Resistance to vancomycin

Acquired resistance to the glycopeptides is transposon-mediated and has so far been largely confined to the enterococci. This has been a problem clinically because many of these strains have been resistant to all other antibiotics and were thus effectively untreatable. Fortunately, the enterococci are not particularly pathogenic and infections have been confined largely to seriously ill, long-term hospital patients. Two types of acquired glycopeptide resistance have been described (Woodford et al. 1995). The VanA phenotype is resistant to vancomycin and teicoplanin, whereas VanB is resistant... 

Enterococcus spp. 50% resistance to methicillin Resistance to vancomycin greater... 

Sievert D.M., M.L. Boulton, G. Stolzman, et al. (2002). Staphylococcus aureus resistant to vancomycin—United States, 2002. Morbidity and Mortality Weekly Report 51 565-567. 

Mechanism of Resistance. Resistance to high levels of dalbaheptides has been described in enterococci. In some isolates, resistance is indutible. Transfer of resistance, in some cases plasmid-mediated, has been described. More recently, strains highly resistant to vancomycin but sensitive 10 teicoplanin have been isolated in the United States. Among the resistant... 

Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC s32. ug/mL), which have acquired the enterococcal resistance determinants. The mechanism for reduced vancomycin susceptibility of vancomycin-intermediate strains (MICs = 8-16 g/mL) is not known. 

CT Walsh, SL Fisher, IS Park, M Prahalad, Z Wu. Bacterial resistance to vancomycin five genes and one missing hydrogen bond tell the story. Curr Biol 3 21-28, 1996. 

Val VanA VanB VanC Xaa valine (V) resistance to vancomycin of type A resistance to vancomycin of type B resistance to vancomycin of type C unspecified amino acid residue... 

Inducible resistance to high levels of vancomycin in enterococci is mediated by transposon Tn 1546 or related transposons [262, 263]. The transposition of Tn 1546 into plasmids with a broad host range or into con-jugative transposons would enable resistance to spread to 5. aureus which can exchange genetic information with enterococci [260]. Plasmid-mediated resistance to vancomycin has been successfully conjugated, in laboratory experiments, from enterococci to S. aureus, provided that erythromycin (6) and not vancomycin was used as the selective agent [265], It was only a question of time before such an event was shown to occur clinically [266, 267] and vancomycin resistance has now been found in an MRSA strain [268]. The seriousness of this cannot be over-emphasized. 

Staphylococcus aureus is one of the major resistant pathogens. Found on the mucous membranes and the skin of around a third of the population, it is extremely adaptable to antibiotic pressure. MRS A was first detected in the early 1960s and is now quite common in hospitals. Strains with intermediate (4-8 J,g/ml) levels of resistance, termed glycopeptide intermediate Staphylococcus aureus (GISA) or vancomycin intermediate Staphylococcus aureus (VISA), began appearing in the late 1990s the first documented strain with complete (> 16 ag/ml) resistance to vancomycin, termed vancomycin-resistant Staphylococcus aureus (VRSA), appeared in 2002. 

Because of its potential toxicity, vancomycin is reserved for serious infections in which less toxic antibiotics are ineffective or not tolerated. Generally, vancomycin is administered intravenously because of poor intestinal absorption. It is the drug of choice for treating infections caused by methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae. Vancomycin has been used to treat enterococcal infections because of their resistance to the P-lactam antibiotics, but most enterococci are now also resistant to vancomycin. Oral administration of rancomycin is important for treatment of some gastrointestinal infections such as pseudomembranous colitis caused by C. difficile. 

In a study of antibiotic resistance in enterococci from raw meat, there was a high prevalence of glycopeptide-resistant strains (49). Resistance to vancomycin was significantly associated with resistance to teicoplanin, erythromycin, tetracycline, and chloramphenicol. 

Vancomycin inhibits bacterial cell wall synthesis and is bactericidal during cell division at therapeutic concentrations. Bacterial resistance to vancomycin has not been an issue during the first decades of its use. More recently, vancomycin-resistant enterococci have been recovered with increasing frequency from hospitalized patients. In some institutions, multidrug-resistant and vancomycin-resistant enterococci have become important nosocomial pathogens, difficult to treat. Vancomycin-resistant enter-ococcal bacteremia is associated with a poor prognosis. Judicious use of vancomycin and broad-spectrum antibiotics is recommended, and strict infection control measures must be implemented to prevent nosocomial transmission of these organisms (5). 

Prostatitis due to vancomycin-resistant enterococci has been reported in a 42-year-old liver transplant recipient (84). The organism. Enterococcus faecium, was resistant to vancomycin, ampicillin, ciprofloxacin, and doxycycline. Treatment with a combination of rifampicin and nitrofurantoin for 6 weeks resulted in a long-lasting cure. 

The first case of methicillin-resistant S. aureus with intermediate resistance to vancomycin was documented in May 1996. Additional cases have been described in the USA ... 

In the last case the strain was identical to eight MRSA isolates obtained from hospitals in the New York City metropolitan area, and all eight isolates, but not control isolates, could be transformed in vitro to develop intermediate resistance to vancomycin. Both the presence of glyco-peptides and environmental factors, as demonstrated by increased resistance of S. aureus to antibiotics in the presence of prosthetic material in animals, can exert selective pressure to develop new resistance mechanisms (93-95). 

Vancomycin/glycopeptide intermediately resistant and methicillin-resistant S. aureus have been described in Japan, Europe, the Far East, and the USA. Some vancomycin-susceptible strains of S. aureus contain subpopulations with intermediate resistance to vancomycin (heterogeneous strains), and these may escape laboratory detection (93,94,97-99). 

However, its a-carboxylate is often amidated or linked to an additional amino acid and in Microbacterium lacticum y-D-Glu is replaced by f/rreo-S-hydroxy-D-glutamic acid (3-Hyg). Most variation is found in position 3. If m-DAP (D,L-configuration) is incorporated, the L center is found in the pentapeptide chain and the D center in the side chain. Positions 4 and 5 (D-Ala-D-Ala) were for a long time thought to be invariant. However, the incidence of bacterial resistance to vancomycin-type glycopeptide antibiotics which recognize specifically the A-acyl-D-Ala-D-Ala terminus led to the discovery that these resistant strains contain altered substituents at position 5 as indicated in Fig. 16b [194,195,196]. 

Vancomycin is most often the antibiotic of last resort for the treatment of resistant bacterial strains, however, bacterial strains resistant to vancomycin are now emerging [19]. The health threat posed by these strains has led to intense research into both the mechanism by which resistance develops and the development of pharmaceutical antibacterial agents with novel modes of action. 

Resistance to vancomycin is via a sensor histidine kinase (VanS) and a response regulator (VanR). VanH encodes a D-lactate dehydrogenase/a-keto acid reductase and generates D-lactate, which is the substrate for VanA, a D-Ala-D-Lac ligase. The result is cell wall precursors terminating in D-Ala-D-... 

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