Prevailed Antimicrobial Resistance Correlated with Antimicrobial Exposure of Late-onset Sepsis in Preterm Infants : A Multicenter Prospective Cohort Study in China

Abstract

Background. Antimicrobial resistance (AMR) poses increasing threats of mortality among neonates in low- and middle-income countries (LMICs). In response, the WHO classified antibiotics for Children into three groups: Access, Watch, and Reserve. We aimed to present data on AMR of late-onset sepsis (LOS) in preterm infants by the Access-Watch-Reserve classification and investigate risk factors of multidrug-resistant (MDR) bacteria. Methods. A prospective observational cohort study was conducted in 31 neonatal intensive care units in China (January 1, 2018, to December 31, 2022). Preterm infants (gestational age<32 weeks or birth weight<1500g) were enrolled, and followed up until discharge or death. LOS was defined as occurrence of sepsis after 3 days of life. We identified factors associated with MDR bacteria through multi-variable logistic regression analysis. Results. Among 8384 infants, 614 (7.3%) were diagnosed with LOS, of which 338 (55%) were caused by gram-negative bacteria (GNB), 181 (29.5%) by gram-positive bacteria, 95 (15.5%) by fungi. Klebsiella spp. (58.3%), Escherichia coli (13.6%), Enterobacter spp. (8.3%), Acinetobacter baumannii (8.0%) and Pseudomonas aeruginosa (5%) were top five common GNB. Amikacin listed as Access antibiotic had the lowest resistance rates ranging from 0–8.1%. Resistance rates remained high in Watch antibiotics, with ceftriaxone or ceftazidime ranging from 5.9–70.7% and meropenem ranging from 4.3–24.9%. Resistance rates of cefepime, classified as Reserve antibiotic, range from 5.9–40.3%. MDR rates ranged from 5.9–47.7%, and extensively drug-resistant rates from 0–7.6%. Antibiotic spectrum index per antibiotic day and a 10% increase in antibiotic use rate before onset of LOS were associated with MDR bacteria infections (p = 0.041, OR = 1.112, 95% CI 1.005–1.230 and p<0.001, OR = 1.383, 95% CI 1.226–1.560). Case fatality rate was higher among preterm infants with MDR bacteria than non-MDR bacteria infections (20.5% vs 11.4%, P = 0.023). Conclusions. GNB predominated in LOS, with a high resistance rate of Watch antibiotics and substantial proportion of MDR bacteria, which had higher mortality rate and were associated with excessive antibiotic exposure before onset of LOS. Conducting AMR surveillance and implementation of antimicrobial stewardship interventions are urgently needed in LMICs.