Finding the Goldilocks zone of antibiotic prescribing in preterm infants

In the fairy tale, Goldilocks tastes three bowls of porridge before finding one that is just right. A team of neonatal researchers writing in Pediatric Research argues that the same logic should govern one of the most consequential decisions in intensive care: how much antibiotic to give a preterm infant in the first days of life. Too little treatment risks a missed or undertreated infection that can kill within hours. Too much exposes a fragile newborn to disrupted microbiome development, antimicrobial resistance and avoidable harm. Between those extremes, the authors contend, lies a Goldilocks zone of optimal antimicrobial stewardship, and finding it has become one of the defining challenges of modern neonatology.

The analogy, borrowed from astronomy, where the Goldilocks zone describes the orbital band around a star in which liquid water can survive, is more than a catchy framing device. It captures a genuine clinical dilemma. Neonatal sepsis, defined as life-threatening organ dysfunction caused by bacterial, viral or fungal infection, remains a leading cause of neonatal mortality worldwide and can leave survivors with serious neurodevelopmental sequelae. Yet the clinical presentation of sepsis in a newborn is notoriously nonspecific, and blood culture, the diagnostic cornerstone, has well-recognised limitations, particularly for early-onset sepsis. Antibiotics therefore remain the mainstay of treatment, and clinicians frequently must decide whether to start them in infants whose risk of infection is uncertain.

The stakes of that decision are amplified in preterm infants. These babies are immunologically immature, have thin skin and invasive lines, and are frequently exposed to maternal and neonatal risk factors that make infection plausible. Empiric antibiotics are started liberally, often within the first hours of life, and are continued for days in many infants who never have a positive culture. Recent studies quantifying this practice have found substantial variation in antibiotic exposure among culture-negative preterm infants, both within single centres over a decade and across international cohorts of late-preterm and term newborns. The question is no longer whether antibiotics are overused in this population, but how to measure the exposure precisely and what the consequences of that exposure actually are.

Those consequences have been examined in a growing body of observational research. Several large cohort studies have reported associations between prolonged duration of initial empiric antibiotic therapy and increased rates of necrotising enterocolitis and death in extremely low birth weight infants. Other analyses have linked extended early antibiotic exposure to subsequent development of late-onset sepsis, and to bronchopulmonary dysplasia in very preterm infants at low risk of early-onset sepsis. Multicentre cohort work has also associated longer empiric courses with necrotising enterocolitis and late-onset sepsis in preterm infants. These findings have fuelled calls for shorter empiric courses and more rapid discontinuation when cultures remain negative.

Yet the picture is not straightforward. Not every study points in the same direction. Some analyses, including a large international cohort of very low birth weight infants, have reported that early antibiotic use was associated with a lower incidence of necrotising enterocolitis, while a single-centre retrospective study found no association between early antibiotic exposure and short-term adverse outcomes in very preterm infants. Additional population-based and single-centre cohort analyses have produced mixed results regarding early empiric antibiotics and adverse clinical outcomes. The authors of the Pediatric Research commentary emphasise that this heterogeneity reflects real methodological complexity: confounding by indication, differences in gestational age, centre-level prescribing culture, and the difficulty of measuring what antibiotics are actually being given, at what dose, for how long, and against which suspected organisms.

Quantifying antibiotic use is itself a technical problem. A systematic review and international multidisciplinary consensus procedure has produced metrics for measuring antibiotic consumption in the hospital setting, recognising that simple days-of-therapy counts may obscure differences in spectrum, dose intensity and route. In neonatal intensive care, where weight-based dosing changes daily and renal clearance matures rapidly, the same number of days may represent very different cumulative exposures in different infants. The commentary argues that stewardship programmes must therefore move beyond crude consumption metrics toward precision prescribing, in which treatment is given to infants likely to benefit while unnecessary exposure is avoided in infants unlikely to have infection.

Achieving that precision requires better diagnostics as much as better prescribing habits. Inflammatory markers such as C-reactive protein and procalcitonin have been proposed as adjuncts to guide antibiotic decisions in early-onset sepsis, but their performance remains debated, with some experts questioning whether they are game changers or gimmicks. The absence of an accepted consensus definition of neonatal sepsis further hinders standardisation of registries, outcome measures, clinical trials and the evaluation of new diagnostics and therapeutics. Progress in developing advanced diagnostics and therapeutics for neonatal sepsis has been slow, which is precisely why antibiotics continue to carry such a heavy clinical load.

Where diagnostics fall short, pharmacology may help. Population pharmacokinetic models and simulation studies are being used to optimise vancomycin dosing in neonates, and a digital twin framework has been proposed for optimal aminoglycoside dosing in neonates with suspected sepsis, allowing clinicians to model individual drug exposure before administering it. Rapid point-of-care genotyping has been deployed in neonatal intensive care to identify infants at risk of aminoglycoside-induced ototoxicity, offering a way to personalise therapy at the genetic level. Best-evidence dosing recommendations for term and preterm neonates have been developed through dedicated projects, and considerations for drug dosing in premature infants continue to evolve as understanding of developmental pharmacology matures. Neonatal drug formularies are also being catalogued on a global scale to support safer prescribing.

The commentary also highlights the NANO trial, a randomised multicentre clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants, as an example of the kind of prospective evidence needed to move the field beyond observational associations. Randomised data are scarce in this population, partly because of ethical and logistical constraints, but without them the field risks perpetuating prescribing patterns based on weak evidence. The authors call for multidisciplinary antimicrobial stewardship programmes that bring together neonatologists, pharmacists, infectious disease specialists and microbiologists to define the optimal duration, spectrum and intensity of antibiotic exposure for preterm infants.

The goal, the authors stress, is not simply less antibiotic use. It is the right antibiotic, for the right infant, for the right duration, guided by evidence rather than habit or fear. In an era of rising antimicrobial resistance and growing recognition of the long-term consequences of early-life microbiome disruption, the Goldilocks zone of neonatal antibiotic prescribing is not a metaphorical luxury. It is a clinical target with measurable outcomes, and the tools to reach it, from precision metrics to pharmacokinetic modelling to point-of-care genotyping, are finally coming within grasp. What remains is the will to test them rigorously in the infants who need them most.

Subject of Research: Antimicrobial stewardship in preterm infants

Article Title: The Goldilocks zone of optimal antimicrobial stewardship in preterm infants

Article References: Molloy, E. J., Johnson, L., Klebanoff, M., Tingay, D., & Wynn, J. L. (2026). The Goldilocks zone of optimal antimicrobial stewardship in preterm infants. Pediatric Research. https://doi.org/10.1038/s41390-026-05558-4

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05558-4

Keywords: neonatology, antimicrobial stewardship, preterm infants, neonatal sepsis, antibiotic exposure, microbiome, necrotizing enterocolitis, precision prescribing, Goldilocks, zone, optimal, antimicrobial