Acquired resistance: genetic transfers

Enterococci show a remarkable ability to acquire genetic materials that confer antimicrobial resistance. Transfer of antibiotic resistance from enterococci to more aggressive pathogens, including Staphylococcus aureus, has been accomplished in vitro.

They have various systems of bacterial mating (conjugation) that can spread genes for resistance to other bacteria. These systems include plasmids that can replicate in several other gram-positive species (e.g., staphylococci and streptococci), pheromone-responsive plasmids that can transfer between E. faecalis strains at frequencies sometimes approaching 100 percent, and a specialized type of transposon (an element that can jump from one DNA site to another intracellularly) that is conjugative (that is, it can transfer intercellularly between a broad range of bacterial genera and can then become integrated into the genome of the new host bacterium). The finding of genes for vancomycin resistance on these conjugative as well as transposable elements heightens concern about the possible transfer of such resistance to other, perhaps more pathogenic, organisms. Such concern is substantiated by reports of the experimental transfer of Vancomycin resistance from enterococci to S. aureus, Listeria monocytogenes, and the finding of these genes in various species in nature. Experimental transfer of Vancomycin resistance together with ampicillin resistance by conjugation between strains of E. faecium has been reported., such a transfer to E. faecalis, streptococci, or pneumococci would have serious consequences should it occur clinically. Unfortunately, the prediction that such a transfer would occur in vivo has probably been realized: a gene cluster that confers vancomycin resistance, vanA, was recovered from both patient isolates of vancomycin-resistant S aureus [MIC ≥ 32 µg/mL] reported to date.

β-lactams

 Action of β –lactam antibiotics and intrinsic resistance

Complete or relative resistance to β-lactams is a characteristic feature of the genus Enterococcus. E. faecalis is typically 10 to 100 times less susceptible to penicillin than are most streptococci, while E. faecium is at least 4 to 16 times less susceptible than E. faecalis. While most isolates of E. faecalis are inhibited by concentrations of penicillin or ampicillin (1 to 8 µg /ml) easily achievable in humans, isolates of E. faecium usually require an average of 16 to 64 µg /ml to inhibit growth, although some isolates are even more resistant. An additional problem with enterococci is that they are typically tolerant to β -lactams.

β-lactam antibiotics act by inhibiting the cell wall synthesis. Penicillin-binding proteins (PBPs) that are involved in the synthesis and assembly of the peptidoglycan layer in the cell wall are the targets for β-lactam antibiotic.

PBPs bind the β-lactam antibiotic, the cell wall synthesis is thereby inhibited. Intrinsic resistance towards β-lactam antibiotics in enterococci is due to low affinity of PBPs for the β-lactam agents. This resistance differs between different β-lactams, with penicillins having the most activity against enterococci, carbapenems having slightly less activity, and with the cephalsporins having the least activity. High-level resistance to penicillins is mainly due to either overproduction of a PBP (enterococci have at least five different PBPs) with a natural low affinity for penicillins or to mutations that make the low-affinity PBP even less susceptible to inhibition by penicillins.  Fontana et al. showed that loss of the ability of a strain of E. faecium to produce PBP5 caused this highly penicillin-resistant strain to become hypersusceptible to penicillin. β-Lactamase-producing enterococci are infrequently isolated. Unlike most staphylococci, where β-lactamase production is inducible, β-lactamase production in enterococci is constitutive, low level, and inoculum dependent.