Measuring procalcitonin levels in newborns with suspected sepsis in the first days of life reduced antibiotic duration by 10 hours compared with standard care. There was no increase in the risk of re-infection or death.
Systemic infection can be rapidly life-threatening in newborn babies, so those with risk factors are often treated pre-emptively with intravenous antibiotics. If sepsis is not confirmed by blood culture the decision whether to discontinue antibiotics needs to be made, but results of the blood culture takes time.
Procalcitonin is released into the blood in response to inflammation, and low levels may give an earlier indication that there is no serious infection. This trial in 1710 term or late-preterm babies compared procalcitonin-guided treatment with standard care, which includes monitoring of an alternative inflammatory marker C-reactive protein.
Reduced antibiotic use and hospital stay are highly relevant outcomes for parents and in the overall aim of reducing unnecessary antibiotic use. Importantly use of the new marker was not inferior to standard care regarding the risk of complications either.
NICE guidance, issued before this study, in 2015 did not recommend using procalcitonin to monitor sepsis due to lack of evidence. This study could inform future updates.
Why was this study needed?
Sepsis is responsible for almost a quarter of deaths in newborn babies, about one baby per week in the UK, and many survivors are left with a long-term handicap. Early diagnosis and treatment are essential to reduce the risk of serious illness and mortality.
Signs of sepsis are not specific, so antibiotics are often given before the diagnosis is confirmed. In the UK it is estimated that around one in 20 babies with suspected sepsis are given intravenous antibiotics. This carries risks such as increased hospital stay, disturbing the baby’s natural microbial balance, increasing costs and encourages antibiotic resistance.
If bacteria are not found in the blood after 36 hours, doctors may decide to stop treatment. Levels of the blood inflammatory marker C-reactive protein are often used to guide this decision, along with clinical condition. Procalcitonin may be another indicator, but few studies compare the accuracy or usefulness of these tests against each other.
This non-inferiority study assessed whether procalcitonin could safely reduce antibiotic duration without increasing risk of complications, compared with standard care.
What did this study do?
The Neonatal PCT Intervention Study (NeoPInS) involved 1710 neonates (born after 34 weeks) with suspected sepsis within 72 hours of birth randomised to procalcitonin-guided treatment or standard care.
Likelihood of infection was scored from 0-3 depending on risk factors, clinical signs and laboratory results. Babies were then divided into four risk categories of proven, probable, possible and unlikely infection within 12 hours of starting antibiotics.
Most (88%) had a possible or unlikely infection. They received antibiotics for 5-7 days or 36-72 hours, respectively, in the standard care groups. In the intervention group, antibiotics were discontinued when two consecutive procalcitonin measures were in the normal range. All babies with proven or probable infection received antibiotics for at least seven days as standard.
The study was conducted at 11 hospitals in the Netherlands, four in Switzerland, two in Canada and one in the Czech Republic.
What did it find?
- Procalcitonin-guided treatment reduced the duration of antibiotic use by a median (average) 9.9 hours compared with standard care (55.1 hours vs 65.0 hours). This was based on intention-to-treat analysis including all babies regardless of whether or not they completed the study. In an analysis restricted to 82% of the study group who received treatment according to the protocol, procalcitonin measurement gave a slightly greater reduction of 12.2 hours compared with the standard.
- Duration of hospital stay was 3.5 hours shorter with procalcitonin-guided treatment (123.0 hours vs 126.5 hours) in the intention-to-treat analysis, 5.2 hours shorter in per protocol analysis (115.8 hours vs 121.0 hours).
- There was no difference between groups in the rate of re-infection within 72 hours of stopping antibiotics. Five out of 866 babies (0.6%) in the procalcitonin group had suspected infection compared with three out of 844 babies (0.5%) in the standard group (intention-to-treat analysis). The proportions were essentially the same when analysing per protocol.
- Neither was there any difference in the risk of death within the first month of life. One baby in the standard care group died due to complications of severe lack of oxygen during birth (asphyxia). There were no deaths reported in the procalcitonin group.
- The difference between groups for re-infection or mortality risk was 0.1% (95% CI -4.6 to 4.8), therefore demonstrating that procalcitonin-guided treatment was not inferior to standard care.
What does current guidance say on this issue?
NICE guidelines (2012) recommend that babies given antibiotics due to the risk of possible infection have C-reactive protein measured at 18-24 hours. Blood culture results should be available at 36 hours. NICE advise considering stopping antibiotics at 36 hours if: blood culture is negative, the initial clinical suspicion of infection was not strong, the baby's clinical condition is reassuring, and the levels and trends of C-reactive protein are reassuring.
NICE 2015 guidance on procalcitonin measurement for diagnosing sepsis and monitoring infection advises that these tests show promise, but that there is currently insufficient evidence to recommend their routine adoption in the NHS.
What are the implications?
This is the first study to show that procalcitonin may help to guide antibiotic discontinuation in babies with suspected early-onset sepsis, without increasing risk of re-infection or mortality. The results come from high-income countries where newborn care is likely to be closely aligned with the UK.
Reduced antibiotic duration and potentially earlier discharge could make a meaningful difference to families. It may also help to reduce unnecessary exposure to antibiotics, avoid overuse and potentially mitigate the growing risk of antibiotic resistance too.
The findings should not be applied to infants born before 34 weeks who have a higher infection risk.
Citation and Funding
Stocker M, van Herk W, El Helou, et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet. 2017;390(10097):871-88.
This project was funded by the Thrasher Foundation, the NutsOhra Foundation (1101-059) and the Sophia Foundation for Scientific Research (681).
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