Neonatal infection and antimicrobial use : can we agree to disagree?

Abstract

 Neonates are highly susceptible to infections. The 2019 annual report of the Canadian Neonatal Network indicated an incidence rate of 13.4% for late-onset sepsis among very-low-birth-weight neonates (birth weight <1500g) in the tertiary neonatal intensive care units (NICU), which was inversely related to gestational age and birth weight. Neonatal sepsis often have nonspecific clinical features that are difficult to distinguish from other evolving non-infectious pathologic processes. Despite continuing research, no reliable diagnostic markers with sufficiently high sensitivity and specificity for infections are available for widespread bedside applications. Not surprisingly, early pre-emptive treatment with potent antimicrobials is the typical clinical mantra in NICU. Antimicrobials are commonly prescribed to neonates as treatment or prophylaxis. There are no widely accepted guidelines pertaining to the appropriate use of antimicrobials for common conditions, with substantial variations in the rates of use among different units. Retrospective studies have revealed that antimicrobials are often continued in clinical situations in which no clear indication or benefit has been demonstrated. Excessive and inappropriate antimicrobial use can lead to gut dysbiosis, emergence of drug-resistant organisms, and adverse neonatal outcomes. A higher antimicrobial utilisation rate has been reported to be associated not only with worse mortality or major morbidity but also with a composite outcome of death or adverse neurodevelopmental outcomes at a corrected age of 18–21 months among preterm infants without culture-proven sepsis or necrotising enterocolitis (NEC). Antimicrobial stewardship programs (ASP) are designed to optimise clinical outcomes while mitigating the unfavourable consequences of antimicrobial misuse. ASP include active monitoring of bacterial resistance and promotion of appropriate antimicrobial use, in addition to an effective infection control program to minimise the secondary spread of resistance. There is no shortage of successful stories in the adult and paediatric populations; nonetheless, the literature on NICU-specific ASP regimes remains very limited due to various challenges. The development of the best evidence-based ASP practices relevant to NICU is urgently needed. In this thesis, I will present an overview of neonatal infections, particularly the best practices on antimicrobial use for culture-proven infections and NEC. Subsequently, I will review controversies concerning culture-negative sepsis and the consequences of antimicrobial overuse in neonates with respect to mortality, morbidity, and neurodevelopmental sequelae. Finally, I will provide insights into the development of NICU-specific ASP. Throughout the thesis, I will share my four key contributions to this field over the past 5 years.