Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial
<p><strong>Background:</strong> Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to asses...
| Principais autores: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | Journal article |
| Idioma: | English |
| Publicado em: |
Elsevier
2021
|
| _version_ | 1826307784252063744 |
|---|---|
| author | Hill, L Clements, MN Turner, MA Dona, D Lutsar, I Jacqz-Aigrain, E Heath, P Roilides, E Rawcliffe, L Alonso-Diaz, C Baraldi, E Dotta, A Ilmoja, M-L Mahaveer, A Metsvaht, T Mitsiakos, G Papevangelou, V Sarafidis, K Walker, AS Sharland, M |
| author_facet | Hill, L Clements, MN Turner, MA Dona, D Lutsar, I Jacqz-Aigrain, E Heath, P Roilides, E Rawcliffe, L Alonso-Diaz, C Baraldi, E Dotta, A Ilmoja, M-L Mahaveer, A Metsvaht, T Mitsiakos, G Papevangelou, V Sarafidis, K Walker, AS Sharland, M |
| author_sort | Hill, L |
| collection | OXFORD |
| description | <p><strong>Background:</strong> Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms.</p>
<p><strong>Methods:</strong> NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996).</p>
<p><strong>Findings:</strong> Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group).</p>
<p><strong>Interpretation:</strong> In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants.</p> |
| first_indexed | 2024-03-07T07:08:16Z |
| format | Journal article |
| id | oxford-uuid:bf2d1e13-a952-4769-be7f-6f7175d2d5cb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:08:16Z |
| publishDate | 2021 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:bf2d1e13-a952-4769-be7f-6f7175d2d5cb2022-05-26T08:35:55ZOptimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trialJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bf2d1e13-a952-4769-be7f-6f7175d2d5cbEnglishSymplectic ElementsElsevier2021Hill, LClements, MNTurner, MADona, DLutsar, IJacqz-Aigrain, EHeath, PRoilides, ERawcliffe, LAlonso-Diaz, CBaraldi, EDotta, AIlmoja, M-LMahaveer, AMetsvaht, TMitsiakos, GPapevangelou, VSarafidis, KWalker, ASSharland, M<p><strong>Background:</strong> Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms.</p> <p><strong>Methods:</strong> NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996).</p> <p><strong>Findings:</strong> Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group).</p> <p><strong>Interpretation:</strong> In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants.</p> |
| spellingShingle | Hill, L Clements, MN Turner, MA Dona, D Lutsar, I Jacqz-Aigrain, E Heath, P Roilides, E Rawcliffe, L Alonso-Diaz, C Baraldi, E Dotta, A Ilmoja, M-L Mahaveer, A Metsvaht, T Mitsiakos, G Papevangelou, V Sarafidis, K Walker, AS Sharland, M Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title | Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title_full | Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title_fullStr | Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title_full_unstemmed | Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title_short | Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial |
| title_sort | optimised versus standard dosing of vancomycin in infants with gram positive sepsis neovanc a multicentre randomised open label phase 2b non inferiority trial |
| work_keys_str_mv | AT hilll optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT clementsmn optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT turnerma optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT donad optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT lutsari optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT jacqzaigraine optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT heathp optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT roilidese optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT rawcliffel optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT alonsodiazc optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT baraldie optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT dottaa optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT ilmojaml optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT mahaveera optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT metsvahtt optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT mitsiakosg optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT papevangelouv optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT sarafidisk optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT walkeras optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial AT sharlandm optimisedversusstandarddosingofvancomycinininfantswithgrampositivesepsisneovancamulticentrerandomisedopenlabelphase2bnoninferioritytrial |