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PubMed1983

Automated fluorescence polarization immunoassay for monitoring vancomycin.

We have extended fluorescence polarization immunoassay (FPIA) technology for the measurement of drugs to include the complex amphoteric glycopeptide antibiotic vancomycin (molecular weight, 1,449). Fluorescein-labeled vancomycin was employed as a tracer, and antisera specific for vancomycin were raised in rabbits by conventional procedures. Tracer, sample, and diluted antiserum were combined, and the polarization of tracer fluorescence is determined in a specially designed fluorometer (Abbott TDx). Because of instrument design, the possibility of fluorescent interferences is minimized. The assay can measure as little as 0.6 mg/L of vancomycin and is free of interferences from hemolysis, lipemia, bilirubin, and changes in protein concentration. The coefficient of variation within assay was 3% (n = 5) and between assays was 5% (n = 5). The FPIA assay (TDx Vancomycin) was compared to a liquid chromatographic (LC) assay for vancomycin and to a commercially available radioimmunoassay (RIA) for 98 clinical specimens. A linear least-squares regression analysis gave a correlation coefficient for LC of 0.980 from the equation FPIA = 1.09 LC + 3.04, and a correlation coefficient for RIA of 0.957 from the equation FPIA = 1.036 RIA + 1.66.

Antibody Specificity↗

PubMed1989

Evaluation of a two-compartment Bayesian forecasting program for predicting vancomycin concentrations.

The application of a two-compartment Bayesian forecasting program for vancomycin was tested retrospectively in 45 adult patients with stable renal function. Serial blood samples from 25 of these patients were used to determine population-based parameter estimates. The predictive performance of the Bayesian program was assessed by using both non-steady-state and steady-state vancomycin concentrations as feedback information. Overall, the program tended to underpredict peak and trough steady-state vancomycin serum concentrations. A larger mean prediction error (ME) was seen when non-steady-state feedback serum concentrations were used compared with using population-based parameter estimates (no feedback). In contrast, a marked improvement in ME (peaks: -1.03 versus -2.61; troughs: -1.60 versus -2.07) was seen when steady-state feedback serum concentrations were used compared with no feedback data. Precision improved when either feedback serum concentrations were used to predict steady-state peak and trough vancomycin concentrations. The results from this clinical evaluation demonstrate that the initial pharmacokinetic parameter estimates for a two-compartment Bayesian model provided accurate prediction of steady-state vancomycin concentrations. Prediction bias and precision were improved when steady-state vancomycin concentrations were used to determine individualized pharmacokinetic parameters.

Adult↗

PubMed1995

Vancomycin pharmacokinetics and dosing in premature neonates.

We prospectively studied the pharmacokinetic parameters of vancomycin in premature neonates given vancomycin according to a dosage protocol developed in our neonatal unit. Study infants were administered vancomycin according to four postconceptional age (PCA) groups: (0) 18 mg/kg every 36 h for PCA < 27 weeks; (I) 16 mg/kg every 24 h for PCA 27-30 weeks; (II) 18 mg/kg every 18 h for PCA 31-36 weeks; and (III) 15 mg/kg every 12 h for PCA > or = 37 weeks. Pharmacokinetic parameters were calculated from peak and trough serum vancomycin concentrations at steady state. Results in 44 infants (PCA, 27-44 weeks) showed that our dosage regimen achieved target peak serum vancomycin concentrations in 64% of neonates in Groups I-III, although it tended to undershoot the target trough concentrations. Volume of distribution (Vd), normalized for body weight, remained constant throughout the PCA range, with a mean value of 0.56 L/kg, whereas absolute clearance (r = 0.81) and normalized clearance (r = 0.48) increased with PCA (p < 0.005). The increase in clearance with PCA is associated with a greater elimination rate constant and shorter half-life. Vancomycin therapy can be initiated in a standard fashion according to our protocol or by individualizing the dosage regimen based on a Vd of 0.56 L/kg and clearance estimated from the infant's body weight and PCA groups.

Anti-Bacterial Agents↗

PubMed1996

Influence of pharmacokinetic model on vancomycin peak concentration targets.

The aim of this study was to adapt the vancomycin therapeutic range to the kinetic models usually employed in clinical settings (one- and two-compartment models). Estimates of vancomycin pharmacokinetic parameters were obtained for both models in 22 hematologically malignant patients on vancomycin treatment using two serum concentrations and a bayesian algorithm. From these individually estimated pharmacokinetic parameters, an estimation of the maximum (Cssmax), 2 h postinfusion (Css2), and minimum (Cssmin) steady-state vancomycin serum concentrations for the one- and two-compartment models was made for a fixed 30 mg/kg/day dose. The linear regression equations between the predicted Css2 and Cssmin for the one- and two-compartment models do not differ significantly from the identity line, whereas the corresponding equation for Cssmax points to a 61% underestimation of Cssmax when the one-compartment model is used. From this latter regression equation, it is possible to define 20 mg/L (range of 18-21 mg/L) as a target Cssmax vancomycin serum concentration when a one-compartment model is used to monitor vancomycin therapy. Another practical approach would be to define the target concentration by a desired range at 2 h, which corresponds to a Cssmax value of 30-40 mg/L.

Anti-Bacterial Agents↗

PubMed1997

Vancomycin monitoring: one or two serum levels?

Based on the principle that vancomycin therapy requires sustained therapeutic concentrations while avoiding high peaks, some authors reported that optimal vancomycin levels could be ensured by measuring trough levels alone (Cmin). The aim of this work was to assess the performance of a one-compartment Bayesian forecasting method for estimating vancomycin 2 hours after infusion (C2h) and mean vancomycin concentration in steady state (Cavgss) on the basis of a single trough sample (Cmin), in different conditions (steady state, patient renal function, and age), and according to clinical significance. Vancomycin serum concentrations (n = 108) were analyzed by fluorescence polarization immunoassay, from 79 adult patients. The predictive performance of the Bayesian method was determined by calculating the mean prediction error (ME), the mean absolute error (MAE) and the root squared prediction error (RMSE). A linear regression analysis was carried out between estimated and observed concentrations. The predicted C2h were not significantly different from the observed, and the least biased (ME = -1.08) and most precise (MAE = 3.81) predictions were from patients with normal renal function and steady state conditions. In this population, the concordance in dosage recommendations with the data pair results was 75% of patients. The best correlation between observed and predicted concentrations was found for Cavgss (r = 0.94; p < 0.00005). Predictions of the Cavgss were more precise (ME = -0.54) and accurate (MAE = 1.74) than the C2h predictions. Vancomycin can be monitored by determining one level in steady state for most patients with normal renal function.

Adolescent↗

PubMed1998

Therapeutic drug monitoring of vancomycin in a morbidly obese patient.

The authors describe the therapeutic drug monitoring of vancomycin in a man who is morbidly obese. Because serum vancomycin concentration (SVC) monitoring continues to be deemphasized, nomogram use will likely increase. However, vancomycin dosing nomograms have not been studied in patients who are morbidly obese. Furthermore, in nomograms that incorporate body weight, it is unclear whether ideal or total body weight (IBW and TBW, respectively) should be used to dose the morbidly obese. Therefore, the authors retrospectively evaluated four nomograms (Moellering, Matzke, Lake-Peterson, and Rodvold) and an individualized method in the simulated vancomycin dosing of their patient. Total body weight was more accurate than IBW in selecting a vancomycin dose when using the individualized method and in all nomograms except the Matzke nomogram. The Rodvold nomogram and the individualized method yielded the most appropriate doses. All nomograms suggested dosing intervals that were unacceptably short; the individualized method suggested an appropriately longer interval. Thus, if nomograms or the individualized method are used to empirically dose vancomycin, TBW--not IBW--should be used. Because these nomograms yielded inappropriately short dosing intervals in the patient, it is likely that patients who are morbidly obese represent a unique population in which at least one set of SVCs are necessary to select an appropriate dosing regimen.

Anti-Bacterial Agents↗

PubMed1999

Non steady state and steady state PKS Bayesian forecasting and vancomycin pharmacokinetics in ICU adult patients.

The pharmacokinetics of vancomycin was investigated in adult ICU patients after the first administration and at steady state. Then the predictive performance of a two-compartment Bayesian forecasting program was assessed in these patients by using population-based parameters and three non steady state vancomycin concentrations as feedback information. Finally a prospective investigation was carried out to search potential covariates. At steady state, a significant decrease (around 30%) in clearance (CL) was observed, while creatinine clearance (CLcr) was stable and a significant increase (around 30%) in volume of distribution (V(SS)) was observed. A two-fold increase in elimination half-life was found. CL was weakly correlated with CLcr at onset of therapy and at steady state. The Bayesian program tended to overpredict vancomycin peak and trough concentrations. A larger mean prediction error and a poorer precision were observed when population-based parameter estimates were used (no feedback) compared to feedback prediction, but the differences were not significant. Mechanical ventilation and concurrent opioid therapy may be pertinent covariates of vancomycin pharmacokinetics. The current work has shown that vancomycin pharmacokinetics in ICU patients displayed a significant variability and a significant change in both clearance and distribution during the course of therapy. Further investigation is necessary to clarify these findings. Moreover, the use of the Bayesian forecasting PKS program in our patients led to a prediction with low bias but rather poor precision. This outcome highlights the need to implement a population modeling approach, to determine the vancomycin pharmacokinetic parameters and covariates in our ICU patients, and to apply this information to provide more accurate concentration predictions.

Adolescent↗

PubMed2003

Evaluation of estimated and measured creatinine clearances for predicting the pharmacokinetics of vancomycin in adult liver transplant recipients.

This study examined the pharmacokinetics and dosing requirements of vancomycin in adult liver transplant recipients and also evaluated the predictability of determining vancomycin-dosing requirements utilizing an estimated creatinine clearance (CrCl) approach. Twenty adult liver transplant recipients were included in this analysis. Vancomycin pharmacokinetic parameters and dosing requirements calculated from estimated CrCl and population-based pharmacokinetic equations were compared with values calculated using serum concentrations and assuming a one-compartment model. Compared with the values obtained using equations to estimate the CrCl and vancomycin pharmacokinetics (t, Cl, and Vd), the actual values were statistically different for half-life and clearance (11.0 vs. 16.4 hours and 52 vs. 36 mL/min, respectively; P < 0.01). Additionally, CrCl that were estimated using population-based formulas significantly overestimated actual CrCl calculated using 24-hour urine collections (65-78 vs. 43 mL/min; P < 0.05). The results from this study indicate that serum creatinine concentrations do not adequately predict glomerular filtration rates (GFR) or vancomycin clearance in adult liver transplant recipients. Based on these results, the use of 24-hour urine CrCl to predict GFR and serum concentrations to properly dose vancomycin is advocated.

Adult↗

PubMedDate not supplied

Comparison of linezolid with oxacillin or vancomycin in the empiric treatment of cellulitis in US hospitals.

In this decision-model analysis, the authors compared overall clinical efficacy and total cost of empiric treatment of hospitalized cellulitis patients prescribed linezolid and oxacillin or vancomycin. The authors hypothesized that, when used appropriately, empiric linezolid treatment is an effective, potentially cost-saving antibiotic compared with treatment initiated with oxacillin or vancomycin. Data on efficacy, duration of antibiotic treatment, and hospital stay for first-line treatment success were obtained from two clinical trials. Other medical resource use data were obtained from an expert panel of clinicians. US hospital direct medical costs were determined using standard costing techniques. Overall efficacy and total cost of treatment were estimated for combinations of the risk of being infected with methicillin-resistant pathogens. Sensitivity analyses were performed to test the impact of changes in major assumptions. Overall first-line efficacy is better for empiric treatment initiated with linezolid than with oxacillin or vancomycin across the spectrum of the risk of being infected with methicillin-resistant bacteria. The average total cost of treatment is lower for treatment initiated with linezolid than with vancomycin across the spectrum, or than with oxacillin when the risk of being infected with methicillin-resistant pathogens is 18.7 % or higher. Linezolid appears to be at least as effective as vancomycin or oxacillin for empiric treatment of hospitalized cellulitis patients. Linezolid is likely to be less costly compared with vancomycin at all resistance rates and with oxacillin when the risk of infection with methicillin-resistant pathogens is greater than 18.7 %, a resistance rate commonly seen in US hospitals.

Acetamides↗

PubMed2004

Gentamicin and vancomycin do not impair experimental fracture healing.

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).

Animals↗

PubMed1993

Arterial and venous blood samplings in pharmacokinetic studies: vancomycin in rabbits.

The pharmacokinetics of vancomycin were evaluated simultaneously using both arterial and venous plasma data in five rabbits after a rapid bolus intravenous (i.v.) dosing. Initial arterial to venous concentration ratios at 5 s after i.v. injection were the highest, with values of 27.1, 36.2, 36.6, 43.7 and 29.7 for rabbits 1-5, respectively. This could be the result of diffusion of vancomycin from the arterial plasma into the extravascular tissues. Both curves decayed in parallel at the terminal phase with the venous levels higher than the arterial levels by 23, 37, 34, 13 and 14% for rabbits 1-5, respectively. This difference could be the result of continuous release of vancomycin from the extravascular tissues to the venous blood. Detailed analysis showed differences in various pharmacokinetic parameters based on arterial and venous data. For example, values for venous Vc were 9.2, 11, 1.9, 7.2 and 8.8 times greater than the arterial values for rabbits 1-5, respectively. The values for both venous Vss and MRT were higher than those of the arterial values in all five rabbits studied. This could be due to more extensive distribution of vancomycin in the extravascular tissues. A plot of 1/Q (urine flow rate) versus 1/ClR of vancomycin yielded a straight line in rabbits 6-10, indicating that the renal clearance of vancomycin in rabbits is dependent upon urine flow.

Animals↗

PubMed2005

Recognition and management of infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) and heterogenous VISA (hVISA).

Vancomycin resistance in Staphylococcus aureus has recently emerged as an important clinical problem with implications for laboratory detection and clinical management of patients infected with resistant strains. To date, low-level vancomycin resistance in the form of vancomycin-intermediate S. aureus (VISA) and heterogenous vancomycin-intermediate S. aureus (hVISA) have been more common, with only four cases of true vancomycin resistant S. aureus (VRSA) reported. This article reviews current knowledge about the epidemiology, clinical manifestations and optimal management of hVISA and VISA infections. VISA and hVISA have now been reported from many countries, and these strains tend to occur in patients with significant comorbidities and previous antibiotic exposure. Despite the difficulties in laboratory detection, there are increasing data linking VISA and hVISA to failure of glycopeptide antimicrobial therapy. Aggressive surgical intervention and non-glycopeptide-based antimicrobial therapy appears to improve outcomes for patients infected with these low-level vancomycin-resistant strains. Clinicians and diagnostic laboratories need to be aware of VISA and hVISA as a clinical problem, and consider aggressive surgical debridement and non-glycopeptide-based therapy where infections with such strains are suspected or proven.

Anti-Bacterial Agents↗

PubMed2006

Use of surveillance cultures and enteral vancomycin to control methicillin-resistant Staphylococcus aureus in a paediatric intensive care unit.

This study assessed the effects of throat and gut surveillance, combined with enteral vancomycin, on gut overgrowth, transmission of methicillin-resistant Staphylococcus aureus (MRSA), infections and mortality in patients admitted to a paediatric intensive care unit (PICU). A 4-year prospective observational study was undertaken with 1241 children who required ventilation for >or=4 days. Patients identified as MRSA carriers following surveillance cultures of throat and rectum received enteral vancomycin. Twenty-nine (2.4%) children carried MRSA, 19 on admission and nine during treatment in the PICU; one patient was not able to be evaluated. Overgrowth was present in 22 (75%) of the carriers. Ten (0.8%) children developed 21 MRSA infections (15 exogenous infections in eight children at a median of 8 days (IQR 3-10.5); five primary endogenous infections at a median of 3 days (IQR 1-25) in three children when they were in overgrowth status; one child developed both types of infection). Enteral vancomycin reduced gut overgrowth significantly, completely preventing secondary endogenous infections. Transmission occurred on nine occasions over a period of 4 years. Four patients died, two (5.9%) with MRSA infection, giving a mortality (11.8%) similar to the study population (9.8%). No emergence of vancomycin-resistant enterococci or S. aureus with intermediate susceptibility to vancomycin was detected. A policy based on throat and gut surveillance, combined with enteral vancomycin, for critically-ill children who were MRSA carriers was found to be effective and safe, and challenges the recommended guidelines of nasal swabbing followed by topical mupirocin.

Anti-Bacterial Agents↗

PubMed2005

A vancomycin-dependent VanA-type Enterococcus faecalis strain isolated in Japan from chicken imported from China.

AIMS: The characterization of KC122.1, which is a vancomycin-dependent VRE (Vancomycin-resistant enterococci) (Enterococcus faecalis) and the first case in Japan of a VRE isolate obtained from chicken meat imported from China. METHODS AND RESULTS: PCR amplification of vanA, vanS and ddl gene and direct sequencing of the PCR products were performed. KC122.1 was a VanA-type VRE showing high-level vancomycin resistance and low-level teicoplanin resistance, and its vanS gene had three point mutations. The ddl gene of KC122.1 was sequenced and two changes were found at the ninth codon (GCC-GAC) and the stop codon (TAA-CAA). The latter change was also found in the laboratory strain E. faecalis FA2-2. CONCLUSIONS: Three point mutations in vanS resulted in high-level vancomycin resistance and low-level teicoplanin resistance. The change at the ninth codon resulted in the inactivation of the ddl gene and vancomycin-dependent growth. An eight amino acid extension at the C-terminal did not impair the function of the D-Ala : D-Ala ligase. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first example of the isolation of VRE from chicken meat imported from China and the first vancomycin-dependent VRE from a nonhuman source.

Animals↗

PubMed1996

A highly vancomycin-resistant laboratory mutant of Staphylococcus aureus.

A resistant mutant with vancomycin MIC of 100 micrograms/ml was isolated relatively easily through step pressure in the laboratory from a Staphylococcus aureus strain with initial MIC of 1.5 micrograms/ml for the antibiotic. Upon addition of vancomycin (50 micrograms/ml) to the growth medium mass increase of the culture and peptidoglycan synthesis continued but cell division (daughter cell separation), cell wall turnover and autolysis were inhibited, resulting in the production of multicellular clumps of bacteria. Parallel with the increase of culture density, the concentration of vancomycin measured both by biological activity and by HPLC gradually declined in the culture medium. Cell division and wall turnover of the culture resumed with the production of cells of normal morphology at the time when the concentration of the drug in the medium decreased below 0.5-1.0 micrograms/ml. There was no detectable change in the antibiotic concentration in the culture medium during growth of a vancomycin-resistant (vanA-positive) strain of Enterococcus faecium and an intrinsically vancomycin-resistant strain of Leuconostoc. The vancomycin-resistant staphylococcal mutant gave no signal with the vanA or vanB DNA probes and contained no detectable D-lactate terminating cell wall precursors. The biochemical mechanism and clinical significance of such glycopeptide-resistant mutants remained to be established.

Anti-Bacterial Agents↗

PubMed2000

Chlorobiphenyl-desleucyl-vancomycin inhibits the transglycosylation process required for peptidoglycan synthesis in bacteria in the absence of dipeptide binding.

Novel glycopeptide analogs are known that have activity on vancomycin resistant enterococci despite the fact that the primary site for drug interaction, D-ala-D-ala, is replaced with D-ala-D-lactate. The mechanism of action of these compounds may involve dimerization and/or membrane binding, thus enhancing interaction with D-ala-D-lactate, or a direct interaction with the transglycosylase enzymes involved in peptidoglycan polymerization. We evaluated the ability of vancomycin (V), desleucyl-vancomycin (desleucyl-V), chlorobiphenyl-vancomycin (CBP-V), and chlorobiphenyl-desleucyl-vancomycin (CBP-desleucyl-V) to inhibit (a) peptidoglycan synthesis in vitro using UDP-muramyl-pentapeptide and UDP-muramyl-tetrapeptide substrates and (b) growth and peptidoglycan synthesis in vancomycin resistant enterococci. Compared to V or CBP-V, CBP-desleucyl-V retained equivalent potency in these assays, whereas desleucyl-V was inactive. In addition, CBP-desleucyl-V caused accumulation of N-acetylglucosamine-beta-1, 4-MurNAc-pentapeptide-pyrophosphoryl-undecaprenol (lipid II). These data show that CBP-desleucyl-V inhibits peptidoglycan synthesis at the transglycosylation stage in the absence of binding to dipeptide.

Anti-Bacterial Agents↗

PubMed1987

The pneumococcus and the mouse-protection test: correlation of in vitro and in vivo activity for beta-lactam antibiotics, vancomycin, erythromycin and gentamicin.

The mouse-protection test with intraperitoneal inoculation of Streptococcus pneumoniae type 3 was employed to compare the effect in vivo and to correlate with activity in vitro of ampicillin, piperacillin, methicillin, cefuroxime, erythromycin, vancomycin and gentamicin. The MICs for these drugs were lowest for the beta-lactam antibiotics, highest for vancomycin and gentamicin. Relative to the MIC, gentamicin and vancomycin showed the highest bactericidal rates against the pneumococcus. Vancomycin was the most effective in vivo as measured by the 50% effective dose (ED50) after single doses 1 h post-inoculation. Serum vancomycin concentrations measured after doses equal to the ED50 were below the minimal concentration measurable by our bioassay (i.e. less than 3.7 micrograms/ml). For the other drugs, peak concentrations in serum were higher than those produced even by high doses in man. Among pharmacokinetic parameters studied at dosages equal to the ED50s, the period during which the serum concentration exceeded the MIC (delta T(MIC] was the factor which varied the least for the beta-lactam antibiotics (range, 2-5 h). For gentamicin and probably also for vancomycin the delta T(MIC) was below 20 min, while it was considerably longer (i.e. 19 h) for erythromycin, although the bactericidal activity of this drug in vitro was comparable to that of the beta-lactam antibiotics.

Animals↗

PubMed2005

Protective effects of different antioxidants and amrinone on vancomycin-induced nephrotoxicity.

We have studied the effects of three antioxidants and amrinone, an inotropic agent, against vancomycin-induced nephrotoxicity in rats by investigating renal function and morphology. Thirty adult female Sprague Dawley rats (168-234 g) were divided into six groups. A saline-treated group served as control. The other five groups were treated for 7 days with vancomycin alone or in combination with alpha-lipoic acid, Ginkgo biloba extract 761, melatonin or amrinone. On day 8, all the rats were sacrificed by decapitation, kidney tissues were excised immediately and blood and kidney samples were collected. Blood urea and creatinine, kidney tissue malondialdehyde levels, and kidney superoxide dismutase and glutathione (GSH) peroxidase activities were measured. The kidneys were also examined for histological changes. Vancomycin administration led to increased urea, creatinine and malondialdehyde levels and decreased superoxide dismutase and GSH peroxidase activities. Co-administration of alpha-lipoic acid, Ginkgo biloba extract, melatonin or amrinone with vancomycin prevented the increases in the urea, creatinine and melondialdehyde levels and also resulted in higher superoxide dismutase and GSH peroxidase activities. The antioxidants and AMR improved the renal pathology compared to rats treated with vancomycin alone (P<0.05). These results indicate that the three antioxidants and amrinone have potential protective effects against vancomycin-induced nephrotoxicity, which might in part be due to inhibition of free oxygen radical production. Amrinone was the most effective drug as judged on the basis of the pathological findings.

Amrinone↗