Vancomycin

J Microbiol Methods, 2005 Mar, 60(3), 395 - 401
The detection of Cryptosporidium parvum and Escherichia coli O157 in UK bivalve shellfish; Macrae M et al.; Optimised immunomagnetic separation methods to detect Cryptosporidium parvum and Escherichia coli O157 in UK shellfish are described . Whole tissue homogenates gave the best recoveries for C . parvum oocysts compared with gill or haemolymph extracts . The sensitivity of recovery from spiked samples was comparable to that achieved when processing water and varied from 12-34% in mussels, 48-69.5% in oysters and 30-65% in scallops . Maximum recovery of E . coli O157 was achieved by enriching in buffered peptone water supplemented with vancomycin at 42 degrees C . Increasing enrichment temperatures from 37 to 42 degrees C gave a significant increase in target number recovery . Implementation of these methods into monitoring programmes and end-product testing will enable shellfish producers to better assess product safety.

J Comb Chem, 2005 Jan-Feb, 7(1), 123 - 9
Conformational Studies of Resin-Bound Vancomycin and the Complex of Vancomycin and Ac(2)-l-Lys-d-Ala-d-Ala; Yao NH et al.; The molecular target of vancomycin, a commonly used glycopeptide antibiotic, is the d-Ala-d-Ala dipeptide subunit on the bacterial cell wall . The molecular basis of interaction between vancomycin and d-Ala-d-Ala in solution is well-known . However, there is no structural data on vancomycin, and its interaction with d-Ala-d-Ala when the drug is tethered to a solid support . In this Article, vancomycin was directly coupled onto TentaGel or PEGA resin through its C terminus . High-resolution magic angle spinning NMR studies indicated that conformation of PEGA bead-bound vancomycin is identical to that of the free drug . Broadening and shifts of the same proton resonances were observed in solution-phase vancomycin or PEGA-bound vancomycin when complexed with Ac(2)-l-Lys-d-Ala-d-Ala . This study demonstrates that bead-bound molecules can behave the same as solution-phase molecules in terms of molecular interaction with its target molecule, thus validating the on-bead screening approach of the "one-bead-one-compound" combinatorial library method.

J Biol Chem . 2005 Jan 4; {Epub ahead of print}
The role of the novel Fem protein VanK in vancomycin resistance in streptomyces coelicolor; Hong HJ et al.; The non-pathogenic, non-glycopeptide-producing actinomycete Streptomyces coelicolor carries a cluster of seven genes (vanSRJKHAX) that confers inducible, high-level resistance to vancomycin . The vanK gene has no counterpart in previously characterized vancomycin resistance clusters, yet vanK is required for vancomycin resistance in S . coelicolor . VanK belongs to the Fem family of enzymes, which add the branch amino acid(s) to the stem pentapeptide of peptidoglycan precursors . Upon exposure to vancomycin, the VanRS two-component system switches on expression of all seven van genes and the VanHAX enzymes reprogram the cell wall, such that precursors terminate D-Ala-D-Lac rather than D-Ala-D-Ala, thus conferring resistance to vancomycin, which only binds D-Ala-D-Ala-containing precursors . Here we provide biochemical and genetic evidence that VanK is required for vancomycin resistance because the constitutively expressed FemX enzyme, encoded elsewhere on the chromosome, cannot recognize D-Lac-containing precursors as a substrate, while VanK can . Consistent with this view, D-Lac-containing precursors carrying the Gly branch are present in the wild type transiently exposed to vancomycin, but are undetectable in a vanK mutant treated in the same way . Further, femX null mutants are viable in the presence of vancomycin but die in its absence . Because only VanK can recognise D-Lac-containing precursors, vancomycin-induced expression of VanHAX in a vanK mutant is lethal, and so vanK is required for vancomycin resistance.

J Chromatogr A, 2004 Dec 10, 1060(1-2), 205 - 14
Temperature and enantioseparation by macrocyclic glycopeptide chiral stationary phases; Berthod A et al.; Seventy-one chiral compounds were separated on four macrocyclic glycopeptide chiral selectors: teicoplanin, its aglycone, ristocetin A and vancomycin, using three possible separation modes: reversed phase with methanol/buffer mobile phases, normal phase with hexane/ethanol mobile phases and polar ionic mode (PIM) with 100% methanol mobile phase with trace amounts of acid and/or base . These 148 separations were studied in a 5-45 degrees C temperature range . Peak efficiencies always increased with temperature, but in only 17% of the separations studied a small increase of the enantioresolution factor was observed . In the majority (83%) of the cases, the enantioresolution decreased or even vanished when temperature increased . All 148 Van't Hoff plots were linear showing that the selector did not change in the temperature range studied . The calculated enthalpy and entropy variations showed that the interaction of the solute with the stationary phase was always enthalpy driven with normal and reversed mobile phases . It could be enthalpy as well as entropy driven with PIM mobile phases strongly dependent on the solute . The plots of delta(deltaH) versus delta(deltaS) were linear in most cases (enthalpy entropy compensation) . This observation cannot be used to give clear information on chiral recognition mechanisms, but it allowed identifying specific stationary phase-solute interactions because the points corresponding to the respective thermodynamic parameters were clearly delineated from the general compensation lines.

Anal Biochem, 2005 Jan 15, 336(2), 172 - 7
Using surface plasmon resonance to directly identify molecules in a tripeptide library that bind tightly to a vancomycin chip; Tseng MC et al.; This paper describes a procedure, based on direct binding, for identifying tight-binding ligands for a receptor immobilized on a sensor chip from an array of equimolar tripeptides using surface plasmon resonance . Vancomycin and a library of 96 tripeptides, with molecular weight ranging from 316 to 560Da, were used as a model system to illustrate the procedure . A consensus structure of the strongest interacting peptides consisted of d-Ala at the C terminus and aromatic amino acid in the penultimate position . Ligands having this structure bound more tightly to vancomycin than the known d-Ala-d-Ala peptide . The throughput of our continuous assay is 96 compounds in 3.3h, and the sample consumption is less than 2mug per peptide and 1ng for vancomycin . This procedure should be applicable to peptide libraries of greater complexity than that used here and to mixtures of small organic compounds.

Rev Neurol, 2004 Dec 1-15, 39(11), 1034 - 7
{Cerebrovascular disease as an initial finding in childhood tuberculosis meningoencephalitis.}; Rotta NT et al.; INTRODUCTION . The prevalence of tuberculosis in developing countries, such as Brazil, remains high with important morbidity and mortality rates among children . Neurological complications are frequent and tuberculous meningo-encephalitis (TBM) is the most dreaded of them in infancy . CASE REPORT . Our case involves a 7-year-old white female patient who was previously in good health . Over a period of two weeks she suffered from high temperatures and vomiting and was given amoxicillin . She later suffered an attack of focal seizures . Electroencephalogram studies showed a temporary double focus and lesions in the left hemisphere . A cranial computerised tomography (CT) scan revealed a periventricular haemorrhage on the left side . The control CT (carried out 20 days later) showed a reduction in the haemorrhage and localised hypodensity . Owing to the suspected existence of an abscess, the patient was administered vancomycin . A new cranial CT scan (40 days after the first) showed gliosis alongside the basal nuclei with impregnation in the carotid trifurcation, which led us to suspect that we were dealing with a case of vasculitis or a granuloma . All the microbacterial cultures were negative and there was no history of contact with tuberculosis . The adenosine deaminase (ADA) value in the sample of cerebrospinal fluid (taken seven weeks after the first) was found to be 21.2 UI . Treatment was started with tuberculostatic compounds . Two weeks later the fever disappeared . The control CT scan showed decreased hypodensity and impregnation . The patient was discharged from hospital, with a slight monoparesis in the upper right limb . Discussion . The presentation of a cerebrovascular disease within a context of TBM, like the case reported here, is relatively rare in the literature . We concluded that the uncommon initial symptoms of TBM, associated with the negative cultures, contributed to the delay in reaching a diagnosis . A cerebrovascular accident must be included in the clinical picture of TBM and this disease has to be taken into account when dealing with a case of cerebrovascular accident.

Pharmazie, 2004 Nov, 59(11), 828 - 32
HPLC enantioseparation of potential beta-blockers of the aryloxyaminopropanol type . Study of the mechanism of enantioseparation, Part VIII; Hrobonova K et al.; This paper presents the results of HPLC enantioseparation of derivatives of aryloxyaminopropanols obtained using six chiral stationary phases {macrocyclic antibiotic (vancomycin, teicoplanin, teicoplanin aglycone, and methylated teicoplanin aglycone) and cyclodextrin (beta and gamma)} and a mixture of methanol/acetonitrile/acetic acid/triethylamine (45/55/0.3/0.2) as the mobile phase . No significant difference was observed in the separation of the enantiomers on the vancomycin and teicoplanin chiral stationary phases . Comparing the separation of enantiomers on teicoplanin-based columns the retention factors were increased in the order: native teicoplanin < teicoplanin aglycone < methylated teicoplanin aglycone . The highest values of resolution were obtained on the column containing carbohydrate moieties . The presence of saccharide moieties in the chiral stationary phase plays an important role, together with charge interactions and steric interactions, in the separation of enantiomers of derivatives of aryloxyaminopropanol.

J Sep Sci, 2004 Nov, 27(15-16), 1303 - 8
Enantiomeric separation of chlorophenoxy acid herbicides by nano liquid chromatography-UV detection on a vancomycin-based chiral stationary phase; Rosales-Conrado N et al.; Enantiomeric separation of mecoprop, dichlorprop, and fenoprop herbicides in their acid form, commonly used to control the growth of broad-leaved weeds, was carried out by nano-liquid chromatography (nano-LC) at a flow rate of 60 nL/min, using a packed capillary column with vancomycin-modified silica particles of 5 microm . The length of chiral stationary phase was 21 cm, while the total and effective lengths were 43 and 33cm, respectively . Inner diameter was 0.075 mm . Separated peaks were detected at 195 nm . Several mixtures of methanol, water, and 500 mM ammonium acetate buffer at different pH's were tested as mobile phase, and experimental parameters such as resolution (Rs), capacity factor (k), efficiency (N/m), and enantioselectivity factor (alpha) were measured under all the test conditions . Baseline enantiomeric separation was obtained for the three studied herbicides with alpha in the range 1.6-1.9, using as the mobile phase aqueous solutions containing 85% methanol, 5% of 500mM ammonium acetate pH4.5 buffer, and 10% water . Experimental results show that the vancomycin stationary phase presents a great enantiorecognition capability towards chlorophenoxy acid herbicides on using nano-LC.

Biochemistry, 2004 Dec 14, 43(49), 15446 - 52
Synchronized conformational fluctuations and binding site desolvation during molecular recognition; Jusuf S et al.; Binding site desolvation is a poorly understood prerequisite to ligand binding . Although structural fluctuations may be expected to have an important role, little is known about which fluctuations are important or the mechanism by which they promote desolvation . This investigation examines whether and how specific structural fluctuations contribute to desolvation of the ligand binding site in glycopeptide antibiotics . Backbone peptide group rotations in vancomycin, known to occur by experimental observation, were examined in this work with a two-dimensional adaptive umbrella sampling molecular dynamics simulation technique . Results indicate that energetic barriers to rotation are relatively small for two of the peptide groups intimately involved in ligand recognition . When they occur, these rotations strip water molecules away from key hydrogen bond donors and simultaneously cause significant distortions in the macrocyclic rings of the antibiotic that force water into and out of the binding site . Both events are intricately synchronized on the molecular level and have consequences that are clearly necessary to prepare the binding site for receiving a ligand . These results suggest that previously reported observations concerning structural dynamics and binding kinetics in these compounds are mechanistically linked, and they illustrate a heretofore unrecognized degree of preorganization, complexity, and synchronization that may be involved in specific molecular recognition . They also suggest that strategies for increasing antibiotic affinity through covalent dimerization may be counterproductive.

Am J Perinatol, 2004 Nov, 21(8), 433 - 8
Large vancomycin overdose in two premature infants with minimal toxicity; Miner LJ et al.; Two premature infants received 10-fold overdoses of vancomycin with resulting peak plasma concentrations > 300 microg/mL . Discontinuation of vancomycin and watchful waiting were employed, with no specific intervention to accelerate vancomycin clearance . Plasma vancomycin concentration < 40 microg/mL was attained at < 48 hours in one infant and < 72 hours in the other . Although one infant sustained a transient increase in serum creatinine to 1.4 mg/dL, no further evidence of renal, auditory, or other toxicity was detected in either infant acutely or long term . Contemporary preparations of vancomycin appear much less toxic than earlier formulations . Aggressive and invasive interventions to hasten clearance may be unnecessary following overdose in infants with normal or near-normal basal renal function, although careful surveillance for clearance and toxic effects still appear warranted.

Eur J Pharm Biopharm, 2005 Jan, 59(1), 139 - 46
Effects of gamma-irradiation on trehalose-hydroxyethylcellulose microspheres loaded with vancomycin; Bartolotta A et al.; Ionizing radiation can be used as a drug sterilization technique, provided that the drug itself is not modified and that no toxic products are produced; moreover, if the irradiated product is a drug delivery system, the drug release characteristics must not be significantly altered by radiation . The aim of this work was to study the effects of sterilization by ionizing radiation on hydroxyethylcellulose/trehalose spherical micromatrices, containing the antibiotic vancomycin . Our experimental results showed that gamma-rays did not alter the chromophore groups of vancomycin (UV measurements), and did not modify the kinetic behavior of drug release from microspheres . Moreover, no significant changes in the shape and in the size distribution of microspheres were found after irradiation . The electron spin resonance (ESR) spectroscopy was proven to be a valid identification method of the executed radiation treatment, even after 5 years . The experimental results showed that the therapeutic application of the pharmacological system investigated was not compromised by irradiation, and that ESR spectroscopy can be used to distinguish irradiated from non-irradiated products.

Asian J Surg, 2004 Jul, 27(3), 236 - 7
Colostomy with vancomycin administration as an effective treatment for toxic megacolon associated with fulminant pseudomembranous colitis: a case report; Haraguchi M et al.; We report a case of toxic megacolon associated with fulminant pseudomembranous colitis . A 72-year-old woman was admitted with severe dehydration and shock . Computed tomography showed evidence of diffuse thickening of the colonic wall, colonic dilatation and ascites . She underwent transverse colostomy and received postoperative vancomycin, both orally and by administration from the stoma . Her clinical situation improved dramatically following surgery . When a patient is unable to tolerate subtotal colectomy and ileostomy because of a severe overall condition, temporary colostomy followed by administration of vancomycin through the stoma is recommended.

Perit Dial Int, 2004 Nov-Dec, 24(6), 590 - 5
Stability of drug additives in peritoneal dialysis solutions in a new container; Voges M et al.; OBJECTIVE: To evaluate the stability of gentamicin, tobramycin, netilmycin, vancomycin, cefazolin, unfractionated heparin, and low molecular weight heparin when added to four different peritoneal dialysis (PD) solutions {Extraneal (Baxter Healthcare, Castlebar, Ireland); Physioneal, Nutrineal, and Dianeal (Baxter Healthcare, Grosotto, Italy)} in new, non-PVC Clear-Flex containers . MEASUREMENTS: Gentamicin, tobramycin, netilmycin, vancomycin, cefazolin, unfractionated heparin, and low molecular weight heparin were injected into separate bags of PD solution . Samples were withdrawn at predefined sampling times and the concentration of each drug was analyzed using high-performance liquid chromatography (for gentamicin, tobramycin, vancomycin, and cefazolin), or bioassay (for netilmycin, gentamicin, and tobramycin in Nutrineal), or coagulation methods (heparins) . RESULTS: Netilmycin, vancomycin, cefazolin, and heparin in Physioneal, Nutrineal, Extraneal, and Dianeal were stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C . Gentamicin in Nutrineal, Extraneal, and Dianeal was stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C; gentamicin in Physioneal was stable for less than 24 hours at 25 degrees C . Tobramycin in Nutrineal and Extraneal was stable for at least 24 hours at 25 degrees C and for an additional 4 hours at 37 degrees C; tobramycin in Physioneal and Dianeal was stable for less than 24 hours at 25 degrees C.

Biomed Chromatogr . 2004 Nov 23; {Epub ahead of print}
Successful management of discovered pH dependence in vancomycin recovery studies: novel HPLC method for microdialysis and plasma samples; Plock N et al.; Vancomycin is a glycopeptide antibiotic approved for the treatment of serious infections or patients allergic to beta-lactams . A rapid HPLC assay using UV detection for the determination in microdialysate and human plasma was developed . After sample preparation, using methanol and trichloroacetic acid for plasma and water for microdialysate, 20 microL were injected and separated on a RP(18) column . Overall, the assay exhibited good precision and accuracy . The diffusion properties of vancomycin investigated in in vitro microdialysis experiments revealed an unfavourable concentration dependence avertable by keeping a constant pH using phosphate buffer as perfusate . The mean relative recoveries were 27.8% {coef fi cient of variation (CV) 11.1%} and 33.2% (CV 8.3%) for retrodialysis and recovery experiments, respectively . Following characterization of vancomycin in in vitro microdialysis, the developed setting is suitable for application in (pre-)clinical studies . Copyright (c) 2004 John Wiley & Sons, Ltd.

Clin Orthop, 2004 Oct, (427), 22 - 4
Gentamicin and vancomycin do not impair experimental fracture healing; Haleem AA et al.; The purpose of this study was to determine whether gentamicin or vancomycin impair experimental fracture healing in rats . Forty-one male Wistar rats were divided into three groups, receiving either 1.5 mg/kg of gentamicin intramuscularly twice daily for 3 weeks (n = 15), 25 mg/kg of vancomycin intraperitoneally twice daily for 3 weeks (n = 14), or no treatment (n = 12), starting 7 days after production of closed, nondisplaced, bilateral femoral fractures . The mean 30 minute serum concentrations of gentamicin and vancomycin were 4.5 microg/mL and 35.1 microg/mL, respectively . Biomechanical and radiographic studies were used to evaluate fracture healing . Torsional strength testing of fracture callus exposed to gentamicin and vancomycin was similar (437 and 424 N-mm, respectively) to controls (334 N-mm) . Radiographs showed similar healing in control animals (Goldberg score, 2.3) compared with rats treated with gentamicin and vancomycin (Goldberg score, 2.6 in both groups) . Results of this study do not show impaired healing of experimental fractures after exposure to gentamicin or vancomycin (such as has been reported after exposure to quinolones).

Clin Exp Dermatol, 2004 Nov, 29(6), 633 - 6
Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis; Waldman MA et al.; Linear IgA bullous dermatosis (LABD) is a rare autoimmune vesiculobullous disorder characterized by variable clinical presentations that may mimic bullous pemphigoid, dermatitis herpetiformis, cicatricial pemphigoid and erythema multiforme . A few cases of drug-induced LABD that clinically resembled toxic epidermal necrolysis (TEN) have been reported . A subset of patients with LABD have been found to be drug-induced; the most common drug being vancomycin . The diagnosis of LABD is confirmed by the presence of a linear band of IgA along the basement membrane zone on direct immunofluorescence microscopy . We report a case of a 77-year-old man who presented to us with vancomycin-induced LABD that presented clinically as TEN . He had a complete recovery over a 3-week period following discontinuation of the vancomycin and the addition of oral dapsone therapy . It is important to be aware that drug-induced LABD can mimic TEN.

Clin Orthop, 2004 Oct, 1(427), 22 - 24
Gentamicin and Vancomycin Do Not Impair Experimental Fracture Healing; Haleem AA et al.; The purpose of this study was to determine whether gentamicin or vancomycin impair experimental fracture healing in rats . Forty-one male Wistar rats were divided into three groups, receiving either 1.5 mg/kg of gentamicin intramuscularly twice daily for 3 weeks (n = 15), 25 mg/kg of vancomycin intraperitoneally twice daily for 3 weeks (n = 14), or no treatment (n = 12), starting 7 days after production of closed, nondisplaced, bilateral femoral fractures . The mean 30 minute serum concentrations of gentamicin and vancomycin were 4.5 mug/mL and 35.1 mug/mL, respectively . Biomechanical and radiographic studies were used to evaluate fracture healing . Torsional strength testing of fracture callus exposed to gentamicin and vancomycin was similar (437 and 424 N-mm, respectively) to controls (334 N-mm) . Radiographs showed similar healing in control animals (Goldberg score, 2.3) compared with rats treated with gentamicin and vancomycin (Goldberg score, 2.6 in both groups) . Results of this study do not show impaired healing of experimental fractures after exposure to gentamicin or vancomycin (such as has been reported after exposure to quinolones).

J Clin Microbiol, 2004 Nov, 42(11), 5429 - 31
Catheter-related bloodstream infection caused by Mycobacterium brumae; Lee SA et al.; Mycobacterium brumae is a rapidly growing environmental mycobacterial species identified in 1993; so far, no infections by this organism have been reported . Here we present a catheter-related M . brumae bloodstream infection in a 54-year-old woman with breast cancer . The patient presented with high fever (39.7 degrees C), and >1,000 colonies of M . brumae grew from a quantitative culture of blood drawn through the catheter . A paired peripheral blood culture was negative, however, suggesting circulational control of the infection . The patient was treated empirically with meropenem and vancomycin, and the fever resolved within 24 h . The catheter was removed a week later, and from the tip M . brumae was isolated a second time, suggesting catheter colonization . The organism was identified by colonial morphology, sequence analysis of the 16S rRNA gene, and biochemical tests.

J Nippon Med Sch, 2004 Oct, 71(5), 340 - 4
Post-cataract surgery endophthalmitis treated with core vitrectomy: a case report; Shiwa T et al.; Postoperative endophthalmitis is one of the most serious complications after cataract surgery though its frequency may be low . We report a case with post-cataract extraction bacterial endophthalmitis treated favorably by core vitrectomy through pars plana with anterior vitrectomy cutter (A-vit) . The patient, a 72-year-old woman, presented with blurred vision 7 days after phacoemulsification and aspiration (PEA) and intraocular lens (IOL) implantation . Her initial visual acuity was counting fingers . As hypopyon and corneal edema progressed in a few hours, we decided to perform vitectomy . Firstly, we performed IOL explantation and anterior vitrectomy through the corneal stab incision with A-vit attached to the phaco machine . The inflammation, however, appeared to be severe . Secondly we performed core vitrectomy with the same cutter as we used in the first operation through pars plana as well as intravitreal injection of vancomycin on the following day . The inflammation was gradually subsided and her corrected visual acuity was recovered to 30/20 at 7 months after the vitrectomy . The results is suggest that for cataract surgeons in the facilities that are not equipped with 3-port vitrectomy machine, post-cataract extraction bacterial endophthalmitis of the emergency stage can be successfully treated by core vitrectomy through pars plana as well as intravitreal injection of antibiotics with neither vitreous shaving at the vitreous base nor artificial posterior vitreous detachment.

Acta Crystallogr D Biol Crystallogr, 2004 Nov, 60(Pt 11), 1935 - 42 Epub 2004 Oct 20.
Recurring main-chain anion-binding motifs in short polypeptides: nests; Milner-White EJ et al.; A novel tripeptide motif called a nest has recently been described in proteins with the function of binding anionic, or partially anionic, atoms such as carbonyl O atoms . In the present work, a search for nests in small polypeptides stored in the Cambridge Structural Database is reported . 37 unique examples were found: over half form part of hydrogen-bond arrangements resembling those in proteins, such as Schellman/paperclip loop motifs, various types of beta-turn and Asx-turns or Ser/Thr-turns, while a third are in novel situations, some involving binding to anionic groups from other molecules within the crystal complex . An example is the antibiotic vancomycin, which incorporates a prominent nest forming part of a peptide-binding site . This nest binds the carboxylate of the C-terminal D-alanine of the bacterial cell-wall precursor peptide, thereby inhibiting the final step of bacterial cell-wall synthesis . As in proteins, a number of nests occur in short peptides with an alternating glycine/L-amino-acid sequence but, uniquely to non-ribosomally synthesized short peptides, several nests within them are constructed from alternating D- and L-amino acids, and such sequences seem to specially favour nests.

Rev Saude Publica, 2004 Oct, 38(5), 723 - 8 Epub 2004 Oct 18.
Detection of pathogens from periodontal lesions; Malheiros Vde J et al.; OBJECTIVE: To comparatively detect A . actinomycetemcomitans and F . nucleatum from periodontal and healthy sites . METHODS: Subgingival clinical samples from 50 periodontitis adult patients and 50 healthy subjects were analyzed . Both organisms were isolated using a trypticase soy agar-bacitracin-vancomycin (TSBV) medium and detected by PCR . Conventional biochemical tests were used for bacteria identification . RESULTS: A . actinomycetemcomitans and F . nucleatum were isolated in 18% and 20% of the patients, respectively, and in 2% and 24% of healthy subjects . Among A . actinomycetemcomitans isolates, biotype II was the most prevalent . Primer pair AA was 100% sensitive in the detection of A . actinomycetemcomitans from both subject groups . Primers ASH and FU were also 100% sensitive to detect this organism in healthy subject samples . Primer pair FN5047 was more sensitive to detect F . nucleatum in patients or in healthy samples than primer 5059S . Primers ASH and 5059S were more specific in the detection of A . actinomycetemcomitans and F . nucleatum, respectively, in patients and in healthy subject samples . CONCLUSIONS: PCR is an effective tool for detecting periodontal pathogens in subgingival samples, providing a faster and safer diagnostic tool of periodontal diseases . The method's sensitivity and specificity is conditioned by the choice of the set of primers used.

Drug Metab Pharmacokinet, 2004 Feb, 19(1), 68 - 75
Protective effect of inactive ingredients against nephrotoxicity of vancomycin hydrochloride in rats; Hodoshima N et al.; A generic form of vancomycin for I.V . infusion (MEEK) is more soluble and stable than the brand-name form of vancomycin hydrochloride (VCM) due to the addition of two inactive ingredients: D-mannitol and Macrogol400 (PEG400) . The aim of the present study was to compare the nephrotoxicity of MEEK with that of brand-name VCM (S-VCM) and to analyze the pharmacokinetics of these preparations . Following administration to rats at the clinical dose of 40 mg/kg, there was no difference between MEEK and S-VCM with regard to pharmacokinetics and effects on the kidneys, indicating that MEEK should be as effective as S-VCM . When administered at the nephrotoxic dose of 400 mg/kg, S-VCM caused impairment of renal function and kidney damage, and an increase of the plasma concentration due to decreased renal clearance was observed . In contrast, MEEK had virtually no effect on renal function or the kidneys and did not cause a marked change of renal clearance . These findings suggest that the inactive ingredients in MEEK play a role in reducing the nephrotoxicity of VCM.

Polim Med, 2004, 34(2), 31 - 8
{Effect of corundum-vancomycin composite on soft tissue reaction}; Rusiecki M et al.; The ceramics on the basis of corundum is used for implantation in the form of porous and solid materials . The solid form was used to produce tissue endoprosthesis while porous form is mainly used to fill in the bone defects . The corundum ceramics are also known to be used as coatings for implants in orthopedics and dentistry . On the other hand there is still a need to find out the new way of treatment of the chronic bone infection, during which the traditional way of antibiotics therapy is no more effective . One of the possibly solution is to use the different biomaterials as drug carriers and in the bone surgery one of the best are porous corundum implants, being themselves of high biocompatibility, and additionally containing Vancomycin . The main target of the investigation presented in this paper was the comparative assessment of the corundum ceramics and its composite containing Vancomycin after implantation into back muscle of the total of 15 rats . During the post mortem macroscopic assessment in the tissues which surrounded the implants there were no any inflammatory neither pathological changes observed . In the microscopic findings, in early periods, the observed inflammatory tissue reaction for implants with vancomycin was significantly greater what could be explained by the high concentration of the antibiotic in the given material . On the basis of the results of macroscopic and microscopic findings we can state that the composite material of corundum ceramic containing vancomycin is of high compatibility and could be regarded as the good drug carrier.

J Sep Sci, 2004 Sep, 27(13), 1109 - 14
Enantiomer separations on a vancomycin stationary phase and retention mechanism of pressurized capillary electrochromatography; Yao C et al.; Several chiral drugs, promethazine, carteolol, celiprolol, and albuterol, were resolved with vancomycin as the chiral stationary phase by pressurized capillary electrochromatography (pressurized CEC) and capillary HPLC . The effects of pressure and electrical field strength on efficiency, resolution, and capacity factor in pressurized CEC were investigated . A mathematical model describing the relationship of capacity factor in pressurized CEC with voltage, pressurized flow velocity, electroosmotic mobility, and electrophoretic mobility was established, which was in good agreement with the experimental data.

Pediatr Dermatol, 2004 Sep-Oct, 21(5), 600 - 2
Extensive fixed drug eruption secondary to vancomycin; Gilmore ES et al.; Fixed drug eruption is an infrequent but well-known adverse event most commonly associated with antibiotics and nonsteroidal anti-inflammatory medications . We herein describe a second reported instance of vancomycin-induced fixed drug eruption involving an extensive area of the body surface.

Ann Thorac Cardiovasc Surg, 2004 Aug, 10(4), 252 - 4
MRSA aortic valve endocarditis treated by pericardium-lined dacron patch and vancomycin-containing fibrin glue; Miyamoto S et al.; A 40-year-old man was admitted with a diagnosis of MRSA aortic valve endocarditis . He was treated conservatively with clindamycin and vancomycin for three days, but embolism occurred into the brain and the right lower limb, and urgent aortic valve replacement was performed . Resecting an aortic annular abscess resulted in a huge defect of the root . The defect was reconstructed with a combined patch: a Dacron graft lined with pericardium using vancomycin-containing fibrin glue . Although complete healing of the infected leg wound was slow, no prosthetic valve endocarditis has been detected in the 11 months since operation.

Biomed Chromatogr, 2004 Nov, 18(9), 735 - 8
An automated analyzer for vancomycin in plasma samples by column-switching high-performance liquid chromatography with UV detection; Saito M et al.; An automated analyzer for vancomycin in rat plasma by column-switching high-performance liquid chromatography (HPLC) with UV detection was developed . The method includes in-line extraction of vancomycin by ion-exchange cartridge column and a separation on a reversed-phase column with UV detection at 215 nm . Plasma samples were diluted by mobile phase solution and directly injected to HPLC . Vancomycin was quantitatively recovered from rat plasma samples . The separation was completed within 15 min . The calibration curve was linear over the range from 0.5 to 100 microg/mL with the detection and quantification limits of 0.5 microg/mL (2.5 ng on column; signal-to-noise ratio = 3) . The values of precision in intra- and inter-day assays (n = 3) were less than 1.92 and 3.69%, respectively . This method does not require time-consuming pre-treatment and is suitable for the routine assay of plasma samples . 2004 John Wiley & Sons, Ltd.

Chem Biol, 2004 Sep, 11(9), 1195 - 203
DpgC is a metal- and cofactor-free 3,5-dihydroxyphenylacetyl-CoA 1,2-dioxygenase in the vancomycin biosynthetic pathway; Tseng CC et al.; 3,5-Dihydroxyphenylglycine is a crucial amino acid monomer in the nonribosomal glycopeptide antibiotic vancomycin . This nonproteinogenic amino acid is constructed from malonyl-CoA by a set of four enzymes, DpgA-D, in the biosynthetic cluster . DpgC is an unusual metal-free, cofactor-free enzyme that consumes O(2) during the conversion of 3,5-dihydroxyphenylacetyl-CoA (DPA-CoA) to the penultimate intermediate 3,5-dihydroxyphenylglyoxylate (DPGx) . We show that in anaerobic incubations, DpgC catalyzes the exchange of the C(2)-methylene hydrogens of DPA-CoA at unequal rates, consistent with enzyme-mediated formation of the substrate-derived C(2)-carbanion as an early intermediate . Incubations with (18)O(2) reveal that DpgC transfers both atoms of an O(2) molecule to DPGx product . This establishes DpgC as a 1,2-dioxygenase that mediates thioester cleavage by the oxygen transfer process . These results are consistent with a DPA-CoA C(2)-peroxy intermediate, followed by enzyme-directed alpha-peroxylactone formation and collapse by O-O bond cleavage.

Anal Chem, 2004 Sep 1, 76(17), 5172 - 9
Production and properties of nanoelectrospray emitters used in fourier transform ion cyclotron resonance mass spectrometry: implications for determination of association constants for noncovalent complexes; Zampronio CG et al.; Electrospray ionization (ESI) is extensively used in the analysis of biological compounds; yet some fundamental properties of this technique are not completely understood . It is widely recognized that care should be exercised when noncovalent complexes are being studied by ESI, since weak noncovalent binding can be broken or formed during the desolvation process . In the present work, spectra from the noncovalent complex, vancomycin/diacetyl-L-lysyl-D-alanyl-D-alanine, obtained from ESI and from nanoelectrospray ionization (nanoESI), have been compared . The results indicated that the milder desolvation conditions arising as a result of the smaller sizes of droplets produced in the nanoESI source attenuated effects upon weak bonds in the desolvation process . The association constant values calculated from the relative peak intensities suggest that, when using ESI, the analyzed noncovalent complex dissociated in the condensed phase during the spraying process . The influences of experimental parameters such as tip diameter and coating for nanoESI needles were investigated . Principal component analysis, a multivariate analysis method, was applied to achieve a better evaluation of the spectra obtained using different needle diameters and coatings for the analysis of the noncovalent complex vancomycin/diacetyl-L-lysyl-D-alanyl-D-alanine . It was found that 2-microm tip diameter resulted in more reproducible spectra than the larger tip diameters tested (6-20 microm) .

Biomaterials, 2005 Mar, 26(9), 1043 - 52
In vivo tissue response to resorbable silica xerogels as controlled-release materials; Radin S et al.; Biodegradable, controlled-release carrier materials with non-toxic degradation products are valuable for local delivery of biologically active molecules . Previously, it was shown that room-temperature processed silica sol-gels (or xerogels) are porous, resorbable materials that can release molecules of various sizes in a controlled, time dependent manner . Previous in vitro studies also demonstrated benefits of silica xerogels as controlled-release materials for the treatment of bone infections . Herein the tissue and cell response to xerogels is documented using a subacute implantation procedure . The tissue response was correlated to composition, surface properties, resorption rate and incorporation of the antibiotic vancomycin . Ca- and P-free and Ca- and P-containing xerogels, with and without apatite (AP) surface, were used . Xerogels were implanted either as discs in a subcutaneous site, or as granules in the iliac crest of New Zealand white rabbits . The samples with surrounding tissue were retrieved after 2 and 4 weeks of implantation . Silica xerogels implanted either as discs subcutaneously or as granules in the iliac crest showed a favorable tissue response . The granules, either with or without Ca and P content, gradually resorbed over time . The resorption was accompanied by extensive trabecular bone growth and a minimal inflammatory response . Ca- and P-containing granules with an AP-surface layer showed a slower resorption rate and more extensive new bone growth than those without AP layer . Among AP-coated granules, those with incorporated vancomycin showed the most favorable tissue response . The present in vivo data together with prior in vitro data suggest that these xerogels have potential as controlled-release materials for the treatment of bone infections and as carrier materials for a variety of other applications.

Electrophoresis, 2004 Aug, 25(16), 2687 - 92
Evaluation of balhimycin as a chiral selector for enantioresolution by capillary electrophoresis; Jiang Z et al.; The glycopeptide antibiotic balhimycin and its haloanalogue bromobalhimycin were evaluated as chiral selectors for enantioresolution by capillary electrophoresis . In order (i) to eliminate the adsorption of the glycopeptide antibiotics on the capillary wall, (ii) to shorten the separation time and (iii) to improve the detection sensitivity, a combined approach of the dynamic surface coating technique, the co-electroosmotic flow electrophoresis technique and the partial filling technique was employed for the enantioresolution of 16 acidic racemates . The effect of experimental parameters (plug length of the partial filling solution containing the chiral selector, selector concentration and buffer pH) on enantiorecognition was investigated . Furthermore, the enantiorecognition ability imparted by balhimycin, bromobalhimycin and vancomycin were compared . For most tested compounds, the highest enantiorecognition was obtained with balhimycin as chiral selector . Only in the case of the enantioresolution of tiaprofenic acid, vancomycin showed a superior enantiorecognition.

Org Biomol Chem, 2004 Sep 21, 2(18), 2658 - 63 Epub 2004 Aug 24.
Ring-closing metathesis for the synthesis of side chain knotted pentapeptides inspired by vancomycin; ten Brink HT et al.; A versatile method for the synthesis of bicyclic side chain knotted peptides inspired by vancomycin is described . The synthetic approach is based on the incorporation of a central amino acid derivative having two allylic groups-introduced by a Stille coupling-into pentapeptide 8 containing two allylated serine residues . Treatment of this bis-ring-closing metathesis precursor with 2nd generation Grubbs catalyst results in the formation of a bicyclic pentapeptide with the correct side chain to side chain connectivity pattern as observed in vancomycin: i- 2-->i, i-->i+ 2 . Modelling studies using MacroModel hint at a cavity-like structure of the bicyclic pentapeptide which may bind suitable ligands.

Klin Monatsbl Augenheilkd, 2004 Aug, 221(8), 674 - 6
{Anti-infectives in eye injuries}; Behrens-Baumann W; BACKGROUND: We present the current concepts for the use of anti-infectives parallel to surgery of traumatic eye injuries . MATERIAL AND METHODS: Data from the national and international literature were collected using the PubMed, Medline, Drugs and Pharmacology, ISI, and Cochrane databanks . In addition, the experience from our tertiary center was taken into consideration . RESULTS: For palpepral and globe injuries prophylactic and therapeutic anti-infectives are recommended as supporting measures to surgical repair . These include antiseptics (PVP-iodine), antibiotics (cefuroxime, vancomycin, ceftazidime), antimycotics (voriconazole) and anti-inflammatory substances (prednisolone) . CONCLUSIONS: Several drugs are useful for the prevention and/or treatment of infection following eye injury.

Br J Clin Pharmacol, 2004 Sep, 58(3), 259 - 68
Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration; DelDot ME et al.; AIMS: To investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance . METHODS: Pharmacokinetic profiles (15) of initial and steady-state doses of 750 mg twice daily intravenous vancomycin were obtained from blood and ultrafiltrate samples from 10 critically ill patients in the intensive care unit, with acute renal failure on CVVHDF (1 l h(-1) dialysate plus 2 l h(-1) filtration solution; 3 l h(-1) effluent; extracorporeal blood flow 200 ml min(-1)) . RESULTS: CVVHDF clearance of vancomycin was 1.8 +/- 0.4 l h(-1) (30 +/- 6.7 ml min(-1)) . This was 1.3-7.2 times that reported previously for vancomycin using other forms of CRRT . Total vancomycin body clearance was 2.5 +/- 0.7 l h(-1) (41.7 +/- 11.7 ml min(-1)) . The clearance of vancomycin by CVVHDF was 76 +/- 16.5% of the total body clearance . CVVHDF removed approximately half the vancomycin dose during the 12-h period (A(CVVHDF) = 413 mg) . The fraction eliminated by all routes was 60% . The sieving coefficient for vancomycin was 0.7 +/- 0.1 and for urea was 0.8 +/- 0.06 . CONCLUSIONS: Vancomycin is cleared effectively by CVVHDF . Clearance was faster than other forms of CRRT, therefore doses need to be relatively high . Urea clearance slightly overestimates vancomycin clearance . The administered doses of 750 mg every 12 h were too high and accumulation occurred, as only approximately 60% of a dose was cleared over this period . The maintenance dose required to achieve a target average steady-state plasma concentration of 15 mg l(-1) can be calculated as 450 mg every 12 h.

Appl Environ Microbiol, 2004 Aug, 70(8), 4899 - 905
Persistence of Mycobacterium paratuberculosis during manufacture and ripening of cheddar cheese; Donaghy JA et al.; Model Cheddar cheeses were prepared from pasteurized milk artificially contaminated with high 10(4) to 10(5) CFU/ml) and low (10(1) to 10(2) CFU/ml) inocula of three different Mycobacterium paratuberculosis strains . A reference strain, NCTC 8578, and two strains (806PSS and 796PSS) previously isolated from pasteurized milk for retail sale were investigated in this study . The manufactured Cheddar cheeses were similar in pH, salt, moisture, and fat composition to commercial Cheddar . The survival of M . paratuberculosis cells was monitored over a 27-week ripening period by plating homogenized cheese samples onto HEYM agar medium supplemented with the antibiotics vancomycin, amphotericin B, and nalidixic acid without a decontamination step . A concentration effect was observed in M . paratuberculosis numbers between the inoculated milk and the 1-day old cheeses for each strain . For all manufactured cheeses, a slow gradual decrease in M . paratuberculosis CFU in cheese was observed over the ripening period . In all cases where high levels (>3.6 log(10)) of M . paratuberculosis were present in 1-day cheeses, the organism was culturable after the 27-week ripening period . The D values calculated for strains 806PSS, 796PSS, and NCTC 8578 were 107, 96, and 90 days, respectively . At low levels of contamination, M . paratuberculosis was only culturable from 27-week-old cheese spiked with strain 806PSS . M . paratuberculosis was recovered from the whey fraction in 10 of the 12 manufactured cheeses . Up to 4% of the initial M . paratuberculosis load was recovered in the culture-positive whey fractions at either the high or low initial inoculum.

Ann Allergy Asthma Immunol, 2004 Jul, 93(1), 101 - 3
A successful challenge in a patient with vancomycin-induced linear IgA dermatosis; Joshi S et al.; BACKGROUND: Linear IgA bullous dermatosis (LABD), a subepidermal, blistering skin disease, is generally believed to be idiopathic . It has been reported in association with multiple medications, including vancomycin . In each case, complete clearance of the skin lesions occurred with discontinued use of the drug . A subsequent rechallenge reproduced the eruption within hours to days . OBJECTIVE: To present a patient with vancomycin-associated LABD who underwent a successful challenge with the antibiotic 4 years after the initial reaction . METHODS: The patient developed blistering lesions over her trunk and extremities 10 days after the initiation of vancomycin for sepsis . A biopsy specimen of a skin eruption was consistent with linear IgA dermatosis . Following discontinued use of the drug, her skin lesions resolved . Four years later, she required vancomycin for osteomyelitis . RESULTS: The patient underwent a vancomycin-graded challenge of 5 doses over 5 days . On day 1, she received 10 mg, and this was increased in a semilog fashion to 1,000 mg on day 5 . She had no recurrence of her skin lesions . CONCLUSIONS: This is the first case, to our knowledge, to show a successful rechallenge in a patient with drug-associated LABD . Since the patient did not have a reaction to the challenge, it is possible that the IgA antibodies responsible for drug-induced LABD are only present transiently and diminish over time.

J Clin Pharm Ther, 2004 Aug, 29(4), 351 - 7
High dose vancomycin for osteomyelitis: continuous vs . intermittent infusion; Vuagnat A et al.; OBJECTIVES: To compare the efficacy, ease of use and safety of intermittent vancomycin infusion (IVI) and continuous vancomycin infusion (CVI) in high-dose therapy of osteomyelitis . Methods: Forty-four patients with an osteomyelitis requiring vancomycin for more than 4 weeks were prospectively included, 21 receiving IVI and 23, CVI . The target serum concentration of vancomycin was 20-25 mg/L . Pharmacokinetics, adverse effects, and clinical efficacy were recorded . RESULTS: The mean daily vancomycin dosing was the same in the two groups, but the serum vancomycin concentrations (trough or plateau) were lower in the IVI group than the CVI group (21.7 +/- 9.3 and 26.0 +/- 6.1 mg/L, respectively; P < 0.0001) . The target concentrations were achieved quicker with CVI, and daily dosing was changed more frequently in the IVI group . After reaching the target, variability of vancomycin serum concentration (trough or plateau concentrations) was higher in the IVI group than in CVI group (standard deviation 7.9 mg/L vs . 5.6 mg/L, respectively; P = 0.001) . CVI did not show clinical superiority, but adverse drug effects were more frequent in the IVI group as compared with the CVI group, 9 (42.9%) and 2 (8.7%), respectively (P = 0.03) . Survival multiple regression using Cox's proportional hazard model showed that IVI (RR = 5.9, P = 0.03) and osteomyelitis of the foot (RR = 5.2, P = 0.01) were the only factors associated with adverse drug reactions leading to treatment termination . CONCLUSIONS: CVI is practical and effective, and may be a good alternative for patients requiring prolonged treatment with high vancomycin serum levels.

J Am Podiatr Med Assoc, 2004 Jul-Aug, 94(4), 389 - 94
Vancomycin: an overview for the podiatric physician; Smith RG; An increased reliance on vancomycin to treat bacterial infections has led to the emergence of vancomycin-resistant organisms . The podiatric physician must select and use vancomycin with due caution . This article presents a general review of vancomycin's pharmacology, pharmacokinetics, and dosing recommendations . Literature citations of clinically based evidence regarding the development and use of vancomycin nomograms are also presented . A vancomycin dosing nomogram is introduced as an effective tool for the prescribing podiatric physician . Appropriate use of the information presented may improve patient outcomes and enable the podiatric physician to treat patients with less effort and at a lower cost.

Surg Neurol, 2004 Aug, 62(2), 142 - 50; discussion 150
Therapeutic vancomycin monitoring in children with hydrocephalus during treatment of shunt infections; Bafeltowska JJ et al.; BACKGROUND: The successful treatment of shunt infections in children with hydrocephalus is still an important problem . Diagnosis of shunt colonization is often very difficult . To treat serious central nervous system (CNS) infections, intraventricular therapy with antibiotics is necessary to reach adequate cerebrospinal fluid (CSF) concentrations and eradicate the infection . For optimal management of shunt infections the concentration of administered antibiotics in CSF should be measured . The antibiotic dosing could be modified in the individual patient after pharmacokinetic studies . METHODS: In our studies, vancomycin was applied to 10 children with hydrocephalus (including 6 with a myelomeningocele) for therapeutic purposes in shunt infections . The drug was administered IV and/or intraventricularly . During treatment the concentration of vancomycin in CSF was determined by fluorescence polarization immunoassay (FPIA) method . RESULTS: Considerable differences in vancomycin concentrations after the same intraventricular antibiotic administration were observed depending on the patient . The vancomycin levels determined at study state were often much higher than the therapeutic recommended range, and the biologic half-life period (T(1/2)) of vancomycin in cerebrospinal fluid after intraventricular administration was prolonged . CONCLUSIONS: The results of our studies give information about the pharmacokinetics of vancomycin in CSF in a group of children with hydrocephalus after intraventricular administration of the drug . In our investigation, the administration of doses smaller than 5 mg/24 hours is appropriate when the removed volume of CSF will be 20 to 30 mL/24 hours.

Clin Podiatr Med Surg, 2004 Jul, 21(3), 335 - 51, vi
Management of osteomyelitis; Mandracchia VJ et al.; Osteomyelitis is an infection of the medullary or cortical bone that is becoming more difficult to cure with the increasing prevalence of methicillin- and vancomycin-resistant organisms . This article discusses the etiology of osteomyelitis and the effectiveness of various treatment options.

Biomed Chromatogr, 2004 Jun, 18(5), 330 - 4
HPLC microdetermination of flurbiprofen enantiomers in plasma with a glycopeptide-type chiral stationary phase column; Pehourcq F et al.; A rapid and stereospecific HPLC micromethod to quantify flurbiprofen enantiomers was developed . Both flurbiprofen enantiomers and indomethacin, used as internal standard, were extracted with methylene chloride from 100 microL of acidified plasma . The resolution of the R- and S-forms was performed on a bonded vancomycin chiral stationary phase (Chirobiotic V) with 20% of tetrahydrofuran in ammonium nitrate (100 mM, pH 5) as mobile phase . Calibration curves were linear in the range 0.5-10 microg/mL for both enantiomers . A good accuracy (< or = 5%) was obtained for all quality controls, with intra-day and inter-day variation coefficients equal or less than 7.7% . Recovery of both enantiomers was found in the range 77.4-86.3% . The lower limit of quantitation was 0.25 microg/mL for both enantiomers, without interference of endogenous components . This validated micromethod has been successfully applied for quantifying R- flurbiprofen and S- flurbiprofen in rat plasma .

Methods Mol Biol, 2004, 276, 153 - 68
Affinity capillary electrophoresis to examine receptor-ligand interactions; Azad M et al.; Afffinity capillary electrophoresis (ACE) is a new analytical technique that has been shown to be an efficient and accurate tool in studying biomolecular noncovalent interactions and determining binding and dissociation constants of formed complexes . ACE uses as its basis the change in migration time of a receptor upon binding to a ligand found in the electrophoresis buffer . Subsequent Scatchard analysis using noninteracting markers realizes a binding constant . Herein, ACE and three modifications in the technique, partial-filling ACE (PFACE), flow through PFACE (FTPFACE), and multiple-step ligand injection ACE (MSLIACE) are used to probe the binding of ristocetin A (Rist A) and vancomycin (Van) from Streptomyces orientalis to D-Ala-D-Ala terminus peptides and carbonic anhydrase B (CAB, E.C.4.2.1.1) to arylsulfonamides.

Methods Mol Biol, 2004, 268, 199 - 205
Detection of Erysipelothrix rhusiopathiae in clinical and environmental samples; Fidalgo SG et al.; Erysipelothrix rhusiopathiae is pathogenic for both animals and humans, causing erysipelas in swine and erysipeloid in humans . In swine, disease may be either acute or chronic, resulting in the development of arthritis and endocarditis . In Japan, erysipelas remains an animal hygiene problem causing great economic loss as infected swine are disused . Human infection closely resembles that seen in swine, with both acute and chronic forms also . The most common presentation is erysipeloid, a localized cutaneous infection . In Western Australia, an erysipeloid-like infection referred to as "crayfish poisoning" occurs in lobster fishermen and handlers . A second type of presentation is a generalized cutaneous form involving lesions that progress from the initial site of infection or appear in remote areas . The third and most serious form of disease is a septicemia that is almost always linked to endocarditis . The mortality rate in Erysipelothrix endocarditis is still high (38%) and can be explained by the use of vancomycin (to which Erysipelothrix spp . are inherently resistant) as empirical therapy . Therefore, it is critical to have an early diagnosis of E . rhusiopathiae infection.Unfortunately, several problems exist with the diagnosis of E . rhusiopathiae infections by conventional cultural procedures, and these infections are often incorrectly diagnosed . First, because of their very small colony size and slow growth rates, it is difficult to isolate E . rhusiopathiae from heavily contaminated specimens . Various selective media have been described to improve the isolation of E . rhusiopathiae from contaminated specimens; however, not all contaminants are inhibited . The development of two polymerase chain reaction (PCR) methods has created an opportunity to greatly improve the efficiency with which these organisms are detected and identified . Makino et al . designed a PCR method that amplifies a 407-bp DNA fragment derived from the 16S rRNA coding sequence . The primers in this method are specific for the genus Erysipelothrix and do not differentiate between the species . A second set of primers designed by Shimoji et al . amplifies a 937-bp DNA fragment which is derived from a sequence associated with virulence of E . rhusiopathiae . These primers are specific for E . rhusiopathiae only . Shimoji et al . also utilized a selective enrichment medium based on tryptic soy broth containing ethidium bromide and sodium azide.

Neurol Res, 2004 Apr, 26(3), 312 - 5
Fluctuations in vancomycin CNS tissue concentrations following intermittent and continuous infusions in the rat; Luer MS et al.; The purpose of this investigation was to compare the variability of vancomycin concentrations in the serum and CNS when administered continuously or as intermittent intravenous infusions in the rat . The hypothesis for this investigation was that the magnitude of change in serum vancomycin concentrations directly relates to the extent of vancomycin concentration fluctuations in the CNS . Microdialysis and serum sampling techniques were employed and biologic samples were analysed for vancomycin using HPLC . Over the dosing interval, the mean changes in concentrations were 71.8 +/- 9.8% and 13.6 +/- 9.3% for serum and 61.7 +/- 7.8% and 6.8 +/- 3.5% for brain extracellular fluid in the intermittent and continuously infused groups, respectively . Accordingly, the relative changes in vancomycin concentrations in brain extracellular fluid were closely associated with corresponding changes in serum concentrations (R2=0.94) . Thus, continuous intravenous administration of vancomycin results in minimal serum and CNS tissue concentration changes as compared to traditional intermittent dosing methods and allows for more consistent vancomycin concentrations in the CNS.

J Pharm Biomed Anal, 2004 May 28, 35(3), 535 - 43
A validated LC method for the determination of vesamicol enantiomers in human plasma using vancomycin chiral stationary phase and solid phase extraction; Hefnawy MM et al.; An enantioseparation high performance liquid chromatographic (HPLC) method was developed and validated to determine D-(+)- and L-(-)-vesamicol in human plasma . The assay involved the use of a solid phase extraction for plasma sample clean up prior to HPLC analysis utilizing a C18 Bond-Elute column . Chromatographic resolution of the vesamicol enantiomers was performed on a vancomycin macrocyclic antibiotic chiral stationary phase (CSP) known as Chirobiotic V with a polar ionic mobile phase (PIM) consisting of methanol:glacial acetic acid:triethylamine (100:0.1:0.05 (v/v/v)) at a flow rate of 1.0 ml/min and UV detection set at 262 nm . All analyses were conducted at ambient temperature . The method was validated over the range of 1-20 microg/ml for each enantiomer concentration (R2>0.999) . Recoveries for D-(+)- and L-(-)-vesamicol enantiomers were in the ranges of 96-105% at 3-16 microg/ml level . The method proved to be precise (within-run precision ranged from 1.3 to 2.7% and between-run precision ranged from 1.5 to 3.4%) and accurate (within-run accuracies ranged from 0.8 to 3.4% and between-run accuracies ranged from 1.7 to 5.0%) . The limit of quantitation (LOQ) and limit of detection (LOD) for each enantiomer in human plasma were 1.0 and 0.5 microg/ml (S/N=3), respectively.

Biomed Sci Instrum, 2004, 40, 111 - 6
Effects of sustained delivery of thymoqiunone on bone healing of male rats; Kirui PK et al.; The use of natural products as an alternative to conventional treatment in healing and treatment of various diseases has been on the rise in the last few decades . Nigella sativa, a natural herb has long been used as a natural medicine for treatment of many acute, as well as, chronic conditions . These include diabetes, hypertension and dermatological conditions . The specific objectives of this study were: (1) to successfully deliver the active component of black seed called Thymoqiunone (TMQ) at sustained level using TCPL drug delivery system; (2) to evaluate the physiological responses associated with sustained delivery of TMQ in femoral defect animal model (bone healing) . A total of 15 adult male rats were randomly divided into three equal groups . Animals in group I served as controls, animals in group II served as sham while animals in group III served as experimental group (femur defect model) . Group III animals were surgically implanted with TCPL capsule loaded with 0.02 grams of TMQ and 200 mg vancomycin . Blood samples, x-rays and body weights were collected and recorded weekly . At the end of 30 days post treatment, all animals were sacrificed and vital as well as reproductive organs were collected and analyzed histopathologically . Metabolic biochemical markers were also evaluated . The results of this study revealed the following: (i) gross anatomical observation indicated difference in healing pattern of animals in group III compared to those in group II (sham); (ii) no significant differences in all levels of cholesterol, proteins, malondialdehyde and alkaline phosphatase in all groups; (iii) no significant differences in the wet weights of vital as well as reproductive organs in all the groups . In conclusion, it appears that sustained levels of TMQ can enhance bone healing with little or no side effects on major vital and reproductive organs.

Biochemistry, 2004 May 11, 43(18), 5170 - 80
Crystal structure of vancosaminyltransferase GtfD from the vancomycin biosynthetic pathway: interactions with acceptor and nucleotide ligands; Mulichak AM et al.; The TDP-vancosaminyltransferase GtfD catalyzes the attachment of L-vancosamine to a monoglucosylated heptapeptide intermediate during the final stage of vancomycin biosynthesis . Glycosyltransferases from this and similar antibiotic pathways are potential tools for the design of new compounds that are effective against vancomycin resistant bacterial strains . We have determined the X-ray crystal structure of GtfD as a complex with TDP and the natural glycopeptide substrate at 2.0 A resolution . GtfD, a member of the bidomain GT-B glycosyltransferase superfamily, binds TDP in the interdomain cleft, while the aglycone acceptor binds in a deep crevice in the N-terminal domain . However, the two domains are more interdependent in terms of substrate binding and overall structure than was evident in the structures of closely related glycosyltransferases GtfA and GtfB . Structural and kinetic analyses support the identification of Asp13 as a catalytic general base, with a possible secondary role for Thr10 . Several residues have also been identified as being involved in donor sugar binding and recognition.

Anal Chem, 2004 Apr 15, 76(8), 2387 - 92
A mechanistic study of enantiomeric separation with vancomycin and balhimycin as chiral selectors by capillary electrophoresis . Dimerization and enantioselectivity; Kang J et al.; The role of the sugar moiety of glycopeptide antibiotics in chiral recognition was investigated with capillary electrophoresis . Two glycopeptide antibiotics, vancomycin and balhimycin, were employed as models since they possess the same aglycon and almost identical sugar moieties, however, with different attachment sites to the aglycon . The observed enantioselectivity of balhimycin for dansylated alpha-amino acids is 2.6 times higher than that of vancomycin . Blocking of the sugar amino group of balhimycin by N-carbamoylation reaction with KOCN led to a significantly decreased enantioselectivity compared to vancomycin, which remained almost the same upon carbamoylation . These results suggest a major role of the amino sugar together with its site of attachment to the aglycon . A dimerization-based mechanism is proposed to explain this phenomenon due to the fact that the dimerization properties of glycopeptides are similarly related to their glycosylation patterns; e.g., the dimerization constant of balhimycin is 78 times higher than that of vancomycin . Furthermore, the dimerization of glycopeptides promotes their affinity to carboxyl-containing ligands via cooperativity effects between the dimerization and the formation of glycopeptide-ligand complexes . The higher dimer stability probably leads to a more favorable conformation for chiral recognition . Thus, it is concluded that a weakened dimerization of N-carbamoylated balhimycin results in a decreased enantioselectivity.

J Appl Microbiol, 2004, 96(5), 1013 - 23
RAPID detection and quantification of E . coli O157/O26/O111 in minced beef by real-time PCR; O'Hanlon KA et al.; AIM: To develop a real-time PCR detection procedure for Escherichia coli O111, O26 and O157 from minced meat . METHODS AND RESULTS: Strains (n = 8) of each of E . coli O26, E . coli O111 and E . coli O157 were inoculated at ca 10-20 CFU g(-1) into minced retail meat and enriched for 6 h at 41.5 degrees C as follows: E . coli O26 in tryptone soya broth (TSB) supplemented with cefixime (50 microg l(-1)), vancomycin (40 mg l(-1)) and potassium tellurite (2.5 mg l(-1)); E . coli O111 in TSB supplemented with cefixime (50 microg l(-1)) and vancomycin (40 mg l(-1)); E . coli O157 in E . coli broth supplemented with novobiocin (20 mg l(-1)) . DNA was extracted from the enriched cultures, and detected and quantified by real-time PCR using verotoxin (vt1 and vt2) and serogroup (O157 per gene; O26 fliC-fliA genes and O111 wzy gene) specific primers . CONCLUSIONS: The methods outlined were found to be sensitive and specific for the routine detection of E . coli O111, O26 and O157 in minced beef . SIGNIFICANCE AND IMPACT OF THE STUDY: The enrichment, isolation and detection procedures used in this study provide a rapid routine-based molecular method for the detection and differentiation of E . coli O26, O111 and O157 from minced meat.

Pharmacoepidemiol Drug Saf, 1999 Oct, 8(6), 405 - 11
Evidence of inappropriate use of vancomycin in a university affiliated hospital in Brazil; de Castro MS et al.; OBJECTIVE: To evaluate the appropriateness of use of vancomycin in a University affiliated Hospital in Brazil . METHODS: One hundred sequential therapeutic courses of vancomycin were retrospectively examined through a chart review . The prescriptions were evaluated in terms of indication, use of critical process indicators, and use of outcome measurements according to an adapted version of the criteria recommended by the American Society of Health-System Pharmacists . RESULTS: The indication for use was appropriate in 39% of the cases . Critical process indicators indicated frequent inappropriate use, mainly in relation to a low frequency of bacterial cultures (54%), infrequent determination of creatinine levels prior to therapy (57%), incorrect dosage (42%), incorrect duration of therapy (63%), and infrequent determination of serum levels of vancomycin (73%) . It was impossible to evaluate outcome measurements, since data were not collected in most patients . Larger discrepancies between recommendation and practice were detected in Paediatrics and Paediatric Pneumology Services . CONCLUSION: The misuse of vancomycin in our hospital is very common according to standard guidelines, demanding new policies of control in order to diminish the possibility of the emergence of multi-resistant strains .

J Chromatogr A, 2004 Apr 9, 1033(1), 91 - 9
Effect of the eluent on enantiomer separation of controlled drugs by liquid chromatography-ultraviolet absorbance detection-electrospray ionisation tandem mass spectrometry using vancomycin and native beta-cyclodextrin chiral stationary phases; Pihlainen K et al.; Enantioseparation of nine amphetamine derivatives, methorphan and propoxyphene was studied by comparing two different chiral stationary phases, macrocyclic antibiotic vancomycin and native beta-cyclodextrin (beta-CD) . Effects of 46 eluent compositions on enantioseparation in reversed-phase (RP) and polar organic phase modes were investigated . beta-CD was found to be more suitable to phenethylamines in general and vancomycin for methorphan and propoxyphene . An eluent system capable of separating the enantiomers of all phenethylamines in one run was developed . Also, systems providing competitive analysis times for enantioseparation of methorphan and propoxyphene were reported . The suitability of the eluent systems to electrospray ionisation (ESI) was discussed and methods using a tandem mass spectrometric (MS/MS) detection were developed . The suitability of chiral LC-ESI-MS/MS was tested with 14 seized drug samples . The results were in agreement with conventional non-chiral methods . Repeatability of the methods was good and limits of detection were 25-100 ng/ml for most compounds using mass spectrometric detection.

J Cutan Pathol, 2004 May, 31(5), 393 - 7
Vancomycin-induced linear IgA disease manifesting as bullous erythema multiforme; Armstrong AW et al.; BACKGROUND: Vancomycin-induced linear immunoglobulin A (IgA) disease, an autoimmune, blistering disease in response to vancomycin administration, is characterized by a subepidermal, vesiculobullous eruption and linear IgA deposition along the basement membrane zone on direct immunofluorescence . CASE REPORT: We report the case of an 81-year-old man treated with vancomycin who developed diffuse erythema multiforme and tense bullae involving the palmoplantar surfaces . Discontinuation of vancomycin therapy resulted in complete resolution of this patient's cutaneous eruption . RESULTS: Biopsy of a representative skin lesion demonstrated lichenoid interface dermatitis with focal subepidermal clefting, dyskeratosis, and prominent eosinophils . Direct immunofluorescence showed linear basement membrane staining with immunoreactants to IgA; indirect immunofluorescence demonstrated the presence of circulating IgG antibodies binding in an intercellular pattern . Immunoprecipitation studies using the patient's serum revealed 210, 130, and 83 kDa target antigens . CONCLUSIONS: Presenting with an initial clinical picture suggestive of bullous erythema multiforme, this patient's subsequent clinical course and direct immunofluorescence confirm the diagnosis of linear IgA bullous disease (LABD) . His indirect immunofluorescence findings and immunoprecipitation results suggest that circulating non-IgA antibodies may represent a newly recognized immunopathologic feature of vancomycin-induced linear IgA disease, underscoring the variable and unpredictable manifestations of this drug-induced cutaneous disease.

Antimicrob Agents Chemother, 2004 Apr, 48(4), 1159 - 67
Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates; Kimura T et al.; Immature renal function in neonates requires antibiotic dosage adjustment . Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem . Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23) . The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g . A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis . In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW . The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg . When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA . Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance . Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

J Antibiot (Tokyo), 2004 Jan, 57(1), 45 - 51
Ototoxicity of a new glycopeptide, norvancomycin with multiple intravenous administrations in guinea pigs; Gao W et al.; Time courses of plasma concentration of a new glycopeptide, norvancomycin (NVCM) after single intravenous (iv) and intraperitoneal (ip) injection, and the peak plasma concentrations (Cmax's) of this drug at various doses after single iv injection were determined in guinea pigs . There were significant differences in pharmacokinetic parameters between the two routes of administration and the Cmax linearly increased with the dose used increasing . Guinea pigs with normal hearing were then used to investigate ototoxic liability of NVCM after multiple intravenous administrations (54, 108, 216mg/kg, qd for 14 days) . Postrotatory vestibular nystagmus (PRN), auditory brainstem response (ABR) and electron microscopy (SEM TEM) results showed that, similarly to vancomycin, there was no functional or morphological evidence of ototoxicity of NVCM at the dose of 54, 108 mg/kg . In the high dose group (216 mg/kg), there was a 0 approximately 4 dB elevation of hearing threshold but no morphological changes . The results suggested that the ototoxicity of NVCM is absent or minimal after multiple iv administrations within this dose range.

Eur J Pharm Biopharm, 2004 Mar, 57(2), 207 - 12
PLGA microspheres for the ocular delivery of a peptide drug, vancomycin using emulsification/spray-drying as the preparation method: in vitro/in vivo studies; Gavini E et al.; The aim of this study was an in vitro/in vivo investigation on poly(lactide-co-glycolide) (PLGA) microspheres as carriers for the topical ocular delivery of a peptide drug vancomycin (VA) . The microspheres were prepared by an emulsification/spray-drying technique that can be proposed as an alternative to the double emulsion method for preparation of peptide-loaded microparticles . The drug encapsulation efficiencies were close to the theoretical values (84.2-99.5%); the average particle size, expressed as dvs, was about 11 microm . The microspheres were able to modulate the in vitro drug release of VA with a behavior dependent on their composition: the highest drug content corresponded to the highest release rate . In vivo studies were carried out by assessing the pharmacokinetic profile of VA in the aqueous humor of rabbits after topical administration of aqueous suspensions of microspheres . High and prolonged VA concentrations and increased AUC values (2-fold) with respect to an aqueous solution of the drug were observed . Increasing the viscosity of the microsphere suspension by addition of a suspending-viscosizing agent (hydroxypropylcellulose) did not produce an increase of the ocular bioavailability . PLGA microspheres can be proposed as a system for ocular delivery of peptide drugs.

Ophthalmic Res, 2004 Jan-Feb, 36(1), 55 - 61
Modified high-performance liquid chromatography technique for detection of vancomycin in human vitreous; Raju B et al.; PURPOSE: To standardize the technique and methodology for estimating the level of vancomycin in human vitreous using a modified high-performance liquid chromatographic method . METHODS: Sample preparation involved spiking the vitreous with known quantities of the drug followed by a brief treatment with 30% trichloroacetic acid . Samples were analyzed on a C18 reverse-phase column using a mobile phase of 50 mM phosphate buffer (pH 4.0) and 10% acetonitrile . RESULTS: Vancomycin was detected at 198 nm . It showed a retention time of 2.2 min in the vitreous . A linear increase in the area under the peak corresponding to the drug was observed with increase in concentration of vancomycin in the vitreous . The method was applied to detect the vancomycin levels in vitreous of 5 patients with exogenous endophthalmitis, 24-48 h after intravitreal injection of vancomycin 1 mg/0.1 ml . The mean concentration of vancomycin in these samples was 120.022 +/- 59.87 microg/ml (43.859-179.09 microg/ml) . The present technique allowed a quantification limit of 1 microg/ml . CONCLUSION: This technique is suitable to estimate vancomycin levels in human vitreous in a variety of clinical and experimental studies . It has the added advantages of being less expensive, simple and rapid .

J Chromatogr A, 2004 Mar 5, 1028(2), 333 - 8
Improved quantification limits in chiral capillary electrochromatography by peak compression effects; Enlund AM et al.; The peak compression effect has been applied to improve quantification limits in chiral capillary electrochromatography (CEC) . A stationary phase based on the chiral selector vancomycin (Chirobiotic V) was used for separations of the enantiomers of mianserin . By adding solvents with a low dielectric constant, e.g . 2-propanol or tetrahydrofuran, to the sample solution, peak compression could be induced . The plate numbers for the minor enantiomer increased from approximately 100,000 to 1.4-1.6 million plates/m, when the composition of the mobile phase was adjusted so that the analyte eluted within either one of two system zones originating from the sample solution . A 10-fold improvement in the quantification limit for the minor enantiomer was obtained compared to elution under non-focused conditions.

Int J Radiat Oncol Biol Phys, 2004 Mar 1, 58(3), 809 - 16
Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: a prospective assessment; Miralbell R et al.; PURPOSE: Patients with malignant hematologic disorders undergoing bone marrow transplantation (BMT) may develop renal insufficiency . A study was undertaken to assess prospectively the subclinical renal function changes with radioisotopic methods in patients undergoing BMT for hematologic malignancies . METHODS AND MATERIALS: We studied 71 patients with normal renal function undergoing BMT for various hematologic malignancies, mostly leukemias . Conditioning included chemotherapy and 12 Gy (45 patients) or 13.5 Gy (26 patients) fractionated total-body irradiation (TBI) . In 21 patients receiving 12 Gy TBI, the kidney dose was limited to 10 Gy using partial transmission blocks fabricated after renal opacification with nonionic, hypo-osmolar contrast medium . The glomerular filtration rate (GFR) and effective renal plasmatic flow (ERPF) were determined radioisotopically before conditioning and at 4, 12, and 18 months, using (51)Cr ethylene-diamine-tetra-acetic acid and (131)I ortho-iodo-hippurate, respectively . Renal insufficiency was defined as a decrease of >/=30% in GFR or ERPF compared with the baseline values . The potential influence of patient- and treatment-related variables on renal dysfunction was assessed . RESULTS: At 4 (early) and 12-18 (late) months, a >/=30% GFR drop was observed in 54% and 49% of patients and a >/=30% ERPF drop in 44% and 34% of patients, respectively . After stepwise logistic analysis, a GFR reduction at 4 months correlated significantly with age (<40 years old, worse), TBI using kidney blocks (partial kidney shielding to 10 Gy was associated with a higher rate of renal dysfunction at 4 months compared with the full TBI dose), and days of aminoglycoside/vancomycin use . An ERPF drop at 4 months was independently related with the days of amphotericin use and days of prostaglandin E(1) use (prophylaxis against hepatic venoocclusive disease) . A GFR and ERPF reduction at 12-18 months correlated with days of amphotericin use and days of prostaglandin E(1) use, respectively . CONCLUSION: Early post-BMT renal dysfunction is associated with the administration of potentially nephrotoxic drugs . An inverse correlation with the prescribed TBI dose was observed; patients whose kidneys received 10 Gy through the use of partial shielding blocks had significantly greater renal dysfunction at 4 months . The administration of potentially nephrotoxic contrast agents used in radiotherapy treatment planning may be responsible for the latter observation . Prostaglandin E(1) use correlated with a significant reduction in ERPF at both 4 and 12-18 months.

Cutis, 2004 Jan, 73(1), 65 - 7
Vancomycin-induced linear IgA bullous dermatosis: morphology is a key to diagnosis; Solky BA et al.; Vancomycin-induced linear IgA bullous dermatosis (LABD) previously has been described; however, past reports have suggested that the clinical presentation is nonspecific . We present a case of vancomycin-induced LABD with a suggestive clinical presentation; specifically, groups of annularly arranged vesicles . We propose that this clinical presentation strongly suggests drug-induced LABD and should raise a clinician's suspicion of vancomycin as the offending agent . This awareness may guide the antibiotic management of the patient while the clinician awaits histopathologic correlation.

Biochemistry, 2004 Feb 3, 43(4), 970 - 80
Role of the active site cysteine of DpgA, a bacterial type III polyketide synthase; Tseng CC et al.; DpgA is a bacterial type III polyketide synthase (PKS) that decarboxylates and condenses four malonyl-CoA molecules to produce 3,5-dihydroxyphenylacetyl-CoA (DPA-CoA) in the biosynthetic pathway to 3,5-dihydroxyphenylglycine, a key nonproteinogenic residue in the vancomycin family of antibiotics . DpgA has the conserved catalytic triad of Cys/His/Asn typical of type III PKS enzymes, and has been assumed to use Cys160 as the catalytic nucleophile to create a series of elongating acyl-S-enzyme intermediates prior to the C(8) to C(3) cyclization step . Incubation of purified DpgA with {(14)C}-malonyl-CoA followed by acid quench during turnover leads to accumulation of 10-15% of the DpgA molecules covalently acylated . Mutation of the active site Cys160 to Ala abrogated detectable covalent acylation, but the C160A mutant retained 50% of the V(max) for DPA-CoA formation, with a k(cat) still at 0.5 catalytic turnovers/min . For comparison, a C190A mutant retained wild-type activity, while the H296A mutant, in which the side chain of the presumed catalytic His is removed, had a 6-fold drop in k(cat) . During turnover, purified DpgA produced 1.2 equivalents of acetyl-CoA for each DPA-CoA, indicating 23% uncoupled decarboxylation competing with condensative C-C coupling . The C160A mutant showed an increased partition ratio for malonyl-CoA decarboxylation to acetyl-CoA vs condensation to DPA-CoA, reflecting more uncoupling in the mutant enzyme . The Cys-to-Ala mutant thus shows the unexpected result that, when the normal acyl-S-enzyme mechanism for this type III PKS elongation/cyclization catalyst is removed, it can still carry out the regioselective construction of the eight-carbon DPA-CoA skeleton with surprising efficiency.

Curr Opin Ophthalmol, 2004 Feb, 15(1), 51 - 5
Pharmacologic considerations for cataract surgery; Tipperman R; PURPOSE OF REVIEW: A variety of options exist for perioperative, intraoperative, and postoperative medications in cataract surgery . This article reviews some of the more timely literature on "controversial" subjects in this area . RECENT FINDINGS: Recent literature may support the rationale for intracameral vancomycin at the time of cataract surgery . The recently released fluoroquinolones moxifloxacin and gatifloxacin are reviewed in terms of their clinical properties . Pharmacologic adjuncts to surgery are discussed, as is the use of intravitreal triamcinolone both at the time of cataract surgery and postoperatively . SUMMARY: Recent advances in ophthalmic pharmacology should aid the practicing anterior segment surgeon . This may affect preoperative, postoperative, and even intraoperative regimens.

Ann Pharmacother, 2004 Jan, 38(1), 62 - 5
Acute delirium associated with combined diphenhydramine and linezolid use; Serio RN; OBJECTIVE: To report a case of delirium with hallucinations presumably caused by the combination of diphenhydramine and linezolid . CASE SUMMARY: A 56-year-old white man was receiving diphenhydramine 300 mg/d for 2 days to treat pruritus caused by a bullous rash possibly induced by vancomycin . He subsequently developed visual and auditory hallucinations, with erratic, aggressive behavior persisting for 3 days . Central anticholinergic syndrome was first suspected, but the long duration and exaggerated response by a patient not prone to anticholinergic toxicity suggest that a second agent may have enhanced the reaction . DISCUSSION: The pharmacodynamic properties of linezolid make this drug a likely contributor to the marked, prolonged effects experienced by this patient . The Naranjo probability scale suggests a possible relationship between the reaction and the combination of diphenhydramine and linezolid . CONCLUSIONS: Drug-induced delirium can occur with several drugs, including diphenhydramine . Linezolid has dopaminergic properties that may enhance the central nervous system effects of anticholinergics . Precautionary monitoring of mental status should be advised when concomitantly administering linezolid with drugs in this class.

J Pharm Pharmacol, 2003 Dec, 55(12), 1623 - 7
Chitosan salts as nasal sustained delivery systems for peptidic drugs; Cerchiara T et al.; The aim of this study was to describe a sustained drug release system based on chitosan salts for vancomycin hydrochloride delivery . Chitosan lactate, chitosan aspartate, chitosan glutamate and chitosan hydrochloride were prepared by spray-drying technique . Vancomycin hydrochloride was used as a model peptidic drug, the nasal sustained release of which should avoid first-pass metabolism in the liver . This in-vitro study evaluated the influence of chitosan salts on the release behaviour of vancomycin hydrochloride from the physical mixtures at pH 5.5 and 7.4 . In-vitro release of vancomycin was retarded by chitosan salts and, in particular, chitosan hydrochloride provided the lowest release of vancomycin.

Nephrol Dial Transplant, 2004 Feb, 19(2), 400 - 5
Evaluation of an in vitro dialysis system to predict drug removal; Hudson JQ et al.; BACKGROUND: Variation in the extent of drug removal under different dialysis conditions presents a challenge for prediction of drug elimination and dosage regimen adjustment during haemodialysis (HD) . Dependence on clinical pharmacokinetic studies in HD patients for dosing guidelines is problematic given the increasing number of dialysers with variable rates of drug removal . Thus, the purpose of this study was to characterize drug removal using an in vitro system and to evaluate its reliability to predict in vivo elimination by HD using vancomycin (VANC) as a model drug . METHODS: In vitro dialysis was performed for 2 h (volume 4.0 l normal saline, initial VANC concentration 30 mg/l, flow rate 300 ml/min, dialysate flow 800 ml/min) using four different dialysers: polymethylmethacrylate (BK-2.1 U), polysulfone (F-80), AN69 (Filtral-20) and hemophan (COBE 700HE) . The in vitro dialysis clearance for VANC (CL(D)) for the polysulfone dialyser was compared with values determined in eight HD patients . In vitro VANC CL(D) for all dialysers was compared with the clearance and KoA for B12 reported for each dialyser . RESULTS: In vitro VANC CL(D) values were 93+/-11 ml/min for the polymethylmethacrylate BK-2.1, 136+/-7 ml/min for the AN69, 65+/-9 ml/min for the hemophan COBE 700HE and 143+/-10 ml/min for the polysulfone F80 . The CL(D) for the polysulfone F80 was not statistically different from the in vivo CL(D) of 135+/-18 ml/min (P = 0.48) . In vitro VANC CL(D) correlated with the B12 CL(D) (r(2) = 0.77) and the B12 KoA (r(2) = 0.63) reported for each dialyser . CONCLUSION: VANC CL(D) in HD patients for the polysulfone dialyser was correctly predicted using the in vitro dialysis system . Use of this system may be superior to estimations of drug CL(D) based on dialyser information provided by the manufacturer for compounds of similar molecular weight.

Polim Med, 2003, 33(3), 19 - 26
{Investigation of tissue reaction of apatite cement implants impregnated with vancomycin}; Juszkiewicz W et al.; Investigation of biocompatibility degree of apatite cement as a carrier of antibiotic--vancomycin was the purpose of the experimental study . Investigation of local reactions of muscular tissue was carried out on 18 rats of Wistar type, by implanting samples of apatite cement with vancomycin in the dorsal muscles . Sections of the animals and microscopic investigations were made 7, 14, 30, 90, 180 and 270 days after the implantation . Investigation of local reactions of bone tissue were carried out on 12 rabbits of New Zealand breed, by implanting the investigated samples into the femoral bone in the region of trochanter . Macroscopic, radiological and microscopic investigations were carried out 1, 3, 6 and 9 months after the surgery . The obtained results of the investigations from muscular and bone tissue, were compared to the investigations in analogical tissues of apatite cement without the medication . In macro- and microscopic investigations in the early period inflammatory reaction of muscles was noticed to be stronger around the samples with vancomycin, in comparison to the control implant . In the later period there was no inflammatory reaction and a thin fibrous connective tissue surrounded the implant and a histological picture was similar, as in cases of an implant without the antibiotic . The local reaction of bone tissue both in the control and in the investigated group (apatite cement with vancomycin) was similar . In the early period the proliferation of rich cellular connective tissue, was noticed . In the later period starting from the 3rd month, formation of young bone tissue was noticed and only locally there were focuses of fibrous tissue . The process observed after splitting of the tested materials into bone tissue, was very similar to healing processes after long bone fraction . The carried out investigations showed, that tissue reaction after implantation of apatite cement and its composite with vancomycin, was very similar and showed a high degree of tissue biocompatibility.

Clin Infect Dis, 2003 Dec 15, 37(12), 1609 - 16 Epub 2003 Nov 20.
Linezolid does not increase the risk of thrombocytopenia in patients with nosocomial pneumonia: comparative analysis of linezolid and vancomycin use; Nasraway SA et al.; Reports from uncontrolled studies suggest that linezolid is associated with rates of thrombocytopenia higher than those reported in clinical studies . We assessed the risk of thrombocytopenia in 686 patients with nosocomial pneumonia who received linezolid or vancomycin for > or =5 days in 2 randomized, double-blind studies and for whom follow-up platelet counts had been measured . New-onset thrombocytopenia (platelet count of <150x10(9) platelets/L) occurred in 19 (6.4%) of 295 linezolid recipients and 22 (7.7%) of 285 vancomycin recipients with baseline platelet counts of > or =150x10(9) platelets/L; severe thrombocytopenia (platelet count of <50x10(9) platelets/L) occurred in only 1 patient in each group . Platelet counts decreased to less than the baseline level in 4 (6.6%) of 61 linezolid recipients and 5 (11.1%) of 45 vancomycin recipients who had baseline counts of <150x10(9) platelets/L . No patient had a decrease to <20x10(9) platelets/L . There were no statistically significant differences between groups in these or any other platelet assessments . Clinically significant thrombocytopenia was uncommon in our analysis, and linezolid was not associated with a greater risk of thrombocytopenia in seriously ill patients than was vancomycin.

J Pediatr (Rio J), 1996 Jul-Aug, 72(4), 225 - 9
{Monitorization of blood levels of vancomycin in children with multi-resistant bacterial infections}; Reis AG et al.; Pharmacokinetics of vancomycin depends on many factors and one of them is the age of the patient . It is better known in adults and there are few studies in children . Therefore, we studied the serum concentrations in 22 children with multi-resistant bacteria infections that received vancomycin . The doses administered followed the recommended rules for its utilization . This study was made at the equilibrium phase and immunofluorescence was the method utilized . The peak serum concentrations varied from 23 to 99 mcg/ml and only in 8 children (36%) they varied from 30 to 40 mcg/ml . In 10 cases (45%) we found valley serum concentration between 5 to 10 mcg/ml . These observations confirm the imprevisibility of serum concentrations obtained from one single recommended dose . Therefore, due to the complexity of vancomycin pharmacokinetics, the monitoring of blood levels is recommended in order to obtain therapeutic success.

J Antimicrob Chemother, 2004 Feb, 53(2), 329 - 34 Epub 2003 Dec 19.
Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty; Bertazzoni Minelli E et al.; AIM: Evaluation of the delivery of gentamicin and vancomycin from polymethylmethacrylate (PMMA) spacers before and after implantation for the treatment of total hip replacement infections . METHODS: Twenty industrially produced spacers containing gentamicin (1.9%) were utilized . Vancomycin (2.5%) mixed with PMMA cement was used to fill holes drilled in the cement of 14 of the 20 spacers immediately before implantation . The spacers were removed from 20 patients 3-6 months after implantation and then immersed in phosphate buffer at 37 degrees C for 10 days . Antibiotic concentrations were determined by fluorescence polarization immunoassay . RESULTS: Gentamicin and vancomycin were still present in all the spacers removed from the patients . The release of gentamicin alone and in combination with vancomycin was in the range 0.05%-0.4% of the initial amount present, whereas the release of vancomycin was in the range 0.8%-3.3% . The release kinetics showed a similar pattern for both drugs . After a high initial release of drug, a reduced, but constant, elution was observed over the next few days . CONCLUSIONS: The delivery of gentamicin and vancomycin from PMMA cement was high initially, with sustained release over several months . Incorporation of vancomycin into the surface of the spacers permitted spacers to be prepared with multiple antibiotics present and without adversely affecting the release kinetics of the agents . The gentamicin-vancomycin combination shows potential for the treatment of infection following total hip replacement in specific patients.

Anal Chem, 2003 Sep 15, 75(18), 4793 - 800
Determination of binding constants on microarrays with confocal fluorescence detection; Elbs M et al.; Confocal laser scanning microscopy was employed for the determination of binding constants of receptor-ligand interactions in a microarray format . Protocols for a localized immobilization of amine containing substances on glass via GOPTS (3-glycidyloxypropyl)trimethoxysilane) were optimized with respect to the detection of ligand binding by fluorescence . Compatibility with miniaturization by nanopipetting devices was ensured during all steps . The interaction of the tripeptide L-Lys-D-Ala-D-Ala with vancomycin immobilized on glass served as a model . To minimize consumption of ligand, binding constants were determined by stepwise titration of binding sites . The binding constant of the unlabeled ligand was determined by competitive titration with a fluorescently labeled analogue . The determined binding constants agreed well with those determined by other techniques, previously . Labeled ligand bound stronger than the unlabeled one . This difference was dye-dependent . Still, binding was specific for the tripeptide moiety confirming that ligand and fluorescent analogue competed for the same binding sites these results validate the determination of binding constants by competitive titration . The protocols established for confocal fluorescence detection are applicable to axially resolved detection modalities and screening for unlabeled ligands by competitive titration in general.

J Appl Microbiol, 2003, 95(5), 949 - 57
Optimization of enrichment and plating procedures for the recovery of Escherichia coli O111 and O26 from minced beef; Catarame TM et al.; AIM: Optimization of enrichment media and selective agars for the detection of Escherichia coli O26 and O111 from minced beef . METHODS AND RESULTS: This study compared a number of different enrichment conditions and plating media for the recovery of E . coli O26 and E . coli O111 from minced beef . The optimum enrichment conditions for E . coli O26 was observed in beef samples enriched at 41.5 degrees C in tryptone soya broth supplemented with cefixime (50 microg l(-1)), vancomycin (40 mg l(-1)) and potassium tellurite (2.5 mg l(-1)) . Similar enrichment conditions were optimal for E . coli O111 with the omission of potassium tellurite . The optimum agar for recovery of E . coli O26 and giving the most effective suppression of contaminants was MacConkey agar {lactose replaced by rhamnose (20 g l(-1))} and supplemented with cefixime (50 microg ml(-1)) and potassium tellurite (2.5 mg l(-1)) . Optimum recovery of E . coli O111 was on chromocult agar, supplemented with cefixime (50 microg ml(-1)), cefsulodin (5 mg l(-1)) and vancomycin (8 mg l(-1)) . Minced beef samples were inoculated with a number of strains of E . coli O26 (n=9) and O111 (n=8), and the developed enrichment and plating methods, used in combination with immunomagnetic separation, were shown to be an effective method for the recovery of all strains . CONCLUSIONS: Routine cultural methods for the recovery of E . coli O26 and O111 from minced beef are described . SIGNIFICANCE AND IMPACT OF THE STUDY: The optimized enrichment and plating procedure described for the recovery of E . coli O111 and O26 from meat can be used to extend research on these emerging pathogens in beef.

Nephrologie, 2003, 24(6), 287 - 92
{Drug induced linear IgA bullous dermatosis}; Montagnac R et al.; Linear IgA disease is an autoimmune subepidermal bullous disease in which linear IgA deposits are found at the basement membrane zone . It is classically idiopathic but a drug-induced variant seems to be individualized in which cutaneous lesions resolve spontaneously after cessation of responsible treatment . Among the commonly implicated drugs, vancomycin is the most frequently reported . One should not however ignore other precipitating events sometimes associated, particularly infectious diseases and non-lymphoid or lymphoproliferative malignancies . Authors present here clinical and histological features of this disease as well as drugs that have been implicated.

J Food Prot, 2003 Oct, 66(10), 1911 - 5
Efficacy of enrichment broths in the recovery of freeze-injured Escherichia coli O157:H7 in inoculated ground beef by PCR; Lionberg WC et al.; Escherichia coli O157:H7 strains ATCC 35150 and ATCC 43894 and five pooled isolates from beef and pork freeze injured at -25 degrees C in beef infusion were used to inoculate ground beef . Samples (25 g each) were added to 225 ml of buffered peptone water with vancomycin, cefsulodin, and cefixime (BPW-VCC), 225 ml of modified EC broth plus novobiocin (mEC+n), and 225 ml of R&F enrichment broth (R&F-EB) and aerobically incubated at 41 to 42 degrees C . After 6, 7, 8, and 24 h of incubation, levels of E . coli O157:H7 recovered from each broth by a PCR assay with the BAX automated system as well as by conventional enrichment with the use of nonaerated mEC+n incubated at 35 degrees C for 24 h were compared with levels recovered by cultural isolation with immunomagnetic separation and plating on BCM E . coli O157:H7 chromogenic agar . For ground beef inoculated with a mean of 4.23 +/- 1.00 total cells (74% freeze injured) per 25 g, after 6 h the PCR assay identified 72.7, 57.6, and 66% of the samples for R&F-EB, BPW-VCC, and mEC+n, respectively, as presumptive positive, whereas the recovery rates after 7 and 8 h exceeded 90%, with the rate for R&F-EB being 100% . For ground beef inoculated with a mean of 1.50 +/- 0.56 total cells (80% freeze injured) per 25 g, after 6 h the PCR assay identified 47.6, 19.1, and 9.5% of the samples for R&F-EB, BPW-VCC, and mEC+n, respectively, as presumptive positive . These values increased to 81.0, 61.9, and 52.4% after 7 h and to 95.2, 61.9, and 71.4% after 8 h . After 24 h, only 55 to 60% of the samples at both inoculum levels tested positive by PCR with conventional enrichment and incubation, whereas >95% of the samples tested positive with R&F-EB aerated at 41 to 42 degrees C . Culture results for R&F-EB and mEC+n after 7 and 8 h of incubation were closely correlated with presumptive positive PCR results.

Pharmacotherapy, 2003 Sep, 23(9), 1195 - 8
Vancomycin-induced thrombocytopenia: a case proven with rechallenge; Marraffa J et al.; In a rare case of vancomycin-induced thrombocytopenia, a 50-year-old man with culture-negative subacute bacterial endocarditis underwent mitral valve replacement surgery and was treated with vancomycin . His platelet count dropped from 346 x 10(3)/mm3 to 13 x 10(3)/mm3 on postoperative day 4, and a differential diagnosis of heparin- versus drug-induced thrombocytopenia was considered . Antiheparin antibodies were detected in the patient's serum on day 5 . He showed no signs of bleeding . His platelet count remained below 5 x 10(3)/mm3 despite two platelet transfusions on day 5 . A hemorrhagic pericardial effusion with tamponade developed, requiring drainage . A trial with intravenous immunoglobulin led to fever and chills, and the infusion was not completed . Vancomycin was changed to clindamycin on day 9, and methylprednisolone therapy was started on day 11 . On day 12, the patient's clinical condition improved, and his platelet count increased from 3 x 10(3)/mm3 to 32 x 10(3)/mm3 with no bleeding . On day 18, his platelet count was 424 x 10(3)/mm3, and he was scheduled for discharge with vancomycin therapy for a total of 6 weeks . He received a single dose of intravenous vancomycin 1 g at the hospital; his platelet count dropped to 160 x 10(3)/mm3 1 hour after the infusion and to 58 x 10(3)/mm3 12 hours later . Vancomycin was discontinued and clindamycin and prednisone were restarted . On day 20, the patient's platelet count increased to 105 x 10(3)/mm3 and he was discharged with warfarin, prednisone, and clindamycin therapy . We suspect that our patient's thrombocytopenia was due to vancomycin.

Rev Invest Clin, 2003 May-Jun, 55(3), 276 - 80
{Pharmacologic clinical monitoring of serum vancomycin levels in pediatric patients}; Nandi-Lozano E et al.; OBJECTIVE: To analyze the results from the clinical monitoring of serum vancomycin levels among pediatric patients receiving this drug . METHODS: Retrospective study of data from routine monitoring of serum vancomycin concentrations . The study population includes children who received vancomycin for more than 3 days and had peak and trough vancomycin serum concentration documented . The vancomycin concentrations were measured by an immunoassay procedure . RESULTS: We obtained 70 vancomycin concentrations from pediatric patients whose ages ranged from newborn to 13 years old . Mean peak and trough concentrations were 45.7 +/- 8.0 and 18.7 +/- 9.6 micrograms/mL, respectively . We used as a reference normal ranges for Cpmax of 25-40 micrograms/mL and Cpmin of 5-40 micrograms/mL . Only 26.1% of the patients were on Cpmax normal ranges, 47.8% were above the range and 26% under the lower limit . In regards to the Cpmin 17% of the cases were between the accepted limits, 41% above the upper limit and 41% under the normal range . CONCLUSION: Our data suggest that less than a fifth of the patients have serum levels on therapeutic range and almost half of these population had serum levels above the normal range . This might be explained by the type of the population sampled, reflecting a selection bias by detecting levels only among patients with an increased risk for toxicity . Finally, we stress the importance of accurately documenting dose, timing, and renal function in the records of all patients subjected to serum vancomycin determinations.

J Infus Nurs, 2003 Sep-Oct, 26(5), 278 - 84
Vancomycin: new perspectives on an old drug; Hadaway L et al.; The use of vancomycin continues to be prevalent in all clinical settings . However, many questions persist about infusion techniques . According to the Infusion Nursing Standards of Practice, peripheral catheters are not the best choice for infusing this drug because of its pH . The key to reducing risk of peripheral phlebitis and extravasation injury is choosing a more appropriate vascular access device . Many healthcare providers correlate systemic side effects with the infusion rate and concentration, although many reports cannot support this correlation . New technologies of vascular access and infusion controlling devices are changing old, established practices . This update provides an examination of the current literature on all aspects of infusing vancomycin and monitoring patients.

J Chromatogr B Analyt Technol Biomed Life Sci, 2003 Sep 25, 795(1), 115 - 21
Role of the vancomycin-ristocetin heterodimerization on the enantioselectivity of D,L-tryptophan and D,L-dansyl tryptophan; Slama I et al.; In this paper, a chromatographic system using immobilized ristocetin as chiral stationary phase and vancomycin as chiral mobile phase additive (CMPA) was described in order to investigate the role of the glycopeptide heterodimerization on the retention and enantioselectivity of D,L-tryptophan and D,L-dansyl tryptophan . A simplified interaction model was derived considering the formation of heterodimers between immobilized ristocetin and vancomycin . This theoretical approach was convenient to describe adequately the retention behavior . When the CMPA concentration increased, the solute retention factor increased for all the solute enantiomers studied indicating that the vancomycin adsorbed on the immobilized ristocetin played a preponderant role in the retention . The D,L-tryptophan enantioselectivity on the dynamically modified stationary phase was improved by a factor of 1.3, probably due to a glycopeptide conformational change upon heterodimerization . On the other hand, a decrease in the chiral discrimination of D,L-dansyl tryptophan was observed . Such a behavior seems to result from the antagonist enantioselective properties of the two glycopeptides for the dansyl amino acids.

Clin Nephrol, 2003 Aug, 60(2), 96 - 104
Comparison of 3 vancomycin dosage regimens during hemodialysis with cellulose triacetate dialyzers: post-dialysis versus intradialytic administration; Mason NA et al.; AIMS: Traditionally, vancomycin is administered following dialysis to minimize drug loss when high-flux membranes are employed . Unfortunately, this approach is extremely inconvenient for patients and staff, requiring the patients to remain in the unit for at least 1 hour following dialysis . This study was designed to evaluate the feasibility of administering vancomycin during hemodialysis . Specifically, this study was designed to compare the pharmacokinetics of vancomycin when administered during the last 1-2 hours of dialysis (i.e . intra-dialytic administration) to that administered after completion of dialysis . MATERIALS AND METHODS: In a randomized, 3-way crossover trial, the pharmacokinetics of vancomycin were evaluated in 9 hemodialysis patients, comparing vancomycin 15 mg/kg following dialysis (Phase I), vancomycin 15 mg/kg during the last hour of hemodialysis (Phase II) or vancomycin 30 mg/kg during the last 2 hours of hemodialysis (Phase III) . Vancomycin plasma concentrations were obtained over an 8-day period and subsequent comparisons between the treatment approaches were made with paired t-tests or ANOVA, as appropriate . Dialysate vancomycin concentrations determined on Day 1 and Day 3 of Phases II and III were used to calculate the fraction of vancomycin dose removed, and were compared to plasma data using paired t-tests . RESULTS: Vancomycin was significantly removed (33.4 to 39.5%) during a 3- to 4-hour high-flux dialysis session occurring on Day 3 after vancomycin administration . Mean serum concentrations immediately following intradialytic vancomycin administration of 15 mg/kg over the last hour of dialysis or 30 mg/kg over the last 2 hours of dialysis were initially high (77.7 and 95.5 mcg/ml respectively), but fell to 25.9 and 40.5 mcg/ml, respectively, by 4 hours post-dialysis . Predialysis concentrations on Days 3, 5 and 8 were similar for vancomycin 30 mg/kg administered over the last 2 hours of dialysis as compared with a 15 mg/kg dose given after dialysis . Vancomycin 15 mg/kg over the last hour of dialysis resulted in significantly lower subsequent predialysis concentrations than the other dosing schemes . CONCLUSIONS: Vancomycin administration of 30 mg/kg over the last 2 hours of dialysis achieves serum concentrations similar to conventional dosing of 15 mg/kg after dialysis and would allow dosing on a weekly basis.

Org Biomol Chem, 2003 Feb 7, 1(3), 472 - 7
Kinetic barriers and ordering of non-covalently bound states; O'Brien SW et al.; Binding of a dimer of a glycopeptide antibiotic to two molecules of a ligand that are bound to a membrane surface (by a hydrocarbon anchor) has been investigated . This binding on a surface is cooperatively enhanced (surface enhancement) relative to the binding in solution, because the former occurs intramolecularly on a template . Previously a correlation between surface enhancement and thermodynamic stability of the dimer in free solution (Kdimsol) was hypothesised . However, we found that two weakly dimerising antibiotics (vancomycin and ristocetin A) with similar Kdimsol give very different surface enhancements . We propose a model to explain the data correlating surface enhancement to the kinetic barrier to dissociation of the dimer . The surface enhancement of binding can be expected to increase with increasing tightness of the non-covalent interactions formed at the dimer interface . The effect should be found in general where cooperativity is exercised within an organised template (e.g., DNA duplexes and proteins).

Kyobu Geka, 2003 Jul, 56(8 Suppl), 712 - 7
{Procedure and problem for short-term outcomes on off-pump coronary artery bypass grafting}; Ishikawa N et al.; We performed off-pump coronary artery bypass grafting (CABG) in all cases without reoperation case from July, 2002 . Advantage of off-pump CABG versus on-pump CABG which is reduced a number of perioperative complication and early patients recovery was previously demonstrated . In our institute, the mean number of grafts per patients was 4.7 +/- 1.3, and the rate of using arterial grafts was 99.5% in all cases without minimally invasive direct coronary artery bypass (MIDCAB) . The mean hospital stay after operation was 10.8 +/- 2.8 . It was shorted remarkably in comparison with on-pump CABG; 19.4 +/- 6 . Furthermore, sever complication was not occurred in any cases after operation though high risk cases were increased . In the early cases, atrial fibrillation complicated frequently (32%), but using after magnesium sulfate it was remarkably decreased (8.4%) . On the other-hand, attention is necessary for the infection caused by the increase of high risk patients . Therefore, we used vancomycin (VCM) at these cases from the viewpoint of prevention . Recently, we performed remnant omental transfer for the sever diabetes mellitus case which was used bilateral internal thoracic artery on CABG . It learned to get the early recovery which was necessary for the off-pump CABG by the above additional treatment.

Electrophoresis, 2003 Aug, 24(15), 2674 - 9
Fast enantiomeric separation with vancomycin as chiral additive by co-electroosmotic flow capillary electrophoresis: increase of the detection sensitivity by the partial filling technique; Kang J et al.; A fast and sensitive method is described by using vancomycin as a chiral additive for enantiomeric separation by capillary electrophoresis (CE) . In order to overcome disadvantages associated with use of vancomycin as chiral additive in CE, several strategies including the dynamic coating technique, the co-electroosmotic flow technique, and the partial filling technique were employed sequentially in this method . Using the polycationic polymer hexadimethrine bromide (HDB) as a buffer additive, the capillary wall was dynamically coated with a thin film formed by the adsorbed HDB . Consequently, the adsorption of vancomycin onto the capillary wall was minimized via electrostatic repulsion between the coating of the capillary wall and the vancomycin molecule . In addition, the reversed electroosmotic flow (from cathode to anode) produced by the positively charged capillary wall migrates in the same direction of negatively charged analytes (co-electroosmotic flow electrophoresis) . Thereby the electrophoretic mobility of negatively charged analytes were drastically accelerated leading to a short separation time of less than 3.4 min . The separation time was further reduced by the use of a short-end-injection technique . For example, the analysis time was achieved by as short as 55 s for a baseline separation of dansyl-alpha-amino-n-butyric acid . Concurrently, the partial filling technique was used to avoid the loss of detection sensitivity caused by the presence of vancomycin in the running buffer . The effect of several parameters, such as HDB concentration, buffer pH, plug length of the chiral selector, concentration of the chiral selector and applied voltage, on enantioselectivity were investigated toward optimization . Besides the advantage of a very short separation time, the method is characterized by high detection sensitivity, high selectivity, and high efficiency.

J Biol Chem, 2003 Nov 21, 278(47), 46727 - 33 Epub 2003 Jul 29.
Crystal structure of OxyC, a cytochrome P450 implicated in an oxidative C-C coupling reaction during vancomycin biosynthesis; Pylypenko O et al.; Gene inactivation studies point to the involvement of OxyC in catalyzing the last oxidative phenol coupling reaction during glycopeptide antibiotic biosynthesis . Presently, the substrate and exact timing of the OxyC reaction are unknown . The substrate might be the bicyclic heptapeptide or a thioester derivative bound to a protein carrier domain . OxyC from the vancomycin producer Amycolatopsis orientalis was produced in Escherichia coli and crystallized, and its structure was determined to 1.9 A resolution . OxyC gave UV-visible spectra characteristic of a P450-like hemoprotein in the low spin ferric state . After reduction to the ferrous state by dithionite the CO-ligated form gave a 450-nm peak in a UV-difference spectrum . The addition of vancomycin aglycone to OxyC produced type I changes to the UV spectrum . OxyC exhibits the typical P450-fold, with the Cys ligand loop containing the signature sequence FGHGX-HXCLG and Cys-356 being the proximal axial thiolate ligand of the heme iron . The observation of a water molecule bound to the heme iron is consistent with the UV-visible spectra of OxyC indicating a low spin heme . A polyethylene glycol molecule occupying the active site might mimic the bicyclic heptapeptide substrate . Analysis of the structure of Oxy-proteins and other P450s indicates regions that might be involved in binding of the redox partner and possibly the protein carrier domain.

Chin Med J (Engl), 2003 Jun, 116(6), 811 - 8
A hospital outbreak of severe acute respiratory syndrome in Guangzhou, China; Wu W et al.; OBJECTIVE: To describe a hospital outbreak of severe acute respiratory syndrome (SARS) and summarize its clinical features and therapeutic approaches . METHODS: The outbreak started with a SARS patient from the community, and a total of 96 people (76 women and 20 men, mean age (29.5 +/- 10.3) years, 93.8% of whom were health care workers) who had exposure to this source patient became infected in a short time . Clinical data in this cohort were collected prospectively as they were identified . RESULTS: (1) The incubation period ranged from 1 to 20 (mean: 5.9 +/- 3.5) days . The duration of hospitalization was (17.2 +/- 8.0) days . (2) The initial temperature was (38.3 +/- 0.6) degrees C, while the highest was (39.2 +/- 0.6) degrees C (P < 0.001), with fever duration of (9.0 +/- 4.2) days . (3) Other most common symptoms included fatigue (93.8%), cough (85.4%), mild sputum production (66.7%), chills (55.2%), headache (39.6%), general malaise (35.4%) and myalgia (21.9%) . (4) The radiographic changes were predominantly bilateral in the middle or lower lung zones . The number of affected lung fields was 1.2 +/- 0.8 on presentation, which increased to 2.9 +/- 1.4 after admission (P < 0.001) . The interval from the beginning of fever to the onset of abnormal chest radiographs was (3.5 +/- 2.3) days, which increased in size, extent, and severity to the maximum (6.7 +/- 3.5) days later . The time before the lung opacities were basically absorbed was (14.9 +/- 7.8) days . (5) Leukopenia was observed in 67.7% of this cohort . The time between the onset of fever and leukopenia was (4.4 +/- 2.3) days, with the lowest white blood cell count of (2.80 +/- 0.72) x 10(9)/L . (6) The lowest arterial oxygen saturation was (94.8 +/- 3.1)% with supplementary oxygen . (7) Antibiotical therapies included tetracyclines (91.0%), aminoglycosides (83.3%), quinolones (79.2%); 18.8% of the patients received a combination of tetracyclines and aminoglycosides, while 11.5% received a combination of tetracyclines and quinolones, and 63.5% received a combination of tetracyclines, aminoglycosides and quinolones . Vancomycin was used in 13.5% of the patients . (8) 68.8% of the patients were treated with methylprednisolones for a mean interval of (4.9 +/- 2.4) days . The initial dose was (67.3 +/- 28.2) mg/d and the maximal dose was (82.4 +/- 30.5) mg/d . (9) Human gamma-globulin, interferon-alpha, antiviral drugs (oral ribavirin or oseltamivir) were used respectively in 68.6%, 46.9% and 92.7% of the patients . (10) Ninety-five patients (99.0%) had a complete clinical recovery, and only 1 patient (1.0%) died . CONCLUSIONS: SARS appears to be quickly infectious and potentially lethal among health care workers, characterized by acute onset and rapid progression, and mostly bilateral lung involvement on chest radiographs . Proper administration of glucocorticosteroids seems to be of some benefits . Antibiotics, human gamma-globulin, interferon-alpha, and antiviral drugs, although empirically, might be useful to shorten the clinical course.

Proc Natl Acad Sci U S A, 2003 Aug 5, 100(16), 9238 - 43 Epub 2003 Jul 21.
Structure of the TDP-epi-vancosaminyltransferase GtfA from the chloroeremomycin biosynthetic pathway; Mulichak AM et al.; During the biosynthesis of the vancomycin-class antibiotic chloroeremomycin, TDP-epi-vancosaminyltransferase GtfA catalyzes the attachment of 4-epi-vancosamine from a TDP donor to the beta-OHTyr-6 of the aglycone cosubstrate . Glycosyltransferases from this pathway are potential tools for the combinatorial design of new antibiotics that are effective against vancomycin-resistant bacterial strains . These enzymes are members of the GT-B glycosyltransferase superfamily, which share a homologous bidomain topology . We present the 2.8-A crystal structures of GtfA complexes with vancomycin and the natural monoglycosylated peptide substrate, representing the first direct observation of acceptor substrate binding among closely related glycosyltransferases . The acceptor substrates bind to the N-terminal domain such that the aglycone substrate's reactive hydroxyl group hydrogen bonds to the side chains of Ser-10 and Asp-13, thus identifying these as residues of potential catalytic importance . As well as an open form of the enzyme, the crystal structures have revealed a closed form in which a TDP ligand is bound at a donor substrate site in the interdomain cleft, thereby illustrating not only binding interactions, but the conformational changes in the enzyme that accompany substrate binding.

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2003 Feb, 15(2), 114 - 6
{Pharmacokinetics of vancomycin in continuous veno-venous hemofiltration}; Gu Q et al.; OBJECTIVE: To investigate the pharmacokinetics of vancomycin in continuous veno-venous hemofiltration(CVVH) in order to determine appropriate vancomycin dosing strategies for patients receiving CVVH . METHODS: The serum concentrations of vancomycin were measured by TDx and the pharmacokinetics parameters were calculated . RESULTS: The pharmacokinetics of vancomycin during CVVH was fitted with open two-compartment model . At the beginning of CVVH, the pharmacokinetic parameters were: maximum plasma concentration (Cmax)=22.18 mg/L, minimum plasma concentration attained (Cmin)=5.82 mg/L, half-life of drug (T1/2)=5.75 h, apparent volume of distribution (Vd)=21.92 L, total body clearance of drug(CL)=3.49 L/h . On the 16 d of CVVH, the pharmacokinetic parameters were Cmax=38.70 mg/L, Cmin=16.50 mg/L, T1/2=33.32 h, Vd=12.92 L, CL=0.38 L/h . CONCLUSION: CVVH can significantly augment the clearance of vancomycin in acute renal failure patients . Dosing strategies for individualization of vancomycin therapy in patients receiving CVVH are proposed . Monitoring the serum concentration during CVVH is necessary.

Chembiochem, 2003 Jul 7, 4(7), 603 - 9
Acceptor specificity and inhibition of the bacterial cell-wall glycosyltransferase MurG; Liu H et al.; A continuous fluorescence coupled enzyme assay was developed to study the acceptor specificity of the glycosyltransferase MurG toward different lipid I analogues with various substituents replacing the undecaprenyl moiety . It was found that most lipid I analogues are accepted as substrates and, amongst these, the saturated C14 analogue exhibits the best activity . This substrate was used to evaluate the inhibition activity of such antibiotics as moenomycin, vancomycin, and two chlorobiphenyl vancomycin derivatives . A vancomycin derivative with a chlorobiphenyl moiety on the aglycon section was identified as a potent inhibitor of MurG.

J Microencapsul, 2003 Jul-Aug, 20(4), 473 - 8
Controlled release of vancomycin from freeze-dried chitosan salts coated with different fatty acids by spray-drying; Cerchiara T et al.; The aim of this study was to describe a controlled drug release system based on chitosan salts for vancomycin hydrochloride delivery . Chitosan aspartate (CH-Asp), chitosan glutamate (CH-Glu) and chitosan hydrochloride (CH-HCl) were prepared by freeze-drying and coated with stearic, palmitic, myristic and lauric acids by spray-drying technique . Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract . This study evaluated, in vitro, the influence of chitosan salts on the release behaviour of vancomycin hydrochloride from the freeze-dried and spray-dried systems at pH 2.0 and 7.4.

J Chromatogr A, 2003 May 9, 996(1-2), 115 - 31
Development and validation of an improved method for the analysis of vancomycin by liquid chromatography selectivity of reversed-phase columns towards vancomycin components; Diana J et al.; The current method prescribed in official monographs for the purity control of vancomycin is inappropriate in that several components are not separated from each other and other components are coeluted with the main component vancomycin B . The method uses an ODS column at pH 3.2 . In this study, several changes were introduced in order to improve the separation . The optimization of the separation method at low pH indicated that pH 1.7 was optimum and that the use of dioxane as organic modifier drastically improved the separation . These conditions were used to test a set of more than 40 reversed-phase columns for their selectivity towards vancomycin components . The selection of the most suitable columns was performed by means of principal component analysis . Most of these columns did not allow the separation of didechlorovancomycin from monodechlorovancomycin 1 . It was found that neutral to slightly alkaline mobile phases allowed better separation . Further optimization of the separation method and a robustness study were performed by means of experimental design . This optimization indicated that pH 7.7 was optimum and gradient elution was also used to effect complete analysis . The final method uses a Kromasil column and the mobile phase comprises dioxane, water and ammonium formate solution pH 7.7 . The separation of monodechlorovancomycin 2 and of some unknown impurities from the main component vancomycin B is described for the first time . The method shows good repeatability, linearity and sensitivity.

Yao Xue Xue Bao, 2003 Mar, 38(3), 211 - 4
{Enantiomeric separation of ketoprofen by HPLC using chirobiotic V CSP and vancomycin as chiral mobile phase additives}; Ye XX et al.; AIM: To establish HPLC chiral separation method for ketoprofen enantiomers by using Chirobiotic V chiral seperation phase (CSP) (A) and vancomycin as chiral mobile phase additives (B) . METHODS: The separation was first performed on Chirobiotic V CSP with the mobile phase of terahydrofran (THF)-0.5% triethylanine acetate(TEAA) buffer (15:85) at the flow rate of 0.7 mL.min-1 . When using vancomycin as chiral mobile phase additive, the separation was carried out on C8 column (150 mm x 4.6 mm), the mobile phase was methanol-0.25% TEAA buffer (50:50), the flow rate was 0.7 mL.min-1 . The effects of the concentration of vancomycin, organic modifier and the pH of the buffer on the resolution of ketoprofen enantiomers were investigated . Also, the feasibility of these two methods to be used as quantitative method was studied . RESULTS: Ketoprofen enantiomers were separated at a baseline level under the chromatographic condition of both methods A and B, the resolution was 2.28 and 2.22, respectively . In method A the linearity of enantiomer was obtained from 0.5 mg.L-1 to 100 mg.L-1, the detectionlimit was 1 microgram.L-1 . When using vancomycin as mobile phase additive the system was shown to have a high efficiency . In this system, the assay of enantiomer is linear from 2.5 mg.L-1 to 250 mg.L-1 . The detection limit was 14.5 micrograms.L-1 . CONCLUSION: Both methods can be used to detect optical purity of S-(+)-ketoprofen.

Anal Bioanal Chem, 2003 Jul, 376(6), 822 - 31 Epub 2003 Jun 26.
Partial-filling affinity capillary electrophoresis; Villareal V et al.; Partial-filling affinity capillary electrophoresis (PFACE) is used to examine the binding interactions between two model biological systems: D-Ala-D-Ala terminus peptides to the glycopeptide antibiotic vancomycin (Van) from Streptomyces orientalis, and arylsulfonamides to carbonic anhydrase B (CAB, EC 4.2.1.1, bovine erythrocytes) . Using these two systems, modifications in the PFACE technique are demonstrated including flow-through PFACE (FTPFACE), competitive flow-through PFACE (CFTPFACE), on-column ligand synthesis PFACE (OCLSPFACE), and multiple-step ligand injection PFACE (MSLIPFACE) . In PFACE small plugs of sample are injected into the capillary column and an equilibrium is established between receptor and ligand during electrophoresis . Binding constants are then obtained by Scatchard analysis using changes in the migration time of the receptor/ligand on changing the concentration of the ligand/receptor . Data demonstrating the quantitative potential of these methods are presented . This review focuses on the unique capabilities of the different PFACE techniques as applied to two model biological systems.

J Pept Res, 2003 Aug, 62(2), 88 - 95
New chromogenic dipeptide substrate for continuous assay of the D-alanyl-D-alanine dipeptidase VanX required for high-level vancomycin resistance; Anissimova M et al.; A direct continuous UV-Vis spectrophotometric assay has been developed for VanX, a D-alanyl-D-alanine aminodipeptidase necessary for vancomycin resistance . This method is based on the hydrolysis of the alternative substrate D-alanyl-alpha-(R)-phenylthio-glycine D-Ala-D-Gly(S-Ph)-OH (H-DAla-DPsg-OH, 5a) . Spontaneous decomposition of the released phenylthioglycine generates thiophenol, which is quantified using Ellman's reagent . The dipeptide behaved as an excellent substrate of VanX, exhibiting Michaelis-Menten kinetics with a kcat of 76 +/- 5/s and a KM of 0.83 +/- 0.08 mm (kcat = 46 +/- 3/s and KM = 0.11 +/- 0.01 mm for D-Ala-D-Ala) . Determination of the kinetic parameters of the previously reported mechanism-based inhibitor D-Ala-D-Gly(SPhip-CHF2)-OH (H-D-Ala-DPfg-OH, 5c) {Araoz, R., Anhalt, E., Rene, L., Badet-Denisot, M.-A., Courvalin, P . & Badet, B . (2000) Biochemistry 39, 15971-15979} using the substrate reported in the present study yielded values of Kirr of 22 +/- 1 microM and kinact of 9.3 +/- 0.4/min in good agreement with values previously obtained in our laboratory (Kirr = 30 +/- 1 mm; kinact = 7.3 +/- 0.3/min) . In addition, inhibition by the competing substrate D-Ala-D-Ala resulted in determination of a Ki = 70 +/- 6 microM close to the previously reported KM value . These results demonstrate that the present assay is a convenient, rapid and sensitive tool in the search for VanX inhibitors.

J Appl Microbiol, 2003, 95(1), 155 - 9
A comparison of two pre-enrichment media prior to immunomagnetic separation for the isolation of E . coli O157 from bovine faeces; Foster G et al.; AIMS: To compare the sensitivity of two pre-enrichment broth media prior to immunomagnetic separation for the isolation of Escherichia coli O157 from cattle faeces . METHODS AND RESULTS: One-gram portions of 721 cattle faeces collected from 43 farms were pre-enriched in buffered peptone water containing vancomycin, cefixime and cefsulodin (BPW-VCC) and buffered peptone water without additives (BPW-WOA), respectively . A total of 137 samples were positive for E . coli O157: 127 pre-enriched with BPW-WOA and 89 pre-enriched in BPW-VCC . Representative isolates were tested for phage type, verotoxin and eae (E . coli attaching and effacing) gene sequences, resulting in the recognition of eight different types . All the E . coli O157 types recognized were isolated by both methods except for three different strains, each of which were isolated only on a single occasion: two by BPW-WOA and another by BPW-VCC . CONCLUSIONS: The results clearly demonstrate, under the conditions of this study, that BPW without antibiotics was the superior pre-enrichment medium for the isolation of E . coli O157 from cattle faeces . SIGNIFICANCE AND IMPACT OF THE STUDY: The use of BPW-WOA in preference to BPW-VCC for the isolation of E . coli O157 from cattle faeces in future research and outbreak studies should lead to a higher number of positive isolates.

Am J Ophthalmol, 2003 Jun, 135(6), 915 - 7
Posttraumatic exogenous Nocardia endophthalmitis; Hudson JD et al.; PURPOSE: To report a case of posttraumatic exogenous Nocardia endophthalmitis . DESIGN: Interventional case report . METHOD: A 46-year-old man presented with counting fingers vision, severe eye pain, hypopyon, and an iris mass consistent with endophthalmitis following a penetrating injury to the left eye . RESULTS: Despite oral fluconazole and repeated intravitreal injections of vancomycin, gentamicin, and amphotericin B, the eye remained painful with a persistent hypopyon and recurrent iris masses . Cultures of the vitreous and iris masses remained negative for organisms . Despite vitrectomy and sector iridectomy of the iris mass with repeat injections of intravitreal antibiotics, the patient continued to have severe pain, poor vision, and developed new iris masses . Enucleation cultures confirmed Nocardia asteroides . CONCLUSIONS: Posttraumatic exogenous Nocardia endophthalmitis is extremely rare, and its clinical signs can mimic a fungal infection.

Chirality, 2003 Jun, 15(6), 494 - 7
Enantiomeric separation by HPLC of 1,4-dihydropyridines with vancomycin as chiral selector; Boatto G et al.; The macrocyclic antibiotics represent a relatively new class of chiral selectors in CE, HPLC, and TLC . We have examined the use of the macrocyclic antibiotic vancomycin as a chiral selector in HPLC for the separation of 1,4-dihydropyridines (DHPs) calcium antagonists (CAs) . Chromatographic data of six 1,4-dihydropyridine calcium channel blockers obtained on the vancomycin chiral stationary phase (Chirobiotic V) were compared with those obtained on an alpha(1)-acid glycoprotein (AGP) HPLC stationary phase . Optimization of pH and organic modifier was carried out in order to modulate the retention properties of each system . All chiral neutral DHPs were resolved on the AGP column, whereas on Chirobiotic V only basic DHPs showed a split peak . The analytical chromatographic procedure on Chirobiotic V proved suitable for semipreparative separation, since the separation factor on the analytical column was high enough to obtain pure enantiomers with high yields .

Electrophoresis, 2003 May, 24(10), 1620 - 6
Salt dependence on vancomycin-herbicide enantiomer binding: capillary electrophoresis study and theoretical approach; Andre C et al.; In a previous paper, a mathematical model was developed for the estimation of binding constants by capillary electrophoresis (Guillaume and Peyrin, Anal . Chem . 1999, 71, 2046-2052) . This model was applied to determinate the binding constant of the guest-vancomycin complex as well as the degree of complexation n(c) (percent of complexed guest) . In this work, the guest molecule were a series of acid herbicide enantiomers (aryloxypropionic, aryloxyphenoxypropionic, and aminopropionic acid) . The effects of the run buffer salt concentration on the herbicide-vancomycin binding was clearly described by the determination of specific physicochemical parameters as well as thermodynamic data . These results demonstrate that a better understanding of the interactions involved in the guest molecule-vancomycin binding allows to optimize the enantiomeric separation of this chiral guest molecule.

Antimicrob Agents Chemother, 2003 Jun, 47(6), 2015 - 7
Vancomycin penetration of uninfected pleural fluid exudate after continuous or intermittent infusion; Byl B et al.; Blood and pleural exudate samples were obtained from 16 patients receiving intermittent or continuous infusions of vancomycin after lung surgery . The areas under the concentration-time curves for blood and pleural exudates were identical for both administration schedules, while continuous infusion allowed the concentrations in pleural exudates to be more sustained (mean concentration, 12 mg/liter).

Pharmazie, 2003 Apr, 58(4), 237 - 41
Synthesis, pharmacological activity and chromatographic separation of some novel potential beta-blockers of the aryloxyaminopropanol type; Cizmarikova R et al.; Following our previous structure-activity relationship studies, some novel compounds of the aryloxyaminopropanol type, derived from 2- or 4-hydroxyphenylalkanones, with phenethyl or 3,4-dimethoxyphenethyl groups in the hydrophilic part of the molecule were synthesized and pharmacologically evaluated . The compounds were prepared by means of two methods and their structures were confirmed by the interpretation of their IR, UV and 1H NMR spectra . The enantiomers were separated by HPLC on vancomycin (Chirobiotic V) and teicoplanin (Chirobiotic T) chiral stationary phases . The affinity of the prepared racemic compounds to beta1- and beta2-adrenergic receptors was pre-determined on isolated guinea pig atria and trachea . The assumed cardioselectivity was expressed as the beta1/beta2 ratio . Reciprocal changes in the position of the phenoxysubstituents did not influence the antiisoprenaline activity of the compounds . On the other hand, the increase of the N-substituent size in the hydrophilic part of molecule (3,4-dimethoxyphenethyl moietyled to a substantially higher affinity for cardiac (beta1) than for tracheal (beta2) tissue.

Pharmacotherapy, 2003 May, 23(5), 643 - 50
Mississippi mud no more: cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity; Darko W et al.; OBJECTIVE: To determine the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity . An analysis was performed for subpopulations of patients receiving nephrotoxic agents (aminoglycosides, amphotericin, and acyclovir), those in the intensive care unit, and those on the oncology service . METHODS: Decision analysis was used to model the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin . The reference case was determined, in part, by a retrospective review of 200 patients randomly selected from our clinical pharmacology consultation service . Patients were aged 18 years or older and had received intravenous vancomycin for at least 48 hours, with at least two--one peak and one trough--vancomycin serum concentrations obtained during therapy . Results of published clinical trials were used to determine the probability of vancomycin-induced nephrotoxicity . RESULTS: The mean cost of treating nephrotoxicity was 11,233 dollars at our institution . The mean cost for all patients was 25,166 dollars (sensitivity analysis 15,000-27,500 dollars)/nephrotoxic episode prevented . The subgroup analysis revealed a cost of 8,363 dollars (sensitivity analysis 4,368-10,500 dollars)/nephrotoxic episode prevented in intensive care patients, 5,000 dollars (sensitivity analysis 1,687-13,250 dollars ) in oncology patients, and a dominant strategy showing a cost savings of 5,564 dollars (sensitivity analysis 2,724-12,428 dollars) in those receiving concomitant nephrotoxins . CONCLUSION: Although pharmacokinetic monitoring and dosage adjustment are effective methods for reducing the toxicity of many drugs, controversy exists regarding the necessity of such monitoring with vancomycin . Evaluation by decision analysis over a range of assumptions, varying probabilities, and costs reveals that pharmacokinetic monitoring and vancomycin dosage adjustment to prevent nephrotoxicity are not cost-effective for all patients . However, such dosage adjustment demonstrates cost-effectiveness for patients receiving concomitant nephrotoxins, intensive care patients, and probably oncology patients.

Clin Pharmacokinet, 2003, 42(5), 403 - 17
Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates; Buck ML; Extracorporeal membrane oxygenation (ECMO) is a prolonged form of cardiopulmonary bypass used to support patients with life-threatening respiratory or cardiac failure . In neonates, ECMO is used for a variety of indications, including sepsis and pulmonary diseases such as meconium aspiration syndrome, persistent pulmonary hypertension or congenital diaphragmatic hernia . In recent years, ECMO has been increasingly used after surgery to correct congenital cardiac defects . Despite the need for numerous drugs to maintain the ECMO circuit and treat the patient's underlying illness, relatively little is known of the disposition of drugs in this patient population . To date, the largest number of pharmacokinetic studies have been conducted with gentamicin and vancomycin . Both drugs have been found to have an increased volume of distribution, probably as a result of the addition of a large exogenous blood volume for circuit priming . Elimination half-lives for both drugs are prolonged during ECMO, with several studies demonstrating a return to expected values after decannulation . The reason for this prolonged elimination is probably multifactorial, with a reduction in renal function as the primary determinant . This same pattern of an increased volume of distribution and prolonged elimination has been found for several other drugs, including tobramycin, bumetanide and ranitidine . Other factors that affect drug disposition during ECMO include loss of the drug from adhesion to the circuit components and loss in the circulating blood volume during changes in the equipment . The benzodiazepines and propofol are largely sequestered within the circuit . Serum concentrations of heparin, morphine, fentanyl, furosemide, phenytoin and phenobarbital are also reduced by these mechanisms . The addition of haemofiltration or dialysis in up to a quarter of ECMO patients further complicates the determination of population pharmacokinetic parameters . The literature published to date on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment; however, more research is needed to identify optimal administration strategies for this patient population.

J Am Acad Dermatol, 2003 May, 48(5 Suppl), S56 - 7
Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis; Dellavalle RP et al.; Vancomycin is the most frequent trigger of drug-induced linear IgA bullous dermatosis . We describe a fulminant case of linear IgA bullous dermatosis in a 74-year-old man who experienced skin sloughing of 90% of his body surface after receiving vancomycin.

Infez Med, 2002 Mar, 10(1), 21 - 4
{Role of prophylaxis for the prevention of wound infection in acoustic neuroma surgery}; Minola E et al.; Wound infection and secondary meningitis represent important complications for patients undergoing acoustic neuroma surgery . The aim of this paper is to evaluate the efficacy of a short-term protocol with vancomycin and netilmicin . We studied 434 patients submitted to acoustic neuroma surgery in the Otorhinolaryngology Division, A.O . Ospedali Riuniti di Bergamo, during the years 1987-1997 . The utility of this protocol was evaluated on the basis of the occurrence of infective episodes during the first ten-day follow-up.

Acc Chem Res, 2003 Apr, 36(4), 246 - 54
Peptido- and glycocalixarenes: playing with hydrogen bonds around hydrophobic cavities; Casnati A et al.; This Account reviews the synthesis, conformations, and supramolecular properties of calixarenes endowed with alpha-amino acids or peptides (Peptidocalixarenes) and carbohydrate units (Glycocalixarenes), with a major emphasis on calix{4}arenes functionalized on the aromatic nuclei (upper or wide rim) . Most properties of N-linked peptidocalix{4}arenes are found to be quite different from those of the corresponding C-linked derivatives . An interesting example is the tendency of C-linked peptidocalix{4}arenes to form self-assembled nanotubes in the solid state . In several cases the hydrogen bonding donor and acceptor groups of the amino acid residues and the cavity of cone calix{4}arenes act cooperatively in guest binding in nonpolar solvents but not in water, where hydrophobic interactions dominate . Upper-rim bridged peptidocalix{4}arenes act as vancomycin mimics being able to bind d-alanyl-d-alanine (d-Ala-d-Ala) residues . Glycocalix{4}arenes show the phenomenon of multivalency in their binding to specific lectins, and those bearing thiourea spacers between the calix{4}arene scaffold and the sugar units are able to bind aromatic carboxylates and phosphates, making them attractive as novel site specific drug delivery systems.

J Am Chem Soc, 2003 Apr 16, 125(15), 4534 - 40
Using bifunctional polymers presenting vancomycin and fluorescein groups to direct anti-fluorescein antibodies to self-assembled monolayers presenting d-alanine-d-alanine groups; Metallo SJ et al.; This paper describes the synthesis of bifunctional polyacrylamides containing pendant vancomycin (Van) and fluorescein groups, and the use of these polymers to direct antibodies against fluorescein to self-assembled monolayers (SAMs) presenting d-alanine-d-alanine (dAdA) groups . These polymers bind biospecifically to these SAMs via interactions between the dAdA and Van groups and serve as a molecular bridge between the anti-fluorescein antibodies and the SAM . The binding events were characterized using surface plasmon resonance spectroscopy and fluorescence microscopy . The paper demonstrates that polyvalent, biospecific, noncovalent interactions between a polymer and a surface can be used to tailor the properties of the surface in molecular recognition . It also represents a first step toward the design of polymers that direct arbitrarily chosen antibodies to the surfaces of cells.

J Am Chem Soc, 2003 Apr 16, 125(15), 4451 - 9
A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules; Lai CY et al.; An MCM-41 type mesoporous silica nanosphere-based (MSN) controlled-release delivery system has been synthesized and characterized using surface-derivatized cadmium sulfide (CdS) nanocrystals as chemically removable caps to encapsulate several pharmaceutical drug molecules and neurotransmitters inside the organically functionalized MSN mesoporous framework . We studied the stimuli-responsive release profiles of vancomycin- and adenosine triphosphate (ATP)-loaded MSN delivery systems by using disulfide bond-reducing molecules, such as dithiothreitol (DTT) and mercaptoethanol (ME), as release triggers . The biocompatibility and delivery efficiency of the MSN system with neuroglial cells (astrocytes) in vitro were demonstrated . In contrast to many current delivery systems, the molecules of interest were encapsulated inside the porous framework of the MSN not by adsorption or sol-gel types of entrapment but by capping the openings of the mesoporous channels with size-defined CdS nanoparticles to physically block the drugs/neurotransmitters of certain sizes from leaching out . We envision that this new MSN system could play a significant role in developing new generations of site-selective, controlled-release delivery nanodevices.

Pharmazie, 2003 Feb, 58(2), 108 - 10
Coupled column chromatography for separation and determination of enantiomers of phenylcarbamic acid derivatives in serum; Rojkovicova T et al.; Columns packed with vancomycin coupled to an achiral C18 column and beta-cyclodextrin were used for the separation and the determination of enantiomers of alkoxysubstituted esters of phenylcarbamic acid in blood serum . The method involves off-line SPE, the separation of the racemate on a reversed-phase stationary phase, and the separation of the enantiomers on a chiral stationary phase . The limit of detection was 1.0 microg/ml for the vancomycin column and 10.0 microg/ml for the beta-cyclodextrin column in standard solution . In vitro degradation studies of enantiomers demonstrated a difference in the concentation of the enantiomers after the treatment . It was found that the rate constants of R(-)- and S(+)-forms of enantiomers are not significantly different.

Ann Pharmacother, 2003 Mar, 37(3), 380 - 3
Possible captopril-induced toxic epidermal necrolysis; Alkurtass DA et al.; OBJECTIVE: To report a case of toxic epidermal necrolysis (TEN) possibly induced by captopril . CASE SUMMARY: An 11-week-old boy was referred to our hospital for tetrology of fallot surgical repair, performed on admission day 2 . On day 3, the patient developed third-degree heart block, necessitating pacemaker connection and oral theophylline 3 mg/kg 3 times daily . Captopril 1 mg orally twice daily, intravenous furosemide 7 mg every 12 hours, and oral aldactone 7 mg twice daily were started . On day 5, the patient developed scaling erythematous skin lesions . On day 7, his temperature spiked to 37.8 degrees C, and pus discharge from the pacing wire site was noticed . Intravenous vancomycin 80 mg 3 times daily and intravenous ceftazidime 200 mg 3 times daily were initiated . On the same day, captopril was discontinued because we suspected that it had induced the skin reaction . On day 15, the infant's skin problem progressed . The dermatologist diagnosed partial TEN . On that day, theophylline and furosemide were also discontinued . On day 16, the patient still had some blisters, but the skin started to show signs of healing, until complete healing occurred on day 22 . The infant was discharged on oral medications: furosemide 7 mg twice daily, aldactone 7 mg twice daily, and enalapril 0.1 mg twice daily . Three weeks later, he was followed up . No recurrences were observed . CONCLUSIONS: This case suggests captopril induces TEN when combined with other sulfonamide medications . An objective causality assessment revealed that the adverse drug event was possible . Although it is a rare complication, healthcare providers should be familiar with its potential to occur and take appropriate treatment and prevention measures.

Clin Infect Dis, 2003 Mar 15, 36(6), 759 - 65 Epub 2003 Mar 06.
Risk factors for postcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)-1-nitrosourea (Gliadel) wafer placement; McGovern PC et al.; Gliadel wafers (1,3-bis {2-chloroethyl}-1-nitrosourea; Guilford Pharmaceuticals) are approved for the treatment of malignant gliomas; however, the incidence of and risk factors associated with infection with respect to this new technology are unknown . We identified 32 patients who received Gliadel wafers from December 1996 through October 1999 . Nine patients (28%) developed >or=1 surgical site infection (SSI), which included 4 cases of brain abscess . All 3 patients who received vancomycin for surgical prophylaxis developed an SSI . In addition, multivariable analysis revealed an association between infection and a clinical diagnosis of depression . The National Nosocomial Infection Surveillance Surgical Site Index did not predict the onset of SSI after Gliadel wafer implantation . Patients who received a Gliadel wafer had a higher incidence of infection than previously has been reported, and additional studies are required to better quantify this risk and describe the epidemiology of such infections.

Am J Health Syst Pharm, 2003 Feb 1, 60(3), 260 - 5
Alteration of vancomycin pharmacokinetics during cardiopulmonary bypass in patients undergoing cardiac surgery; Ortega GM et al.; The alteration of vancomycin pharmacokinetics during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery was studied . Eighteen patients were enrolled in the study . Vancomycin (1 g) was intravenously infused one to two hours before surgery . Blood samples were taken before, during, and after CPB . Serum drug concentrations were determined by an automated fluorescence polarization immunoassay and adjusted, with a bayesian analysis, to a bi-compartmental model implemented in a pharmacokinetic system program . Serum creatinine, hematocrit, and plasma proteins were also measured before, during, and after CPB . During CPB, serum creatinine, hematocrit, and plasma protein values all decreased significantly (p < 0.05) . Serum vancomycin concentration also diminished abruptly with CPB (7.04 micrograms/mL; 95% confidence interval, 5.70-8.38 micrograms/mL) but increased moderately during the next 30 minutes, probably attributable to redistribution into plasma from tissue stores . Vancomycin's apparent volume of distribution showed an important increase during CPB (58.8%) (p < 0.0005), and its systemic clearance also increased significantly after CPB (19.7%) (p < 0.0005) . The decrease in serum vancomycin concentration seems mediated by the hemodilution associated with the pump prime volume . Vancomycin's mean +/- S.D . nadir serum concentration before the next dose was 7.13 +/- 2.1 micrograms/mL . In patients undergoing cardiac surgery and treated prophylactically with a 1-g preoperative i.v . dose of vancomycin, the onset of CPB was associated with a drop in serum vancomycin concentration.

Intensive Care Med, 2002 Nov, 28(11), 1664 - 7
Clearance of vancomycin during high-volume haemofiltration: impact of pre-dilution; Uchino S et al.; OBJECTIVE: To measure the sieving coefficient (SC) and clearance of vancomycin during high-volume haemofiltration (HVHF) and to evaluate the impact of different pre-dilution regimens on these variables . DESIGN AND SETTING: Prospective interventional study in the intensive care unit in a tertiary university hospital . PATIENTS: Seven patients with septic shock and multi-organ dysfunction . INTERVENTIONS: HVHF (6 l/h fluid exchange) was performed in septic shock patients using variable proportions of their replacement fluid in pre- and post-dilution mode . MEASUREMENTS AND RESULTS: Pre-filter, post-filter and ultrafiltrate vancomycin concentrations were measured simultaneously, and SC and clearance calculated . The measurements were repeated following each change in the proportion of pre-dilution fluid . SC steadily decreased as the proportion of pre-dilution decreased, changing from 0.76 in pure pre-dilution to 0.57 in pure post-dilution (p=0.0004) . Clearance, however, increased with decreasing pre-dilution fluid rate, from 53.9 ml/min at pure pre-dilution to 67.2 ml/min at 2 l/h pre-dilution with 4 l/h post-dilution . CONCLUSIONS: HVHF achieves high vancomycin clearances, which despite some deterioration in SC increase with the proportion of replacement fluid given post-filter . Clinicians applying HVHF need to be aware of such clearances to avoid inadequate vancomycin dosing and to adjust therapy according to variations in HVHF technique.

Int Orthop, 2003, 27(1), 53 - 5 Epub 2002 Aug 09.
In vitro release of vancomycin from vancomycin-loaded blood coated demineralised bone; Rhyu KH et al.; In vitro and in vivo studies have demonstrated the possibility that cancellous bone could be used as a carrier of antibiotics for local delivery . However, the release of antibiotics from the loaded cancellous bone is too rapid and uncertain . We hypothesised that demineralisation of cancellous bone would increase the amount of antibiotic adsorbed, and coating of the freeze-dried antibiotic-impregnated cancellous bone with bio-compatible material would prolong antibiotic release . Bovine cancellous bone blocks of equal size were demineralised using a 0.5 N HCl solution and loaded with vancomycin solution under vacuum . The loaded bone blocks were then freeze-dried . To obtain a bio-compatible coating, the vancomycin-impregnated bone blocks were soaked in fresh human venous blood for 3 h . The release of impregnated antibiotic from the bone blocks was evaluated in phosphate-buffered saline and foetal bovine serum . It was found that significantly larger amounts of vancomycin were adsorbed into the demineralised bone blocks than into the un-demineralised blocks . The blood coating was found to increase the duration of vancomycin release from the blocks . With demineralisation and blood coating, the blocks eluted vancomycin higher than therapeutic concentration for a 5-week period.

Anal Sci, 2003 Jan, 19(1), 111 - 5
The immunoassay of methotrexate by capillary electrophoresis with laser-induced fluorescence detection; Suzuki Y et al.; Immunoassay is widely employed as a highly sensitive, specific analytical method for hormones and drugs in biological samples . A technique utilizing capillary electrophoresis with laser-induced fluorescence detection was examined based on the reaction process of these immunoassays in order to develop a protocol characterized by high sensitivity and high speed . The conditions of the antigen-antibody reaction and capillary electrophoresis were variously examined using fluorescein-labeled methotrexate and the antibody of methotrexate . As a result, the immunoassay could be completed within a few minutes . Moreover, detection in the pg range could be accomplished . The sensitivity corresponded to that of radioimmunoassay . A simultaneous multi-component analysis of the immunoassay is also possible due to the high resolving power of capillary electrophoresis . In this study, the possibility of a simultaneous analysis of methotrexate and vancomycin was also investigated.

Analyst, 2002 Dec, 127(12), 1633 - 7
Competitive immunoassay for vancomycin using capillary electrophoresis with laser-induced fluorescence detection; Lam MT et al.; A competitive immunoassay using capillary electrophoresis with laser-induced fluorescence was developed for vancomycin . Capillary electrophoresis using a Tris-glycine running buffer provided adequate separation of the antibody-bound from the unbound fluorescent probe (tracer) in less than 4 min . Laser-induced fluorescence polarization (LIFP) provided high sensitivity detection and simultaneous monitoring of fluorescence intensity and polarization . A fluorescence polarization value of 0.30 confirmed the formation of the antibody-tracer complex . Calibration curves showed a working linear range of 2-3 orders of magnitude with a minimum detectable concentration of 0.98 ng mL(-1) (or 1.1 fg vancomycin) . Clinical samples obtained from patients undergoing vancomycin treatment were analyzed for vancomycin and the results correlated well with a standard immunoassay based on latex particle detection that was routinely used by a hospital laboratory . Only 1/10 of the reagents were needed as compared with the standard immunoassay.

J Pediatr, 2003 Jan, 142(1), 41 - 6
Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss; de Hoog M et al.; OBJECTIVE: To investigate the chance of detecting hearing loss with neonatal hearing screening in relation to exposure to tobramycin and vancomycin . STUDY DESIGN: Automated auditory brainstem response (A-ABR) hearing screening was performed in all neonates with at least one risk factor . Data on drug administration were abstracted from patient files . Exposure to these drugs was related to the result of hearing screening . In patients failing hearing screening, exposure to ototoxic medication was assessed in the light of other risk factors for hearing loss . RESULTS: Six hundred twenty-five patients were analyzed; 45 neonates failed hearing screening . Tobramycin, vancomycin, and furosemide were used in 508, 130, and 174 patients, respectively . Exposure to vancomycin, tobramycin, or furosemide or a combination, defined in terms of treatment duration, total dose, or serum concentrations of antibiotics, was not related to failure to pass A-ABR screening . Ototoxic medication was not the most probable risk factor in any of the patients with serum concentrations outside the therapeutic range . CONCLUSIONS: Routine therapeutic drug monitoring of vancomycin and tobramycin in neonates for ototoxicity reasons is not helpful in detecting patients at risk for clinically important hearing loss in the 2- to 4-kHz range . A longer period of audiometric follow-up is needed to determine any long-term effects.

Chem Biol, 2002 Dec, 9(12), 1305 - 14
Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides; Losey HC et al.; Analogs of the glycopeptide antibiotics vancomycin and teicoplanin with alterations in one or both sugar moieties of the disaccharide have been prepared by tandem action of the vancomycin pathway glycosyltransferases GtfE and GtfD . All four regioisomers (2-, 3-, 4-, 6-) of TDP-deoxyglucoses and UDP/TDP-aminoglucoses were prepared, predominantly by action of D-glucopyranosyl-1-phosphate thymidylyltransferase, E(p) . GtfE transferred the deoxyglucoses or aminoglucoses onto the 4-OH of 4-hydroxyphenylglycine of both the vancomycin and teicoplanin aglycone scaffolds . Kinetic analysis indicated the 2-, 3-, 4-, and 6-amino-glucoses were transferred by GtfE with only a 4- to 30-fold drop in k(cat) and no effect on K(m) compared to the native substrate, UDP/TDP-glucose, suggesting preparative utility . The next enzyme, GtfD, could utilize the variant glucosyl-peptides as substrates for transfer of L-4-epi-vancosamine . The aminosugar moieties in these variant glycopeptides introduce sites for acylation or reductive alkylation.

J Chromatogr A, 2002 Dec 6, 979(1-2), 191 - 9
Separation and enantioseparation of derivatized amino acids and biogenic amines by high-performance liquid chromatography with reversed and chiral stationary phases; Shpigun OA et al.; This study demonstrates that an amino-beta-cyclodextrin-bonded phase column exhibits enantioselectivity for various amino acid derivatives . Mixtures of methanol, acetonitrile, tetrahydrofuran or dioxan and triethylamine buffers (pH 4.0-7.0) were used as mobile phases . The effect of the mobile phase on the resolution process was studied by varying the mobile phase composition (type and percentage of organic modifiers, pH, and ionic strength of the buffer solution) . The 1-octanol-water partition coefficients are calculated and tabulated for 16 derivatized amino acids . The chromatographic data for 42 pairs of derivatized amino acids resolved on the amino-beta-cyclodextrin-bonded phase are summarised . The separation of adrenaline, noradrenaline and amphetamine on a novel vancomycin stationary phase is demonstrated.

Electrophoresis, 2002 Nov, 23(22-23), 4036 - 51
Chiral capillary electrophoresis-mass spectrometry: modes and applications; Shamsi SA; A review is presented to highlight several approaches for coupling capillary electrophoresis (CE) and electrospray ionization-mass spectrometry (ESI-MS) for analysis of chiral compounds . A short discussion of commercially available CE-MS instruments and interface design is followed by a detail review on various modes of chiral CE-MS . In general, for each CE-MS mode, the capabilities, applications and limitations for chiral analysis have been pointed out . The first mode, chiral capillary zone electrophoresis-mass spectrometry (CZE-MS) in which neutral derivatized cyclodextrins (CDs) are used is possible using either column coupling with voltage switching or a partial-filling technique (PFT) . However, some applications of direct coupling of CZE-MS mode are also reported . The second mode is a chiral electrokinetic chromatography-mass spectrometry (EKC-MS) in which a charged chiral selector such as a sulfated beta-CD or a vancomycin could be conveniently employed . This is because these chiral selectors have a significantly higher countercurrent electrophoretic mobility which prevents the entrance of these selectors into the mass spectrometer . The combination of counter-migration and PFT demonstrates that this synergism could be successfully applied to chiral analysis of a broader range of compounds . It is well-known that the on-line coupling of micellar electrokinetic chromatography to mass spectrometry (MEKC-MS) is problematic because the high surface activity and nonvolatile nature of conventional surfactant molecules lower the electrospray ionization efficiency . However, a recent report demonstrates that this hyphenation is now possible with the use of molecular micelles . Various MEKC-ESI-MS parameters that can be used to optimize both chiral resolution and ESI response are discussed . Finally, two recent examples that demonstrate the feasibility of using either open-tubular or packed chiral CEC with MS are reviewed . This survey will attempt to cover the state-of-the-art on various modes of CE-MS from 1998 up to 2002.

J Spinal Disord Tech, 2002 Dec, 15(6), 526 - 8
Pyogenic lumbar facet joint arthritis with intradural extension: a case report; Coscia MF et al.; There have been 40 previously reported cases of lumbar facet joint pyogenic infection . These have been well characterized earlier . Intradural pyogenic extension has never been reported from a facet joint origin . This case demonstrates an elderly diabetic man with acute onset of nontraumatic back pain with no other source of infectious pathology . Surgical exploration identified a purulent left L4-L5 facet joint with epidural and intradural extension . Minimal spinal fluid leak was present . Wound cultures were positive for Group B beta Full resolution occurred with appropriate intravenous vancomycin antibiotic therapy.

Int J Antimicrob Agents, 2002 Nov, 20(5), 326 - 32
TDM coupled with Bayesian forecasting should be considered an invaluable tool for optimizing vancomycin daily exposure in unstable critically ill patients; Pea F et al.; A randomized two-arm prospective study was planned to assess the role of therapeutic drug monitoring (TDM) coupled with a Bayesian approach in tailoring vancomycin dosages in unstable critically ill patients . Group A (n=16) had their regimen adjusted day-by-day according to TDM and Bayesian forecasting (D(a)); group B (n=16) had their regimen adjusted day-by-day according to Moellering's nomogram (D(M)) . Blood samples were collected every 1-2 days to assess the trough and peak plasma concentrations . In group A, the tailored D(a) required for optimizing vancomycin exposure were considerably higher than the D(M) in 7/16 cases, and lower than the D(M) in 1/16 cases . In group B, standard D(M) caused under-treatment in 3/16 cases and over-treatment in 4/16 cases . Most of these patients concomitantly had some conditions that might have altered vancomycin disposition . The TDM-guided Bayesian-based approach should be considered an invaluable tool for clinicians to handle appropriately on real-time vancomycin therapy in critically ill patients.

Biomaterials, 2003 Feb, 24(3), 443 - 9
Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone) microparticles for bone implantation . Influence of the formulation process on size, drug loading, in vitro release and cytocompatibility; Le Ray AM et al.; Vancomycin encapsulation in biodegradable poly(epsilon-caprolactone) microparticles (200 microm mean diameter) was most efficient with a simple emulsion technique that dispersed 122.5 mg/g of polymer . Scanning electron micrographs showed smooth or pitted particles . Dissolution studies were correlated with microparticle morphology, indicating higher release with pitted particles when vancomycin was encapsulated in a dissolved state . The cytocompatibility of these poly(epsilon-caprolactone) microparticles was demonstrated by a direct contact cytotoxic assay . This material can be considered as an efficient drug delivery system for bone implantation.

J Biomed Mater Res, 2002, 63(6), 807 - 13
In vivo release of vancomycin from biodegradable beads; Liu SJ et al.; The current delivery system of antibiotics for the treatment of osteomyelitis uses polymethylmethacrylate (PMMA) beads as a local drug-release agent . The nonbiodegradable nature of the PMMA, however, necessitates a second operation to remove the beads . This article explores the alternative of using biodegradable polymers as antibiotic beads for a long-term drug release in vivo . To manufacture an antibiotic bead, lactide-glycolide copolymers were mixed with vancomycin . The mixture was compressed and sintered at 55 degrees C to form beads 8 mm in diameter . An in vivo animal model was proposed to characterize the elution rate of antibiotic over a 55-day period . Biodegradable beads released high concentrations of antibiotic (well above the breakpoint sensitivity concentration) in vivo for the period of time needed to treat bone infection; that is, 4-6 weeks . A bacterial inhibition test was also carried out to determine the relative activity of the released antibiotics . The diameter of the sample inhibition zone ranged from 8 to 18 mm, which is equivalent to 9.1 to 100% of relative activity . In addition, the antibiotic concentration of systemic blood was found to be very low . Antibiotic-impregnated biodegradable beads may have a potential role in the prevention and management of surgical infections .

Anal Chem, 2002 Oct 15, 74(20), 5205 - 11
Vancomycin dimerization and chiral recognition studied by high-performance liquid chromatography; Slama I et al.; The retention and separation of D,L-dansylvaline enantiomers (used as test solutes) were investigated using silica gel as stationary phase and vancomycin as chiral mobile-phase additive . A retention model was developed to describe the mechanistic aspects of the interaction between solute and vancomycin in the chromatographic system . It considered the formation of vancomycin dimers both "free" in the mobile phase and adsorbed on silica . By fitting the model equation to experimental data, it appeared clearly that the approach taking into account the vancomycin dimerization described accurately the retention behavior of the compounds . The examination of the model equation parameters showed that the glycopeptide dimerization increased the enantioselectivity by a factor of approximately 3.7 . This study demonstrated the preponderant role of the vancomycin dimerization on the chiral recognition process of D,L-dansylvaline . Also, an additional analysis on a vancomycin chiral stationary phase indicated that the addition of vancomycin in the mobile phase promoted a greater enantioselectivity mediated by the formation of dimers in the stationary phase.

Biol Pharm Bull, 2002 Oct, 25(10), 1333 - 8
Evaluation of predictability for vancomycin dosage regimens by the Bayesian method with Japanese population pharmacokinetic parameters; Teramachi H et al.; The predictability of serum vancomycin (VCM) concentrations by means of the Bayesian method was evaluated to establish whether the method can be used to select safe and effective VCM treatment regimens for individual patients . Serum VCM concentrations at the trough and 2 h after the end of infusion (peak) were measured . Pharmacokinetic parameters were calculated for VCM dosage regimens based on a two-compartment model with the Bayesian method, using the Japanese population pharmacokinetic parameters estimated by Yasuhara et al . (1998) . The predictive performance for serum VCM concentrations and the dosage regimens were analyzed using two points of serum VCM concentration in 41 patients whose serum creatinine and age were in the ranges of 0.4-4.6 mg/dl and 24-92 years, respectively . Although the predicted values for trough and peak VCM concentrations were slightly lower than measured VCM concentrations, the predictive performance was generally good . There were no differences among the groups classified by serum creatinine or age . An examination of predicted data that differed markedly from the measured serum VCM concentrations indicated that a larger difference in volume of distribution at the steady state (Vdss) calculated from serum VCM concentrations at the beginning and revision of dosage regimens resulted in a poorer correlation of predicted values and measured values . This finding indicates that therapeutic drug monitoring should be conducted frequently, and the dosage regimen revised accordingly, in the case of patients who may have a change of Vdss of VCM, for example, due to a complication such as heart failure or edema.

Arch Dis Child Fetal Neonatal Ed, 2002 Nov, 87(3), F214 - 6
Dose regimen for vancomycin not needing serum peak levels?
Tan WH, Brown N, Kelsall AW, McClure RJ.
AIM: To determine the safety, efficacy, and need to measure peak serum vancomycin concentrations in a neonatal population using a standard vancomycin dosage regimen . METHOD: A total of 101 infants who were admitted to a regional neonatal intensive care unit and received vancomycin (15 mg/kg every 12 or 18 hours depending on postnatal age) were studied retrospectively . Infants who had been started on vancomycin before they were transferred to the unit were excluded . The proportion of infants was measured whose serum vancomycin concentrations were within a conservative therapeutic range of trough 5-10 mg/l, peak 20-40 mg/l, and a less conservative, but still safe, range of trough 5-12 mg/l, peak 15-60 mg/l . RESULTS: Trough concentrations of 5-10 mg/l were achieved by 46.5% of infants, and 5-12 mg/l by 55.4% . Peak concentrations of 20-40 mg/l were found in 83.2% of infants, and 15-60 mg/l in 99.0% . Highest peak concentration was 47.2 mg/l . Some 89.4% of infants with trough concentrations of 5-10 mg/l had a peak concentration of 20-40 mg/l . CONCLUSIONS: The vancomycin dosage regimen used in this study produces acceptable therapeutic serum vancomycin concentrations . Peak serum vancomycin concentrations do not need to be measured in neonates using this dosage regimen.

Acta Neurochir (Wien), 2002 Oct, 144(10), 989 - 95
Empirical treatment of adult postsurgical nosocomial meningitis; De Bels D et al.; BACKGROUND: The combination of cefotaxime and fosfomycin (CTX-FOS) has been proposed in France for the empirical treatment of postoperative nosocomial meningitis since the late 1980s . The purpose of this work was to evaluate this strategy today, as well as other possible treatments . METHODS: Each patient undergoing a neurosurgical procedure was prospectively included in a database designed for the surveillance of surgical site infection (SSI) . For each meningitis detected, we analysed the in vitro susceptibility of the causative micro-organisms to cefotaxime alone (CTX), cefotaxime-fosfomycin (CTX-FOS), vancomycin (VAN) and cefotaxime-vancomycin (CTX-VAN) combinations . The patient population was divided into two groups according to the presence or absence of CSF shunting material . FINDINGS: 116 patients had had a postoperative meningitis/ventriculitis during the last 36 months, among 6447 patients undergoing neurosurgery in our department (1.8%) . Ten patients had aseptic meningitis (8.6%) . Overall sensitivity to CTX was 69.8%, as compared to 77.3% with CTX-FOS combination (NS) . This result was due to a large proportion of fosfomycin resistant cocci in our population . The CTX-VAN combination increased the overall in vitro susceptibility up to 91.5%, but the benefit of this combination was only significant in CSF shunting material patients . In these latter patients, VAN was as effective as CTX-FOS combination . INTERPRETATION: CTX-FOS combination is no longer the best choice for empirical treatment of post neurosurgical meningitis . CTX alone can be safely used in patients without a CSF shunt; in those with either a ventriculostomy or a CSF shunt associated ventriculitis, a CTX-VAN combination could improve treatment efficacy, provided that high doses of vancomycin are used to ensure correct CSF diffusion.

J Biol Chem, 2002 Dec 6, 277(49), 47476 - 85 Epub 2002 Aug 30.
Crystal structure of OxyB, a cytochrome P450 implicated in an oxidative phenol coupling reaction during vancomycin biosynthesis; Zerbe K et al.; Gene-inactivation studies point to the involvement of OxyB in catalyzing the first oxidative phenol coupling reaction during glycopeptide antibiotic biosynthesis . The oxyB gene has been cloned and sequenced from the vancomycin producer Amycolatopsis orientalis, and the hemoprotein has been produced in Escherichia coli, crystallized, and its structure determined to 1.7-A resolution . OxyB gave UV-visible spectra characteristic of a P450-like hemoprotein in the low spin ferric state . After reduction to the ferrous state by dithionite or by spinach ferredoxin and ferredoxin reductase, the CO-ligated form gave a 450-nm peak in a UV-difference spectrum . Addition of putative heptapeptide substrates to resting OxyB produced type I changes to the UV spectrum, but no turnover was observed in the presence of ferredoxin and ferredoxin reductase, showing that either the peptides or the reduction system, or both, are insufficient to support a full catalytic cycle . OxyB exhibits the typical P450-fold, with helix L containing the signature sequence FGHGXHXCLG and Cys(347) being the proximal axial thiolate ligand of the heme iron . The structural similarity of OxyB is highest to P450nor, P450terp, CYP119, and P450eryF . In OxyB, the F and G helices are rotated out of the active site compared with P450nor, resulting in a much more open active site, consistent with the larger size of the presumed heptapeptide substrate.

Electrophoresis, 2002 Sep, 23(17), 3035 - 40
Enantioseparation of amino acid derivatives by capillary zone electrophoresis using vancomycin as chiral selector; Fanali S et al.; The separation of racemic derivatized amino acids (N-acetyl) into their enantiomers was achieved using capillary zone electrophoresis employing vancomycin as a chiral selector . Due to the strong absorption properties of the chiral selector at the low wavelengths used, the partial-filling countercurrent method was adopted in order to improve method sensitivity . In the separation system studied, the chiral selector filled only a part of the capillary and, due to the appropriate selection of the pH, was moving in the opposite direction of the analytes keeping the detector free from absorbing compounds . The effect of several experimental parameters on the enantioresolution of analytes was studied, e.g., vancomycin concentration (0-5 mM), pH of the background electrolyte (pH 4-7), capillary temperature (15-35 degrees C), and the presence of an organic modifier in the run buffer (methanol or ethanol or n-propanol) . N-Acetyl glutamic acid, serine, cystine, tyrosine, and proline were all baseline-resolved into their enantiomers and the enantioresolution factor (R(s)) was increased by raising the vancomycin concentration . pH 4 allowed the baseline resolution of the five studied analytes in the presence of 2.5 mM of chiral selector and an increase in pH caused a decrease of R(s).

J Infect, 2002 Aug, 45(2), 90 - 5
Vancomycin sequestration during cardiopulmonary bypass surgery; Krivoy N et al.; OBJECTIVE: The present study was designed to analyze vancomycin disposition in adult patients undergoing coronary bypass grafting during and following cardiopulmonary bypass (CPB) . METHODS: Coronary bypass surgery was performed on 11 adults with a mean age (SD) of 62.9 (9.0) years old, who received a mean (SD) vancomycin prophylactic dose of 12.7 (1.0) mg/kg in a mean period of 41 (0.7) min . Using a two-compartment open model for pharmacokinetic analysis, the following parameters were obtained: alpha half-life, minutes (t(1/2alpha)); beta half-life, hours (t(1/2beta)); apparent volume of distribution, (V(d) l/kg); volume of the central compartment, (V(c) l/kg), constant between the "central to the peripheral" compartment, (k(12)); constant between the "peripheral to the central" compartment, (k(21)); total area under the concentration-time curve, (AUC mg/lxh) and a vancomycin clearance, (Cl(van) ml/min), respectively . RESULTS: The mean (SD) calculated pharmacokinetic parameters were: t(1/2alpha)17.6 (6) min, t(1/2beta) 8.4 (3.8) h, V(d) 0.803 (0.259) l/kg, V(c) 0.270 (0.162) l/kg, k(12) 0.03 (0.015), k(21) 0.012 (0.012), total AUC 10377.2 (3687.6) mg/lxh . The mean (SD) vancomycin clearance by the CPB machine was 9.51 (2.66) l/h, and the mean (SD) total vancomycin sequestrated by CPB was 331.7 (84) mg . A significant difference (6.3%; p = 0.001) was measured between the mean measured AUC during CPB (1088.1 +/- 253.9) and the same calculated parameter (1160.2 +/- 282) . Five minutes after starting CPB, a decrease in vancomycin level was detected; this difference was found to be nearly 11% in absolute values . CONCLUSIONS: This confirmatory study demonstrated that the vancomycin blood concentrations obtained during the study allow recommending a safety prophylactic dose of 12mg/kg in adults who undergo open-heart surgery under CPB conditions . Sequestration of vancomycin by the oxygenator or/and tubing system of the CPB machine had occurred and had been measured in this study.

Braz J Infect Dis, 2002 Aug, 6(4), 196 - 200
Uncommon vancomycin-induced side effects; Rocha JL et al.; Vancomycin has been used with increased frequency during the past 15 years and the most common toxicity with this drug is the red man syndrome . Other adverse effects include neutropenia, fever, phlebitis, nephrotoxicity, ototoxicity, thrombocytopenia, interstitial nephritis, lacrimation, linear IgA bullous dermatosis, necrotizing cutaneous vasculitis and toxic epidermal necrolysis . Only two cases of vancomycin-induced Stevens-Johnson syndrome and one case of pancytopenia have been reported in the medical literature . The treatment for both situations is based on cessation of the vancomycin therapy; in cases of Stevens-Johnson syndrome, antihistamine and/or steroid agents can be used . This article reports a case of pancytopenia and a case of erythema major associated with neutropenia.

Nephrol Dial Transplant, 2002 Sep, 17(9), 1649 - 54
CAHP-210 dialyzer influence on intra-dialytic vancomycin removal; Lucksiri A et al.; BACKGROUND: Vancomycin is often administered during the last hour of haemodialysis because it was not removed significantly by older hemodialyzers . However, newer higher permeability hemodialyzers remove vancomycin, although the amount removed varies considerably between dialyzers . The purpose of this study was to determine the apparent amount of vancomycin removed during the last hour of haemodialysis with a CAHP-210 hemodialyzer . METHODS: Eight subjects with end-stage renal disease (ESRD) received i.v . vancomycin 15 mg/kg after their regular haemodialysis session ended . Serum samples for the determination of vancomycin concentrations were obtained serially for 44 h . After a 3-week washout, the study was repeated with the vancomycin infused during the last hour of their regular haemodialysis session using a CAHP-210 hemodialyzer . Vancomycin concentrations were determined by the Enzyme Multiplied Immunoassay Technique . Differential equations describing a two-compartment open infusion model were fitted to the serum concentration vs time data and pharmacokinetic parameters and apparent vancomycin removal was estimated . RESULTS: The median age and weight of the subjects were 52 years (range 37-71) and 75.6 kg (range 37.6-89.8), respectively . The apparent vancomycin intra-dialytic removal was 0.24 (range -0.07-0.35), which was statistically significantly different from zero . CONCLUSIONS: Vancomycin administered during the last hour of CAHP-210 dialysis results in 24% less vancomycin exposure than when administered post-haemodialysis . This intra-dialytic drug loss should be accounted for when dosing vancomycin in this manner.

Org Lett, 2002 Aug 22, 4(17), 2833 - 6
On the verge of axial chirality: atroposelective synthesis of the AB-biaryl fragment of vancomycin; Bringmann G et al.; {structure: see text} Using the "lactone concept", differently substituted AB-biaryl fragments (P)-2 (R = Me, t-Bu) of vancomycin have been synthesized atroposelectively . Their otherwise configurational instability was remedied by inclusion of two chlorine atoms in the B ring to give (M)-29 . Starting from a still configurationally unstable lactone-bridged precursor, we obtained this biaryl with high atroposelectivity (dr 94:6) by ring cleavage with dynamic kinetic diastereomeric resolution.

J Arthroplasty, 2002 Aug, 17(5), 619 - 26
The in vitro elution characteristics of vancomycin combined with imipenem-cilastatin in acrylic bone-cements: a pharmacokinetic study; Cerretani D et al.; The aim of this in vitro study was to compare the elution characteristics of vancomycin alone and in combination with imipenem-cilastatin from 3 acrylic bone-cements (CMW1 {DePuy International, Blackpool, UK}, Palacos R {Schering-Plough, Wehrheim, Germany}, and Simplex P {Howmedica International, London, UK}) . Six groups of 3 antibiotic-loaded cement disks were prepared, incorporating 2 g of vancomycin (3 groups) and 2 g of vancomycin plus 2 g of imipenem-cilastatin (3 groups) . The disks were placed in saline baths for 5 weeks, with the baths being sampled periodically and the elution rates calculated . The total amount of vancomycin released by the cements treated with vancomycin alone was 7.98 mg for CMW1, 7.74 mg for Palacos R, and 6.76 mg for Simplex P; with the addition of imipenem-cilastatin, the total amount of vancomycin released by the 3 cements increased by 30.58%, 50.52%, and 50.15% . CMW1 had better elution characteristics than the other cements when treated with vancomycin alone; the elution of Palacos R and Simplex P was better than that of CMW1 when vancomycin was combined with imipenem-cilastatin .

Pathol Res Pract, 2002, 198(6), 421 - 3
The effect of netilmicin and vancomycin on lipid peroxidation processes in cerebrospinal fluid in children with hydrocephalus; Radwanska-Wala B et al.; In biological systems, it is difficult to determine free radicals because of their reactivity and their very short time of existence . On the basis of markers, which come into being as a result of radical processes, one might believe that there exist reactive oxygen species . One of the determinants of free radical activity of oxygen is the presence of malondialdehyde (MDA), a final product of lipid peroxidation . This study aimed at finding the answer to the question whether the concentration of netylmicin and vancomycin influences the amount of substances reacting with thiobarbituric acid (TBA) in cerebrospinal fluid (CSF) in children with hydrocephalus . Applying the TBA test for examinations with antibiotics added both in vivo and in vitro, we could demonstrate that increased concentration of the examined antibiotics in cerebrospinal fluid reduces the amount of MDA . The results obtained demonstrate that products of lipid peroxidation are present in the CSF samples analyzed . In this study, we found that the concentration of vancomycin and netilmicin influenced the lipid peroxidation process in cerebrospinal fluid in children with hydrocephalus, thus confirming anti-inflammatory properties of the antibiotics applied.

Anal Biochem, 2002 Aug 1, 307(1), 84 - 91
Measuring antibody affinity and performing immunoassay at the single molecule level; Tetin SY et al.; Fluorescence correlation spectroscopy (FCS) enables direct observation of the translational diffusion of single fluorescent molecules in solution . When fluorescent hapten binds to antibody, analysis of FCS data yields the fractional amounts of free and bound hapten, allowing determination of the equilibrium binding constant . Equilibrium dissociation constants of anti-digoxin antibodies and corresponding fluorescein-labeled digoxigenin obtained by FCS and fluorescence polarization measurements are identical . It is also possible to follow a competitive displacement of the tracer from the antibody by unlabeled hapten using FCS in an immunoassay format . The fluorescence polarization immunoassay for vancomycin detection was used to test the FCS approach . Fitting of the FCS data for the molar fractions of free and bound fluorescein-labeled vancomycin yielded a calibration curve which could serve for determination of the vancomycin concentration in biological samples.

Crit Care, 2002 Jun, 6(3), 234 - 9 Epub 2002 Apr 25.
Pruritus: a useful sign for predicting the haemodynamic changes that occur following administration of vancomycin; Bertolissi M et al.; INTRODUCTION: The aim of this study was to investigate the haemodynamic changes that follow the appearance of pruritus during vancomycin administration . METHODS: We studied 50 patients scheduled for coronary artery bypass surgery, and we compared data from patients who exhibited pruritus with those from patients who did not . After the monitoring devices had been positioned, vancomycin (15 mg/kg) was continuously infused at a constant rate over 30 min, before induction of anaesthesia . Haemodynamic profiles were recorded before vancomycin infusion (time point 1); at 15 (time point 2) and 30 min (time point 3) after the beginning of vancomycin infusion; and 15 min after vancomycin infusion had been stopped (time point 4) . At each time arterial and mixed venous blood samples were drawn to calculate the shunt fraction (Qsp/Qt) . RESULTS: In patients who exhibited pruritus (group A, n = 17) at time point 3 versus time point 1, systemic vascular resistance index (SVRI) and arterial oxygen tension (PaO2) decreased significantly; cardiac index (CI), stroke volume index (SVI) and Qsp/Qt increased significantly; and mean systemic pressure and heart rate were stable . Those changes were observed only in patients not treated with a beta-blocker before surgery, whereas no change occurred in patients treated with the drug . In the patients who were free from pruritus (group B, n = 28), we did not observe any significant change . CONCLUSION: The appearance of pruritus during vancomycin administration indicates that SVRI is declining, thus exposing the patient to risk for hypotension . Therapy with a beta-blocker appears to confer protection against this hemodynamic reaction.

J Pharm Biomed Anal, 2002 Aug 1, 29(6), 989 - 97
An experimental design methodology applied to the enantioseparation of a non-steroidal anti-inflammatory drug candidate; Ficarra R et al.; An experimental design methodology has been applied to the enantioseparation of a new synthesized aryl propionic acid of pharmaceutical interest, namely 2-{(4'-benzoyloxy-2'-hydroxy)phenyl-propionic acid} (DF-1770y) by chiral capillary zone electrophoresis (CCZE) . The chiral separation of the studied compound has been achieved employing vancomycin as the chiral selector . The partial filling-counter current method has been used in order to avoid the presence of the absorbing chiral selector in the path length of the detector and to increase the method sensitivity . A central composite design has been employed to optimize the experimental conditions for a fast separation of the enantiomers of the new synthesized aryl propionic acid . Critical parameters such as chiral selector concentration, pH and temperature have been studied to evaluate how they affected responses such as resolution and migration times . The desirability function approach has been employed in order to find the best compromise between the different experimental responses . The proposed CCZE method provided the baseline enantioseparation of the investigated drug . A Britton-Robinson buffer at pH 6.4 supplemented with 7 mM of vancomycin at 22 degrees C and -20 kV were the optimum experimental conditions allowing to achieve the highest enantioresolution of DF-1770y in less than 8.5 min.

Nephrol Dial Transplant, 2002, 17 Suppl 5, 2 - 7
Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anaemia?
Eschbach JW, Varma A, Stivelman JC.
An increasing number of reports documenting resistance to human recombinant erythropoietin (rHuEPO) therapy are challenging the concept that erythropoietin deficiency is the main cause of the anaemia of chronic kidney disease (CKD) . In an attempt to establish whether other factors play a more predominant role in the anaemia of CKD, 988 patients receiving dialysis were assessed for a wide range of variables . Data were collected on haematocrit (Hct) levels, rHuEPO dose, dry weight, serum ferritin, transferrin saturation, serum albumin, serum aluminium, serum parathyroid hormone intact, eKt/V for urea, gender, dose of i.v . iron administered, time in hospital, and use of i.v . vancomycin . Hyporesponsiveness to rHuEPO was defined as patients requiring >500 IU/kg/week or failing to achieve Hct levels of >30% . Ninety-two (9.2%) of the 988 patients met the above criteria for hyporesponsiveness to rHuEPO . In 21 of these patients, Hct concentrations remained <30% at 6-month follow-up . There were known haematological causes of refractoriness to rHuEPO in nine of these patients . During extended follow-up, probable causes of hyporesponsiveness were discovered in all but two of the remaining 13 patients . Of 62 dialysis patients who received rHuEPO at doses >500 IU/kg/week, 45 (73%) had Hct concentrations of 33-42% . These patients were responding to the higher doses of rHuEPO with no obvious adverse effects . Lower values of serum ferritin, transferrin saturation, and eKt/V, or higher levels of parathyroid hormone or serum aluminium were not associated with higher rHuEPO dose requirements . These results suggest that erythropoietin deficiency is still the main cause of the anaemia of CKD . Erythropoietin replacement therapy can correct the anaemia in almost all iron replete patients providing enough hormone is given, functional iron deficiency is avoided, aluminium levels and parathyroid toxicities are controlled and that no de novo haematological condition that affects erythropoiesis or red blood cell survival develops . Consideration should be given to modifying the definition of rHuEPO hyporesponsiveness . The US Hct target of 33-36% for haemodialysis patients is narrow and the European target of Hct >33% may be significantly more practical and physiologically relevant.

Acta Orthop Scand, 2002 Apr, 73(2), 199 - 205
Release of netilmicin and vancomycin from cancellous bone; Witso E et al.; First, we studied the effect of the following variables used for netilmicin- and vancomycin-impregnation of cancellous bone: a) antibiotic concentration of the impregnation fluid, b) time used for impregnation, c) pH of the impregnation fluid, d) the degree of bone morselizing and e) antibiotic combination . An increase in the antibiotic concentration of the impregnation fluid increased the amount of antibiotics released from bone . In addition, the amount of vancomycin eluted was also dependent on the time used for impregnation . The fraction of the total amount of netilmicin and vancomycin released after 24 h was 80% and 30%, respectively . More netilmicin and vancomycin were eluted from bone impregnated with antibiotics at pH 7 than the amount eluted from bone impregnated at pH 3 . More netilmicin was eluted from fine morselized bone than from coarse morselized bone . By combining netilmicin and vancomycin in the impregnation fluid, the release of vancomycin was reduced . Secondly, we analyzed if the release of antibiotics from bone was complete: 99.9% of the total amount of netilmicin adsorbed to the bone was released by elution during 6 weeks . Finally, after implantation of netilmicin-impregnated bone in rabbit femur condyle, we measured netilmicin and vancomycin in serum: peak serum values of netilmicin were 4.2 (3.7-4.7) mg/L 2-3 h postoperatively.

Ann Fr Anesth Reanim, 2002 May, 21(5), 414 - 7
{The use of glycopeptides in intensive care and anaesthesia}; Gauzit R; Club d'infectiologie en anesthesie-reanimation; With the objective of clarifying the modes of using glycopeptides in intensive care, a survey with a declared intention was performed in June 2001, in the form of a postal questionnaire; it was possible to exploit 742 answers . Analysis of the results showed that 15% of the doctors completing the questionnaire had not employed glycopeptides within the past six months . Preference was given to vancomycin, and 65% of practitioners prescribed this drug only, while 1% of them only prescribed teicoplanin . For vancomycin, a central route is used in 9 out of 10 cases, with a preference for continuous infusion (69% versus 48%) . A loading dose is prescribed in 70% of continuous infusions (> or = 15 mg.kg-1 in 69% of cases), and in 19% of intermittent infusions (> or = 15 mg.kg-1 in 90% of cases) . The mean vancomycin dosage is 30 mg.kg-1.d-1; in the case of intermittent administration this involves two (51%), three (17%) or four (27%) injections per day . The target concentrations are residual serum vancomycin levels of between 13.5 and 23.6 mg.L-1 with intermittent administration or plateau levels of 18.3 to 29.4 mg.L-1 with continuous infusion . Teicoplanin is administered intravenously (92%) and/or via the i.m . route (34%) . The mean dosage is < 10 mg.kg-1.d-1 in seven out of ten cases . A loading dose is administered every 12 hours at the same dosage in 77% of cases (< or = 3 injections for 65% of prescribers) . The residual teicoplanin concentrations sought are between 14.3 and 25 mg.L-1 . Monitoring of serum levels is ensured at least once a week in 97% of cases with vancomycin and 66% of cases with teicoplanin . In conclusion, is seems that the methods of using glycopeptides vary considerably . The great heterogeneity of practices suggests a lack of compliance by prescribing practitioners with current recommendations . It also seems that a precise definition of the target plasma levels to be achieved in different indications is necessary.

Anal Biochem, 2002 Jul 1, 306(1), 17 - 22
A multitarget assay for inhibitors of membrane-associated steps of peptidoglycan biosynthesis; Barbosa MD et al.; Peptidoglycan synthesis begins in the cytoplasm with the condensation of UDP-N-acetyl glucosamine (UDP-GlcNAc) and phosphoenolpyruvate catalyzed by UDP-N-acetylglucosamine enolpyruvoyl transferase . UDP-GlcNAc is also utilized as substrate for the glycosyltransferase MurG, a membrane-bound enzyme that catalyzes the production of lipid II . Membranes from Escherichia coli cells overproducing MurG support peptidoglycan formation at a rate approximately fivefold faster than membranes containing wild-type levels of MurG . Conditions have been optimized for the production of large amounts of membranes with increased levels of MurG, allowing the development of an assay suitable for high-throughput screening of large compound libraries . The quality of the purified membranes was assessed by electron microscopy and also by testing cross-linked peptidoglycan production . Moreover, kinetic studies allowed the determination of optimal concentrations of the substrates and membranes to be utilized for maximum sensitivity of the assay . Using a 96-well assay format, the IC50 values for vancomycin, tunicamycin, flavomycin, and bacitracin were 1.1 microM, 0.01 microg/ml, 0.03 microg/ml, and 0.7 microg/ml, respectively.

J Chromatogr A, 2002 Apr 26, 955(1), 53 - 69
Separation of chiral sulfoxides by liquid chromatography using macrocyclic glycopeptide chiral stationary phases; Berthod A et al.; A set of 42 chiral compounds containing stereogenic sulfur was prepared . There were 31 chiral sulfoxide compounds, three tosylated sulfilimines and eight sulfinate esters . The separations were done using five different macrocyclic glycopeptide chiral stationary phases (CSPs), namely ristocetin A, teicoplanin, teicoplanin aglycone (TAG), vancomycin and vancomycin aglycone (VAG) and seven eluents, three normal-phase mobile phases, two reversed phases and two polar organic mobile phases . Altogether the macrocyclic glycopeptide CSPs were able to separate the whole set of the 34 sulfoxide enantiomers and tosylated derivatives . Five of the eight sulfinate esters were also separated . The teicoplanin and TAG CSPs were the most effective CSPs able to resolve 35 and 33 of the 42 compounds . The three other CSPs each were able to resolve more than 27 compounds . The normal-phase mode was the most effective followed by the reversed-phase mode with methanol-water mobile phases . Few of these compounds could be separated in the polar organic mode with 100% methanol mobile phases . Acetonitrile was also not a good solvent for the resolution of enantiomers of sulfur-containing compounds, neither in the reversed-phase nor in the polar organic mode . The structure of the chiral molecules was compared to the enantioselectivity factors obtained with the teicoplanin and TAG CSP . It is shown that the polarity, volume and shape of the sulfoxide substituents influence the solute enantioselectivity factor . Changing the oxidation state of the sulfur atom from sulfoxides to sulfinate esters is detrimental to the compound's enantioselectivity . The enantiomeric retention order on the teicoplanin and TAG CSPs was very consistent: the (S)-(+)-sulfoxide enantiomer was always the less retained enantiomer . In contrast, the (R)-(-)-enantiomer was less retained by the ristocetin A, vancomycin and vancomycin aglycone columns, showing the complementarity of these CSPs . The macrocyclic glycopeptide CSPs provided broad selectivity and effective separations of chiral sulfoxides.

Arch Pharm (Weinheim), 2002 Mar, 335(2-3), 89 - 93
Hydrogels formed by crosslinked poly(vinyl alcohol) as sustained drug delivery systems; Orienti I et al.; Poly(vinyl alcohol) was crosslinked with ethylene glycol diglycidyl ether to obtain hydrogel-forming polymers . The polymers were also substituted with oleoyl chloride, providing hydrogels with weak solubility . These new polymeric materials were evaluated for the formulation of sustained drug delivery systems . Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract . Spray-dried mixtures of the drug and the polymer {at 1:4 and 1:8 (w:w) ratios} were prepared and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, 7.4, and 8.0 . The results indicated that the crosslinked polymers slowed down the release of the drugs with respect to the pure drug at each pH . The degree of crosslinking of ethylene glycol diglycidyl ether and the extent of substitution with oleoyl chloride were found to influence drug release.

Oral Microbiol Immunol, 2002 Jun, 17(3), 137 - 42
Actinobacillus actinomycetemcomitans in a rural adult population in southern Thailand; Dahlen G et al.; The prevalence of Actinobacillus actinomycetemcomitans isolates was examined in a rural population of southern Thailand . Sixty individuals aged 30-39 and 50-59 years were randomly selected from a group of 363 persons, living in four villages, who had been clinically examined previously . A subgingival plaque sample was taken with a curette from the mesial aspect of the two upper and lower first molars . Each sample was dispersed in 3.3 ml of VMGA III transport medium and spread onto Trypticase Soy Broth with Bacitracin and Vancomycin (TSBV)-agar plates on the same day . After incubation in 10% CO2 for 5 days the plates were examined for typical A . actinomycetemcomitans colonies which were tested for catalase activity . Each strain was further tested for biochemical characteristics, serotyped against serotype-specific antisera a-e and ribotyped after DNA digestion using the restriction endonucleases HindIII and EcoRI . For 53 (88%) of the 60 individuals, A . actinomycetemcomitans was present in at least one subgingival sample, which is considerably higher than the prevalence in Western European adults . In 11 individuals, two or three different strains were found . Serotypes a and c were the most prevalent, and serotype b was found only once among 46 tested isolates . Eleven ribotypes were found among the 46 strains . While the same ribotype could be found among individuals of the same village, no ribotype of A . actinomycetemcomitans was unique for individuals of any one village . The study demonstrated a high prevalence of A . actinomycetemcomitans among adults of the rural population of southern Thailand and indicates that this species is present as part of the resident oral flora in this population.

Curr Opin Chem Biol, 2002 Jun, 6(3), 289 - 96
Combinatorial carbohydrate chemistry; Marcaurelle LA et al.; The application of combinatorial chemistry to the synthesis of carbohydrate-based compound collections has received increased attention in recent years . New strategies for the solution-phase synthesis of oligosaccharide libraries have been reported, and the use of monosaccharides as scaffolds in the generation of combinatorial libraries has been described . Novel approaches to the assembly of carbohydrate-based antibiotics, such as aminoglycoside analogs and vancomycin derivatives, have also been disclosed.

Am J Med Sci, 2002 May, 323(5), 273 - 8
Bullous skin disease: an unusual allergic reaction to vancomycin; Neughebauer BI et al.; Severe reactions due to vancomycin are uncommon . We describe a case of vancomycin-induced linear immunoglobulin A bullous disease and review the literature pertinent to this entity . This is a rare subepidermal blistering disorder, with a heterogenous clinical presentation . It is characterized by IgA deposition in a linear pattern along the basement membrane zone . It seems to be autoantibody-mediated and is not dose-dependent . Spontaneous and complete skin healing follows vancomycin withdrawal; rechallenge reproduces the disease with a more rapid and severe onset . Because vancomycin is almost never suspected to be the cause of such manifestations, awareness of this rare autoimmune reaction is crucial . Early diagnosis through direct immunofluorescence of the perilesional skin would avoid unnecessary laboratory investigations and therapeutic measures and would shorten significantly the pain and suffering of these patients.

J Chromatogr B Analyt Technol Biomed Life Sci, 2002 Apr 25, 770(1-2), 63 - 9
Study of the stability of promethazine enantiomers by liquid chromatography using a vancomycin-bonded chiral stationary phase; Bosakova Z et al.; Three chiral stationary phases based on macrocyclic antibiotics (teicoplanin, vancomycin and ristocetin A) have been tested for chiral separations of promethazine . The vancomycin phase permits the best, baseline enantioseparation of promethazine, with a mobile phase of a 80:20 (v/v) mixture of methanol with a 1% aqueous triethylamine acetate buffer of pH 4.1 and with the analysis time not exceeding 15 min . The limits of detection amount to 27.5 and 31.0 ng/ml for the earlier and later eluting enantiomers, respectively . This separation system, that also permits a sufficient resolution between the promethazine enantiomers and their degradation products, has further been used for the monitoring of the effects of light, temperature and the promethazine concentration in solution on the stability of methanolic promethazine solutions over a period of 19 days . It has been found that the stability of more concentrated solutions is primarily affected by the temperature, whereas the effects of the temperature and light are comparable with more dilute solutions . After 19 days, a solution of 0.5 mg/ml promethazine stored in darkness at a low temperature still contained 84.0% of the original amount of the enantiomers; this value was 89.6% for a solution with the ten times lower promethazine concentration . If the solutions were stored in darkness but at laboratory temperature, the respective values decreased to 38.1 and 62.6% and for the solutions exposed to light at laboratory temperature they decreased even more to 36.7 and 52.6% of the initial promethazine amount.

Arch Pharm (Weinheim), 2002 May, 335(2), 89 - 93
Hydrogels Formed by Crosslinked Poly(vinyl alcohol) as Sustained Drug Delivery Systems; Orienti I et al.; Poly(vinyl alcohol) was crosslinked with ethylene glycol diglycidyl ether to obtain hydrogel-forming polymers . The polymers were also substituted with oleoyl chloride, providing hydrogels with weak solubility.These new polymeric materials were evaluated for the formulation of sustained drug delivery systems . Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract . Spray-dried mixtures of the drug and the polymer {at 1:4 and 1:8 (w:w) ratios} were prepared and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, 7.4, and 8.0 . The results indicated that the crosslinked polymers slowed down the release of the drugs with respect to the pure drug at each pH.The degree of crosslinking of ethylene glycol diglycidyl ether and the extent of substitution with oleoyl chloride were found to influence drug release.

J Am Acad Dermatol, 2002 May, 46(5 Suppl), S161 - 4
Drug-induced epidermolysis bullosa acquisita with antibodies to type VII collagen; Delbaldo C et al.; We describe a 73-year-old patient who had a subepidermal bullous eruption develop after a course of antibiotics, including vancomycin . The patient had deposits of IgA and IgG in the cutaneous basement membrane zone that were located on the dermal side of 1 M NaCl-treated autologous skin . By an enzyme-linked immunosorbent assay, the patient was found to have circulating IgG antibodies directed against type VII collagen, the target antigen of epidermolysis bullosa acquisita . Our observation expands the spectrum of immune-mediated subepidermal bullous skin eruptions precipitated by drugs and lends support to the idea that a subset of these cases represents an unusual variant of drug-triggered epidermolysis bullosa acquisita.

J Control Release, 2002 May 17, 81(1-2), 25 - 32
Elucidation of the mechanism of incorporation of insulin in controlled release systems based on complexation polymers; Morishita M et al.; The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) microparticles as a function of copolymer composition . These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral/basic environments . The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%) . Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions . In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral/basic media . In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluorescein-isothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs . The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin . Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin . The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution . On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles . These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.

J Clin Microbiol, 2002 May, 40(5), 1783 - 90
Application of the C(18)-carboxypropylbetaine specimen processing method to recovery of Mycobacterium avium subsp . paratuberculosis from ruminant tissue specimens; Thornton CG et al.; The causative agent of Johne's disease is Mycobacterium avium subsp . paratuberculosis . This is a chronic, debilitating gastrointestinal disorder that affects ruminants and is responsible for significant economic loss . The specimen processing method that combines C(18)-carboxypropylbetaine (CB-18) treatment and lytic enzyme decontamination has been shown to improve the diagnosis of mycobacterioses . This processing method was applied to the isolation of M . avium subsp . paratuberculosis from ruminant tissue samples . The BACTEC 12B liquid culture system was used but was supplemented with 1% egg yolk emulsion, 4 microg of mycobactin J, and 0.5% pyruvate (12B/EMP) for use in conjunction with this method . The final concentration of antibiotics used was 10 microg of vancomycin, 30 microg of amphotericin B, and 20 microg of nalidixic acid (VAN) per ml . A 7H10-based solid medium was also used that included mycobactin J, pyruvate, and VAN but excluded the egg yolk emulsion (7H10/MPV) . Several M . avium subsp . paratuberculosis isolates were examined during the evaluation of this processing method . It was observed that treatment with lytic enzymes stimulated the growth of M . avium subsp . paratuberculosis; however, the growth of one isolate was markedly inhibited due to the presence of vancomycin . Subsequently, the vancomycin concentration in the VAN formulation was reduced to 2 microg/ml . A blinded panel of 60 previously characterized tissue samples from bovine and bison were then processed and analyzed by smear and culture . Historically, 31 and 37 specimens were classified as positive by histology and culture, respectively . The overall sensitivity and specificity of smear relative to culture following CB-18 processing were 97.6 and 89.5%, respectively . The 12B/EMP/VAN liquid culture system recovered M . avium subsp . paratuberculosis from 39 specimens, whereas 7H10/MPV and Herrold's egg yolk media recovered M . avium subsp . paratuberculosis from 26 and 16 specimens, respectively . The average times to positive were 7.4 +/- 8.3, 29.9 +/- 2.6, and 24 +/- 0 days, respectively . The contamination rates were 4.8, 22.6, and 20.0%, respectively.

Pharmacoepidemiol Drug Saf, 2001 Dec, 10(7), 601 - 5
Ethical issues in a Brazilian hospital; de Castro MS et al.; PURPOSE: The objective of this paper is to discuss ethical issues such as data protection, confidentiality, and patient freedom taking two ongoing studies as examples . METHODS: The two studies are being carried out at a public hospital in southern Brazil . Study 1 evaluates inadequate use of drugs (mainly vancomycin) and aims at reviewing criteria for drug use control . It includes records of 100 patients whose prescriptions are dispensed at the hospital's pharmacy . A major ethical concern in this study was to ensure data confidentiality . Study 2 evaluates treatment adherence by hypertension patients with a focus on hydrochlorothiazide . Here, in addition to data protection, a major ethical concern was the ability of patients to understand the informed consent form and therefore freely enter or refuse to enter the study . Both projects were approved by the Institutional Review Board at Hospital de Clinicas de Porto Alegre . RESULTS: In both studies, data confidentiality is ensured by the removal of all personal information from the forms used for data analysis . In Study 2, readability of the informed consent was considered adequate by the IRB for the population served by the clinic, and one-third of the patients who were contacted agreed to participate in the study . CONCLUSIONS: To obtain reliable results, basic ethical principles must be observed throughout the planning and execution of research projects, whether data are obtained from medical records or from actual interaction with patients . Thus, monitoring by an Institutional Review Board or equivalent is of paramount importance.

Yakugaku Zasshi, 2002 Apr, 122(4), 269 - 75
Clinical estimation of vancomycin measurement method on hemodialysis patient; Tanaka M et al.; The fluorescence polarization immunoassay (FPIA) method is used to perform measurement of vancomycin hydrochloride (VCM) at many institutions . However, the values measured by the FPIA method are more vulnerable to overestimation than the high performance liquid chromatography (HPLC) method . In particular, it was not reported to perform exact therapeutic drug monitoring (TDM) measurement . Since overestimation is likely in patients with renal dysfunction, the HPLC method is preferable for TDM measurement . This study investigates the clinical conditions that lead to overestimation in the FPIA method, paying attention to the relation of clinical laboratory data inspection values and the existence of hemodialysis (HD) . Overestimation in the evaluation of TDM using the FPIA method was clinically examined with 116 serum samples obtained from 18 cases medicated with VCM . The relevance between overestimation of patients who had not had HD performed was 72.7 +/- 61.7% (means +/- SD) . In short, the overestimation was greatest in HD patients . Since overestimation did not affect the evaluation of clinical TDM, such as an effect and a side-effect, the TDM of VCM was shown to be satisfactorily evaluated by the simple FPIA method.

Bioorg Med Chem Lett, 2002 Mar 25, 12(6), 861 - 4
Antibody-catalyzed cleavage of the D-Ala-D-Lac depsipeptide: an immunological approach to the problem of vancomycin resistance; Isomura S et al.; Vancomycin resistance is currently a major healthcare problem . The development of a catalytic monoclonal antibody (mAb) that hydrolyzes the D-Ala-D-Lac depsipeptide provides a potentially novel antibiotic strategy . A phosphonate hapten design was used to program antibody catalysis . The characteristics of the hapten were shown to be important for obtaining a viable immune response and several catalytic mAbs that cleave a peptidoglycan model substrate . The best mAb afforded a >500-fold rate enhancement over background.

J Biomed Mater Res, 2002 Jun 5, 60(3), 360 - 7
In vitro behavior of albumin-loaded carbonate hydroxyapatite gel; Barralet JE et al.; Hydroxyapatite (HA) powder, porous HA, plasma-sprayed HA, apatite cements, and sintered HA have all been investigated as delivery systems for compounds such as human growth hormone and vancomycin . However, many previous studies showed that the period of release was limited to 2-3 weeks . The concept of using a nanoporous matrix as a means of immobilizing proteins is well known but has largely been confined to silica-based systems . Carbonate hydroxyapatite (CHA) is more soluble in vivo than HA, and when formed as an aqueous precipitate, it is often formed as nanocrystals . This study investigated the release profiles of ovine albumin (OVA) from CHA gel stored in phosphate-buffered saline (PBS) and double distilled water (DDW) for times of up to 1 year . It was found that 7.9% OVA could be loaded onto apatitic gels by means of a purely aqueous process . This process provided a simple low-temperature method of protein adsorption on a high surface area apatitic matrix at physiological pH . The rate of short-term release of OVA was lower from CHA gels than from microcrystalline HA powder . However, the period of release from the CHA gel was short term and may have been associated with recrystallization of the gel . OVA loaded into CHA gel was found to remain undegraded in vitro at 37 degrees C for periods of up to 1 year .

Clin J Oncol Nurs, 2001 Nov-Dec, 5(6), 279 - 80
Management of a widely disseminated skin rash; Gallagher E; T.J.'s case was interesting from the standpoint of both diagnosis and management . The recommended treatment for this drug reaction was prednisone: however, the use of a steroid in a patient who is neutropenic and has a fever is risky because the because the steroid can mask the symptoms of infection (e.g., fever) . Administration of prednisone did help, and the patient experienced a rapid resolution of the skin rash . T.J . will need to avoid the use of these antibiotic agents in the future . Because it is unknown which antibiotic, vancomycin or ceftazidime, caused the allergic reaction, both medicines should be avoided . The decision to rechallenge a patient with a specific drug must be made on an individual basis . Rechallenging of a drug in patients who have had urticarial, bullous, or erythema multiforme-like eruptions can be very dangerous (Padial et al., 2000) . Pinpointing the cause of a skin rash can be puzzling . Always ask the patient "Do you take any medicine for any condition (including aspirin, laxatives, vitamins, etc.)? Have you received any shots any shots in the last month?" Keep in mind that any chemical that is ingested can cause a cutaneous drug eruption.

Ann Oncol, 2002 Feb, 13(2), 327 - 30
Significant impairment of high-dose methotrexate clearance following vancomycin administration in the absence of overt renal impairment; Blum R et al.; BACKGROUND: Methotrexate is an antimetabolite cytotoxic drug which is predominantly renally excreted . Vancomycin, a glycopeptide antibiotic that is used in the febrile neutropaenic patient, can be nephrotoxic . There are no previous reports of any interactions between these two drugs . PATIENTS AND METHODS: We describe two patients with osteosarcoma treated with high-dose methotrexate-containing chemotherapy who had significantly delayed methotrexate clearance several weeks following exposure to vancomycin . RESULTS: These patients were treated with alternating chemotherapy consisting of 12 g/m2 methotrexate, 60 mg/m2 cisplatin, 75 mg/m2 adriamycin and 15 g/m2 ifosfamide . In both patients, serum methotrexate levels fell to below 0.2 micromol/l within 48-96 h during initial treatment cycles . However, following recent exposure to therapeutic vancomycin in the preceding 10 days and in the absence of overt renal impairment, both patients manifested markedly prolonged methotrexate clearance, requiring 170-231 h to reach serum levels of less than 0.2 microM . Subclinical renal impairment was documented by impaired glomerular filtration rates in both cases by technetium 99 m diethylene triamine penta-acetic acid scanning . Subsequent methotrexate cycles using an unmodified schedule were cleared within 72 h . Both cases had their glomerular filtration rate re-assessed, which showed marked improvement . CONCLUSIONS: Recent exposure to vancomycin, even in the absence of overt renal impairment, may adversely affect methotrexate excretion, which can subsequently lead to increased toxicity of the antimetabolite . The glomerular filtration rate should be measured in such cases so that appropriate dose modification of methotrexate can be made.

J Chromatogr Sci, 2002 Feb, 40(2), 83 - 6
Displacement study on a vancomycin-based stationary phase using N-acetyl-D-alanine as a competing agent; Slama I et al.; The analysis of the binding data of D,L-dansyl amino acids on a vancomycin stationary phase is investigated in relation to the addition of N-acetyl-D-alanine in the mobile phase . This eluent additive acts as a specific competing agent for the aglycone pocket of the immobilized chiral selector . A model taking into account both stereoselective and nonstereoselective interactions between the solutes and the stationary phase is used to fit the experimental data . From the results, the theoretical approach is considered to be adequate to describe the competing agent dependence on solute retention . To the best of our knowledge, this report constitutes the first example of a displacement study on a macrocyclic antibiotic stationary phase . This work shows that dansyl amino acids bind to the active aglycone pocket of the selector and that this interaction is enantioselective . The results also demonstrate that additional enantioselective sites at the vancomycin surface are involved in the chiral discrimination of these solutes.

Electrophoresis, 2002 Feb, 23(3), 477 - 85
Use of vancomycin silica stationary phase in packed capillary electrochromatography: III . enantiomeric separation of basic compounds with the polar organic mobile phase; Fanali S et al.; The separation of basic compounds into their enantiomers was achieved using capillary electrochromatography in 50 or 75 microm inner diameter (ID) fused-silica capillaries packed with silica a stationary phase derivatized with vancomycin and mobile phases composed of mixtures of polar organic solvents containing 13 mM ammonium acetate . Enantiomer resolution, electroosmotic flow, and the number of theoretical plates were strongly influenced by the type and concentration of the organic solvent . Mobile phases composed of 13 mM ammonium acetate dissolved in mixtures of acetonitrile/methanol, ethanol, n-propanol, or isopropanol were tested and the highest enantioresolutions were achieved using the first mobile phase, allowing the separation of almost all investigated enantiomers (9 from 11 basic compounds) . The use of capillaries with different ID (50 and 75 microm ID) packed with the same chiral stationary phase revealed that a higher number of theoretical plates and higher enantioresolution was achieved with the tube with lowest ID.

Am J Ther, 1996 Oct, 3(10), 681 - 687
Analysis of Vancomycin in the Hindlimb Vascular Bed of the Rat; Jahr JS et al.; Previously, studies have demonstrated that the effects of both a laboratory-produced vancomycin and a clinically available vancomycin were mediated, in part, by activation of both H(1) and H(2) receptors; however, other mechanisms may play a role in the vascular changes associated with vancomycin, since neither H(1) and H(2) receptor blockade has completely abolished the vasodilator responses to vancomycin in any model system . To study the mechanisms of vancomycin interactions in the hindlimb vascular bed of the rat, responses of two types of vancomycin preparations were studied . Vancomycin prepared for either clinical or laboratory use produced an initial short-lived period of vasoconstriction followed by a prolonged period of vasodilation in the hindlimb vascular bed . Responses to both the vancomycins and histamine on systemic arterial vasodilation were significantly decreased after administration of both the H(1)-receptor antagonist diphenhydramine and the H(2)-receptor antagonist famotidine . Verapamil, an L-type calcium channel blocker, significantly reduced the vasopressor responses to clinical vancomycin but not the vasopressor responses to laboratory vancomycin . Enalaprilat, and angiotensin-converting enzyme blocker, significantly reduced the vasodilator responses but not the vasoconstrictor responses of clinical vancomycin and significantly reduced the vasoconstrictor responses but not the vasodilator responses to laboratory vancomycin . Meclofenamate, a cyclo-oxygenase inhibitor, and N(omega)-L-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthetase inhibitor, had no significant effect on the biphasic responses with either vancomycin preparations . Atropine, an anticholinergic-antimuscarinic receptor antagonist, and propranolol, a beta adrenergic blocker, had no significant effect on vancomycin responses . Finally, ondansetron, a serotonin receptor blocker, and HOE 140, a bradykinin receptor blocker, also had no significant effect on vancomycin responses . These data suggest that both vancomycin preparations (clinically available and laboratory prepared) caused biphasic responses that differed from the dose-dependent vasodilation elicited by histamine . Both vancomycin preparations' vasodilator responses appear to be modulated, in part, by a histamine receptor--sensitive mechanism, while vancomycin-induced vasoconstrictor responses appear to be modulated, in part, by angiotensin-converting enzyme and L-type calcium channel--sensitive mechanisms in the rat hindlimb vascular bed . These data also suggest that the vascular responses of vancomycin are preparation dependent.

Rapid Commun Mass Spectrom, 2002, 16(5), 332 - 8
Enantiomeric separation and quantification of fluoxetine (Prozac) in human plasma by liquid chromatography/tandem mass spectrometry using liquid-liquid extraction in 96-well plate format; Shen Z et al.; Fluoxetine (Prozac) is currently one of the widely prescribed selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression . A high-throughput sample preparation procedure using liquid-liquid extraction (LLE) in a 96-well plate format in conjunction with liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed and validated for quantification of fluoxetine enantiomers in human plasma . After addition of internal standard and ammonium hydroxide, samples were extracted with ethyl acetate . The organic extract was evaporated to dryness and reconstituted in methanol . Where possible, sample transfer and LLE steps were automated using a Tomtec Quadra 96 workstation . Adequate separation of fluoxetine enantiomeric pairs (resolution of 1.17) was achieved on a vancomycin column eluted with methanol containing 0.075% (by weight) ammonium trifluoroacetate . A triple quadrupole mass spectrometer, operated in the multiple reaction monitoring mode at m/z 310-->44 for fluoxetine enantiomeric pairs and m/z 287-->241 for oxazepam (internal standard), was used . Analysis was performed in the positive ion mode using atmospheric pressure chemical ionization (APCI) . The standard curve range was 2.0-1000 ng/mL for each fluoxetine enantiomer . The intra- and inter-day precision and accuracy of the quality control (QC) samples were <12.5% (CV) and <13.6% (CV), respectively, for each fluoxetine enantiomer; the correlation coefficient was >0.990 . Method ruggedness was demonstrated by the reproducible performance of the assay during a three-day validation period .

Lett Appl Microbiol, 2002, 34(2), 100 - 4
Long-term survival of Escherichia coli O157 on pasture following an outbreak associated with sheep at a scout camp; Ogden ID et al.; AIMS: To monitor the decay of E . coli O157 in soil (loamy sand) on a scout campsite following an outbreak in humans . METHODS AND RESULTS: Samples of soil and sheep faeces were collected from the campsite and tested for the presence of E . coli O157 by immunomagnetic separation (IMS) after enrichment in buffered peptone water + vancomycin at 42 degrees C for 6 h . Enumeration of target was carried out by direct plating onto sorbitol MacConkey agar plates supplemented with cefixime and tellurite (CTSMAC) incubated at 37 degrees C for 24 h . Low numbers (< 100 g(-1)) were estimated by the most probable number (3-tube MPN) technique . CONCLUSIONS: Survival was observed for 15 weeks . SIGNIFICANCE AND IMPACT OF THE STUDY: A number of laboratory studies have followed the decay of E . coli O157 in soil, animal faeces and water . This study follows (for the first time) the decay of the organism in soil after an outbreak associated with sheep . It demonstrates the long-term persistence of the organism in the environment and the results will be potentially important in performing risk assessments for both human and animal infection.

J Bone Joint Surg Br, 2002 Jan, 84(1), 70 - 2
The use of vancomycin-impregnated cement beads in the management of infection of prosthetic joints; Taggart T et al.; Although the incidence of infection associated with hip and knee prostheses is low, with the increasing number of arthroplasties being carried out, the total number of such cases is increasing . The pattern of infecting organisms after total joint arthroplasty has changed and gentamicin-resistant organisms are becoming increasingly common . In conjunction with surgical debridement, vancomycin added to a bone-cement carrier can be very effective in the treatment of infection caused by such organisms . We report the results of its use in proven deep infection in 26 hip and seven knee arthroplasties . After a mean follow-up of 67 months, 32 patients remained clinically and radiologically free from infection . There was one recurrence and positive second-stage cultures of uncertain significance in three other patients . Vancomycin is potentially very useful in the management of deep infection after arthroplasty.

J Microencapsul, 2002 Jan-Feb, 19(1), 83 - 94
Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks; Ozalp Y et al.; A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses . Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared . Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions . Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC . SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37 degrees C for up to 5 weeks . NMR showed a decrease in the CH2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded . In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for approximately 2 months in a static system . It was observed that release was according to Higuchi kinetics (Q vs . t(1/2)), and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.

Anal Chem, 2002 Jan 1, 74(1), 282 - 7
A framework based on the extended Wyman concept for analyzing the salt effects on the solute retention in high-performance affinity chromatography; Slama I et al.; The analysis of binding data of a ligand to a macromolecule in the presence of an additive can be classically formulated in terms of the linked functions of Wyman . In the case of a salt, this approach has been extended by Tanford such that the contributions of both salt and water are taken into account . In this paper, the extended Wyman theory was applied to high-performance affinity chromatography (HPAC) in order to define a general model describing the effects of the mobile-phase salts on the ligand binding . Various HPAC literature data, as well as our data concerning dansyl amino acid retention on a vancomycin stationary phase, were examined in relation to this model . From the results, this theoretical approach was considered to be adequate to describe accurately the salt dependence on solute retention . This work shows the importance of taking into account the effects of both ionic species and water in the investigation of relative contributions of the interactions involved in the ligand binding to immobilized receptor.

J Antimicrob Chemother, 2002 Feb, 49 Suppl 1, 63 - 7
Suspected infection in children with cancer; Shaw PJ; A common complication of the intensive therapy that children with cancer receive is infection . The Oncology Unit of The Children's Hospital at Westmead maintains a comprehensive database of all admissions for suspected sepsis . From July 1994 to June 1999 broad-spectrum antibiotics were commenced in 2331 episodes . With early and aggressive use of empirical amphotericin B, 545 courses were given . Bacteraemia was documented in 701 episodes and invasive fungal disease in 73 . Trends seen during the study included: (i) the proportion of febrile neutropenic patients receiving granulocyte colony stimulating factor increased from 40% to 60%; (ii) the mean neutrophil count at cessation of antibiotics fell from 0.97 to 0.63 x 10(9) cells/L for patients not receiving growth factors; (iii) the proportion of non-albicans Candida species infections increased . In addition, an outbreak of infection caused by Scedosporium sp . was documented; (iv) first-line empirical antibiotic combinations containing vancomycin fell from 20% to 7%; and (v) the ability to maintain or escalate anti-fungal therapy with reduced nephrotoxicity through use of lipid formulations of amphotericin was increasingly apparent in high-risk patients . During the study, infection was the primary cause of death in 11 non-bone marrow transplant (BMT) patients (five fungal, four viral, one bacterial infection and one sepsis syndrome) and five BMT patients (two bacterial and three viral) . A prospective randomized study of toxicity due to amphotericin B given in either lipid emulsion or dextrose showed no significant difference, but both groups showed a lower incidence of amphotericin B intolerance in comparison with the adult series . The inability to reduce toxicity of amphotericin B by simple mixing with lipid emulsion has led to increasing use of commercially available lipid formulations of amphotericin B.

Pediatr Nephrol, 2001 Dec, 16(12), 1019 - 21
Hemodiafiltration for vancomycin overdose in a patient with end-stage renal failure; Akil IO et al.; A 17-year-old anuric female patient with end-stage renal failure received a massive overdose of vancomycin and was treated with high-flux hemodiafiltration, as described in this report . The hemodiafiltration procedure with a polysulfone membrane was performed 3 times . The vancomycin concentration was decreased from 101 mg/l to 16.59 mg/l at the end of the procedure . No adverse effects were noted from either vancomycin or hemodiafiltration . Hemodiafiltration with a high-flux polysulfone membrane is a novel and safe treatment modality for vancomycin overdose in pediatric patients.

J Immunol Methods, 2002 Feb 1, 260(1-2), 235 - 49
Complete sequencing of anti-vancomycin fab fragment by liquid chromatography-electrospray ion trap mass spectrometry with a combination of database searching and manual interpretation of the MS/MS spectra; Adamczyk M et al.; Sequencing of anti-vancomycin monoclonal antibody (mAb) Fab region (48,000 Da) was carried out using liquid chromatography-electrospray ionization ion trap mass spectrometry (LC/ESI-MS) . Comprehensive strategies were employed to ensure complete sequence coverage . The sequence information was obtained from the spectra of collision-induced dissociation (CID) (MS/MS) of the protonated proteolytic peptides resulting from multiple enzymatic digestions of reduced/S-carboxymethylated (RCM) light chain and Fd fragment . Database searching of the spectra against the published immunoglobulin G (IgG) sequences allowed the identification of all the peptides in constant domains as well as partial sequences in variable domains . The rest of the sequences were deduced by manual interpretation of the peptide tandem mass spectrometry (MS/MS) spectra . The analysis showed that the N-terminus of the heavy chain was modified by the conversion of a glutamine residue to pyroglutamic acid.

Biol Pharm Bull, 2001 Dec, 24(12), 1446 - 50
Evaluation of Bayesian predictability of vancomycin concentration in patients with various degrees of renal function; Ohnishi A et al.; To assess the usefulness of the population pharmacokinetic parameters of vancomycin (VCM) based on a two-compartment model in Japanese adult patients, predictability by a Bayesian method was evaluated using a concentration time course after single dosing to 22 patients with various degrees of renal function . Using one or two points from the observed data for each patient, the concentrations predicted by a Bayesian method were compared with the observed data for each sampling time . The patients were separated into five groups based on their renal functions indicated by creatinine clearance, and the mean prediction error (MPE) and root mean squared error (RMSE) were calculated for each group as measures of accuracy and precision, respectively . In both one- and two-point methods, the absolute MPE values at each sampling time in the elimination phase were less than 2.5 microg/ml, and the RMSE values were also small . No clear differences were found in MPE and RMSE among the groups . In the distribution phase, the MPE and RMSE were somewhat greater, and RMSE in some groups was around 15 microg/ml when trough data was used to predict the peak concentration . Also, the theoretical RMSE using this population parameter setting could well explain the observed RMSE . These results confirmed this population parameter setting is useful for at least predicting concentration in the elimination phase after single dosing, and the predictability was independent of renal function.

Leukemia, 2001 Dec, 15(12), 1885 - 91
Factors influencing post-transfusional platelet increment in pediatric patients given hematopoietic stem cell transplantation; Balduini CL et al.; Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) always require platelet transfusions, but the increase in platelet count is often less than expected . Since factors responsible for poor response to platelet transfusions in this clinical setting are largely unknown, we performed a prospective study in 87 consecutive children transplanted in a single institution . The mean 16-h corrected count increment (CCI) of 598 platelet transfusions was 5.76 +/- 8.32 x 10(9)/l . Both before and after HSCT, 13.8% of patients had antibodies against HLA and/or platelet-specific antigens . Univariate analysis identified 12 factors significantly associated with a lower post-transfusion CCI, but only four reached statistical significance in the multivariate analysis . These four factors were concomitant therapy with vancomycin, alloimmunization, use of an Autopheresis cell separator for preparation of platelet concentrates and cytomegalovirus infection . We, therefore, suggest that a better response to platelet transfusions could be obtained by choosing a suitable cell separator, by avoiding the use of vancomycin and by adopting measures that reduce alloimmunization and CMV infection . Moreover, screening patients for HLA and platelet-specific antibodies before HSCT would identify the majority of subjects who will develop alloimmune refractoriness after transplantation and would allow the search for a compatible donor in advance.

Br J Dermatol, 2001 Nov, 145(5), 816 - 20
Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285; Palmer RA et al.; Linear IgA disease (LAD) is an acquired autoimmune subepidermal bullous disease characterized by the linear deposition of IgA at the basement membrane zone . A minority of cases are induced by drugs, of which the most frequently implicated is vancomycin . The target antigens in idiopathic LAD are heterogeneous, but have not previously been reported in vancomycin-induced LAD . We report three cases, and in two of these we investigated the target antigens . In both we identified IgA antibodies to LAD285 and IgA and IgG antibodies (dual response) to BP180.

Ann Pharmacother, 2001 Nov, 35(11), 1458 - 64
Desensitization protocols for vancomycin hypersensitivity; Wazny LD et al.; OBJECTIVE: To discuss the pathophysiology of vancomycin-induced immediate hypersensitivity reactions, review the process of vancomycin desensitization, and provide specific directions for ordering and preparing rapid and slow desensitization protocols . DATA SOURCES: A MEDLINE search (1966-February 2001) of English-language literature pertaining to vancomycin desensitization and hypersensitivity reactions was performed . Tertiary sources were also used . DATA EXTRACTION: Published clinical studies and case reports . DATA SYNTHESIS: The pathophysiology of vancomycin-induced hypersensitivity reactions is discussed along with the procedure of vancomycin desensitization . Desensitization should be considered in Red Man syndrome (RMS) that does not respond to the usual treatment measures, and in vancomycin-induced anaphylaxis . Rapid desensitization is preferred as it is effective in the majority of patients and enables therapeutic dosing of vancomycin within 24 hours . In patients who fail rapid desensitization, a slow desensitization protocol may be tried . CONCLUSIONS: Vancomycin-induced immediate hypersensitivity reactions include RMS and anaphylaxis . Vancomycin desensitization should be considered for severe RMS reactions not responding to usual measures and in anaphylactic reactions to vancomycin, when substitution of another antbiotic is not feasible.

Ann Pharmacother, 2001 Nov, 35(11), 1400 - 2
Vancomycin removal during a plasma exchange transfusion; Foral MA et al.; OBJECTIVE: To report a case of clinically significant removal of vancomycin during a plasma exchange transfusion in a patient with sickle-cell anemia . CASE SUMMARY: A 46-year-old African American woman with sickle-cell disease was admitted on three separate occasions and treated with vancomycin . Vancomycin serum drug concentrations were obtained on all three admissions . During one of the admissions, a plasma exchange transfusion was performed the same day vancomycin concentrations were obtained . The vancomycin serum drug concentrations were considerably lower than predicted, resulting in potentially subtherapeutic vancomycin concentrations . Bayesian pharmacokinetic forecasting was used in interpreting the vancomycin concentrations . DISCUSSION: Searches from MEDLINE (1966-September 2000) and Drugs and Pharmacology (1990-September 2000) were performed to obtain pertinent published literature . CONCLUSIONS: Plasma exchange transfusions may result in clinically significant removal of vancomycin from the plasma . The potential exists of underdosing vancomycin in patients who are receiving frequent plasma exchange transfusions . Further research may be warranted to determine whether these patients may be candidates for more frequent and vigilant monitoring of vancomycin concentrations.

Am J Respir Crit Care Med, 2001 Nov 1, 164(9), 1595 - 600
Pulmonary administration of perfluorodecaline- gentamicin and perfluorodecaline- vancomycin emulsions; Franz AR et al.; The aim of this study was to examine pharmacokinetics and pulmonary antibiotic tissue concentrations (PATC) of gentamicin and vancomycin after intrapulmonary administration of a perfluorodecaline (PFD)-gentamicin and a PFD-vancomycin emulsion during partial liquid ventilation (PLV) . PLV was initiated in 19 healthy rabbits and 18 surfactant-depleted rabbits . The animals were randomized to receive either 5 mg/kg gentamicin and 15 mg/kg vancomycin intravenously, or 5 mg/kg gentamicin intrapulmonary, or 15 mg/kg vancomycin intrapulmonary . Antibiotic plasma levels were measured after 15, 30, 45, and 60 min, and hourly thereafter . After 5 h animals were sacrificed and lungs were removed to evaluate PATC and histology . PATC were significantly higher after intrapulmonary administration of both gentamicin and vancomycin . In healthy rabbits, peak plasma concentrations were lower and 5 h plasma concentrations were higher after intrapulmonary administration, whereas plasma concentrations were not different in surfactant-depleted rabbits . There were no differences in lung histology, hemodynamics, lung mechanics, or gas exchange between the treatment groups . We conclude that during PLV, higher PATC can be achieved after intrapulmonary administration of PFD-antibiotic emulsions compared with intravenous administration of the same dose without apparent short-term adverse effects . We speculate that intrapulmonary antibiotic administration during PLV may be beneficial in treating severe pneumonia.

Postgrad Med, 2001 Oct, 110(4), 43 - 8; quiz 11
Containing methicillin-resistant S aureus . Surveillance, control, and treatment methods; Simor AE; In the past two decades, the prevalence of MRSA has increased in healthcare facilities in many countries around the world . The organism, which has caused nosocomial outbreaks, also has become endemic in many hospitals and long-term care facilities . Recently, reports of community-acquired MRSA in persons without known risk factors for the organism have been increasing . Transmission occurs primarily from colonized or infected patients to others through the hands of healthcare personnel . MRSA infection may be life-threatening and cause considerable morbidity, the need for prolonged hospitalization, and increased costs . Treatment options are limited because organisms are typically resistant to multiple antibiotics, but newer agents are being developed . However, there is also reason for concern about the recent emergence of MRSA resistant to glycopeptides, such as vancomycin . Efforts to limit the spread of MRSA should include surveillance and control measures, such as adequate hand hygiene and appropriate contact isolation or barrier precautions.

Arzneimittelforschung, 2001 Sep, 51(9), 763 - 8
Voltametric determination of vancomycin in dosage forms through treatment with nitrous acid; Belal F et al.; Two methods are described for the determination of vancomycin (vancomycin hydrochloride, CAS 1404-93-9) in its dosage forms . The two methods involve a prior treatment with nitrous acid then measuring the formed nitroso derivative, either spectrophotometrically or polarographically . In the spectrophotometric method, the absorbance-concentration plot is rectilinear over the range of 4-32 micrograms/ml with minimum detectability of 2.7 micrograms/ml (1.8 x 10(-6) mol/l) . The apparent molar absorptivity is 4.084 x 10(-4)l.mol-1.cm-1 and A (1%, 1 cm) is 275 . The reaction product was also found to be polarographically reducible at the Dropping Mercury Electrode (DME) with E1/2 of-0.9 V vs . Ag/AgCl electrode and a diffusion current constant (Id) of 0.85 +/- 0.02 . The cathodic current produced was found to be diffusion controlled with some adsorption contribution . The calibration plot was linear over the range of 0.015-0.06 mmol l-1 for direct current (DCt) mode and from 0.005-0.05 mmol l-1 for differential pulse polarography (DPP) mode with minimum detectability of 2.4 x 10(-7) mol l-1 using the latter technique . The results obtained were statistically compared with those given with the official B.P . method and were in good agreement.

J Arthroplasty, 2001 Oct, 16(7), 882 - 92
Impregnation of vancomycin, gentamicin, and cefotaxime in a cement spacer for two-stage cementless reconstruction in infected total hip arthroplasty; Koo KH et al.; Twenty-two patients with infected total hip arthroplasty were treated with 2-stage arthroplasty, using a cement spacer impregnated with a combination of 3 thermostable antibiotics (vancomycin, gentamicin, and cefotaxime) . Initially, implants were removed, and a spacer was inserted . Six to 12 weeks later, the spacer was removed, and the patients underwent reconstruction using cementless components . The patients were followed for an average of 41 months . One patient had a recurrence of infection and was treated with resection arthroplasty . The remaining 21 patients (95%) had no evidence of infection at the final follow-up . We recommend using the combination of these 3 antibiotics in the cement spacer for 2-stage reconstruction in infected hip arthroplasty when the causative organism is not identified in the culture of preoperative aspiration.

Jt Comm J Qual Improv, 2001 Oct, 27(10), 509 - 21
Patient safety and computerized medication ordering at Brigham and Women's Hospital; Kuperman GJ et al.; BACKGROUND: Medications are important therapeutic tools in health care, yet creating safe medication processes is challenging for many reasons . Computerized physician order entry (CPOE), one important way that technology can be used to improve the medication process, has been in place at Brigham and Women's Hospital (BWH; Boston) since 1993 . CPOE AT BWH: The CPOE application, designed and developed internally by the BWH information systems team, allows physicians and other clinicians to enter all patient orders into the computer . Physicians enter 85% of orders, with the remainder entered electronically by other clinicians . CPOE AND SAFE MEDICATION USE: The CPOE application at BWH includes several features designed to improve medication safety--structural features (for example, required fields, use of pick lists), enhanced workflow features (order sets, standard scales for insulin and potassium), alerts and reminders (drug-drug and drug-allergy interaction checking), and adjunct features (the pharmacy system, access to online reference information) . RESULTS AT BWH: Studies of the impact of CPOE on physician decision making and patient safety at BWH include assessment of CPOE's impact on the serious medication error and the preventable adverse drug event rate, the impact of computer guidelines on the use of vancomycin, the impact of guidelines on the use of heparin in patients at bed rest, and the impact of dosing suggestions on excessive dosing . CONCLUSION: CPOE and several forms of clinical decision support targeted at increasing patient safety have substantially decreased the frequency of serious medication errors and have had an even bigger impact on the overall medication error rate.

Electrophoresis, 2001 Sep, 22(15), 3335 - 8
Continuous beds with vancomycin as chiral stationary phase for capillary electrochromatography; Kornysova O et al.; Enantiomeric separations in capillary electrochromatography (CEC) carried out using a continuous-bed chiral stationary phase (CSP) based on the macrocyclic antibiotic, vancomycin, is presented . The continuous beds were prepared from methacryloxypropyl modified fused silica capillaries (100 microm ID) by in situ copolymerization of N-(hydroxymethyl)acrylamide and piperazine diacrylamide with vinyl sulfonic acid comonomer used to introduce ionic functionality and thus a strong electroosmotic flow (EOF) . The CSP was subsequently prepared by immobilizing the vancomycin stationary phase by reductive amination . Preliminary results have indicated that an extremely strong EOF is obtained in both the nonaqueous polar organic (15.2 x 10(-5) cm2 V(-1) s(-1) and the aqueous reversed-phase modes of operation (8.5 x 10(-5) cm2 V(-1) s(-1)) . Enantioselectivity was obtained for four racemic compounds, the best of which was in the case of thalidomide which was separated in 10 minutes with high resolution (Rs = 2.5) and efficiency (120,000 plates meter(-1)) values.

J Chromatogr A, 2001 Sep 14, 928(2), 233 - 41
On-column ligand synthesis coupled to partial-filling affinity capillary electrophoresis to estimate binding constants of ligands to a receptor; Zhang Y et al.; This paper describes a two-step procedure whereby on-column ligand synthesis and partial-filling affinity capillary electrophoresis (PFACE) are sequentially coupled to each other to determine the binding constants of 9-fluorenylmethoxy carbonyl (Fmoc)-amino acid-D-Ala-D-Ala species to vancomycin (Van) from Streptomyces orientalis . In this technique four separate plugs of sample are injected onto the capillary column and electrophoresed . The initial sample plug contains a D-Ala-D-Ala terminus peptide and two non-interacting standards . Plugs two and three contain solutions of Fmoc-amino acid-N-hydroxysuccinimide (NHS) ester and running buffer, respectively . The fourth sample plug contains an increasing concentration of Van partially-filled onto the capillary column . Upon electrophoresis the initial D-Ala-D-Ala peptide reacts with the Fmoc-amino acid NHS ester yielding the Fmoc-amino acid D-Ala-D-Ala peptide . Continued electrophoresis results in the overlap of the plugs of Van and Fmoc-amino acid-D-Ala-D-Ala peptide and non-interacting markers . Analysis of the change in the relative migration time ratio of the Fmoc-amino acid-D-Ala-D-Ala peptide relative to the non-interacting standards, as a function of the concentration of Van, yields a value for the binding constant . These values agree well with those estimated using other binding and ACE techniques.

Chang Gung Med J, 2001 Jul, 24(7), 451 - 4
Collagen as a drug carrier for deep sternal wound infection after open heart surgery; Yeh CH et al.; How to optimally treat deep sternal wound infection after open wound infection remains controversial . Biomaterial advances have made local antibiotics-releasing systems a promising alternative for treating deep sternal wound infection . Two patients with deep sternal wound complications were treated with radical wound debridement, sternal refixation, retrosternal suction drainage, bilateral pectoralis major muscle flaps and placement of collagenous drug carriers loaded with vancomycin underneath, above and between the sternal edges . No treatment failure and death occurred in these patients . There were no side effects, treatment failures or deaths after adjuvant treatment with collagenous vancomycin . Preliminary results of these 2 case studies demonstrate the feasibility of successfully treating deep sternal wound infections with collagenous vancomycin in combination with surgical debridement . This technique is easily performed, reliable and safe.

Curr Med Chem, 2001 Sep, 8(11), 1303 - 28
Glycosides in medicine: "The role of glycosidic residue in biological activity"; Kren V et al.; Numbers of biologically active compounds are glycosides . Sometimes, the glycosidic residue is crucial for their activity, in other cases glycosylation only improves pharmacokinetic parameters . Recent developments in molecular glycobiology brought better understanding to the aglycone vs . glycoside activities, and made possible to develop new, more active or more effective glycodrugs based on these findings - very illustrative recent example is the story of vancomycin . This paper deals with an array of glycosidic compounds currently used in medicine but also with biological activity of some glycosidic metabolites of the known drugs . It involves glycosides of vitamins, polyphenolic glycosides (flavonoids), alkaloid glycosides, glycosides in the group of antibiotics, glycopeptides, cardiac glycosides, steroid and terpenoid glycosides etc . The physiological role of the glycosyl and structure-activity relations (SAR) in the glycosidic moiety (-ies) are discussed.

J Clin Pharmacol, 2001 Sep, 41(9), 927 - 34
The influences of renal function and maturation on vancomycin elimination in newborns and infants; Capparelli EV et al.; The purpose of this study was to describe the maturation of vancomycin (V) clearance and the influence of altered renal function in infants on vancomycin using population pharmacokinetic methods . A population pharmacokinetic model was developed using NONMEM from clinical data obtained from 374 newborns and infants < 2 years of age (median age = 27 days) from four institutions . A total of 1103 serum V concentrations were used in the model development, including 311 with elevated serum creatinine (CR) (> 0.8 mg/dl) and more than 104 evaluations in infants older than 2 months of age . The final model was evaluated against a second data set of 160 concentrations from 67 infants at one of the institutions and then used to develop dosing guidelines . The data were best described by a two-compartment model . Weight and CR greatly influenced vancomycin elimination, while postnatal age and prematurity (< 28 weeks) were significant but less important predictors of V elimination . For the typical study infant (age = 27 days, CR = 0.6, WT= 1.8 kg, gestational age = 33.5 weeks), this results in VdSS = 0.79 l/kg and Cl = 0.066 l/h/kg . The validation data set showed the model to be unbiased . Dosing guidelines from this model, based on serum creatinine and gestational age at birth, performed better than published guidelines based on postconceptional age . Vancomycin clearance is initially reduced in premature infants and increases with postnatal age . Most of the age-related changes could be predicted by the concomitant fall in serum creatinine . Dosing guidelines that incorporate these factors are more likely to produce therapeutic V concentrations in infants.

J Paediatr Child Health, 2001 Aug, 37(4), 342 - 7
Glycopeptide prescribing in an Australian tertiary paediatric hospital; Jones DA et al.; OBJECTIVE: To assess the extent and appropriateness of glycopeptide use in a tertiary Australian Paediatric hospital . METHODOLOGY: A retrospective analysis of prescriptions during a six-month period between July 1999 and January 2000 . Medical records were examined and prescribing practices compared with the recommendations of the Hospital Infectious Control Practices Advisory Committee (HICPAC) and the Infectious Diseases Society of America (IDSA) . RESULTS: Fifty-one patients were identified who received a total of 98 glycopeptide prescriptions . The Haematology/ Oncology unit prescribed 71/98 (72.4%) . 68/98 (69.4%) patients received vancomycin, 9/98 (9.2%) received teicoplanin and 21/98 (21.4%) a combination of both . 81/98 (82.7%) had central venous catheters and 69/98 (70.4%) were immunocompromised . 48/98 (49%) prescriptions were for empiric treatment with 38/98 (38.8%) for prophylaxis and 11/98 (12.2%) therapeutic . 19/98 (19.4%) prescriptions were deemed appropriate, 6 (6.1%) by HICPAC criteria, and a further 13 (13.3%) by IDSA or other criteria . Of 19 prescriptions started appropriately, only 7/17 (41.1%) were continued appropriately beyond 48 h . Appropriate cultures were taken before prescription in 93.3% of cases . Dose was appropriate in 91/98 (92.9%) and frequency appropriate in all cases . The cost of inappropriate prescribing was approximately $9500 . DISCUSSION: A high rate of inappropriate glycopeptide prescribing was evident in this paediatric population . Inappropriate prescribing existed across all subspecialties . Use was primarily for empiric therapy and prophylaxis in young children with an oncology diagnosis . A number of situations existed where glycopeptide prescription was felt appropriate despite not being included in HICPAC/IDSA guidelines . Areas with high rates of inappropriate prescribing were identified and will be targeted for education and intervention . Audit of practice continues.

Science, 2001 Oct 12, 294(5541), 361 - 4 Epub 2001 Aug 23.
Genetic basis for activity differences between vancomycin and glycolipid derivatives of vancomycin; Eggert US et al.; Small molecules that affect specific protein functions can be valuable tools for dissecting complex cellular processes . Peptidoglycan synthesis and degradation is a process in bacteria that involves multiple enzymes under strict temporal and spatial regulation . We used a set of small molecules that inhibit the transglycosylation step of peptidoglycan synthesis to discover genes that help to regulate this process . We identified a gene responsible for the susceptibility of Escherichia coli cells to killing by glycolipid derivatives of vancomycin, thus establishing a genetic basis for activity differences between these compounds and vancomycin.

Electrophoresis, 2001 Aug, 22(12), 2588 - 92
Analysis of vancomycin and related impurities by micellar electrokinetic capillary chromatography . Method development and validation; Kang JW et al.; A fast and highly selective micellar electrokinetic capillary chromatography (MEKC) method for quantitative analysis of vancomycin and related impurities is described . Among the tested surfactants, cetyltrimethylammonium chloride (CTAC) offered the best selectivity . Another important parameter, which strongly influenced the selectivity, was buffer pH . It was found that the selectivity increased with buffer pH decreasing from 9 to 5 . Using Tris-phosphate buffer containing CTAC, satisfactory separation could be obtained in the pH range from 5.0 to 5.5 . Excellent repeatability in terms of migration time and peak area could be obtained when the capillary was carefully washed between two runs . In order to obtain optimal conditions and to evaluate the method robustness, a central composite experimental design was carried out . The optimal conditions were: 44 cm length of fused-silica capillary with 50 microm ID, 120 mM Tris-phosphate buffer (pH 5.2) containing 50 mM CTAC, -15 kV applied voltage, UV detection at 210 nm, and a column temperature of 25 degrees C . Under the optimal conditions, more than 20 peaks could be separated within 8 min . The method has a linearity range from 0.004 to 1.2 mg/ml (concentration of vancomycin B, active component) . The limit of detection (LOD) and limit of quantitation (LOQ) were 0.4 microg/mL vancomycin, equivalent to 0.3 microg/mL vancomycin B (0.04%) and 1.1 microg/mL vancomycin, equivalent to 0.9 microg/mL vancomycin B (0.1%), respectively.

J Biol Chem, 2001 Oct 19, 276(42), 38370 - 7 Epub 2001 Aug 08.
A polyketide synthase in glycopeptide biosynthesis: the biosynthesis of the non-proteinogenic amino acid (S)-3,5-dihydroxyphenylglycine; Pfeifer V et al.; Balhimycin, a vancomycin-type antibiotic from Amycolatopsis mediterranei, contains the unusual amino acid (S)-3,5-dihydroxyphenylglycine (Dpg), with an acetate-derived carbon backbone . After sequence analysis of the biosynthetic gene cluster, one gene, dpgA, for a predicted polyketide synthase (PKS) was identified, sharing 20-30% identity with plant chalcone synthases . Inactivation of dpgA resulted in loss of balhimycin production, and restoration was achieved by supplementation with 3,5-dihydroxyphenylacetic acid, which is both a possible product of a PKS reaction and a likely precursor of Dpg . Enzyme assays with the protein expressed in Streptomyces lividans showed that this PKS uses only malonyl-CoA as substrate to synthesize 3,5-dihydroxyphenylacetic acid . The PKS gene is organized in an operon-like structure with three downstream genes that are similar to enoyl-CoA-hydratase genes and a dehydrogenase gene . The heterologous co-expression of all four genes led to accumulation of 3,5-dihydroxyphenylglyoxylic acid . Therefore, we now propose a reaction sequence . The final step in the pathway to Dpg is a transamination . A predicted transaminase gene was inactivated, resulting in abolished antibiotic production and accumulation of 3,5-dihydroxyphenylglyoxylic acid . Interestingly, restoration was only possible by simultaneous supplementation with (S)-3,5-dihydroxyphenylglycine and (S)-4-hydroxyphenylglycine, indicating that the transaminase is essential for the formation of both amino acids.

Ann Pharmacother, 2001 Jul-Aug, 35(7-8), 891 - 3
Linear immunoglobulin A bullous dermatosis induced by gemcitabine; del Pozo J et al.; OBJECTIVE: To report a case of linear immunoglobulin (Ig) A bullous dermatosis (LABD) induced by gemcitabine . CASE SUMMARY: A 59-year-old man was diagnosed with squamous-cell carcinoma of the lung in T4N2M0 stage and treated with cisplatin, vinorelbine, and gemcitabine . Twenty-four hours after the administration of gemcitabine, a symmetric, bullous, herpetiform eruption appeared on his trunk and upper limbs . Histopathologic examination and direct immunofluorescence test were consistent with IgA bullous dermatosis . Cutaneous lesions resolved two weeks after the drug was withdrawn and topical steroid treatment was instituted . DISCUSSION: Drug-induced LABD is a variant of classic or idiopathic LABD . Vancomycin is the most frequently implicated drug, but other agents have been reported to cause LABD . According to the Naranjo probability scale, the relationship of gemcitabine treatment with cutaneous eruption in our patient is possible . CONCLUSIONS: We report the first case of gemcitabine-induced LABD . Clinicians should monitor patients receiving this drug for signs of LABD.

Ther Drug Monit, 2001 Aug, 23(4), 441 - 4
Fluorescence polarization immunoassay: can it result in an overestimation of vancomycin in patients not suffering from renal failure?
Sym D, Smith C, Meenan G, Lehrer M.
It has been reported in scientific data that fluorescence polarization immunoassay (FPIA) results in overestimation of vancomycin in patients with renal failure . This overestimation is caused by interference of the degradation product, CDP-1, in this assay . Increases in vancomycin levels have also been reported in patients not suffering from renal failure (nonrenal failure patients) who are receiving vancomycin therapy for approximately 10 days or more . The authors tested whether this increase in vancomycin in nonrenal failure patients is a result of CDP-1 interfering with FPIA or a change in the pharmacokinetics of the drug . Serum vancomycin peak and trough samples were obtained from 10 adult (mean age +/- SD: 55.9 years +/- 17.5) nonrenal failure patients (mean ClCr +/- SD: 76.2 mL/min +/- 29.20) receiving vancomycin therapy for at least 10 days . These peaks and troughs were obtained at steady state and again at approximately 10 days of therapy . All serum samples were analyzed initially by fluorescence polarization immunoassay (FPIA, TDx) (Abbot Diagnostics; Irving, TX) and again by enzyme multiplied immunoassay (EMIT Vancomycin Assay) (Dade Behring; San Jose, CA) . Statistical analysis (Wilcoxon signed-rank test) determined that there was no difference between the values obtained from the two assays . This demonstrates that the increase in vancomycin levels is not caused by the accumulation of CDP-1 and may be the result of a change in the pharmacokinetics of the drug.

Ophthalmic Surg Lasers, 2001 Jul-Aug, 32(4), 325 - 9
Endogenous Pseudallescheria boydii endophthalmitis in a patient with ring-enhancing brain lesions; Luu KK et al.; A 46-year-old man, status post liver transplantation and taking immunosuppressive medications, was admitted after suffering a generalized seizure . Magnetic resonance imaging of the brain revealed two ring-enhancing lesions and treatment was begun for presumed toxoplasmic encephalitis . He was already receiving amphotericin B for a skin lesion suspected to be caused by candidiasis . One day after the seizure, he complained of photophobia in the left eye . Intraocular inflammation and a small infiltrate in the macula were seen . Vision deteriorated over the next three days . Vitreous tap and injection of amphotericin B and vancomycin were performed, but the intraocular inflammation continued to increase . On day 15, a vitrectomy was performed . The vitreous specimen ultimately grew Pseudallescheria boydii . The patient died on hospital day 30 from complications of the brain abscesses . Pseudallescheria boydii should be considered in the differential diagnosis of endophthalmitis, especially in patients with immunosuppression, serious medical disease, or ring-enhancing brain lesions.

J Appl Microbiol, 2001 Aug, 91(2), 373 - 9
The optimization of isolation media used in immunomagnetic separation methods for the detection of Escherichia coli O157 in foods; Ogden ID et al.; AIMS: To compare media used in immunomagnetic separation (IMS) techniques for the isolation of Escherichia coli O157 from food . METHODS AND RESULTS: Foods, both naturally contaminated and spiked, with low numbers (< 1 g(-1)) of stressed E . coli O157 were enriched in media based on buffered peptone water (BPW), tryptone soya and EC broths incubated at 30, 37, 40 and 42 degrees C . Following immunomagnetic separation, beads were plated on a range of selective agars . CONCLUSION: BPW supplemented with vancomycin (8 mg l(-1)) incubated at 42 degrees C, followed by IMS and subsequent plating of immunobeads onto cefixime tellurite sorbitol MacConkey agar plus either Rainbow or CHROMagar agars, proved optimum for the recovery of spiked, stressed E . coli O157 in minced beef, cheese, apple juice and pepperoni . The same protocol was optimum for recovery from naturally-contaminated minced beef and cheese . SIGNIFICANCE AND IMPACT OF THE STUDY: The optimum protocol would increase isolation rates of E . coli O157 from foods.

Pharm World Sci, 2001 Jun, 23(3), 93 - 7
Evaluation of vancomycin use in a large university-affiliated hospital in eastern France in 1999; Floret N et al.; OBJECTIVE: In 1999, we conducted a retrospective drug utilization review to determine the volume and pattern of vancomycin use in a university-affiliated hospital in eastern France . METHODS: Total vancomycin use was determined and expressed as vancomycin courses per 100 admitted patients and defined daily doses (DDD) of vancomycin per 100 patient-days . The indication for vancomycin use was classified as appropriate or inappropriate according to the guidelines issues by the HICPAC . RESULTS: A total of 311 vancomycin courses were given, as 2098 DDD, giving crude incidences of 1.17 courses per 100 admitted patients and of 1.19 defined daily doses per 100 patient-days . The frequency of appropriate courses was 66.7% . Of the 63 inappropriate courses of vancomycin, 39.7% and 28.6% were empiric therapy for nosocomial and community-acquired infections, respectively, 20.6% and 6.3% were specific therapy for nosocomial and community-acquired infections, respectively, and 4.7% were prophylactic . CONCLUSIONS: This study shows that vancomycin use in our hospital resulted in a lower selection pressure than has been reported for US university-affiliated hospitals and that comprehensive programs to improve use of vancomycin are needed in our institution.

Electrophoresis, 2001 Jun, 22(10), 1974 - 8
Practical evaluation of the influence of excessive sample concentration on the estimation of dissociation constants with affinity capillary electrophoresis; Lynen F et al.; A practical approach for the evaluation of binding constants with affinity capillary electrophoresis (ACE) is presented using the different linear and nonlinear regression methods . The influence of the sample concentration on the different obtained curves is depicted and it is shown that the different representations should always be compared . The well-known strong molecular interaction between the macrocyclic antibiotic vancomycin and a (D)-Ala-(D)-Ala terminating peptide is used as model in this study.

J Chromatogr A, 2001 Jun 1, 919(1), 195 - 203
Use of vancomycin silica stationary phase in packed capillary electrochromatography . II . Enantiomer separation of venlafaxine and O-desmethylvenlafaxine in human plasma; Fanali S et al.; A capillary electrochromatography method, using vancomycin chiral stationary phase packed capillary, was optimized for the simultaneous chiral separation of the antidepressant drug venlafaxine and its main active metabolite O-desmethylvenlafaxine . Simultaneous baseline enantiomeric separation of the two compounds was obtained using a mobile phase composed of 100 mM ammonium acetate buffer pH 6/water/acetonitrile (5:5:90, v/v) . The electrokinetic injection for sample introduction provided a limit of quantitation for both the compounds of 0.05 microg/ml racemate concentration suitable for the analysis of venlafaxine and metabolite in biological samples . The acetonitrile mobile phase concentration was found to modulate the analytes elution times, the enantiomeric resolution and the efficiency of the separation . The column was tested for repeatability and linearity showing RSD values (%) in the range of 0.13-0.24, 2.47-3.66 and 1.35-2.50 for migration time, sample/internal standard peak area ratio and enantiomeric resolution, respectively and correlation coefficients higher than 0.9990 . The method was applied to the analysis of clinical samples of patients under depression therapy showing a stereoselective metabolism for venlafaxine.

J Am Chem Soc, 2001 Mar 7, 123(9), 1862 - 71
First and second generation total synthesis of the teicoplanin aglycon; Boger DL et al.; Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided . Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%) . Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall) . This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure . Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.

Proc Natl Acad Sci U S A, 2001 Jul 17, 98(15), 8548 - 53 Epub 2001 Jul 10.
Molecular cloning and sequence analysis of the complestatin biosynthetic gene cluster; Chiu HT et al.; Streptomyces lavendulae produces complestatin, a cyclic peptide natural product that antagonizes pharmacologically relevant protein-protein interactions including formation of the C4b,2b complex in the complement cascade and gp120-CD4 binding in the HIV life cycle . Complestatin, a member of the vancomycin group of natural products, consists of an alpha-ketoacyl hexapeptide backbone modified by oxidative phenolic couplings and halogenations . The entire complestatin biosynthetic and regulatory gene cluster spanning ca . 50 kb was cloned and sequenced . It consisted of 16 ORFs, encoding proteins homologous to nonribosomal peptide synthetases, cytochrome P450-related oxidases, ferredoxins, nonheme halogenases, four enzymes involved in 4-hydroxyphenylglycine (Hpg) biosynthesis, transcriptional regulators, and ABC transporters . The nonribosomal peptide synthetase consisted of a priming module, six extending modules, and a terminal thioesterase; their arrangement and domain content was entirely consistent with functions required for the biosynthesis of a heptapeptide or alpha-ketoacyl hexapeptide backbone . Two oxidase genes were proposed to be responsible for the construction of the unique aryl-ether-aryl-aryl linkage on the linear heptapeptide intermediate . Hpg, 3,5-dichloro-Hpg, and 3,5-dichloro-hydroxybenzoylformate are unusual building blocks that repesent five of the seven requisite monomers in the complestatin peptide . Heterologous expression and biochemical analysis of 4-hydroxyphenylglycine transaminon confirmed its role as an aminotransferase responsible for formation of all three precursors . The close similarity but functional divergence between complestatin and chloroeremomycin biosynthetic genes also presents a unique opportunity for the construction of hybrid vancomycin-type antibiotics.

J Comb Chem, 2001 Jul-Aug, 3(4), 374 - 86
Monitored selection of DNA-hybrids forming duplexes with capped terminal C:G base pairs; Mokhir AA et al.; Reported here are the results of a search for modified oligodeoxynucleotides with a 5'-terminal cytidine residue whose affinity for target strands is enhanced by 5'-acylamido groups . These acylamido groups were envisioned to act as molecular caps that bind to the exposed terminal base pair of the duplex with the target strand . A total of 52 capped oligonucleotides of the sequence R-CGGTTGAC, where R denotes the 5'-appendage and C a 5'-amino-2',5'-dideoxycytidine residue, were tested . Among the building blocks employed to modify the 5'-amino group of the DNA strand were carboxylic acid residues, either appended directly or via an amino acid residue, and aromatic aldehydes, coupled via reductive amination . The carboxylic acids employed ranged from Fmoc-glycine to (Fmoc)(2)-vancomycin and included a number of aromatic acids and bile acids . Small libraries were subjected to MALDI-monitored nuclease selection experiments, and selected compounds were tested in UV-melting assays with target strands . Cholic acid appendages stabilized terminal C:G base pairs to the greatest extent, with melting point increases of up to 10 degrees C . Further, the cholic acid residue enhanced base pairing fidelity at the terminus, as determined in melting analyses with target strands containing a mismatched nucleobase at the 3'-terminus.

Pharm Res, 2001 Mar, 18(3), 316 - 22
Formulation and evaluation of a folic acid receptor-targeted oral vancomycin liposomal dosage form; Anderson KE et al.; PURPOSE: To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin . via the oral route . METHODS: Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability . A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces . Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitro in the Caco-2 cell model and in vivo in male Sprague-Dawley rats . Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces . RESULTS: Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion . Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail . Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin . Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution . CONCLUSIONS: The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution . It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.

Clin Appl Thromb Hemost, 2001 Jul, 7(3), 219 - 24
Singlet oxygen inhibits agonist-induced P-selectin expression and formation of platelet aggregates; Stief TW et al.; Major mediators of activated polymorphonuclear leukocytes (PMN) are the oxidants HOCl and chloramine, which are a source for the nonradical photon-emitting oxidant singlet oxygen (1O2) . We were interested in a possible platelet-modulating activity of 1O2 . As a stable 1O2 source we chose the mild oxidant chloramine T (CT), which mimics the natural chloramine N-chloro-taurine . Freshly drawn native whole blood from donors (n = 5) was incubated at 0 to 3 mM CT for 1 minute at 37 degrees C . Then saline . 10 microM adenosine diphosphate (ADP), 5 microg/mL collagen, or 6.25 microM thrombin receptor activator peptide (TRAP) were added and the mixtures were allowed to incubate for 3 minutes at 37 degrees C . Aliquots of activated blood were fixed in 1% para-formaldehyde . After removal of the fixative, platelets were labeled with anti-CD61-FITC and anti-CD62P-PE antibodies and analyzed by flow cytometry . An oxidant concentration-dependent decrease in the expression of P-selectin appeared (at 3 mM CT to 39, 23, and 20% of the 100% saline control level for ADP, collagen, and TRAP, respectively) . There was also an oxidant concentration-dependent decrease in the formation of platelet aggregates (at 3 mM CT to 8, 12, and 13% of the 100% saline control level for ADP, collagen, and TRAP, respectively; the 50% effective dose was 1.0 to 1.5 mM chloramine) . In ADP- and TRAP-stimulated platelets, an oxidant-mediated increase in platelet fragments appeared (at 3 mM CT: three- to fourfold of the initial value) . The addition to the blood of 30 mM of the oxyradical scavenger mannitol in contrast to excess methionine did not antagonize these oxidative modulations of platelet activation . The results were confirmed using equimolar concentrations of NaOCI and N-chloro-taurine . This study shows that 1O2 inhibits platelets, decreasing the expression of CD62P and the formation of platelet aggregates . Activated PMN might modulate hemostasis, shifting it into an antithrombotic state . The physiologic signal action and the direct anticoagulant action of 1O2 (released by chloramines such as vancomycin) might be a new principle for pharmacologic intervention in atherothrombosis.

Eur J Pharm Biopharm, 2001 Jul, 52(1), 83 - 9
Trehalose-hydroxyethylcellulose microspheres containing vancomycin for topical drug delivery; Giandalia G et al.; A new formulation, in which vancomycin is entrapped into trehalose and hydroxyethylcellulose (Natrosol) spherical matrices, is described . Microspheres were produced by the solvent evaporation method . The entrapped drug was fully recovered following microspheres dissolution . Differential scanning calorimetry analyses proved that Natrosol maintains trehalose in its amorphous form . The stabilizing effects of trehalose on vancomycin were evaluated even after long storage and heating of microspheres . Calorimetric data indicated no decomposition of the entrapped drug . In vitro drug release, already performed by using a general two-compartment linear time-invariant open model, suggests that the new delivery system is suitable for topical application on extensive and purulent or burn wounds, when the skin is heavily damaged and the barrier disrupted . The system activation is determined by osmotic phenomena . The prepared new delivery system seems to have characteristics suitable for topical applications on extensive and purulent wounds . The system is able to take away serous exudates from wounds, thus letting the matrix to swell and form a viscous gel-like dispersion that, in turn, enables drug diffusion.

J Am Chem Soc, 2001 Jul 4, 123(26), 6262 - 7
An enthalpic component in cooperativity: the relationship between enthalpy, entropy, and noncovalent structure in weak associations; Calderone CT et al.; Attempts to quantify binding interactions of noncovalent complexes in aqueous solution have been stymied by complications arising from enthalpy-entropy compensation and cooperativity . We have extended work detailing the relationship between noncovalent structure and free energy of binding to include the roles of enthalpy and entropy of association . On the basis of van't Hoff measurements of the dimerization of vancomycin type antibiotics, we demonstrate that positive cooperativity manifests itself in a more favorable enthalpy of association and a partially compensating less favorable entropy of association . Finally, we extend these results to rationalize thermodynamic observations in unrelated systems.

Acta Crystallogr D Biol Crystallogr, 2001 Jul, 57(Pt 7), 977 - 80 Epub 2001 Jun 21.
De novo structure determination of vancomycin aglycon using the anomalous scattering of chlorine; Loll PJ; The crystal structure of vancomycin aglycon has been determined by exploiting the anomalous scattering of Cl atoms present within the molecule . Real-space-reciprocal-space cycling with Shake-and-Bake successfully located the chlorine positions from the Bijvoet differences, even though the anomalous difference Patterson map proved to be uninterpretable . The chlorine anomalous differences lacked sufficient phasing power to produce interpretable electron-density maps . However, when combined with high-resolution native data, the chlorine positions were sufficient to determine the structure using either Shake-and-Bake or a tangent-formula expansion.

Org Lett, 2001 Jun 28, 3(13), 2033 - 6
Stereoselective synthesis of the axially chiral A-B ring system of vancomycin utilizing a planar chiral arene chromium complex; Kamikawa K et al.; {reaction: see text} The axial biaryl ring system of vancomycin was stereoselectively synthesized by utilizing a planar chiral tricarbonyl(arylhalide)chromium complex . Both enantiomers of the planar chiral (arylbromide)chromium complexes, (+)-9 and ent-(-)-9, can be stereoselectively transferred to an absolutely identical key intermediate 23 for the vancomycin A-B ring system by the diastereoselective Suzuki-Miyaura cross-coupling reaction as key step.

Biomed Chromatogr, 2001 May, 15(3), 217 - 22
Chiral resolution of flurbiprofen and ketoprofen enantiomers by HPLC on a glycopeptide-type column chiral stationary phase; Pehourcq F et al.; Vancomycin is an amphoteric, glycopeptide, macrocyclic antibiotic . When attached to 5 microspherical silica gel, vancomycin proved to be an effective chromatographic chiral stationary phase that could be used in the reversed-phase mode . In this study, a bonded vancomycin chiral stationary phase (Chirobiotic Vtrade mark) was investigated for the chiral liquid chromatography analysis of ketoprofen and flurbiprofen . The selectivity factor (alpha) and the chiral resolution factor (RS) of Chirobiotic Vtrade mark were evaluated first as a function of the buffer pH and molarity, and second as a function of organic modifier type and composition of the mobile phase . Four organic modifiers (tetrahydrofuran, 2-propanol, 1,4-dioxane and methanol) have been tested for their selectivity . Optimized conditions using 20% of tetrahydrofuran in ammonium nitrate (100 mM, pH 5) were selected for the enantioseparation of flurbiprofen and ketoprofen from their racemic forms . At pH 5, these acidic compounds are almost negatively charged, while the chiral selector possesses a positive charge allowing it to interact electrostatistically with the analytes . Using these chromatographic conditions, the column stability was excellent over several months of experiments .

Cutis, 2001 May, 67(5), 423 - 6
Linear IgA bullous dermatosis associated with vancomycin and disseminated varicella-zoster infection; Ahkami R et al.; Linear IgA bullous dermatosis (LABD) is characterized by linear deposits of IgA at the basement membrane zone . Most cases are idiopathic, but medications, infections, autoimmune disorders, and malignancies have been documented as potential inducers . We report a case where both vancomycin and varicella-zoster infection were present as triggers.

BETA . 1995 Sep;:11-2.
Medicare may not reimburse for certain AIDS and cancer drugs; Baker R; AIDS: The Durable Medical Equipment Regional Carriers has recommended excluding ganciclovir, acyclovir, and vancomycin from the list of Medicare-covered drugs . Only drugs infused by a pump, as indicated in the drug's product labeling, will be covered . IV ganciclovir is not covered, even though it is the drug of choice for treating cytomegalovirus retinitis . IV acyclovir, a standard therapy for disseminated herpes simplex infection among people with AIDS, is also not covered .

J Biochem Biophys Methods, 2001 Apr 24, 48(2), 163 - 74
Synergistic chiral separations using the glycopeptides ristocetin A and vancomycin; Ward TJ et al.; The effectiveness of using a mixture of the chiral selectors vancomycin and ristocetin A to achieve chiral recognition was examined in this study . The results of using the mixed chiral selector vancomycin and ristocetin A in capillary electrophoresis were compared with the results of using each chiral selector alone . Chiral separations were carried out using a coated capillary column to suppress electroosmotic flow and minimize interactions with the capillary wall . We employed a countercurrent process where the solute reaches the detection cell window after the chiral selector has cleared the window, minimizing the background absorbance from the chiral selector and improving sensitivity . Using a mixture of vancomycin and ristocetin A, separations were achieved which often exceeded the resolving power of either chiral selector when used alone . The effect of voltage on resolution was also studied, and the optimal voltage was found to be between -5 and -8 kV.

J Chromatogr B Biomed Sci Appl, 2001 Apr 15, 754(1), 141 - 51
Determination of albumin and myoglobin in dialysate and ultrafiltrate samples by high-performance size-exclusion chromatography; Liang H et al.; A high-performance size-exclusion chromatographic method was developed, validated and implemented for simultaneous and quantitative determination of albumin and myoglobin along with inulin, vancomycin and creatinine in dialysate and ultrafiltrate samples from in vitro hemodialysis experiments . The experimental parameters including mobile phase pH, ionic strength, detection wavelength, flow-rate, injection volume were first optimized for the determination of albumin, myoglobin, inulin, vancomycin and creatinine . The peak height ratio and detection limits of the proteins were then comparatively studied at 210, 254 and 280 nm by UV and diode array detection . The method was further validated by evaluating the linearity, precision and accuracy of the proteins . The assay was finally implemented to the simultaneous and quantitative determination of the proteins in dialysate and ultrafiltrate samples.

Pharmacotherapy, 2001 Apr, 21(4), 443 - 51
Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs; Streetman DS et al.; STUDY OBJECTIVE: To examine the impact of individualized pharmacokinetic monitoring (IPM) on the development of aminoglycoside-associated nephrotoxicity (AAN) . DESIGN: Retrospective case-control study . SETTING: Two teaching hospitals . SUBJECTS: Two thousand four hundred five patients who received aminoglycosides . INTERVENTION: Aminoglycoside therapy dosed by either IPM or physicians' directions . MEASUREMENTS AND MAIN RESULTS: Patients receiving IPM were significantly less likely to develop AAN by both univariate (7.9% vs 13.2%, p=0.02) and multivariate methods (odds ratio 0.42, p=0.002) . Female sex was protective against AAN . Age 50 years and above, high initial aminoglycoside trough, long duration of therapy, and concurrent piperacillin, clindamycin, or vancomycin increased risk of AAN . We estimated that IPM decreased AAN costs by $90,995/100 patients . CONCLUSION: Individualized pharmacokinetic monitoring significantly decreased the frequency of AAN and its associated economic costs.

Biochemistry, 2001 Apr 17, 40(15), 4745 - 55
Tandem action of glycosyltransferases in the maturation of vancomycin and teicoplanin aglycones: novel glycopeptides; Losey HC et al.; The glycopeptides vancomycin and teicoplanin are clinically important antibiotics . The carbohydrate portions of these molecules affect biological activity, and there is great interest in developing efficient strategies to make carbohydrate derivatives . To this end, genes encoding four glycosyltransferases, GtfB, C, D, E, were subcloned from Amycolatopsis orientalis strains that produce chloroeremomycin (GtfB, C) or vancomycin (GtfD, E) into Escherichia coli . After expression and purification, each glycosyltransferase (Gtf) was characterized for activity either with the aglycones (GtfB, E) or the glucosylated derivatives (GtfC, D) of vancomycin and teicoplanin . GtfB efficiently glucosylates vancomycin aglycone using UDP-glucose as the glycosyl donor to form desvancosaminyl-vancomycin (vancomycin pseudoaglycone), with k(cat) of 17 min(-1), but has very low glucosylation activity, < or = 0.3 min(-1), for an alternate substrate, teicoplanin aglycone . In contrast, GtfE is much more efficient at glucosylating both its natural substrate, vancomycin aglycone (k(cat) = 60 min(-1)), and an unnatural substrate, teicoplanin aglycone (k(cat) = 20 min(-1)) . To test the addition of the 4-epi-vancosamine moiety by GtfC and GtfD, synthesis of UDP-beta-L-4-epi-vancosamine was undertaken . This NDP-sugar served as a substrate for both GtfC and GtfD in the presence of vancomycin pseudoaglycone (GtfC and GtfD) or the glucosylated teicoplanin scaffold, 7 (GtfD) . The GtfC product was the 4-epi-vancosaminyl form of vancomycin . Remarkably, GtfD was able to utilize both an unnatural acceptor, 7, and an unnatural nucleotide sugar donor, UDP-4-epi-vancosamine, to synthesize a novel hybrid teicoplanin/vancomycin glycopeptide . These results establish the enzymatic activity of these four Gtfs, begin to probe substrate specificity, and illustrate how they can be utilized to make variant sugar forms of both the vancomycin and the teicoplanin class of glycopeptide antibiotics.

Electrophoresis, 2001 Feb, 22(3), 535 - 43
Use of vancomycin silica stationary phase in packed capillary electrochromatography I . Enantiomer separation of basic compounds; Desiderio C et al.; Chiral separation of basic compounds was achieved by using 75 or 100 microm ID fused-silica capillaries packed with a vanoomycin-modified diol silica stationary phase . The capillary was firstly packed for about 12 cm with a slurry mixture composed of diolsilica (3:1) then with the vancomycin modified diol-silica (3:1) (23 cm), and finally with diol-silica (3:1) for about 2 cm . Frits were prepared by a heating wire at the two ends of the capillary; the detector window was prepared at 8.5 cm from the end of the capillary where vancomycin was not present . The influence of the mobile phase composition (pH and concentration, organic modifier type and concentration) on the velocity of the electroosmotic flow, chiral resolution and enantioselectivity was studied . Good enantiomeric resolution was achieved for atenolol, oxprenolol, propranolol, and venlafaxine using a mobile phase composition of 100 mM ammonium acetate solution (pH 6)/water/acetonitrile (5:5:90 v/v/v) while for terbutaline a mixture of 5:15:80 v/v/v provided the best separations . The use of methanol instead of acetonitrile caused a general increase of enantiomer resolution of the studied compounds together with a reduction of efficiency and detector response . However, the combination of acetonitrile and methanol in the mobile phase (as, e.g., 10% methanol and 80% acetonitrile) allowed to improve the enantiomer resolution with satisfactory detector response.

J Antimicrob Chemother, 1999 Feb, 43(2), 233 - 42
Ability of teicoplanin and vancomycin to induce contraction of, and histamine release from, pulmonary tissue of humans, monkeys and guinea pigs; Nabe T et al.; To assess the safety of teicoplanin and vancomycin with respect to airway tissue, we evaluated whether these two antibiotics induce pulmonary tissue contraction and histamine release in human, monkey and guinea pig specimens in vitro . The effects of these drugs on the release of histamine from monkey blood leucocytes and mouse bone marrow-derived mast cells (BMMC) were also studied . Neither teicoplanin nor vancomycin (10(-6)-10(-3) g/mL) induced contractions of guinea pig trachea or lung parenchyma . Similarly, these drugs induced no appreciable change in the resting tonus of cynomolgus monkey bronchus or lung parenchyma . The tonus of monkey trachea was not influenced by teicoplanin, whereas 10(-3) g/mL vancomycin caused contraction . The spontaneous tonus of human lung parenchyma was not altered by teicoplanin or vancomycin, and that of the bronchus was not influenced by teicoplanin; however, 10(-3) g/mL vancomycin elicited obvious contraction of the bronchus . Neither drug promoted the release of significant amounts of histamine from these pulmonary tissues or from monkey blood leucocytes and BMMC . These results suggest that, compared with vancomycin, teicoplanin may be associated with a lower risk of inducing bronchospasm when used for inhalation therapy.

Int J Food Microbiol, 2001 Feb 15, 63(3), 281 - 6
Survival of Helicobacter pylori in ready-to-eat foods at 4 degrees C; Poms RE et al.; The survival of Helicobacter pylori (NCTC 11638) in various semiprocessed and fresh, ready-to-eat foods, and one raw chicken was studied at 4 degrees C and under aerobic conditions by experimentally inoculating these with 10(4) CFU . Cells were concentrated by two centrifugation cycles followed by plating onto selective blood agar medium made from Wilkins-Chalgren agar supplemented with 5% whole horse blood, and 30 mg/l colistin methanesulfonate, 100 mg/l cycloheximide, 30 mg/l nalidixic acid, 30 mg/l trimethoprim, and 10 mg/l vancomycin . H . pylori was recovered from spiked pasteurized milk and tofu samples up to 5 days and from spiked leaf lettuce and raw chicken up to 2 days . H . pylori could not be recovered from yogurt after any length of storage time . H . pylori is unlikely to grow in foods; however, it may survive in low acid-high moisture environments under refrigeration and pose a possible risk for transmission of infection via foods.

Am J Ophthalmol, 2001 Mar, 131(3), 293 - 300
The effect of topical povidone-iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery; Mendivil Soto A et al.; PURPOSE: To investigate whether the use of topical povidone-iodine before surgery, the addition of vancomycin to the irrigating solutions during phacoemulsification, or both reduces the frequency of positive intraocular cultures at the end of surgery . METHODS: A two-part, clinical study was performed . In the preliminary study, intracameral antibiotic concentrations were measured immediately after surgery (in 11 eyes) and 2 hours after surgery (in 11 eyes) in patients treated with vancomycin . In the primary study, 400(1) patients were divided into four groups composed of 100 eyes each . The first and the second groups received vancomycin (20 microg/ml) in the irrigating fluid . The third and the fourth groups received irrigating fluid only without antibiotics . The first and third groups received a topical 5% povidone-iodine solution 10 and 5 minutes before surgery; a topical placebo solution was used in the second and the fourth groups . All patients in the primary study underwent anterior chamber aspiration after surgery, and culturing was performed 2 hours later . Identification and quantification of positive cultures in thioglycolate broth and chocolate agar were performed . RESULTS: In the preliminary study, the half-life of intraocular vancomycin was less than 2 hours . In the primary study, intraocular aspirates yielded positive cultures in two (2%), five (5%), 11 (11%), and 13 (13%) specimens from the first, second, third, and fourth groups, respectively . CONCLUSIONS: We found a lower rate of positive cultures in the group that received vancomycin in the irrigating fluid; 2 hours of contact between the antibiotic solution and bacteria produced results that reached statistical significance (P = 0.032).

J Chromatogr B Biomed Sci Appl, 2001 Feb 25, 751(2), 377 - 82
New sensitive assay of vancomycin in human plasma using high-performance liquid chromatography and electrochemical detection; Favetta P et al.; A method using reversed-phase high-performance liquid chromatography with electrochemical detection for the analysis of vancomycin in human plasma was developed . Chromatographic conditions included an octadecyl column, a mobile phase of acetonitrile-sodium phosphate buffer (pH 7) (12:88), a total run time of 12 min, and coulometric electrochemical detection at +700 mV . Linear detector response was found in the range 5-100 microg ml(-1) after a 1:80 dilution or from 0.5 to 50 microg ml(-1) after a 1:20 dilution of the samples . In both cases the correlation coefficient (r) of the calibration curve standard was better than 0.995 . Vancomycin determination was based on a denaturation of plasma proteins with methanol, then a dilution with mobile phase was performed . Recovery of vancomycin from plasma was 103.1+/-3.9%, and no interference from commonly used drugs or endogenous compounds was observed . A significant correlation was shown with the EMIT assay (r=0.92, P<0.001) using clinical samples from children . This HPLC technique is simple, sensitive, rapid, precise, selective and requires only 100 microl of plasma for completion.

Rinsho Biseibutshu Jinsoku Shindan Kenkyukai Shi, 2000, 11(2), 79 - 85
{Comparative evaluation of two different formulae of Middlebrook 7H9 broth in a fully automated mycobacteria culture system, MB/BacT; the effect of Tween 80}; Saitoh H et al.; Two different formulae of Middlebrook 7H9 broth, one containing Tween 80 {Tween (+) broth} and the other containing vancomycin but not Tween 80 {Tween (-) broth}, were evaluated in parallel for a fully automated mycobacteria culture system, MB/BacT(Organon Teknika, Durham, NC, U.S.A.) . A total of 586 clinical sputum specimens were digested and decontaminated by the semi-alkaline protease-N-acetyl-L-cysteine-NaOH (SAP-NALC-NaOH) . Each part of sample treated was inoculated into the MB/BacT Process Bottle containing the respective Middlebrook 7H9 broth . Culture bottles were incubated in the MB/BacT at 37 degrees C for up to 56 days . Of 586 samples, 110 isolates of Mycobacterium tuberculosis complex and 77 of nontuberculous mycobacteria (NTM) were isolated . The occurrence of false alarm due to breakthrough contamination was 3.2 in Tween (+) broth and 2.9% in Tween (-) broth . Also, the positivities of mycobacteria by the respective culture media were comparable . However, Tween (-) broth could detect positive cultures for mycobacteria, particularly for M . tuberculosis complex at the earlier incubation cycle when compared to Tween (+) broth . The time to detect 50% positive cultures for M . tuberculosis complex was 20.5 days for Tween (-) broth and 34.3 days for Tween (+) broth, respectively . With the results, it was concluded that; Tween (+) broth produced homogeneous mycobacterial growth in culture media, and thus, it was easy to prepare the inoculum directly adjusted to McFarland turbidity to the susceptibility test . However, the present formula of Middlebrook 7H9 broth supplemented with Tween 80 was not enough suitable for the rapid detection of positive cultures and needs some revisions to improve.

Arch Soc Esp Oftalmol, 2000, 75(5), 339 - 46
{Treatment of chronic pseudophakic endophthalmitis after cataract surgery}; Casas AP et al.; PURPOSE: To review our experience on the treatment of chronic pseudophakic endophthalmitis . METHODS: A retrospective and descriptive review of 6 consecutive cases: 4 after extracapsular cataract extraction and one after phacoemulsification with implant of posterior chamber intraocular lenses, and one aphakic patient after extracapsular cataract extraction . Treatment options included one or more of these techniques: intravitreal injection or anterior chamber injection or irrigation of the capsular bag with vancomycin (1.0 mg in 0.1 cc); pars plana vitrectomy with total or partial capsulectomy (with removal of the plaque) and the removal of the capsular bag and the intraocular lens through a limbal incision . RESULTS: 2 cases were managed with initial intravitreal vancomycin, associated in a third patient to a capsular bag irrigation . The two formers eventually required vitrectomy with posterior capsulotomy and removing of the white plaque; in a fourth patient, this technique was our initial step . Intraocular lens removal with capsular bag extraction was chosen as our first treatment measure on 2 patients and after vitrectomy failure in another case . Inflammation control was achieved in all our patients, although it took some time and some patients needed corticosteroids treatment during the meantime . CONCLUSIONS: Treatment indications of chronic postoperative endophthalmitis are not clearly established . In our experience, the best results are achieved with the techniques that remove completely the white plaque or the capsular bag and the intraocular lens.

J Chemother, 2000 Nov, 12 Suppl 5, 21 - 5
Comparative safety of teicoplanin and vancomycin; Wood MJ; Although modern preparations of vancomycin are associated with a lower incidence of adverse events than the early preparations, a number of clinically significant problems remain . Consequently monitoring of serum concentrations is required . In a meta-analysis of comparative trials adverse events were significantly less likely to occur with teicoplanin (13.9%) than with vancomycin (21.9%) (P = 0.0003) . This was particularly significant when nephrotoxicity was considered: 4.8% vs . 10.7%, for teicoplanin and vancomycin, respectively (P = 0.0005) . Red man syndrome, which may be due to histamine release, occurs after rapid infusion of vancomycin but is very rare following teicoplanin administration . In USA trials, thrombocytopenia was more commonly seen with teicoplanin administration but this was almost exclusively in patients receiving much larger doses than are now recommended . The lower rate of adverse events supports the choice of teicoplanin over vancomycin in treating infections where the two antibiotics have similar efficacy.

J Chemother, 2000 Nov, 12 Suppl 5, 15 - 20
Comparative pharmacokinetics of teicoplanin and vancomycin; Harding I et al.; Teicoplanin has unique properties that should be used to the advantage of patients . Due to its pharmacokinetic profile, teicoplanin is more effectively administered once daily than vancomycin and offers a choice of administration routes (i.v./i.m.) . At the recommended dosing regimen (6 mg/kg/day, with an additional loading dose of 12 mg/kg in the first 24 hours) efficacious serum levels of teicoplanin are almost guaranteed . Unlike vancomycin, routine drug monitoring is not required for safety reasons, but is, in certain clinical situations, useful for predicting teicoplanin's therapeutic effect.

J Chromatogr A, 2000 Nov 3, 897(1-2), 339 - 47
Multiple-step ligand injection affinity capillary electrophoresis for determining binding constants of ligands to receptors; Zhang Y et al.; This work demonstrates the use of multiple-step ligand injection affinity capillary electrophoresis (ACE) using two model systems: vancomycin from Streptomyces orientalis and carbonic anhydrase B (CAB, EC 4.2.1.1) . In this technique a sample plug of receptor and non-interacting standards is injected by pressure and electrophoresed in a buffer containing a given concentration of ligand . The sequence is repeated for all concentrations of ligand generating a single electropherogram containing a series of individual sample plugs superimposed on environments of buffer containing increasing concentrations of ligand . Analysis of the change in the relative migration time ratio, RMTR, relative to the non-interacting standards, as a function of the concentration of the ligand, yields a value for the binding constant . A competitive assay using the technique is also demonstrated using neutral ligands for CAB . These values agree well with those estimated using other binding and ACE techniques . Data demonstrating the quantitative potential of this method are presented.

J Chromatogr A, 2000 Nov 3, 897(1-2), 113 - 29
Evaluation of the macrocyclic glycopeptide A-40,926 as a high-performance liquid chromatographic chiral selector and comparison with teicoplanin chiral stationary phase; Berthod A et al.; A new macrocyclic antibiotic of the vancomycin family, referred to by its industrial designation as A-40,926, was bonded to 5 microm silica particles and utilised as a chiral stationary phase (CSP) . Since A-40,926 is structurally related to teicoplanin, the A-40,926 CSP was compared to a commercially available teicoplanin CSP . A set of 28 chiral compounds, including amino-acids and related compounds, compounds with a ring containing the stereogenic centre, compounds bearing aromatic structures near their stereogenic centres and alcohols, was tested for enantioseparation on the two CSPs . The results are compared and discussed in terms of enantioselective Gibbs energy difference . The A-40,926 CSP was able to resolve one compound that was not resolved by the teicoplanin CSP . However, it could not separate four compounds that the teicoplanin CSP did separate . It is shown that the A-40,926 CSP is complementary to the teicoplanin CSP, thereby enlarging the number of enantiomers that can be separated by the macrocyclic glycopeptide based CSPs.

Biochemistry, 2000 Dec 26, 39(51), 15971 - 9
Mechanism-based inactivation of VanX, a D-alanyl-D-alanine dipeptidase necessary for vancomycin resistance; Araoz R et al.; VanX is a zinc-dependent D-Ala-D-Ala amino dipeptidase required for high-level resistance to vancomycin . The enzyme is also able to process dipeptides with bulky C-terminal amino acids {Wu, Z., Wright, G . D., and Walsh, C . T . (1995) Biochemistry 34, 2455-2463} . We took advantage of this observation to design and synthesize the dipeptide-like D-Ala-D-Gly(SPhip-CHF(2))-OH (7) as a potential mechanism-based inhibitor . VanX-mediated peptide cleavage generates a highly reactive 4-thioquinone fluoromethide which is able to covalently react with enzyme nucleophilic residues, resulting in irreversible inhibition . Inhibition of VanX by 7 was time-dependent (K(irr) = 30+/-1 microM; k(inact) = 7.3+/- 0.3 min(-1)) and active site-directed, as deduced from substrate protection experiments . Nucleophilic compounds such as sodium azide, potassium cyanide, and glutathione did not protect the enzyme from inhibition, indicating that the generated nucleophile inactivates VanX before leaving the active site . The failure to reactivate the dead enzyme by gel filtration or pH modification confirmed the covalent nature of the reaction that leads to inactivation . Inactivation was associated with the elimination of fluoride ion as deduced from (19)F NMR spectroscopy analysis and with the production of fluorinated thiophenol dimer 12 . These data are consistent with suicide inactivation of VanX by dipeptide 7 . The small size of the VanX active site and the presence of a number of nucleophilic side chains at the opening of the active site gorge {Bussiere, D . E., et al . (1998) Mol . Cell 2, 75-84} associated with the high observed partition ratio of 7500+/-500 suggest that the inhibitor is likely to react at the entrance of the active site cavity.

Adv Drug Deliv Rev, 2000 Dec 6, 45(1), 5 - 26
Preparation and evaluation of w/o/w type emulsions containing vancomycin; Okochi H et al.; The objective of this contribution is to summarize the preparation and application of water-in-oil-in-water type multiple emulsions (w/o/w emulsions) entrapping vancomycin (VCM) . Formulations of the emulsions (the composition of an oily phase or the type and concentrations of surfactants) and emulsification methods (a stirring method and a membrane method) or conditions (rotation rates, pore sizes of membrane or operation pressures) were evaluated in order to prepare stable w/o/w emulsions . The pharmaceutical properties of the w/o/w emulsions - particle sizes, viscosity, phase separation and drug entrapment efficiency were measured and evaluated . We prepared stable w/o/w emulsions with a particle size of about 3 micrometer and an entrapment efficiency of VCM of about 70% . When this emulsion was administered intravenously to rats, plasma concentrations of VCM were prolonged compared to the VCM solution alone . The results of this study show the potential of the w/o/w emulsions for several clinical applications as one of the drug delivery systems.

Am J Kidney Dis, 2000 Dec, 36(6), 1262 - 6
Management of hypophosphatemia induced by high-flux hemodiafiltration for the treatment of vancomycin toxicity: intravenous phosphorus therapy versus use of a phosphorus-enriched dialysate; Gatchalian RA et al.; Intensive high-flux hemodiafiltration is often used in the management of vancomycin toxicity . We describe two patients who developed hypophosphatemia as a consequence of this form of therapy . The first patient was treated with an intravenous phosphorus infusion . For the second patient, hypophosphatemia was corrected, during hemodiafiltration, with the use of a phosphorus-enriched dialysate . The latter dialysate was prepared by adding sodium phosphate salts to the "base concentrate" of a dual-concentrate, bicarbonate-based dialysate delivery system . This simple method was more efficient than intravenous therapy in ameliorating the hypophosphatemia secondary to aggressive hemodiafiltration treatment.

Curr Treat Options Gastroenterol, 2000 Jun, 3(3), 203 - 210
Pseudomembranous Colitis Caused by C . difficile; Surawicz CM et al.; Pseudomembranous colitis (PMC) is a considerable clinical concern for several reasons, including disease severity, increasing frequency, complications, and development of antibiotic-resistant organisms . C . difficile infection should be considered in anyone who develops diarrhea during or after antibiotic therapy; PMC is the most serious manifestation of C . difficile disease . PMC is effectively treated with either metronidazole or vancomycin . Metronidazole should be first-line therapy, reserving vancomycin for those who are very ill or who do not respond to metronidazole or cannot take it (ie, first trimester pregnancy, side effects) . Recurrent C . difficile disease (which occurs in approximately 20% of C . difficile cases) is best treated with an antibiotic in combination with a biotherapeutic agent . Prevention of epidemics of C . difficile requires careful hand washing and cleaning of environmental surfaces . Antibiotic restriction may be necessary in some cases.

Adv Perit Dial, 2000, 16, 199 - 203
Preoperative vancomycin prophylaxis for newly placed peritoneal dialysis catheters prevents postoperative peritonitis; Gadallah MF et al.; The role of vancomycin and other antibiotics in treatment of acute peritonitis in peritoneal dialysis patients is well established . However, the role of preoperative vancomycin or cephalosporins in preventing early infection in newly placed peritoneal dialysis catheters remains controversial . We performed a prospective randomized study to examine the role of vancomycin or cefazolin prophylaxis in decreasing the incidence of postoperative peritonitis . Over 8-year period, 265 patients undergoing 305 permanent peritoneal catheter placement procedures were randomized into three groups . Group I (103 procedures) received a single intravenous (i.v.) dose of 1000 mg vancomycin 12 hours before the peritoneal catheter placement procedure . Group II (102 procedures) received a single i.v . dose of 1000 mg of Ancef (cefazolin) 3 hours before the procedure . Group III (100 procedures) received no antibiotics preoperatively for a least one week before the procedure . Patients were monitored for peritonitis during the following 14 days . Peritonitis developed in 1 patient (1%) in Group I (vancomycin group) compared to 12 patients (12%) in Group III (control group), p = 0.002, and in 9 patients (9%) in Group II (cefazolin group) compared to Group III, p = 0.68 . We conclude that the use of preoperative single-dose i.v . vancomycin prophylaxis for permanent peritoneal dialysis catheter placement reduces the risk of postoperative peritonitis . Cefazolin did not achieve a statistically significant difference from the control group and may not provide adequate prophylaxis.

Ther Drug Monit, 2000 Oct, 22(5), 522 - 31
Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients; Wrishko RE et al.; The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1) . Based on steady state serial vancomycin concentrations, the estimates of mean t1/2, Vd, and Cl derived by the Sawchuk and Zaske method (1) were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively . NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model . The two-compartment estimates of mean t1/2alpha, t1/2beta, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively . The relatively long mean t1/2alpha suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations . NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model . The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations . Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations . This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.

Clin Chim Acta, 2000 Nov, 301(1-2), 31 - 9
Rapid serum vancomycin assay by high-performance liquid chromatography using a semipermeable surface packing material column; Furuta I et al.; A new isocratic high-performance liquid chromatographic (HPLC) assay has been developed for vancomycin that uses direct injection of microquantities of serum into a separation column filled with octyl-C(8) silica support that has a semipermeable surface . A mixture of disodium hydrogen phosphate buffer (pH 7.0) and acetonitrile is used as the mobile phase, and vancomycin is directly detected at 240 nm . The minimum limit of detection was 0.5 microg/ml at a signal-to-noise ratio of 3:1 . Linearity was established from 0 to 100 microg/ml . The coefficient of variation for within-run reproducibility was 1.1-2.7% for a concentration range of 2.9-52.5 microg/ml; for day-to-day reproducibility it was 4.0% and 3.1% for a concentration range of 5.8-26.4 microg/ml, and the recovery rate was 94-105% . There was no interference from 41 antibiotics or other drugs currently in use . The correlation coefficient between the fluorescence polarization immunoassay (x) and this method (y) was 0.995 with a linear equation, y = 1.06x - 0.924 . This method is simple, rapid, and provides an economical quantification of serum vancomycin.

Clin Infect Dis, 2000 Sep, 31(3), 824 - 5
Vancomycin-induced neutropenia resolves after substitution with teicoplanin; Sanche SE et al.; Neutropenia is an uncommon adverse effect associated with prolonged vancomycin therapy . Neutrophil counts normally recover after discontinuation of vancomycin in this situation, but treatment options are needed for those patients who require ongoing antibiotic therapy . We describe a case of vancomycin-induced neutropenia in which the neutropenia resolved after vancomycin was replaced by the structurally related compound teicoplanin.

Anal Chem, 2000 Sep 15, 72(18), 4394 - 401
Evaluation of a vancomycin chiral stationary phase in capillary electrochromatography using polar organic and reversed-phase modes; Karlsson C et al.; A vancomycin chiral stationary phase (CSP) was fully evaluated in capillary electrochromatography (CEC) in reversed-phase and polar organic modes for a number of racemic pharmaceutical compounds . High efficiency and resolution values were obtained for a number of compound classes including thalidomide in both the polar organic mode (190000 plates meter(-1) and Rs = 13.8) and reversed-phase mode (125000 plates meter(-1) and Rs = 13.0) . Experimental parameters, including organic modifier, organic solvent ratio, ionic strength, pH, temperature, and voltage, were examined in both the aqueous and nonaqueous modes to deduce their effect on the resultant EOF, retention times, resolution, and efficiency of chiral separations . All results were consistent with and found to be a combination of what is known from existing literature on CEC theory and experience obtained with macrocyclic antibiotic CSPs in LC . Column stability was excellent, and each column packed was found to offer repeatable separations even when switching from the aqueous to the nonaqueous mode.

Jpn J Pharmacol, 2000 Aug, 83(4), 300 - 5
Influences of everninomicin, vancomycin and teicoplanin on chemical mediator release from rat peritoneal mast cells; Sugimoto Y et al.; We examined influences of certain antibiotics on the release of chemical mediators from isolated rat peritoneal mast cells in vitro . Isolated peritoneal mast cells were obtained from male Wistar strain rats . Everninomicin (0.06-1.2 mg/ml), vancomycin (0.05-1.0 mg/ml), teicoplanin (0.07-1.4 mg/ml) and concanavalin A (0.01 mg/ml) were used . Isolated mast cells were incubated in the presence of various concentrations of the test compound at 37 degrees C for 10 min . Histamine contents of the supernatant and cell pellet were measured by an automated fluorometric method . Prostaglandin D2 (PGD2) contents of the supernatant were determined by enzyme immunoassay . Everninomicin (0.06-1.2 mg/ml) had no influence on histamine and PGD2 release from mast cells . On the other hand, vancomycin significantly released both histamine (0.5 and 1.0 mg/ml) and PGD2 (1.0 mg/ml) from mast cells, but vancomycin did not affect concanavalin A-induced histamine and PGD2 release . Teicoplanin (more than 0.07 mg/ml) significantly stimulated histamine and PGD2 release from mast cells and it also significantly potentiated concanavalin A-induced histamine and PGD2 release . These results suggest that everninomicin causes no chemical mediator release from mast cells, different from vancomycin and teicoplanin.

J Chromatogr B Biomed Sci Appl, 2000 Aug 4, 745(1), 159 - 66
Chiral separation by simultaneous use of vancomycin as stationary phase chiral selector and chiral mobile phase additive; Sun Q et al.; Improved chiral selectivity was observed for numerous compounds when vancomycin was added to the mobile phase on a Chirobiotic-V column . This chiral mobile phase additive (CMPA) is the same chiral selector as that bonded to the stationary phase of this Chirobiotic-V column . A substantial increase in the difference in enthalpy of transfer, deltadeltaH, and in the difference in entropy of transfer, deltadeltaS, for two enantiomers was observed when vancomycin was used as both the mobile phase and the stationary phase chiral selector . The importance of mobile phase composition, analytical column, CMPA concentration was investigated . Also, higher resolution was observed for the separations of acidic compounds when a fluidity enhancing solvent, such as fluoroform, was added into the mobile phase . However, the most commonly used fluidity enhancement solvent, CO2, was ineffective.

J Pharm Pharm Sci, 2000 May-Aug, 3(2), 259 - 66
Colonization and immune responses in mice to Helicobacter pylori expressing different Lewis antigens; Suresh MR et al.; BACKGROUND AND AIMS: A mouse model was established to compare colonization by the H . pylori Sydney strain SS1 with several clinical isolates expressing different Lewis antigens on their surface . In addition, both humoral and cell mediated immune responses were determined for different H . pylori strains . METHODS: Mice were inoculated intragastrically separately with the Sydney strain as well as with five clinical isolates of H . pylori expressing different Lewis (Le) antigen phenotypes . Colonization of the mouse stomach by the bacteria was monitored from two to fourteen weeks post inoculation by four independent methods namely, urease, PCR (using CagA primers), bacterial culture and histology . Antibody titers and cellular immune responses were monitored by ELISA and antigen stimulation test respectively . RESULTS: Different degrees of colonization were observed in C57, CD1 and Balb/c mice inoculated with H . pylori strain SS1 (Le(x), Le(y)) and clinical isolates UA948 (Le(a), Le(x)), UA861 (alpha-glucosyl polyLacNAc), UA1258 (Le(y)), UA802 (Le(y)) and UA1264 (no Le antigen) starting from week two post inoculation . All three mice strains mounted high immune responses against different H . pylori antigens . Treatment of mice with vancomycin prior to inoculation has no effect either on colonization of the stomach or the immune response of the mice . Histological evaluation established colonization after 10 weeks post inoculation but not gastritis . CONCLUSIONS: Stomach of mice can be colonized consistently, with H . pylori strain SS1, and colonization was also achieved with all clinical isolates that were not mouse adapted . These strains could be detected more consistently by PCR in the early stages, then by culture only after 8 - 10 weeks . In our study, Lewis(x) expressing bacterial strain (UA948) failed to colonize Balb/c mice, whereas the Le(y) expressing strain (UA1258) did not colonize C57/BL6 mice.

J Pharm Sci, 2000 Oct, 89(10), 1243 - 52
Enhanced enteral bioavailability of vancomycin using water-in-oil-in-water multiple emulsion incorporating highly purified unsaturated fatty acid; Kajita M et al.; The aim of this study was to evaluate the potential of an emulsion incorporating unsaturated fatty acids to improve the mucosal absorption of poorly absorbed drugs from rat intestinal loops in situ, using a water-in-oil-in-water (W/O/W) multiple emulsion . Vancomycin hydrochloride (VCM) was used as a model drug with low oral bioavailability . The entrapment efficiency of VCM in the emulsion was approximately 60% and remained constant over storage for 1 month at 4 degrees C . The emulsion incorporating C18 unsaturated fatty acids or docosahexaenoic acid (DHA) markedly enhanced VCM absorption after colonic and rectal dosing . The effectiveness of DHA on VCM colonic absorption improvement was the same as that of oleic acid, and less than that of linoleic and linolenic acids . For rectal dosing, bioavailability was similar among various emulsions, in the range 40-50% . The effect of the emulsion incorporating oleic acid or DHA on improving VCM enteral bioavailability was not increased proportional to the incorporated amount . The electrical resistance of membranes was not changed by the incorporation of various fatty acids in emulsions . Our results indicated that W/O/W emulsions incorporating C18 unsaturated fatty acid or DHA were useful carriers for improving the absorption of poorly absorbable drugs via the intestinal tract without gross changes to tight junction function .

J Antimicrob Chemother, 2000 Sep, 46(3), 391 - 5
Intrinsic resistance of Mycobacterium tuberculosis to clarithromycin is effectively reversed by subinhibitory concentrations of cell wall inhibitors; Bosne-David S et al.; Subinhibitory concentrations of bacitracin, vancomycin and other inhibitors of cell wall synthesis reversed to varying extents the intrinsic resistance of Mycobacterium tuberculosis to clarithromycin . Ethambutol reversed clarithromycin resistance in all of the M . tuberculosis strains studied regardless of their susceptibility to this drug.

J Ocul Pharmacol Ther, 2000 Aug, 16(4), 373 - 81
Pharmacokinetics of 0.5 mg of a single and a multiple dose of intravitreal vancomycin in infected rabbit eyes; Coco RM et al.; The purpose of this study was to determine the pharmacokinetics governing distribution and elimination of 0.5 mg of intravitreal vancomycin in a single dose and in a multiple therapeutic regime in infected rabbit eyes . A total of 96 rabbits was injected with approximately 200 CFU of S . aureus intravitreally . Four days later, a single dose of 0.5 mg of vancomycin was administered to Group I (n=36) . Group II (n=60) was injected with a maximum of 4 doses of 0.5 mg every 36 hr . Four animals were sacrificed at different time points in each group . Samples of vitreous, aqueous and blood were taken from each animal for analyses by HPLC . These results were evaluated using the RSTRIP program . High vancomycin concentrations were demonstrated in the vitreous of Group I, with a calculated half-life of 12 hr . In Group II, vancomycin levels were within the therapeutic range during the entire experiment . There was minimal accumulation of the drug, and the half-life did not seem to be longer with multiple doses . In conclusion, the pharmacokinetics do not change significantly when a multidose regime is used compared with a single dose . Therapeutic intravitreal concentrations of vancomycin can be achieved by using repeated doses of 0.5 mg of vancomycin.

Foot Ankle Int, 2000 Aug, 21(8), 643 - 50
Tibiocalcaneal arthrodesis for the management of severe ankle and hindfoot deformities; Myerson MS et al.; PURPOSE: The purpose of this investigation was to evaluate the outcome of tibiocalcaneal arthrodesis using an adolescent condylar blade plate for severe ankle and hindfoot deformities . MATERIALS AND METHODS: We retrospectively reviewed the records of patients managed at our institutions between 1989 and 1996 whose tibiocalcaneal arthrodeses were performed with adolescent condylar blade plates and allograft bone . In these 30 patients (14 men, 16 women; average age, 53 years), the etiologies of the nonbraceable deformity included: diabetic neuroarthropathy with talar fragmentation and resorption (26), inflammatory arthritis (3), and posttraumatic avascular necrosis of the talus with collapse (1) . Due to the severity of the deformity in 28 of these patients, the alternative treatment would have been amputation . Thirteen patients had undergone previous surgeries, eight had documented osteomyelitis, and 13 had ulcers ranging from 2 to 27 mm . At surgery, the remnants of the talus were removed . Morcellized bone graft mixed with tobramycin/vancomycin powder was inserted into the arthrodesis site and then fixed with a rigid plate . Intravenous antibiotics, followed by oral antibiotics, were given until wound healing and suture removal . Follow-up averaged 48 months (19 to 112 months) . RESULTS: Tibiocalcaneal fusion was achieved in 28/30 patients at an average of 16 weeks (12 to 18 weeks) . Complications occurred in seven patients: two developed stress fractures of the tibia at the proximal end of the blade plate, three had superficial cellulitis that resolved with antibiotic therapy, and two had nonunions . CONCLUSION: Tibiocalcaneal arthrodesis using an adolescent condylar blade plate and allograft bone can be a successful procedure in the patient with severe neuropathic ankle deformity and can achieve a stable plantigrade foot for limited community ambulation with relatively few complications.

Org Lett, 2000 Aug 10, 2(16), 2459 - 62
Asymmetric synthesis of actinoidic acid derivatives; Boisnard S et al.; Synthesis of fully protected actinoidic acid derivative 3 and selectively protected biaryl bisamino acid 4, intermediates for vancomycin total synthesis, are reported.

Electrophoresis, 2000 Jul, 21(12), 2343 - 51
Evaluation of new adsorbed coatings in chiral capillary electrophoresis and the partial filling technique; Chiari M et al.; When using chiral selectors and the partial filling technique in capillary electrophoresis, a suitable and reproducible suppression of the electroosmotic flow is still a challenging issue, and there are a number of reasons to find alternatives to the use of covalently coated capillaries for such a particular application . In this paper, new achiral, neutral, and water-soluble polymers are evaluated as adsorbed polymers for the suppression of electroosmotic flow (EOF) when employing chiral capillary electrophoresis and the partial filling technique . Four chiral selectors, namely a cationic cyclopeptide, vancomycin, human serum albumin and riboflavin binding protein have been chosen for this study and some analytes such as derivatized amino acids, promethazine and prilocaine have been used as test compounds . Reproducibility of migration times, resolution, and selectivity as well as efficiency are reported to critically evaluate the performance of the adsorbed coatings . Results are compared to parallel data obtained with fused-silica and polyvinyl alcohol-coated capillaries.

Rev Latinoam Microbiol, 1999 Apr-Jun, 41(2), 63 - 6
{Serotyping of strains of Serpulina hyosenteriae isolated form swine with porcine dysentery symptoms in the province of Buenos Aires}; Moredo FA et al.; Seventeen Serpulina hyodysenteriae strains isolated from faeces, rectal swabs and intestinal contents of pigs with Swine Dysentery, from farms located in Buenos Aires province were serotyped . Samples on selective media (trypticase soy agar added by 5% ovine blood, 400 mg/l spectinomicin, 30 mg/l colistin, 30 mg/l vancomycin) were streaked and incubated under anaerobic atmosphere for 72 h at 42 degrees C . Suspected S . hyodysenteriae growth were identified by strong beta-hemolytic zone, without colonies, and the spirillar morphology, using the Victoria Blue 4-R stain were criteria following by S . hyodysenteriae preliminar identification . The following antigens were made by phenolic extraction from a concentrated inocula washed twice in PBS pH 7: whole-cell (WC), boiled cell (BC) and lipopolysaccharide (LPS) . Two serological test were: coagglutination and immunodiffusion, using polyclonal rabbit antisera against the 9 serotypes of S . hyodysenteriae and S . innocens, using WC and BC like antigens for the first test and BC and LPS for the second . The Dot-ELISA Test was performed using BC and LPS antigens and monoclonal antibodies (AbM) against serotypes 1, 2, 3, 8, 9 of S . hyodysenteriae, AbM species-specific and AbM against S . innocens . All isolated S . hyodysenteriae strains belonged to serotype 8 . Like in other countries occurred, it would exit a high regional prevalence of S . hyodysenteriae serotype, being the serotype 8 in Argentine.

Am J Health Syst Pharm, 2000 Jul 15, 57(14), 1326 - 31
Home care pharmacy: extending clinical pharmacy services beyond infusion therapy; Triller DM et al.; A clinical pharmacy program was developed at an established home health care (HHC) agency to demonstrate the need for clinical pharmacy services in the HHC population and to explore opportunities for providing pharmaceutical care beyond infusion-related therapies . Initial experiences of this pilot project are described . Patients were found to be primarily elderly (mean age, 70 years) and to use a substantial number of medications . While only 11% of patients referred to the agency required infusion therapy, multiple opportunities for pharmacist involvement in patient care were identified and a variety of projects were undertaken . A drug information service was developed, a retrospective evaluation of patients with congestive heart failure led to an interventional study, a cisapride intervention was implemented, home vancomycin monitoring was assessed, pharmaceutical care services were provided to patients enrolled in a long-term home care program, a pain management initiative was begun, adverse drug reactions were identified and reported, and pharmacists participated in agency policy development . Preliminary data suggest that pharmacist involvement positively affected patient care . Drug information was provided on 232 occasions . Cisapride was discontinued in five patients with contraindications to the agent . Comprehensive pharmacotherapy assessments were performed on 29 long-term-care patients, generating 129 therapy recommendations of which 33% were accepted . Pharmacists working with a home care agency identified numerous opportunities for improving patient care . Many of the patients receiving home care services were elderly, took a substantial number of medications, and were at risk for drug-related problems and suboptimal therapy.

Kansenshogaku Zasshi, 2000 Jun, 74(6), 527 - 35
{Evaluation of enrichment cultures for detection of Escherichia coli O157 from human stool specimens by using immunomagnetic separation}; Nakayama H et al.; We investigated the conditions of enrichment cultures preceding the immunomagnetic separation (IMS) procedure to detect Escherichia coli O157 (E . coli O157) from human stool specimens in routine laboratory examinations . Samples were made by adding either of the three selected strains of E . coli O157 to stools from three healthy human subjects in three different doses . The enrichment cultures were done for 18 hours at 37 degrees C or 42 degrees C, using five different media such as trypticase soy broth (TSB) . TSB containing cefixime, tellurite and vancomycin, modified EC broth (mEC), mEC containing novobiocin (N-mEC) and BGLB . The IMS procedure following enrichment culture increased the detection rate of E . coli O157, irrespective of the kinds of the media and the temperatures . It recovered E . coli O157 in 42 samples out of 90, while only 31 samples were positive when the IMS was not applied . The N-mEC showed the best recovery rate of the five enrichment media, and it was the only media that recovered the E . coli O157 Gunmma 298 strains at a level of 2-3 cells per ml . In 73 stool samples collected from probable patients with E . coli O157 infection and subjects who made close contact with the patients, positive results were obtained in six samples with the N-mEC enrichment followed by the IMS procedure, while only three samples were positive by the direct isolation culture . It was concluded, therefore, that, in routine laboratory examinations of E . coli O157 from human stools, the N-mEC enrichment culture for 18 hours followed by the IMS procedure is a sensitive method even when the dose of E . coli O157 in the stool is minimal.

Bioorg Med Chem Lett, 2000 Jul 17, 10(14), 1613 - 5
Binding interactions of vancomycin tracers with a bacterial cell wall peptidoglycan analogue; Adamczyk M et al.; Binding interactions between several vancomycin tracers and (N,N'-diacetyl)KDADA in solution were evaluated in a competition format using a surface plasmon resonance instrument . Tracers derivatized from the carboxy terminus or the N-vancosaminyl sugar moiety of vancomycin bind the peptide with an affinity similar to that of underivatized vancomycin . In contrast, N-methylleucyl derivatized vancomycin tracers bind the peptide with a reduced affinity relative to vancomycin.

Chirality, 2000 Aug, 12(8), 606 - 13
Polar organic phase liquid chromatography with packed capillary columns using a vancomycin chiral stationary phase
Svensson LA, Donnecke J, Karlsson KE, Karlsson A, Vessman J.
Vancomycin immobilized on silica served as the chiral stationary phase (CSP) in this investigation with polar organic solvents as the mobile phase in liquid chromatography (LC) . It was shown that trace amounts of water were beneficial for improving peak shape and efficiency . To regulate the retention and selectivity an acid and/or base were added to the mobile phase where an excess of acid was shown to be preferential for enantioseparation . An unusual increase in selectivity with increasing temperature was shown for the acidic drug, thalidomide . Additionally, nonlinear van't Hoff plots were obtained for metoprolol enantiomers that showed increased retention with increasing temperature . Metoprolol also showed unusual behavior in the polar organic phase when water was added to resemble reversed-phase chromatography, with minimum retention observed at high water or high methanol concentrations . In both instances a high degree of electrostatic interaction between metoprolol and vancomycin was concluded . Metoprolol and ten of its analogs were examined on this CSP to evaluate the enantiorecognition process . A comparison in enantioselectivity for a number of acidic and basic drugs using this CSP was also carried out using the polar organic phase, reversed phase, and normal phase LC which were all compared to the results obtained in supercritical fluid chromatography (SFC) . Polar organic phase LC offered a better separation of basic molecules while reversed phase LC was preferred for the resolution of acids . SFC showed the broadest enantioselectivity overall and normal phase LC indicated similar properties, as expected, to SFC but with lower column efficiency .

Rapid Commun Mass Spectrom, 2000, 14(13), 1128 - 35
High-throughput chiral liquid chromatography/tandem mass spectrometry; Bakhtiar R et al.; Chiral liquid chromatography is a well-established area of bioanalytical chemistry and is often used during the processes of drug discovery and development . The development and use of a chiral drug require the understanding of the pharmacokinetic characteristics of each of the enantiomers, including potential differences in their absorption, distribution, metabolism, and excretion . Chromatographic techniques coupled to atmospheric pressure ionization-tandem mass spectrometry have shown potential as sensitive and robust tools in the quantitative and qualitative determination of enantiomers in biologic fluids and tissue extracts . However, development of a chiral liquid chromatography method requires time-consuming procedures that are devised empirically . Clearly, there is an incentive to design chromatographic approaches that are easy to use, compatible with mass spectrometry ionization interface conditions, exhibit relatively short run times without compromising sensitivity, and offer a broad analyte specificity . For these reasons, the present paper explores the feasibility of the bonded macrocyclic glycopeptide phases (teicoplanin and vancomycin) for analysis by chiral liquid chromatography/tandem mass spectrometry . Ritalinic acid, pindolol, fluoxetine, oxazepam, propranolol, terbutaline, metoprolol, and nicardipine were tested in this study . Furthermore, an example of a simultaneous chiral LC/MS/MS detection (chromatographic run time approximately 10 min) of four pharmaceutical products resulting in baseline resolutions of all four pairs of enantiomers is presented . Methanol, an MS-compatible mobile phase, was utilized in all the experiments .

Nephrol Dial Transplant, 2000 Jul, 15(7), 1035 - 7
Insufficient penetration of systemic vancomycin into the PermCath lumen; Bastani B et al.; BACKGROUND: Catheter infection is a major cause of morbidity and catheter loss in chronic haemodialysis patients . There has been a large discrepancy in the catheter salvage rate, after an episode of documented bacteraemia, whether the patients receive systemic antibiotic alone or systemic antibiotics concomitant with 'antibiotic-lock technique' (20-30% vs 100%, respectively) . To test the hypothesis that vancomycin may not adequately penetrate into the lumen of the catheter, despite therapeutic plasma levels, a series of in-vivo, ex-vivo, and in-vitro experiments were performed . METHODS: We compared serum and intralumenal (0.3-0.5 ml aspirate from venous port of the catheter) vancomycin concentrations in 24 chronic haemodialysis patients, with documented bacteraemia, who had received prior systemic vancomycin therapy with 14 similar patients who had additionally received 'vancomycin-lock technique' (100 microg/ml of vancomycin in heparin solution) after each haemodialysis session . RESULTS: Despite serum vancomycin concentration of approximately 17 microg/ml in each group, the vancomycin concentration in the venous hub of the catheter was only 0.2+/-0.6 microg/ml in the former group, in sharp contrast to 125 . 6+/-13 microg/ml in the latter group . In the ex-vivo experiment, four uninfected PermCaths which had been removed were immediately fixed and studied with scanning electron microscopy . No cellular or fibrin barrier could be found at the terminal pore of the catheter interfering with the diffusion of vancomycin from plasma into the catheter lumen . In the in-vitro experiments, three PermCaths filled with standard heparin solution were incubated for 48 h in 100 ml of plasma containing 20 microg/ml of vancomycin . Vancomycin concentration was measured in 0.3-0.5 ml solution aspirated from each port of the catheters . Vancomycin concentration was 0.2+/-0.1 microg/ml in the aspirated samples . Finally, two PermCaths filled with the standard heparin solution were incubated for 48 h in 100 ml of plasma containing 20 microg/ml of vancomycin, after which the catheters were sectioned at 4-cm intervals . Only the distal 4 cm of the catheters had vancomycin concentrations of 2 and 5 microg/ml, the remaining segments had levels </=0.5 microg/ml . CONCLUSION.: Our results indicate that diffusion of vancomycin from plasma into the haemodialysis catheter is negligible . Thus, haemodialysis patients with central venous catheter who have to be treated for bacteraemia with systemic antibiotic therapy must always receive 'antibiotic-lock technique' of the catheter after each haemodialysis session.

Biomed Chromatogr, 2000 Jun, 14(4), 243 - 8
Enantioselective determination of bromoisovalerylurea by liquid chromatography on chiral stationary phase in reversed- or normal-phase partition mode; Nishikawa T et al.; Bromoisovalerylurea (bromvalerylurea) is a sedative-hypnotic given orally as a racemate . Enantiomers of this drug could be separated by high-performance liquid chromatography on the three chiral stationary phases (a vancomycin-bonded, beta-cyclodextrin derivative-bonded, or urea derivative-bonded phase) . Biological fluids of human subjects who had ingested toxic or therapeutic doses of the racemate were chromatographed after liquid-liquid extraction . The (+)-enantiomer concentration was almost equal to the (-)-enantiomer concentration in the serum of one overdosed patient . In all the other subjects, the (+)-enantiomer was less than the (-)-enantiomer in their sera and saliva . The data suggest that the drug is absorbed non-stereoselectively from the gastrointestinal tract and eliminated from the blood stereoselectively .

Int J Antimicrob Agents, 2000 Jun, 15(1), 65 - 71
Comparative pharmacoeconomic study of vancomycin and teicoplanin in intensive care patients; Abad F et al.; Randomized clinical trials and meta-analyses have not demonstrated any statistically significant differences between teicoplanin and vancomycin with regard to efficacy . A cost-minimization analysis was conducted to compare the economical impact of the treatment with vancomycin and teicoplanin in intensive care patients . Information on resource utilization was retrospectively collected from 100 consecutive clinical histories of patients hospitalized in a Spanish Intensive Care Unit, who had been given a glycopeptide antibiotic (50 teicoplanin and 50 vancomycin) for the treatment of a suspected or proven infection . Although personnel, material, and monitoring costs were higher in the vancomycin group, the acquisition costs and the total costs were much lower in this group, so the resulting total costs per day were 5508 ptas (33 euros) for vancomycin-treated patients and 9893 ptas (59.5 euros) for teicoplanin-treated patients . The savings with vancomycin for a 10-day course of treatment would be approximately 40697 ptas (244.5 euros) per patient . Results were consistent for a variety of conditions that were included in the sensitivity analysis.

Pharmacotherapy, 2000 Jun, 20(6), 653 - 6
Vancomycin assay performance in patients with end-stage renal disease receiving hemodialysis; Kingery JR et al.; STUDY OBJECTIVE: To compare the performance of polyclonal fluorescence polarization immunoassay (pFPIA) with that of enzyme-multiplied immunoassay technique (EMIT) in patients receiving vancomycin and hemodialysis . SETTING: Outpatient hemodialysis center . PATIENTS: Seven subjects with end-stage renal disease treated with hemodialysis 3 times/week with a cellulose triacetate hemodialyzer . INTERVENTION: Subjects received vancomycin 1000 mg intradialytically during the first study session and 750 mg every other hemodialysis session thereafter for 4 weeks . MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained throughout the study, and vancomycin serum concentrations were determined by pFPIA and EMIT . The mean +/- SD difference (estimate of bias) between assays was -1.10 +/- 1.35 mg/L . The limits of agreement (mean difference +/- 1.96 x SD) between them were -3.80-1.60 mg/L . CONCLUSION: Our data suggest that the manufacturer's changes in the vancomycin pFPIA eliminated overestimation of drug concentrations in patients undergoing high-permeability hemodialysis.

J Burn Care Rehabil, 2000 May-Jun, 21(3), 246 - 7
Drug-induced linear immunoglobulin A bullous disease that clinically mimics toxic epidermal necrolysis; Mofid MZ et al.; Drug-induced linear immunoglobulin A bullous disease is a subepidermal blistering disorder that most commonly occurs after exposure to vancomycin . It can clinically mimic toxic epidermolytic necrolysis . We describe an 87-year-old white woman in whom linear immunoglobulin A bullous disease developed while she was taking vancomycin and phenytoin . A few days after the linear immunoglobulin A bullous disease developed, both medications were discontinued . No new bullae developed, and the eruption completely resolved within 2 weeks . The patient was treated with only topical therapy.

Ther Drug Monit, 2000 Jun, 22(3), 346 - 53
Achieving target goals most precisely using nonparametric compartmental models and "multiple model" design of dosage regimens; Jelliffe R et al.; Multiple model (MM) design and stochastic control of dosage regimens permit essentially full use of all the information contained in either a Bayesian prior nonparametric EM (NPEM) population pharmacokinetic model or in an MM Bayesian posterior updated parameter set, to achieve and maintain selected therapeutic goals with optimal precision (least predicted weighted squared error) . The regimens are visibly more precise in the achievement of desired target goals than are current methods using mean or median population parameter values . Bayesian feedback has now also been incorporated into the MM software . An evaluation of MM dosage design using an NPEM population model versus dosage design based on conventional mean population parameter values is presented, using a population model of vancomycin . Further feedback control was also evaluated, incorporating realistic simulated uncertainties in the clinical environment such as those in the preparation and administration of doses.

Ther Drug Monit, 2000 Jun, 22(3), 325 - 9
Goal-oriented, model-based drug regimens: setting individualized goals for each patient; Jelliffe R; Serum drug concentrations have commonly been described in terms of therapeutic ranges within which most patients have a therapeutic effect and a low incidence of toxicity . However, truly individualized drug dosage regimens cannot be developed without first setting a specific individualized target goal, such as a target serum drug concentration, at a desired target time after the dose (usually at a peak or trough), for each patient . For example, it is well known that the dosage of digoxin, or of any drug with a narrow therapeutic range, should somehow be individualized . One can begin this process by considering each patient as an individual, with his/her own individual need for the drug . If the need is small, so is the upper acceptable risk of toxicity . This would lead to a gently regimen, adjusted to the patient's body weight and renal function, to best achieve that specific target goal . Alternatively, if previous therapy has not sufficed and a significant or urgent need exists, then a higher goal may justifiably be selected, a greater risk of toxicity accepted, and a dosage regimen developed to meet that greater need . After such an individualized target goal is chosen, it should be achieved as precisely as possible . After the regimen is given, serum levels need to be measured and an individualized, patient-specific pharmacokinetic model should be made . Without the model, with only the raw serum level data, one cannot perceive the important exchanges that occur between serum and nonserum compartments of the drug, and we lack the precision given by the combination of the assay and the model to evaluate properly, optimally, the patient's clinical sensitivity to the drug . These concepts have been discussed here for digoxin, but they are general and apply to all drugs . This approach has also been applied to therapy with aminoglycoside antibiotics, vancomycin, lidocaine, theophylline, antiviral agents, a variety of anesthetic agents, psychiatric drugs, and anticancer agents.

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