Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Model-Informed Vancomycin Dosing Optimization to Address Delayed Renal Maturation in Infants and Young Children with Critical Congenital Heart Disease.

Ensuring safe and effective drug therapy in infants and young children often requires accounting for growth and organ development; however, data on organ function maturation are scarce for special populations, such as infants with congenital diseases. Children with critical congenital heart disease (CCHD) often require multiple staged surgeries depending on their age and disease severity. Vancomycin (VCM) is used to treat postoperative infections; however, the standard pediatric dose (60-80 mg/kg/day) frequently results in overexposure in children with CCHD. In this study, we characterized the maturation of VCM clearance in pediatric patients with CCHD and determined the appropriate dosing regimen using population pharmacokinetic (PK) modeling and simulations. We analyzed 1,254 VCM serum concentrations from 152 postoperative patients (3 days-13 years old) for population PK analysis. The PK model was developed using a two-compartment model with allometrically scaled body weight, estimated glomerular filtration rate (eGFR), and postmenstrual age as covariates. The observed clearance in patients aged ≤ 1 year and 1-2 years was 33% and 40% lower compared with that of non-CCHD patients, respectively, indicating delayed renal maturation in patients with CCHD. Simulation analyses suggested VCM doses of 25 mg/kg/day (age ≤ 3 months, eGFR 40 mL/min/1.73 m2 ) and 35 mg/kg/day (3 months < age ≤ 3 years, eGFR 60 mL/min/1.73 m2 ). In conclusion, this study revealed delayed renal maturation in children with CCHD, could be due to cyanosis and low cardiac output. Model-informed simulations identified the lower VCM doses for children with CCHD compared with standard pediatric guidelines.

Decreased vancomycin clearance in patients with congestive heart failure.

PURPOSE: Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent. METHODS: After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator. RESULTS: Patients with an LVEF of <40 % (16 patients) or those with an LVEF of ≥ 40 % and <60 % (40 % ≤ LVEF < 60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of ≥ 60 % (53 patients) (2.29 ± 0.95 or 2.79 ± 0.99 vs. 3.50 ± 1.04 L/h; p < 0.001 or p < 0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of <40 % (r = 0.828) and 40 % ≤ LVEF < 60 % (r = 0.773), but also with an LVEF in patients with a CLcr of <60 mL/min (r = 0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r(2) = 0.649). CONCLUSIONS: Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.

Systemic inflammatory response syndrome criteria and vancomycin dose requirement in patients with sepsis.

PURPOSE: Vancomycin has been used in patients with sepsis infected by MRSA and shows large interindividual variability in its dosing. In this observational study the potential influence of sepsis status on the vancomycin dose requirement in relation to systemic inflammatory response syndrome (SIRS) criteria was assessed. METHODS: From about 250 patients receiving serum vancomycin monitoring from May 2006 to April 2011 at the Osaka National Hospital, 105 adult patients who had been assessed using the SIRS criteria were identified. Patients on chemotherapy or intermittent positive pressure ventilation in whom the SIRS criteria could not accurately evaluate inflammatory status were excluded. Using two vancomycin serum concentrations at peak and trough, individual pharmacokinetic parameters were calculated by the Bayesian estimation method using a two-compartment model. Creatinine clearance rate was estimated by the Cockcroft-Gault formula (eCcr). RESULTS: Patients with SIRS had a significantly higher vancomycin clearance than those without SIRS, indicating that SIRS patients had a higher elimination capacity. The vancomycin clearance was positively correlated with the SIRS score defined as the number of positive items in the criteria, and negatively with age, except in patients with renal dysfunction. A linear relationship between the vancomycin clearance and eCcr remained even in the supernormal eCcr phase (more than approximately 120 mL/min). CONCLUSIONS: This study provides a new insight into the need for quick prediction of dose requirement. That is, an increased vancomycin dosage would be needed in patients with a higher SIRS score to maintain the therapeutic target concentration, in particular in those with a high eCcr value.

Destructive pulmonary embolism in a patient with community-acquired staphylococcal bacteremia.

We report a 17-year-old man with destructive pulmonary embolism caused by Staphylococcus aureus bacteremia. The patient was not immunocompromised and had neither underlying diseases nor risk factors, such as concomitant influenza viral infection, which exacerbate staphylococcal infections. The rapid and extensive progression of pulmonary involvement in all lung fields make this a rare case; there have been few reports in the literature describing a similar radiographic appearance in patients with community-acquired staphylococcal bacteremia. In-vitro studies did not demonstrate the production of enterotoxins or toxic shock syndrome toxin 1 (TSST-1) by the isolated strain, but genetic analysis detected Panton-Valentine leukocidine gene from the strain. Subsequent empyema with bilateral pneumothorax was prolonged because of superinfection with both methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Optional surgical treatments, including thoracostomy and thoracopneumoplasty, finally improved his condition.