Subjects

Abstract

Background

Prolonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.

Methods

Cohort study of infants from 13 centers born without a major birth defect from 2008–2014 who were 401–1000 grams birth weight, 22–28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.

Results

A total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30–69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99–1.40], p = 0.07) and was not associated with NEC.

Conclusions

The proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Hsieh, E. M. et al. Medication use in the neonatal intensive care unit. Am. J. Perinatol. 31, 811–821 (2014).

  2. 2.

    Schrag, S. J. et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics 138, e20162013 (2016). pii.

  3. 3.

    Kumar, Y. et al. Time to positivity of neonatal blood cultures. Arch. Dis. Child. Fetal Neonatal Ed. 85, F182–F186 (2001).

  4. 4.

    Jardine, L., Davies, M. W. & Faoagali, J. Incubation time required for neonatal blood cultures to become positive. J. Paediatr. Child Health 42, 797–802 (2006).

  5. 5.

    Cotten, C. M. et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123, 58–66 (2009).

  6. 6.

    Kuppala, V. S. et al. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J. Pediatr. 159, 720–725 (2011).

  7. 7.

    Cordero, L. & Ayers, L. W. Duration of empiric antibiotics for suspected early-onset sepsis in extremely low birth weight infants. Infect. Control. Hosp. Epidemiol. 24, 662–666 (2003).

  8. 8.

    Flannery, D. D. et al. Temporal trends and center variation in early antibiotic use among premature infants. JAMA Netw. Open 1, e180164 (2018).

  9. 9.

    Alexander, G. R. et al. A United States national reference for fetal growth. Obstet. Gynecol. 87, 163–168 (1996).

  10. 10.

    Bell, M. J. Neonatal necrotizing enterocolitis. N. Engl. J. Med. 298, 281–282 (1978).

  11. 11.

    Walsh, M. C. & Kliegman, R. M. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr. Clin. North Am. 33, 179–201 (1986).

  12. 12.

    Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, Pediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect. Control. Hosp. Epidemiol. 33, 322–327 (2012).

  13. 13.

    Vermont Oxford Network. https://public.vtoxford.org/quality-education/inicq-2018. Accessed 2018.

  14. 14.

    Flett, K. B. et al. Impact of mandatory public reporting of central line-associated bloodstream infections on blood culture and antibiotic utilization in pediatric and neonatal intensive care units. Infect. Control. Hosp. Epidemiol. 36, 878–885 (2015).

  15. 15.

    Zingg, W. et al. Secular trends in antibiotic use among neonates: 2001-2008. Pediatr. Infect. Dis. J. 30, 365–370 (2011).

  16. 16.

    Makri, V. et al. Managing antibiotics wisely: a quality improvement programme in a tertiary neonatal unit in the UK. BMJ Open Qual. 7, e000285 (2018).

  17. 17.

    Dukhovny, D. Antimicrobial stewardship in neonatal intensive care: The Oregon and Southwest Washington Collaboration. https://blogs.cdc.gov/safehealthcare/antimicrobial-stewardship-in-neonatal-intensive-care-the-oregon-and-southwest-washington-collaboration/. Accessed 2018.

  18. 18.

    Ting, J. Y. 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. 170, 1181–1187 (2016).

  19. 19.

    Ting, J. Y. et al. Reduction of inappropriate antimicrobial prescriptions in a tertiary neonatal intensive care unit following antimicrobial stewardship care bundle implementation. Pediatr. Infect. Dis. J. https://doi.org/10.1097/INF.0000000000002039 (2018).

  20. 20.

    Nzegwu, N. I. et al. Implementation of an antimicrobial stewardship program in a neonatal intensive care unit. Infect. Control. Hosp. Epidemiol. 38, 1137–1143 (2017).

  21. 21.

    Abdel Ghany, E. A. & Ali, A. A. Empirical antibiotic treatment and the risk of necrotizing enterocolitis and death in very low birth weight neonates. Ann. Saudi. Med. 32, 521–526 (2012).

  22. 22.

    Schulman, J. et al. Neonatal intensive care unit antibiotic use. Pediatrics 135, 826–833 (2015).

  23. 23.

    Benjamin, D. K. et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics 126, e865–e873 (2010).

  24. 24.

    Cotten, C. M. et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 118, 717–722 (2006).

  25. 25.

    Arboleya, S. et al. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J. Pediatr. 166, 538–544 (2015).

  26. 26.

    Dardas, M. et al. The impact of postnatal antibiotics on the preterm intestinal microbiome. Pediatr. Res. 76, 150–158 (2014).

  27. 27.

    Greenwood, C. et al. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter. J. Pediatr. 165, 23–29 (2014).

  28. 28.

    Patel, K. et al. Trends and determinants of gastric bacterial colonization of preterm neonates in a NICU setting. PLoS ONE 10, e0114664 (2015).

  29. 29.

    Puopolo, K. M. et al. Identification of extremely premature infants at low risk for early-onset sepsis. Pediatrics 140, e20170925 (2017).

  30. 30.

    Parry, G., Tucker, J. & Tarnow-Mordi, W. UK Neonatal Staffing Study Collaborative Group. CRIB II: an update of the clinical risk index for babies score. Lancet 361, 1789–1791 (2003).

  31. 31.

    Richardson, D. K. et al. SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J. Pediatr. 138, 92–100 (2001).

  32. 32.

    Clark, R. H. et al. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics 117, 67–74 (2006).

  33. 33.

    Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs. https://www.cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html.

Download references

Acknowledgements

The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network’s Generic Database Study (high-risk registry) through cooperative agreements. While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD.

Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Ms. Dhuly Chowdhury and Ms. Nellie Hansen (DCC Statisticians) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The sites with data included in this study are denoted with an asterisk.

We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:

NRN Steering Committee Chair: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine; Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University (2011–present).

*Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Abbot R. Laptook, MD; Martin Keszler, MD; Angelita M. Hensman, MS RNC-NIC; Kristin M. Basso, MaT RN; Elisa Vieira, RN BSN; Emily Little, BSN RN.

*Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80)—Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Anna Marie Hibbs, MD; Nancy S. Newman, BA RN; Bonnie S. Siner, RN.

Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284)—William E. Truog, MD; Howard W. Kilbride, MD; Eugenia K. Pallotto, MD MSCE; Cheri Gauldin, RN BSN CCRC; Anne Holmes RN MSN MBA-HCM CCRC; Kathy Johnson RN, CCRC; Allison Knutson, BSN RNC-NIC.

*Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084)—Brenda B. Poindexter, MD MS; Kurt Schibler, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Lenora D. Jackson, CRC; Kristin Kirker, CRC; Greg Muthig, BS.

*Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, M01 RR30, UL1 TR83)—Ronald N. Goldberg, MD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandra Grimes, RN BSN; Joanne Finkle, RN JD; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN.

*Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 TR454)—David P. Carlton, MD; Ellen C. Hale, RN BS CCRC; Ann Blackwelder, RN MSN; Yvonne C. Loggins, RN BSN; Diane I. Bottcher, RN MSN.

Eunice Kennedy Shriver National Institute of Child Health and Human Development—Stephanie Wilson Archer, MA.

*Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750, UL1 TR6)—Brenda B. Poindexter, MD MS; Gregory M. Sokol, MD; Leslie Dawn Wilson, BSN CCRC; Dianne E. Herron, RN CCRC.

*McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital (U10 HD21373)—Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Julie Arldt-McAlister, MSN APRN; Katrina Burson, RN BSN; Carmen Garcia, RN BSN CCRP; Beverly Foley Harris, RN BSN; Karen Martin, RN; Sara C. Martin, RN BSN; Georgia E. McDavid, RN; Shawna Rodgers, RN BSN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT (ASCP).

Nationwide Children’s Hospital and the Ohio State University Medical Center (U10 HD68278)—Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Christine A. Fortney, PhD RN; Gail E. Besner; Nehal A. Parikh, MD.

RTI International (U10 HD36790)—Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS CCRP; Jenna Gabrio, MPH CCRP; Carolyn M. Petrie Huitema, MS CCRP; Kristin M. Zaterka-Baxter, RN BSN CCRP.

*Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70, UL1 TR93)—Krisa P. Van Meurs, MD; Marian M. Adams, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Andrew W. Palmquist, RN BSN; Melinda S. Proud, RCP.

Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54)—Ivan D. Frantz III, MD; John M. Fiascone, MD; Brenda L. MacKinnon, RNC; Ellen Nylen, RN BSN.

*University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32)—Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN.

University of California—Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270) – Uday Devaskar, MD; Meena Garg, MD; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.

*University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59)—Edward F. Bell, MD; Dan L. Ellsbury, MD; John A. Widness, MD; Tarah T. Colaizy, MD MPH; Karen J. Johnson, RN BSN; Donia B. Campbell, RNC-NIC; Jacky R. Walker, RN.

*University of New Mexico Health Sciences Center (U10 HD53089, UL1 TR41)—Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Rebecca A. Tomson, BSN RNC; Carol Hartenberger, BSN MPH; Sandra Sundquist Beauman, MSN RNC-NIC.

University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244)—Barbara Schmidt, MD MSc; Haresh Kirpalani, MB MSc; Sara B. DeMauro, MD MSCE; Kevin C. Dysart, MD; Aasma S. Chaudhary, BS RRT; Soraya Abbasi, MD; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Erik A. Jensen, MD MSCE.

University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (U10 HD68263, M01 RR44, UL1 TR42)—Carl T. D’Angio, MD; Ronnie Guillet, MD PhD; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD, MPH; Linda J. Reubens, RN CCRC; Rosemary Jensen; Deana Maffett, RN; Holly I.M. Wadkins, MA; Michael G. Sacilowski, MAT; Ashley Williams, MS Ed; Stephanie Guilford, BS; Mary Rowan, RN; Diane M. Prinzing, AAS; Julianne Hunn, BS; Ann Marie Scorsone, MS CCRC; Karen Wynn, RN; Melissa Bowman, RN; Dale L. Phelps, MD; Aimee Horan, LPN.

*University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633)—Myra H. Wyckoff, MD; Pablo J. Sánchez, MD; Luc P. Brion, MD; Lijun Chen, PhD RN; Alicia Guzman; Janet S. Morgan, RN; Lara Pavageau, MD; Diana M. Vasil, MSN BSN RNC-NIC; Lizette E. Torres, RN.

University of Utah University Hospital, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64, UL1 TR105)—Roger G. Faix, MD; Bradley A. Yoder, MD; Karen A. Osborne, RN BSN CCRC; Karie Bird, RN BSN; Jill Burnett, RNC BSN; Jennifer J. Jensen, RN BSN; Cynthia Spencer, RNC BSN; Kimberlee Weaver-Lewis, RN MS; Karen Zanetti, RN.

*Wayne State University, University of Michigan, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385)—Seetha Shankaran, MD; John Barks, MD; Rebecca Bara, RN BSN; Mary Johnson, RN BSN; Mary Christensen, RT; Stephanie Wiggins, MS.

Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 TR142)—Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Patricia Cervone, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN.

Author information

Affiliations

  1. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    • Rachel G. Greenberg
    • , P. Brian Smith
    •  & C. Michael Cotten
  2. Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC, Durham, USA

    • Dhuly Chowdhury
    •  & Nellie I. Hansen
  3. Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA

    • Barbara J. Stoll
  4. Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA

    • Pablo J. Sánchez
  5. Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, MD, USA

    • Abhik Das
  6. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Karen M. Puopolo
    •  & Sagori Mukhopadhyay
  7. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    • Rosemary D. Higgins

Authors

  1. Search for Rachel G. Greenberg in:

  2. Search for Dhuly Chowdhury in:

  3. Search for Nellie I. Hansen in:

  4. Search for P. Brian Smith in:

  5. Search for Barbara J. Stoll in:

  6. Search for Pablo J. Sánchez in:

  7. Search for Abhik Das in:

  8. Search for Karen M. Puopolo in:

  9. Search for Sagori Mukhopadhyay in:

  10. Search for Rosemary D. Higgins in:

  11. Search for C. Michael Cotten in:

Consortia

  1. for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

    Contributions

    R.G.G. conceptualized and designed the study, drafted the initial manuscript, interpreted the data analyses, and reviewed and revised the manuscript. D.C., N.I.H., and A.D. carried out the data analysis, assisted with interpretation of the data analyses, and reviewed and revised the manuscript for important intellectual content. C.M.C. assisted with acquisition of the data, interpreted the data analyses, reviewed and revised the manuscript for important intellectual content, and obtained funding to support the study. B.J.S. assisted with acquisition of data and critical revision of the manuscript for important intellectual content. R.D.H. conceptualized and designed the study, assisted with data analysis and interpretation, and provided critical revision of the manuscript for intellectual content. P.B.S., K.M.P., and S.M. provided analysis and interpretation of the data and critical revision of the manuscript for important intellectual content. P.J.S. conceptualized and designed the study, assisted with acquisition of data, provided analysis and interpretation of the data, and obtained funding for support of the study. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

    Competing interests

    The authors declare no competing interests.

    Corresponding author

    Correspondence to Rachel G. Greenberg.

    Supplementary information

    About this article

    Publication history

    Received

    Revised

    Accepted

    Published

    DOI

    https://doi.org/10.1038/s41390-019-0300-4