A poly(acrylic acid)-modified copper-organic framework for electrochemical determination of vancomycin.

A copper(II) benzene-1,3,5-tricarboxylate (BTC) metal-organic framework (MOF) was modified with poly(acrylic acid) (PAA) and then used in an electrochemical sensor for vancomycin. The MOF, synthesized via a single-pot method, has enhanced solubility and dispersibility in water as compared to HKUST-1 but without compromising its crystallinity and porosity. The MOF was placed on a glassy carbon electrode (GCE) where it shows enhanced electrocatalytic properties. This is assumed to be due to the presence of the poly(acrylic acid) that forms a network between various HKUST-1 crystals through dimer formation between the carboxy groups of BTC and PAA. This also led to better dispersion of the MOF and to improved interaction between MOF and vancomycin. The structural, spectral and electrochemical properties of the MOFs and their vancomycin complexes was characterized. The modified GCE is shown to be a viable tool for electrochemical determination (best at a working potential of 784 mV vs. Ag/AgCl) of the antibiotic vancomycin in spiked urine and serum samples. Response is linear in the 1-500 nM vancomycin concentration range, and the detection limit is 1 nM, with a relative standard deviation of ±4.3%. Graphical abstractSchematic representation of a method for determination of vancomycin. Poly(acrylic acid) modified HKUST-1 (P-HKUST-1) forms a complex with vancomycin [Van-P-HKUST-1] which is coated over glassy carbon electrode (GCE). The decrease in peak current is recorded as response to vancomycin via cyclic voltammetry.

A ratiometric fluorescent probe for sensitive determination of the important glycopeptide antibiotic vancomycin.

A novel sensitive and selective probe for the important antibiotic vancomycin (Van) has been synthesized by integrating a coumarin and a fluorescein as dual fluorescence reporters and a Van binding peptide D-Ala-D-Ala. Only weak green fluorescence was initially observed, which was mostly attributed to fluorescence self-quenching induced by fluorophore stacking. Upon the binding of Van with the D-Ala-D-Ala peptide, the fluorescence turned on, probably due the disaggregation of fluorophores. The intensity ratio of the dual emission bands I519/I446 exhibited an excellent linear relationship with the concentration of Van increasing from 0-20 µM in synthetic urine. The lowest detection limit was calculated to be 92.8 nM in urine, which made the probe applicable in clinically relevant concentration ranges. The synthetic probe has also shown the potential for Van detection in human serum. More interestingly, this probe has been successfully applied for in vivo imaging of Van in zebrafish. Graphical Abstract.

Evaluating Renal Stress Using Pharmacokinetic Urinary Biomarker Data in Critically Ill Patients Receiving Vancomycin and/or Piperacillin-Tazobactam: A Secondary Analysis of the Multicenter Sapphire Study.

INTRODUCTION: A drug combination that has gained recent attention for an additive risk of nephrotoxicity is vancomycin plus piperacillin-tazobactam. Clinicians need to better understand whether tubular cell stress occurs with piperacillin-tazobactam administration to establish whether renal injury associated with this combination is a valid clinical concern. OBJECTIVE: An evaluation of the pharmacokinetics of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding-protein 7 (IGFBP7) for patients receiving vancomycin alone, piperacillin-tazobactam alone, and vancomycin plus piperacillin-tazobactam in combination was conducted to understand the impact on acute kidney cell stress and compare the rates of dialysis or death at 9 months among these three drug exposure types. METHODS: A secondary analysis of the prospective, multicenter Sapphire study (ClinicalTrials.gov identifier NCT01209169) including 35 intensive care units (ICUs) in North America and Europe was performed. Critically ill adult patients at risk for acute kidney injury (AKI) were included. Urinary [TIMP-2]∙[IGFBP7] was measured serially. Patients who received vancomycin alone, piperacillin-tazobactam alone, or vancomycin plus piperacillin-tazobactam were grouped according to their maximum AKI stage within 3 days of the first drug dose. RESULTS: Of 723 critically ill adults admitted to the ICU, 46% received either piperacillin-tazobactam (n = 110), vancomycin (n = 156), or both (n = 67). The urinary [TIMP-2]∙[IGFBP7] was highest on day 1 for the combination group. AKI stage 2/3 occurred more frequently in patients receiving the drug combination than in those receiving piperacillin-tazobactam alone (p = 0.03) but not vancomycin alone (p = 0.29). Risk of death or dialysis at 9 months was greatest for vancomycin plus piperacillin-tazobactam (48%) and similar for patients receiving vancomycin alone (29%) or piperacillin-tazobactam alone (35%) (p = 0.03 for unadjusted and p = 0.048 after adjusting for covariates). CONCLUSION: After exposure to piperacillin-tazobactam and vancomycin in combination, there was a greater release of AKI biomarkers in patients who develop AKI than with piperacillin-tazobactam or vancomycin monotherapy and the combination is associated with possible increased long-term adverse outcomes.

Urine Vancomycin Level as a Method for Drug Monitoring in Patients With Normal and Decreased Kidney Function.

INTRODUCTION: Therapeutic drug monitoring of vancomycin is an important issue in clinical decision-making and dosage modifying, particularly among patients in critical conditions and decreased kidney function. Urine is typically readily available in hospitalized patients and therapeutic drug monitoring in urine may be a reliable and noninvasive procedure compared to frequent blood sampling. We aimed to determine and validate the diagnostic yield of vancomycin trough level in urine. MATERIALS AND METHODS: In a prospective study, 95 patients who were treated with vancomycin for any clinical condition were enrolled in this study. Patients were divided into 2 groups according to their glomerular filtration rate (greater than 80 mL/min/1.73 m2 versus 15 mL/min/1.73 m2 to 80 mL/min/1.73 m2). Vancomycin serum trough levels and simultaneous urine trough levels were detected by high-pressure liquid chromatography. RESULTS: The mean serum and urine trough levels of vancomycin were 13.13 ± 1.34 mg/L and 7.79 ± 1.23 mg/L, respectively. The serum and urine trough levels had a positive linear correlation (r = 0.38, P < .001), which was also significant in patients with normal kidney function (r = 0.43, P = .001). The estimated serum concentration was equal to urine vancomycin concentration plus 5.3 mg/L. CONCLUSIONS: Urine levels of vancomycin correlate with simultaneous serum levels and may consistently predict serum levels in patients with normal kidney function. Therefore, urine vancomycin monitoring might be used as a noninvasive alternative to blood sampling, particularly in patients with normal kidney function.

An LC-MS/MS method to determine vancomycin in plasma (total and unbound), urine and renal replacement therapy effluent.

AIM: Critical illness and medical interventions, such as renal replacement therapy, can cause changes to vancomycin pharmacokinetics and lead to suboptimal dosing. To comprehensively characterize vancomycin pharmacokinetic a method must measure vancomycin in a range of clinical matrices. RESULTS: A LC-MS/MS method was developed using hydrophilic interaction liquid chromatography and microsample volumes, where possible. For all matrices, the linear concentration range was 1-100 µg/ml, interassay accuracy and precision was within 15%, and recovery above 80%. No matrix effects were observed. Calibration equivalence may be applied for some matrix combinations. CONCLUSION: A method for the analysis of vancomycin in plasma (total, unbound), urine and renal replacement therapy effluent, suitable for use in any patient pharmacokinetic study, has been developed and validated.

Unbound fraction of vancomycin in intensive care unit patients.

Published data on the unbound fraction of vancomycin in patient samples exhibit high variability. In the present study, a robust ultrafiltration method was developed and applied to 102 clinical samples from 22 intensive care unit patients who were treated with continuous infusion of vancomycin. A validated HPLC method was used for determination of total and unbound concentrations. The mean unbound fraction was 67.2% (standard deviation 7.5%, range 47.2-92.1%) and independent of total concentration of vancomycin or of albumin. The unbound fraction was significantly correlated (r = +0.67, P = .0009) with the renally filtered fraction (drug clearance/creatinine clearance), providing functional evidence for the validity of the measurements. Ultrafiltration proved to be susceptible to variations in the experimental conditions such as pH, temperature and centrifugal force. The measured unbound fraction increased from 60% at pH 6 to 100% at pH 9, from 57% at 4°C to 80% at 37°C, and was 76% at 1,000 g compared with 45% at 10,000 g. Lack of standardization may therefore partly explain the variable results reported in the literature.

Rapid UHPLC method for simultaneous determination of vancomycin, terbinafine, spironolactone, furosemide and their metabolites: application to human plasma and urine.

The ultra high performance liquid chromatography (UHPLC)-UV method for the simultaneous determination of furosemide, saluamine (furosemide metabolite), spironolactone, carnenone (spironolactone active metabolite), terbinafine, N-desmethylcarboxy terbinafine (terbinafine metabolite) and vancomycin in human plasma and urine is proposed. Good separation of the analytes was achieved with the gradient RP-UHPLC-UV with the mobile phase composed as acetonitrile and 0.1% formic acid. The determined substances were eluted from a Hypersil GOLD C(18)e (50 mm x 2.1 mm, 1.7 microm particles) column in 3.3 min. Good linear relationships were observed for all of the analytes (R(2) higher than 0.994). The limit of detection (LOD) values varied from 0.01 to 0.07 microg ml(-1), with vancomycin as an exception (0.11 microg ml(-1)). After protein precipitation and solid-phase extraction, samples of plasma and urine were analyzed. Thanks to the short analysis time and small quantities of urine or plasma needed, this method can be applied to routine clinical analysis.

Protective effect of inactive ingredients against nephrotoxicity of vancomycin hydrochloride in rats.

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.

Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates.

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.

Topical vancomycin applied on closure of the sternotomy wound does not prevent high levels of systemic vancomycin.

OBJECTIVE: Vancomycin is effective in reducing the risk of mediastinits and topical vancomycin has been hypothesised to give high local dose concentrations while avoiding high systemic levels, thus avoiding the risk of bacterial resistance to this second-line antibiotic. However, this theory has never been tested and the degree to which vancomycin is absorbed systemically is unknown. METHODS: Fourteen patients undergoing elective coronary artery bypass grafts (CABG) received 500mg of topical vancomycin prior to sternotomy closure. Serum samples were taken at 30, 60, 120, 180 and 720min post-operatively. In addition, samples were taken from the drain bottles and urine samples taken daily for 5 days. Vancomycin levels were measured by fluorescence polarisation immunoassay, using the reverse dilution method to give a detection limit of 0.8mg/l. RESULTS: Vancomycin was detected in almost all serum samples. Peak concentration was at 30min and the mean value was 2.96mg/l (range, 0.99-5.00mg/l). This mean fell to 1.32mg/l at 6h. Of the 500mg of vancomycin applied, a mean of only 8.8mg was found to have been lost into the drain bottles in the first 24h (range, 0.17-12.5mg). When 5 consecutive days of urine collection was achieved, a mean of 151mg of vancomycin was excreted (range, 40-195mg) and vancomycin was detectable in the urine till day 5. The mean concentration of vancomycin in the urine was maximal on day 1 and was 24.4mg/l (range, 4.49-44.98mg/l). CONCLUSIONS: Topical vancomycin causes significant systemic concentrations in the 6h post-surgery and can be detected in the urine for up to 5 days post-surgery.

Rapid bioanalysis of vancomycin in serum and urine by high-performance liquid chromatography tandem mass spectrometry using on-line sample extraction and parallel analytical columns.

A novel high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS) method is described for the determination of vancomycin in serum and urine. After the addition of internal standard (teicoplanin), serum and urine samples were directly injected onto an HPLC system consisting of an extraction column and dual analytical columns. The columns are plumbed through two switching valves. A six-port valve directs extraction column effluent either to waste or to an analytical column. A ten-port valve simultaneously permits equilibration of one analytical column while the other is used for sample analysis. Thus, off-line analytical column equilibration time does not require mass spectrometer time, freeing the detector for increased sample throughput. The on-line sample extraction step takes 15 seconds followed by gradient chromatography taking another 90 seconds. Having minimal sample pretreatment the method is both simple and fast. This system has been used to successfully develop a validated positive-ion electrospray bioanalytical method for the quantitation of vancomycin. Detection of vancomycin was accurate and precise, with a limit of detection of 1 ng/mL in serum and urine. The calibration curves for vancomycin in rat, dog and primate were linear in a concentration range of 0.001-10 microg/mL for serum and urine. This method has been successfully applied to determine the concentration of vancomycin in rat, dog and primate serum and urine samples from pharmacokinetic and urinary excretion studies.

Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits.

The nephrotoxic effects of vancomycin hydrochloride (VCM) and the potential drug-drug interaction with cilastatin sodium (CS) were examined in rabbits. The aim of the study was to measure the possible dose-related suppressive effects or elimination by cilastatin of the adverse reactions generated by vancomycin in the kidneys of rabbits. To clarify the interactions of these two drugs, we examined the nephrotoxicity and pharmacokinetics of VCM in the rabbit when administered alone and when coadministered with CS. VCM administered alone (300 mg/kg of body weight as an intravenous bolus; n = 5) caused typical symptoms of nephrotoxicity, such as increases in serum creatinine and blood urea nitrogen (BUN) levels, as well as morphological changes in the kidneys. A lack of such signs of nephrotoxicity was observed in the groups administered VCM plus CS (i.e., CS at 150 mg/kg plus VCM at 300 mg/kg or CS at 300 mg/kg plus VCM at 300 mg/kg, intravenous bolus; n = 5/group). At a reduced combination ratio of VCM plus CS (4:1 ratio, VCM at 300 mg/kg plus CS at 75 mg/kg, intravenous bolus; n = 5) some symptoms of nephrotoxicity induced by VCM were present, but the degree of this effect was much reduced and was significantly different from preadministration values by only modest increases of the BUN and N-acetyl-beta-D-glucosaminidase levels (P < 0.05). Overall clearance of VCM was accelerated by coadministration of CS and was found to be dose dependent upon CS. No changes in renal function values from the preadministration values were observed for animals receiving CS alone (300 mg/kg, intravenous bolus; n = 3). These results suggest that CS has the ability to reduce or eliminate in a dose-dependent manner the nephrotoxic effects caused by VCM administration in rabbits.

In-vivo clearance study of vancomycin in rats.

The renal handling of vancomycin in rats and the effects of various drugs (probenecid, cimetidine and quinidine) on urinary excretion of the antibiotic were investigated by in-vivo clearance. The vancomycin-to-inulin excretion ratio (ER) was greater than unity at various infusion rates of vancomycin. Quinidine, co-administered with vancomycin, significantly decreased the total, renal and net secretory clearance of the antibiotic. Cimetidine also decreased, though not significantly, the secretory clearance of vancomycin by about 20%, but probenecid did not. These results suggested that vancomycin is secreted in renal tubules in rats, and that quinidine decreases the total clearance of vancomycin partly by inhibiting its tubular secretion in the kidney.

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.

Vancomycin pharmacokinetics in burn patients and intravenous drug abusers.

The pharmacokinetics of vancomycin were evaluated in 34 patients (10 burn patients, 14 intravenous drug abusers [IVDA], and 10 controls). Multiple serum samples were drawn following a 1-h vancomycin infusion at steady state over an 8- to 12-h dosing interval. Pharmacokinetic parameters were derived by noncompartmental analysis. There were no significant differences among the groups with respect to age, weight, serum creatinine, volume of distribution, or protein binding. Burn patients had a significantly higher creatinine clearance than did IVDA or controls. Vancomycin clearances averaged 142.8, 98.0, and 67.7 ml/min in burn patients, IVDA, and controls, respectively. The renal clearance of vancomycin was also higher in burn patients than in the other groups. IVDA tended to have a higher vancomycin clearance (31% higher) than did controls, but the difference was not statistically significant. Vancomycin clearance was much higher in burn patients requiring dosage individualization and close monitoring. A considerable amount of vancomycin was eliminated through renal tubular secretion, making dosage predictions based on creatinine clearance more difficult. Further work with IVDA will be needed to determine if they represent a group requiring aggressive vancomycin dosages.

Pharmacokinetics and cerebrospinal fluid (CSF) concentrations of vancomycin in pediatric patients undergoing CSF shunt placement.

Staphylococcus epidermidis has been established as the common pathogen causing cerebrospinal fluid shunt infections. In addition, clinical isolates of S. epidermidis from infected shunts are typically resistant to methicillin. Vancomycin is often used for neurosurgical prophylaxis due to its excellent in vitro activity against methicillin-resistant staphylococci. Limited data are available about the pharmacokinetics and cerebrospinal fluid concentrations of vancomycin in pediatric patients intraoperatively. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations of vancomycin. Eight patients (mean age 8.3 +/- 7.0 years) received three doses of intravenous vancomycin, 15 mg/kg every 6 h. The first dose was administered 1 h prior to surgery. Blood samples were collected at 0, 0.5, 1, 2, 4, and 5 h after the end of the infusion. A cerebrospinal fluid sample was collected at the time of shunt insertion. Urine samples were collected over a 24-hour period. Vancomycin was measured with a fluorescence polarization immunoassay. The peak serum concentrations ranged from 15.6 to 33.7 micrograms/ml; cerebrospinal fluid concentrations ranged from less than 0.6 to 0.8 microgram/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.11 +/- 0.05 l/h/kg, 0.07 +/- 0.02 l/h/kg, 0.54 +/- 0.15 l/kg, and 4.8 +/- 4.0 h, respectively. Approximately 70% of total vancomycin dose was excreted in the urine. A 2- to 5-fold variation in total clearance and a 2.5-fold variability in renal clearance were observed. Low cerebrospinal fluid concentrations of vancomycin were present at the time of shunt insertion in these pediatric patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrarenal distribution of vancomycin in endotoxemic rats.

We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg). The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxin-infused rats than in the normal rats (P less than 0.01). Endotoxin was associated with an increase in the half-life in serum (P less than 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P less than 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.

Vancomycin elimination in patients with burn injury.

Patients with burns clinically appear to require considerably larger doses of vancomycin than normal to attain therapeutic serum concentrations. It has been presumed that this phenomenon is a result of increased renal elimination of this drug consequent to increased glomerular filtration rates in such patients, as has been documented with aminoglycoside antibiotics. We measured the serum clearance of vancomycin in 10 patients with burns and found this parameter to correlate closely with creatinine clearance (serum clearance = 12.5 + 0.695 creatinine clearance; r = 0.932; P less than 0.001). The slope of this relationship was similar to that reported by other investigators in patients not suffering from thermal injury. We conclude that at all levels of renal function, patients with burns clear vancomycin in a manner similar to that of other patients. Consequently, renal function can be used to select a dosing regimen for vancomycin in such patients.

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)

Vancomycin disposition: the importance of age.

We examined the influence of age on vancomycin kinetics in 12 normal healthy men (six young and six elderly) after an intravenous infusion of 6 mg/kg. Serial blood and urine samples were collected for up to 2 days after dosing and were assayed for unchanged drug by a specific radioimmunoassay. Serum concentrations of vancomycin after infusion declined in a multiphasic manner. Both serum and urinary excretion data were simultaneously fit by a three-compartment model with SAAM-27 computer programs. Estimates of mean t1/2 obtained from the terminal phase of the drug disposition profile showed the t1/2 to be longer in the elderly than in the young subjects (12.1 and 7.2 hr). Although there was no change in the initial distribution volume of the central compartment, total systemic and renal clearances were reduced in the elderly and did not correlate with renal function. The increase in the vancomycin volume of distribution at steady state was ascribed to enhanced tissue binding of drug in the elderly, since the mean fraction of vancomycin bound in systemic pool of the young and elderly did not differ (0.53 and 0.56). In-depth analysis of excretion data tends to support suggestions of vancomycin excretion solely by glomerular filtration. Our data strongly suggest the need for adjustment or modification of recommended vancomycin dosing schedules in the elderly.