The NICU Antibiotics and Outcomes (NANO) trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants

Michael J Morowitz, Anup C Katheria, Richard A Polin, Elizabeth Pace, David T Huang, Chung-Chou H Chang, Johathan G Yabes, Michael J Morowitz, Anup C Katheria, Richard A Polin, Elizabeth Pace, David T Huang, Chung-Chou H Chang, Johathan G Yabes

Abstract

Background: Early-onset sepsis is an important cause of neonatal morbidity and mortality in the preterm population. Infants perceived to be at increased risk for early-onset sepsis are often treated empirically with broad-spectrum antibiotics while awaiting confirmatory blood cultures, despite an overall incidence of early-onset sepsis of 2-3% among extremely-low-birthweight (ELBW) infants. Recent observational studies associate perinatal antibiotic use with an increased incidence of necrotizing enterocolitis, late-onset sepsis, and mortality among ELBW infants. Given currently available data and variability in clinical practice, we designed a prospective multi-institutional randomized controlled trial to determine the safety of early antibiotic use in ELBW infants.

Methods: The NICU Antibiotics and Outcomes (NANO) trial is a multicenter, double-blinded, randomized controlled trial. A sample of 802 ELBW preterm infants will undergo web-based stratified block randomization to receive empiric antibiotics (EA; ampicillin and gentamicin) or placebo during routine evaluation for early-onset sepsis. Participating sites will use preexisting institutional protocols for antibiotic dosage and duration. Infants born at participating sites with a gestational age of 29 weeks or less are eligible for enrollment. Exclusion criteria include maternal intrauterine infection, hemodynamic or respiratory instability, delivery by caesarean section for maternal indications without labor or prolonged rupture of membranes, and prior administration of antibiotics. The primary outcome is the composite incidence of necrotizing enterocolitis, late-onset sepsis, or death during participants' index hospitalization. Maternal and infant samples will be collected longitudinally and assessed for differences in microbiome composition and diversity.

Discussion: The NANO trial is designed to compare the rate of adverse outcomes of EA use at birth versus placebo in ELBW preterm infants. If EA at birth worsens clinical outcomes, then the results of the trial may help providers decrease antibiotic utilization in the NICU and subsequently decrease the incidence of complications associated with early antibiotic use in ELBW infants. If we instead find that EA improve outcomes, then the trial will validate a longstanding clinical practice that has not previously been supported by high-quality data. Future studies will assess long-term clinical and microbial outcomes in infants who received empiric antibiotics following delivery.

Trial registration: Trial registration data: June 25, 2019 NCT03997266 .

Keywords: Early-onset neonatal sepsis; Extremely-low-birthweight; Late-onset neonatal sepsis; Microbial colonization; Morbidity; Mortality; Necrotizing enterocolitis; Prematurity.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

References

    1. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039. doi: 10.1001/jama.2015.10244.
    1. Afjeh S-A, Sabzehei M-K, Fahimzad S-A-R, Shiva F, Shamshiri A-R, Esmaili F. Antibiotic therapy for very low birth weight newborns in NICU. Iran J Pediatr. 2016;26(2):e2612.
    1. Tripathi N, Cotten CM, Smith PB. Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol. 2012;39(1):61–68. doi: 10.1016/j.clp.2011.12.003.
    1. Tzialla C, Borghesi A, Serra G, Stronati M, Corsello G. Antimicrobial therapy in neonatal intensive care unit. Ital J Pediatr. 2015;41 Available from: [cited 27 Sep 2017].
    1. Puopolo KM, Benitz WE, Zaoutis TE, Committee on fetus and newborn, committee on infectious diseases Management of Neonates Born at ≤34 6/7 Weeks’ Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018;142(6):e20182894. doi: 10.1542/peds.2018-2894.
    1. Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28(2):141–149. doi: 10.1097/MOP.0000000000000338.
    1. Esmaeilizand R, Shah PS, Seshia M, Yee W, Yoon EW, Dow K, et al. Antibiotic exposure and development of necrotizing enterocolitis in very preterm neonates. Paediatr Child Health. 2018;23(4):e56–e61. doi: 10.1093/pch/pxx169.
    1. Esaiassen E, Fjalstad JW, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858–1870. doi: 10.1093/jac/dkx088.
    1. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr. 2011;159(3):392–397. doi: 10.1016/j.jpeds.2011.02.035.
    1. Ting JY, Synnes A, Roberts A, Deshpandey A, Dow K, Yoon EW, et al. Association between antibiotic use and neonatal mortality and morbidities in very low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis. JAMA Pediatr. 2016;170(12):1181–1187. doi: 10.1001/jamapediatrics.2016.2132.
    1. Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit antibiotic use. Pediatrics. 2015;135(5):826–833. doi: 10.1542/peds.2014-3409.
    1. Ho T, Buus-Frank ME, Edwards EM, Morrow KA, Ferrelli K, Srinivasan A, et al. Adherence of newborn-specific antibiotic stewardship programs to CDC recommendations. Pediatrics. 2018;142(6):e20174322. doi: 10.1542/peds.2017-4322.
    1. Gibson MK, Wang B, Ahmadi S, Burnham C-AD, Tarr PI, Warner BB, et al. Developmental dynamics of the preterm infant gut microbiota and antibiotic resistome. Nat Microbiol. 2016;1:16024. doi: 10.1038/nmicrobiol.2016.24.
    1. Mu C, Zhu W. Antibiotic effects on gut microbiota, metabolism, and beyond. Appl Microbiol Biotechnol. 2019;103(23):9277–9285. doi: 10.1007/s00253-019-10165-x.
    1. Gasparrini AJ, Crofts TS, Gibson MK, Tarr PI, Warner BB, Dantas G. Antibiotic perturbation of the preterm infant gut microbiome and resistome. Gut Microbes. 2016;7(5):443–449. doi: 10.1080/19490976.2016.1218584.
    1. Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352(6285):544–545. doi: 10.1126/science.aad9358.
    1. Bokulich NA, Chung J, Battaglia T, Henderson N, Jay M, Li H, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra82. doi: 10.1126/scitranslmed.aad7121.
    1. Korpela K, Blakstad EW, Moltu SJ, Strømmen K, Nakstad B, Rønnestad AE, et al. Intestinal microbiota development and gestational age in preterm neonates. Sci Rep. 2018;8(1):2453. doi: 10.1038/s41598-018-20827-x.
    1. Munyaka PM, Eissa N, Bernstein CN, Khafipour E, Ghia J-E. Antepartum antibiotic treatment increases offspring susceptibility to experimental colitis: a role of the gut microbiota. PLoS One. 2015;10(11):e0142536. doi: 10.1371/journal.pone.0142536.
    1. Bender JM, Li F, Purswani H, Capretz T, Cerini C, Zabih S, et al. Early exposure to antibiotics in the neonatal intensive care unit alters the taxonomic and functional infant gut microbiome. J Matern Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2019;34:1–9.
    1. Sharma R, Tepas JJ, Hudak ML, Mollitt DL, Wludyka PS, Teng R-J, et al. Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg. 2007;42(3):454–461. doi: 10.1016/j.jpedsurg.2006.10.038.
    1. Cantey JB, Wozniak PS, Pruszynski JE, Sánchez PJ. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. Lancet Infect Dis. 2016;16:1178–1184. doi: 10.1016/S1473-3099(16)30205-5.
    1. Lavoie PM, Popescu CR, Molyneux EM, Wynn JL, Chiume M, Keitel K, et al. Rethinking management of neonates at risk of sepsis. Lancet Lond Engl. 2019;394(10195):279–281. doi: 10.1016/S0140-6736(19)31627-7.
    1. Wynn JL. Prolonged early antimicrobials in ELBWs: too much for too little. Pediatr Res. 2019;85(7):929–930. doi: 10.1038/s41390-019-0360-5.
    1. Levit O, Bhandari V, Li F-Y, Shabanova V, Gallagher PG, Bizzarro MJ. Clinical and laboratory factors that predict death in very low birth weight infants presenting with late-onset sepsis. Pediatr Infect Dis J. 2014;33(2):143. doi: 10.1097/INF.0000000000000024.
    1. Puopolo KM, Mukhopadhyay S, Hansen NI, Cotten CM, Stoll BJ, Sanchez PJ, et al. Identification of extremely premature infants at low risk for early-onset sepsis. Pediatrics. 2017;140:e20170925. doi: 10.1542/peds.2017-0925.
    1. Wortham JM, Hansen NI, Schrag SJ, Hale E, Van Meurs K, Sánchez PJ, et al. Chorioamnionitis and culture-confirmed, early-onset neonatal infections. Pediatrics. 2016;137(1) Available from: [cited 11 Sep 2020].
    1. Oliver EA, Reagan PB, Slaughter JL, Buhimschi CS, Buhimschi IA. Patterns of empiric antibiotic administration for presumed early-onset neonatal sepsis in neonatal intensive care units in the United States. Am J Perinatol. 2017;34(07):640–647.
    1. Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, et al. A quantitative, risk-based approach to the management of neonatal early-onset sepsis. JAMA Pediatr. 2017;171(4):365–371. doi: 10.1001/jamapediatrics.2016.4678.
    1. 2016-NCIBestPractices.pdf. Available from: . [cited 7 Dec 2020].
    1. Cantey JB, Pyle AK, Wozniak PS, Hynan LS, Sánchez PJ. Early antibiotic exposure and adverse outcomes in preterm, very low birth weight infants. J Pediatr. 2018;203:62–67. doi: 10.1016/j.jpeds.2018.07.036.
    1. Mukhopadhyay S, Sengupta S, Puopolo KM. Challenges and opportunities for antibiotic stewardship among preterm infants. Arch Dis Child Fetal Neonatal Ed. 2018;104:F327–F332. doi: 10.1136/archdischild-2018-315412.
    1. Stoll BJ, Hansen NI, Higgins RD, Fanaroff AA, Duara S, Goldberg R, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002???2003. Pediatr Infect Dis J. 2005;24(7):635–639. doi: 10.1097/01.inf.0000168749.82105.64.
    1. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–826. doi: 10.1542/peds.2010-2217.
    1. Nanduri SA, Petit S, Smelser C, Apostol M, Alden NB, Harrison LH, et al. Epidemiology of invasive early-onset and late-onset group B streptococcal disease in the United States, 2006 to 2015: Multistate Laboratory and Population-Based Surveillance. JAMA Pediatr. 2019;173(3):224. doi: 10.1001/jamapediatrics.2018.4826.
    1. Schrag SJ, Farley MM, Petit S, Reingold A, Weston EJ, Pondo T, et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics. 2016;138(6):e20162013. doi: 10.1542/peds.2016-2013.
    1. McGovern M, Giannoni E, Kuester H, Turner MA, van den Hoogen A, Bliss JM, et al. Challenges in developing a consensus definition of neonatal sepsis. Pediatr Res. 2020;88(1):14–26. doi: 10.1038/s41390-020-0785-x.
    1. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443–456. doi: 10.1542/peds.2009-2959.
    1. Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early onset sepsis. Semin Perinatol. 2012;36(6):408–415. doi: 10.1053/j.semperi.2012.06.002.
    1. Joshi NS, Gupta A, Allan JM, Cohen RS, Aby JL, Weldon B, et al. Clinical monitoring of well-appearing infants born to mothers with chorioamnionitis. Pediatrics. 2018;141(4) Available from: [cited 9 Nov 2020].
    1. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2014;9(4):CD005496.
    1. Gregory KE, DeForge CE, Natale KM, Phillips M, Van Marter LJ. Necrotizing enterocolitis in the premature infant. Adv Neonatal Care Off J Natl Assoc Neonatal Nurses. 2011;11(3):155–166. doi: 10.1097/ANC.0b013e31821baaf4.
    1. Mukhopadhyay S, Eichenwald EC, Puopolo KM. Neonatal early-onset sepsis evaluations among well-appearing infants: projected impact of changes in CDC GBS Guidelines. J Perinatol Off J Calif Perinat Assoc. 2013;33(3):198–205.
    1. Escobar GJ, Li DK, Armstrong MA, Gardner MN, Folck BF, Verdi JE, et al. Neonatal sepsis workups in infants >/=2000 grams at birth: a population-based study. Pediatrics. 2000;106(2 Pt 1):256–263. doi: 10.1542/peds.106.2.256.
    1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364(3):255–264. doi: 10.1056/NEJMra1005408.
    1. Mϋller MJ, Paul T, Seeliger S. Necrotizing enterocolitis in premature infants and newborns. J Neonatal-Perinatal Med. 2016;9(3):233–242. doi: 10.3233/NPM-16915130.
    1. Vongbhavit K, Underwood MA. Intestinal perforation in the premature infant. J Neonatal-Perinatal Med. 2017;10(3):281–289. doi: 10.3233/NPM-16148.
    1. Shah J, Singhal N, da Silva O, Rouvinez-Bouali N, Seshia M, Lee SK, et al. Intestinal perforation in very preterm neonates: risk factors and outcomes. J Perinatol Off J Calif Perinat Assoc. 2015;35(8):595–600.
    1. Suply E, Leclair M-D, Neunlist M, Roze J-C, Flamant C. Spontaneous intestinal perforation and necrotizing enterocolitis: a 16-year retrospective study from a single center. Eur J Pediatr Surg Off J Austrian Assoc Pediatr Surg Al Z Kinderchir. 2015;25(6):520–525.
    1. Ting JY, Roberts A, Sherlock R, Ojah C, Cieslak Z, Dunn M, et al. Duration of initial empirical antibiotic therapy and outcomes in very low birth weight infants. Pediatrics. 2019;143(3):e20182286. doi: 10.1542/peds.2018-2286.
    1. Cotten CM, Smith PB. Duration of empirical antibiotic therapy for infants suspected of early-onset sepsis. Curr Opin Pediatr. 2013;25(2):167–171. doi: 10.1097/MOP.0b013e32835e01f6.
    1. Yassour M, Vatanen T, Siljander H, Hämäläinen A-M, Härkönen T, Ryhänen SJ, et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016;8(343):343ra81. doi: 10.1126/scitranslmed.aad0917.
    1. Zwittink RD, Renes IB, van Lingen RA, van Zoeren-Grobben D, Konstanti P, Norbruis OF, et al. Association between duration of intravenous antibiotic administration and early-life microbiota development in late-preterm infants. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2018;37(3):475–483. doi: 10.1007/s10096-018-3193-y.
    1. Arboleya S, Sánchez B, Milani C, Duranti S, Solís G, Fernández N, et al. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J Pediatr. 2015;166(3):538–544. doi: 10.1016/j.jpeds.2014.09.041.
    1. Ferguson AN, Olsen IE, Clark RH, Yockey BD, Boardman J, Biron K, et al. Differential classification of infants in United States neonatal intensive care units for weight, length, and head circumference by United States and international growth curves. Ann Hum Biol. 2020;47(6):564–571. doi: 10.1080/03014460.2020.1817555.
    1. Committee on Obstetric Practice. Prevention of group B streptococcal early-onset disease in newborns: ACOG Committee Opinion, Number 797. Obstet Gynecol. 2020;135(2):e51–72.
    1. Hooven TA, Randis TM, Polin RA. What’s the harm? Risks and benefits of evolving rule-out sepsis practices. J Perinatol Off J Calif Perinat Assoc. 2018;38(6):614–622.
    1. Schulman J, Profit J, Lee HC, Dueñas G, Bennett MV, Parucha J, et al. Variations in neonatal antibiotic use. Pediatrics. 2018;142(3) Available from: [cited 30 Sep 2020].

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera