CEFTRIAXONE NEONATAL THERAPY (CEFSINT) : A RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE EFFECT OF CEFTRIAXONE ON HYPERBILIRUBINEMIA

Ceftriaxone (CFT), a third generation cephalosporin, is a broad spectrum
antibiotic which is efficacious against majority of the *-lactamases. CFT
covers most of the bacteria (gram positive, gram negative and anaerobic)
involved in neonatal serious bacterial infections (SBI) and is indicated for
the treatment of sepsis, meningitis and ophthalmia neonatorum. Its broad
spectrum of activity, once daily dosing because of a long half-life and good
penetration into cerebrospinal fluid (CSF) favour the use of CFT as an
excellent choice of empiric treatment of neonatal SBI.
Clinical studies evaluating the adverse effects of CFT in neonates are scanty
and inconclusive. Both a retrospective study of 72 neonates with bacterial
meningitis and a comparative study between CFT and Cefotaxime showed CFT to be
effective and safe. However recent case-report based evidence suggests that
use of this drug can cause serious adverse events in neonates, especially those
who received CFT treatment in combination with calcium containing total
parenteral nutrition (TPN). This has made the Food and Drug Administration to
issue a warning against the combination therapie of CFT and calcium infusion or
TPN. Though in-vitro studies have suggested that CFT could replace bilirubin
from albumin, leading to neonatal hyperbilirubinemia, this relation has not
been confirmed by in-vivo studies. However, in most hospitals CFT is no longer
a first choice antibiotic in neonatal care TThird generation cephalosporins
have been associated with an increased risk of nosocomial infections with
Extended Spectrum Beta Lactamase (ESBL) producing bacteria strains, mainly in
neonatal intensive care units (NICU). The pharmacokinetic properties of CFT in
neonates have not been studies in relation to its eventual adverse effects. For
almost two decades CFT has been used in neonates in the two hospitals in the
city of Tilburg in the recommended dosages, without the observation of
clinically more significantly morbidity or mortality than nationally reported
in the national neonatal register (Dutch National Perinatal Registration).

To compare in a randomized controlled trail (RCT) the risk of neonatal
hyperbilirubinaemia between neonates treated with CFT and
amoxicillin-clavulanic acid (augmentin, AUGM) combination versus neonates
treated with the aminoglycoside, tobramycin (TOBI) and AUGM combination, an
alternative antibiotic combination for the treatment of neonatal SBI treatment.
The secondary objective is to compare the incidence of pseudolithiasis in the
biliary and urogenital tracts in neonates treated with CFT-AUGM combination
compared to neonates treated with TOBI-AUGM combination.
The tertiary objective is to test the relationship between neonatal
hyperbilirubinemia and the to be tested adverse reactions and the
pharmacokinetic properties of CFT in neonates.

CEFSINT is a single center, single blind, prospective RCT to be carried out in
the neonatal unit of the Department of Pediatrics of St. Elisabeth Hospital
Tilburg.
Inclusion criteria
All neonates, 0-28 days old, with a gestational age (GA) of * 34 weeks,
admitted to the neonatal unit and requiring antibiotic treatment for a SBI.
Exclusion criteria:
GA <34 weeks; congenital malformations; erythrocyte transfusion; blood group or
other types of antibody antagonism; haemoglobinopathy; malignancy; serious
perinatal asphyxia ; concomitant use of intravenous calcium containing
solutions (intravenous fluid or TPN or transfer to another hospital before
completion of study.
Study plan (summary)
After inclusion: After obtaining written informed consent patients will be
randomized (computer-generated, in sealed opaque envelopes) into the two study
groups; CFT-AUGM (the present standard of care) or TOBI-AUGM.
Clinical data collection :
At inclusion: data to be collected include detailed neonatal demographic,
antropometric, birth and clinical data, and maternal obstetric and medical
history. Other relevant data are the history at presentation, physical
examination and measurements.
Laboratory measurements: hematological, biochemical and bacteriological
measurements and imaging (ultrasound of the urogenital and biliary systems)
which will be obtained prior to initiation of antibiotic treatment, on day 3 of
antibiotics in all children, and on day 7 in those who receive prolonged
antibiotic treatment.
Microbiological data: on the last day of antibiotic treatment, feces will be
collected to culture for extended spectrum beta-lactamase (ESBL) organisms.
Pharmacokinetic measurements: peak, median and trough serum CFT and TOBI
concentrations will be measured at day 1, 3 and weekly during antibiotic
treatment. Serum concentrations of CFT will be analyzed with High Performance
Liquid Chromatography (HPLC).
Statistical analyses
The aim of the statistical analyses is to compare the relationship between the
occurrence of major clinical and biochemical adverse reactions in neonates
receiving CFT-AUGM combination compared to those receiving TOBI-AUGM
combination, and to investigate the effect of potential confounding and
interaction variables. Analyses will be done based on numbers needed to treat.
Chi-squared test or the Fisher*s exact test will be used for the analysis of
categorical data and the student t-test for continuous variables with normal
distribution. The Mann-Whitney test Based on power calculations, a total number
of at least 150 patients (75 in each group) is needed to achieve a
significance level of * < 0,05 and a power (ß) of 0,80. Statistical analysis
will be performed with SPSS version 17.0 for Windows.

Ceftriaxone-augmentin antibiotic therapy.

Ethical considerations
Blood collection at baseline will be carried out by venipuncture, a routine
practice in which both blood collection and antibiotic administration are
achieved in the clinical practice. Follow-up blood measurements will be
obtained through heel prick. In all cases sucrose is administered 2 minutes
before to achieve analgesia. This is a routine practice in the neonatal unit.
If the value of one or more of the study exit measurement(s) is/are abnormal
without any detrimental clinical consequence , this measurement(s) will be
monitored on an outpatient basis, until normalization. The need for extra
laboratory or imaging testing or outpatient control visit will be left to the
discretion of the patient*s pediatrician.