Why carry out this study?
|
Mortality is higher in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) than in patient with carbapenem-susceptible K. pneumonia (CSKP) BSI. |
This study tried to provide an insight into the reasons underlying this mortality difference exploiting the advantages of an individual patient data (IPD) meta-analysis. |
What was learned from the study?
|
BSI by CRKP is associated with a worse outcome compared with CSKP BSI even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. |
This study confirmed the increased mortality associated with resistance to carbapenems in KP BSI, at least in a scenario of colistin-based therapy. |
Further studies are needed to address the role of virulence and the impact of novel drugs anti-CRKP. |
Digital Features
Introduction
Methods
Eligibility Criteria
Setting | Cohort and case-control studies in adult populations hospitalized in acute-care hospitals or intensive care units |
---|---|
Inclusion criteria | Availability of mortality data for patients with CRKP and CSKP BSI Availability of patient-level information regarding: sex, age, Charlson Comorbidity Index, strain (CRKP versus CSKP), administered antibiotics (empirical and targeted) and their activity according to AST Studies published after 1994 |
Exclusion criteria | Studies involving < 10 patients per group Studies without a control group (e.g., only CRKP or only CSKP cases) or with an uninfected control group (e.g., colonized patients) |
Note on CSKP selection | In case of several comparison groups, the one with the worst pattern of resistance regarding CSKP (i.e., ESBL producers) was selected |
Note on carbapenem-resistance definition | CDC criteria were adopted: non-susceptibility to ≥ 1 carbapenem or expression of a carbapenemase; therefore, strains carbapenemase-producing but susceptible to the drug class were considered CRKP |
Literature Search
Data Extraction and Quality Assessment
Data Synthesis and Analysis
Outcomes
Ethics
Results
Overview of Data
First author (year) [Ref.] | Design/time/ country | Setting | Carbapenem resistance | Control | Mortality outcomesa | Included patients (CRKP vs. CSKP, n)b | Notes |
---|---|---|---|---|---|---|---|
Daikos (2009) [16] | Prospective cohort, 2004–2006, Greece | Multicenter (3 sites), 33% ICU | PCR pos for VIM (100%) (21% carbapenem-R) | PCR neg for VIM (all carbapenem-S) | 14 day | 56 vs. 37 | 69 cases missing at random (out of 162 in the original work, 11 vs. 58). Incomplete information about therapy as for 2 out of 93 provided cases (2 vs. 0) |
Mouloudi (2010) [17] | Case control, 2007–2008, Greece | Single center, 100% ICU | Imipenem-non-S AND PCR pos for KPC (51%) or VIM (49%) | Imipenem-S, no KPC or VIM, 77% ESBL | In hospital, infection related | 29 vs. 30 | No data provided about Charlson Index score |
Ben David (2011) [18] | Retrospective cohort, 2006, Israel | Single center, 42% ICU | Carbapenem-R and PCR pos for KPC | Carbapenem-S and ESBL producer | In hospital, infection related | 37 vs. 60 | 10 cases missing at random (out of 107 in the original work, 5 vs. 5) |
Tabah (2012) [19] | Prospective cohort, 2010–2011, 24 countries | Multicenter (162 sites), 100% ICU | Carbapenem-R, no PCR | Carbapenem-S | 28 day | 59 vs. 78 | 13 cases missing at random (out of 150 in the original work, 1 vs. 12) |
Hussein (2013) [20] | Case-control, 2006–2008, Israel | Single center | R to imipenem | S to imipenem | 30 day | 103 vs. 214 | All patient-level data provided |
Ghafur (2014) [21] | Retrospective cohort, 2012, India | Single center, 44% neutropenic | R to meropenem | S to meropenem | 28 day | 16 vs. 15 | 8 cases missing at random (out of 39 in the original work, 1 vs. 7) |
Girometti (2014) [22] | Retrospective cohort, 2010–2012, Italy | Single center, 19% ICU | Non-S to carbapenems and PCR pos for KPC (100%) | S to carbapenems ESBL producer | 30 day | 93 vs. 49 | All patient-level data provided (slightly deviating from those published – 1 additional CRKP case) |
Alicino (2015) [23] | Retrospective cohort, 2007–2014, Italy | Single center | R to erta-, imi- or meropenem, no PCR | Non-R to carbapenems | 30 day | 342 vs. 145 | 24 cases missing at random (out of 511 in the original work, 7 vs. 17). Incomplete information about therapy as for 42 out of 487 provided cases (30 vs. 12) |
Gomez-Simmonds (2015) [24] | Retrospective cohort, 2012–2013, USA | Single center, 62% ICU | Non-S to any carbapenem (100% KPC) | Carbapenem-S ceftriaxone-R | In hospital, 30 day | 29 vs. 24 | All patient-level data provided |
Trecarichi (2015) [25]c | Prospective cohort, 2009–2012, Italy | Multicenter, 92% neutropenic | Carbapenem-R, no PCR | Carbapenem-S | 21 day | 149 vs. 115c | 28 versus 15 cases in the original workc |
Vardakas (2015) [26] | Retrospective cohort, 2006–2009, Greece | Single center, 100% ICU | R to imi- or meropenem no PCR | S to imi- and meropenem | ICU related | 52 vs. 13 | All patient-level data provided |
Trecarichi (2016) [27]c | Prospective cohort, 2010–2014, Italy | Multicenter, 83% neutropenic | Carbapenem-R, no PCR | Carbapenem-S | 21 day | 149 vs. 115c | 161 versus 117 cases in the original workc |
Villegas (2016) [28] | Prospective cohort, 2013–2014, Latin America | Multicenter (11 centers) | R to ertapenem AND R to 1 other carbapenem and PCR pos for KPC | ESBL-producer matched (1:2) by year, age, and gender | 28 day, infection related | 35 vs. 66 | 12 cases missing at random (out of 113 in the original work, 4 vs. 8). No data provided about age, gender and Charlson Index score. Incomplete information about therapy as for 5 out of 101 provided cases (0 vs. 5) |
Veeraraghavan (2017) [29] | Retrospective cohort, 2015–2016, India | Single center | R to meropenem | S to carbapenems ESBL producer | In hospital | 93 vs. 13 | 7 cases missing at random (out of 113, 6 vs. 1). Incomplete information about therapy as for 2 out of 106 provided cases (0 vs. 2) |
Variable | CRKP group (n = 1093) | CSKP group (n = 859) | ||||
---|---|---|---|---|---|---|
Valid sample | Missing | Measure | Valid sample | Missing | Measure | |
Age, mean years (SD) | 1058 | 35 | 59.7 (18.3) | 793 | 66 | 60.4 (18.4) |
Sex (male, %) | 1058 | 35 | 686 (64.8) | 793 | 66 | 472 (59.5) |
Charlson Comorbidity Index, median (IQR) | 1029 | 64 | 4 (2–5) | 763 | 96 | 3 (2–5) |
Active empirical therapy (%) | 1061 | 32 | 353 (33.3)a | 840 | 19 | 495 (58.9)a |
Active empirical therapy based on 1 drug, alone or in combination with inactive agents (%) | 345 | 8 (out of 353) | 220 (63.8) | 483 | 12 (out of 495) | 354 (73.3) |
Most frequent active drug when only one empirical agent was active (n, %) | 220 | Colistin (122, 54.5) | 483 | Carbapenem agentb (139, 39.2) | ||
Most frequent inactive empirical therapy | 708 | No therapy (260, 36.7) | 840 | No therapy (142, 16.9) | ||
No. of active empirical antibiotics, median (IQR) | 352 | 1 (out of 353) | 1 (1–2) | 480 | 15 (out of 495) | 1 (1–2) |
Active targeted therapy (%) | 896 | 60 | 706/896 (78.8) | 781 | 8 | 678/781 (86.8) |
Active targeted therapy based on 1 drug, alone or in combination with inactive agents (%) | 896 | 364 (40.6) | 781 | 543 (69.5) | ||
Most frequent active drug when only one targeted agent was active (n, %) | 364 | Colistin (225, 61.8) | 543 | Carbapenem agentc (309, 56.9) | ||
No. of active targeted antibiotics, median (IQR) | 896 | 2 (1–2) | 781 | 1 (1–1) | ||
Mortality (%) | 1093 | 466 (42.6) | 859 | 231 (26.9) |
Primary Analyses
Secondary Analyses
Outcome: mortality | uOR (95% CI) [I2] | aOR (95% CI) [I2] |
---|---|---|
Targeted monotherapy vs. targeted combination regimens | 0.91 (0.58–1.43) [36.9%] | 0.78 (0.43–1.45) [53.3%] (Suppl. Figure 4) |
Targeted colistin plus another active drug vs. colistin alone | 1.13 (0.70–1.83) [9%] | 1.24 (0.58–2.66) [43.3%] (Suppl. Figure 5) |
Targeted colistin plus an active aminoglycoside agent vs. colistin alone | 0.74 (0.34–1.61) [10%] | 0.63 (0.26–1.56) [47%] (Suppl. Figure 6) |
Additional carbapenem to a targeted regimen vs. active regimens without carbapenem agents | 1.40 (0.26–7.66) [73%] | 1.37 (0.20–9.38) [71%] (Suppl. Figure 7) |