Editor’s Note: In low- and middle-income countries, the health of newborns faces numerous challenges, with neonatal sepsis being a particularly grave concern. At the 34th European Congress of Clinical Microbiology and Infectious Diseases (ESCMID Global 2024), a study (abstract number: O0158) focused on the threat posed by Coagulase-Negative Staphylococci (CoNS) to newborn health. These bacteria, increasingly reported in low- and middle-income countries, exhibit insensitivity to multiple commonly used antibiotics, complicating treatment. Professor Qing Cao from the Shanghai Children’s Medical Center, affiliated with Shanghai Jiao Tong University School of Medicine, provides a detailed commentary on this study, sharing her professional insights and recommendations.

Research Overview

Higher Mortality from Emerging Staphylococcus Group: A Systematic Review and Meta-Analysis of Neonatal Sepsis Mortality Outcomes (Abstract Number: O0158)

Background

Coagulase-Negative Staphylococci (CoNS) represent the most common cause of late-onset sepsis in newborns in high-income countries and are increasingly reported in low- and middle-income countries (LMICs). Staphylococcus aureus bloodstream infections are believed to have a more severe clinical course compared to CoNS bloodstream infections. With the emergence of multidrug-resistant CoNS, including the vancomycin-heteroresistant Staphylococcus epidermidis NRCS-A clone associated with severe morbidity, there is a need for a reassessment of outcome data.

Methods

Observational studies reporting clinical outcomes of neonatal Staphylococcus bloodstream infections in randomized controlled trials were retrieved from Medline, EMBASE, Cochrane CENTRAL, and Clinicaltrials.gov. Crude fatality rates (CFRs) were the primary mortality outcome, analyzed using random-effects meta-analysis. Subgroup analyses and meta-regression were conducted to compare CFRs between different Staphylococcus groups, with methicillin-sensitive Staphylococcus aureus (MSSA) as the reference.

Results

Data from 52 studies conducted in 26 countries representing all WHO regions were included in the meta-analysis, with 38.5% (20/52) of studies conducted in LMICs.

The overall CFR for Staphylococcus bloodstream infections was 0.06 (95% CI: 0.04–0.08). In subgroup analyses, the highest CFRs were observed for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-heteroresistant CoNS, and Staphylococcus epidermidis bloodstream infections, at 0.16 (0.07–0.28), 0.15 (0.00–0.39), and 0.11 (0.04–0.21) respectively. The lowest rates were observed for untyped CoNS and MSSA bloodstream infections, at 0.03 (0.02–0.05) and 0.04 (0.01–0.09) respectively. Meta-regression results indicated significant differences between Staphylococcus groups (QM=17.77, df=5, P=0.003), with MRSA (estimate=0.16, SE=0.08, P=0.04) being a significant moderator.

In LMICs, CFR was significantly higher (QM=34.559, df=1, P<0.001). Significant heterogeneity was observed between studies (QE=636.75, df=84, P<0.01, I2=86.8%).

Conclusion

Mortality from neonatal bloodstream infections caused by vancomycin-heteroresistant CoNS, Staphylococcus epidermidis, and MRSA is similar and higher than that from MSSA. Conventional classification of CoNS species and further data will help better define outcomes for specific strains.

Expert Commentary

A recent study published in The Lancet reported that bacterial infections are the second leading cause of death globally, with 1 in 8 deaths in 2019 attributed to this cause. In 2019, there were 7.7 million deaths associated with 33 common bacterial infections, with just five pathogens accounting for over half of these deaths. Among these, Staphylococcus aureus stands out. Compared to Staphylococcus aureus, CoNS typically do not cause acute or life-threatening infections. However, as an important pathogen, the impact of CoNS is increasingly evident in immunocompromised patients, those with implanted devices, and newborns.

This study provides a meta-analysis of neonatal Staphylococcus bloodstream infections and related mortality rates. The results reveal that besides the well-known MRSA, mortality rates are also high for bloodstream infections caused by vancomycin-heteroresistant CoNS and Staphylococcus epidermidis.

Furthermore, the NRCS-A clone of Staphylococcus epidermidis has recently been described as a common cause of late-onset sepsis (LOS) in premature neonates globally. This clone exhibits insensitivity to first-line drugs used for LOS, such as vancomycin. Despite vancomycin treatment, cases of persistent NRCS-A LOS have been reported. The NRCS-A strain typically colonizes non-infected infants in neonatal intensive care units (NICUs) and serves as a potential reservoir for infection. More evidence is needed to understand how NRCS-A survives in NICUs, aiding in the development of infection control measures targeted at this clone.

Medical Doctor

Chief Physician, Master’s Supervisor

National Children’s Medical Center, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Children’s Medical Center

Director of Department of Pediatrics, Director of Department of Infectious Diseases, Director of Pediatric Education and Research Office, Director of Pediatric Training Base, Director of Infection and Immunity Center at Shanghai Children’s Medical Center, Deputy Director of Infection Research Laboratory at Pediatric Translational Medicine Institute

Deputy Director of Shanghai Medical Association, Infectious Diseases and Chemotherapy Society

Deputy Head of Pediatrics Group at Shanghai Medical Association, Infectious Diseases Society

Secretary of Pediatric Committee at Shanghai Medical Association

Member of Pediatric Infectious Diseases Society at Chinese Medical Association

Member of Expert Committee on Rational Use and Management of Antimicrobial Drugs in Shanghai

Reviewer for “Chinese Journal of Pediatrics” and “Pediatrics & Neonatology,” among others.

Primary research interests: Pathogen-host immune mechanisms, Pathogenesis of sepsis, Pharmacogenomics and blood drug concentration monitoring in sepsis anti-infective therapy, Mechanisms of bacteriocins in sepsis intestinal endogenous infection and bacterial translocation, Clinical application of pediatric fecal microbiota transplantation, Evaluation of preventive vaccination in special populations, and more.