Does a procalcitonin-guided approach to term and late-preterm neonates with suspected early-onset sepsis safely decrease unnecessary antibiotic exposure?

MANUSCRIPT CITATION

Stocker M, van Herk W, Helou El S, Dutta S, Fontana MS, Schuerman FABA, van den Tooren-de Groot RK, Wieringa JW, Janota J, van der Meer-Kappelle LH, Moonen R, Sie SD, de Vries E, Donker AE, Zimmerman U, Schlapbach LJ, de Mol AC, Hoffman-Haringsma A, Roy M, Tomaske M, Korenelisse RF, van Gijsel J, Visser EG, Willemsen SP, van Rossum AMC, NeoPIns study group. 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):871–81. PMID 28711318.

REVIEWED BY

Thomas A. Hooven, MD
Assistant Professor of Pediatrics
Columbia University, New York, NY

TYPE OF INVESTIGATION

Treatment

QUESTION

  • Patients: Among neonates ³ 34 weeks’ gestation with suspected early-onset sepsis
  • Intervention: Is a procalcitonin-based protocol for discontinuation of antibiotic therapy non-inferior
  • Comparison: To a standard time-based antibiotic course
  • Outcome: For re-infection or death and does the procalcitonin-based protocol lead to shorter courses of antibiotic administration?
  • Time: 72 hours (reinfection); first month of life (death)

METHODS

  • Design: Multi-center randomized controlled trial
  • Allocation: Concealed
  • Blinding:
    • Principle investigators blinded
    • Parents, nursing staff, physicians, and local investigators unblinded
  • Follow-up period: One month
  • Setting: 18 hospitals in four countries (the Netherlands, Switzerland, Canada, and Czech Republic)
  • Patients: Neonates ³ 34 weeks’ gestation requiring empiric antibiotic therapy within the first 72 hours of life for suspected early-onset sepsis based on risk factors, clinical symptoms, and/or laboratory data.
    • Exclusion criteria:
      • Requiring surgery within the first week of life
      • Major congenital malformations
  • Intervention:
    • Enrolled patients were assigned to one of four sepsis risk groups based on the presence of historical risk factors, clinical symptoms, and laboratory findings.
    • Those assigned to the two lowest risk groups (low risk=either historical risk factors, clinical signs consistent with sepsis, laboratory findings suggesting sepsis, or none of the above; medium risk=evidence of sepsis based on two categories, such as historical risk factors and clinical signs consistent with sepsis) were randomized to either a procalcitonin-guided antibiotic protocol or “standard treatment.”
    • The procalcitonin-guided cohort was treated with antibiotics for a minimum of 24 hours. While receiving antibiotics, this cohort had procalcitonin values checked every 12-24 hours. Physicians were instructed to discontinue antibiotics after two consecutive normal procalcitonin values (using an age-based nomogram), as long as the patient’s overall status supported that decision.
    • In the standard treatment cohort, low risk patients received antibiotics for 36-72 hours, while those with medium risk were treated for 5-7 days. The exact timing of antibiotic discontinuation was up to the treating physician.
    • All patients in the top two risk groups (positive blood culture or high risk=historical risk factors, clinical signs, and laboratory evidence of sepsis) were treated with antibiotics for 7-21 days without procalcitonin measurement. Although not randomized, these patients were included in the analysis in order to reflect normal NICU patient populations.
  • Primary outcomes:
    • Re-infection within 72 hours of stopping antibiotics or death within the first month of life (non-inferiority aspect)
    • Duration of antibiotic treatment (superiority aspect)
  • Secondary outcome: Duration of hospital stay
  • Analysis and Sample Size:
    • The study design called for randomization of 1600 infants (800 in each treatment group). The power analysis that yielded this number was based on a plan to assign a 95% confidence interval to the difference between probability of reinfection or death in the two treatment groups. If the upper bound of the confidence interval was <2% (suggesting that the outcome rates were nearly identical in the two groups), the procalcitonin-based strategy would be deemed non-inferior.
    • Assuming reinfection or death rates of 1.7% following antibiotic administration (based on a pilot study), 1540 patients would permit detection of an inferiority margin ≥2% with 80% power and two-tailed a = 0.05. 800 patients per group would also allow detection of a 10-hour difference in antibiotic duration with 95% power. Ultimately 1710 neonates were randomized. Data were analyzed in both an intention-to-treat and a per-protocol paradigm, with both result sets reported. 86% of patients in the procalcitonin group and 79% in the standard treatment group were included in the per-protocol analysis. Multivariate regression analysis was performed for duration of antibiotic administration and hospital stay.
  • Patient follow-up: 98.9%

MAIN RESULTS

In both the intention-to-treat and per-protocol analyses, the authors demonstrate that the procalcitonin-guided protocol reduced overall antibiotic exposure (primary outcome) and hospital admission length (secondary outcome).

Intention-to-Treat analysis Per-protocol analysis
Median  95% C.I.  P value  Median 95% C.I.   P value
Duration of Antibiotic Administration (h)  PC: 55.1

ST: 65

PC: 50.5-60

ST: 63-69

 <0.0001 PC: 51.8

ST: 64

PC: 48.2-56

ST: 61-68.1

<0.0001
 Hospital Stay (h)  PC: 123

ST: 126.5

PC: 113-134.5

ST: 117.5-144.3

0.0019 PC: 115.8

ST: 121

PC: 107.5-126

ST: 111.2-138

 0.0039

PC=Procalcitonin group
ST=Standard treatment group

The non-inferiority of the procalcitonin-guided protocol could not be statistically demonstrated due to complete absence of culture-proven reinfection or study-related mortality. The planned confidence interval comparison therefore could not be conducted.

CONCLUSION

In late-preterm (³34 weeks’ gestation) and term neonates with suspected early-onset sepsis, procalcitonin-guided decisions about stopping empiric antibiotics can reduce unnecessary antibiotic therapy and hospitalization durations. Ultimately the study was not powered to detect non-inferiority of the procalcitonin-guided protocol.

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COMMENTARY

Empiric antibiotic therapy for suspected early-onset sepsis is common in NICUs worldwide. Uncertainty about when antibiotics can be safely stopped leads to unnecessary neonatal antibiotic administration (1), with consequently longer hospital stays, disruption of maternal bonding and breastfeeding, and interference with normal microbiome establishment (2).

Procalcitonin is a nonspecific acute-phase reactant whose elevation can reflect infectious and non-infectious causes of inflammation (3). However, a persistently normal procalcitonin has excellent negative predictive value for sepsis, signaling that infection is not present.

Stocker et al. envision normal procalcitonin as a useful decision aid, enabling discontinuation of empiric antibiotics for at-risk babies who might otherwise receive longer treatment.

For this multi-center, randomized controlled trial, the authors developed a standardized sepsis risk scoring system. Low or medium risk newborns ³ 34 weeks’ gestation who were starting empiric antibiotics as part of a rule-out sepsis were randomized to have antibiotic discontinuation driven by persistently normal procalcitonin or to receive a standard course (the span of which was determined by overall sepsis risk).

The study’s primary aims were a) to validate results from a pilot study (4) that showed procalcitonin-guided antibiotic decisions reduced total antibiotic exposure (superiority aspect); and b) to demonstrate that the approach was safe in terms of reinfection within 72 hours of antibiotic discontinuation or death (non-inferiority aspect).

The paper convincingly reports that the procalcitonin cohort received shorter antibiotic courses. Unfortunately, the study ended up underpowered for the non-inferiority aspect. With no proven reinfection or study-related deaths in either group, statistical comparisons between them are meaningless. As the authors point out, the data do not suggest that the procalcitonin approach is unsafe.

The major weakness of the study is that the standard treatment courses that served as comparison controls for the procalcitonin group were unnecessarily long. Babies in the lowest risk category randomized to the standard treatment arm received 36-72 hours of antibiotics, even if they were always asymptomatic and only had maternal historical risk factors. Babies in the medium risk category—which could include clinically asymptomatic newborns whose only sepsis risks were maternal factors and abnormal screening lab results (such as C-reactive protein >10 mg/L)—were treated with antibiotics for 5-7 days.

Since the overwhelming majority (>98%) of these low and medium risk babies were uninfected, it’s not surprising that their normal procalcitonin measurements permitted significantly shorter antibiotic courses. Official recommendations suggest limiting antibiotic therapy to 48-72 hours in culture-negative cases where the baby is otherwise well (5,6). The lengthy courses in this study—which amplify the desired outcome—should, therefore, be viewed as outside normal practice. If the control group received shorter courses of antibiotics (which would be in line with official recommendations), the difference between the two groups would appear less significant.

Stocker et al. illustrate that serial procalcitonin measurements are a safe and effective tool for avoiding unnecessarily prolonged antibiotic courses. However, NICUs that already practice judicious antibiotic stewardship may achieve less dramatic reductions in antibiotic exposure from serial procalcitonin measurement than this study suggests.

REFERENCES

  1. Cantey JB, Patel SJ. Antimicrobial stewardship in the NICU. Infect Dis Clin North Am. 2014 Jun;28(2):247–61.
  2. Torrazza RM, Murgas Torrazza R, Neu J. The developing intestinal microbiome and its relationship to health and disease in the neonate. Journal of Perinatology. 2011 Apr;31 Suppl 1:S29–34.
  3. Lam HS, Ng PC. Biochemical markers of neonatal sepsis. Pathology. 2008 Feb;40(2):141–8.
  4. Stocker M, van Herk W, Helou El S, Dutta S, Fontana MS, Schuerman FABA, 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 Aug 26;390(10097):871–81.
  5. Polin RA, Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012 May;129(5):1006–15.
  6. Brady MT, Polin RA. Prevention and management of infants with suspected or proven neonatal sepsis. Pediatrics. 2013 Jul;132(1):166–8.

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