Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial

Andrew A. Udy, Joel M. Dulhunty, Jason A. Roberts, Joshua S. Davis, Steven A.R. Webb, Rinaldo Bellomo, Charles Gomersall, Charudatt Shirwadkar, Glenn M. Eastwood, John Myburgh, David L. Paterson, Therese Starr, Sanjoy K. Paul, Jeffrey Lipman, Leah Peck, Helen Young, Catherine Boschert, Jason Fletcher, Julie Smith, Kiran Nand & 83 others Treena Sara, Amy Harney, Helen Rodgers, Frank Van Haren, Sally Clarke, David Durham, Catherine Hannan, Elisha Matheson, Kate Schwartz, Karen Thomas, Allison Bone, Claire Cattigan, Tania Elderkin, Tania Salerno, Robert Cameron, Katrina Ellis, Sheridan Hatter, Milind Sanap, Natalie Soar, Josette Wood, Karen Chan, Aaron Heffernan, Nai An Lai, Catherine Moss, Kate Sheehy, Maree Duroux, Megan Ratcliffe, Samantha Shone, Timothy Warhurst, Rachel Dunlop, Janine Stuart, David Cooper, Rick McAllister, Andrew Cheng, Deborah Inskip, Jennene Miller, Serena Knowles, Claire Reynolds, Sam Rudham, Stuart Baker, Kristy Hepburn, Brigit Roberts, Paul Woods, Indranil Chatterjee, Judy Smith, Martin Cullen, Jing Kong, Vineet Nayyar, Christina Whitehead, Patricia Leung, Eileen Gilder, Lianne McCarthy, Shay McGuiness, Rachael Parke, Kirsten Benefield, Yan Chen, Colin McArthur, Lynette Newby, Seton Henderson, Jan Mehrtens, Sascha Noble, Lesley Chadwick, Ross Freebain, Chantal Hogan, Alex Kazemi, Laura Rust, Rima Song, Anna Tilsley, Anthony Williams, John Durning, Robert Frengley, Mary La Pine, Geoff McCracken, Swarna Baskar Sharma, Lynn Andrews, Richard Dinsdale, Anna Hunt, Sally Hurford, Diane Mackle, Jessica Ongley, Paul Young, Marin Kollef, John Turnidge

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144–198) mL/min]. ARC patients were younger (P < 0.001), more commonly male (P = 0.04) and had less organ dysfunction (P < 0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12–24) days; no ARC, 21 (11–25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

LanguageEnglish
Pages624-630
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume49
Issue number5
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • Augmented renal clearance
  • Critical illness
  • Sepsis
  • β-Lactams

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Udy, Andrew A. ; Dulhunty, Joel M. ; Roberts, Jason A. ; Davis, Joshua S. ; Webb, Steven A.R. ; Bellomo, Rinaldo ; Gomersall, Charles ; Shirwadkar, Charudatt ; Eastwood, Glenn M. ; Myburgh, John ; Paterson, David L. ; Starr, Therese ; Paul, Sanjoy K. ; Lipman, Jeffrey ; Peck, Leah ; Young, Helen ; Boschert, Catherine ; Fletcher, Jason ; Smith, Julie ; Nand, Kiran ; Sara, Treena ; Harney, Amy ; Rodgers, Helen ; Van Haren, Frank ; Clarke, Sally ; Durham, David ; Hannan, Catherine ; Matheson, Elisha ; Schwartz, Kate ; Thomas, Karen ; Bone, Allison ; Cattigan, Claire ; Elderkin, Tania ; Salerno, Tania ; Cameron, Robert ; Ellis, Katrina ; Hatter, Sheridan ; Sanap, Milind ; Soar, Natalie ; Wood, Josette ; Chan, Karen ; Heffernan, Aaron ; Lai, Nai An ; Moss, Catherine ; Sheehy, Kate ; Duroux, Maree ; Ratcliffe, Megan ; Shone, Samantha ; Warhurst, Timothy ; Dunlop, Rachel ; Stuart, Janine ; Cooper, David ; McAllister, Rick ; Cheng, Andrew ; Inskip, Deborah ; Miller, Jennene ; Knowles, Serena ; Reynolds, Claire ; Rudham, Sam ; Baker, Stuart ; Hepburn, Kristy ; Roberts, Brigit ; Woods, Paul ; Chatterjee, Indranil ; Smith, Judy ; Cullen, Martin ; Kong, Jing ; Nayyar, Vineet ; Whitehead, Christina ; Leung, Patricia ; Gilder, Eileen ; McCarthy, Lianne ; McGuiness, Shay ; Parke, Rachael ; Benefield, Kirsten ; Chen, Yan ; McArthur, Colin ; Newby, Lynette ; Henderson, Seton ; Mehrtens, Jan ; Noble, Sascha ; Chadwick, Lesley ; Freebain, Ross ; Hogan, Chantal ; Kazemi, Alex ; Rust, Laura ; Song, Rima ; Tilsley, Anna ; Williams, Anthony ; Durning, John ; Frengley, Robert ; La Pine, Mary ; McCracken, Geoff ; Sharma, Swarna Baskar ; Andrews, Lynn ; Dinsdale, Richard ; Hunt, Anna ; Hurford, Sally ; Mackle, Diane ; Ongley, Jessica ; Young, Paul ; Kollef, Marin ; Turnidge, John. / Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion : a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 49, No. 5. pp. 624-630.
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title = "Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial",
abstract = "Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7{\%}) manifested ARC [median (IQR) CLCr 165 (144–198) mL/min]. ARC patients were younger (P < 0.001), more commonly male (P = 0.04) and had less organ dysfunction (P < 0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12–24) days; no ARC, 21 (11–25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3{\%}) vs. 115/209 (55.0{\%}) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.",
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author = "Udy, {Andrew A.} and Dulhunty, {Joel M.} and Roberts, {Jason A.} and Davis, {Joshua S.} and Webb, {Steven A.R.} and Rinaldo Bellomo and Charles Gomersall and Charudatt Shirwadkar and Eastwood, {Glenn M.} and John Myburgh and Paterson, {David L.} and Therese Starr and Paul, {Sanjoy K.} and Jeffrey Lipman and Leah Peck and Helen Young and Catherine Boschert and Jason Fletcher and Julie Smith and Kiran Nand and Treena Sara and Amy Harney and Helen Rodgers and {Van Haren}, Frank and Sally Clarke and David Durham and Catherine Hannan and Elisha Matheson and Kate Schwartz and Karen Thomas and Allison Bone and Claire Cattigan and Tania Elderkin and Tania Salerno and Robert Cameron and Katrina Ellis and Sheridan Hatter and Milind Sanap and Natalie Soar and Josette Wood and Karen Chan and Aaron Heffernan and Lai, {Nai An} and Catherine Moss and Kate Sheehy and Maree Duroux and Megan Ratcliffe and Samantha Shone and Timothy Warhurst and Rachel Dunlop and Janine Stuart and David Cooper and Rick McAllister and Andrew Cheng and Deborah Inskip and Jennene Miller and Serena Knowles and Claire Reynolds and Sam Rudham and Stuart Baker and Kristy Hepburn and Brigit Roberts and Paul Woods and Indranil Chatterjee and Judy Smith and Martin Cullen and Jing Kong and Vineet Nayyar and Christina Whitehead and Patricia Leung and Eileen Gilder and Lianne McCarthy and Shay McGuiness and Rachael Parke and Kirsten Benefield and Yan Chen and Colin McArthur and Lynette Newby and Seton Henderson and Jan Mehrtens and Sascha Noble and Lesley Chadwick and Ross Freebain and Chantal Hogan and Alex Kazemi and Laura Rust and Rima Song and Anna Tilsley and Anthony Williams and John Durning and Robert Frengley and {La Pine}, Mary and Geoff McCracken and Sharma, {Swarna Baskar} and Lynn Andrews and Richard Dinsdale and Anna Hunt and Sally Hurford and Diane Mackle and Jessica Ongley and Paul Young and Marin Kollef and John Turnidge",
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Udy, AA, Dulhunty, JM, Roberts, JA, Davis, JS, Webb, SAR, Bellomo, R, Gomersall, C, Shirwadkar, C, Eastwood, GM, Myburgh, J, Paterson, DL, Starr, T, Paul, SK, Lipman, J, Peck, L, Young, H, Boschert, C, Fletcher, J, Smith, J, Nand, K, Sara, T, Harney, A, Rodgers, H, Van Haren, F, Clarke, S, Durham, D, Hannan, C, Matheson, E, Schwartz, K, Thomas, K, Bone, A, Cattigan, C, Elderkin, T, Salerno, T, Cameron, R, Ellis, K, Hatter, S, Sanap, M, Soar, N, Wood, J, Chan, K, Heffernan, A, Lai, NA, Moss, C, Sheehy, K, Duroux, M, Ratcliffe, M, Shone, S, Warhurst, T, Dunlop, R, Stuart, J, Cooper, D, McAllister, R, Cheng, A, Inskip, D, Miller, J, Knowles, S, Reynolds, C, Rudham, S, Baker, S, Hepburn, K, Roberts, B, Woods, P, Chatterjee, I, Smith, J, Cullen, M, Kong, J, Nayyar, V, Whitehead, C, Leung, P, Gilder, E, McCarthy, L, McGuiness, S, Parke, R, Benefield, K, Chen, Y, McArthur, C, Newby, L, Henderson, S, Mehrtens, J, Noble, S, Chadwick, L, Freebain, R, Hogan, C, Kazemi, A, Rust, L, Song, R, Tilsley, A, Williams, A, Durning, J, Frengley, R, La Pine, M, McCracken, G, Sharma, SB, Andrews, L, Dinsdale, R, Hunt, A, Hurford, S, Mackle, D, Ongley, J, Young, P, Kollef, M & Turnidge, J 2017, 'Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial', International Journal of Antimicrobial Agents, vol. 49, no. 5, pp. 624-630. https://doi.org/10.1016/j.ijantimicag.2016.12.022

Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion : a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. / Udy, Andrew A.; Dulhunty, Joel M.; Roberts, Jason A.; Davis, Joshua S.; Webb, Steven A.R.; Bellomo, Rinaldo; Gomersall, Charles; Shirwadkar, Charudatt; Eastwood, Glenn M.; Myburgh, John; Paterson, David L.; Starr, Therese; Paul, Sanjoy K.; Lipman, Jeffrey; Peck, Leah; Young, Helen; Boschert, Catherine; Fletcher, Jason; Smith, Julie; Nand, Kiran; Sara, Treena; Harney, Amy; Rodgers, Helen; Van Haren, Frank; Clarke, Sally; Durham, David; Hannan, Catherine; Matheson, Elisha; Schwartz, Kate; Thomas, Karen; Bone, Allison; Cattigan, Claire; Elderkin, Tania; Salerno, Tania; Cameron, Robert; Ellis, Katrina; Hatter, Sheridan; Sanap, Milind; Soar, Natalie; Wood, Josette; Chan, Karen; Heffernan, Aaron; Lai, Nai An; Moss, Catherine; Sheehy, Kate; Duroux, Maree; Ratcliffe, Megan; Shone, Samantha; Warhurst, Timothy; Dunlop, Rachel; Stuart, Janine; Cooper, David; McAllister, Rick; Cheng, Andrew; Inskip, Deborah; Miller, Jennene; Knowles, Serena; Reynolds, Claire; Rudham, Sam; Baker, Stuart; Hepburn, Kristy; Roberts, Brigit; Woods, Paul; Chatterjee, Indranil; Smith, Judy; Cullen, Martin; Kong, Jing; Nayyar, Vineet; Whitehead, Christina; Leung, Patricia; Gilder, Eileen; McCarthy, Lianne; McGuiness, Shay; Parke, Rachael; Benefield, Kirsten; Chen, Yan; McArthur, Colin; Newby, Lynette; Henderson, Seton; Mehrtens, Jan; Noble, Sascha; Chadwick, Lesley; Freebain, Ross; Hogan, Chantal; Kazemi, Alex; Rust, Laura; Song, Rima; Tilsley, Anna; Williams, Anthony; Durning, John; Frengley, Robert; La Pine, Mary; McCracken, Geoff; Sharma, Swarna Baskar; Andrews, Lynn; Dinsdale, Richard; Hunt, Anna; Hurford, Sally; Mackle, Diane; Ongley, Jessica; Young, Paul; Kollef, Marin; Turnidge, John.

In: International Journal of Antimicrobial Agents, Vol. 49, No. 5, 01.05.2017, p. 624-630.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion

T2 - International Journal of Antimicrobial Agents

AU - Udy, Andrew A.

AU - Dulhunty, Joel M.

AU - Roberts, Jason A.

AU - Davis, Joshua S.

AU - Webb, Steven A.R.

AU - Bellomo, Rinaldo

AU - Gomersall, Charles

AU - Shirwadkar, Charudatt

AU - Eastwood, Glenn M.

AU - Myburgh, John

AU - Paterson, David L.

AU - Starr, Therese

AU - Paul, Sanjoy K.

AU - Lipman, Jeffrey

AU - Peck, Leah

AU - Young, Helen

AU - Boschert, Catherine

AU - Fletcher, Jason

AU - Smith, Julie

AU - Nand, Kiran

AU - Sara, Treena

AU - Harney, Amy

AU - Rodgers, Helen

AU - Van Haren, Frank

AU - Clarke, Sally

AU - Durham, David

AU - Hannan, Catherine

AU - Matheson, Elisha

AU - Schwartz, Kate

AU - Thomas, Karen

AU - Bone, Allison

AU - Cattigan, Claire

AU - Elderkin, Tania

AU - Salerno, Tania

AU - Cameron, Robert

AU - Ellis, Katrina

AU - Hatter, Sheridan

AU - Sanap, Milind

AU - Soar, Natalie

AU - Wood, Josette

AU - Chan, Karen

AU - Heffernan, Aaron

AU - Lai, Nai An

AU - Moss, Catherine

AU - Sheehy, Kate

AU - Duroux, Maree

AU - Ratcliffe, Megan

AU - Shone, Samantha

AU - Warhurst, Timothy

AU - Dunlop, Rachel

AU - Stuart, Janine

AU - Cooper, David

AU - McAllister, Rick

AU - Cheng, Andrew

AU - Inskip, Deborah

AU - Miller, Jennene

AU - Knowles, Serena

AU - Reynolds, Claire

AU - Rudham, Sam

AU - Baker, Stuart

AU - Hepburn, Kristy

AU - Roberts, Brigit

AU - Woods, Paul

AU - Chatterjee, Indranil

AU - Smith, Judy

AU - Cullen, Martin

AU - Kong, Jing

AU - Nayyar, Vineet

AU - Whitehead, Christina

AU - Leung, Patricia

AU - Gilder, Eileen

AU - McCarthy, Lianne

AU - McGuiness, Shay

AU - Parke, Rachael

AU - Benefield, Kirsten

AU - Chen, Yan

AU - McArthur, Colin

AU - Newby, Lynette

AU - Henderson, Seton

AU - Mehrtens, Jan

AU - Noble, Sascha

AU - Chadwick, Lesley

AU - Freebain, Ross

AU - Hogan, Chantal

AU - Kazemi, Alex

AU - Rust, Laura

AU - Song, Rima

AU - Tilsley, Anna

AU - Williams, Anthony

AU - Durning, John

AU - Frengley, Robert

AU - La Pine, Mary

AU - McCracken, Geoff

AU - Sharma, Swarna Baskar

AU - Andrews, Lynn

AU - Dinsdale, Richard

AU - Hunt, Anna

AU - Hurford, Sally

AU - Mackle, Diane

AU - Ongley, Jessica

AU - Young, Paul

AU - Kollef, Marin

AU - Turnidge, John

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144–198) mL/min]. ARC patients were younger (P < 0.001), more commonly male (P = 0.04) and had less organ dysfunction (P < 0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12–24) days; no ARC, 21 (11–25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

AB - Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144–198) mL/min]. ARC patients were younger (P < 0.001), more commonly male (P = 0.04) and had less organ dysfunction (P < 0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12–24) days; no ARC, 21 (11–25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

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DO - 10.1016/j.ijantimicag.2016.12.022

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EP - 630

JO - International Journal of Antimicrobial Agents

JF - International Journal of Antimicrobial Agents

SN - 0924-8579

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