with subsequent transpeptidation and strand crosslinkage, allowing formation of structurally intact cell walls of vancomycin-resistant Gram-positive bacteria.

Gram-positive bacteria other than Enterococcus spp. also may be resistant to vancomycin. Some clinical isolates of S. hemolyticus have shown resistance to vancomycin (53). Inherent resistance to vancomycin is a feature of Leuconostoc spp., Pediococcus spp., and Lactobacillus spp., all three rarely causing human infections.

A threat exists of further dissemination of vancomycin resistance to other species via transposition of Tn1546 into broad-host-range plasmids. Barriers do not exist to heterospecific expression of enterococcal resistance genes in Listeria monocytogenes, Bacillus spp., and Streptococcus spp. (50). Transfer of vancomycin resistance from E. faecalis to S. aureus via conjugation in the laboratory raises the frightening possibility of the emergence of glycopeptide resistance in MRSA (54).

RESISTANCE TO THIRD-GENERATION CEPHALOSPORINS AMONG GRAM-NEGATIVE AEROBIC BACILLI

Resistance of Gram-negative pathogens to β-lactam antibiotics is mediated by any one of three mechanisms (production of β-lactamases, reduced permeation of the drug, or alteration of the target site, i.e., PBP) or by several acting in concert. In the mid-1980s, it was noted that resistance was developing among Gram-negative bacilli possessing inducible chromosomal cephalosporinases (e.g., Enterobacter cloacae, Proteus spp., Serratia spp., Citrobacter freundii) when certain of the newer cephalosporins and cephamycins were used in therapy (55). Spontaneous mutation of such organisms to a stably derepressed (induced) state resulted in persistence in these mutants of high levels of β-lactamase even without the presence of an inducer. Such resistance is not transmissible but has been responsible for many instances of therapeutic failure, relapse, or nosocomial spread of such infections (56). Most outbreaks of such nosocomial infections have involved Enterobacter spp., and resistance has been present to virtually all β-lactam antibiotics (including newer cephalosporins and aztreonam) except imipenem.

Further problems in the treatment of infections due to Gram-negative bacilli became evident in the mid 1980s in France and Germany when Klebsiella isolates with plasmid-mediated resistance to broad-spectrum cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and aztreonam appeared (57). Such resistance soon became evident worldwide (58). The basis of such resistance is the emergence of new extended-spectrum β-lactamases, observed first in Klebsiella pneumoniae and subsequently in E. coli, C. freundii, Serratia marcescens, and Enterobacter



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