Vancomycin activity

The story of the involvement of glycosyl moieties in vancomycin activity is probably one of the most illustrative and also very topical as glycosyl derivatives of vancomycin quite recently proved to be very effective against multiply resistant (even vancomycin-resistant) bacteria. 

Because of the ultimate importance of vancomycin in the treatment of often fatal infections caused by multiply resistant bacteria, extensive efforts have been directed toward the discovery of vancomycin derivatives with activity against the drug-resistant bacteria [77]. As a result of these efforts, several derivatives such as 52 (LY264826) have been found to be up to 500 times more effective than vancomycin itself. The most notable difference is the presence of another aminosugar (R ) attached to the amino acid 6. This extra sugar possibly facilitates the dimerization of the antibiotic and/or anchors the antibiotic to the cell membrane, both of which have been shown to be important for vancomycin activity [75]. It was also demonstrated that the conformations of vancomycin and its aglycon differ in their alignment of the amide protons... 

Other specific discovery assays have been used such as differential inhibition of a vancomycin resistant S. aureus strain and its susceptible parent, and an assay based on antagonism of the antibacterial activity by N,A/-diacetyl-L-Lys-D-Ala-D-Ala [24570-39-6] a tripeptide analogue of the dalbaheptides receptor. AppHcation of this latter test to 1936 cultures (90) led to the isolation of 42 dalbaheptides, six of which, including kibdelin (Table 3), parvodicin (Table 3), and actinoidin A2 (68) were novel. A colorimetric assay based on competition between horseradish peroxidase bound teicoplanin and the... 

In Vivo Properties. The efficacy of dalbaheptides has been assessed ia various models of experimental septicemia ia mice. In general there was good correlation between the ED qS (effective doses which prevent death ia 50% of test animals) and the MICs on test strains. Teicoplanin was very effective, ED q values ranged from 0.11 to 0.72 mg/kg sc administration for septicemias caused by S. pyogenes S. pneumoniae and S. aureu whereas for vancomycin ED qS were from 0.58 to 7.2 mg/kg (33). Eremomycin (52) had therapeutic activity 2—3 times greater than vancomycin. Therapeutic indices... 

This resistance, inducible by low concentrations of dalbaheptides, is plasmid mediated and is transferable. Concomitant with the induction of resistance is the appearance or increased expression of a protein having a molecular weight of either 39,500 or 39,000. The enzymatic activity of this material has been postulated (112). Although the mechanism of resistance induction by dalbaheptides is unknown, different dalhabaheptides have different induction capacity. Vancomycin (39) is the most powerful inducer teicoplanin is a very weak inducer. 

As recently as 1970, only about 30 naturally occurring organohalogen compounds were known. It was simply assumed that chloroform, halogenated phenols, chlorinated aromatic compounds called PCBs, and other such substances found in the environment were industrial pollutants. Now, only a third of a century later, the situation js quite different. More than 5000 organohalogen compounds have been found to occur naturally, and tens of thousands more surely exist. From a simple compound like chloromethane to an extremely complex one like vancomycin, a remarkably diverse range of organohalogen compounds exists in plants, bacteria, and animals. Many even have valuable physiological activity. Vancomycin, for instance, is a powerful antibiotic produced by the bacterium Amycolatopsis orientalis and used clinically to treat methicillin-resistant Staphylococcus aureus (MRSA). 

Teicoplanin is a naturally occurring complex of five closely related tetracyclic molecules. Its mode of action and spectrum of activity are essentially similar to vancomycin, although it might be less active a inst some strains of coagulase-negative staphylococci. Teicoplanin can be administered by intramuscular injection. 

Nagarajan R. (1991) Antibacterial activities and modes of action of vancomycin and related giycopeptides. Antimicrob Agents Chemother, 35, 605-609. 

If the isolate is determined to be vancomycin-resistant, it is most important to know the exact species because some of the treatment options, such as quinupristin/dalfopristin, are not active against E. faecalis. Currently, the treatment options for vancomycin-resistant enterococci (VRE) are not well established by clinical studies or patient experience. The treatment recommendations for vancomycin-resistant E. faecium include linezolid or quinupristin/dalfopristin for a minimum of 8 weeks. However, newer agents, such as daptomycin, may provide another option for treatment for either enterococci species (E. faecium and E. faecalis). Additionally, guidelines suggest the use of imipenem-cilistatin plus ampicillin or ceftriaxone plus ampicillin for the treatment of E. faecalis with a minimum of 8 weeks of therapy. Consultation with an infectious diseases specialist is recommended. 

Besides constipation-related IBS, several studies have also suggested abnormalities of colonic bacterial composition in chronic idiopathic constipation [125]. Here again antibiotic treatment with vancomycin [126, 127], rova-mycin (in combination with diphetarsone, an amebicidal agent) [128,129] or erythromycin [130], which, however, displays a prokinetic activity [131, 132], proved to be capable of reversing long-lasting constipation. Furthermore, the efficacy in both clinical conditions of probiotics [133-135] lends further support to the pathogenic role of bowel flora. 

Table 8. Activity of rifaximin, vancomycin and metronidazole against 93 clinical isolates of C. difficile (from Marchese et al. [48])... 

Marchese A, Salerno A, Pesce A, Debbia EA, Schito GC In vitro activity of rifaximin, metronidazole and vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species. Chemotherapy 2000 46 253-266. 

Antibiotics with activity against urease-producing bacteria, such as neomycin [42], paromomycin [44] or metronidazole [45], also reduce the production of intestinal ammonia and have proved to be of value. Vancomycin has also been used in patients with lactulose-resistant chronic encephalopathy [46]. The efficacy of neomycin is similar to that of lactulose [42]. However, a small percentage of this drug is absorbed from the gastrointestinal tract and may cause ototoxic and nephrotoxic effects, especially with continuous use over several months [47]. This drug should be used with particular caution by patients with renal insufficiency. The efficacy of metronidazole for... 

---