NIHR Signal Blood test could shorten antibiotic treatment in newborns with suspected sepsis

Published on 28 November 2017

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.

Blood test could shorten antibiotic treatment in newborns with suspected sepsis

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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).

Bibliography

NHS Choices. Sepsis. London: Department of Health; updated 2016.

NHS Digital. Hospital Admitted Patient Care Activity 2015-1016. NHS Digital. 2016.

NICE. Neonatal infection (early onset): antibiotics for prevention and treatment. CG149. London: National Institute for Health and Care Excellence; 2012.

NICE. Neonatal Infection. QS75. London: National Institute for Health and Care Excellence; 2014.

NICE. Procalcitonin testing for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay). DG18. London: National Institute for Health and Care Excellence; 2015.

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).

Bibliography

NHS Choices. Sepsis. London: Department of Health; updated 2016.

NHS Digital. Hospital Admitted Patient Care Activity 2015-1016. NHS Digital. 2016.

NICE. Neonatal infection (early onset): antibiotics for prevention and treatment. CG149. London: National Institute for Health and Care Excellence; 2012.

NICE. Neonatal Infection. QS75. London: National Institute for Health and Care Excellence; 2014.

NICE. Procalcitonin testing for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay). DG18. London: National Institute for Health and Care Excellence; 2015.

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

Published on 18 July 2017

Stocker, M.,van Herk, W.,El Helou, S.,Dutta, S.,Fontana, M. S.,Schuerman, Faba,van den Tooren-de Groot, R. K.,Wieringa, J. W.,Janota, J.,van der Meer-Kappelle, L. H.,Moonen, R.,Sie, S. D.,de Vries, E.,Donker, A. E.,Zimmerman, U.,Schlapbach, L. J.,de Mol, A. C.,Hoffman-Haringsma, A.,Roy, M.,Tomaske, M.,Kornelisse, R. F.,van Gijsel, J.,Visser, E. G.,Willemsen, S. P.,van Rossum, A. M. C.

Lancet , 2017

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.

Probability of infection was scored from 0-3 by giving one point if any variable in each of the following three groups was present:

  • Risk factors: maternal group B streptococcus carriage, clinical signs of infection of the fetal membranes, preterm rupture of membranes >18 hours or preterm birth <37 weeks’ pregnancy.
  • Clinical symptoms: respiratory signs, heart rate abnormalities, perfusion problems, temperature fluctuation, neurological signs or abdominal signs.
  • Laboratory tests: low white blood cell count or raised C-reactive protein (>10 mg/L).

The resulting risk categories within 12 hours of starting antibiotics were:

  • Category 1 – proven infection: positive blood culture and risk score o1
  • Category 2 – probable infection: total risk score 3
  • Category 3 – possible infection: total risk score 2
  • Category 4 – unlikely infection: total risk score 0 or 1

Expert commentary

There are growing concerns about antibiotic resistance as well as possible deleterious effects of early life antibiotic exposure on the microbiome and long-term health outcomes.

Use of markers like procalcitonin with a high negative predictive value (i.e. the high likelihood of infection not present when test negative), along with standardised risk assessment, are useful steps in minimising unnecessary antibiotic use in neonates.

These should be explored, making sure there is prospective surveillance and adequate safety netting.

Minesh Khashu, Consultant Neonatologist & Professor of Perinatal Health, Poole Hospital NHS Foundation Trust