{"doi":"10.1093/jac/dkab413","title":"Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis","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 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). 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 ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index &amp;lt; 0.5 (synergy) and most in the range 0.5–1 (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>","journal":"Journal of Antimicrobial Chemotherapy","year":2022,"id":672579,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1757265,"name":"Christina Obiero","orcid":null,"position":1,"is_corresponding":false},{"id":1757266,"name":"Zoe Kane","orcid":"0000-0002-5596-8532","position":2,"is_corresponding":false},{"id":1757267,"name":"Phoebe Williams","orcid":null,"position":3,"is_corresponding":false},{"id":1757268,"name":"John Readman","orcid":null,"position":4,"is_corresponding":false},{"id":1757269,"name":"Sheila Murunga","orcid":null,"position":5,"is_corresponding":false},{"id":1757270,"name":"Johnstone Thitiri","orcid":null,"position":6,"is_corresponding":false},{"id":1757271,"name":"Sally Ellis","orcid":null,"position":7,"is_corresponding":false},{"id":623556,"name":"Erika Correia","orcid":"0009-0007-9672-8352","position":8,"is_corresponding":false},{"id":1279691,"name":"Borna Nyaoke","orcid":"0000-0001-9563-7108","position":9,"is_corresponding":false},{"id":1757272,"name":"Karin Kipper","orcid":null,"position":10,"is_corresponding":false},{"id":593285,"name":"John van den Anker","orcid":"0000-0002-3585-321X","position":11,"is_corresponding":false},{"id":572531,"name":"Mike Sharland","orcid":"0000-0001-8626-8291","position":12,"is_corresponding":false},{"id":298911,"name":"James A. Berkley","orcid":"0000-0002-1236-849X","position":13,"is_corresponding":false},{"id":721773,"name":"Joseph F. Standing","orcid":"0000-0002-4561-7173","position":14,"is_corresponding":false},{"id":1757264,"name":"Silke Gastine","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis","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 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). 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 ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index &amp;lt; 0.5 (synergy) and most in the range 0.5–1 (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>","is_dataset_classified":null,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35107141","pmcid":"PMC8809196","openalex_id":"https://openalex.org/W4213189595","authors":[],"funders":[{"funder_name":"Medical Research Council","grant_id":"MR/M007367/1","title":"First Line Antimicrobials in Complicated Severe Acute Malnutrition (FLACSAM)"},{"funder_name":"Medical Research Council","grant_id":"MR/M008665/1","title":"Mathematical and Statistical Modelling to Optimise Paediatric Medicines Research"},{"funder_name":"Wellcome Trust","grant_id":"unidentified","title":"unidentified"},{"funder_name":"German Federal Ministry of Education and Research","grant_id":"","title":null},{"funder_name":"Wellcome Trust","grant_id":"","title":null},{"funder_name":"National Institute for Health Research (NIHR)","grant_id":"","title":null},{"funder_name":"Wellcome Trust","grant_id":"","title":null},{"funder_name":"Department of Health","grant_id":"","title":null}],"total_grants":8,"fwci":0.6022,"citation_percentile":0.68882606,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2024,"count":2},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://academic.oup.com/jac/article-pdf/77/2/448/42466871/dkab413.pdf","host_type":"journal"},{"url":"https://academic.oup.com/jac/article-pdf/77/2/448/42466871/dkab413.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/jac/dkab413","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35107141","host_type":"repository"},{"url":"https://openaccess.sgul.ac.uk/id/eprint/114140/2/dkab413_supplementary_data.docx","host_type":"repository"},{"url":"https://ora.ox.ac.uk/objects/uuid:ebdb8762-e091-44b8-9bf6-c22469e095c3","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8809196","host_type":"repository"},{"url":"https://discovery.ucl.ac.uk/id/eprint/10143492/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8809196","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8809196?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.60692/6s5rv-ggh33","host_type":""},{"url":"https://dx.doi.org/10.60692/mhvt9-88v20","host_type":""},{"url":"http://dx.doi.org/10.1093/jac/dkab413","host_type":""},{"url":"https://openaccess.sgul.ac.uk/id/eprint/114140/1/dkab413.pdf","host_type":""},{"url":"https://discovery-pp.ucl.ac.uk/id/eprint/10143492/","host_type":""}],"fields_of_study":["Antibiotics Pharmacokinetics and Efficacy","Neonatal and Maternal Infections","Antibiotic Resistance in Bacteria","03 medical and health sciences","0303 health sciences","Ampicillin","Anti-Bacterial Agents","Escherichia coli","Gentamicins","Humans","Infant, Newborn","Neonatal Sepsis","Sepsis"],"mesh_terms":["Neonatal Sepsis","Ampicillin","Anti-Bacterial Agents","Escherichia coli","Gentamicins","Humans","Infant, Newborn","Sepsis"],"keywords":["Gentamicin","Ampicillin","Pharmacokinetics","Medicine","Pharmacodynamics","Dosing","Renal function","Pharmacology","Sepsis","Antibiotics","Internal medicine","Biology","Microbiology","Epidemiology","FOS: Basic medicine","Global Challenge of Antibiotic Resistance in Bacteria","Epidemiology and Treatment of Urinary Tract Infections","Biochemistry, Genetics and Molecular Biology","Health Sciences","Escherichia coli","Humans","Original Research","Pharmacodynamic","Infant, Newborn","Life Sciences","Anti-Bacterial Agents","Pharmacokinetics of Antibiotics in Critically Ill Patients","FOS: Biological sciences","Molecular Medicine","Gentamicins","Neonatal Sepsis"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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