Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study

Abstract

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003).Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. What is Known:• Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis.• The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. What is New:• Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged.• A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.

Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review

“…The authors found that limited early antibiotics (≤3 days) was associated with a reduction in NEC compared to untreated controls (0.74, 95% CI 0.55–0.99); but prolonged early antibiotics (>3 days) was not associated with either increased or decreased NEC risk when compared to either 0 days or ≤3 days. Dierikx et al ( 23 ) also performed additional analysis based on duration of treatment and found similar results of protective effects of limited early antibiotics given for ≤3 days; whereas prolonged early antibiotics (>3 days) was neither harmful nor protective. While these two studies suggest that a limited course of early antibiotics (≤3 days) may help reduce the risk for NEC in preterm infants, the study by Vatne et al ( 34 ) had different results.…”

“…Using prospective data collected from 13 neonatal intensive care units from five continents, Li et al found that NEC incidence was lower among infants treated with early antibiotics compared to infants with no antibiotic exposure (aOR 0.25, 95% CI 0.12-0.47). Lastly, Dierikx et al (23) studied 1,259 very low birth weight (VLBW) infants from 9 centers in the Netherlands and Belgium and found that early antibiotics was associated with decreased risk for NEC compared to no antibiotics (aOR 0.47, 95% CI 0.23-0.96). Analysis based on duration of treatment provided additional insights regarding the relationship between early antibiotics and NEC.…”

“…Berkhout et al ( 39 ) also conducted a matched case-control study ( n = 336 infants) and found a similar association of decreased NEC with early antibiotics. Three subsequent studies ( 21 – 23 ) were large, multi-center studies with approximately 1,200 to 14,000 infants. The largest of these studies was Ting et al ( 22 ) ( n = 14,207 infants).…”

“…However, some studies have shown opposite results – that of a protective effect of early antibiotics and NEC. In fact, randomized controlled trials (RCTs) from the late 1970s to late 1990s indicate that prophylactic treatment with oral antibiotics can reduce NEC by half ( 16 – 20 ); and other retrospective studies have demonstrated that early antibiotics is associated with a decrease in NEC incidence compared to infants not exposed to early antibiotics ( 21 – 23 ).…”

Fetal–neonatal exposure to antibiotics and NEC development: A systematic review and meta-analysis

“…The subgroup analysis including only the studies by Boo and Cheah and Reed et al shows no association of MAB with NEC. The effect of antibiotics given shortly before birth can be overshadowed by confounding factors, such as being born by cesarean section, feeding methods, or probiotic supplementation ( 58 ). In the two studies reporting on this, the use of cesarean sections was higher in the control group.…”