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Ampicillin dosing in premature infants for early-onset sepsis: exposure-driven efficacy, safety, and stewardship

Journal of Perinatology volume 42, pages 959–964 (2022)Cite this article

Subjects

Abstract

Objective

Define optimal ampicillin dosing for empiric early-onset sepsis (EOS) therapy in preterm neonates.

Study design

We simulated ampicillin concentrations in newborns (birthweight < 1500 g; gestational age 22–27 weeks), summarizing three 48 h regimens: high 100 mg/kg Q8hr, medium 100 mg/kg Q12hr, and standard 50 mg/kg Q12hr. Concentration data were analyzed for concentration above minimum inhibitory concentration (MIC), below neurotoxicity threshold (Cmax ≤ 140 mcg/mL), and duration limited to 48 h.

Results

Among 34,689 newborns, all dosing regimens provided concentrations above MIC through 48 h, but Cmax exceeded the neurotoxicity threshold. With the 4-dose standard regimen, >90% maintained concentrations >MIC beyond 48 h. With the 2-dose regimen, newborns maintained the mean concentration >MIC within the 48 h culture window and below neurotoxicity level. Infants 22–24 weeks’ gestation had higher drug concentrations and more prolonged exposure duration than 25–27 weeks’ gestation.

Conclusions

For EOS in preterm infants, two ampicillin doses (50 mg/kg) provided optimal bactericidal exposures, while minimizing potential toxicity.

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Fig. 1: Probability of therapeutic target attainment over time from therapy initiation.
Fig. 2: Mean predicted concentration versus time curve of ampicillin 50 mg/kg/dose.

Data availability

To help expand the knowledge base for pediatric medicine, the Pediatric Trials Network is pleased to share data from its completed and published studies with interested investigators. For requests, please contact: PTN-Program-Manager@dm.duke.edu.

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Acknowledgements

Erin Campbell, MS provided editorial review and submission of this manuscript. Ms. Campbell did not receive compensation for her contributions, apart from her employment at the institution where this study was conducted. This work was funded under the National Institute of Child Health and Human Development (NICHD) contract (HHSN275201000003I) for the Pediatric Trials Network (PI Danny Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. A list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, La Jolla, CA, USA

    Jennifer Le & YoungJun Yoo

  2. Department of Pediatrics, Duke University, Durham, NC, USA

    Rachel G. Greenberg, Daniel K. Benjamin Jr., Kanecia O. Zimmerman & Michael Cohen-Wolkowiez

  3. Duke Clinical Research Institute, Duke University, Durham, NC, USA

    Rachel G. Greenberg, Daniel K. Benjamin Jr., Kanecia O. Zimmerman & Michael Cohen-Wolkowiez

  4. CREQS, MEDNAX, Sunrise, FL, USA

    Reese H. Clark

  5. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kelly C. Wade

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

    Kelly C. Wade

  7. Department of Pediatrics, Duke University, Durham, NC, USA

    Daniel K. Benjamin Jr. & Kanecia O. Zimmerman

  8. Duke Clinical Research Institute, Duke University, Durham, NC, USA

    Daniel K. Benjamin Jr. & Kanecia O. Zimmerman

Authors
  1. Jennifer Le
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Consortia

Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

  • Daniel K. Benjamin Jr.
  •  & Kanecia O. Zimmerman

Contributions

JL assisted in data acquisition, study design, and interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. RGG assisted in data acquisition and interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. YY assisted in data acquisition and interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. RHC assisted in data acquisition and interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. DKB assisted in data interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. KOZ assisted in data interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. MCW assisted in data interpretation, reviewing the manuscript, has approved the final version, and agrees to be accountable for all aspects of the work. KCW conceived the work, assisted in data acquisition, study design, and interpretation, drafted the manuscript, has approved the final version of the manuscript, agrees to be accountable for all aspects of the work, had full access to the data in the study, and takes final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Kelly C. Wade.

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The authors declare no competing interests.

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Le, J., Greenberg, R.G., Yoo, Y. et al. Ampicillin dosing in premature infants for early-onset sepsis: exposure-driven efficacy, safety, and stewardship. J Perinatol 42, 959–964 (2022). https://doi.org/10.1038/s41372-022-01344-2

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