Short course antibiotic therapy: when is no difference the same?

TO THE EDITOR: In the most recent issue of _the Journal of Perinatology_, Sanchez et al. report their results of a retrospective review assessing duration of empiric antibiotic use in 414

newborns undergoing an early onset sepsis (EOS) evaluation [1]. 24-hour and 48-hour empiric antibiotic courses were compared for safety endpoints including mortality and re-initiation of

antibiotics within 7 days of discontinuation. The population was comprised of term, preterm and surgical infants admitted at six Nationwide Children’s Hospital network NICUs, with the

majority of infants (62%) being ≥34 weeks gestational age. While the authors also included extremely low birth weight (ELBW) and very low birthweight (VLBW) infants in their cohort, they

composed a much smaller percentage of the population (10 and 19% respectively). The authors found no differences in overall in-hospital mortality (sepsis-related or overall) and noted that

antibiotics were more often restarted within 7 days of discontinuation in the 48-hour group. The authors concluded that a 24-hour antibiotic course for the evaluation of EOS in infants was

therefore safe and preferable. While other studies have proposed shorter antibiotic courses for EOS [2, 3], there are caveats to consider before concluding safety and adapting such practice

changes. For example, the relative rarity of EOS in neonates, especially in full-term and late preterm infants (0.3–0.6 per 1000 livebirths) [4], requires a very large sample size to detect

one true case of EOS. In this sample size of 414 newborns, only 3 infants (1 in the 24-hour group and 2 in the 48-hour group) had positive blood cultures, again proving the paucity of

infection in this population. While the authors should be commended in their efforts to decrease antibiotic use in the NICU, given the mounting data regarding antibiotic exposure and

subsequent risk of neonatal morbidity and mortality [5,6,7,8,9], the power analysis used to plan this study in order to detect differences between the two antibiotic groups should have been

reported. If one were to attempt to answer the question of safety for these two approaches, given the authors’ focus on no difference with respect to safety, the appropriate design would be

a non-inferiority trial, which requires an even larger sample size. Post-hoc analysis based on the results available to us in this publication, we can examine the potential for

non-inferiority or equivalence (to allow the conclusions made by the authors) via a measure of association (in this case, odds ratio, OR) and its 95% confidence interval. If we were to have

planned the study a priori with non-inferiority in mind, we would set an OR level that would conclude that the new paradigm, the 24-hour group, was “safe” with respect to sepsis-related

deaths. So for instance, we may say an OR = 1.1 (24-hour vs. 48-hour) would be considered safe. If the upper bound of the 95% CI does not contain that threshold, then we could conclude that

24-hour is no worse with respect to sepsis than 48 h. In this case, post-hoc, the OR cannot be computed because of the 0 cell in sepsis-related mortality in the 48-hour group, but using the

Haldane-Anscombe correction [10, 11] (adding 0.5 to each cell), the observed OR = 7.90 with a 95% CI = (0.41, 154.0). The point estimate and corresponding confidence interval do not provide

evidence to support the authors’ conclusion that the 24-hour regimen is no worse than the 48-hours with respect to sepsis-related deaths. When the authors discuss the ≤28 weeks’ gestation

infants, which are the highest risk group for EOS (18.47 per 1000 live births) [12], they correctly state that one dose of gentamicin covers this sub-group for 48 h. Therefore, while many of

these infants were characterized as being part of the 24-hour group, they were effectively receiving 48-hours of empiric gram-negative coverage. This is reassuring, as this subgroup is at

the highest risk for gram-negative EOS (usually _Escherichia coli_) [12]. However, given the differences in antibiotic pharmacokinetics for the ≤28-week gestational age group, it would be

appropriate to keep these infants separate from the overall analysis. While this will require an even larger sample size, focusing on a cohort of infants ≥34 weeks’ gestation who meet

criteria for empiric antibiotics per the Kaiser Sepsis Calculator, will allow for a more applicable comparison of safety endpoints. Readers should be reminded that finding no statistical

difference between two approaches does not mean that the approaches are, by default, similar. REFERENCES * Sánchez PJ, Prusakov P, de Alba Romero C, Zamora-Flores E, Reyes Escamilla MC,

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AUTHORS AND AFFILIATIONS * Department of Pediatrics, Division of Neonatology, Yale School of Medicine, New Haven, CT, USA Noa Fleiss * Department of Pediatrics, Pediatric Research Hub,

University of Florida, Gainesville, FL, USA Matthew J. Gurka * Department of Pediatrics, Division of Neonatology, University of Florida, Gainesville, FL, USA David J. Burchfield Authors *

Noa Fleiss View author publications You can also search for this author inPubMed Google Scholar * Matthew J. Gurka View author publications You can also search for this author inPubMed 

Google Scholar * David J. Burchfield View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors have contributed equally to this work.

CORRESPONDING AUTHOR Correspondence to Noa Fleiss. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature

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Fleiss, N., Gurka, M.J. & Burchfield, D.J. Short course antibiotic therapy: When is no difference the same?. _J Perinatol_ 43, 683–684 (2023). https://doi.org/10.1038/s41372-023-01671-y

Download citation * Received: 06 March 2023 * Revised: 28 March 2023 * Accepted: 31 March 2023 * Published: 07 April 2023 * Issue Date: June 2023 * DOI:

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