Optimalisation of vancomycine dosage regimens in pediatric patients

Vancomycin is used therapeutically for the treatment of (suspected) systemic
infections with Gram positive bacteria (e.g. coagulase negative Staphylococci).
In children different dosage regimens are used for each age category. Children
from 4 weeks of age are given a dose of 20-30 mg/kg bid. As part of their
treatment therapeutic drug monitoring of vancomycine takes place 48 hours after
the intial dose, according to a local protocol. To ensure optimally effective
therapy dosing is aimed at serum concentrations above 8 mg/l, based on the time
dependent characteristic of vancomycin pharmacodynamics. Individual dosage
advices are given accordingly by the pharmacy department of the institution,
for which pharmacokinetic population data are taken into account.
A retrospective analysis in our institute in 2005 revealed that 51% of all
vancomycin concentration measurements are below the target serum concentration
of 8 mg/l. During this evaluation adequate concentrations were shown to be
achieved after approximately 1 week. Unfortunately the accuracy of the timing
of vancomycine doses and blood sampling was insufficient to enable the proper
calculation of optimal dosage regimens.

Dividing the study population in four categories (oncological patients,
critically ill patients admitted to intensive care, neonates and other
children) answers to the following questions are sought:
- which initial dosage regimen for vancomycin leads to adequate serum
concentrations (>8 mg/l) in an early stage of therapy.
- are the chosen patient groups identified by specific pharmacokinetic
behaviour or relevant co-factors.

At het end of the study the optimized dosage regimens are established and
pharmacokinetic population models are revised.

Design
Open cohort study

Vancomycin dosing
Children will be treated with intravenous vancomycin and will be randomized
within the first 24 hours to a treatment group (A or B) according to the
schedule shown below, depending on the clinical ward.
The dosages are within the normal range for non-neonates (40 mg/kg/day) except
for the index group for oncological patient who will receive (80 mg/kg/day).
For this group a higher initial dose is chosen based on data from literature.
For neonates a higher initial dose in the index group is chosen based on
retrospective concentration data.
For every patient the initial dose will be evaluated after the first
concentration measurement and adapted if necessary to obtain concentrations
above 8 mg/l.


Ward Control group (A) Index group (B)

G8ZW (ICK) 20 mg/kg bid 30 mg/kg bid

H3NO (NICU) prematuren < 7 dagen: prematuren < 7 dagen:
en neonates <7 d 10 mg/kg bid 15 mg/kg bid
on other wards à terme < 7 dagen: à terme < 7dagen:
15 mg/kg bid 20
mg/kg bid
> 1 week: 20 mg/kg bid > 1 week: 30
mg/kg bid

F8NO (kinderoncologie) 15 mg/kg qid 20 mg/kg qid

Overige kinderafdelingen 20 mg/kg bid 30 mg/kg bid


Sampling
Blood sampling for determination of vancomycin serum concentrations is done
according to local protocol. To gain insight into the population
pharmacokinetics of vancomycin in children the collection of as many additional
samples as possible, taken on different time points after dosing, is
important. To achieve this, waste material (plasma or serum) collected for
other tests will be used. During vancomycin treatment the laboratory order form
will be labeled with a request to send waste material to the pharmacy
department for this purpose. If insufficient waste material is available extra
blood samples will be drawn to have a minimum of two samples available for
every day of treatment, unless sampling is medically contraindicated (decided
by the treating physician).
Before treatment with vancomycin is started blood samples sent to the
microbiology department for microbiological determination of the antibiotic
susceptibility and/or to determine the MIC.

Half of the included number of patients will receive a higher vancomycin dosage
at the start of therapy. However this dosage is within the limits of the normal
dosage range.

Vancomycine treatment will be started following current local treatment
guidelines which are also applicable to patients not participating in this
study. The objective of this study is to optimize vancomycin intravenous dosage
schedules to be able to implement efficacious therapy as soon as possible after
diagnosis. This can be achieved with dosages within the normal dosage range.
The additional risk of (dose related) adverse effects in the index group is
therefore minimal.
Extra blood sampling is avoided by using waste material as much as possible.
Only when insufficient samples (less than two samples per day) are available,
extra samples will be taken.