4.

964

Review

Carbapenem-Resistant Klebsiella
pneumoniae Infections in ICU
COVID-19 Patients—A Scoping
Review

Wioletta Mędrzycka-Dąbrowska, Sandra Lange, Katarzyna Zorena, Sebastian Dąbrowski,

Dorota Ozga and Lucyna Tomaszek

https://doi.org/10.3390/jcm10102067
 Journal of
Clinical Medicine

Review
Carbapenem-Resistant Klebsiella pneumoniae Infections in ICU
COVID-19 Patients—A Scoping Review
Wioletta M˛edrzycka-Dabrowska
˛ 1, * , Sandra Lange 2 , Katarzyna Zorena 3 , Sebastian Dabrowski
˛ 4,

Dorota Ozga 5 and Lucyna Tomaszek 6

1 Department of Anaesthesiology Nursing & Intensive Care, Faculty of Health Sciences,

Medical University of Gdańsk, D˛ebinki 7, 80-211 Gdańsk, Poland
2 Department of Anesthesiology and Intensive Care, Hospitals Tczewskie SA, 30 Stycznia 57,
83-110 Tczew, Poland; [email protected]
3 Department of Immunobiology and Environment Microbiology, Faculty of Health Sciences,
Medical University of Gdańsk, D˛ebinki 7, 80-211 Gdańsk, Poland; [email protected]
4 Departament of Medical Rescue, Faculty of Health Sciences, Medical University of Gdańsk, D˛ebinki 7,
80-211 Gdańsk, Poland; [email protected]
5 Institute of Health Sciences, College of Medical Sciences of the University of Rzeszow, St. Warzywna1A,
35-310 Rzeszow, Poland; [email protected]
6 Department of Specialist Nursing, Faculty of Medicine and Health Sciences, Kraków Academy of Andrzej
Frycz Modrzewski, St. Gustawa Herlinga-Grudzińskiego 1, 30-705 Kraków, Poland;
[email protected]
* Correspondence: [email protected]

Abstract: Introduction: The spread of multidrug-resistant pathogens is a serious problem and



challenge for the whole medical community. Carbapenem-resistant Klebsiella pneumoniae (CRKP)


infections in immunocompromised patients have a severe course and may be fatal. Increasingly,
Citation: M˛edrzycka-Dabrowska,
˛ W.;
these bacteria are exhibiting resistance to carbapenem antibiotics, which have been used as so-called
Lange, S.; Zorena, K.; Dabrowski,
˛ S.;
drugs of last resort. The emergence of the new coronavirus and the pandemic that it has caused
Ozga, D.; Tomaszek, L. Carbapenem-
require changes to protect against the spread of the new SARS-CoV-2. These changes paradoxically
Resistant Klebsiella pneumoniae
may contribute to the spread of other infections. Methods: PubMed, Cochrane Library databases
Infections in ICU COVID-19
Patients—A Scoping Review. J. Clin.
were searched using relevant keywords. A literature review of carbapenem-resistant Klebsiella
Med. 2021, 10, 2067. https://doi.org/ pneumoniae infection in patients hospitalized for COVID-19 was conducted according to PRISMA
10.3390/jcm10102067 recommendations. A written review protocol was not prepared. Results: 1016 studies in scientific
databases were searched. After rejecting duplicate studies, 964 results were obtained. Inclusion and
Academic Editor: Pedro Póvoa exclusion criteria were then applied, and studies were qualitatively analyzed. Finally, 11 studies
were included in the review. The results of infected patients were from six countries. The prevalence
Received: 15 March 2021 of CRKP in Covid-19 patients ranged from 0.35–53%. The majority of CRKP infected patients
Accepted: 10 May 2021 were male (85%), with a mean age of 61 years. Among isolates, the predominant genes were KPC,
Published: 12 May 2021
OXY-48, CTX-M, TEM, NDM and SHV. Conclusion: The results presented in our review indicate
the necessity of paying attention to carbapenem-resistant Klebsiella pneumoniae infections in patients
Publisher’s Note: MDPI stays neutral
with COVID-19. In order to prevent the increase of bacterial resistance, rational antibiotic therapy
with regard to jurisdictional claims in
should be used, as well as continuous control and surveillance of hospital infections caused by
published maps and institutional affil-
multidrug-resistant organisms.
iations.

Keywords: carbapenem-resistance; Klebsiella pneumoniae; COVID-19

Copyright: © 2021 by the authors.

Licensee MDPI, Basel, Switzerland.
1. Introduction
This article is an open access article
distributed under the terms and Bacterial resistance has become a worldwide problem. The spread of pathogens that
conditions of the Creative Commons are insensitive to multiple classes of antibiotics—multidrug-resistant bacteria (MDRB),
Attribution (CC BY) license (https:// especially in intensive care units (ICUs), is a serious problem and challenge for the whole
creativecommons.org/licenses/by/ medical community [1,2]. Klebsiella pneumoniae is a Gram-negative species included among
4.0/). Enterobacterales. The bacterium can reside in the gastrointestinal tract as a physiological

J. Clin. Med. 2021, 10, 2067. https://doi.org/10.3390/jcm10102067 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021, 10, 2067 2 of 13

component of the intestinal flora, on the skin, and in the oral cavity. Unfortunately, in
immunocompromised patients, it can cause severe infections, including urinary tract
infections, respiratory infections, soft tissue infections, peritonitis and sepsis [3–6]. The
envelope, lipopolysaccharides (LPS) and cell wall protein receptors are responsible for the
pathogenicity of Klebsiella pneumoniae. These factors determine the process of binding to
host cells and provide protection against response from the human immune system [7,8].
Recently, these bacteria more and more frequently demonstrate resistance to antibiotics
of the carbapenem group, which were used as so-called drugs of last resort (DoLR) in the
course of severe infections caused by Gram-negative bacilli [6].

1.1. Resistance in Klebsiella pneumoniae

Resistance to carbapenem in Enterobacterales is created by two mechanisms. The
first mechanism is represented by the production of enzymes that are able to hydrolyze
cephalosporins (ESBL [extended-spectrum beta-lactamase] and AmpC beta-lactamases) [9,10]
combined to functional alteration or loss of porins. A second, increasingly common mecha-
nism is the production of β-lactamases capable of hydrolyzing most antibiotics, including
carbapenems, called carbapenemases. These include: Klebsiella pneumoniae producing
carbapenemases (KPC), metallo-beta-lactamases (NDM, IMP, VIM) and OXY-48-like car-
bapenemases [10,11]. KPC is a pathogen that has the capacity for clonal expansion and
genetic exchange that contributes to resistance. Moreover, it can survive in human reser-
voirs and form biofilms that are resistant to disinfectants used in hospitals [12–14]. The
mechanism of NDM-1 (New Delhi metallo-beta-lactamase-1) resistance was first described
in 2009. The bacterium was isolated from urine. From a therapeutic standpoint, this is
the most dangerous resistance mechanism, because the bacteria are resistant to almost all
available antibiotics. The exceptions are colistin and tigecycline. In addition, the genes
encoding NDM-1 show ease in transferring to other species of Enterobacteriaceae family
strains [8,15].

1.2. Co-Infections in Patients with COVID-19

A new virus was defined by the International Committee on Taxonomy of Viruses
(ICTV) as severe acute respiratory syndrome coronavirus (SARS-CoV-2). The disease was
named COVID-19 (“coronavirus disease 2019”) by the World Health Organization (WHO).
The number “19” in the abbreviation stands for the year 2019, when the virus was first
observed [16]. The emergence of the new coronavirus and the pandemic that it caused
required significant changes throughout the healthcare system [17,18]. The opening of
temporary hospitals and intensive care units (ICUs), the necessity to work in personal
protective equipment (PPE), work overload and isolation of health care workers (HCWs)
necessitated the hiring of additional personnel, who were often not experienced in working
in ICUs. In addition, the widespread use of broad-spectrum antibiotics, deficiencies in
the availability of PPE equipment, and reduced infection control and prevention have led
to the increasing emergence of multidrug-resistant bacteria [19,20]. Available data show
that secondary infections in patients with COVID-19 occur in 4% to 15% of hospitalized
patients, particularly in patients with severe COVID-19 infection, and are associated with
increased mortality [21–25].

1.3. Objective
The aim of this study was to review the literature in available scientific databases on
carbapenem-resistant Klebsiella pneumoniae (CRKP) bacterial infection in patients hospital-
ized for COVID-19 and to identify reasons that may contribute to the spread of MDROs
(multi-drug resistant organisms) during the SARS-CoV-2 pandemic.

2. Methods
2.1. Study Design
Scoping review was conducted in the first quarter of 2021.
J. Clin. Med. 2021, 10, 2067 3 of 13

2.2. Definition of Scoping Review

Scoping reviews are a relatively new approach to synthesizing evidence, and there
is currently little guidance on deciding between a systematic review and a scoping ap-
proach during the synthesis of evidence, especially when the literature has not yet been
comprehensively reviewed or shows a large, complex or heterogeneous nature that cannot
be subject to a more thorough systematic review [26].

2.3. Search Strategy

The following words were used to verify the search: carbapenem-resistance, Klebsiella
pneumoniae, COVID-19. Keyword combinations with AND, OR and both operators were
entered. The number of articles retrieved during each search test was limited to studies
conducted between 2019 and 2021. Strict inclusion and exclusion criteria were applied
(Table 1). The last search was conducted in March 2021. Finally, 10 articles were included in
our review. The search was conducted by two experts in the field of scientific information
in health sciences. Discrepancies were resolved through discussion.

Table 1. Inclusion and exclusion criteria, search strategies.

Inclusion Criteria Exclusion Criteria

Years considered/ All evidence published in the last
Time period 2 years, period 2019–2021
Healthcare settings for
Setting Other healthcare settings
COVID-19 patients
Type of study Observational studies, cases Descriptive studies,
design/references report, letters to the editor single-case report
Participants Positive COVID-19 patients Negative COVID-19 patients
Interventions to detect Studies without a clearly
Interventions
CRKP infection described intervention
General outcome of
Patient outcomes, co-infections in COVID-19
Outcome measures
culture outcomes patients (without
specification)
Language English Other lenguage
MEDLINE (PubMed),
Databases Other databases
Cochrane Library
Carbapenem-resistance, Klebsiella
Key words
pneumoniae, COVID-19
COVID-19, co-infections,
Additional search terms, Intensive Care Units
with which the central Klebsiella pneumoniae,
search terms were Carbapenem-Resistant
combined Enterobacteriaceae, COVID-19
COVID-19, CRKP, ICU

2.4. Study Selection

Inclusion criteria: hospitalized patients for COVID-19 with a positive CRKP result.
Exclusion criteria: non-COVID-19 patients, articles published in languages other than
English and articles for which the full version could not be accessed.

2.5. Selection Process

The quality of articles selected for review was assessed using the Newcastle Ottawa
Scale. Articles that were reviewed were given a score of 5–8 (Table 2). The AMSTAR
2 quality assessment checklist for systematic reviews and Preferred Reporting Items for
J. Clin. Med. 2021, 10, 2067 4 of 13

Systematic Reviews and Meta-Analyses (PRISMA) [27–29] were used. This review does
not include meta-analyses; any associated AMSTAR 2 or PRISMA checklist items were
considered not applicable. A summary of the methodological quality assessment using
the AMSTAR 2 checklist is presented in Table 3. The contents of two electronic databases,
PubMed and the Cochrane Library, were searched.

2.6. Data Extraction

Studies were evaluated using a formalized form of data extraction that included the
following data: first author, year of publication, country, study population, number of
infected patients, resistance gene.

Table 2. Quality assessment of the included studies by the Newcastle–Ottawa Scale.

First Author, Year Study Design Selection ComparabilityOutcome Total Scores

Karruli A. et al. Retrospective
** ** ** 6
2019 [30] study
Yang X. et al. Retrospective
*** ** * 6
2020 [31] study
Retrospective
Li J. et al. 2020 [32] *** * ** 6
study
Ramadan,
Prospective
H.K.A et al. 2020 *** ** ** 7
study
[33]
Gomez-Simmonds, Retrospective
**** ** *** 8
A. et al. 2020 [34] study
García–Menioño, Retrospective
*** ** *** 8
I. et al. 2021 [35] study
Montrucchioa, Retrospective
*** ** *** 8
G. et al. 2020 [36] study
Arcari, G. et al. Retrospective
** ** *** 7
2021 [37] study
Magnasco, L. et al. Retrospective
*** * *** 7
2021 [38] study
Arteaga-Livias, Prospective
*** ** ** 7
K. et al. 2021 [39] study
* A study can be awarded a maximum of one star for each numbered item within the Selection and outcome
categories (categories Selection max. 4 stars; categories Comparability max. 2 stars; categories Exposure/Outcome
max. 3 stars).
J. Clin. Med. 2021, 10, 2067 5 of 13

Table 3. Summary of the AMSTAR 2 quality assessment.

(14) Explanation for Heterogeneity

(7) Excluded Studies Justification

(13) RoB in Individual Studies

(8) Included Studies Details
(1) Question and Inclusion

(12) RoB on Meta-Analysis

(4) Comprehensive Search

(11) Statistical Methods

(16) Conflict of Interest

(9) Risk of Bias (RoB)

(10) Funding Sources

(15) Publication Bias

(5) Study Selection

(6) Data Extraction

(3) Study Design
(2) Protocol
First Author, Year

Karruli A. et al. 2019 [30] Yes No Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes No
Yang X. et al. 2020 [31] Yes No Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes No
Li J. et al. 2020 [32] Yes No Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes No
Ramadan, H.K.A. et al.
Yes No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No
2020 [33]
Gomez-Simmonds,
Yes No Yes Yes Yes Yes Yes Yes Yes Yes N/a N/a Yes Yes No No
A. et al. 2020 [34]
García—Menioño, I., et al.
Yes No Yes Yes Yes Yes Yes Yes Yes Yes N/a N/a Yes Yes No No
2020 [35]
Montrucchioa, G. et al.
Yes No Yes Yes Yes Yes Yes Yes Yes No N/a N/a Yes Yes No No
2020 [36]
Arcari, G., et al. 2021 [37] Yes No Yes Yes Yes Yes Yes Yes Yes Yes N/a N/a Yes Yes No No
Magnasco, L. et al.
Yes No Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes No
2021 [38]
Arteaga-Livias, K. et al.
Yes No Yes Yes Yes Yes Yes Yes Yes No N/a N/a Yes Yes No No
2021 [39]
10 0 10 10 10 10 10 10 10 3 5 1 10 10 5 0
Total, N (%)
(100%) (0%) (100%) (100%) (100%) (100%) (100%) (100%) (100%) (27%) (50%) (9%) (100%) (100%) (45%) (0%)
Abbreviations: N/a—not applicable, RoB, Risk of Bias. Percent is based on number of eligible reviews per domain.
J. Clin. Med. 2021, 10, 2067 6 of 13

3. Results
3.1. Results of the Scoping Review
Studies in which CRKP positivity was identified in patients hospitalized with COVID-
19 were included in the review. A total of 1016 articles were found in scientific databases.
After removing duplicates, 964 papers remained for analysis. In the next step, 109 full-text
articles were retained after reviewing abstracts. The next step focused on inclusion and
exclusion criteria (94 were rejected). At the stage of qualitative text analysis, four articles
were rejected. Finally, 10 articles were accepted for systematic analysis (Figure 1).

Figure 1. Flow diagram of study selection and inclusion.

3.2. Demographic and Social Data

Reports of the CRKP patients came from six countries. The cases were diagnosed in
Italy (Napoli, Umbria, Turin, Rome, Genoa), China (Wuhan), Egypt (Assiut), United States
(New York City), Spain (Oviedo, Asturias), and Peru. The prevalence of infected CRKP in
Covid-19 patients ranged from 0.35% to 53%. The distribution of cases for which sex was
J. Clin. Med. 2021, 10, 2067 7 of 13

available was as follows: 5 women (16%) and 26 men (84%). For patients with reported
age, the mean age was 61 years, ranging from 23 to 76 years. These data are presented in
Tables 4 and 5.

Table 4. Demographic and social data.

First Author, Year Sex (%) Age * [Years]

Karruli A. et al. 2019 [30] n/d n/d
Yang X. et al. 2020 [31] n/d n/d
Li J. et al. 2020 [32] n/d n/d
Ramadan, H.K.A. et al. 2020 [33] n/d n/d
1 F (9)
Gomez-Simmonds, A. et al. 2020 [34] 62 (23–74)
10 M (91)
1 F (14)
García–Menioño, I. et al. 2020 [35] 67 (54–76)
6 M (86)
3 F (43)
Montrucchioa, G. et al. 2020 [36] 57 (41–71)
4 M (57)
Arcari, G. et al. 2021 [37] n/d n/d
0 F (0)
Magnasco, L. et al. 2021 [38] 65 (63,66)
2 M (100)
0 F (0)
Arteaga-Livias, K. et al. 2021 [39] 56 (45–66)
4 M (100)
* average, F–Female, M–Male, n/d–no data.

Table 5. Analysis of articles included in the scoping review.

Number of Infected
First Author, Year Country (Region) Population Resistance Gene
Patients (%)
Karruli A. et al. 2019 [30] Italy (Napoli) 32 n/d KPC
Yang X. et al. 2020 [31] China (Wuhan) 52 1(2%) n/d
Li J. et al. 2020 [32] China (Wuhan) 102 32 (31.4%) n/d
Ramadan, H.K.A. et al. 2020 [33] Egypt (Assiut) 260 n/d KPC, CTX-M, TEM, SHV
United States
Gomez-Simmonds, A. et al. 2020 [34] 3152 11(0.35%) KPC
(New York City)
Spain
García–Menioño, I. et al. 2020 [35] 62 3(4.8%) OXA-48, CTX-M
(Oviedo, Asturias)
Montrucchioa, G. et al. 2020 [36] Italy (Turyn) 35 6(17.1%) KPC
Arcari, G. et al. 2021 [37] Italy (Rome) 65 7(10.8%) KPC, OXY-48
Magnasco, L. et al. 2021 [38] Italy (Genoa) 118 2(1.7%) n/d
Arteaga-Livias, K. et al. 2021 [39] Peru n/d 4 NDM, CTX-M
n/d—no data.

3.3. Characteristics of the Study Population

Sixteen (50%) patients in the study by Karruli A. et al. developed MDR infection in
the ICU. Patients who were found to be colonized with MDRB were not included in the
group of patients with MDR infection. A total of 23 isolates were cultured, of which the
most common pathogens were carbapenem-resistant K. pneumoniae (32%) and A. baumannii
(19%) Eight K. pneumoniae isolates were resistant to carbapenems, all due to KPC-type
carbapenemase production. The most common infectious syndromes caused by MDR
pathogens were bloodstream infection and ventilator-associated pneumonia [30]. In a
single-centered, retrospective, observational study by Yang X. et al., hospital-acquired
J. Clin. Med. 2021, 10, 2067 8 of 13

infection was reported in 7 of 52 hospitalized patients. Moreover, one patient (2%) had
pulmonary infection and blood stream infection of CRKP [31]. Li J. et al., in their study on
the etiology and resistance of secondary bacterial infections in COVID-19 patients, sampled
cultures from 102 patients. Furthermore, 35 (34.3%) patients had K. pneumoniae, of which
32 (31.4%) were resistant to carbapenems. The main type of infection was pulmonary,
followed by bloodstream infections [32]. As for Ramadan, in H.K.A. et al.’s study, in
28 cases, bacterial and/or fungal co-infections were found in respiratory samples. The
total number of clinical isolates obtained was 42, of which 37 were bacteria. Furthermore,
12 of these were K. pneumoniae [33]. Gomez-Simmonds, A. et al., among 3152 patients with
COVID-19, identified 13 patients positive for CRE, including 11 with K. pneumoniae—KPC.
The main source of infection was the respiratory tract. Additionally, 7/13 CRE cases
(54%) subsequently developed bacteremia [34]. In a study presented by García -Menioño
I. et al., 62 patients were treated in the ICU for COVID-19, and none of these patients
were colonized before admission. From clinical and epidemiological surveillance samples,
7 (11.3%) patients positive for CRKP were identified; 4 were colonized, 2 developed VAP
and 1 patient developed primary bacteremia [35]. Among 35 patients, 7 (20%) had a positive
rectal swab for carbapenemase-producing K. pneumoniae in a Montrucchioa, G. et al. study.
One patient became colonized in the unit and 6 developed invasive infection [36]. Overall,
65/80 patients hospitalized in the ICU for COVID-19, in a study by Arcari, G. et al., were
screened with smears for carbapenemase-producing Enterobacterales colonization. Positive
cultures for carbapenemase-producing K. pneumoniae were found in 14 patients (22%). Seven
patients developed co-infection that was confirmed in 5 bronchoalveolar lavages and 2
blood cultures [37]. In a Magnasco, L. et al. study, 2 ICU patients were colonized with
CRKP. In one, colonization occurred after transplantation and subsequently developed
into ventilator-associated pneumonia (VAP). The other one also developed VAP caused by
both CRKP and CRPA (carbapenem-resistant P. aeruginosa] [38]. Arteaga-Livias, K. et al.
described 4 cases of MDR K. pneumoniae; two of these developed co-infection [39].

4. Discussion
The review data on identification of Carbapenem-resistant K. pneumoniae are from
different continents, i.e., Europe, Asia, North and South America and Africa. The preva-
lence of coinfection in COVID-19 patients ranged from 0.35% to 53%. The majority of
CRKP patients were males with a mean age of 61 years. The most frequently isolated
resistance gene was KPC, followed by OXY-48, CTX-M, TEM, NDM, and SHV. The main
type of infection was pulmonary and bloodstream. This may be associated with the use
of mechanical ventilation and central catheters in ICUs. Li J. et al., in their study, showed
that the incidence of invasive mechanical ventilation and central catheter placement was
higher in the critically ill group. At the same time, a higher incidence of secondary bacterial
infections was observed in this group [32]. Reducing the spread of MDROs in medical
facilities and particularly in ICUs has become a challenge for the medical community. In
many countries, infection control programs have been implemented to prevent the colo-
nization and infection of patients. In accordance with guidelines of the European Society
of Clinical Microbiology and Infectious Diseases (ESCMID), educational training on hand
hygiene, patient contact precautions, the implementation of a rapid pathway to identify
and isolate patients colonized or infected with the bacterium, and a screening culture pro-
cedure have been initiated [6,14,31]. The emergence of the new SARS-CoV-2 coronavirus in
2019 has necessitated additional precautions. In order to minimize the spread and infection
with the virus, all ward staff were equipped with PPE such as coveralls, goggles, masks,
leggings, and several pairs of gloves. Although the steps taken were supposed to reduce
the risk of spreading the new virus, paradoxically, they may have favored the spread of
other multidrug-resistant bacteria [35,39]. In a study by Tiri et al. (Umbria, Italy), CRE
(carbapenem-resistant Enterobacteriaceae) cases increased from an average of 6.7% to as
much as 50%, during the pandemic, when the ICU was designated exclusively for intubated
COVID-19 patients. It is important to highlight the fact that the use of PPE protected staff
J. Clin. Med. 2021, 10, 2067 9 of 13

from contracting the virus. None of the workers became SARS-CoV-2 positive [40]. A
study by Belvisi V. et al. also showed an increasing trend in the prevalence of the fecal
carriage of K. pneumoniae—KPC during the pandemic. After implementation of anti-KPC
program, the prevalence of K. pneumoniae—KPC colonization in the ICU decreased from
71.4 to 0% and in the contiguous sub-intensive EM (emergency medicine) from 42.9% to
11.1%. In March, the hospital was assigned to hospitalize COVID-19 patients and the
training program against K. pneumoniae—KPC mainly focused on PPE. Consequently, an
increase in the prevalence of K. pneumoaniae—KPC carriage was recorded in the following
months [41]. Chinese researchers—Li J. et al. showed in their study that A. baumannii, K.
pneumoniae, and S. maltophilia were the main causes of secondary bacterial lung infections
in COVID-19 patients, where the etiology is significantly different from the pre-pandemic
of COVID-19 [32]. García-Menioño et al. (Spain), who identified the occurrence of the
OXA-48 gene among their patients, highlighted the fact that, so far, none of the patients had
been previously colonized by Enterobacteriaceae producing this gene [35]. Furthermore,
Arcari et al. (Italy) pointed out that while the occurrence of KPC strains has been described
in their country, the OXY-48 gene has rarely been reported [37]. Ramadan et al., who in
their study undertook the characterization of patients with COVID-19 from Upper Egypt,
noted that no co-infections were observed in patients in the mild severity group. They
occurred only in the group with moderate and severe courses of COVID-19. Additionally,
these cases were associated with greater severity and respiratory complications [33]. Simi-
larly, in the study by Gomez-Simmonds et al., 12/13 patients with positive CPE bacteria
(11- Kp-KPC, 2 NDM-E. cloacae complex) required intubation and intensive care [34]. In
5/7 patients presented by Montrucchio et al., septic shock occurred [38]. Similarly, in a
study by Li J. et al. secondary bacterial infection was more likely to develop in the critical
versus severe patient group, 26.7% (69/258) vs. 3.1% (33/1050). Furthermore, 49% of
patients who acquired a bacterial infection died during hospitalization. The mortality rate
of patients with acquired infection was also significantly higher in the critically ill group,
65.2% (45/69) vs. 15.2% (5/33) [31]. In a study by Soriano MC., the ICU mortality rate
in the group of patients with ward-acquired infection was higher than in the group of
patients without infection. They were 75.0% (15/20) and 44.4% (28/63), respectively [42].
However, researchers Karruli A. et al. pointed out that MDR infection was a common
complication in ICU COVID-19 patients. However, their study showed that it appeared as
a late complication associated with longer ICU stays [30]. The steadily increasing number
of SARS-CoV-2 infections has necessitated the opening of temporary hospitals and ICUs
dedicated only to COVID-19 patients. Several authors have hypothesized that the con-
taminated PPE of medical workers may be the main cause of cross-transmission. Factors
such as using the same protective facemasks to care for different patients on the same
unit and the use of double gloves where the outer gloves were changed and the inner
gloves were disinfected with alcohol may have been causative factors. Although the unit
implemented a procedure to use additional layer of fabric or plastic disposable gowns,
this did not prevent the occurrence of further MDR infections [31,35,39]. Another reason
for the spread of CRKP may have been the need to employ additional medical staff who
often had no experience of working in the ICU (trainee doctors, doctors and nurses from
other departments, physiotherapists, volunteers) [31,39]. Tiri et al. observed an interesting
phenomenon in patients where positioning (prone position) was used in the treatment
process. In their study, 67% of patients who were repositioned developed CRE colonization,
whereas among patients who were not prone-positioned, the percentage was 37% [31].
An important aspect of bacterial dissemination is the widespread use of broad-spectrum
antibiotics in COVID-19 patients [34,39]. Given the small number of scientific studies
on the occurrence of co-infections in hospitalized COVID-19 patients, it is challenging to
differentiate between a viral infection due to COVID-19 and the presence of a bacterial
infection based on clinical data [43,44]. Although antibiotic therapy for COVID-19 infection
is not effective, antibiotics are prescribed to many patients. There are several studies
that show that approximately 70% of patients hospitalized for COVID-19 received broad
J. Clin. Med. 2021, 10, 2067 10 of 13

spectrum antibiotics [19,45,46]. Chedid M. et al., in their review of antibiotic therapy in

COVID-19 patients, showed that the frequency of antibiotic use was 74%. They noted a
trend toward antibiotic use in patients with mild to moderate disease. Of the patients
who received antibiotics, only 17.6% had a secondary infection. Lansbury et al. in their
review found co-infection in 14% of patients admitted to the wards and in 7% of hos-
pitalized patients [47]. Rawson TM. et al. showed that 72% of patients received broad
spectrum antibiotics. Only 8% of COVID-19 patients had bacterial or fungal co-infection
identified [17]. These findings may raise concerns of overuse of antibiotic therapy and
a subsequent contribution to the development of increased bacterial resistance [19,43].
Therefore, further research on co-infections is needed to provide rational antibiotic therapy
in the era of the SARS-CoV-2 pandemic [48,49]. It is also important to remember that
altered, difficult working conditions and fatigue can cause burnout among HCWs, thereby
decreasing commitment to their work and adherence to infection prevention and control.
Additionally, the PPE use may give an apparent sense of security to medical workers and
contribute to the negligence of infection control [31,35,39]. The authors agree that infection
control measures should be increased to minimize the spread of CRE. Loosening the rules
of prophylaxis and surveillance of infections, irrational use of antibiotics may not only
negatively affect the treatment process and mortality of patients with COVID-19, but also
lead to the outbreak of a pandemic of bacterial infections caused by CRE. Not without
reason, the authors give alarming titles to their publications: “ . . . The storm after the
storm, “ . . . Keep an eye on the ball”, “ . . . One Step Back in Antimicrobial Stewardship”,
“ . . . What Did Not Work?” [31,35,36,38].

5. A Limitation of Scoping Review

This review is a first step in expanding knowledge in this area. Further studies should
be conducted using more extensive data and more detailed designs. The decision to include
studies that identified only CRKP does not provide a view on the overall rate of CRE in
patients hospitalized for COVID-19. In some presented studies, the discrimination between
colonization and infection was not clear enough [31,34,38]. Although the use of broad
spectrum antibiotics is the major drive for MDR pathogens, four (out of ten), studies did
not mention their use in COVID 19 patients prior to MDR organism infection [31,33,37,38].
Studies from Italy are overpresented. It may be due to the fact that, according to the
European Center for Disease Control, 7.5% of carbapenem-resistant K. pneumoniae were
isolated from cultures in Europe before the pandemic, while in Italy, it was 26.8%. At
that time, infection control and prophylaxis programs were put to the test. In the course
of the pandemic in Italy, control of bacterial infections took a back seat and they saw an
increase in infections again. It should also be noted that the nature of the relatively new
SARS-CoV-2 virus is still under investigation and data on it are constantly being updated.

6. Conclusions
The results presented here indicate the need for attention to infections caused by
carbapenem-resistant Klebsiella pneumoniae. It is particularly true in patients with COVID-
19, in whom the immune mechanisms seem to be weakened by this viral infection. Rational
antibiotic therapy should be pursued with the goal of not allowing bacterial resistance
to increase. There is also a need for the ongoing surveillance and control of hospital-
acquired infections. These should not only focus on minimizing the spread of SARS-
CoV-2 infection, but also on reducing bacterial cross-transmission, particularly of MDR
organisms. The critically ill patients are the most susceptible to infection. Therefore, it
should not be forgotten to continue the implementation of prophylaxis against ventilator-
associated pneumonia, as well as bloodstream infections related to the poor management
of central catheters.
J. Clin. Med. 2021, 10, 2067 11 of 13

7. Implications for Practice

Further research should be conducted on the causes of cross-transmission of infective
organisms, with particular attention paid to the contaminated PPE of medical workers and
patient positioning (prone position), as well as their impact on CRE colonization.

Author Contributions: Conceptualization, W.M.-D., S.L., S.D.; methodology, W.M.-D., S.D., K.Z.;
formal analysis, W.M.-D., S.L., S.D.; writing—original draft preparation, W.M.-D., S.L., S.D.; writing—
review and editing, W.M.-D., S.L., K.Z., S.D.; visualization, W.M.-D.; D.O., L.T.; supervision, K.Z.;
D.O., L.T.; All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The authors declare that the data of this research are available from
the correspondence author on request.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Carvalhaes, C.G.; Cayô, R.; Gales, A.C. Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae in the Intensive
Care Unit: A Real Challenge to Physicians, Scientific Community, and Society. Shock 2013, 39, 32–37. [CrossRef]
2. Logan, L.K.; Weinstein, R.A. The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a
Global Menace. J. Infect. Dis. 2017, 215, S28–S36. [CrossRef]
3. Martin, R.M.; Bachman, M.A. Colonization, Infection, and the Accessory Genome of Klebsiella pneumoniae. Front. Cell. Infect.
Microbiol. 2018, 8, 4. [CrossRef]
4. Alves, A.; Sucena, I.; Ribeiro, C.; Silva, E.; Shiang, T.; Vanzeller, M. Factors associated with colonization and infection by
Carbapenem Resistant Enterobacteriaceae. Eur. Respir. J. 2018, 52, PA4702. [CrossRef]
5. Sievert, D.M.; Ricks, P.; Edwards, J.R.; Schneider, A.; Patel, J.; Srinivasan, A.; Kallen, A.; Limbago, B.; Fridkin, S. Antimicrobial-
resistant pathogens associated with healthcare-associated infections: Summary of data reported to the National Healthcare Safety
Network at the Centers for Disease Control and Prevention, 2009–2010. Infect. Control Hosp. Epidemiol. 2013, 34, 1–14. [CrossRef]
6. Kotb, S.; Lyman, M.; Ismail, G.; El Fattah, M.A.; Girgis, S.A.; Etman, A.; Hafez, S.; El-Kholy, J.; Zaki, M.E.S.; Rashed, H.-A.G.; et al.
Epidemiology of Carbapenem-resistant Enterobacteriaceae in Egyptian intensive care units using National Healthcare–associated
Infections Surveillance Data, 2011–2017. Antimicrob. Resist. Infect. Control 2020, 9, 1–9. [CrossRef]
7. Yuling, Z.; Zhao, Y.; Liu, C.; Chen, Z.; Zhou, D. Molecular pathogenesis of Klebsiella pneumoniae. Future Microbiol. 2014, 9,
1071–1081. [CrossRef]
8. Czekaj, T.; Ciszewski, M. Klebsiella pneumoniae NDM—New emerging superbacteria. Med. Rodz. 2015, 1, 23–27.
9. Xu, L.; Sun, X.; Ma, X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella
pneumoniae. Ann. Clin. Microbiol. Antimicrob. 2017, 16, 1–12. [CrossRef]
10. Reyes, J.; Aguilar, A.C.; Caicedo, A. Carbapenem-Resistant Klebsiella pneumoniae: Microbiology Key Points for Clinical Practice.
Int. J. Gen. Med. 2019, 12, 437–446. [CrossRef]
11. Nordmann, P.; Dortet, L.; Poirel, L. Carbapenem resistance in Enterobacteriaceae: Here is the storm! Trends Mol. Med. 2012, 18,
263–272. [CrossRef]
12. Molton, J.S.; Tambyah, P.A.; Ang, B.S.P.; Ling, M.L.; Fisher, D.A. The Global Spread of Healthcare-Associated Multidrug-Resistant
Bacteria: A Perspective from Asia. Clin. Infect. Dis. 2013, 56, 1310–1318. [CrossRef] [PubMed]
13. McConville, T.H.; Sullivan, S.B.; Gomez-Simmonds, A.; Whittier, S.; Uhlemann, A.-C. Carbapenem-resistant Enterobacteriaceae
colonization (CRE) and subsequent risk of infection and 90-day mortality in critically ill patients, an observational study. PLoS
ONE 2017, 12, e0186195. [CrossRef]
14. Kang, J.S.; Yi, J.; Ko, M.K.; Lee, S.O.; Lee, J.E.; Kim, K.-H. Prevalence and Risk Factors of Carbapenem-resistant Enterobacteriaceae
Acquisition in an Emergency Intensive Care Unit in a Tertiary Hospital in Korea: A Case-Control Study. J. Korean Med. Sci. 2019,
34, e140. [CrossRef] [PubMed]
15. Kumarasamy, K.K.; Toleman, M.A.; Walsh, T.R.; Bagaria, J.; Butt, F.; Balakrishnan, R.; Chaudhary, U.; Doumith, M.; Giske, C.G.;
Irfan, S.; et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and
epidemiological study. Lancet Infect. Dis. 2010, 10, 597–602. [CrossRef]
16. Ludwig, S.; Zarbock, A. Coronaviruses and SARS-CoV-2: A Brief Overview. Anesth Analg. 2020, 20. [CrossRef]
17. Rawson, T.M.; Moore, L.S.P.; Zhu, N.; Ranganathan, N.; Skolimowska, K.; Gilchrist, M.; Satta, G.; Cooke, G.; Holmes, A. Bacterial
and Fungal Coinfection in Individuals with Coronavirus: A Rapid Review to Support COVID-19 Antimicrobial Prescribing. Clin.
Infect. Dis. 2020, 71, 2459–2468. [CrossRef]
J. Clin. Med. 2021, 10, 2067 12 of 13

18. Phelan, A.L.; Katz, R.; Gostin, L.O. The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health
Governance. JAMA 2020, 323, 709. [CrossRef]
19. Bengoechea, J.A.; Bamford, C.G. SARS-CoV-2, bacterial coinfections, and AMR: The deadly trio in COVID-19? EMBO Mol. Med.
2020, 12, e12560. [CrossRef]
20. Bogossian, E.G.; Taccone, F.S.; Izzi, A.; Yin, N.; Garufi, A.; Hublet, S.; Njimi, H.; Ego, A.; Gorham, J.; Byl, B.; et al. The Acquisition
of Multidrug-Resistant Bacteria in Patients Admitted to COVID-19 Intensive Care Units: A Monocentric Retrospective Case
Control Study. Microorganisms 2020, 8, 1821. [CrossRef] [PubMed]
21. Moledina, S.M.; Maini, A.A.; Gargan, A.; Harland, W.; Jenney, H.; Phillips, G.; Thomas, K.; Chauhan, D.; Fertleman, M. Clinical
Characteristics and Predictors of Mortality in Patients with COVID-19 Infection Outside Intensive Care. Int. J. Gen. Med. 2020, 13,
1157–1165. [CrossRef] [PubMed]
22. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors
for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062.
[CrossRef]
23. Leung, V.; Westwood, D.; MacFadden, D.R.; Soucy, J.P.J.; Daneman, N. Bacterial co-infection and secondary infection in patients
with COVID-19: A living rapid review and meta-analysis. Clin. Microbiol. Infect. 2020, 26, 1622–1629. [CrossRef]
24. Zhu, X.; Ge, Y.; Wu, T.; Zhao, K.; Chen, Y.; Wu, B.; Zhu, F.; Zhu, B.; Cui, L. Co-infection with respiratory pathogens among
COVID-2019 cases. Virus Res. 2020, 285, 198005. [CrossRef]
25. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of
150 patients from Wuhan, China. Intensiv. Care Med. 2020, 46, 846–848. [CrossRef]
26. Munn, Z.; Peters, M.D.J.; Stern, C.; Tufanaru, C.; McArthur, A.; Aromataris, E. Systematic review or scoping review? Guidance
for authors when choosing between a systematic or scoping review approach. BMC Med. Res. Methodol. 2018, 18, 143. [CrossRef]
27. Shea, B.J.; Reeves, B.C.; Wells, G.; Thuku, M.; Hamel, C.; Moran, J.; Moher, D.; Tugwell, P.; Welch, V.; Kristjansson, E.; et al.
AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare
interventions, or both. BMJ 2017, 358, j4008. [CrossRef]
28. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available online:
http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed on 5 February 2021).
29. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; for the PRISMA Group. Preferred reporting items for systematic reviews and
meta-analyses: The PRISMA statement. BMJ 2009, 339, b2535. [CrossRef]
30. Karruli, A.; Boccia, F.; Gagliardi, M.; Patauner, F.; Ursi, M.P.; Sommese, P.; De Rosa, R.; Murino, P.; Ruocco, G.; Corcione, A.; et al.
Multidrug-Resistant Infections and Outcome of Critically Ill Patients with Coronavirus Disease 2019: A Single Center Experience.
Microb. Drug Resist. 2021. [CrossRef]
31. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically
ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir.
Med. 2020, 8, 475–481, Erratum in Lancet Respir Med. 2020, 8, e26. [CrossRef]
32. Li, J.; Wang, J.; Yang, Y.; Cai, P.; Cao, J.; Cai, X.; Zhang, Y. Etiology and antimicrobial resistance of secondary bacterial infections in
patients hospitalized with COVID-19 in Wuhan, China: A retrospective analysis. Antimicrob. Resist. Infect. Control 2020, 9, 153.
[CrossRef] [PubMed]
33. Ramadan, H.K.-A.; Mahmoud, M.; Aburahma, M.Z.; Elkhawaga, A.; El-Mokhtar, M.; Sayed, I.M.; Hosni, A.; Hassany, S.M.;
Medhat, M. Predictors of Severity and Co-Infection Resistance Profile in COVID-19 Patients: First Report from Upper Egypt.
Infect. Drug Resist. 2020, 13, 3409–3422. [CrossRef] [PubMed]
34. Gomez-Simmonds, A.; Annavajhala, M.K.; McConville, T.H.; Dietz, D.; Shoucri, S.M.; Laracy, J.C.; Rozenberg, F.D.; Nelson,
B.; Greendyke, W.G.; Furuya, E.Y.; et al. Carbapenemase-producing Enterobacterales causing secondary infections during the
COVID-19 crisis at a New York City hospital. J. Antimicrob. Chemother. 2021, 76, 380–384. [CrossRef] [PubMed]
35. García-Meniño, I.; Forcelledo, L.; Rosete, Y.; García-Prieto, E.; Escudero, D.; Fernández, J. Spread of OXA-48-producing Klebsiella
pneumoniae among COVID-19-infected patients: The storm after the storm. J. Infect. Public Health 2021, 14, 50–52. [CrossRef]
36. Montrucchio, G.; Corcione, S.; Sales, G.; Curtoni, A.; De Rosa, F.; Brazzi, L. Carbapenem-resistant Klebsiella pneumoniae in
ICU-admitted COVID-19 patients: Keep an eye on the ball. J. Glob. Antimicrob. Resist. 2020, 23, 398–400. [CrossRef]
37. Arcari, G.; Raponi, G.; Sacco, F.; Bibbolino, G.; Di Lella, F.M.; Alessandri, F.; Coletti, M.; Trancassini, M.; Deales, A.; Pugliese,
F.; et al. Klebsiella pneumoniae infections in COVID-19 patients: A 2-month retrospective analysis in an Italian hospital. Int. J.
Antimicrob. Agents 2021, 57, 106245. [CrossRef]
38. Magnasco, L.; Mikulska, M.; Giacobbe, D.; Taramasso, L.; Vena, A.; Dentone, C.; Dettori, S.; Tutino, S.; Labate, L.; Di Pilato,
V.; et al. Spread of Carbapenem-Resistant Gram-Negatives and Candida auris During the COVID-19 Pandemic in Critically Ill
Patients: One Step Back in Antimicrobial Stewardship? Microorganisms 2021, 9, 95. [CrossRef]
39. Arteaga-Livias, K.; Pinzas-Acosta, K.; Perez-Abad, L.; Panduro-Correa, V.; Rabaan, A.A.; Pecho-Silva, S.; Dámaso-Mata, B. A
multidrug-resistant Klebsiella pneumoniae outbreak in a Peruvian hospital: Another threat from the COVID-19 pandemic. Infect.
Control Hosp. Epidemiol. 2021, 1–2. [CrossRef]
40. Tiri, B.; Sensi, E.; Marsiliani, V.; Cantarini, M.; Priante, G.; Vernelli, C.; Martella, L.A.; Costantini, M.; Mariottini, A.; Andreani,
P.; et al. Antimicrobial Stewardship Program, COVID-19, and Infection Control: Spread of Carbapenem-Resistant Klebsiella
pneumoniae Colonization in ICU COVID-19 Patients. What Did Not Work? J. Clin. Med. 2020, 9, 2744. [CrossRef]
J. Clin. Med. 2021, 10, 2067 13 of 13

41. Belvisi, V.; Del Borgo, C.; Vita, S.; Redaelli, P.; Dolce, P.; Pacella, D.; Kertusha, B.; Carraro, A.; Marocco, R.; De Masi, M.; et al. Impact
of SARS CoV-2 pandemic on carbapenemase-producing Klebsiella pneumoniae prevention and control programme: Convergent or
divergent action? J. Hosp. Infect. 2021, 109, 29–31. [CrossRef]
42. Soriano, M.C.; Vaquero, C.; Ortiz-Fernández, A.; Caballero, A.; Blandino-Ortiz, A.; de Pablo, R. Low incidence of co-infection, but
high incidence of ICU-acquired infections in critically ill patients with COVID-19. J. Infect. 2021, 82, e20–e21. [CrossRef]
43. Mahmoudi, H. Bacterial co-infections and antibiotic resistance in patients with COVID-19. GMS Hyg. Infect. Control 2020, 15.
[CrossRef]
44. Hughes, S.; Troise, O.; Donaldson, H.; Mughal, N.; Moore, L. Bacterial and fungal coinfection among hospitalized patients with
COVID-19: A retrospective cohort study in a UK secondary-care setting. Clin. Microbiol. Infect. 2020, 26, 1395–1399. [CrossRef]
[PubMed]
45. Norton, A. Many COVID-19 Patients Given Useless Antibiotics, Study Finds; Isle of Man; Medical Xpress: Bradford, UK, 4 August
2020; Available online: https://medicalxpress.com/news/2020-08-covid-patients-useless-antibiotics.html (accessed on 15
February 2021).
46. Getahun, H.; Smith, I.; Trivedi, K.; Paulin, S.; Balkhy, H.H. Tackling antimicrobial resistance in the COVID-19 pandemic. Bull.
World Health Organ. 2020, 98, 442. [CrossRef]
47. Chedid, M.; Waked, R.; Haddad, E.; Chetata, N.; Saliba, G.; Choucair, J. Antibiotics in treatment of COVID-19 complications: A
review of frequency, indications, and efficacy. J. Infect. Public Health 2021, 14, 570–576. [CrossRef]
48. Pelfrene, E.; Botgros, R.; Cavaleri, M. Antimicrobial multidrug resistance in the era of COVID-19: A forgotten plight? Antimicrob.
Resist. Infect. Control 2021, 10, 21. [CrossRef] [PubMed]
49. Baiou, A.; Elbuzidi, A.A.; Bakdach, D.; Zaqout, A.; Alarbi, K.M.; Bintaher, A.A.; Ali, M.M.B.; Elarabi, A.M.; Ali, G.A.M.; Daghfal,
J.; et al. Clinical characteristics and risk factors for the isolation of multi-drug-resistant Gram-negative bacteria from critically ill
patients with COVID-19. J. Hosp. Infect. 2021, 110, 165–171. [CrossRef]