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PubMedDate not supplied

Evaluation of the vancomycin-clearance:creatinine-clearance relationship for predicting vancomycin dosage.

Four methods of predicting vancomycin maintenance doses on the basis of the relationship between total-body or renal clearance of the drug and creatinine clearance were evaluated retrospectively using data from 24 patients who received vancomycin hydrochloride. Data for 18 men and 6 women with creatinine clearances of 10-130 mL/min were used; the mean (+/- S.D.) vancomycin maintenance dose was 22.0 +/- 11.2 mg/kg/day. The actual vancomycin maintenance dose needed to sustain an average steady-state vancomycin concentration of 15 mg/L was determined based on individual pharmacokinetic values. Predicted vancomycin maintenance doses were generated using the vancomycin-clearance:creatinine-clearance relationships derived separately by Nielsen, Moellering, Rotschafer, and Matzke. Orthogonal regression analysis was used to determine relationships between actual and predicted maintenance doses. Predictive ability of each method was assessed for bias (mean error) and precision (root mean squared error). Mean error and root mean squared error (+/- S.D.), respectively, for the four methods were as follows: Nielsen -262 +/- 451, 522 +/- 718; Moellering -91 +/- 439, 448 +/- 547; Rotschafer 192 +/- 602, 632 +/- 682; and Matzke -76 +/- 101, 408 +/- 517. Doses predicted by the Nielsen relationship were significantly lower than the actual vancomycin maintenance doses. Use of the Rotschafer relationship resulted in substantial overprediction, which increased as creatinine clearance declined. Doses predicted by the Moellering and Matzke relationships were slightly less than but not significantly different from the actual dose. The Matzke method demonstrated the least bias and was the most precise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

In vitro exposure of community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains to vancomycin: does vancomycin resistance occur?

Vancomycin is the preferred parenteral antibiotic for the treatment of all methicillin-resistant Staphylococcus aureus (MRSA) infections, including the newly emerging community-associated MRSA (CA-MRSA) infections. Vancomycin-intermediate nosocomial MRSA strains have developed in vitro and in vivo after exposure to vancomycin. The aim of this study was to determine whether daily serial passage of CA-MRSA strains onto vancomycin-supplemented agar selects for the development of vancomycin resistance. Twelve clinical isolates of the six commonest Australian and US strains of CA-MRSA were serially passaged daily for 25 days onto brain-heart infusion agar plates supplemented with 4 microg/mL vancomycin and then subcultured for a further 15 days onto antibiotic-free agar to assess the stability of the resistance phenotype. Minimum inhibitory concentrations (MICs) were determined by standard Etest every 5 days from day 0 to day 40. Serial passaging resulted in increased MICs in all strains but the rises were modest, with an increase of < 2 doubling dilutions. All strains remained vancomycin susceptible throughout the experiment according to Clinical Laboratory Standards Institute criteria.

Australia↗

PubMed2000

In vivo activities of evernimicin (SCH 27899) against vancomycin-susceptible and vancomycin-resistant enterococci in experimental endocarditis.

To assess the potential efficacy of evernimicin (SCH 27899) against serious enterococcal infections, we used a rat model of aortic valve endocarditis established with either a vancomycin-susceptible Enterococcus faecalis or a vancomycin-resistant Enterococcus faecium strain. Animals infected with either one of the test strains were assigned to receive no treatment (controls) or 5-day therapy with one of the following regimens: evernimicin 60-mg/kg of body weight intravenous (i.v.) bolus once daily, 60-mg/kg i.v. bolus twice daily (b.i.d.), 60 mg/kg/day i.v. by continuous infusion, or 120 mg/kg/day i.v. by continuous infusion. These regimens were compared with vancomycin at 150 mg/kg/day. In animals infected with E. faecalis, evernimicin at 120 mg/kg/day by continuous infusion significantly reduced bacterial counts in vegetations (final density, 5.75+/-3.38 log(10) CFU/g) compared with controls (8.51+/-1.11 log(10) CFU/g). In animals infected with 0.5 ml of an 8 x 10(7)-CFU/ml inoculum of the vancomycin-resistant E. faecium, both 60-mg/kg bolus once a day and b.i.d. dose regimens of evernimicin were very effective (viable counts, 3.45+/-1.44 and 3.81+/-1.98 log(10) CFU/g, respectively). Vancomycin was unexpectedly active against infections induced with that inoculum. In animals infected with a 10(9)-CFU/ml inoculum of the vancomycin-resistant E. faecium, the evernimicin 60-mg/kg i.v. bolus b.i.d. reduced viable counts in vegetations compared with controls (6.27+/-1.63 versus 8.34+/-0.91 log(10) CFU/g; P<0.05), whereas vancomycin was ineffective. Although resistant colonies could be selected in vitro, we were not able to identify evernimicin-resistant clones from cardiac vegetations. An unexplained observation from these experiments was the great variability in final bacterial densities within cardiac vegetations from animals in each of the evernimicin treatment groups.

Aminoglycosides↗

PubMed2003

Efficacy of vancomycin-beta-lactam combinations against heterogeneously vancomycin-resistant Staphylococcus aureus (hetero-VRSA).

There have been conflicting data about the interactions between vancomycin and beta-lactam agents against Staphylococcus aureus strains with heterogeneous resistance to vancomycin. We evaluated the efficacy of these combinations against Mu 3 and heterogeneously vancomycin-resistant S. aureus (hetero-VRSA) strains which were isolated from Korean patients using a population analysis method. Antagonistic effects were observed when less than 1 g/mL of beta-lactam antibiotics was combined with vancomycin, whereas synergistic effects were noticed with more than 4 microgram/mL of beta-lactam antibiotics. The antagonistic effects at low concentrations of beta-lactams were most prominent at 2 microgram/mL of vancomycin, which were the vancomycin MICs of tested hetero-VRSA strains. This study showed the variable effects of vancomycin- beta-lactam combinations depending on the concentrations of beta-lactam antibiotics and this property could be used to develop screening methods for hetero-VRSA strains.

Anti-Bacterial Agents↗

PubMed2001

Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis.

Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria.

Anti-Bacterial Agents↗

PubMedDate not supplied

Conformational studies of resin-bound vancomycin and the complex of vancomycin and Ac2-L-Lys-D-Ala-D-Ala.

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.

Combinatorial Chemistry Techniques↗

PubMed2001

Persistence of a vancomycin-resistant Enterococcus faecium in an anaerobic continuous-flow culture of porcine microflora in the presence of subtherapeutic concentrations of vancomycin.

Recombined porcine continuous-flow culture (RPCF) maintained in a continuous-flow fermentation system is effective in protecting neonatal and weaned pigs against infection by enteropathogens. In the current study, we demonstrate the effect of RPCF on vancomycin-resistant enterococci (VRE) in the presence and absence of subtherapeutic levels of vancomycin. Also examined was the ability of VRE to transfer vancomycin resistance to endogenous Enterococcus faecalis 137.1. When RPCF was challenged with VRE, the rate of VRE clearance was dependent on the method of challenge. In the control experiment, RPCF was challenged with 7.0 log10/CFU/ml VRE. Clearance of VRE from the culture was observed within 7 days at a rate of 1.44 log10/day. RPCF containing 0.001 microg/ml vancomycin cleared VRE at a slightly lower rate of 0.94 log10/day. RPCF containing 0.01 microg/ml or 0.1 microg/ml vancomycin reduced the level of VRE from 7.0 log10/CFU/ml to 2.0 log10/CFU/ml within 9 days, but failed to clear the VRE after 24 days. During the period of decline, the VRE clearance rate for the 0.01 microg/ml and 0.1 microg/ml vancomycin-treated cultures was 0.52 log10/day, and 0.53 log10/day, respectively. E. faecalis 137.1 endogenous to RPCF did not acquire the vancomycin resistance genes throughout the experiment as evidenced by direct selection, ribotyping, and pulsed-field gel electrophoresis.

Anaerobiosis↗

PubMed1992

Absence of synergistic activity between ampicillin and vancomycin against highly vancomycin-resistant enterococci.

The emergence of clinical enterococcal isolates resistant to both ampicillin and vancomycin is a cause of great concern, as there are few therapeutic alternatives for treatment of infections caused by such organisms. We evaluated the effects of the combination of ampicillin with vancomycin against vancomycin-resistant clinical enterococcal isolates. Using both the checkerboard technique and time-kill curves, we examined 28 strains of enterococci (17 Enterococcus faecalis and 11 Enterococcus faecium strains) with different levels of resistance to vancomycin. Of these, 15 strains were also highly gentamicin resistant, and 9 demonstrated resistance to ampicillin. Only seven strains of E. faecalis were inhibited synergistically by the combination of vancomycin with ampicillin, and even then, the concentrations of vancomycin at which synergism was demonstrated were above levels achievable in serum. None of the ampicillin-resistant isolates (all E. faecium) were inhibited synergistically at any concentration of the drugs. In no instance was bactericidal synergism observed, and in most cases the combination resulted in less killing than with ampicillin alone. Antagonism was not observed at clinically relevant concentrations. The results of this study suggest that the combination of vancomycin with ampicillin has little to offer against these emerging pathogens.

Ampicillin↗

PubMed2004

Penicillin-binding protein 2 is essential for expression of high-level vancomycin resistance and cell wall synthesis in vancomycin-resistant Staphylococcus aureus carrying the enterococcal vanA gene complex.

A combination of biochemical and genetic experiments were performed in order to better understand the mechanism of expression of high-level vancomycin resistance in Staphylococcus aureus. The transcription of pbp2 of the highly vancomycin- and oxacillin-resistant strain COLVA200 and its mutant derivative with inactivated mecA were put under the control of an inducible promoter, and the dependence of oxacillin and vancomycin resistance and cell wall composition on the concentration of the isopropyl-beta-D-thiogalactopyranoside inducer was determined. The results indicate that mecA--the genetic determinant of oxacillin resistance--while essential for oxacillin resistance, is not involved with the expression of vancomycin resistance. Penicillin binding protein 2A, the protein product of mecA, appears to be unable to utilize the depsipeptide cell wall precursor produced in the vancomycin-resistant cells for transpeptidation. The key penicillin binding protein essential for vancomycin resistance and for the synthesis of the abnormally structured cell walls characteristic of vancomycin-resistant S. aureus (A. Severin, K. Tabei, F. Tenover, M. Chung, N. Clarke, and A. Tomasz, J. Biol. Chem. 279:3398-3407, 2004) is penicillin binding protein 2.

Bacterial Proteins↗

PubMed2005

Survivability of vancomycin resistant enterococci and fitness cost of vancomycin resistance acquisition.

AIMS: To investigate the survivability of vancomycin resistant enterococci (VRE) under dry starvation conditions and the fitness cost of vancomycin resistance. METHODS: VRE colonies on cotton swabs were incubated at room temperature in a sterile box and cultured weekly until cultures no longer showed growth. Negative swabs inoculated into brain heart infusion (BHI) broth were subcultured to blood agar after 24, 48, and 72 hours of incubation to resuscitate viable but non-culturable cells. Stability of the vancomycin resistance determinant and of the DNA fingerprint pattern was determined by multiplex polymerase chain reaction (PCR) and repetitive PCR, respectively. Tests for fitness cost were carried out on the same VRE isolates and 28 hospital vancomycin sensitive enterococci (VSE) isolates by incubation and measurement of optical density using a microplate reader and comparing maximum growth rate and lag phase duration between VRE and VSE, using independent samples t tests. RESULTS: Mean maximum time of recovery by primary culture was 8.5 weeks for Enterococcus faecalis VRE and 21.8 weeks for E. faecium VRE. Two of two E. faecalis isolates were resuscitated after 24 hours in BHI broth, and two of five E. faecium isolates after 72 hours. No fitness cost of vancomycin resistance was demonstrated. CONCLUSIONS: VRE can survive for prolonged periods in a dry starvation state, retaining their genetic complement, including vancomycin resistance determinants, and show little or no fitness cost of vancomycin resistance. Thus, the rate of entry required for VRE to become, and remain, endemic in the community is relatively small.

Cross Infection↗

PubMed2005

Impact of a series of interventions in vancomycin prescribing on use and prevalence of vancomycin-resistant enterococci.

BACKGROUND: In response to vancomycin-resistant bacteria, particularly vancomycin-resistant enterococci (VRE), measures have been recommended to improve on the appropriate use of vancomycin. METHODS: Intervention 1 consisted of an automatic 72-hour vancomycin stop order; Intervention 2, a standardized procedure for sampling of blood cultures; and Intervention 3, an interdisciplinary critical care team. RESULTS: After Intervention 1, inappropriate use decreased, particularly in treatment of febrile neutropenia and undocumented gram-positive infections. After Intervention 2, the baseline rate of inappropriately drawn blood cultures (IDBCs) was unchanged, and use in patients with IDBCs was comparable during both periods. Before Intervention 3, 38/55 orders continuing > 72 hours were considered inappropriate versus 24/53 (p < .025) after. After the interventions, hospitalwide vancomycin use was reduced. Yet the overall rate of VRE infection initially decreased but then increased once again over time. DISCUSSION: Despite substantial reduction in hospitalwide vancomycin use, the impact on the overall rate of VRE was inconsistent and ward dependent.

California↗

PubMed2003

D-Ala-D-lac binding is not required for the high activity of vancomycin dimers against vancomycin resistant enterococci.

Covalent dimerization and oligomerization of vancomycin is an important and extensively used strategy to develop analogues active against vancomycin resistant enteroccoci (VRE). Here, we have carried out investigations to probe the role of peptide binding (Lys-d-Ala-d-Lac) in the high anti-VRE activities of covalently linked vancomycin dimers. Covalent dimers of damaged vancomycin (desleucyl) were prepared, and their anti-VRE activities and binding affinities toward various model peptides were measured. Despite the dramatic loss in affinity toward several model peptides in comparison to the corresponding intact vancomycin dimers, these damaged dimers maintained good activity against VRE. These results strongly suggest that the high anti-VRE activities of covalent vancomycin dimers are conferred from mechanisms other than Lys-d-Ala-d-Lac binding.

Alanine↗

PubMed2002

Dissemination of vancomycin-resistant enterococci harboring vanA through disposal of waste derived from industrial production of vancomycin.

We demonstrated the occurrence of vancomycin-resistant enterococci (VRE) in waste derived from the industrial production of vancomycin and their dissemination through disposal of such waste into a sewage treatment plant. Bacteriological counts on a medium selective for enterococci (Slanetz-Bartley agar) revealed the presence of high numbers of presumptive VRE (approximately 10(6) CFU/ml) in the waste originating from the fermentation biomass used for vancomycin production. The waste was also found to contain active residues of vancomycin (64-1,024 microg/ml) by bioassays using a vancomycin-susceptible enterococcal strain. Randomly amplified polymorphic DNA (RAPD) analysis of 65 presumptive VRE isolates from the waste allowed distinction of four genotypes, two of which (A and D) belonged to the genus Enterococcus, most likely E. faecium, and harbored the vanA gene conferring high-level vancomycin resistance. The same VRE strains found in the waste occurred also in the biological tanks and the final effluent of the sewage treatment plant receiving the waste, as demonstrated by the detection of undistinguishable pulsed-field gel electrophoresis (PFGE) patterns in VRE isolated from these sources. These results indicate the need to assess the possible dissemination of VRE and other antibiotic-resistant bacteria through disposal of waste derived from antibiotic production.

Anti-Bacterial Agents↗

PubMed1992

The influence of vancomycin concentration and the pH of plasma on vancomycin protein binding.

A review of numerous studies of the protein binding of vancomycin suggests major discrepancies among their results. The reported percent protein binding of vancomycin varies from 0% to 98%. The influence of pH and concentration on the protein binding of vancomycin was investigated in this study. There was a significant difference (p < 0.001) in percent protein binding in vancomycin-spiked plasma samples across the pH range of 7.0-8.0. There was no significant difference (p > 0.05) in percent protein binding in vancomycin-spiked plasma samples across the concentration range of 2-80 mg/L. It is likely that some of the variation reported to date may be due to a lack of control of pH during the measurement of protein binding of vancomycin.

Blood Proteins↗

PubMed2005

Ventriculitis due to a hetero strain of vancomycin intermediate Staphylococcus aureus (hVISA): successful treatment with linezolid in combination with intraventricular vancomycin.

A 67-year male presented with relapse 14 days after treatment with vancomycin for a MRSA ventriculitis. CSF samples taken at the time of relapse grew MRSA with a MIC for vancomycin of 4 mg/L by E-test and therapy with linezolid (600 mg bd) and intraventricular vancomycin (20 mg od) was initiated. Using the macrodilution E-test, the isolate was found to have sub-populations with a MIC for vancomycin of 8 mg/L and teicoplanin of 12 mg/L and a population analysis profile almost identical to the hVISA strain MU3, indicative of a hVISA strain. Concentrations of vancomycin in the CSF over the period of therapy ranged from 25.6-192.5 mg/L after intraventricular administration and those of linezolid ranged from 3.4-6.7 mg/L after intravenous administration, exceeding the MICs for this isolate. The patient made a successful recovery, with no further episodes of ventriculitis at 1-year follow-up. We report the first case of ventriculitis due to hVISA. It was successfully treated with intrathecal vancomycin and intravenous linezolid. We also believe this to be the first documented case of clinical infection due to hVISA in South Africa.

Acetamides↗

PubMed1999

Vancomycin use in a hospital with vancomycin restriction.

We evaluated vancomycin use in a hospital with endemic vancomycin-resistant enterococci and a vancomycin restriction program. Only 68% of vancomycin was prescribed appropriately. Inappropriate use was due primarily to empirical therapy. In the patients with a microbiological diagnosis following empirical therapy, 83% (25/30) had infections due to bacteria sensitive to an appropriate antibiotic other than vancomycin. However, only 60% (15/25) of these patients had their vancomycin orders changed.

Anti-Bacterial Agents↗

PubMed1997

Inhibition of cell wall turnover and autolysis by vancomycin in a highly vancomycin-resistant mutant of Staphylococcus aureus.

A highly vancomycin-resistant mutant (MIC = 100 microg/ml) of Staphylococcus aureus, mutant VM, which was isolated in the laboratory by a step-pressure procedure, continued to grow and synthesize peptidoglycan in the presence of vancomycin (50 microg/ml) in the medium, but the antibiotic completely inhibited cell wall turnover and autolysis, resulting in the accumulation of cell wall material at the cell surface and inhibition of daughter cell separation. Cultures of mutant VM removed vancomycin from the growth medium through binding the antibiotic to the cell walls, from which the antibiotic could be quantitatively recovered in biologically active form. Vancomycin blocked the in vitro hydrolysis of cell walls by autolytic enzyme extracts, lysostaphin and mutanolysin. Analysis of UDP-linked peptidoglycan precursors showed no evidence for the presence of D-lactate-terminating muropeptides. While there was no significant difference in the composition of muropeptide units of mutant and parental cell walls, the peptidoglycan of VM had a significantly lower degree of cross-linkage. These observations and the results of vancomycin-binding studies suggest alterations in the structural organization of the mutant cell walls such that access of the vancomycin molecules to the sites of wall biosynthesis is blocked.

Anti-Bacterial Agents↗

PubMed1999

Heterogeneously vancomycin-resistant Staphylococcus epidermidis strain causing recurrent peritonitis in a dialysis patient during vancomycin therapy.

Methicillin-resistant Staphylococcus epidermidis (MRSE) was recovered over a 2-month period from the dialysis fluid of a peritoneal dialysis (PD) patient who experienced recurrent episodes of peritonitis during therapeutic and prophylactic use of vancomycin. Characterization of five consecutive MRSE isolates by molecular and microbiological methods showed that they were representatives of a single strain, had reduced susceptibility to vancomycin, did not react with DNA probes specific for the enterococcal vanA or vanB gene, and showed characteristics reminiscent of the properties of a recently described vancomycin-resistant laboratory mutant of Staphylococcus aureus. Cultures of these MRSE isolates were heterogeneous: they contained-with a frequency of 10(-4) to 10(-5)-bacteria for which vancomycin MICs were high (25 to 50 microg/ml) which could easily be selected to "take over" the cultures by using vancomycin selection in the laboratory. In contrast, the five consecutive MRSE isolates recovered from the PD patient during virtually continuous vancomycin therapy showed no indication for a similar enrichment of more resistant subpopulations, suggesting the existence of an "occult" infection site in the patient (presumably at the catheter exit site) which was not accessible to the antibiotic.

Adult↗