Vancomycin and Teicoplanin

Vancomycin, a tricyclic glycopeptide antibiotic (Fig. 6.4a) produced by Amycolatopsis (formerly 

It became apparent that appearance of reactions, and their severity, were subject to both the dose of vancomycin and the rate of its infusion. A clinical study involving the measurement of plasma histamine levels every 10 min during the first infusion of each regimen revealed that the largest increases in histamine levels occurred in subjects given 1 g doses those given half that 

Despite a number of reports that cover a range of systemic and dermatologic reactions, severe reactions including true type I responses are rare. An anaphylactoid reaction to infused vancomycin reported in a patient with vancomycin-induced red man syndrome was interpreted, somewhat obscurely, as a possible case of true vancomycin allergy. Other cases induced by vancomycin, but also showing cross-sensitization 

The chemically similar teicoplanin, not approved in the USA, is not inferior to vancomycin with regard to efficiency of treating grampositive infections. It shows a lower rate of adverse reactions, particularly nephrotoxicity and, as already discussed, is used as a substitute for vancomycin in red man syndrome. When hypersensitivity reactions do occur with teicoplanin they are generally of the delayed type, but there are a few documented cases of apparent IgE antibody-mediated reactions implicated, for example, by an immediate wheal and flare skin reaction to the drug or by teicoplanin-induced histamine release from a patient s basophils. Despite the chemical and pharmacological 

Skin testing with vancomycin and teicoplanin has not been well studied and the procedure remains to be validated with both positive and negative predictive values unknown. Skin test results, and particularly details of drug concentrations used and methodologies employed, are hard to find in the vancomycin-teicoplanin literature on adverse reactions. In a case study of vancomycin anaphylaxis followed by successful desensitization, intradermal skin tests with the drug were positive at a concentration of 0.1 pg/ml. Control subjects showed positive responses at concentrations of 10 pg/ml or greater. A loss of skin test reactivity to vancomycin has been demonstrated in one case study after successful desensitization to the drug. 

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Clinical Use. Vancomycin and teicoplanin as fomiulated dmgs are lyophilized powders to be reconstituted with sterile water for injection. Vancomycin hydrochloride [1404-93-9] is presented in vials of 500 mg that give 100—200 mL solution of pH 2.5—4.2. It is administered by slow (60 min) infusion at a dose of 500 mg every 6 h or 1 g every 12 h/d. The teicoplanin contains the five factors (87%) plus 13% of the pseudoaglycone T-A3-1. It is presented in vials containing 200 mg of lyophili ed power that after dissolution with 3 mL of solvent gives a solution at pH 7.5. The dose regimen is 200—800 mg/d by iv bolus adrninistration. 

Vancomycin, ristocetin A and teicoplanin are produced as fermentation products of Streptomyces orientalis, Nocardia lurida and Actinoplanes teichomyceticus, respectively. All three of these related compounds consist of an aglycone basket made up of fused macrocyclic rings and pendant carbohydrate moieties (Fig. 2-1). The macrocycles contain both ether and peptide linkages. The aglycones of vancomycin and teicoplanin contain two chloro-substituted aromatic rings, while the analogous portion of ristocetin A contains no chloro substituents. 

When analytes lack the selectivity in the new polar organic mode or reversed-phase mode, typical normal phase (hexane with ethanol or isopropanol) can also be tested. Normally, 20 % ethanol will give a reasonable retention time for most analytes on vancomycin and teicoplanin, while 40 % ethanol is more appropriate for ristocetin A CSP. The hexane/alcohol composition is favored on many occasions (preparative scale, for example) and offers better selectivity for some less polar compounds. Those compounds with a carbonyl group in the a or (3 position to the chiral center have an excellent chance to be resolved in this mode. The simplified method development protocols are illustrated in Fig. 2-6. The optimization will be discussed in detail later in this chapter. 

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... 

Very recently, ethoxynonafluorobutane (ENFB) was evaluated as a safe and environmentally friendly NP solvent for the enantioselective separation of 15 compounds on two commercially available glycopeptides CSPs (vancomycin and teicoplanin), with APCI-MS detection [126]. 

Rojkovieova, T. et al.. Study of the mechanism of enantioseparation. X. Comparison study of thermodynamic parameters on separation of phenylcarbamic acid derivatives using vancomycin and teicoplanin CSPs, J. Liq. Chrom. Rel. TechnoL, 27, 3213, 2004. 

Lehotay, J. et al.. Chiral separation of enantiomers of amino acid derivatives by HPLC on vancomycin and teicoplanin chiral stationary phases, Pharmazie, 53, 863, 1998. 

Tesafova, E., Zaruba, K., and Flieger, M., Enantioseparation of semisynthetic ergot alkaloids on vancomycin and teicoplanin stationary phases, J. Chromatogr. A, 844, 137, 1999. 

Lee, J.-G., Sagui, C., and Roland, C., First principles investigation of vancomycin and teicoplanin binding to bacterial cell wall termini,/. Am. Chem. Soc., 126, 8384,... 

Brush-type, proteins, CDs, natural molecular imprint-based polymers (MIP), and macrocyclic antibiotics have been immobilized as chiral selectors on packed-CEC columns. Zheng and Shamsi demonstrated the possibility of using chiral CEC—ESI/MS with a commercially packed column for the determination of warfarin enantiomers in human plasma using coumachlor as an internal standard (IS). Robustness of this chiral CEC capillary was recently improved by a novel procedure and applied for the simultaneous enantiosepara-tion of height /1-blockers with multimodal CSP using different combinations of vancomycin and teicoplanin, as presented in Figure 5. ... 

Vancomycin and teicoplanin display excellent activity against staphylococci and streptococci, but because of the wide availability of equally effective and less toxic drugs, they are second-line drugs in the treatment of most infections. As antistaphylococcal agents they are less effective than 3-lactam cephalosporin antibiotics, such as nafciUin and cefazoUn. They have attained much wider use in recent years as a consequence of the emergence of methicUlin-resistant S. aureus (MRSA) infections, in particular the growing importance of Staphylococcus epidermidis infections associated with the use of intravascular catheters and in patients with peritonitis who are on continuous ambulatory peritoneal dialysis. 

Only three dalbaheptides are commercialized vancomycin and teicoplanin for human health, and avoparcin for animal usage. 

Clinical Use. Vancomycin and teicoplanin as formulated drugs are lyophilized powders to be reconstituted with sterile water for injection. 

Thiostrepton is a macrocyclic polypeptide antibiotic that is structurally different from vancomycin and teicoplanin. It is soluble in water and acetic acid. It is obtained from Streptomyces azureus bacterium. There are 17 chiral centers in this antibiotic, with 2 large cavities (A and B in Fig. 1). Five thiazole rings, 1 quinoline ring, 5 hydroxyl groups, 10 amide linkages, and 1 secondary amine make the molecule stereo-specific in nature. 

In addition to the common use of vancomycin and teicoplanin, the use of other antibiotics as chiral selectors in HPLC were limited. Only a few reports are available in the literature dealing with these antibiotics as HPLC CSPs. Armstrong et al. [42] resolved about 230 racemates on the ristocetin A antibiotic covalently bonded to silica gel. The resolution was carried out using the three modes of mobile phases. The results were complimentary to those obtained on vancomycin and teicoplanin CSPs. In another study, the effect of selector coverage and mobile phase composition on enantiomeric resolution with ristocetin A CSP was carried out by Armstrong et al. [43]. Thiostrepton-based CSP was also used to resolve the enantiomers of thioridazine, 2,2,2-trifluoro-l-... 

Two EPMEs based on macrocyclic glycopeptide antibiotics—vancomycin and teicoplanin—were designed for the assay of acetyl-L-carnitine [44]. The linear concentration ranges for the proposed electrodes were 10 5-10-2 mol/L for the vancomycin-based electrode and 10 4-10-2 mol/L for the teicoplanin-based electrode, with slopes of 58.1 and 55.0mV/p(acetyl-L-camitine), respectively. The enantioselectivity was determined over D-carnitine. 

Three EPMEs based on macrocyclic glycopeptide antibiotics— vancomycin and teicoplanin (modified or not with acetonitrile)—were proposed for the determination of l- and D-enantiomers of methotrexate (Mtx) [48]. The linear concentration ranges for the proposed enantioselective membrane electrodes were between 10 6 and 10-3 mol/L for l- and D-Mtx. The slopes of the electrodes were 58.00 mV/pL-Mtx for vancomycin-based electrode, 57.60 mV/pD-Mtx for teicoplanin-based electrode and 55.40 mV/pD-Mtx for teicoplanin modified with acetonitrile-based electrode. The detection limits of the proposed electrodes were of 10 8 mol/L magnitude order. All proposed electrodes proved to be successful for the determination of the enantiopurity of Mtx as raw material and of its pharmaceutical formulations (tablets and injections). 

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