Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis
<p><strong>Objectives</strong></p> This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. <p><strong>Methods</strong></p> Pharmacokinetic data...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2020
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| _version_ | 1797107436254920704 |
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| author | Gastine, S Obiero, C Kane, Z Williams, P Readman, J Murunga, S Thitiri, J Ellis, S Correia, E Nyaoke, B Kipper, K van den Anker, J Sharland, M Berkley, JA Standing, JF |
| author_facet | Gastine, S Obiero, C Kane, Z Williams, P Readman, J Murunga, S Thitiri, J Ellis, S Correia, E Nyaoke, B Kipper, K van den Anker, J Sharland, M Berkley, JA Standing, JF |
| author_sort | Gastine, S |
| collection | OXFORD |
| description | <p><strong>Objectives</strong></p>
This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.
<p><strong>Methods</strong></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.
<p><strong>Results</strong></p>
<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.</p>
<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 < 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.</p>
<p><strong>Conclusions</strong></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. |
| first_indexed | 2024-03-07T07:16:04Z |
| format | Journal article |
| id | oxford-uuid:ebdb8762-e091-44b8-9bf6-c22469e095c3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:16:04Z |
| publishDate | 2020 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:ebdb8762-e091-44b8-9bf6-c22469e095c32022-07-29T08:00:18ZSimultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ebdb8762-e091-44b8-9bf6-c22469e095c3EnglishSymplectic ElementsOxford University Press2020Gastine, SObiero, CKane, ZWilliams, PReadman, JMurunga, SThitiri, JEllis, SCorreia, ENyaoke, BKipper, Kvan den Anker, JSharland, MBerkley, JAStanding, JF<p><strong>Objectives</strong></p> This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. <p><strong>Methods</strong></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. <p><strong>Results</strong></p> <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.</p> <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 < 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.</p> <p><strong>Conclusions</strong></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. |
| spellingShingle | Gastine, S Obiero, C Kane, Z Williams, P Readman, J Murunga, S Thitiri, J Ellis, S Correia, E Nyaoke, B Kipper, K van den Anker, J Sharland, M Berkley, JA Standing, JF Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title | Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title_full | Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title_fullStr | Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title_full_unstemmed | Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title_short | Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
| title_sort | simultaneous pharmacokinetic pharmacodynamic pkpd assessment of ampicillin and gentamicin in the treatment of neonatal sepsis |
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