Abstract
BackgroundEarly diagnosis and treatment of the newborn infant with suspected sepsis are essential to prevent severe and life threatening complications. Diagnosis of neonatal sepsis is difficult because of the variable and nonspecific clinical presentation. Therefore, many newborns with nonspecific symptoms are started on antibiotic treatment before the presence of sepsis has been proven. With our recently published single-centre intervention study we were able to show that Procalcitonin determinations allowed to shorten the duration of antibiotic therapy in newborns with suspected early-onset sepsis.Methods/DesignThe study is designed as randomized controlled international multicenter intervention trial on the efficacy and safety of Procalcitonin guided treatment. Term and near-term infants (gestational age ≥ 34 0/7 weeks) with suspected sepsis in the first 3 days of life requiring empiric antibiotic therapy will be included. The duration of antibiotic therapy in the standard group is based on the attending physician's assessment of the likelihood of infection (infection unlikely, possible, probable or proven). In the Procalcitonin group, if infection is considered to be unlikely or possible, antibiotic therapy is discontinued when two consecutive Procalcitonin values are within the normal range. Co-primary outcome measures are the duration of antibiotic therapy (superiority aspect of the trial) and the proportion of infants with a recurrence of infection requiring additional courses of antibiotic therapy and/or death in the first month of life (safety of study intervention, non-inferiority aspect of the trial). The number of infants to be included equals 800 per arm. With these numbers the power of the study to demonstrate superiority for duration of antibiotic therapy as well as non-inferiority regarding safety, i.e. excluding a disadvantage difference larger than 2% for the experimental arm, will both be greater than 80%.DiscussionBenefit of the study is a possible limitation of unnecessary use of antibiotics. The results of our first study suggest that there is a low risk on discontinuing antibiotic treatment too early, resulting in the development of a neonatal infection with its morbidity and mortality.Trial registrationThis trial is registered in the U.S. National Institutes of Health's register, located at http://www.clinicaltrials.gov. (NCT00854932).
Highlights
Diagnosis and treatment of the newborn infant with suspected sepsis are essential to prevent severe and life threatening complications
The results of our first study suggest that there is a low risk on discontinuing antibiotic treatment too early, resulting in the development of a neonatal infection with its morbidity and mortality
Neonatal sepsis is classified into two major categories: early onset sepsis, which usually presents with respiratory distress within 72 hours of age and late onset sepsis that usually presents with septicemia after 72 hours of age
Summary
It is essential for observational studies to compare new markers with the gold standard. We choose the design of a non-inferiority trial to show that a reduced duration of antibiotic therapy (superiority aspect) doesn’t change the outcome (recurrence of infection, mortality). The purpose of the choice to not interact with this clinical decision is to evaluate current clinical practice the closest without creating a bias towards biomarker started (or withheld) therapy When designing this intervention study, the definition of sepsis is less crucial than in an observation study, because in an intervention study all newborns are suspected to have bacterial infection and are treated with antibiotics. There is a low risk on discontinuing antibiotic treatment too early, resulting in the development of a neonatal infection with its morbidity and mortality. In only two children antibiotic treatment was restarted with good outcome and without proof for secondary infections due to early stop of primary antibiotic therapy
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