Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae

TLDR: It is suggested that patients infected with CRKP have higher mortality than those infected with CSKP, especially in association with BSI, ICU admission, or SOT, and that strict infection control measures and new antibiotics are required to protect againstCRKP infection.

Abstract: Carbapenem resistant K. pneumoniae (CRKP) has aroused widespread attention owing to its very limited therapeutic options, and this strain has increased rapidly in recent years. Although it is accepted that drug resistance is associated with increased mortality in general, but some other studies found no such relationship. To estimate mortality of patients infected with CRKP in general and analyze factors for mortality of this infection, thus, we conducted this systematic review and meta-analysis. A systematic literature review of relevant studies published until December 2015 was conducted. We selected and assessed articles reporting mortality of patients infected with CRKP. Pooled mortality was 42.14% among 2462 patients infected with CRKP versus 21.16% in those infected with carbapenem-susceptible K. pneumoniae (CSKP). The mortality of patients with bloodstream infection (BSI) or urinary tract infection was 54.30 and 13.52%, respectively, and 48.9 and 43.13% in patients admitted to the intensive care unit (ICU) or who underwent solid organ transplantation (SOT). Mortality was 47.66% in patients infected with K. pneumoniae carbapenemase-producing K. pneumoniae and 46.71% in those infected with VIM-producing K. pneumoniae. Geographically, mortality reported in studies from North America, South America, Europe, and Asia was 33.24, 46.71, 50.06, and 44.82%, respectively. Our study suggests that patients infected with CRKP have higher mortality than those infected with CSKP, especially in association with BSI, ICU admission, or SOT. We also considered that patients’ survival has a close relationship with their physical condition. Our results imply that attention should be paid to CRKP infection, and that strict infection control measures and new antibiotics are required to protect against CRKP infection.

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Xu
et al. Ann Clin Microbiol Antimicrob (2017) 16:18
DOI 10.1186/s12941-017-0191-3
RESEARCH
Systematic review andmeta-analysis
ofmortality ofpatients infected
withcarbapenem-resistant Klebsiella
pneumoniae
Liangfei Xu, Xiaoxi Sun and Xiaoling Ma
*
Abstract
Purpose: Carbapenem resistant K. pneumoniae (CRKP) has aroused widespread attention owing to its very limited
therapeutic options, and this strain has increased rapidly in recent years. Although it is accepted that drug resistance
is associated with increased mortality in general, but some other studies found no such relationship. To estimate mor-
tality of patients infected with CRKP in general and analyze factors for mortality of this infection, thus, we conducted
this systematic review and meta-analysis.
Methods: A systematic literature review of relevant studies published until December 2015 was conducted. We
selected and assessed articles reporting mortality of patients infected with CRKP.
Results: Pooled mortality was 42.14% among 2462 patients infected with CRKP versus 21.16% in those infected with
carbapenem-susceptible K. pneumoniae (CSKP). The mortality of patients with bloodstream infection (BSI) or urinary
tract infection was 54.30 and 13.52%, respectively, and 48.9 and 43.13% in patients admitted to the intensive care unit
(ICU) or who underwent solid organ transplantation (SOT). Mortality was 47.66% in patients infected with K. pneu-
moniae carbapenemase-producing K. pneumoniae and 46.71% in those infected with VIM-producing K. pneumoniae.
Geographically, mortality reported in studies from North America, South America, Europe, and Asia was 33.24, 46.71,
50.06, and 44.82%, respectively.
Conclusions: Our study suggests that patients infected with CRKP have higher mortality than those infected with
CSKP, especially in association with BSI, ICU admission, or SOT. We also considered that patients’ survival has a close
relationship with their physical condition. Our results imply that attention should be paid to CRKP infection, and that
strict infection control measures and new antibiotics are required to protect against CRKP infection.
Keywords: CRKP, Carbapenem-resistant, K. pneumoniae, Mortality
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Background
It is well known that Klebsiella pneumoniae is ubiquitous
in nature, one of the most relevant opportunistic patho
-
gens, and causes various human infections such as blood-
stream infection (BSI), urinary tract infection (UTI),
surgical-site infection, and pneumonia [
1–3]. Resist
-
ance can develop in K. pneumoniae isolates, notably
producing extended-spectrum β-lactamases (ESBLs).
ESBL-producing strains of K. pneumoniae are currently
found throughout the world and have caused numerous
outbreaks of infection [
4, 5]. Carbapenems represent the
first-line therapy for severe infection by ESBL-produc
-
ing K. pneumoniae [
6]. However, since Yigit etal. [7, 8]
reported the first K. pneumoniae carbapenem (KPC)-
producing K. pneumoniae isolate in North Carolina in
1996, carbapenem-resistant strains have increased rap
-
idly, rising from 1.6 to 10.4% associated with central line
blood-stream infections between 2001 and 2011 in the
Open Access
Annals of Clinical Microbiology
and Antimicrobials
*Correspondence: xiaolingma@126.com
Department of Laboratory Medicine, Anhui Provincial Hospital, Anhui
Medical University, Hefei 230001, Anhui, China

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et al. Ann Clin Microbiol Antimicrob (2017) 16:18
United States, and have aroused widespread attention,
presenting a challenge because the antimicrobial treat
-
ment options remain very restricted [
7, 9].
Carbapenem-resistant K. pneumoniae (CRKP) deacti
-
vates the carbapenems through two main mechanisms:
(1) acquisition of carbapenemase genes that encode for
enzymes capable of hydrolyzing carbapenems—the three
most important carbapenemase types being KPC-type
enzymes, metallo-β-lactamases (VIM, IMP, NDM), and
OXA-48 type enzymes; and (2) reduction in the accumu
-
lation of antibiotics by a quantitative and/or qualitative
deficiency of porin expression in combination with over
-
expression of β-lactamases that possess weak affinity for
carbapenems [
10].
Most researchers reported higher mortality rates
among persons infected with CRKP isolates [
11–30]
while others reported contrary results [
31, 32]. In recent
years, many studies from single medical centers or indi
-
vidual countries have reported mortality rates in patients
infected with CRKP, but until now there has been no
systematic review focusing on mortality resulting from
carbapenem-resistant infections in general. Although in a
recent meta-analysis Falagas etal. [
33] reported a higher
all-cause mortality among patients infected with carbap
-
enem-resistant Enterobacteriaceae than in those with
carbapenem-susceptible infections, but their research
included only nine studies. Considering this scenario,
we conducted a systematic review and meta-analysis to
estimate the mortality of patients infected with CRKP,
and analyzed mortality resulting from multiple infection
types and patients conditions.
Methods
Search strategy
Two independent examiners (LF.X. and XX.S.) searched
entries in the PubMed and EMBASE databases from their
inception until December 22, 2015 to identify potentially
relevant studies. e search terms included “Klebsiella
pneumoniae” AND resistance AND (“carbapenem” OR
“imipenem” OR “meropenem” OR “ertapenem”). e lan
-
guage was restricted to English.
Inclusion andexclusion criteria
Studies were considered in accordance with inclusion
criteria if articles reported mortality of patients infected
with CRKP. Research that focused on children, did not
differentiate mortality between infection and coloniza
-
tion, did not define the strains that were carbapenem
resistant, and did not present the exact death toll were
excluded. In this analysis, carbapenem resistance was
defined as resistance to carbapenems such as imipenem,
meropenem, and ertapenem, irrespective of susceptibility
to other antibiotics.
Assessment ofstudy quality
e articles were assessed for quality of the cohort or
case–control studies included in the systematic analysis
according to the Newcastle-Ottawa scale (NOS) score
[
34], ranging from 0 to 9. Studies with a NOS score of 5
or greater were included in this analysis.
Data extraction
Two independent investigators (LF.X. and XX.S.)
extracted information from eligible articles. Divergences
were solved by discussion and consultation of the rel
-
evant literature. e information extracted from original
publications included title, first author, year of publica
-
tion and experiment, type of study, sample size, char-
acteristics of the study population (mean age, sex, type
of infection, mean severity of underlying disease), and
crude mortality rates in patients infected with CRKP and
carbapenem-susceptible K. pneumoniae (CSKP). If arti
-
cles reported mortality from both infection and coloniza-
tion, we extracted information only regarding infections.
Statistical analysis
We calculated the pooled odds ratio (OR) and 95% con-
fidence interval (CI) by comparing crude mortality in
patients with CRKP with that in patients with CSKP.
Between-study heterogeneity was assessed by the χ
2
test
(p < 0.10 was selected to indicate the presence of het
-
erogeneity, in which case a random-effects model was
adopted; otherwise a fixed-effects model was applied)
and I
2
test (to assess the degree of heterogeneity) [
35, 36].
We then calculated pooled rates of mortality in patients
infected with CRKP, and stratified analyses with respect
to geographic location, infection types, carbapenemase
types, and patients conditions performed. Freeman–
Tukey arcsine transformations were used to stabilize the
variances, and after the meta-analysis we transformed
the summary estimates and the CI boundaries back to
proportions using the sine function [
37]. We used Stata
version 12.0 software for all statistical calculations.
Results
Results ofthe systematic literature search
We identified and screened 3168 articles. After exclusion
by title and abstract, the remaining 87 articles were sub
-
jected to full-text assessment for eligibility. Among these
articles, 12 were duplicates, seven did not differentiate
between infection- and colonization-related mortality,
and six did not report valid data. Ultimately, 62 studies
were analyzed based on the inclusion and exclusion cri
-
teria (Fig.
1).
e basic characteristics of these 62 studies are sum
-
marized in Table
1 [11–32, 38–77]. ese articles were
published from 1999 to 2015 and the sample size varied

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et al. Ann Clin Microbiol Antimicrob (2017) 16:18
across studies, ranging from 7 to 1022. e total number
of patients in this systematic review was 4701, of whom
2462 had CRKP infection and the remainder CSKP infec
-
tion. Among these patients, the reported death was 1018
among the CRKP patients and 398 among the CSKP
patients. In the pooled analysis, the overall mortality
was 42.14% (95% CI 37.06–47.31) in patients infected
with CRKP and 21.16% (95% CI 16.07–26.79) in CSKP
patients (Table
2).
Comparison ofmortality inCRKP andCSKP patients
Among the included articles, 22 compared mortality
between patients infected with CRKP and CSKP. e
summary estimate of these studies from the random-
effects model suggested that patients with CRKP had a
significantly higher mortality than those with CSKP in
the univariate analysis (pooled crude OR 2.80; 95% CI
2.15–3.65) with a moderate heterogeneity I
2
of 33.9%
(p=0.031) (Fig.
2).
Mortality inmultiple patient conditions
As shown in Table
2, 722 patients had BSI and 284 had
UTI, 479 were in an intensive care unit (ICU), and 362
underwent solid organ transplantation (SOT). In the
pooled analysis, the mortality was 54.30% (95% CI
47.51–61.02), 13.52% (95% CI 7.50–20.92), 48.9% (95% CI
44.47–53.46), and 43.13% (95% CI 32.40–54.16) in BSI,
UTI, ICU-admission, and SOT patients, respectively.
Mortality inmultiple carbapenemase types
In this subgroup analysis, we mainly analyzed the mortal-
ity of patients infected with KPC-producing K. pneumo-
niae and VIM-producing K. pneumoniae. In the articles
included, 302 patients were infected with KPC-producing
K. pneumoniae and 73 were infected with VIM-produc
-
ing K. pneumoniae. e mortality among these two types
of carbapenemases was 47.66% (95% CI 38.61–56.79) and
46.71% (95% CI 35.81–57.73), respectively (Table
2).
Mortality indierent geographic locations
Twenty-three studies were carried out in North America,
eight in South America, twenty-one in Europe, and ten
in Asia. e rate of mortality was 33.24% (95% CI 25.08–
42.00) of 980 patients in North America, 46.71% (95%
CI 39.83–53.66) of 191 in South America, 50.06% (95%
CI 41.45–58.62) of 860 in Europe, and 44.82% (95% CI
37.83–51.91) of 431 in Asia (Table
2).
Discussion
ESBL-producing K. pneumoniae as an opportunistic
pathogen is becoming more challenging to treat because
of the emergence of carbapenem resistance, and has a
significant influence on patient mortality. e primary
result of this analysis was the pooled crude mortality of
42.14% among patients with CRKP, which is intimately
connected with patients’ health and physical status.
Although it is accepted that drug resistance is associ
-
ated with increased mortality because patients tend to
receive inappropriate empiric therapy in general [
4, 78],
other studies have found no such relationship. Bhav
-
nani etal. [
79] reported that clinical success was similar
between patients with ESBL and those with non-ESBL-
producing K. pneumoniae, and ESBL production alone
did not appear to be an independent risk factor for treat
-
ment failure. Kim et al. [
80] also found that ESBL pro-
duction was not significantly associated with death. In
addition, García-Sureda et al. [
81] reported that CRKP
isolates are less virulent and fit than CSKP isolates in an
antibiotic-free environment. We conducted this system
-
atic review and meta-analysis to estimate the mortality
of patients infected with CRKP in general and to study
the factors related to mortality resulting from this infec
-
tion. We found that patients infected with CRKP had
significantly higher mortality in comparison with CSKP
(crude OR 2.80). To identify risk factors associated with
the higher mortality of CRKP infections, we conducted
a stratified analysis of patient condition, carbapenemase
types, and study location.
Based on multiple patient conditions, our analysis con
-
firmed that patients with CRKP in association with BSI,
ICU admission, or SOT have a higher mortality than the
pooled mortality, although UTI patients have a lower
mortality than the pooled overall mortality, even lower
than that of CSKP patients. From this result, we assumed
that patient survival has a close relationship with patients’
underlying illness and comorbidities. Mouloudi etal. [
26]
reported that BSI, ICU admission, and recent receipt of a
Fig. 1 Flow diagram of included studies

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et al. Ann Clin Microbiol Antimicrob (2017) 16:18
Table 1 Characteristics ofthe eligible studies
Author, year Study type Region/
study year
Resistance CRKP
mortality (%)
CSKP
mortality (%)
P value Carbapenemases Infection
type
ICU SOT
Vardakas (2015) [
11] Retrospective cohort
study
Greece 2006.1–2009.10 CLSI 2010 58/80 (72.5) 14/24 (58.3) 0.19 NA BSI:44/65 80 0
Brizendine (2015)
[
16]
Retrospective cohort
study
USA 2011.12–2013.10 CLSI 2012 16/157 (10.2) NA NA NA UTI:16/157 0 0
Pouch (2015) [
12] Nested case–control
study
USA 2007.1–2010.12 CLSI 2009 6/20 (30) 8/80 (10) 0.03 NA UTI:6/20 0 20
Ny (2015) [
13] Retrospective cohort
study
USA 2011.1–2013.12 NA 7/48 (14.6) 5/48 (10.4) 0.76 NA UTI:2/27 0 0
Girmenia (2015) [
39] Retrospective cohort
study
Italy 2010.1–2013.7 NA 65/112 (58.1) NA NA NA Any infection:65/112 0 112
Hoxha (2015) [
14] Prospective
matched cohort
study
Italy 2012.11–2013.7 Eucast Guideline 30/49 (61) 10/49 (20) NA NA Any infection:30/49 0 0
Cubero (2015) [
15] Retrospective cohort
study
Spain 2010.10–2012.12 EUCAST 2015 8/20 (40) 1/9 (11.1) NA NA Any infection:8/20 0 0
Chang (2015) [
40] Retrospective study Taiwan 2012.1–2012.12 CLSI 2012 21/41 (51.2) NA NA KPC:6/8 Any infection:21/41 41 0
Chen (2015) [
68] Retrospective study Taiwan 2014.4–10 NA 12/41 (29.3) NA NA NA Any infection:12/41 0 0
Madrigal (2015) [
66] Retrospective study Spain 2014.5–9 NA 2/5 (40) NA NA NA Any infection:2/5 0 0
Bias (2015) [
70] Retrospective,
observational
cohort study
USA –2014.8 NA 5/30 (16.7) NA NA NA Any infection:5/30 0 30
Katsiari (2015) [
67] Prospective, obser-
vational study
Greece 2010.4–2012.3 CLSI 2012 14/32 (43.8) NA NA KPC:11/28VIM:3/5 BSI:9/16 32 0
Maristela Freire
(2015) [
69]
Retrospective cohort
study
Brazil 2009.1–2013.12 CLSI 2012 13/31 (41.9) NA NA KPC:13/31 BSI:7/11
UTI:1/10
0 31
Brizendine (2015)
[
16]
Retrospective cohort
study
USA 2006–2012 NA 4/22 (18) 1/64 (1.5) NA NA UTI:4/22 0 22
Sarah Welch (2015)
[
65]
Retrospective cohort
study
USA NA 19/51 (37.3) NA NA NA Pneumonia:19/51 0 0
van Duin (2014) [
16] Prospective, multi-
center, observa-
tional study
USA 2011.12–2013.3 CLSI 26/114 (22.8) NA NA NA BSI:5/26 0 0
Simkins (2014) [
17] Retrospective case–
control study
USA 2006.1–2010.12 NA 6/13 (46.2) 3/39 (7.7) 0.005 NA Any infection:6/13 0 13
Viviana Gómez
Rueda (2014) [
18]
Case–case–control
study
Colombia 2008.1–
2011.1
CLSI 31/61 (50.8) 20/61 (32.8) NA NA Any infection:31/61 0 0
Christoph Lübbert
(2014) [
71]
Retrospective study Germany 2010.9–
2011.9
NA 7/8 (87.5) NA NA KPC:7/8 Any infection:7/8 0 8
Qureshi (2014) [
42] Retrospective cohort
study
USA 2009.1–2012.10 NA 0/21 (0.00) NA NA NA UTI:0/21 0 0

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et al. Ann Clin Microbiol Antimicrob (2017) 16:18
Table 1 continued
Author, year Study type Region/
study year
Resistance CRKP
mortality (%)
CSKP
mortality (%)
P value Carbapenemases Infection
type
ICU SOT
Mouloudi (2014) [
43] Retrospective cohort
study
Greece 2008.1–2011.12 EUCAST 2012 14/17 (82.4) NA NA NA BSI:14/17 17 17
Bulent Aydinl (2014)
[
72]
Retrospective
analysis
Turkey 2012.1–2013.11 NA 2/5 (40) NA NA NA Any infection:2/5 0 5
Gallagher (2014) [
44] Retrospective case–
case–control study
USA 2005.6–2010.10 CLSI 2009 19/43 (44.2) NA NA NA BSI:19/43 0 0
Graziella Hanna
Pereira (2013) [
47]
Retrospective cohort
study
Brazil 2008.10–2010.10 CLSI 2010 16/33 (48) NA NA NA BSI:9/11
UTI:3/21
Pneumonia:3/7
0 0
Orsi (2013) [
19] Case–case–control
study
Italy 2008.7–2011.6 EUCAST 25/65 (38.5) 12/43 (27.9) NA KPC:14/36 Any infection:25/65 0 0
Kontopidou (2013)
[
48]
Retrospective cohort
study
Greece 2009.9–2010.6 CLSI 2010 29/127 (22.8) NA NA NA Any infection:29/127 127 0
Hussein (2013) [
20] Retrospective case
control study
Israel 2006.1–2008.12 CLSI 2006 45/103 (43.7) 62/214 (29) NA NA BSI:45/103 0 0
Luci Correa (2013)
[
22]
Matched case–con-
trol study
Brazil 2006.1–2008.8 CLSI 2009 10/20 (50) 11/40 (27.5) 0.085 NA Any infection:10/20 0 0
Clancy (2013) [
49] Single-center, retro-
spective study
USA 2008.8–2011.7 CLSI 2012 3/17 (17.6) NA NA NA BSI:3/17 0 17
Cober (2013) [
21] Retrospective cohort
study
USA 2006–2009 NA 8/19 (42.1) 7/46 0.005 NA BSI:8/19 0 19
Grossi (2013) [
73] Retrospective cohort
study
Italy 2009.1–2012.10 NA 11/36 (30.6) NA NA NA Any infection:11/36 0 36
Cicora (2013) [
50] Observational, retro-
spective study
Argentina 2011.4–
2012.6
CLSI 2010 2/6 (33.3) NA NA KPC:2/6 UTI:2/6 0 6
Paola Di Carlo (2013)
[
46]
Prospective case
series study
Italy 2011,8–2012.8 EUCAST 12/30 (40) NA NA KPC:12/30 Any infection:12/30 30 0
Fligou (2013) [
88] Retrospective cohort
study
Greece CLSI 21/48 (43.8) NA NA KPC:21/48 BSI:21/48 48 0
Rose (2012) [
74] Retrospec-
tive, cohort study
USA 2006–2011 NA 20/44 (45.5) NA NA NA BSI:20/44 0 0
Sanchez-Romero
(2012) [
51]
Retrospective cohort
study
Spain 2009.1–2009.12 CLSI 2011 13/28 (46.4) NA NA VIM:13/28 Any infection:13/28 28 0
Liu (2012) [
23] Matched case–con-
trol study
Taiwan 2007.1–2009.12 CLSI 2009 15/25 (60) 20/50 0.102 NA BSI:15/25 0 0
Kalpoe (2012) [
52] Retrospective cohort
study
USA 2005.1–2006.10 NA 10/14 (71.4) NA NA NA Any infection:10/14 0 14
Borer (2012) [
53] Retrospective case
control study
Israel 2007.5–2010.1 CLSI 2006 13/42 (31) NA NA NA Any infection:13/42 0 0
Bergamasco (2012)
[
54]
Retrospective cohort
study
Brazil 2009.7–2010.2 CLSI 2009 5/12 (41.7) NA NA KPC:2/12 Any infection:5/12 0 12