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Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella

pneumoniae: A review of epidemiological and clinical aspects

Article  in  Expert opinion on biological therapy · April 2012

DOI: 10.1517/14712598.2012.681369 · Source: PubMed

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 Original Research

Klebsiella pneumoniae
carbapenemase (KPC)-producing
Klebsiella pneumoniae: a review
1. Introduction
2. Material and methods
of epidemiological and clinical
3. Results and discussion aspects
4. Conclusion
5. Expert opinion Rosemeri Maurici da Silva, Jefferson Traebert & Dayani Galato†
University of Southern Santa Catarina, Unisul, Master Programme in Health Sciences, Tubara˜o,
Brazil

Introduction: The indiscriminate use of antibiotics associated with other

situations has revealed a considerable increase in outbreaks caused by micro-
organisms resistant to antimicrobial drugs. Among these is the Klebsiella
pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae.
Areas covered: This review provides an overview of the KPC-producing
K. pneumoniae with emphasis on the epidemiological and clinical aspects.
Expert opinion: The KPC-producing K. pneumoniae was first described in the
US. Most cases were reported between 2007 and 2009. It is widespread in
almost all continents. The presence of severe comorbidities, previous use of
fluoroquinolones and broad-spectrum cephalosporin are independent factors
for this type of infection. Besides the increasing number of resistant strains
that greatly complicates the therapeutic management of patients, the clinical
characteristics of infection make the diagnosis difficult, resulting in high
morbidity and mortality rates. The spread of KPC-producing K. pneumoniae
shows how we are prone to pandemics. Transport systems, the exchange
of healthcare professionals, the transfer of patients between hospitals
and, mainly, the lack of preventive measures such as hand washing are
related to the spread of KPC-producing Klebsiella pneumoniae in virtually
all continents.

Keywords: antibiotics, antimicrobial resistance, carbapenemase, Klebsiella pneumoniae

Expert Opin. Biol. Ther. (2012) 12(6):663-671

1. Introduction

The first cases of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella

pneumoniae emerged in the US in 1996 [1] being released in 2001 [1,2]. It was sub-
sequently identified in many countries worldwide [2].
Carbapenemase is a type of b-lactamase resistant to virtually all b-lactam antibio-
tics including carbapenems such as imipenem and meropenem [3]. This resistance is
mediated by plasmid that carries the KPC enzyme from K. pneumoniae [4]. Corro-
borating this information, it was possible to identify E. coli with such resistance in
many patients with KPC [5-7].
KPC-producing K. pneumoniae infection is related to high mortality rates [2,8].
However, some people do not develop the infection, where the bacteria are only col-
onized and can be transmitted to more vulnerable individuals [9,10]. The infections
are usually hospital associated but can also be community acquired [5,11].
In this context, the objective of the study was to carry out a systematic literature
review on KPC-producing K. pneumoniae with emphasis on the epidemiological and

10.1517/14712598.2012.681369 © 2012 Informa UK, Ltd. ISSN 1471-2598 663

All rights reserved: reproduction in whole or in part not permitted
R. M. da Silva et al.
Article highlights.
. Klebsiella pneumoniae carbapenemase (KPC)-producing
Klebsiella pneumoniae infection is related to high
mortality. However, some people do not develop the
infection, where the bacteria are only colonized but can
be transmitted to more vulnerable individuals.
. Severe comorbidities and previous use
of fluoroquinolones and broad-spectrum cephalosporins
are independent factors for KPC-producing
K. pneumoniae infection.
. Transport systems, the exchange of healthcare
professionals, the transfer of patients between hospitals
and, mainly, the lack of preventive measures such
as hand washing, are related to the spread of
KPC-producing K. pneumoniae in virtually all continents.
. When the antibiotics commonly used in infections
caused by KPC-producing K. pneumoniae become
ineffective, other drugs have been used in the
management of infected patients, among which are the
colistin and the tigecycline.
. Effective hospital infection control and guidelines for the
use of antimicrobials are necessary for infection
prevention. Interventions combining intensified infection
control measures with routine rectal cultures are useful
in reducing the incidence of infection in endemic areas.
This box summarizes key points contained in the article.
clinical aspects. There are several types of KPC. KPC2, KPC3
and KPC 258 genes will be mainly discussed in this review.
2. Material and methods
Articles were retrieved from Health Virtual Library (BVS --
Biblioteca Virtual em Sa ude) using the following index terms:
i) Klebsiella pneumoniae carbapenemase, ii) Carbapenemase
and iii) KPC. Virtual library database included LILACS,
MEDLINE, IBECS, Cochrane and SciELO.
The selection criteria included articles written in English,
Portuguese and Spanish. Some relevant articles were also
included in the references. The articles were reviewed according
to the historical aspects and geographical location, diagnosis,
patients’ characteristics, treatment, prognosis and prevention
of infections.
3. Results and discussion
Out of the 156 recovered articles, 121 were excluded because
they reported KPC in bacteria other than K. pneumoniae.
Thirty-five articles were included in this review. Other 12
relevant articles about diagnostic techniques, prevention and
treatment were also included.
3.1Historical aspects and geographical location
of cases
Table 1 shows the reviewed studies according to the country of
occurrence, date, number of cases and detected gene.
664 Expert Opin. Biol. Ther. (2012) 12(6)
KPC-producing K. pneumoniae was first described in the
study of Intensive Care Antimicrobial Resistance Epidemiol-
ogy (ICARE) in North Carolina (US) in 2001 [1]. It was later
described in China [12] and in Israel in 2004 [13] and in France
in 2005 [14]. It was also described in Greece (2007) and several
other European countries, such as Belgium, Scotland, Eng-
land, Italy and Denmark [6,15-17]. In these studies, infections
were related to the transfer of patients from hospitals in
Greece [6,16,17] and Israel [15]. A possible contamination of a
patient in Italy was also described by Giani et al. [5], possibly
from a healthcare provider who had come from a region of
Israel with confirmed cases.
No reports were found regarding the origin of the infection
in Asia. With regard to Europe, the first French patient had
been hospitalized previously in the US, which could explain
the entry of this resistant bacterium in Europe [14]. The cases
reported in Canada indicated that the patients had been
transferred from the US [18].
Latter information shows that not all individuals who
have contact with KPC-producing K. pneumoniae develop
infections, because sometimes just the colonization occurs [9,10].
It was also noted that, in addition to the transmission
between hospitals, the transmission between patients treated
in the same hospital is quite frequent. This fact occurred in
France in 2009 [17] when several cases of patients with KPC
type 2 were reported. In this case, the first patient surveyed
had been transferred from Greece. The other 12 cases pre-
sented by Carbonne et al. [17] were infected persons from
the first one through common healthcare providers. For
these authors, in addition to contamination mediated by
healthcare providers, problems with equipments steriliza-
tion, such as endoscopes, may have also occurred, which
would explain the transmission between patients from two
different French hospitals.
The first case reported in South America was in Colombia in
2005 [19]. The previous source of infection could not be identi-
fied because the patient had no history of hospitalization or
travel to another country. However, researchers alerted that
there might be more unreported cases in the country, which
would explain cases of patients already infected in the country.
3.2 Diagnosis
The diagnosis of this type of infection is incomplete when based
only on antibiotic susceptibility testing [4,19,20]. An alternative
would be the validation of confirmatory screening methods for
the phenotypic dosage of carbapenemase. In this case,
Pillai et al. [20] suggest the use of ertapenem disk followed by
the modified Hodge test to confirm the carbapenemase activity.
Gastrointestinal carriers may serve as the reservoir for
cross-transmission. Three agar-based methods for direct
carbapenem-resistant enterobacteriaceae (CRE) from rectal
swabs can be used: CHROMagar-KPC, MacConkey agar with
imipenem 1 µg/ml and MacConkey plates with imipenem,
meropenem and ertapenem disks [21]. This method was also
defined by the Centers for Disease Control and Prevention
 Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae

Table 1. Spatial and temporal distribution, number of cases and detected gene relating to carbapenemase-
producing Klebsiella pneumoniae.

Location Date Number of patients/cases Detected gene Ref.

US 1996 -- 2007 248 70% 258 clone [26]

China 2004 1 KPC-2 [12]
Israel 2004 (Jan) -- 2006 (Dec) 51 KPC-2 e KPC-3 [13]
France 2005 1 KPC-2 [14]
New York 2005 14 Not available [27]
Colombia 2005 2 Not available [19]
China 2006 2 Conjugative plasmid [46]
(blakpc-2 plus qnrB4) and blaIMP-4
United Kingdom 2007 2 Not available [15]
Greece 2007 (Aug) 12 Not available [11]
Greece 2007 (Oct) -- 2008 (Sep) 47 KPC-2 [37]
Greece 2007 (Jan) -- 2008 (Dec) 32 (colonization) KPC-2 [38]
18 (infection)
California(US) 2007 (Aug) -- 2009 (Mar) 4 KPC-3 [31]
Brazil 2007 (Sep) -- 2008 (May) 6 Not available [18]
Canada 2007 (Oct) 3 Not available [32]
Canada 2008 1 Not available [20]
Germany 2008 9 KPC-2 [47]
Italy 2008 (Oct) 1 KPC 258 clone [5]
Belgium 2009 3 KPC-3 [6]
Italy 2009 (Apr -- Sep) 13 70% clone 258 [9]
Denmark 2009 (Jun) 1 KPC-2 258 clone [16]
France 2009 (Sep) 13 Not available [17]
Italy 2009 (Feb -- Mar) 2 KPC-2 [39]
Spain 2009 (Sep) -- 2010 (Feb) 5 (infection) KPC-3 [29]
3 (colonization)
Ireland 2009 1 KPC-2 [33]

(CDC) for identification of Enterobacteriaceae, including E. coli
and KPC-producing K. pneumoniae [22]. The procedure was
based on that presented by Landman et al. [23]. The test is based
on the use of MacConkey medium (culture medium for selective
isolation of Enterobacteriaceae) with a 10 µg meropenem disk.
When bacteria showed reduced susceptibility, the KPC must
be confirmed by the modified Hodge method [24]. This second
method also uses a 10 µg meropenem diffusion disk. However,
in this case, the growth of the microorganism is compared
with E. coli ATCC 25922 susceptible to carbapenems. There
are also automated systems such as Vitek 1 and Vitek 2, but
the performance of these products is highly variable, with differ-
ent sensitivity and specificity depending on the species
evaluated [24].
The test with boronic acid is very accurate and easily per-
formed. In this test, the diameter of the growth-inhibitory
zone around a b-lactamic disk with boronic acid is compared
with that around the corresponding b-lactamic disk without
boronic acid. The test is considered positive for the detection
of KPC enzyme when the diameter of the growth-inhibitory
zone is 5 mm larger in the disk with boronic acid than in
that without boronic acid [25].
Besides the phenotypic identification, several stud-
ies [4,5,9,11,26,27,19,18,28] show the importance of genotypic
characterization of the bacterium, which has been performed
using the polymerase chain reaction (PCR) technique.
This characterization relates to antimicrobial susceptibility.
According to Curiaou et al. [29], KPC-producing K. pneumoniae
can present at least nine types of KPC genes named KPC-1 or
KPC-2 to KPC-10. The most common is KPC-2 [26,27,19,18]
and KPC-3 genes [5,9,26,27].
The distinction of these genes is related to amino acid changes
in carbapenemase. The KPC-1 and KPC-2 are the same enzyme.
The other KPC variants differ in one or two amino acids.
KPC-5 is 99% identical to KPC-2 and KPC-4 [29]. The sequen-
ces for blaKPC genes can be recovered at the GenBank database
(http://www.ncbi.nlm.nih.gov/GenBank/index.html).
The KPC-2 is related with K. pneumoniae, K. oxytoca,
Salmonella enterica and Enterobacter sp. The KPC-3 is related
with K. pneumoniae and E. cloacae. It has a higher catalytic
efficiency against carbapenems, but in the clinical practice,
the significance is not clear [27,30].
3.3 Patients’ characteristics
Table 2 presents data of patients with KPC-producing
K. pneumoniae. Most patients with KPC-producing
K. pneumoniae were men of advanced age, with underlying
diseases and exposed to antibiotics in the period prior to
diagnosis of infection. Most underlying diseases were
serious disorders, such as cancer, heart failure, chronic
obstructive pulmonary disease, coronary disease and diabetes
mellitus [6,10,31,32,20,33].

Expert Opin. Biol. Ther. (2012) 12(6) 665

 666
Table 2. Distribution of surveyed studies by country according to the cases’ characteristics.

Country (n) Mean Gender (n) Underlying Source of isolate (n) Possible origin Mean total Previous use of Outcome (n) Ref. (n)
R. M. da Silva et al.

age (n) disease (n) of isolated (n) length of antibiotics (n)

stay (n)

Canada (4) 78 Male (2) Yes (4) Urine (3); Blood (1) NA (1) NA NA (1) NA [20]; (n = 1)
Female (2) US (3) Not done (1) [32]; (n = 3)
Done (2)
China (2) 56 Male (1) Yes (2) NA (2); Sputum (1) NA (3) NA Done (3) Death (1) [46]; (n = 2)
Female (2) No (1) Discharge (2) [12]; (n = 1)
NA (1)
Belgium (3) NA NA Yes (3) Urine (1); Rectal swabs (2) Greece (3) NA NA NA [5]; (n = 3)
Italy (16) NA (1) NA (1) Yes (14) NA (1); Urine (4); Sputum/ Israel (1) NA (1) Not done (5) NA (4) [5]; (n = 1)
63 (15) Female (8) No (2) Blood (3); Rectal swabs (2); Same hospital (15) 23 (15) Done (11) Discharge (6) [9]; (n = 13)
Male (7) Blood (5); Nose (1) Death (6) [39]; (n = 2)
United Kingdom (2) NA Male (1) NA (1) Blood (1); Urine (1) Scotland (1) NA Not done (2) NA [15]; (n = 2)
Female (1) Yes (1) London/Israel (1)
Denmark (2) 54 Male (2) Yes (2) Nose/Skin (1); Wound/ Greece (2) 41 Done (2) Discharge (2) [16]; (n = 2)
Tracheal aspirate (1)
France 80 Man (1) Yes Urine/Blood (1) US (1) NA (1) NA (1) NA (1) [14]; (n = 1)
US (11) 68 NA (4) Yes (11) Sputum, Urine (2); Blood (3); Same hospital (11) 21 (4) Done (7) NA (4) [31]; (n = 4)
Male (5) Urine (5); Urine and blood NA (7) Not done (4) Death (4) [10]; (n = 7)

Expert Opin. Biol. Ther. (2012) 12(6)

Female (2) (1) Discharge (3)
Greece (77) 72 Male (21) Yes (76) Urine (21); Blood (29); Community (12) NA (59) Done (73) NA (12) [11]; (n = 12)
Female (9) No (1) Wound (9); Other (7); Same hospital (55) 58 (18) NA (2) Discharge (41) [37]; (n = 47)
NA (47) Colonization (9); Sputum (1); NA (10) Not Done (2) Death (24) [38]; (n = 18)
Sputum and blood (1)
Spain (9) 77 Male (3) Yes (7) Urine (3); Rectal swabs (2); Same hospital (9) 19 Done (6) Discharge (5) [29]; (n = 9)
Female (6) No (2) Surgical site (2);Blood and NA (3) NA (3)
urine (1); Sputum (1) Death (1)
Germany (10) 64 Female (7) Yes (8) Sputum (3); Rectal swabs (2); Same hospital (9) 114 NA (10) Death (4) [47]; (n = 10)
Male (3) No (2) Urine (3); Surgical site (2) Greece (1) NA (5)
Discharged (1)
Ireland 60 Male Yes Sputum Same hospital 3 Done Discharged [33]; (n = 1)

NA: Not available.

 Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae
Reinforcing these observations, Gasink et al. [34] described
the presence of severe comorbidities, previous fluoroquino-
lone use and broad-spectrum cephalosporins as independent
risk factors for KPC-producing K. pneumoniae.
3.4 Treatment
This bacterium is generally resistant to all b-lactams, includ-
ing carbapenems [6,9,20]. Often the resistance is maintained
even when associated with b-lactamase inhibitors such as
clavulanic acid and tazobactam [4,5,8,18]. However, depending
on the phenotypic characteristics, some case reports [16] have
shown that the association with b-lactamase inhibitors slightly
improves the action of some b-lactam antibiotics.
Resistance to quinolone antibiotics such as ciprofloxacin
and levofloxacin was also observed [6,9,32,16]. Gasink et al. [34]
argued that the prior usage of this class of drugs increases the
probability of infection by KPC-producing K. pneumoniae.
The susceptibility profile of KPC-producing K. pneumoniae
to aminoglycosides has generally shown sensitive or partially
sensitive results to amikacin [32] and gentamicin [5,6,9,27,16].
This alteration in susceptibility to aminoglycosides has been
explained by the fact that carbapenemase genes are often
physically linked to aminoglycoside-resistance genes [4].
Regarding the association of sulfamethoxazole and trimetho-
prim, the available information is contradictory. Some
authors [6,32] have shown that KPC-producing K. pneumoniae
is sensitive. Moreover, in Italy [5,9] and in Denmark [16],
resistance was detected including this association.
Knowing the genetic characterization of KPC-producing
K. pneumoniae is important because it was identified that
KPC-2 is less susceptible to carbapenems, and KPC-4
and KPC-5 are more sensitive to inhibition by clavulanic
acid [28].
A study carried out by Pournaras et al. [35] demonstrated
that KPC-KP, apparently susceptible to meropenem, may
contain resistant subpopulations and therefore, if treated
with this antimicrobial agent only, will result in treatment
failure. It is known that ompK36 expression tends to have
lower minimal inhibitory concentrations (MIC) to carbape-
nems, which is another mechanism that interferes with the
antimicrobial susceptibility [36]. These genes are also identified
by PCR. However, despite resistance in vitro, there is not
always a resistant phenotype [28].
In this context, when the antibiotics commonly used in infec-
tions caused by K. pneumoniae become ineffective, other drugs
have been used in the management of infected patients, such
as colistin [5,9,11,15,37,38,16] and tigecycline [5,9,11,15,37,18,39,40].
In the case of tigecycline, in the review conducted by
Hirsch and Tam [40], two studies were identified showing an
in vitro susceptibility of 100% of the samples tested (156 cul-
tures). On the other hand, an in vivo success rate of 71% was
obtained. According to these authors, this drug has been quite
adequate for the treatment of blood-stream infections. In uri-
nary tract infections, there are reports of successful treatment
using off-label high dose.
Expert Opin. Biol. Ther. (2012) 12(6)
However, colistin has a low response to treatment of infec-
tions due to KPC-producing K. pneumoniae when used alone.
When used in combination with tigecycline, it presented a
clinical success rate of 73% [40].
Recently Livermore et al. (2011) [41] analyzed some medi-
cines for the treatment of CRE. They have observed that the
CREs were susceptible to minocycline (11/11), colistin
(10/11) and fosfomycin (6/11). In this study, the tigecycline
had a low activity for the CREs (2/11). It should be noted
that the therapeutic data are still scarce, since most of the
information described in the literature refers to case reports
or case series.
3.5 Prognosis
Infection by KPC-producing K. pneumoniae is related
to high rates of morbidity and mortality. In a study
conducted in Cleveland (US), the crude mortality rate was
approximately 69% [10]. In another study conducted by
Mammina et al. [9], the infection by KPC-producing
K. pneumoniae was considered a contributing factor in the
death of 5 of the 13 patients hospitalized in an intensive
care unit.
Corroborating these data, Patel et al. [42] observed that
patients infected by KPC-producing K. pneumoniae have a
three times higher risk of death when compared with infec-
tions caused by carbapenem-sensitive strains. The study by
Gasink et al. [34] demonstrated that in-hospital mortality was
independently associated with KPC-producing K. pneumoniae.
Some studies [2,20,39,29] reported the length of hospital stay
of patients with KPC-producing K. pneumoniae, but early
mortality of some individuals interferes with this variable,
making it difficult to assert that the infection increases the
length of hospital stay.
3.6 Prevention
Insufficient therapy to combat the bacterial resistance requires
vigilance to detect the cases as early as possible [2,31]. This detec-
tion should be linked to the preparation of microbiology labo-
ratories for the dissemination of results with recommendations
for controlling the transmission [2,17].
One action for the preparation of microbiology labo-
ratories was the recent publication of a guideline by
Clinical and Laboratory Standards Institute [43]. In this
document, the interpretation of the MIC breakpoints for
cephalosporins and carbapenem for Enterobacteriaceae was
changed. In this guideline, antimicrobial MIC was revised
resulting in the reduction of the concentrations for the
resistance classification.
Effective hospital infection control [9,31,18] and guidelines
for the use of antimicrobials [9] are also necessary. According
to Kochar et al. [8], interventions combining intensified infec-
tion control measures with routine rectal cultures are useful in
reducing the incidence of infection in endemic areas. More-
over, Peirano et al. [18] have emphasized that understanding
the mechanism of resistance may help to determine the
667
R. M. da Silva et al.
epidemiological risk factors and to define appropriate thera-
peutic strategies for resistance management.
According to Carbonne et al. [17], preventive disinfection
of devices and periodic microbiological testing of endo-
scopes are required. Furthermore, the authors have sug-
gested the following procedures: i) to limit the transfer of
patients and contact with others until the suspect case is
resolved; ii) to follow up cases through cohort studies to
perform infection tracking; iii) to identify the locations
where there are infected patients to avoid contact with
other patients; iv) to strengthen hand hygiene measures
and contact precaution; and v) to conduct a systematic
patient screening.
Giani et al. [5] pointed out to the greater need for healthcare
providers in locations where this bacterium is endemic. In this
context, Schwaber et al. [44] showed that actions taken in hos-
pitals in Israel decreased significantly the incidence of infec-
tions by KPC-producing K. pneumoniae. Those actions were
implemented through a national intervention and were based
on systematic evaluation of the hospital infection services, lab-
oratory methods of diagnosis and adherence to care measures
to prevent transmission by isolating patients. In addition, a
commission was formed with professionals working in hospi-
tal infection control, clinical microbiology and public health
to monitor interventions.
Bilavsky et al. [45] discussed the importance of proactive
strategies versus a reactive approach to confront the risk of
KPC-producing Enterobacteriaceae. These authors reinforced
the need for preventive actions and discussed the impor-
tance of policies to encourage drug companies to develop
new antimicrobials.
4. Conclusion
The results from the surveyed studies showed that the
KPC-producing K. pneumoniae is widespread in almost all
continents. It often shows a profile of bacterial resistance to
multiple types of antibiotics making treatment more difficult
and increasing morbidity and mortality rates.
668 Expert Opin. Biol. Ther. (2012) 12(6)
Investments are needed to standardize the diagnosis of
KPC-producing K. pneumoniae in infected and colonized
individuals. Phenotypic and genotypic analyses as well as
determining the characteristics of infected patients should be
used. Such a characterization would allow earlier initiation
of treatment with appropriate selection of antimicrobials.
There is a diversity in the ways of KPC-producing
K. pneumoniae transmission. Such versatility means that
taking appropriate control measures is vital to prevent
infection spreading.
5. Expert opinion
The presence of severe comorbidities and previous use of
fluoroquinolones and broad-spectrum cephalosporins are inde-
pendent factors for KPC-producing K. pneumoniae infection.
Besides the increasing number of resistant strains,
which greatly complicates the therapeutic management of
patients, the clinical characteristics of this type of infection
make the diagnosis difficult, resulting in a high rate of
morbidity and mortality. Antibiotics such as colistin and
tigecycline have been adopted; however, their use should
be done rationally.
The spread of KPC-producing K. pneumoniae showed how
we are prone to pandemics. Transport systems, the exchange
of healthcare professionals, the transfer of patients between
hospitals and mainly the lack of preventive measures, such
as hand washing, are related to the spread of KPC-producing
K. pneumoniae in virtually all continents.
Therefore, preventive actions are necessary, since the devel-
opment of resistance causes a serious public health problem.
Many classes of drugs become ineffective increasing signifi-
cantly morbidity and mortality rates, as well as the treatment
and hospitalization costs.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.

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pneumoniae carbapenemase 3 in
intensive care unit in Italy.
J Clin Microbiol 2010;48:1506-7
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
10. Endimiani A, DePasquale JM, Forero S,
et al. Emergence of blakpc-containing
Klebsiella pneumoniae in a long-term
acute care hospital: a new challenge to
our healthcare system.
J Antimicrob Chemother
2009;64:1102-10
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
11. Poulou A, Spanakis N, Pournaras S,
et al. Recurrent healthcare-associated
community-onset infections due to
Klebsiella pneumoniae producing
VIM-1 metallo-beta-lactamase.
J Antimicrob Chemother
2010;65:2538-42
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
12. Wei ZQ, Du XX, Yu YS, et al.
Plasmid-mediad KPC-2 in Klebsiella
pneumoniae isolad from China.
Antimicrob Agents Chemother
2007;51:763-5
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
13. Leavitt A, Navon-Venezia S,
Chmelnitsky I, et al. Emergence of
KPC-2 and KPC-3 in
carbapenem-resistant Klebsiella
penumoniae strains in an Israeli
Expert Opin. Biol. Ther. (2012) 12(6)
Hospital. Antimicrob Agents Chemother
2007;51:3026-9
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
14. Nass T, Nordmann P, Vedel G, et al.
Plasmid-mediated carbapenem-hydrolyzing
beta-lactamase KPC in a Klebsiella
pneumoniae isolate from France.
Antimicrob Agents Chemother
2005;49:4423-4
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
15. Woodford N, Zhang J, Warner M, et al.
Arrival of Klebsiella pneumoniae
producing KPC carbapenemase in the
United Kingdom.
J Antimicrob Chemother
2008;62:1261-4
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
16. Hammerum AM, Hansen F, Lester C,
et al. Detection of the first two Klebsiella
pneumoniae isolates with sequence
type 258 producing
KPC-2 carbapenemase in Denmark. Int J
Antimicrob Agents 2010;35:610-12
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
17. Carbonne A, Thiolet JM, Fournier S, et al.
Control of a multi-hospital outbreak of
KCP-producing Klebsiella pneumoniae
type 2 in France, September to October
2009. Euro Surveill 2010;15(48):
pii=19734-Available from: http://www.
eurosurveillance.org/viewArticle.aspx?
articleld=19734 [[Accessed 1 March 2011]
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
18. Peirano G, Seki LM, Passos VLV, et al.
Carbapenem-hidrolysind beta-lactamase
KPC-2 in Klebsiella pneumoniae isolated
in Rio de Janeiro, Brazil.
J Antimicrob Chemother 2009;63:265-8
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
19. Villegas MV, Lolans K, Correa A, et al.
First detection of plamid-mediated class
A carbapenemase KPC-2 in clinical
isolates of Klebsiella pneumoniae from
South America.
669
R. M. da Silva et al.
Antimicrob Agents Chemother
2006;50:2880-2
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
20. Pillai DR, Melano R, Rawte P, et al.
Klebsiella pneumoniae carbapenemase,
Canada. Emerg Infect Dis 2009;5:827-9
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
21. Adler A, Navon-Venezia S,
Moran-Gilard J, et al. Laboratory and
clinical evaluation of screening agar plates
for the detection of carbapenem-resistant
enterobacteriaceae from surveillance rectal
swabs. J Clin Microbiol
2011;49(6):2239-2
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
22. CDC. Centers for Disease Control and
Prevention. Laboratory Protocol for
Detection of Carbapenem-Resistant or
Carbapenemase-Producing, Klebsiella
spp. And E. coli from Rectal Swabs 2009
[Internet site]. Available from: http://
www.ndhealth.gov/microlab/Uploads/
Lab_Protocol_KPC.pdf [Accessed March
28 2011]
. Of importance to the
manuscript contextualization.
23. Landman D, Salvani JK, Bratu S, et al.
Evaluation of techniques for detection of
carbapenem-resistent Klebsiella
penumoniae in stool surveillance cultures.
J Clin Microbiol 2005;43(11):5639-41
. Of importance to the
manuscript contextualization.
24. CDC. Centers for Disease Control and
Prevention. Modified hodge test for
carbapenemase detection in
Enterobacteriaceae 2009 [Internet site].
Available from: http://www.ndhealth.gov/
microlab/Uploads/HodgeTest.pdf.
Accessed March 28 2011
. Of importance to the
manuscript contextualization.
25. Tsakris A, Krista I, Poulou A, et al.
Evaluation of boronic acid disk tests for
differentiating KPC-possessing Klebsiella
pneumoniae isolates in the clinical
laboratory. J Clin Microbiol
2009;47:362-7
. Of importance to the
manuscript contextualization.
26. Kitchel B, Rasheed JK, Patel JB, et al.
Molecular epidemiology of (KPC)-
670
producing Klebsiella pneumoniae isolates
in the United States: clonal expansion of
multilocus sequence type 258.
Antimicrob Agents Chemother
2009;53:3365-70
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
27. Gootz TD, Lescoe MK, Dib-Haij F,
et al. Genetic organization of transponase
regions surrounding blaKPC
carbapenemase genes on plasmids
from Klebsiella strains isolate in a
New York City Hospital.
Antimicrob Agents Chemother
2009;53:1998-2004
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
28. Wolter DJ, Kurpiel PM, Woodford N,
et al. Phenotypic and enzymatic
comparative analysis of the novel KPC
variant KPC-5 and its evolutionary
variants, KPC-2 and KPC-4.
Antimicrob Agents Chemoter
2009;53:557-62
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
29. Curiaou T, Morosini MI,
Ruiz-Garbajosa P, et al. Emergence of
blakpc3-Tn4401a associated with a
pKPN3/4-like plasmid within ST384 and
ST388 Klebsiella pneumoniae clones in
Spain. J Antimicrob Chemother
2010;65:1608-14
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
30. Naas T, Cuzon G, Villegas MV, et al.
Genetic structures at the origen of
acquisition of the beta-lactamase blakpc
gene. Antimicrob Agents Chemoter
2008;52:1257-63
. Of importance to the
manuscript contextualization.
31. Le J, Castanheira M, Burgess DS, et al.
Clonal dissemination of Klebsiella
pneumoniae carbapenemase KPC-3 in
Long Beach, California. J Clin Microbiol
2010;48:623-5
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
32. Goldfarb D, Harvey SB, Jessamine K,
et al. Detection of plasmid-mediated
(KPC)-producing Klebsiella pneumoniae
in Otawa, Canada: evidence of
Expert Opin. Biol. Ther. (2012) 12(6)
intrahospital transmission.
J Clin Microbiol 2009;47:1920-2
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
33. Roche C, Cotter M. O´Connell N, et al.
First identification of class
A carbapenemase-producing Klebsiella
pneumoniae in the Republic of Ireland.
Euro Surveill
2009;14(13):pii=19163-Available from:
http://www.eurosurveillance.org/
ViewArticle.aspx?ArticleId=19163
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
34. Gasink LB, Edelstein PH, Lautenbach E,
et al. Risk factors and clinical impact of
Klebsiella pneumoniae
carbapenemase-producing K.
pneumoniae. Infect Control
Hosp Epidemiol 2009;30:1180-5
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
35. Pournaras S, Krista I, Vrioni G, et al.
Characteristics of meropenem
heteroresistance in Klebsiella pneumoniae
KPC-producing clinical isolates of
K. pneumoniae. J Clin Microbiol
2010;48:2601-4
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
36. Landman D, Bratu S, Quale J.
Contribution of OmpK36 to carbapenem
susceptibility in KPC-producing
Klebsiella pneumoniae. J Med Microbiol
2009;58:1303-8
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
37. Pournaras S, Protonotariou E,
Voulgari E, et al. Clonal spread of
KPC-2 carbapenemase-producing
Klebsiella pneumoniae strains in Greece.
J Antimicrob Chemoter 2009;64:348-52
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
38. Souli M, Galani I, Antoniadou A, et al.
An outbreak of infection due to
beta-lactamase Klebsiella pneumoniae
carbapenemase 2-producing K.
pneumoniae in a Greek University
Hospital: molecular characterization,

epidemiology and outcomes.
Clin Infect Dis 2010;50:364-73
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
39. Fontana C, Favaro M, Sarmati L, et al.
Emergence of (KPC)-producing
Klebsiella pneumoniae in Italy.
BMC Res Notes 2010;3:40
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
40. Hirsch EB, Tam VH. Detection and
treatment options for Klebsiella
peneumoniae carbapenemases (KPCs):
an emerging cause of multidrug-resistant
infection. J Antimicrob Chemother
2010;65:1119-25
. Of importance to the
manuscript contextualization.
41. Livermore DM, Warner M, Mushtaq S,
et al. What remains against
carbapenem-reistent Enterobacteriaceae?
Evaluation of chloramphenicol,
ciprofloxacin, colistin, fosfomycin,
minocycline, nitrofurantoin, termocillin
and tigecycline. Int J Antimicrob Chem
2011;37:415-19
. Of importance to the
manuscript contextualization.
42. Patel G, Huprikar S, Factor SH, et al.
Outcomes of carbapenem-resistant
Klebsiella pneumoniae infection and the
View publication stats
Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae
impact of antimicrobial and adjunctive
therapies. Infect Control Hosp Epidemiol
2008;29:1099-106
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
43. Clinical and Laboratory Standards
institute. CLSI M100-S20 (2010)
Cephalosporins and Aztreonam
breakpoint revisions Fact Sheet. Available
from: http://www.clsi.org/Content/
NavigationMenu/Committees/
Microbiology/AST/
CephalosporinandAztreonam
BreakpointRevisionFactSheet/
CephalosporinAztreonam
BreakpointFactSheet.pdf [Accessed
15 March 2012]
. Of importance to the
manuscript contextualization.
44. Schwaber MJ, Lev B, Israeli A, et al.
Containment of a country-wide outbreak
of carbapenem-resistant Kleibsiella
peneumoniae in Israeli hospitals via a
nationally implemented intervention.
Clin Infect Dis 2011;52:848-55
. of importance to the
manuscript contextualization.
45. Bilavsky E, Schwaber MJ, Carmeli Y.
How to stem the tide of
carbapenemase-producing
Enterobacteriaceae? Proactive versus
Expert Opin. Biol. Ther. (2012) 12(6)
reactive strategies. Current Opin
Infect Dis 2010;23:327-31
. Of importance to the
manuscript contextualization.
46. Mendes RE, Bell JM, Turnidge JD,
et al. Carbapenem-resistant isolates of
Klebsiella pneumoniae in China
and detection of conjugative plasmid
(blakpc-2 plus qnrB4) and blaIMP-4 gene.
Antimicrob Agents Chemother
2008;52:789-99
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
47. Wendt C, Schutt S, Dalpke AH, et al.
First outbreak of Klebsiella pneumoniae
KPC-producing K. pneumoniae in
Germany. Eur J Clin Microbiol
Infect Dis 2010;29:563-70
.. Of considerable importance since it
was recovered according to paper’s
methods and selection criteria.
Affiliation
Rosemeri Maurici da Silva, Jefferson Traebert &
Dayani Galato†
†
Author for correspondence
University of Southern Santa Catarina,
Unisul, Master Programme in Health Sciences,
Av. José Acácio Moreira,
Tubarão, 88704-900, Brazil
E-mail: dayani.galato@unisul.br
671