{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:56:05Z","timestamp":1790042165977,"version":"4.0.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education and Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic\/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89\u2009L\/h\/70\u2009kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3\u2009L\/h\/70\u2009kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.<\/jats:p>\n                  <jats:p>Simulation-based PKPD assessments suggest good Gram-positive (MIC\u200a\u2264\u200a0.25\u2009mg\/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC\u200a\u2264\u200a2\u2009mg\/L). The benefit of the ampicillin\/gentamicin combination was limited, with only 2\/23 E. coli clinical strains showing FIC index\u200a&amp;lt;\u200a0.5 (synergy) and most in the range 0.5\u20131 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkab413","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T11:17:24Z","timestamp":1634901444000},"page":"448-456","source":"Crossref","is-referenced-by-count":9,"title":["Simultaneous pharmacokinetic\/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis"],"prefix":"10.1093","volume":"77","author":[{"given":"Silke","family":"Gastine","sequence":"first","affiliation":[{"name":"Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Obiero","sequence":"additional","affiliation":[{"name":"KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5596-8532","authenticated-orcid":false,"given":"Zoe","family":"Kane","sequence":"additional","affiliation":[{"name":"Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK"},{"name":"Quotient Sciences, Mere Way, Ruddington, Nottingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Williams","sequence":"additional","affiliation":[{"name":"KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya"},{"name":"Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of 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Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Correia","sequence":"additional","affiliation":[{"name":"Global Antibiotic Research & Development Partnership (GARDP), Gen\u00e8ve, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borna","family":"Nyaoke","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative (DNDi), Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Kipper","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Tartu, Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"van den Anker","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pharmacology and Pharmacometrics, University Children\u2019s Hospital Basel, University of Basel, Switzerland"},{"name":"Division of Clinical Pharmacology, Children\u2019s National Hospital, 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