396 - Antibiotic-induced dilation of the ductus arteriosus: mechanisms and implications for ductus closure and postnatal reopening

Publication Number: 3383.396

Elaine L.. Shelton, Vanderbilt University School of Medicine, Nashville, TN, United States; Edith M. Charron, Monroe Carell Jr. Children's Hospital at Vanderbilt, Brentwood, TN, United States; Sarah Lanza, Vanderbilt University School of Medicine, Nashville, TN, United States; Stephanie Rager, Columbia University Irving Medical Center, New York, NY, United States; Kimberly Fernandez Trahan, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN, United States; Naoko Boatwright, Vanderbilt University Medical Center, Franklin, TN, United States; Charmaine R. Rock, Vanderbilt University Medical Center, Nashville, TN, United States; Jeff Reese, Vanderbilt University Medical Center, Nashville, TN, United States

Background: The ductus arteriosus (DA) is an essential artery that shunts blood away from the high-resistance pulmonary circulation in utero. Postnatally, the DA must close to allow perfusion of the newly inflated lungs. “Functional DA closure” occurs within the first few hours after birth, involves contraction of DA smooth muscle, and is followed by “anatomic closure” which involves remodeling of the DA into a permanently sealed structure. Failure to close, termed patent DA (PDA), is common in premature infants and linked to major morbidities and increased mortality. Sepsis is a known risk factor for PDA. We previously showed aminoglycosides, first line sepsis drugs, induce DA dilation and are associated with an increased incidence of PDA in infants.

Objective: We hypothesized other classes of antibiotics may also have off target vascular effects that would alter initial DA constriction and postnatal DA remodeling.

Design/Methods: Fetal or postnatal mouse DAs were isolated, mounted in myography chambers, and challenged with various antibiotics. Changes in DA diameter were continually measured using digital image dimensioning software. Postnatal vessel reopening was determined by assessing whether buffer could successfully flow through the lumen. For in vivo studies, newborn mouse pups received IP injections of antibiotics or vehicle at timepoints from 3-24h after birth. The degree of ductal patency was assessed by necropsy and visual scoring. Data were analyzed by t-test or ANOVA and best-fit curves were plotted for analysis (GraphPad Prism).

Results: Several antibiotics (ampicillin, azithromycin, ceftazidime, gentamicin, unasyn, and vancomycin) significantly inhibited initial DA constriction and induced postnatal DA reopening to varying degrees. Of note, piperacillin-tazobactam caused DA constriction (~40% from baseline diameter) and did not induce DA reopening. The mechanisms underlying antibiotic-induced DA dilation include inhibition of voltage-gated calcium channels and activation of prostaglandin or nitric oxide signaling pathways.

Conclusion(s): To our knowledge, these are the first studies examining the effects of pharmacologic factors on postnatal DA reopening. Antibiotics are commonly prescribed in the NICU, yet we have an incomplete understanding of the range of their off-target effects. Future work will focus on examining a large clinical data set to contextualize our mouse work and determine whether antibiotic exposure is associated with DA reopening and PDA in infants. These studies will provide clinically relevant information that can be used to guide antibiotic selection in the NICU.