PHARMACOKINETICS OF INTRAVENOUS CEFOTAXIME IN CHILDREN

Cefotaxime is a bactericide third phase cephalosporin with an activity against
gram-positive streptococcal species, including S. pneumoniae, and against
gram-negative Haemophilus and Neisseria species. The metabolite,
desacetyl-cefotaxime, acts synergistically with cefotaxime against, for
instance, Bacterioides species [1, 2]. The drug has been used in paediatrics
for decennia to treat neonatal infections, pulmonary and urinary tract
infections, and as prophylaxis after gastro-intestinal surgery. Despite its
widespread use in paediatrics, the literature on cefotaxime pharmacokinetics in
children is scanty. In particular, there is a lack of information concerning
continuous intravenous infusion of cefotaxime, as it is used in our hospital
for over 15 years. In adults, by contrast, several studies are available
indicating the advantages of continuous infusion of beta-lactam antibiotics. As
the time above the minimal inhibitory concentration (MIC) is much longer during
continuous infusion, the killing rate of bacteria is greater [3, 4]. Current
literature, limited to intermittent dosing of cefotaxime in children, shows a
prolonged half life in neonates because of diminished renal excretion [5-9].
Recent work from our group, based on continuous infusion, revealed great
variability in cefotaxime concentrations in neonates [10]. This might be due to
the contribution to total cefotaxime body clearance of liver metabolism and
renal excretion, which both increase during the first week of life. This study
focused on neonates, although differences in metabolism and excretion are
expected in older children as well. For instance, some drugs are absorbed,
metabolised and excreted faster or more slowly compared to adults [11]. In
children, drug dosing should be very precise: low enough to prevent adverse
effects, but high enough to reach serum concentrations enabling the eradication
of the micro-organisms causing the infection. To accomplish this, study is
needed on the pharmacokinetics of drugs in different age groups. This study is
aimed to contribute to the knowledge of pharmacokinetics of cefotaxime in
children of all ages. Thereby we will get information whether the current
dosing regimen is accurate or needs adjustments.

The study described in this protocol is designed to determine the
pharmacokinetics of cefotaxime and its metabolite, desacetyl-cefotaxime, in
children on continuous intravenous infusion of cefotaxime. Using these data we
will be able to delineate further the dose regimen for continuous intravenous
infusion of cefotaxime in children.

Observational study

Burden
- maximum of 3 capillary punctures
- total blood taken: 1,2 ml over 3-5 days

Risks
- pain and fear: will be reduced by a good preparation by nurses.
- haematoma
- in neonates: anemia, though not expected because of minimal blood taken and
spread over 5 days