae carbapenemase-2).In a subsequent report from New York City in 2007, seven strains of Escherichia coli out of 1417 tested had a similar enzyme.Resistance to the carbapenems in these strains was not always detected by currently available automated susceptibility methods.

The New Delhi metallo-β-lactamase 1 (NDM-1) is another plasmid-mediated enzyme that mediates broad resistance to all currently available beta-lactams (including the carbapenems) and is linked to other resistance genes on the plasmid that confer resistance to all available antibiotics, with the exceptions of colistin and tigecycline. This enzyme was originally found in a number of Enterobacteriaceae in India and Pakistan, as well as in individuals returning to the UK, US, and other countries who have travelled there, particularly for medical care; they have now been described more broadly. These organisms have been referred to in the lay media as "superbugs" because of their extensive resistance.