Association Between Antibiotic Use and Neonatal Mortality and Morbidities in Very Low-Birth-Weight Infants Without Culture-Proven Sepsis or Necrotizing Enterocolitis

Abstract

IMPORTANCE Excessive antibiotic use has been associated with altered bacterial colonization and may result in antibiotic resistance, fungemia, necrotizing enterocolitis (NEC), and mortality. Exploring the association between antibiotic exposure and neonatal outcomes other than infection-related morbidities may provide insight on the importance of rational antibiotic use, especially in the setting of culture-negative neonatal sepsis. OBJECTIVE To evaluate the trend of antibiotic use among all hospitalized very low-birth-weight (VLBW) infants across Canada and the association between antibiotic use rates (AURs) and mortality and morbidity among neonates without culture-proven sepsis or NEC. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted among VLBW infants (<1500 g) admitted to level III neonatal intensive care units between January 1, 2010, and December 31, 2014, using data obtained from the Canadian Neonatal Network database. EXPOSURE Duration of antibiotic use during the hospitalization period. MAIN OUTCOMES AND MEASURES The AUR was defined as the number of days an infant was exposed to 1 or more antimicrobial agents divided by the total length of hospital stay. The composite primary outcome was defined as mortality or major morbidity, including any of the following: persistent periventricular echogenicity or echolucency on neuroimaging, chronic lung disease, and stage 3 or higher retinopathy of prematurity. Multivariable regression analysis was used to calculate adjusted odds ratios (aORs) and 95% CIs for the association between AURs and outcomes. RESULTS Among 13 738 eligible VLBW infants, 11 669 (84.9%) (mean [SD] gestational age, 27.7 [2.5] weeks; 47.4% female) received antibiotics during their hospital course and were included in the study. The annual AUR decreased from 0.29 in 2010 to 0.25 in 2014 (slope for the best-fit line, −0.011; 95% CI, −0.016 to −0.006; P < .01), which occurred in parallel with a reduction in the rate of late-onset sepsis from 19.0% in 2010 to 13.8% in 2014 during the same period. Of the 11 669 infants who were treated with antibiotics of varying duration during their hospital stay, 2845 were diagnosed as having sepsis-related complications. Among the remaining 8824 infants without early-onset sepsis, late-onset sepsis, or NEC, a 10% increase in the AUR was associated with an increased odds of the primary composite outcome (aOR, 1.18; 95% CI, 1.13-1.23), mortality (aOR, 2.04; 95% CI, 1.87-2.21), and stage 3 or higher retinopathy of prematurity (aOR, 1.18; 95% CI, 1.06-1.32). CONCLUSIONS AND RELEVANCE Antibiotic use in VLBW infants decreased between 2010 and 2014 in Canada. However, among infants without culture-proven sepsis or without NEC, higher AURs were associated with adverse neonatal outcomes.

Variations in Neonatal Antibiotic Use

“…Overall, the evidence reveals that although surgical case volume and illness severity might sometimes drive the AUR, a relatively high AUR also may be used to independently predict mortality and average length of stay. In a recent report, the Canadian Neonatal Network found that higher AURs were associated with adverse neonatal outcomes among infants without culture-proven sepsis or NEC, including a twofold increase in mortality odds associated with a 10% AUR increase 20 . A possible contributing factor is dysbiosis associated with neonatal antibiotic exposure 21 ,.…”

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

“…Adverse neonatal outcomes are increased in very-low-birthweight infants treated with antibiotics that did not have culture-proven sepsis [21]. While in adults, all-cause mortality, appropriate therapy and shorter mean duration of therapy was improved in surgical ICU patients that followed conservative antimicrobial treatment as compared to aggressive antimicrobial administration [22, 23].…”

Bacterial infections in children after liver transplantation: A single‐center surveillance study of 345 consecutive transplantations

“…We do not think that prolonged perioperative prophylaxis will reduce the rate of bacterial infection complications, but might pose other risks to the patient such as selection of multi‐resistant bacteria, increasing the risk for invasive candidiasis or changes of the microbiome. Indeed, there is a growing body of evidence that prolonged or unnecessary antibiotic therapy leads to a worse outcome in different patient populations . Nevertheless, for pediatric liver transplant patients, neither short nor long perioperative prophylaxis has been proven to be superior.…”