Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns)

Summary

Background

Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment.

Methods

We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932.

Findings

Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI −4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (−5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group).

Interpretation

Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death.

Funding

The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

Introduction

Neonatal sepsis is a leading cause of global mortality in children younger than 5 years.¹ Proven early-onset sepsis has mortality rates as high as 30% in high-income countries and up to 60% in low-income countries.2, 3 Prompt diagnosis and treatment of neonatal early-onset sepsis are crucial to prevent severe morbidity and mortality.⁴ However, the initial, clinical presentation is often subtle and nonspecific, and commonly used biomarkers have low predictive values for early sepsis, which presents a daily challenge to clinicians involved in neonatal care.⁵

In high-income countries, between 4·0–7·4% of term and late-preterm neonates are given intravenous antibiotics within the first 3 days of life if they are suspected to have early-onset sepsis. However, the prevalence of culture-proven early-onset sepsis is less than 0·1%, which suggests that antibiotic treatment—with its ensuing hospital admission, neonatal and parental discomfort, medical costs, and use of resources—is unnecessary in many neonates.6, 7, 8, 9 Additionally, evidence is accumulating that antibiotic treatment in early life disturbs the microbial flora that colonises the neonate and might be associated with health problems such as eczema, allergies, inflammatory bowel diseases, and increased weight gain.¹⁰

Research in context

Evidence before this study

The National Institute for Health and Care Excellence (NICE) guideline CG149 Neonatal infection (early-onset): antibiotics for prevention and treatment, published in August, 2012, states that evidence to guide the decision to stop antibiotic treatment in neonates receiving antibiotics for suspected early-onset neonatal infection is scant. The guideline recommends initiating studies answering the question: What is the clinical effectiveness of laboratory investigations used individually or in combination to exclude early-onset neonatal infection in neonates receiving antibiotics for suspected infection? The ideal study design was described as a randomised controlled trial comparing clinical outcomes associated with particular investigation and treatment termination strategies. No literature search was done.

Added value of this study

To our knowledge, the Neonatal Procalcitonin Intervention Study (NeoPInS) is the first neonatal intervention study on suspected early-onset sepsis aiming to show superiority (duration of antibiotic treatment) and non-inferiority (re-infection or death in the first month of life) of biomarker-guided antibiotic therapy improving antimicrobial stewardship. NeoPInS is well aligned with the ideal study design as recommended by NICE clinical guideline 149 and with the need for pragmatic studies. In a group of 1710 neonates from high-income countries with a low prevalence of proven early-onset sepsis, we found that standardised risk assessment for suspected early-onset sepsis with procalcitonin-guided decision making reduces the duration of antibiotic therapy and hospital stay, with a low rate of re-infections and without study-related mortality.

Implications of all the available evidence

The results of NeoPInS can help to improve patient care and clinical practice in newborn babies' first days of life. Reducing unnecessary antibiotic treatment is important, as we now have accumulating evidence of the adverse effects of antibiotic resistance and the consequences of disturbing the microbiome in early life, such as eczema, allergies, inflammatory bowel diseases, and increased weight gain. Additionally, the reduction of hospital admission will improve families' experiences of this special period of life and might reduce the burden for health-care facilities and services.

Procalcitonin has the highest negative predictive value (87–100%) of all established biomarkers for severe, invasive bacterial infections in neonates.11, 12 The interpretation of procalcitonin values in neonates is complicated by a physiological increase up to 48 h post partum, and other perinatal factors—such as chorioamnionitis, hypoxaemia, perinatal asphyxia, and maternal pre-eclampsia—can also cause it to increase.¹³ Reference values of procalcitonin in neonates with and without early-onset sepsis have been established.14, 15

Procalcitonin-guided decision making has been used to safely reduce antibiotic treatment in critically ill adults and children with suspected or proven invasive bacterial infections.16, 17 To our knowledge, no neonatal intervention studies to reduce antibiotic treatment including a safety endpoint have been done. In a single-centre pilot intervention study¹⁸ in term and near-term neonates with suspected early-onset sepsis, we previously showed that procalcitonin-guided decision making can reduce the duration of antibiotic treatment in this population. However, we could not assess safety due to the limited sample size, so we initiated a multicentre, multinational intervention study in both academic and non-academic hospitals to assess whether procalcitonin-guided decision making for neonates with suspected early-onset sepsis could safely reduce the duration of antibiotic treatment (superiority aspect) without increasing re-infection or death in the first month of life (non-inferiority aspect).