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Published in: Infectious Diseases and Therapy 1/2021

Open Access 01-03-2021 | Carbapenem Antibiotic | Original Research

The Impact of Carbapenem Resistance on Mortality in Patients With Klebsiella Pneumoniae Bloodstream Infection: An Individual Patient Data Meta-Analysis of 1952 Patients

Authors: Alberto E. Maraolo, Silvia Corcione, Adriano Grossi, Alessio Signori, Cristiano Alicino, Khetam Hussein, Enrico M. Trecarichi, Pierluigi Viale, Jean-François Timsit, Balaji Veeraraghavan, Maria V. Villegas, Galia Rahav, George L. Daikos, Konstantinos Z. Vardakas, Emmanuel Roilides, Anne-Catrin Uhlemann, Abdul K. Ghafur, Simone Mornese Pinna, Matteo Bassetti, Philipp P. Kohler, Daniele R. Giacobbe

Published in: Infectious Diseases and Therapy | Issue 1/2021

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Abstract

Introduction

Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined.

Methods

We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256).

Results

IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56–3.04; I2 = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24–2.47; I2 = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70–4.16; I2 = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36–3.59; I2 = 58%).

Conclusion

Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.
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Literature
1.
go back to reference Suay-García B, Pérez-Gracia MT. Present and future of carbapenem-resistant enterobacteriaceae (CRE) Infections. Antibiotics (Basel). 2019;8:E122.CrossRef Suay-García B, Pérez-Gracia MT. Present and future of carbapenem-resistant enterobacteriaceae (CRE) Infections. Antibiotics (Basel). 2019;8:E122.CrossRef
2.
go back to reference Bartsch SM, McKinnell JA, Mueller LE, et al. Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect. 2017;23(48):e9-48.e16. Bartsch SM, McKinnell JA, Mueller LE, et al. Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect. 2017;23(48):e9-48.e16.
3.
go back to reference Stewardson AJ, Marimuthu K, Sengupta S, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19:601–10.CrossRef Stewardson AJ, Marimuthu K, Sengupta S, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19:601–10.CrossRef
4.
go back to reference Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:318–27.CrossRef Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18:318–27.CrossRef
5.
go back to reference Li Y, Li J, Hu T, et al. Five-year change of prevalence and risk factors for infection and mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in a tertiary hospital in North China. Antimicrob Resist Infect Control. 2020;9:79.CrossRef Li Y, Li J, Hu T, et al. Five-year change of prevalence and risk factors for infection and mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in a tertiary hospital in North China. Antimicrob Resist Infect Control. 2020;9:79.CrossRef
6.
go back to reference Martin A, Fahrbach K, Zhao Q, et al. Association Between Carbapenem Resistance and Mortality Among Adult, Hospitalized Patients With Serious Infections Due to Enterobacteriaceae: Results of a Systematic Literature Review and Meta-analysis. Open Forum Infect Dis. 2018; 5: ofy150 Martin A, Fahrbach K, Zhao Q, et al. Association Between Carbapenem Resistance and Mortality Among Adult, Hospitalized Patients With Serious Infections Due to Enterobacteriaceae: Results of a Systematic Literature Review and Meta-analysis. Open Forum Infect Dis. 2018; 5: ofy150
7.
go back to reference Kohler PP, Volling C, Green K, et al. Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella Pneumoniae Bacteremia: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38:1319–28.CrossRef Kohler PP, Volling C, Green K, et al. Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella Pneumoniae Bacteremia: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2017;38:1319–28.CrossRef
8.
go back to reference Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ. 2010;340:c221.CrossRef Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ. 2010;340:c221.CrossRef
9.
go back to reference Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313:1657–65.CrossRef Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313:1657–65.CrossRef
11.
go back to reference Burke DL, Ensor J, Riley RD. Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ. Stat Med. 2017;36:855–75.CrossRef Burke DL, Ensor J, Riley RD. Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ. Stat Med. 2017;36:855–75.CrossRef
12.
go back to reference DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRef DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRef
13.
go back to reference Daikos GL, Petrikkos P, Psichogiou M, et al. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009;53:1868–73.CrossRef Daikos GL, Petrikkos P, Psichogiou M, et al. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009;53:1868–73.CrossRef
14.
go back to reference Mouloudi E, Protonotariou E, Zagorianou A, et al. Bloodstream infections caused by metallo-beta-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol 2010 ;31: 1250–56. Mouloudi E, Protonotariou E, Zagorianou A, et al. Bloodstream infections caused by metallo-beta-lactamase/Klebsiella pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit patients in Greece: risk factors for infection and impact of type of resistance on outcomes. Infect Control Hosp Epidemiol 2010 ;31: 1250–56.
15.
go back to reference Ben-David D, Kordevani R, Keller N, et al. Outcome of carbapenem resistant Klebsiella pneumoniae bloodstream infections. Clin Microbiol Infect. 2012;18:54–60.CrossRef Ben-David D, Kordevani R, Keller N, et al. Outcome of carbapenem resistant Klebsiella pneumoniae bloodstream infections. Clin Microbiol Infect. 2012;18:54–60.CrossRef
16.
go back to reference Tabah A, Koulenti D, Laupland K, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med. 2012;38:1930–45.CrossRef Tabah A, Koulenti D, Laupland K, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med. 2012;38:1930–45.CrossRef
17.
go back to reference Hussein K, Raz-Pasteur A, Finkelstein R, et al. Impact of carbapenem resistance on the outcome of patients’ hospital-acquired bacteraemia caused by Klebsiella pneumoniae. J Hosp Infect. 2013;83:307–13.CrossRef Hussein K, Raz-Pasteur A, Finkelstein R, et al. Impact of carbapenem resistance on the outcome of patients’ hospital-acquired bacteraemia caused by Klebsiella pneumoniae. J Hosp Infect. 2013;83:307–13.CrossRef
18.
go back to reference Ghafur AK, Vidyalakshmi PR, Kannaian P, et al. Clinical study of carbapenem sensitive and resistant Gram-negative bacteremia in neutropenic and nonneutropenic patients: The first series from India. Indian J Cancer. 2014;51:453–5.CrossRef Ghafur AK, Vidyalakshmi PR, Kannaian P, et al. Clinical study of carbapenem sensitive and resistant Gram-negative bacteremia in neutropenic and nonneutropenic patients: The first series from India. Indian J Cancer. 2014;51:453–5.CrossRef
19.
go back to reference Girometti N, Lewis RE, Giannella M, et al. Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine (Baltimore). 2014;93:298–309.CrossRef Girometti N, Lewis RE, Giannella M, et al. Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine (Baltimore). 2014;93:298–309.CrossRef
20.
go back to reference Alicino C, Giacobbe DR, Orsi A, et al. Trends in the annual incidence of carbapenem-resistant Klebsiella pneumoniae bloodstream infections: a 8-year retrospective study in a large teaching hospital in northern Italy. BMC Infect Dis. 2015;15:415.CrossRef Alicino C, Giacobbe DR, Orsi A, et al. Trends in the annual incidence of carbapenem-resistant Klebsiella pneumoniae bloodstream infections: a 8-year retrospective study in a large teaching hospital in northern Italy. BMC Infect Dis. 2015;15:415.CrossRef
21.
go back to reference Gomez-Simmonds A, Greenman M, Sullivan SB, et al. Population structure of Klebsiella pneumoniae causing bloodstream infections at a New York City tertiary care hospital: diversification of multidrug-resistant isolates. J Clin Microbiol. 2015;53:2060–7.CrossRef Gomez-Simmonds A, Greenman M, Sullivan SB, et al. Population structure of Klebsiella pneumoniae causing bloodstream infections at a New York City tertiary care hospital: diversification of multidrug-resistant isolates. J Clin Microbiol. 2015;53:2060–7.CrossRef
22.
go back to reference Trecarichi EM, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect. 2015;21:337–43.CrossRef Trecarichi EM, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect. 2015;21:337–43.CrossRef
23.
go back to reference Vardakas KZ, Matthaiou DK, Falagas ME, et al. Characteristics, risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae infections in the intensive care unit. J Infect. 2015;70:592–9.CrossRef Vardakas KZ, Matthaiou DK, Falagas ME, et al. Characteristics, risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae infections in the intensive care unit. J Infect. 2015;70:592–9.CrossRef
24.
go back to reference Trecarichi EM, Pagano L, Martino B, et al. Bloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey. Am J Hematol. 2016;91:1076–81.CrossRef Trecarichi EM, Pagano L, Martino B, et al. Bloodstream infections caused by Klebsiella pneumoniae in onco-hematological patients: clinical impact of carbapenem resistance in a multicentre prospective survey. Am J Hematol. 2016;91:1076–81.CrossRef
25.
go back to reference Villegas MV, Pallares CJ, Escandon-Vargas K, et al. Characterization and clinical impact of bloodstream infection caused by carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS ONE. 2016;11:e0154092.CrossRef Villegas MV, Pallares CJ, Escandon-Vargas K, et al. Characterization and clinical impact of bloodstream infection caused by carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS ONE. 2016;11:e0154092.CrossRef
26.
go back to reference Veeraraghavan B, Shankar C, Karunasree S, et al. Carbapenem resistant Klebsiella pneumoniae isolated from bloodstream infection: Indian experience. Pathog Glob Health. 2017;111:240–6.CrossRef Veeraraghavan B, Shankar C, Karunasree S, et al. Carbapenem resistant Klebsiella pneumoniae isolated from bloodstream infection: Indian experience. Pathog Glob Health. 2017;111:240–6.CrossRef
27.
go back to reference Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80:629–61.CrossRef Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80:629–61.CrossRef
28.
go back to reference Iredell J, Brown J, Tagg K. Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications. BMJ. 2016;352:h6420.CrossRef Iredell J, Brown J, Tagg K. Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications. BMJ. 2016;352:h6420.CrossRef
29.
go back to reference Cassini A, Högberg LD, Plachouras D, et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis. 2019;19:56–66.CrossRef Cassini A, Högberg LD, Plachouras D, et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis. 2019;19:56–66.CrossRef
30.
go back to reference Vardakas KZ, Rafailidis PI, Konstantelias AA, et al. Predictors of mortality in patients with infections due to multi-drug resistant gram-negative bacteria: the study, the patient, the bug or the drug? J Infect. 2013;66:401–14.CrossRef Vardakas KZ, Rafailidis PI, Konstantelias AA, et al. Predictors of mortality in patients with infections due to multi-drug resistant gram-negative bacteria: the study, the patient, the bug or the drug? J Infect. 2013;66:401–14.CrossRef
31.
go back to reference Viale P, Giannella M, Lewis R, et al. Predictors of mortality in multidrug-resistant Klebsiella pneumoniae bloodstream infections. Expert Rev Anti Infect Ther. 2013;11:1053–63.CrossRef Viale P, Giannella M, Lewis R, et al. Predictors of mortality in multidrug-resistant Klebsiella pneumoniae bloodstream infections. Expert Rev Anti Infect Ther. 2013;11:1053–63.CrossRef
32.
go back to reference Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of Carbapenem-Resistant Klebsiella pneumoniae Acquisition among Hospitalized Adults and Effect of Acquisition on Mortality. Antimicrob Agents Chemother. 2008; 1028–1033. Schwaber MJ, Klarfeld-Lidji S, Navon-Venezia S, Schwartz D, Leavitt A, Carmeli Y. Predictors of Carbapenem-Resistant Klebsiella pneumoniae Acquisition among Hospitalized Adults and Effect of Acquisition on Mortality. Antimicrob Agents Chemother. 2008; 1028–1033.
33.
go back to reference Tamma PD, Goodman KE, Harris AD, et al. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant enterobacteriaceae bacteremia. Clin Infect Dis. 2017;64:257–64.CrossRef Tamma PD, Goodman KE, Harris AD, et al. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant enterobacteriaceae bacteremia. Clin Infect Dis. 2017;64:257–64.CrossRef
34.
go back to reference Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the american college of clinical pharmacy (ACCP), European society of clinical microbiology and infectious diseases (ESCMID), infectious diseases society of America (IDSA), international society for anti-infective pharmacology (ISAP), society of critical care medicine (SCCM), and society of infectious diseases pharmacists (SIDP). Pharmacotherapy. 2019;39:10–39.CrossRef Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the american college of clinical pharmacy (ACCP), European society of clinical microbiology and infectious diseases (ESCMID), infectious diseases society of America (IDSA), international society for anti-infective pharmacology (ISAP), society of critical care medicine (SCCM), and society of infectious diseases pharmacists (SIDP). Pharmacotherapy. 2019;39:10–39.CrossRef
35.
go back to reference Giacobbe DR, Saffioti C, Losito AR, et al. Use of colistin in adult patients: a cross-sectional study. J Glob Antimicrob Resist. 2020;20:43–4.CrossRef Giacobbe DR, Saffioti C, Losito AR, et al. Use of colistin in adult patients: a cross-sectional study. J Glob Antimicrob Resist. 2020;20:43–4.CrossRef
36.
go back to reference Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The, “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front Public Health. 2019;7:151.CrossRef Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The, “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front Public Health. 2019;7:151.CrossRef
37.
go back to reference Paul M, Leibovici L. Observational studies examining patient management in infectious diseases. Clin Microbiol Infect. 2017;23:127–8.CrossRef Paul M, Leibovici L. Observational studies examining patient management in infectious diseases. Clin Microbiol Infect. 2017;23:127–8.CrossRef
38.
go back to reference Giacobbe DR, Maraolo AE, Viscoli C. Pitfalls of defining combination therapy for carbapenem-resistant Enterobacteriaceae in observational studies. Eur J Clin Microbiol Infect Dis. 2017;36:1707–9.CrossRef Giacobbe DR, Maraolo AE, Viscoli C. Pitfalls of defining combination therapy for carbapenem-resistant Enterobacteriaceae in observational studies. Eur J Clin Microbiol Infect Dis. 2017;36:1707–9.CrossRef
Metadata
Title
The Impact of Carbapenem Resistance on Mortality in Patients With Klebsiella Pneumoniae Bloodstream Infection: An Individual Patient Data Meta-Analysis of 1952 Patients
Authors
Alberto E. Maraolo
Silvia Corcione
Adriano Grossi
Alessio Signori
Cristiano Alicino
Khetam Hussein
Enrico M. Trecarichi
Pierluigi Viale
Jean-François Timsit
Balaji Veeraraghavan
Maria V. Villegas
Galia Rahav
George L. Daikos
Konstantinos Z. Vardakas
Emmanuel Roilides
Anne-Catrin Uhlemann
Abdul K. Ghafur
Simone Mornese Pinna
Matteo Bassetti
Philipp P. Kohler
Daniele R. Giacobbe
Publication date
01-03-2021
Publisher
Springer Healthcare
Published in
Infectious Diseases and Therapy / Issue 1/2021
Print ISSN: 2193-8229
Electronic ISSN: 2193-6382
DOI
https://doi.org/10.1007/s40121-021-00408-8

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