NCBI Bookshelf. Boston: Massachusetts Eye and Ear Infirmary; Christopher J. KristichPhD, Louis B. RiceMD, and Cesar A. Authors Christopher J. KristichPhD, 1 Louis B. Rice Enterococcus fekalis in der Prostata, MD, 2 and Cesar A. Arias 3. The clinical importance of the genus Enterococcus is directly related to its antibiotic resistance, which contributes to the risk of colonization and infection. The species of the greatest clinical importance are Enterococcus faecalis and Enterococcus faecium.
Although the resistance characteristics of these two species differ in important ways, they can generally be categorized as intrinsic resistance, acquired resistance, and tolerance. Relative to the streptococci, enterococci are intrinsically resistant to many commonly used antimicrobial agents. All enterococci exhibit decreased susceptibility to penicillin and ampicillin, as well as high-level resistance to most cephalosporins and all semi-synthetic penicillins, as the result of expression of low-affinity penicillin-binding proteins.
For many strains, their level of resistance to ampicillin does not preclude the clinical use of this agent. In fact, ampicillin remains the treatment of choice for enterococcal infections that lack other mechanisms for high-level resistance. Enterococci are also intrinsically resistant to clindamycin, which is mediated by the product of the lsa gene, although the mechanism remains poorly defined. Enterococci also have a native resistance to clinically achievable concentrations of aminoglycosides, which precludes their use as single agents.
Although E. Tolerance implies that the bacteria can Enterococcus fekalis in der Prostata inhibited by clinically achievable concentrations of the antibiotic, but will only be killed by concentrations far in excess of the inhibitory concentration.
Enterococcal tolerance can be overcome Enterococcus fekalis in der Prostata combining cell-wall active agents with an Enterococcus fekalis in der Prostata. Tolerance is normally detected in vitro by plotting survival in kill curves, and can be observed for a number of antibiotic-bacteria combinations. I n vitro tolerance has an important impact on therapy for treating enterococcal infections.
The treatment of endocarditis requires bactericidal therapy, due to the inaccessibility of the bacteria within the cardiac vegetations to the mammalian immune system. Despite considerable effort, investigators have yet to find other combinations of antibiotics that are synergistically bactericidal against enterococci.
In addition to intrinsic resistance and tolerance, enterococci have been extraordinarily successful at rapidly acquiring resistance to virtually any antimicrobial agent put into clinical use.
Introduction of chloramphenicol, erythromycin and tetracyclines was quickly followed by the emergence of resistance, in some cases reaching a prevalence that precluded their empirical use.
While the occurrence of ampicillin resistance in E. High-level aminoglycoside resistance, which negates the synergism between cell-wall active agents and aminoglycosides, has been recognized for several decades.
Vancomycin resistance is widely Enterococcus fekalis in der Prostata in E. Enterococcus fekalis in der Prostata response to the growing problem of vancomycin resistance in enterococci, the pharmaceutical industry has developed a number of newer agents that have activity against vancomycin-resistant enterococci VRE. However, none of these newly licensed agents quinupristin-dalfopristin, linezolid, daptomycin, tigecycline has been entirely free of resistance. Thus, the widespread resistance of enterococci has had a substantial impact on our use of both empirical Enterococcus fekalis in der Prostata definitive antibiotics Enterococcus fekalis in der Prostata the treatment of enterococcal infections, a situation that is likely to persist for the foreseeable future.
As previously noted, enterococci exhibit significant resistance to a wide variety of antimicrobial agents. This resistance is almost certainly relevant in most natural ecological settings in which enterococci dwell.
As normal commensals of the human gastrointestinal tract, enterococci are routinely exposed to a myriad of antibiotics in the course of contemporary medical treatment, and enterococcal resistance plays a key role in the ecological dynamics that occur during and after antibiotic therapy.
In addition, their resistance has confounded the best efforts of contemporary medicine to cope with Enterococcus fekalis in der Prostata caused by enterococci. Intrinsic resistance—that which is encoded within the core genome of all members of the species—differs from acquired resistance, in that the latter Enterococcus fekalis in der Prostata present in only some members of the species and is obtained via the horizontal exchange of mobile genetic elements or via selection upon antibiotic exposure.
A great deal of effort has been devoted to understanding the molecular mechanisms of resistance in enterococci. This has resulted in identification of determinants that specify Enterococcus fekalis in der Prostata for many antibiotics, including those that are or once were clinically useful as therapeutics to treat enterococcal infections, as well as those to which enterococci, as commensals of humans, are incidentally exposed in the course of therapy for infections caused by other bacteria.
In many cases, this research has led to the development of an understanding of the regulation and biochemical activities of the resistance determinants, and, in selected cases, has provided insight into the consequences of antibiotic resistance on the biological fitness of enterococci.
This section will provide Enterococcus fekalis in der Prostata overview of mechanisms of resistance that have been examined in the past 10 years. The glycopeptides vancomycin, teicoplanin, and newer derivatives, are used to treat serious infections due to resistant Gram-positive bacteria.
Most Gram-negative bacteria are not susceptible to glycopeptides because their outer membrane prevents access to the peptidoglycan targets located in the periplasmic space. Glycopeptides inhibit bacterial growth by interfering with peptidoglycan biosynthesis. The antibiotics form complexes with the D-Ala-D-Ala peptide termini of peptidoglycan precursors on the outer surface of the cell, which prevents the cell wall biosynthetic enzymes i.
The biochemical basis for resistance derives from modification of the antibiotic target. The altered precursors can still serve as substrates for the cell wall biosynthetic enzymes to enable the construction of functional peptidoglycan, but the reduced affinity of glycopeptides renders the drugs unable to inhibit cell wall biosynthesis.
The capacity to produce the alternative glycopeptide-resistant peptidoglycan precursors is encoded by resistance operons usually encoded on mobile genetic elements and thus transferable to otherwise susceptible hosts. Specific types of glycopeptide resistance are encoded in the chromosome as part of the core genome of certain enterococcal species. Nine distinct gene clusters conferring glycopeptide resistance have been described in enterococci. These determinants differ from each other both genetically and phenotypically, based on their physical location encoded on a mobile genetic element or in the core genome ; the specific glycopeptides to which they confer resistance often distinguished operationally as providing resistance to both vancomycin and teicoplanin, or providing resistance to vancomycin but not teicoplanin ; the level of resistance they confer; whether resistance is inducible or constitutively expressed; and the type of peptidoglycan precursor that is produced by their gene products.
The Van gene clusters encode several functions: i a regulatory module, namely a two-component signal transduction system that is responsible for sensing the presence of glycopeptides and activating expression of the resistance genes in inducible Van types; ii enzymes that produce the modified peptidoglycan precursors, including enzymatic machinery that is required to produce the appropriate substitute D-Lac or D-Serand a ligase that fuses D-Ala to either D-Lac or D-Ser to make the corresponding dipeptide that can be incorporated into peptidoglycan precursors via the normal biosynthetic machinery of the cell; and iii D,D-carboxypeptidases that eliminate any of the normal unmodified peptidoglycan precursor synthesized by the natural biosynthetic machinery of the cell, thereby ensuring that nearly all precursors reaching the cell surface are of the modified variety.
The VanA Enterococcus fekalis in der Prostata VanB types are the most common among clinical isolates and have been studied in the greatest detail. The VanA determinant Figure 1 confers a high level of resistance to vancomycin and teicoplanin. VanA is typically encoded on Tn or related transposons, and includes seven open reading frames transcribed from two separate promoters. The regulatory apparatus is encoded by the VanR response regulator and VanS sensor kinase two-component system, which are transcribed from a common promoter, while the remaining genes are transcribed from a second promoter.
Gene products that specify the production of modified peptidoglycan precursors include VanH dehydrogenase that converts pyruvate to lactate and VanA ligase that forms D-Ala-D-Llac dipeptide. Regulation of vancomycin resistance gene clusters. The VanS or VanSB sensor kinases are anchored in the cytoplasmic membrane by two transmembrane segments TM that flank the predicted more The VanB locus Figure 1 confers moderate to high-level resistance to vancomycin, but is not induced by teicoplanin. The genetic organization of VanB is similar to that of VanA, in that it contains two distinct promoters transcribing seven open reading frames, but there are some significant differences.
However VanB lacks a homolog of VanZ, and instead encodes a protein named VanW, whose role in resistance is not fully understood. The VanS sensor kinase is thought to recognize a poorly defined stimulus that signals Enterococcus fekalis in der Prostata presence of vancomycin in the environment. VanS thereby becomes activated and autophosphorylates a conserved histidine residue on the cytoplasmic side of the protein.
As a result, the phosphatase activity of VanS is critical to maintain the signaling pathway in the off state in the absence of an inducing antibiotic. In fact, constitutively resistant mutants that Enterococcus fekalis in der Prostata lesions in VanS can be isolated from patients during glycopeptide therapy.
For example, examination of successive isolates of E. Although both VanA and VanB rely on two-component signaling systems to control Van expression, it is clear that there are important differences between these regulatory systems.
For example, the VanS and VanS B sensor kinases exhibit relatively little sequence identity in the N-terminal portion that serves as the site of stimulus recognition. Given the distinct architecture of these two sensor kinases, it seems plausible that they recognize and respond to different molecular signals to trigger kinase activation and expression of the resistance genes.
In fact, this predicted difference in ligand binding—and consequently, in the inducibility of the signaling system—underlies the difference in teicoplanin susceptibility of enterococci that contain VanA vs. Although the molecular identity of the actual inducing signal s remain unclear, the VanA resistance genes are induced by the presence of both vancomycin and Enterococcus fekalis in der Prostata thereby conferring resistance to bothbut the VanB resistance genes are only induced by vancomycin—hence, VanB strains remain susceptible to teicoplanin.
Of note, VanS B can acquire mutations of various types that lead to constitutive expression of the resistance genes or to inducibility by teicoplanin, thereby altering the phenotype of such mutants carrying the VanB locus.
Some evidence suggests that one or more sensor kinases Enterococcus fekalis in der Prostata in the genome of the enterococcal host can contribute to the regulation of the Van resistance genes. Similarly, the VanE cluster in E. Such findings suggest that enterococci encode endogenous two-component signaling Enterococcus fekalis in der Prostata whose natural function is to monitor the integrity of the cell wall for perturbations, and activate appropriate adaptive responses to ensure cell wall maintenance; and further, that the glycopeptide resistance gene cassettes have managed to exploit these endogenous systems to assist in the regulation of glycopeptide resistance.
Other host factors may also play a role in regulation of Van expression. For example, expression of the VanE vancomycin resistance genes may be influenced by the alteration of DNA supercoiling in E.
While the VanA- and VanB-type vancomycin resistance clusters continue to be the predominant forms that account for vancomycin resistance Enterococcus fekalis in der Prostata hospitals, new Van resistance gene clusters have been recently described, which brings the number of known gene clusters capable of conferring Van resistance to nine.
Despite the complex mechanism that underlies glycopeptide resistance, resistant enterococci have disseminated worldwide, suggesting that resistance imposes little or no biological cost to the bacteria.
The investigators found that expression of vancomycin resistance imposed a significant fitness cost, both when expression is induced by the antibiotic and when expression is constitutive due to mutation of the regulatory apparatus.
However, uninduced vancomycin resistance did not impose a measurable fitness cost. A novel mechanism of glycopeptide resistance has been described in laboratory-selected vancomycin-resistant mutants of E. This mechanism is unrelated to that encoded by the Van gene clusters namely, those with production of peptidoglycan precursors containing D-Lac or D-Ser substitutions.
The investigators selected highly resistant mutants in vitro and performed extensive analysis of peptidoglycan structure in the mutants.
Their analysis revealed that the beta-lactam insensitive L,D-transpeptidase pathway discussed in more detail below, under Ampicillin resistance was activated. This alternative transpeptidase named Ldt fm is capable of crosslinking enterococcal peptidoglycan using the L-Lys found at the 3 rd position of the Enterococcus fekalis in der Prostata stem rather than the D-Ala found at position 4, as is typical of most PBPs.
The investigators found that a cryptic D,D-carboxypeptidase was activated in Enterococcus fekalis in der Prostata glycopeptide-resistant mutants, whose activity resulted in production of peptidoglycan peptide stem precursors that are tetrapeptides lacking the terminal D-Alarather than pentapeptides.
Such precursors are not substrates for binding by Enterococcus fekalis in der Prostata antibiotics, but can be cross-linked by the Ldt fm transpeptidase. However, it remains unknown whether this mechanism of glycopeptide resistance is relevant in clinical isolates.
Daptomycin is a lipopeptide antibiotic with potent in vitro bactericidal activity against Gram-positive bacteria. The mechanism of antimicrobial action for daptomycin has not been unequivocally established, but is thought to involve calcium-dependent Enterococcus fekalis in der Prostata into the cytoplasmic membrane followed by membrane depolarization, release of intracellular potassium ions, and rapid cell death Alborn, Jr.
Because its mechanism of action Enterococcus fekalis in der Prostata distinct from those of other antibiotics, daptomycin is useful for treatment of infections that are caused by multidrug-resistant Gram-positive strains. Daptomycin resistance has been observed in clinical isolates following daptomycin therapy, typically as a result of mutations in chromosomal genes. Daptomycin-nonsusceptible clinical E.
The investigators determined that these strains did not carry mutations in homologs of genes known to confer nonsusceptibility to daptomycin in S.
However, the genes responsible for resistance were not identified. Recent studies have begun to explore the genetic basis of daptomycin resistance in enterococci Arias, et al.