Pharmacokinetic Assessment of Vancomycin Loading Dose in Critically Ill Patients

ABSTRACT The vancomycin loading dose (LD) of 25 to 30 mg/kg is a frequently practiced strategy to achieve effective concentrations from the first-treatment dose. However, considering only the body weight for dosing might be inadequate in critically ill patients due to pharmacokinetics changes. We sought to assess achieving optimal trough serum levels of vancomycin and AUC0–24/MIC in the first 24 h of treatment by using an LD based on population pharmacokinetic parameters of critically ill patients. We performed a concurrent cohort study over 22 months of patients with severe sepsis who received intravenous vancomycin. The patients were treated with three different strategies to initiate vancomycin: without an LD (group A), with an LD of 25 to 30 mg/kg (group B), and with an LD based on population pharmacokinetic parameters of the critically ill patient (group C). An optimal trough serum concentration was achieved in 5, 9, and 83% of patients in groups A, B, and C, respectively. The number of patients that reached optimal AUC0–24 was 2 of 18 (11%), 5 of 11 (46%), and 11 of 12 (92%) in groups A, B, and C, respectively. The statistical analysis for both parameters revealed significant differences in group C with respect to other groups. The administration of the LD calculated from population pharmacokinetic parameters from the beginning of therapy is a more efficient strategy to obtain adequate trough serum concentrations and AUC0–24/MIC in critical patients.

Download Full-text

New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03508-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7324-7330 ◽

Cited By ~ 50

Author(s):

N. Grégoire ◽

O. Mimoz ◽

B. Mégarbane ◽

E. Comets ◽

D. Chatelier ◽

...

Keyword(s):

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Multidrug Resistant ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Loading Dose ◽

Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

Download Full-text

ABO Blood Group and RhD status Are Not Associated with Mortality and Morbidity in Critically Ill Patients; a Multicentre Observational Study of 29 512 Patients

10.21203/rs.3.rs-944620/v2 ◽

2022 ◽

Author(s):

Thomas Kander ◽

Martin F. Bjurström ◽

Attila Frigyesi ◽

Magnus Jöud ◽

Caroline U. Nilsson

Keyword(s):

Critically Ill ◽

Blood Group ◽

Critically Ill Patients ◽

Blood Groups ◽

Blood Type ◽

Circulatory Support ◽

Critically Ill Patient ◽

Abo Blood Groups ◽

Number Of Patients ◽

Transfusion Requirements

Abstract Background. Previous studies have demonstrated an association between ABO blood groups and many types of disease. The present study primarily aimed to identify associations between ABO blood groups, RhD groups and mortality/morbidity outcomes in critically ill patients both in a main cohort and in six pre-defined subgroups. The secondary aim was to investigate any differences in transfusion requirement between the different ABO blood groups and RhD status.Methods. Adult patients admitted to any of the five intensive care units (ICUs) in Skåne, Sweden, between February 2007 and April 2021 were eligible for inclusion. The outcomes were mortality analysed at 28– and 90–days as well as at the end of observation and morbidity measured using days alive and free of (DAF) invasive ventilation (DAF ventilation) and DAF circulatory support, including vasopressors or inotropes (DAF circulation), maximum Sequential Organ Failure Assessment score (SOFAmax) the first 28 days after admission and length of stay. All outcomes were analysed in separate multivariable regression models (adjusted for age and sex), generating odds or hazard ratios for each blood group and RhD status using blood group O and RhD negative as reference. Transfusion requirements were also investigated.Results. In total, 29 512 unique patients were included in the analyses. There were no significant differences for any of the outcomes between non-O blood groups and blood group O, or between RhD groups. In five pre-defined subgroups (sepsis, septic shock, acute respiratory distress syndrome, cardiac arrest and trauma) there were no differences in mortality between non-O blood groups and blood group O or between the RhD groups. The Covid-19 cohort was not investigated given the low number of patients. Furthermore, we could not demonstrate any differences in the number of transfused patients between the ABO blood groups or between the RhD groups.Conclusions. ABO blood type and RhD status do not appear to influence mortality or morbidity in a general critically ill patient population. There were no differences in the number of transfused patients between the ABO blood groups or between the RhD status groups.

Download Full-text

Attributable nephrotoxicity of vancomycin in critically ill patients: a marginal structural model study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz520 ◽

2020 ◽

Vol 75 (4) ◽

pp. 1031-1037 ◽

Cited By ~ 3

Author(s):

Frederico Carlos de Sousa Arnaud ◽

Alexandre Braga Libório

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Structural Model ◽

Trough Level ◽

Kidney Injury ◽

Serum Levels ◽

Marginal Structural Model ◽

Model Study ◽

Trough Serum ◽

Serum Trough

Abstract Background Although vancomycin nephrotoxicity is recognizable, critically ill patients have other potential reasons for acute kidney injury (AKI) and determining its attributable nephrotoxic risk in this population can be cumbersome. Objectives To determine the risk of AKI attributable to vancomycin, controlling for baseline and time-dependent confounders. Methods Time-fixed and daily time-varying variables were extracted from a large public database. The exposures analysed were: (i) IV vancomycin; (ii) serum trough level greater than 15 and 20 mg/L; and (iii) concomitant exposure to vancomycin and piperacillin/tazobactam or other antipseudomonal β-lactams. Censoring and exposure inverse probability of treatment weighting were calculated. Marginal structural models were plotted to evaluate AKI, severe AKI (stage 2/3) and need of renal replacement therapy (RRT). Results A total of 26 865 patients were included; 19.7% received vancomycin during ICU stay. After adjusting for fixed and time-variable confounders, vancomycin exposure was associated with AKI (HR = 1.24, 95% CI = 1.09–1.38), but not with severe AKI or need of RRT (HR = 1.05, 95% CI = 0.91–1.23 and HR = 0.97, 95% CI = 0.74–1.29, respectively). A serum trough level greater than 20 mg/L was associated with AKI (HR = 1.90, 95% CI = 1.52–2.30) and severe AKI (HR = 1.69, 95% CI = 1.31–2.19), but showed no statistically significant association with need of RRT (HR = 1.48, 95% CI = 0.92–2.56). The vancomycin + piperacillin/tazobactam combination was not associated with a greater risk than vancomycin alone. Conclusions The attributable nephrotoxicity of vancomycin in critically ill patients is significantly lower than previously suggested and severe AKI is related to vancomycin only when trough serum levels are greater than 20 mg/L.

Download Full-text

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01088-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6550-6557 ◽

Cited By ~ 18

Author(s):

Abdulaziz S. Alobaid ◽

Steven C. Wallis ◽

Paul Jarrett ◽

Therese Starr ◽

Janine Stuart ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Maintenance Dose ◽

Central Compartment ◽

Pharmacokinetic Analysis ◽

Morbidly Obese ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Intercompartmental Clearance

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

Download Full-text

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

Critical Care ◽

10.1186/s13054-021-03863-4 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Marcus Kirwan ◽

Reema Munshi ◽

Hannah O’Keeffe ◽

Conor Judge ◽

Mary Coyle ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Maintenance Dose ◽

Structural Model ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Loading Dose ◽

Dose Monitoring ◽

Population Pk ◽

Vasopressor Use

Abstract Background Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. Methods This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. Results A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. Conclusions PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Download Full-text

Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00554-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7240-7248 ◽

Cited By ~ 61

Author(s):

Ilias Karaiskos ◽

Lena E. Friberg ◽

Konstantinos Pontikis ◽

Konstantinos Ioannidis ◽

Vasiliki Tsagkari ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Gram Negative ◽

Link Type ◽

Colistin Methanesulfonate

ABSTRACTColistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009,http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012,http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011,http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

Download Full-text

Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00892-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 94-101 ◽

Cited By ~ 8

Author(s):

Thomas Horvatits ◽

Reinhard Kitzberger ◽

Andreas Drolz ◽

Christian Zauner ◽

Walter Jäger ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

High Performance ◽

Area Under The Curve ◽

Antiviral Agent ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Target Area ◽

Continuous Venovenous Hemodiafiltration

ABSTRACTGanciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.

Download Full-text

Elimination of fosfomycin during dialysis with the Genius system in septic patients

Scientific Reports ◽

10.1038/s41598-021-91423-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

T. Dimski ◽

T. Brandenburger ◽

M. Janczyk ◽

T. Slowinski ◽

C. MacKenzie ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Prospective Observational Study ◽

Kidney Injury ◽

Serum Levels ◽

Therapeutic Drug ◽

Loading Dose ◽

Dialysis Therapy ◽

Daily Dialysis ◽

Wide Variability

AbstractTo assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4–6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.

Download Full-text

Achievement of Vancomycin Therapeutic Goals in Critically Ill Patients: Early Individualization May Be Beneficial

Critical Care Research and Practice ◽

10.1155/2016/1245815 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Bita Shahrami ◽

Farhad Najmeddin ◽

Sarah Mousavi ◽

Arezoo Ahmadi ◽

Mohammad Reza Rouini ◽

...

Keyword(s):

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Parameters ◽

Serum Concentrations ◽

Therapeutic Goals ◽

Dose Monitoring ◽

Trough Serum ◽

Group 2 ◽

Group 1

Objective.The aim of our study was to assess and validate the effectiveness of early dose adjustment of vancomycin based on first dose monitoring in achieving target recommended goal in critically ill patients.Methods.Twenty critically ill patients with sepsis received loading dose of 25 mg/kg of vancomycin and then were randomly assigned to 2 groups. Group 1 received maximum empirical doses of vancomycin of 15 mg/kg every 8 hrs. In group 2, the doses were individualized based on serum concentrations of vancomycin. First dose nonsteady state sampling was used to calculate pharmacokinetic parameters of the patients within 24 hours.Results.Steady state trough serum concentrations were significantly higher in group 2 in comparison with group 1 (19.4 ± 4.4 mg/L versus 14.4 ± 4.3 mg/L) (P=0.03). Steady state AUCs were significantly higher in group 2 compared with group 1 (665.9 ± 136.5 mg·hr/L versus 490.7 ± 101.1 mg·hr/L) (P=0.008).Conclusions.With early individualized dosing regimen, significantly more patients achieved peak and trough steady state concentrations. In the context of pharmacokinetic/pharmacodynamic goal of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) ≥400 and also to obtain trough serum concentration of vancomycin of ≥15 mg/L, it is necessary to individualize doses of vancomycin in critically ill patients.

Download Full-text

Vancomycin Dosing in Critically Ill Patients: Robust Methods for Improved Continuous-Infusion Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01708-10 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2704-2709 ◽

Cited By ~ 135

Author(s):

Jason A. Roberts ◽

Fabio Silvio Taccone ◽

Andrew A. Udy ◽

Jean-Louis Vincent ◽

Frédérique Jacobs ◽

...

Keyword(s):

Continuous Infusion ◽

Critically Ill ◽

Critically Ill Patients ◽

Large Population ◽

Total Body Weight ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Time Data

ABSTRACTDespite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m2would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.

Download Full-text