Search

Your search keyword '"Derde, L.P.G."' showing total 19 results
Start Over Author "Derde, L.P.G."
19 results on '"Derde, L.P.G."'

1. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Author

Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., Lawler, P.R., Higgins, A.M., Berry, L.R., Lorenzi, E., Murthy, S., McQuilten, Z., Mouncey, P.R., Al-Beidh, F., Annane, D., Arabi, Y.M., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Charles, W.N., Cove, M., Detry, M.A., Estcourt, L.J., Fagbodun, E.O., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Horvat, C.M., Huang, D.T., Ichihara, N., Lamontagne, F., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Parry-Billings, K., Peters, S.E.C., Reyes, L.F., Rowan, K.M., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Stronach, L.M., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Gordon, A.C., Webb, S.A., and Lawler, P.R.

Abstract

Item does not contain fulltext, IMPORTANCE: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. OBJECTIVE: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. INTERVENTIONS: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). MAIN OUTCOMES AND MEASURES: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. RESULTS: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06

Published
2023

2. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Author

Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., Webb, S.A., Lawler, P.R., Derde, L.P.G., Veerdonk, F.L. van de, McVerry, B.J., Huang, D.T., Berry, L.R., Lorenzi, E., Kimmenade, R.R.J. van, Gommans, F., Vaduganathan, M., Leaf, D.E., Baron, R.M., Kim, E.Y., Frankfurter, C., Epelman, S., Kwan, Y., Grieve, R., O'Neill, S., Sadique, Z., Puskarich, M., Marshall, J.C., Higgins, A.M., Mouncey, P.R., Rowan, K.M., Al-Beidh, F., Annane, D., Arabi, Y.M., Au, C., Beane, A., Bentum-Puijk, W. van, Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Burrell, A., Buzgau, A., Buxton, M., Cecconi, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Ezekowitz, J., Fitzgerald, M., Gattas, D., Godoy, L.C., Goossens, H., Haniffa, R., Harrison, D.A., Hills, T., Horvat, C.M., Ichihara, N., Lamontagne, F., Linstrum, K.M., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McQuilten, Z., Murthy, S., Nichol, A.D., Owen, D.R.J., Parke, R.L., Parker, J.C., Pollock, K.M., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Singh, V., Turgeon, A.F., Turner, A.M., Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., Berry, S., Gordon, A.C., McArthur, C.J., and Webb, S.A.

Abstract

Item does not contain fulltext, IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital surv

Published
2023

3. Decision-making regarding antibiotic therapy duration: An observational study of multidisciplinary meetings in the intensive care unit

Author

Janssen, R.M.E., Oerlemans, A.J.M., Hoeven, J.G. van der, Oostdijk, Evelien A. N., Derde, L.P.G., Oever, J. ten, Wertheim, H.F.L., Hulscher, M.E.J.L., Schouten, J.A., Janssen, R.M.E., Oerlemans, A.J.M., Hoeven, J.G. van der, Oostdijk, Evelien A. N., Derde, L.P.G., Oever, J. ten, Wertheim, H.F.L., Hulscher, M.E.J.L., and Schouten, J.A.

Abstract

Item does not contain fulltext

Published
2023

4. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Author

Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., Gordon A.C., Bradbury C.A., Lawler P.R., Stanworth S.J., McVerry B.J., McQuilten Z., Higgins A.M., Mouncey P.R., Al-Beidh F., Rowan K.M., Berry L.R., Lorenzi E., Zarychanski R., Arabi Y.M., Annane D., Beane A., Van Bentum-Puijk W., Bhimani Z., Bihari S., Bonten M.J.M., Brunkhorst F.M., Buzgau A., Buxton M., Carrier M., Cheng A.C., Cove M., Detry M.A., Estcourt L.J., Fitzgerald M., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Hills T., Huang D.T., Horvat C.M., Hunt B.J., Ichihara N., Lamontagne F., Leavis H.L., Linstrum K.M., Litton E., Marshall J.C., McAuley D.F., McGlothlin A., McGuinness S.P., Middeldorp S., Montgomery S.K., Morpeth S.C., Murthy S., Neal M.D., Nichol A.D., Parke R.L., Parker J.C., Reyes L., Saito H., Santos M.S., Saunders C.T., Serpa-Neto A., Seymour C.W., Shankar-Hari M., Singh V., Tolppa T., Turgeon A.F., Turner A.M., Van De Veerdonk F.L., Green C., Lewis R.J., Angus D.C., McArthur C.J., Berry S., Derde L.P.G., Webb S.A., and Gordon A.C.

Abstract

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective(s): To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participant(s): In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Intervention(s): Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from-1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Result(s): The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespe

Published
2022

5. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., Gordon, A.C., Bradbury, C.A., Lawler, P.R., Stanworth, S.J., McVerry, B.J., McQuilten, Z., Higgins, A.M., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Berry, L.R., Lorenzi, E., Zarychanski, R., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Bhimani, Z., Bihari, S., Bonten, M.J.M., Brunkhorst, F.M., Buzgau, A., Buxton, M., Carrier, M., Cheng, A.C., Cove, M., Detry, M.A., Estcourt, L.J., Fitzgerald, M., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Hills, T., Huang, D.T., Horvat, C.M., Hunt, B.J., Ichihara, N., Lamontagne, F., Leavis, H.L., Linstrum, K.M., Litton, E., Marshall, J.C., McAuley, D.F., McGlothlin, A., McGuinness, S.P., Middeldorp, S., Montgomery, S.K., Morpeth, S.C., Murthy, S., Neal, M.D., Nichol, A.D., Parke, R.L., Parker, J.C., Reyes, L.F., Saito, H., Santos, M.S., Saunders, C.T., Serpa-Neto, A., Seymour, C.W., Shankar-Hari, M., Singh, V., Tolppa, T., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Derde, L.P.G., Pickkers, P., Schouten, J.A., Webb, S.A., and Gordon, A.C.

Abstract

Item does not contain fulltext, IMPORTANCE: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified c

Published
2022

6. The Renin-Angiotensin System in Acute Lung Injury

Author

Lawler, P.R., Derde, L.P.G., McVerry, B.J., Russell, James A., Veerdonk, F.L. van de, Lawler, P.R., Derde, L.P.G., McVerry, B.J., Russell, James A., and Veerdonk, F.L. van de

Abstract

Item does not contain fulltext

Published
2022

7. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Author

Gordon, A.C., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Nichol, A.D., Arabi, Y.M., Annane, D., Beane, A., Bentum-Puijk, W. van, Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buzgau, A., Cheng, A.C., Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Lamontagne, F., Lawler, P.R., Leavis, H.L., Linstrum, K.M., Litton, E., Lorenzi, E., Marshall, J.C., Mayr, F.B., McAuley, D.F., McGlothlin, A., McGuinness, S.P., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Murthy, S., Orr, K., Parke, R.L., Parker, J.C., Patanwala, A.E., Pettilä, V., Rademaker, E., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Sligl, W.I., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Lewis, R.J., Angus, D.C., McArthur, C.J., Berry, S., Schouten, J.A., Pickkers, P., Webb, S.A., Derde, L.P.G., Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), REMAP-CAP Investigators, Pour la France: Bruno Megarbane, Inserm U1144, European Project: 602386,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,CREDITS4HEALTH(2013), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Gordon, Anthony C [0000-0002-0419-547X], Mouncey, Paul R [0000-0002-8510-8517], Beane, Abi [0000-0001-7046-1580], Bradbury, Charlotte A [0000-0001-5248-8165], Detry, Michelle A [0000-0002-2794-1439], Duffy, Eamon J [0000-0002-4515-5116], Estcourt, Lise J [0000-0003-4309-9162], Haniffa, Rashan [0000-0002-8288-449X], Higgins, Alisa M [0000-0001-8295-7559], Hills, Thomas E [0000-0003-0322-5822], Horvat, Christopher M [0000-0002-1593-2252], Lawler, Patrick R [0000-0001-5155-5071], Litton, Edward [0000-0002-5125-6829], Mayr, Florian B [0000-0002-2298-9011], McVerry, Bryan J [0000-0002-1175-4874], Patanwala, Asad E [0000-0003-3999-4703], Saunders, Christina T [0000-0003-4325-9568], Shankar-Hari, Manu [0000-0002-5338-2538], Angus, Derek C [0000-0002-7026-5181], Derde, Lennie PG [0000-0002-3577-5629], Apollo - University of Cambridge Repository, Investigators, REMAP-CAP, HAL UVSQ, Équipe, Credits-based, people-centric approach for the adoption of healthy life-styles and balanced Mediterranean diet in the frame of social participation and innovation for health promotion. - CREDITS4HEALTH - - EC:FP7:HEALTH2013-09-01 - 2016-08-31 - 602386 - VALID, and Platform foR European Preparedness Against (Re-)emerging Epidemics - PREPARE - - EC:FP7:HEALTH2014-02-01 - 2019-01-31 - 602525 - VALID

Subjects
Male, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, middle aged, Credible interval, Odds Ratio, odds ratio, 030212 general & internal medicine, Hospital Mortality, humans, 11 Medical and Health Sciences, adult, Hazard ratio, Covid19, General Medicine, Middle Aged, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], aged, Intensive Care Units, Antibodies, Monoclonal, Humanized/adverse effects, COVID-19/complications, Original Article, Female, Adult, medicine.medical_specialty, Critical Care, Critical Illness, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Tocilizumab, male, Internal medicine, General & Internal Medicine, medicine, Humans, Aged, hospital mortality, business.industry, SARS-CoV-2, COVID-19, Odds ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment, Coronavirus, Sarilumab, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Receptors, Interleukin-6/antagonists & inhibitors, REMAP-CAP Investigators, interleukin-6 receptor antagonists, coronavirus disease, business
Abstract

BACKGROUNDThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.METHODSWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support–free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.RESULTSBoth tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.CONCLUSIONSIn critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707. opens in new tab.)

Published
2021
Full Text
View/download PDF

8. Dysregulated Innate and Adaptive Immune Responses Discriminate Disease Severity in COVID-19

Author

Janssen, N.A.F. Grondman, I. de Nooijer, A.H. Boahen, C.K. Koeken, V.A.C.M. Matzaraki, V. Kumar, V. He, X. Kox, M. Koenen, H.J.P.M. Smeets, R.L. Joosten, I. Brüggemann, R.J.M. Kouijzer, I.J.E. van der Hoeven, H.G. Schouten, J.A. Frenzel, T. Reijers, M.H.E. Hoefsloot, W. Dofferhoff, A.S.M. van Apeldoorn, M.J. Blaauw, M.J.T. Veerman, K. Maas, C. Schoneveld, A.H. Hoefer, I.E. Derde, L.P.G. van Deuren, M. van der Meer, J.W.M. van Crevel, R. Giamarellos-Bourboulis, E.J. Joosten, L.A.B. van den Heuvel, M.M. Hoogerwerf, J. de Mast, Q. Pickkers, P. Netea, M.G. van de Veerdonk, F.L.

Abstract

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity. © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Published
2021

9. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, E.C., Bradbury, C.A., McVerry, B.J., Lawler, P.R., Berger, J.S., Gong, M.N., Carrier, M., Reynolds, H.R., Kumar, A., Turgeon, A.F., Kornblith, L.Z., Kahn, S.R., Marshall, J.C., Kim, K.S., Houston, B.L., Derde, L.P.G., Cushman, M., Tritschler, T., Angus, D.C., Godoy, L.C., McQuilten, Z., Kirwan, B.A., Farkouh, M.E., Brooks, M.M., Lewis, R.J., Berry, L.R., Lorenzi, E., Gordon, A.C., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T.W., Brouwer, S., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Eng, H.F., Escobedo, J., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Froess, J.D., Fu, Z., Galanaud, J.P., Galen, B.T., Gandotra, S., Girard, T.D., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Haniffa, R., Hegde, S.M., Hendrickson, C.M., Higgins, A.M., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Huang, D.T., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A., King, A.J., Knudson, M.M., Kornblith, A.E., Kutcher, M.E., Laffan, M.A., Lamontagne, F., Gal, G. Le, Veerdonk, F.L. van de, Middeldorp, S., Schouten, J.A., Pickkers, P., Webb, S.A., Zarychanski, R., Goligher, E.C., Bradbury, C.A., McVerry, B.J., Lawler, P.R., Berger, J.S., Gong, M.N., Carrier, M., Reynolds, H.R., Kumar, A., Turgeon, A.F., Kornblith, L.Z., Kahn, S.R., Marshall, J.C., Kim, K.S., Houston, B.L., Derde, L.P.G., Cushman, M., Tritschler, T., Angus, D.C., Godoy, L.C., McQuilten, Z., Kirwan, B.A., Farkouh, M.E., Brooks, M.M., Lewis, R.J., Berry, L.R., Lorenzi, E., Gordon, A.C., Ahuja, T., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T.W., Brouwer, S., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Eng, H.F., Escobedo, J., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Froess, J.D., Fu, Z., Galanaud, J.P., Galen, B.T., Gandotra, S., Girard, T.D., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Haniffa, R., Hegde, S.M., Hendrickson, C.M., Higgins, A.M., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Huang, D.T., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A., King, A.J., Knudson, M.M., Kornblith, A.E., Kutcher, M.E., Laffan, M.A., Lamontagne, F., Gal, G. Le, Veerdonk, F.L. van de, Middeldorp, S., Schouten, J.A., Pickkers, P., Webb, S.A., and Zarychanski, R.

Abstract

Item does not contain fulltext, BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulati

Published
2021

10. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, P.R., Goligher, E.C., Berger, J.S., Neal, M.D., McVerry, B.J., Nicolau, J.C., Gong, M.N., Carrier, M., Rosenson, R.S., Reynolds, H.R., Turgeon, A.F., Escobedo, J., Huang, D.T., Bradbury, C.A., Houston, B.L., Kornblith, L.Z., Kumar, A., Kahn, S.R., Cushman, M., McQuilten, Z., Slutsky, A.S., Kim, K.S., Gordon, A.C., Kirwan, B.A., Brooks, M.M., Higgins, A.M., Lewis, R.J., Lorenzi, E., Berry, S.M., Berry, L.R., Aday, A.W., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Costantini, T.W., Brouwer, S., Derde, L.P.G., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Galanaud, J.P., Galen, B.T., Gandotra, S., García-Madrona, S., Girard, T.D., Godoy, L.C., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Hamburg, N.M., Haniffa, R., Hanna, G., Hanna, N., Hegde, S.M., Hendrickson, C.M., Hite, R.D., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Iyer, V.N., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A.L., King, A.J., Knudson, M.M., Kornblith, A.E., Krishnan, V., Veerdonk, F.L. van de, Schouten, J.A., Pickkers, P., Hochman, J.S., Zarychanski, R., Lawler, P.R., Goligher, E.C., Berger, J.S., Neal, M.D., McVerry, B.J., Nicolau, J.C., Gong, M.N., Carrier, M., Rosenson, R.S., Reynolds, H.R., Turgeon, A.F., Escobedo, J., Huang, D.T., Bradbury, C.A., Houston, B.L., Kornblith, L.Z., Kumar, A., Kahn, S.R., Cushman, M., McQuilten, Z., Slutsky, A.S., Kim, K.S., Gordon, A.C., Kirwan, B.A., Brooks, M.M., Higgins, A.M., Lewis, R.J., Lorenzi, E., Berry, S.M., Berry, L.R., Aday, A.W., Al-Beidh, F., Annane, D., Arabi, Y.M., Aryal, D., Kreuziger, L. Baumann, Beane, A., Bhimani, Z., Bihari, S., Billett, H.H., Bond, L., Bonten, M., Brunkhorst, F., Buxton, M., Buzgau, A., Castellucci, L.A., Chekuri, S., Chen, J.T., Cheng, A.C., Chkhikvadze, T., Coiffard, B., Costantini, T.W., Brouwer, S., Derde, L.P.G., Detry, M.A., Duggal, A., Džavík, V., Effron, M.B., Estcourt, L.J., Everett, B.M., Fergusson, D.A., Fitzgerald, M., Fowler, R.A., Galanaud, J.P., Galen, B.T., Gandotra, S., García-Madrona, S., Girard, T.D., Godoy, L.C., Goodman, A.L., Goossens, H., Green, C., Greenstein, Y.Y., Gross, P.L., Hamburg, N.M., Haniffa, R., Hanna, G., Hanna, N., Hegde, S.M., Hendrickson, C.M., Hite, R.D., Hindenburg, A.A., Hope, A.A., Horowitz, J.M., Horvat, C.M., Hudock, K., Hunt, B.J., Husain, M., Hyzy, R.C., Iyer, V.N., Jacobson, J.R., Jayakumar, D., Keller, N.M., Khan, A., Kim, Y., Kindzelski, A.L., King, A.J., Knudson, M.M., Kornblith, A.E., Krishnan, V., Veerdonk, F.L. van de, Schouten, J.A., Pickkers, P., Hochman, J.S., and Zarychanski, R.

Abstract

Item does not contain fulltext, BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagul

Published
2021

11. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., Webb, S.A., Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Murthy, S., Beidh, F.A., Annane, D., Swaidan, L.A., Beane, A., Beasley, R., Berry, L.R., Bhimani, Z., Bonten, M.J.M., Bradbury, C.A., Brunkhorst, F.M., Buxton, M., Buzgau, A., Cheng, A., Jong, Menno de, Detry, M.A., Duffy, E.J., Estcourt, L.J., Fitzgerald, M., Fowler, R., Girard, T.D., Goligher, E.C., Goossens, H., Haniffa, R., Higgins, A.M., Hills, T.E., Horvat, C.M., Huang, D.T., King, A.J., Lamontagne, F., Lawler, P.R., Lewis, R., Linstrum, K., Litton, E., Lorenzi, E., Malakouti, S., McAuley, D.F., McGlothlin, A., McGuinness, S., McVerry, B.J., Montgomery, S.K., Morpeth, S.C., Mouncey, P.R., Orr, K., Parke, R., Parker, J.C., Patanwala, A.E., Rowan, K.M., Santos, M.S., Saunders, C.T., Seymour, C.W., Shankar-Hari, M., Tong, S.Y.C., Turgeon, A.F., Turner, A.M., Veerdonk, F.L. van de, Zarychanski, R., Green, C., Berry, S., Marshall, J.C., McArthur, C., Schouten, J.A., Angus, D.C., and Webb, S.A.

Abstract

Item does not contain fulltext, PURPOSE: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. RESULTS: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). CONCLUSION: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Published
2021

13. The Association between Colonization with Carbapenemase-Producing Enterobacteriaceae and Overall ICU Mortality: An Observational Cohort Study

Author

Dautzenberg, M.J.D. Wekesa, A.N. Gniadkowski, M. Antoniadou, A. Giamarellou, H. Petrikkos, G.L. Skiada, A. Brun-Buisson, C. Bonten, M.J.M. Derde, L.P.G.

Abstract

Objectives: Infections caused by carbapenemase-producing Enterobacteriaceae are increasing worldwide, especially in ICUs, and have been associated with high mortality rates. However, unequivocally demonstrating causality of such infections to death is difficult in critically ill patients because of potential confounding and competing events. Here, we quantified the effects of carbapenemase-producing Enterobacteriaceae carriage on patient outcome in two Greek ICUs with carbapenemase-producing Enterobacteriaceae endemicity. Design: Observational cohort study. Setting: Two ICUs with carbapenemase-producing Enterobacteriaceae endemicity. Patients: Patients admitted to the ICU with an expected length of ICU stay of at least 3 days were included. Interventions: None. Measurements and Main Results: Carbapenemase-producing Enterobacteriaceae colonization was established through screening in perineum swabs obtained at admission and twice weekly and inoculated on chromogenic plates. Detection of carbapenemases was performed phenotypically, with confirmation by polymerase chain reaction. Risk factors for ICU mortality were evaluated using cause-specific hazard ratios and subdistribution hazard ratios, with carbapenemase-producing Enterobacteriaceae colonization as time-varying covariate. One thousand seven patients were included, 36 (3.6%) were colonized at admission, and 96 (9.5%) acquired carbapenemase-producing Enterobacteriaceae colonization during ICU stay, and 301 (29.9%) died in ICU. Of 132 carbapenemase-producing Enterobacteriaceae isolates, 125 (94.7%) were Klebsiella pneumoniae and 74 harbored K. pneumoniae carbapenemase (56.1%), 54 metallo-β-lactamase (40.9%), and four both (3.0%). Carbapenemase-producing Enterobacteriaceae colonization was associated with a statistically significant increase of the subdistribution hazard ratio for ICU mortality (subdistribution hazard ratio = 1.79; 95% CI, 1.31-2.43), not explained by an increased daily hazard of dying (cause-specific hazard ratio for death = 1.02; 95% CI, 0.74-1.41), but by an increased length of stay (cause-specific hazard ratio for discharge alive = 0.73; 95% CI, 0.51-0.94). Other risk factors in the subdistribution hazard model were Acute Physiology and Chronic Health Evaluation II score (subdistribution hazard ratio = 1.13; 95% CI, 1.11-1.15), female gender (subdistribution hazard ratio = 1.29; 95% CI, 1.02-1.62), presence of solid tumor (subdistribution hazard ratio = 1.54; 95% CI, 1.15-2.06), hematopoietic malignancy (subdistribution hazard ratio = 1.61; 95% CI, 1.04-2.51), and immunodeficiency (subdistribution hazard ratio = 1.59; 95% CI, 1.11-2.27). Conclusions: Patients colonized with carbapenemase-producing Enterobacteriaceae have on average a 1.79 times higher hazard of dying in ICU than noncolonized patients, primarily because of an increased length of stay. © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Published
2015

14. MLST reveals potentially high-risk international clones of Enterobacter cloacae

Author

Izdebski, R. Baraniak, A. Herda, M. Fiett, J. Bonten, M.J.M. Carmeli, Y. Goossens, H. Hryniewicz, W. Brun-buisson, C. Gniadkowski, M. Grabowska, A. Nikonorow, E. Derde, L.P.G. Dautzenberg, M.J. Adler, A. Kazma, M. Navon-venezia, S. Malhotra-kumar, S. Lammens, C. Dumpis, U. Giamarellou, H. Muzlovic, I. Nardi, G. Petrikkos, G.L. Stammet, P. Salomon, J. Lawrence, C. Legrand, P. Rossini, A. Salvia, A. Samso, J.V. Fierro, J. Paul, M. Lerman, Y. MOSAR WP2, WP3 WP5 study groups

Subjects
bacterial infections and mycoses
Abstract

Objectives: To perform the first multinational Enterobacter cloacae clonality study, using the MLST scheme newly developed in Japan. Methods: The analysis included 195 rectal carriage E. cloacae isolates resistant to expanded-spectrum cephalosporins (ESCs), collected from patients in 12 hospital units across Europe and Israel. All of the isolates were typed by PFGE and 173 isolates were subjected to MLST. ESC resistance was analysed phenotypically; genes encoding ESBLs and carbapenemases were identified by PCR and sequencing. Results: MLST distinguished 88 STs, which correlated with the PFGE data. PFGE was more discriminatory, producing 129 pulsotypes (169 patterns). Numerous STs were observed in several countries each. The most widespread were ST66, ST78, ST108 and ST114, each having at least 10 isolates from three to five countries, diversified into multiple pulsotypes, with clusters of related isolates in one or more centres. Analysis of the STs against the MLST database revealed several epidemic clonal complexes, such as those with central genotypes ST74 (including ST78) or ST114 (including ST66). ESC resistance was equally related to overexpression of the AmpC cephalosporinase and to ESBL production. Among ESBL producers some spreading subclones were identified, including specific ST66, ST78 and ST114 pulsotypes, associated with CTX-M-15 production. Several isolates produced carbapenemase VIM-1 or KPC-2. Conclusions: Together with the information available in the MLST database, our results suggest that, like Escherichia coli and Klebsiella pneumoniae, E. cloacae harbours clonal lineages of increased epidemic potential that may be associated with resistance spread. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Published
2015

15. Phylogenetic lineages, clones and β-lactamases in an international collection of Klebsiella oxytoca isolates non-susceptible to expanded-spectrum cephalosporins

Author

Izdebski, R. Fiett, J. Urbanowicz, P. Baraniak, A. Derde, L.P.G. Bonten, M.J.M. Carmeli, Y. Goossens, H. Hryniewicz, W. Brun-Buisson, C. Brisse, S. Gniadkowski, M. Herda, M. Dautzenberg, M.J. Adler, A. Kazma, M. Navon-Venezia, S. Malhotra-Kumar, S. Lammens, C. Legrand, P. Chalfine, A. Giamarellou, H. Petrikkos, G.L. Balode, A. Dumpis, U. Stammet, P. Aragăo, I. Esteves, F. Torres Martí, A. Lawrence, C. Salomon, J. Paul, M. Lerman, Y. Rossini, A. Salvia, A. Vidal Samso, J. Fierro, J. MOSAR WP2, WP3 WP5 Study Groups

Subjects
biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Objectives: The objective of this study was to examine Klebsiella oxytoca clonal and phylogenetic diversity, based on an international collection of carriage isolates non-susceptible to expanded-spectrum cephalosporins (ESCs). Methods: The study material comprised 68 rectal carriage K. oxytoca isolates non-susceptible to ESCs recovered in 2008-11 from patients in 14 hospitals across Europe and Israel. ESC resistance was tested phenotypically; genes encoding ESBLs, AmpC cephalosporinases and carbapenemases were amplified and sequenced. The isolates were typed by PFGE and MLST, followed by sequencing of blaOXY genes. Results: MLSTand PFGE distinguished 34 STs and 47 pulsotypes among the isolates, respectively. Six STswere split into several pulsotypes each. Five STs were more prevalent (n=2-9) and occurred in several countries each, including ST2, ST9 and ST141, which belong to a growing international clonal complex (CC), CC2. Four phylogenetic lineages were distinguished, each with another type of chromosomal OXY-type β-lactamase. Three of these, with OXY-1/-5, OXY-2 types and OXY-4, corresponded to previously described phylogroups KoI, KoII and KoIV, respectively. A single isolate from Israel represented a distinct lineage with a newly defined OXY-7 type. The phylogroups showed interesting differences in mechanisms of ESC resistance; KoI strains rarely overexpressed the OXY enzymes but commonly produced ESBLs, whereas KoII strains often were OXY hyperproducers and carried ESBLs much less frequently. AmpCs (DHA-1) and carbapenemases (VIM-1) occurred sporadically. Conclusions: The study confirmed the high genetic diversity of the collection of K. oxytoca ESC-non-susceptible isolates, composed of phylogroups with distinct types of OXY-type β-lactamases, and revealed some STs of broad geographical distribution.

Published
2015

16. Survey of metallo-β-lactamase-producing Enterobacteriaceae colonizing patients in European ICUs and rehabilitation units, 2008-11

Author

Papagiannitsis, C.C. Izdebski, R. Baraniak, A. Fiett, J. Herda, M. Hrabák, J. Derde, L.P.G. Bonten, M.J.M. Carmeli, Y. Goossens, H. Hryniewicz, W. Brun-Buisson, C. Gniadkowski, M. Grabowska, A. Nikonorow, E. Dautzenberg, M.J. Adler, A. Kazma, M. Navon-Venezia, S. Malhotra-Kumar, S. Lammens, C. Legrand, P. Annane, D. Chalfine, A. Joseph, S. Giamarellou, H. Petrikkos, G.L. Nardi, G. Balode, A. Dumpis, U. Stammet, P. Aragâo, I. Esteves, F. Muzlovic, I. Tomic, V. Martí, A.T. Lawrence, C. Salomon, J. Paul, M. Lerman, Y. Rossini, A. Salvia, A. Samso, J.V. Fierro, J. MOSAR WP2, WP3 WP5 study groups

Subjects
biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Objectives: The objective of this study was to perform a multinational survey of patients' colonization by metallo-β-lactamase (MBL)-producing Enterobacteriaceae, including their molecular characterization. Methods: Patients in 18 hospital units across Europe and Israel (n = 17 945) were screened between mid-2008 and mid-2011. MBL-producing isolates were typed by PFGE and MLST. MBL genes were amplified and sequenced within their integrons. Plasmids with MBL genes were analysed by nuclease S1 plus hybridization profiling, mating and transformation assays, and by PCR-based replicon typing. Results: Ninety-one patients in nine centres (six countries), including 62 patients in two Greek ICUs, carried 94 non-duplicate MBL-producing organisms. Klebsiella pneumoniae isolates from Greece dominated (n = 57) and belonged mainly to ST147, ST36 and ST383. All but one of the isolates expressed VIM-1-type MBLs. Isolates of Greek origins produced five enzymes, including new VIM-39, encoded by class 1 integrons of four types. In-e541-like elements prevailed, comprising six variants located on IncR, IncFIIK, IncR + FIIK, IncR + A/C or non-typeable plasmids. The other group were new In4873 and In4863, being the first In416-like elements identified in Greece, which were present on IncA/C or non-typeable plasmids. Isolates from other countries produced only VIM-1 and the major integron was In916, identified in 16 organisms from France, Italy and Spain. In916 was carried by four plasmid types, including IncA/C, IncFIIK and IncHI2. Other integrons included a new element, In3103, in Spain and In110 identified only in Latvia. Conclusions: This study provided fully comparable data on the occurrence and molecular characteristics of VIM-producing Enterobacteriaceae in a group of hospital units across Europe, documenting recent changes in their epidemiology. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Published
2015

17. Controlling antibiotic resistance in the ICU

Author

Derde, L.P.G., Bonten, Marc, and University Utrecht

Subjects
biochemical phenomena, metabolism, and nutrition
Abstract

Patients admitted to intensive care units (ICUs) are frequently colonized with (antibiotic-resistant) bacteria, which may lead to healthcare associated infections. Antimicrobial-resistant bacteria (AMRB), such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and highly-resistant Enterobacteriaceae (HRE) have been increasing worldwide and are associated with delayed appropriate therapy, failure of therapy, and increased morbidity and mortality. The global increase in AMRB necessitates more effective control measures, especially in intensive care units. The main part of this thesis was an international study in 13 ICUs in which we aimed to control antibiotic resistance: the MOSAR-ICU trial. After a 6 months baseline phase, we implemented chlorhexidine body-washing (CBW), combined with hand hygiene improvement (P2) in all ICUs. In phase three (P3), ICUs were additionally randomized to universal screening (PCR-based tests for MRSA and VRE and chromogenic screening for HRE); or to screening for MRSA and VRE with chromagar without HRE screening. In all ICUs, carriers detected were treated with contact precautions. Implementation of a hand hygiene improvement program in these ICUs yielded a rapid and sustained improvement of compliance from 52% (baseline), to 69% (P2) and eventually 77% in P3. Adding feedback of results appeared to increase effectiveness. In P2, there was a 3.6% weekly reduction of MRSA-acquisition. There was a trend towards a similar effect for VRE, but no trend was observed for HRE-acquisition. This suggests that patient-to-patient transmission may not be the dominant acquisition route for HRE in ICUs. The interventions in P3 failed to further reduce acquisition rates. Thus, we recommend that all ICUs implement the hand hygiene improvement program and universal CBW; and do not recommend universal screening to control antibiotic resistance in ICUs. There was some published evidence that CBW is effective in preventing carriage, and possibly bloodstream infections, with MRSA and VRE in ICU patients. There was no evidence (or lack of evidence) that it reduces carriage or infections with HRE. Our study on molecular epidemiology of MRSA revealed that MRSA epidemiology was homogenous within ICUs of the same country, but heterogeneous between countries. LA-MRSA and CA-MRSA were nearly absent in these European ICUs. ForHRE, there waslarge heterogeneity in antibiotic resistance mechanisms and sequence types of E. coli and K. pneumoniae; and a difference in clonality between these two pathogens. If confirmed in other studies, this would demand different control policies for E. coli and K. pneumoniae. Of all patients at risk for HRE acquisition in one French participant, 13% acquired HRE carriage during their ICU stay. No carbapenemase-producing Enterobacteriaceae were detected. Prior exposure to third generation cephalosporins or to a beta-lactam inhibitor (within 3 months of ICU admission) was strongly associated with acquisition. Thus, we would not recommend empirical treatment with carbapenems in this setting. In a sub-study on duration until decolonization, 127 included patients were colonized with AMRB during their first admission and had at least one readmission. The median times until decolonization were 1-2 months for all bacterial types, with no significant differences between the survival curves of the different bacteria. In view of these findings, interventions targeted at recently readmitted patients may be most effective.

Published
2013

19. Controlling antibiotic resistance in the ICU

Author

Infection & Immunity, JC onderzoeksprogramma Infectieziekten, Epidemiology & Health Economics, Intensive Care Centrum, Bonten, Marc, Derde, L.P.G., Infection & Immunity, JC onderzoeksprogramma Infectieziekten, Epidemiology & Health Economics, Intensive Care Centrum, Bonten, Marc, and Derde, L.P.G.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results