Review
Gut bacteria and late-onset neonatal bloodstream infections in preterm infants

https://doi.org/10.1016/j.siny.2016.06.002Get rights and content

Summary

Late-onset neonatal bloodstream infections remain challenges in neonatology. Hand hygiene, line care, and judicious use of indwelling lines are welcome interventions, but might not reduce the incidence of late-onset neonatal bloodstream infections from bacteria originating in the gut. Accumulating data suggest that many pathogens causing late-onset neonatal bloodstream infections are of gut origin, including Gram-positive cocci. In addition to the host-canonical paradigm (i.e., all bacteria have equal risk of invasion and bloodstream infections are functions of variable infant susceptibility), we should now consider bacteria-canonical paradigms, whereby late-onset neonatal bloodstream infection is a function of colonization with a specific subset of bacteria with exceptional invasive potential. In either event, we can no longer be content to reactively approach late-onset neonatal bloodstream infections; instead we need to reduce the occurrences of these infections by broadening our scope of effort beyond line care, and determine the pre-invasive habitat of these pathogens.

Introduction

Late-onset neonatal bloodstream infections in preterm infants are illnesses (i) in which a credible pathogen is recovered from the blood, and (ii) that occur after the first 72 h of age [1], [2], [3], [4], [5]. The Gram-negative bacilli, Gram-positive cocci, and fungi that represent the majority of infections have differing pre-invasion habitats in the body, control strategies, treatments, and prognoses when they cause extraintestinal infections.

Infants who have had culture-proven late-onset neonatal bloodstream infections have higher mortality than those who have not had these infections [1], [6]. Late-onset neonatal bloodstream infections in very low birth weight infants bestow independent risks to long-term child development, in addition to the well-recognized risks bestowed by brain injury, bronchopulmonary dysplasia, and retinopathy of prematurity [2]. Indeed, it has been calculated that a single late-onset neonatal bloodstream infection in a preterm infant approximately quadruples the likelihood of cerebral palsy, independent of intracranial structural abnormalities [7]. Neonatal infections are also associated with lower Bayley Scale of Infant Development II scores, worse psychomotor development, abnormal vision, and lesser occipital frontal circumferences, among those infants who survive their episode of late-onset neonatal bloodstream infections and who are discharged to home [3].

Our understanding of late-onset neonatal bloodstream infections is severely limited by their unpredictable onset in infants at risk. In this review, we emphasize data from human cohorts, and cite animal data only if they might illuminate human biology relevant to late-onset neonatal bloodstream infections.

Section snippets

Prospects for preventing late-onset neonatal bloodstream infections beyond line care and hand hygiene

Lessons can be learned from attempts to control early-onset (occurring <72 h after birth) infection with Streptococcus agalactiae (Group B streptococcus (GBS)). Screening for maternal colonization with GBS, and the treatment of mothers and their newborns with parenteral antibiotics (usually β-lactam agents), have reduced the incidence of early-onset bloodstream infections with GBS [8], [9]. In contrast, the incidence of late-onset neonatal bloodstream infections caused by GBS is increasing [10]

The gut as the pre-invasion habitat/reservoir of bacterial bloodstream invaders

Several observations support the concept that the gut is the reservoir of Gram-negative pathogens before late-onset neonatal bloodstream infections are clinically apparent. Though it is intuitive that increased gut permeability would permit the extra-intestinal dissemination (translocation) of bacteria harbored by this organ, it was not until Graham et al. demonstrated that, among 20 episodes of bloodstream infections in 15 infants caused by Gram-negative bacilli, 19 of the bloodstream isolates

Probiotics to prevent late-onset neonatal bloodstream infections

Probiotics offer a possible intervention to prevent late-onset neonatal bloodstream infections, especially those of gut origin. Two recent meta-analyses have addressed the efficacy of probiotics in preventing late-onset neonatal bloodstream infections. Zhang et al. [46] proposed that probiotics might prevent bloodstream infections in low birthweight infants, but no effect was seen in children weighing <1000 g at birth. Rao et al. also concluded that probiotics had a preventive effect [47] and

The future

Worldwide, neonatologists approach late-onset neonatal bloodstream infections in a reactive “rule out sepsis” mode. It is critical that neonatologists remain vigilant and respond to the earliest signs of bloodstream infections in all preterm infants, as these are not normal hosts. However, in many cases, the specific pathogens that subsequently invade the bloodstream may be found in the stool prior to clinical signs of systemic infection. Moreover, accumulating data suggest that colonization

Acknowledgements

We are grateful to Ms Maida Redzic for assistance with manuscript preparation, Drs Michael Carl and Carey-Ann Burnham for helpful conversations, and to Dr Chrisoph Haertel for critical reading of the manuscript.

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