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. And cultures take 3 or more days for their
outcome. 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. Furthermore is
antibiotica-resitance caused by too much antibiotica prescription.

1. To decrease the proportion of infants treated with antibiotics for > 48 - 72
hours with possible or unlikely infection, with unchanged outcome.
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 will be to either a standard treatment based on conventional
laboratory parameters (standard group) or to PCT-guided treatment (PCT group)
blocked by center: Randomization by drawing group assignment cards in opaque
sealed 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-group will be done an additional puncture at t = 12.
Based on riskfactors, clinical symptoms and results from conventional
laboratory parameters, patients will be divided into 3 risk classification
categories: 4. low risk (infection unlikely), 3. Intermediate risk (infection
possible), 2. High risk (infection probable). 1. infection proven
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 category 1/2 patients, antibiotics are given for 7 - 21
days, in category 3 patients for 5 - 7 days and in category 4 patients for 2 -
3 days. In the PCT group, if infection is considered to be at low or
intermediate risk, 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 risk classification during
hospitalisation: in category 1/2 patients, antibiotics are given for 7 - 21
days, in category 3 patients for 5 - 7 days and in category 4 patients for 2 -
3 days. In the PCT group, if infection is considered to be at low or
intermediate risk, 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, only in the PCT-group. For the other time points 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.

A pilot study with 120 neonates has been perfomed in Switserland (see the
manuscipt that is in press in the scientific journal Neonatology, in the
Research protocol, Appendix III). Based on follow-up data of this pilot study
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 that
explains the respiratory insufficiency. The other neonate was restarted on
antibiotic treatment because of Ecoli found in tracheal aspirate. This study
used the same age-dependent reference range values for procalcitonin as the
current study will use.

Safety will be garanteed by the standard Dutch health system. This system is
applicable for all neonates, as infection can also become apparent after the
first three days of life. Parents and their neonates have 24 hours a day, 7
days a week access to medical help by their pediatricians. In addition, during
the first week of life a nurse is assisting the mother and her baby at home.
These nurses check basic medical parameters (temperature, heartrate,
respiratory frequency, weight) on a daily basis and are trained in the
observation of baby's to detect symptoms and signs of infection. Again, each
and every neonate can develop an infection, also after the first 3 days of
life.

To make parents of studyparticipants extra aware of the symptoms and signs of
an infection and to facilitate seeking medical help even more, parents will
receive, in addition to the routinely given oral information, a card upon
discharge. This card will state when parents should contact a physician and how
they can do that (Researchprotocol Appendix II).