Effect of procalcitonin-guided decision making on duration of antibiotic therapy in suspected early-onset neonatal sepsis: multicenter prospective randomized intervention study

Neonatal infections are important causes of morbidity and mortalitiy in the
neonatal period. The diagnosis of neonatal infections is difficult, because
clinical symptoms are often non specific and can be absent when the neonate has
become infected just before birth. Current laboratory tests have low positive
and negative predictive values. A relatively new marker for infections in blood
is procalcitonin (PCT). Multiple observational studies in neonates have been
performed on the use of PCT as a parameter for bacterial infection in neonates.
Compared to the conventional marker in blood for infection, CRP, sensitivity
and specificity of PCT are higher in neonatal infection. Pitfall in the use of
PCT during the first days of life is the use of age-specific reference values
in these neonates. The value of PCT as a marker for bacterial infection in
neonates is complicated by a physiological increase of PCT during the first 3
days of life. After a peak value that is reached after 18-30 hours, PCT
decreases and normalizes to reference values comparable to adults after 42-48
hours.

Based on data generated by a pilot single center intervention study in
Switzerland on the use of PCT in neonatal infection, it was concluded that 1.
PCT analysis is feasible in newborn infants 2. serial PCT determinations
allowed to significantly reduce the duration of empiric antibiotic therapy in
term and near-term infants with suspected early-onset sepsis, 3. the
age-dependent PCT nomogram with a maximal threshold value of 10 ng/ml seemed to
be reasonable, and 4. a multi-center study will be required to test the
reliability of a PCT-based strategy in a larger cohort of neonates

To shorten the duration of administration of empiric parenteral antibiotics is
important. Because of the high risk of not treating neonates with a bacterial
infection, all neonates with any suspicion of infection are being treated for 7
days. Because the treatment consists of intravenously administered antibiotics,
this means admission to the hospital for the neonate with separation of mother
and child during these important first days of life.

1. To decrease the proportion of infants treated with antibiotics for > 48 - 72
hours with possible or unlikely infection.
2. To reduce the duration of antibiotic therapy

A multi-center, prospective, open, randomized controlled intervention study in
which serial PCT measurements will guide the treatment with intravenously
administered antibiotics of neonates suspected of early-onset neonatal
infection. Based on data of a pilot study in 120 neonates (60 neonates the PCT
intervention arm and 60 neonates in the control arm) a poweranalysis has been
performed. To answer the objectives of this study, with a power assumption of
80% and a duration of hospitalization in the pilot study of 5,4 days, 400
neonates should be enrolled.

Randomization:
Randomization to the standard therapy group (duration of intravenously
administration of antibiotics based on the judgement of the attending
physician), or the PCT intervention group (duration of intravenously
administration of antibiotics based on serial measurements of PCT) will be done
per center as a block by opening blinded envelopes.

Laboratory parameters:
In both groups at t = 0 hours (= start antibiotics), t = 18-36 hours , t =
36-72 hours en 72-120 hours CRP and hematology screen will be done. In the PCT
groep the measurement of PCT will be added, and one extra time-point (t = 12)
will be added.

Based on riskfactors, patient characteristics and results from conventional
laboratory parameters, patients will be divided into 4 groups: 1. infection
proven, 2. infection probably, 3. infection possible, 4. infection unlikely.
The duration of antibiotic therapy in the standard group is based on the
attending physician*s assessment of the probability of infection during
hospitalisation: in group 1 and 2 patients, antibiotics are given for 7 - 21
days, in group 3 patients for 5 - 7 days and in group 4 patients for 2 - 3
days. In the PCT group, if infection is considered to be unlikely or possible,
antibiotic therapy is discontinued when two consecutive PCT values are within
the normal range. Antibiotic therapy can be continued despite fulfilled PCT
criteria at the discretion of the attending physician.

The duration of antibiotic therapy in the standard group is based on the
attending physician*s assessment of the probability of infection during
hospitalisation: in group 1 and 2 patients, antibiotics are given for 7 - 21
days, in group 3 patients for 5 - 7 days and in group 4 patients for 2 - 3
days. In the PCT group, if infection is considered to be unlikely or possible,
antibiotic therapy is discontinued when two consecutive PCT values are within
the normal range. Antibiotic therapy can be continued despite fulfilled PCT
criteria at the discretion of the attending physician.

The burden is minimal, because only one extra time point for blood drawing will
be done in the intervention group. For the other time points and for the
children in the standard group no additional diagnostic procedures are needed.
The additional burden consists of a couple of extra blood drops during routine
bloodsampling.

The estimated risk is low. There is a low risk on discontinuing antibiotic
treatment too early, resulting in the development of a neonatal infection with
its morbidity and mortality.
Neonates will be divided in high and low risk neonates (groups 1 and 2 vs 3 and
4). Only in low risk neonates antibiotic treatment will be discontinued on the
basis of PCT. In addition, a high maximal reference value will be applied to
add extra safety.
Based on follow-up data of the pilot study as mentioned earlier, in 120
neonates no mortality was observed. In two children antibiotic treatment was
restarted. In one neonate because of respiratory insufficiency, this neonate
was born at a gestational age of 35 6/7 weeks with a clinical surfactant
deficiency. The other neonate was restarted on antibiotic treatment because of
Ecoli found in tracheal aspirate.