Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study

REIPI/ESGBIS/INCREMENT Investigators, REIPI/ESGBIS/INCREMENT Investigators

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0–7 [low mortality score] vs 8–15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0–33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33–0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67–3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34–0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56–2·56]; p=0·62). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

Original languageEnglish
Pages (from-to)726-734
Number of pages9
JournalThe Lancet Infectious Diseases
Volume17
Issue number7
DOIs
Publication statusPublished - 07-2017

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Enterobacteriaceae
Cohort Studies
Retrospective Studies
Mortality
Infection
Therapeutics
carbapenemase
Enterobacteriaceae Infections
Propensity Score

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

Cite this

@article{46f655fcbbdf462cbb2b7599f274b04f,
title = "Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study",
abstract = "Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0–7 [low mortality score] vs 8–15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91{\%}) in this study. 343 (78{\%}) patients received appropriate therapy compared with 94 (22{\%}) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86{\%}] of 437; 291 [85{\%}] of 343 patients receiving appropriate therapy vs 84 [89{\%}] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75{\%}]; 253 [74{\%}] vs 76 [81{\%}]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5{\%}] of 343 patients died vs 57 [60·6{\%}] of 94; absolute difference 22·1{\%} [95{\%} CI 11·0–33·3]; adjusted hazard ratio [HR] 0·45 [95{\%} CI 0·33–0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39{\%}) received combination therapy and 208 (61{\%}) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35{\%}] of 135 vs 85 [41{\%}] of 208; adjusted HR 1·63 [95{\%} CI 0·67–3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48{\%}] of 63 vs 64 [62{\%}] of 103; adjusted HR 0·56 [0·34–0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24{\%}] of 72 vs 21 [20{\%}] of 105; adjusted odds ratio 1·21 [0·56–2·56]; p=0·62). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.",
author = "{REIPI/ESGBIS/INCREMENT Investigators} and {REIPI/ESGBIS/INCREMENT Investigators} and Bel{\'e}n Guti{\'e}rrez-Guti{\'e}rrez and Elena Salamanca and {de Cueto}, Marina and Hsueh, {Po Ren} and Pierluigi Viale and Pa{\~n}o-Pardo, {Jos{\'e} Ram{\'o}n} and Mario Venditti and Mario Tumbarello and George Daikos and Rafael Cant{\'o}n and Yohei Doi and Tuon, {Felipe Francisco} and Ilias Karaiskos and Elena P{\'e}rez-Nadales and Schwaber, {Mitchell J.} and Azap, {{\"O}zlem Kurt} and Maria Souli and Emmanuel Roilides and Spyros Pournaras and Murat Akova and Federico P{\'e}rez and Joaqu{\'i}n Bermejo and Antonio Oliver and Manel Almela and Warren Lowman and Benito Almirante and Bonomo, {Robert A.} and Yehuda Carmeli and Paterson, {David L.} and Alvaro Pascual and Jes{\'u}s Rodr{\'i}guez-Ba{\~n}o and {del Toro}, {M. D.} and J. G{\'a}lvez and M. Falcone and A. Russo and H. Giamarellou and Trecarichi, {E. M.} and Losito, {A. R.} and E. Garc{\'i}a-V{\'a}zquez and A. Hern{\'a}ndez and J. G{\'o}mez and G. Bou and E. Iosifidis and N. Prim and F. Navarro and B. Mirelis and A. Skiada and J. Orig{\"u}en and Juan, {R. San} and M. Fern{\'a}ndez-Ruiz",
year = "2017",
month = "7",
doi = "10.1016/S1473-3099(17)30228-1",
language = "English",
volume = "17",
pages = "726--734",
journal = "The Lancet Infectious Diseases",
issn = "1473-3099",
publisher = "Lancet Publishing Group",
number = "7",

}

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT) : a retrospective cohort study. / REIPI/ESGBIS/INCREMENT Investigators; REIPI/ESGBIS/INCREMENT Investigators.

In: The Lancet Infectious Diseases, Vol. 17, No. 7, 07.2017, p. 726-734.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT)

T2 - a retrospective cohort study

AU - REIPI/ESGBIS/INCREMENT Investigators

AU - REIPI/ESGBIS/INCREMENT Investigators

AU - Gutiérrez-Gutiérrez, Belén

AU - Salamanca, Elena

AU - de Cueto, Marina

AU - Hsueh, Po Ren

AU - Viale, Pierluigi

AU - Paño-Pardo, José Ramón

AU - Venditti, Mario

AU - Tumbarello, Mario

AU - Daikos, George

AU - Cantón, Rafael

AU - Doi, Yohei

AU - Tuon, Felipe Francisco

AU - Karaiskos, Ilias

AU - Pérez-Nadales, Elena

AU - Schwaber, Mitchell J.

AU - Azap, Özlem Kurt

AU - Souli, Maria

AU - Roilides, Emmanuel

AU - Pournaras, Spyros

AU - Akova, Murat

AU - Pérez, Federico

AU - Bermejo, Joaquín

AU - Oliver, Antonio

AU - Almela, Manel

AU - Lowman, Warren

AU - Almirante, Benito

AU - Bonomo, Robert A.

AU - Carmeli, Yehuda

AU - Paterson, David L.

AU - Pascual, Alvaro

AU - Rodríguez-Baño, Jesús

AU - del Toro, M. D.

AU - Gálvez, J.

AU - Falcone, M.

AU - Russo, A.

AU - Giamarellou, H.

AU - Trecarichi, E. M.

AU - Losito, A. R.

AU - García-Vázquez, E.

AU - Hernández, A.

AU - Gómez, J.

AU - Bou, G.

AU - Iosifidis, E.

AU - Prim, N.

AU - Navarro, F.

AU - Mirelis, B.

AU - Skiada, A.

AU - Origüen, J.

AU - Juan, R. San

AU - Fernández-Ruiz, M.

PY - 2017/7

Y1 - 2017/7

N2 - Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0–7 [low mortality score] vs 8–15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0–33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33–0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67–3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34–0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56–2·56]; p=0·62). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

AB - Background The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. Methods In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0–7 [low mortality score] vs 8–15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Findings Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0–33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33–0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67–3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34–0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56–2·56]; p=0·62). Interpretation Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Funding Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

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