ABSTRACT
BACKGROUND: Gut dysbiosis contributes to the high risk of bloodstream infection (BSI) among premature infants. Most prior studies of the premature infant gut microbiota were conducted in Western countries and prior to development of current tools for strain-resolved analysis. METHODS: We performed metagenomic sequencing of weekly fecal samples from 75 premature infants at a single hospital in Singapore. We evaluated associations between clinical factors and gut microbiota composition using PERMANOVA and mixed effects linear regression. We used inStrain to perform strain-level analyses evaluating for gut colonization by BSI-causing strains. RESULTS: Median (interquartile range) gestation was 27 (25, 29) weeks, and 63% of infants were born via Cesarean section. Antibiotic exposures (PERMANOVA; R2 = 0.017, p = 0.001) and postnatal age (R2 = 0.015, p = 0.001) accounted for the largest amount of variability in gut microbiota composition. Increasing postnatal age was associated with higher relative abundances of several common pathogens (Enterococcus faecalis: p < 0.0001; Escherichia coli: p < 0.0001; Klebsiella aerogenes: p < 0.0001; Klebsiella pneumoniae: p < 0.0001). Antibiotic exposures were generally associated with lower relative abundances of both frequently beneficial bacteria (e.g., Bifidobacterium species) and common enteric pathogens (e.g., Enterobacter, Klebsiella species). We identified strains identical to the blood culture isolate in fecal samples from 12 of 16 (75%) infants who developed BSI, including all infections caused by typical enteric bacteria. CONCLUSIONS: Antibiotic exposures were the dominant modifiable factor affecting gut microbiota composition in a large cohort of premature infants from South-East Asia. Strain-resolved analyses indicate that the gut is an important reservoir for organisms causing BSI among premature infants.
ABSTRACT
OBJECTIVE: To determine the risk factors for mortality associated with late onset sepsis (LOS) among preterm very-low-birthweight (VLBW) infants. STUDY DESIGN: We performed a retrospective cohort study of infants born <32 weeks gestation and <1,500 gm admitted to a Singaporean tertiary-level neonatal intensive care unit. We determined the clinical, microbial, and laboratory risk factors associated with mortality due to culture-positive LOS in this cohort. RESULTS: A total of 1,740 infants were admitted, of which 169 (9.7%) developed LOS and 27 (16%) died. Compared to survivors, those who died had lower birth gestational age (median 24 vs. 25 weeks, p = 0.02) and earlier LOS occurrence (median 10 vs. 17 days, p = 0.007). There was no difference in the incidence of meningitis (11.1 vs. 16.9%, p = 0.3), NEC (18.5 vs. 14.8%, p = 0.6), or intestinal surgery (18.5 vs. 23.3%, p = 0.6) among infants who died compared to survivors. Gram-negative bacteria accounted for 21/27 (77.8%) LOS-associated deaths and almost all (13/14, 93%) fulminant episodes. The presence of multiorgan failure, as evidenced by the need for mechanical ventilation (100 vs. 79.0%, p = 0.008), elevated lactate (12.4 vs. 2.1 mmol/L, p < 0.001), and inotropic support (92.6 vs. 37.5%, p < 0.001), was significantly associated with mortality. Infants who died had significantly lower white blood cell (WBC) counts (median 4.2 × 109/L vs. 9.9 × 109/L, p = 0.001), lower platelet count (median 40 × 109/L vs. 62 × 109/L, p = 0.01), and higher immature to total neutrophil (I: T) ratio (0.2 vs. 0.1, p = 0.002). Inotrope requirement [AOR 22.4 (95%CI 2.9, 103.7)], WBC <4 × 109/L [AOR 4.7 (1.7, 13.2)], and I: T ratio >0.3 [AOR 3.6 (1.3, 9.7)] were independently associated with LOS mortality. CONCLUSIONS: In a setting with predominantly Gram-negative bacterial infections, the need for inotropic support, leukopenia, and elevated I: T ratio were significantly associated with LOS mortality among preterm VLBW infants.