Evaluation of once-daily gentamicin dosing in children with febrile neutropenia

Once-Daily Gentamicin Dosing in Children with Febrile Neutropenia Resulting from Antineoplastic Therapy

Miriam Inparajah, B.Sc.Phm. | Cecile Wong, B.Sc.Phm. | Cathryn Sibbald, B.Sc.Phm. | Sabrina Boodhan, B.Sc.Phm. | Eshetu G. Atenafu, M.Sc. | Ahmed Naqvi, M.B.B.S., MCPS, MRCP | L. Lee Dupuis, M.Sc.Phm., FCSHP

Pharmacotherapy. 2010 Jan;30(1):43-51

Abstract

Study Objectives. To evaluate an existing once-daily gentamicin dosing guideline in children with febrile neutropenia resulting from antineoplastic therapy and, if necessary, to develop a new simulated dosing guideline that would achieve pharmacokinetic targets more reliably after the first dose.

Design. Pharmacokinetic analysis of data froma retrospective medical record review.

Setting. Hematology-oncology unit of a university-affiliated pediatric hospital in Canada.

Patients. One hundred eleven patients aged 1–18 years who received once-daily gentamicin between April 2006 and January 2008 for the treatment of febrile neutropenia resulting from antineoplastic therapy, and who had plasma gentamicin concentrations determined after their first dose.

Measurements and Main Results. Demographic data, gentamicin dosing information, blood sampling times, and plasma gentamicin concentrations were noted. Plasma gentamicin concentrations were determined at approximately 3 and 6 hours after the start of the 30-minute infusion of the first dose. Pharmacokinetic parameters were calculated according to standard first-order, one-compartment equations. The proportion of children who achieved pharmacokinetic targets after the first gentamicin dose was used as a measure of dosing guideline performance; the guideline achieved maximum concentration (Cmax) values below the target range (20–25mg/L) in 51% of patients. Ideal dosing guidelines were then developed using the mean dose required to achieved a Cmax of 23 mg/L for each patient. Univariate analysis or the Student t test was used to determine the existence of significant relationships between pharmacokinetic parameters and patient age and sex. The recursive binary partitioningmethod was used to determine critical values of age for dosage guideline development; analysis of variance was then used to compare the different levels obtained after use of this technique. Simulated administration of once-daily gentamicin in the following doses achieved a Cmax within or above target in 73% of patients: 1 year to 6 years, 10.5mg/kg/dose; girls ≥ 6 years, 9.5mg/kg/dose; and boys ≥ 6 years, 7.5mg/kg/dose. Doses were based on actual body weight for children who weighed less than 125% of ideal body weight or based on effective body weight for children 125%ormore of ideal body weight.

Conclusion. The initial gentamicin dosing guidelines were not effective in achieving Cmax. The new proposed dosing guidelines are predicted to achieve a Cmax within or above the target range in almost three quarters of patients. Subsequent dosing should be tailored according to plasma gentamicin concentrations.

Summary of Consensus Recommendations for Vancomycin Monitoring in Adults

A recent article in November 2009 issue Pharmacotherapy summarizes the recommendations from the American Society of Health-System Pharmacists, the Infections Diseases Society of America, and the Society of Infectious Diseases Pharmacists on the monitoring of vancomycin in adults.

“The American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists published a consensus statement on therapeutic monitoring of serum vancomycin levels in adults. These organizations established an expert panel to review the scientific data and controversies associated with vancomycin monitoring and to make recommendations based on the available evidence. As the members of this panel, we summarize the conclusions and highlight the recommendations from the consensus statement. We determined that the area under the concentration-time curve (AUC):minimum inhibitory concentration (MIC) ratio is the most useful pharmacodynamic parameter to predict vancomycin effectiveness and suggested a target ratio of 400 or greater to eradicate S. aureus. In addition, trough serum concentration monitoring is the most accurate and practical method to monitor vancomycin serum levels. Increasing trough concentrations to 15–20 mg/L to attain the target AUC:MIC ratio may be desirable but is currently not supported by clinical trials. Alternative therapies should be considered in patients with S. aureus infections that demonstrate a vancomycin MIC of 2 mg/L or greater because the target AUC:MIC ratio ( 400) is unlikely to be achieved in this setting. Increasing the dosage to result in higher trough concentrations may increase the potential for toxicity; however additional clinical experience is required to determine the extent.”

While the article contains nothing new in terms of vancomycin monitoring and kinetics, the recommendation to consider alternate therapy for S. aureus infections with an MIC >/= 2 mg/L is important to note.

Can antibiotic choice be based on MIC alone?

This questions was recently addressed by Michael J. Postelnick, Senior Infectious Diseas Pharmacist of Northwestern Memorial Hospital in Chicago, Illinois in an Ask-the-Experts post on the Medscape website. Postelnick gives a good explanation of how various pharmacokinetic and pharmacodynamic principles are related to antibiotic choice for infectious pathogens. According to Postelnick “research into antimicrobial pharmacokinetics and pharmacodynamics has established surrogate relationships between the 2 that correlate with outcomes such [as] bacterial eradication or clinical cure. These relationships include the ratio of Cmax to the MIC, time above the MIC (defined as the amount of time during the dosing interval that the antimicrobial concentration in the blood or at the site of infection remains above the MIC of the organism), and the ratio of the AUC to the MIC. For concentration-dependent antimicrobial agents such as fluoroquinolones and aminoglycosides, Cmax/MIC or AUC/MIC most closely correlates with clinical and microbiological outcomes. For time-dependent antimicrobial agents such as beta-lactams, the percentage of time during the dosing interval that the drug concentration remains above the MIC of the organism is the measure that most closely predicts outcomes.” In other words, selection of an antibiotic requires more than the MIC. Knowledge of the organism in addition to pharmacokinetic and pharmacodynamic principles of the drug is necessary to make an informed choice.