REVIEW

CURRENT
OPINION Antimicrobial resistance in ICUs: an update in the
light of the COVID-19 pandemic
Rafael Cantón a,b, Desirèe Gijón a,b, and Patricia Ruiz-Garbajosa a,b

Purpose of review
To describe current antimicrobial resistance in ESKAPE Gram-negative microorganisms and their situation in
the ICUs, the implication of the so-called high-risk clones (HiRCs) involved in the spread of antimicrobial
resistance as well as relevance of the COVID-19 pandemic in the potential increase of resistance.
Downloaded from http://journals.lww.com/co-criticalcare by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 12/07/2020

Recent findings
Extended-spectrum and carbapenemase producing Enterobacterales and multidrug and extensive drug-
resistant Pseudomonas aeruginosa and Acinetobacter baumannii have increased worldwide. Sequence
type (ST)131 Escherichia coli, ST258, ST11, ST10, ST147 and ST307 Klebsiella pneumoniae, ST111,
ST175, ST235 and ST244 P. aeruginosa HiRCs are responsible for this increase in the ICUs, and some of
them are implicated in the emergence of resistance mechanisms affecting new antimicrobials. A similar
situation can be found with European clonal complex 1 and clonal complex 2 of A. baumannii. The high
use of antimicrobials during the COVID-19 pandemic, particularly in ICUs, might have a negative influence
in future trends of antimicrobial resistance.
Summary
The increase of antimicrobial resistance in ICUs is mainly due to the spread of HiRCs and is exemplified
with the ESKAPE Gram-negative microorganisms. The COVID-19 pandemic might have a negative impact
in the increase of antimicrobial resistance and should be monitored through specific surveillance studies in
ICUs.
Keywords
antimicrobial resistance surveillance, COVID-19 pandemics, ESKAPE Gram-negative pathogens, high-risk
clones, ICUs

INTRODUCTION the so-called high-risk clones (HiRCs), including

Currently, healthcare-related infections are a major emerging ones, in the spread of antimicrobial resis-
public health problem worldwide, and infections tance has been emphasized [1]. In this review, we
caused by multidrug resistant (MDR) bacteria are present the current situation of resistance trends in
becoming more relevant. It has been demonstrated Gram-negative ESKAPE microorganisms (Klebsiella
that indiscriminate use of antibiotics favors the pneumoniae, Acinetobacter baumannii, Pseudomonas
appearance and rapid dissemination of these micro- aeruginosa and Enterobacter spp.) in ICUs, and the
organisms. The problem is emphasized in ICUs implication of the HiRCs in the spread of antimi-
where patients present higher risk factors for noso- crobial resistance. Moreover, due to the emergence
comial infections, mainly due to MDR microorgan- of SARS-CoV-2 during the last year and heavy
isms. Moreover, the cost of antimicrobial resistance
in these infections is very high since infections a
Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal and
caused by these pathogens have worse clinical out- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and bSpanish
comes, prolonged hospital stays and high mortality Network for the Research in Infectious Diseases (REIPI), Instituto de
Salud Carlos III, Madrid, Spain
rates.
Correspondence to Rafael Cantón, PhD, Servicio de Microbiologı́a,
Surveillance of antimicrobial resistance is recog-
Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de
nized as an important tool at local, national and Investigación Sanitaria (IRYCIS), Carretera de Colmenar Km 9, 100;
global levels for establishing better guidelines for 28034 Madrid, Spain. Tel: +34 91 3368832;
empiric antimicrobial therapy and preventing e-mail: [email protected]
the dissemination of antimicrobial resistance. Curr Opin Crit Care 2020, 26:433–441
Moreover, during the last years, the relevance of DOI:10.1097/MCC.0000000000000755

1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections

ICUs should adopt this new definition for the pre-

KEY POINTS sentation of antimicrobial resistance data.
 Antimicrobial resistance in Gram-negative ESKAPE On the other hand, a recent publication
microorganisms in ICUs has reached a relevant rate reported a 2017 survey carried out among physi-
and is associated with the spread of the so- cians working in European ICUs to determinate
called HiRCs. their perception of infections caused by antibiotic-
resistant bacteria and the use of last-line antibiotics
 Difficult-to-treat pathogens should be included in the &

surveillance studies in ICUs. [6 ]. Overall, infections due to MDR bacteria were

considered a major (24.2%) or moderate (33.9%)
 COVID-19 pandemics could have had a negative problem. Third-generation cephalosporin-resistant
impact on antimicrobial resistance and should be Enterobacterales were the most frequently reported
analyzed in future surveillance studies involving ICUs.
MDR bacteria followed by methicillin-resistant
Staphylococcus aureus (MRSA), carbapenem-resistant
Enterobacterales and P. aeruginosa, and vancomycin-
&
antibiotic use in these patients [2 ], we review dif- resistant enterococci. Regarding the use of last-line
ferent aspects of the potential implication of antibiotics, linezolid, colistin, tigecycline and dap-
COVID-19 patients admitted in ICUs in the spread tomycin were the most commonly prescribed, how-
of MDR pathogens. ever, not all of them were available in all European
ICUs. This survey indicates that infections with
bacteria resistant to almost all available antibiotics
MULTIDRUG-RESISTANT AND DIFFICULT- are a reality in ICUs and that the access to last-line
TO-TREAT ANTIMICROBIAL-RESISTANT antibiotics is sometimes limited. Moreover, differ-
GRAM-NEGATIVE MICROORGANISMS ences between subregions emphasize the need for a
During the last decade and according to a joint panel national and worldwide uniform analysis of the
of the European Center for Disease Prevention and antimicrobial resistance trend. The newly defined
Control (ECDC) and the US Centers for Diseases ‘difficult-to-treat antimicrobial resistant pathogen’
Control and Prevention (CDC), bacterial pathogens concept might be an opportunity for this approach.
related to antimicrobial resistance have been classi- Also, the survey illustrates the need for actions for
fied as MDR, extensive-drug resistant (XDR) and monitoring local epidemiology to address the prob-
pan-drug resistance (PDR) [3]. This classification lem of antimicrobial resistance in ICUs.
reflects the increasing number of antimicrobial
agents affected by the presence of different resis-
tance mechanisms in the same pathogen. MDR is ANTIMICROBIAL RESISTANCE TRENDS IN
defined as nonsusceptible to at least one antimicro- ESKAPE GRAM-NEGATIVE ORGANISMS
bial in three or more antimicrobial categories; XDR IN THE ICU
is defined as nonsusceptible to at least one antimi- Several surveillance studies have exemplified the
crobial in all but two or fewer antimicrobial catego- increase of resistance trends over the last year.
ries; and lastly PDR is defined as nonsusceptible to Within these studies, the SENTRY Antimicrobial
all antimicrobial agents. Recently and for the better Surveillance Program and the Study for Monitoring
understanding of the implications of antimicrobial Antimicrobial Resistance Trends (SMART) programs
resistance in the selection of antimicrobial therapy have collected and recently published data on the
and in the prevention of the spread of antimicrobial global and regional resistance levels of the main
resistance pathogen, a new designation has been ESKAPE organisms causing relevant bacterial infec-
proposed and named as ‘difficult-to-treat antimicro- tions for over 20 years [7,8]. These programs have
&&
bial resistant pathogens’ [4 ]. This concept implies demonstrated increasing resistance trends to spe-
that the microorganism is resistant to all first-line cific antimicrobial classes among the main species.
high efficacy, low-toxicity agents, whereas it is sus- With regard to expanded spectrum cephalosporin-
ceptible to ‘reserve agents’, including colistin, ami- resistance [extended-spectrum beta-lactamase
noglycosides and tigecycline. From a practical point (ESBL) phenotype], a dramatic increase in Escheri-
of view, it is roughly defined as in-vitro resistance to chia coli after the 2005–2008 period (4.6–10.4% in
all beta-lactams (including carbapenems) and fluo- 2009–2012) was demonstrated. This increase has
roquinolones. This classification has been used by been related with the worldwide spread of the E.
the CDC to classify bloodstream pathogens in coli sequence type (ST)131 lineage that carries the
patients requiring an ICU stay and also to establish ESBL Active on cefotaxime, first isolated at Munich
mortality risk in patients infected by these micro- (CTX-M)-15. With regard to K. pneumoniae isolates,
&&
organisms [4 ,5]. Future surveillance studies in the increase in resistance to carbapenems occurred

434 www.co-criticalcare.com Volume 26  Number 5  October 2020

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

 Antimicrobial resistance in ICUs Cantón et al.

exponentially, and the ESBL-phenotype rates et al. [14] investigated epidemiological trends of car-
increased almost 15% from 1997–2000 to 2013– bapenem-resistant Acinetobacter spp. isolated from
2016 (21.7–36.1%) [7]. An additional significant patients with invasive infections using EARS-net
finding in this program was the overall increase in data. This study showed that most carbapenem-resis-
carbapenem resistance and dominantly among K. tant Acinetobacter spp. isolates also revealed nonsus-
pneumoniae. Not only was a significant increase in ceptibility to ciprofloxacin and gentamicin. It is of
carbapenem resistant rates (0.6–2.9%) observed note that coresistances to ciprofloxacin and genta-
worldwide, but a remarkable change in the epide- micin were especially high in south and east Euro-
miology of the different type of carbapenemase pean areas, where antibiotic use is higher than in
enzymes was reported. Overall, K. pneumoniae car- north European countries.
bapenemase (KPC) producing Enterobacterales con- Rates of resistant bacteria in ICUs vary between
tinue to predominate in several geographic areas but country, hospitals and even hospital settings. Surveil-
other carbapenemases such as New Delhi Metallo- lance reports from the ECDC roughly give an idea of
beta-lactamase (NDM) and Active on oxacillin the problem of antimicrobial resistance in ICUs from
(OXA)-48 enzymes have contributed significantly Europe: ceftazidime resistance was found in 26.5% of
to the increasing carbapenem resistant rates after P. aeruginosa and carbapenem resistance in 15.2 and
2012. The presence of KPC producing Enterobacter- 25.9% of Klebsiella spp. and P. aeruginosa isolates,
&
ales was confirmed in the SMART surveillance study respectively [15 ]. Resistance trends in ESKAPE
in the United States, whereas in other geographical Gram-negative pathogens in the ECDC reports
&
areas like Turkey the most common carbapenemase regarding ICUs are shown in Fig. 1 [15 ,16–18].
was OXA-48 [9,10]. These results highlight the Because patients infected by MDR bacteria are
importance of monitoring local epidemiology, increasingly being reported in the ICUs, it is neces-
which might be relevant for antimicrobial use and sary to assess the in-vitro activity of new antibiotics
stewardship programs. against these microorganisms. As an example, Gar-
On the other hand, the SENTRY Program has cı́a-Fernández et al. [19] evaluated the new combina-
also reviewed geographic and temporal trends in tion ceftolozane–tazobactam against Enterobacterales
resistant phenotypes of P. aeruginosa over the and P. aeruginosa clinical isolates collected from ICU
20 years of the study [11]. Usually, MDR P. aerugi- patients with urinary tract and complicated intra-
nosa isolates are resistant to carbapenems and other abdominal infections in Spain. This study revealed
b-lactams, which is mediated through multiple resis- that 23.0 and 26.4% of P. aeruginosa isolates were
&&
tance mechanisms [12 ]. This study revealed that resistant to third-generation cephalosporins and car-
colistin was the most active agent overall (99.4% bapenems, respectively, whereas ceftolozane–tazo-
susceptible with CLSI/EUCAST criteria) and against bactam resistance was less than 5%. Moreover,
isolates with MDR and XDR phenotypes. MDR iso- 21.0% of E. coli and 24.6% of K. pneumoniae isolates
lates were most frequently found in Latin America were resistant to fluoroquinolones. Concerning
(41.1%), followed by Europe (28.4%), North America third-generation cephalosporins, 12.4% of E. coli
(18.9%) and Asia-Pacific (18.8%). In addition, the and 25.7% of K. pneumoniae isolates were resistant.
rates of MDR and other resistant phenotypes for P. Resistance to ceftolozane–tazobactam in ESBL-pro-
aeruginosa were highest in 2005–2008 and decreased ducing E. coli isolates was 19.3% with higher rates in
in the most recent period of the study. ESBL-producing K. pneumoniae isolates (40.9%)
Finally, A. baumannii complex frequently causes (EUCAST breakpoints). No activity of ceftolozane–
nosocomial infections, particularly in ICUs where tazobactam was observed in carbapenemase-produc-
the incidence has increased over time. The SENTRY ing isolates. The activity of ceftazidime–avibactam as
program evaluated the frequency of cases and anti- well as imipenem–relebactam has also been evalu-
microbial susceptibility profiles of the A. baumannii ated in isolates recovered from ICUs. Asempa et al.
collection from medical centers registered in this [20] study the role of this new combination in non-
program [13]. This study showed that these isolates susceptible P. aeruginosa isolates recovered from
were recovered mainly from patients with pneumo- patients admitted to the ICU in different US hospi-
nia and bloodstream infections and evidenced tals. Carbapenem nonsusceptibility was observed in
reduced susceptibility to most antimicrobials tested. 35% of tested isolates, whereas ceftazidime–avibac-
In all regions, colistin was the most active agent tam and imipenem–relebactam nonsusceptibility
followed by minocycline. Imipenem and merope- were just 7.2 and 8.5%, respectively. The activity of
nem showed poor activity against these isolates. ceftazidime–avibactam was also studied in Taiwan by
On the other hand, because of the limited therapeutic Liao et al. [21] observing that 99, 100 and 91% of the
options and the high morbi-mortality associated E. coli, K. pneumoniae and P. aeruginosa, respectively,
with infections caused by Acinetobacter spp. Ayobami were susceptible to this combination. All these results

1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 435

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections

FIGURE 1. Resistance trends in Gram-negative pathogens to (a) third-generation cephalosporins (CEF3-R) and (b)
carbapenems (CARB-R) from 2014 to 2015. Data obtained from different reports of the European Center for Disease
Prevention and Control of healthcare-associated infections acquired in the ICU in Europe [15 ,16–18].
&

highlight the need to research and develop new anti- HiRCs have the ability to accumulate resistant deter-
biotics. However, in recent years, only a few new minants and have played an important role in the
antibiotics have been marketed and are not always global emergence of MDR bacteria such as ESKAPE
& &&
available for use in different ICUs [6 ]. pathogens [23 ] (Table 1). For instance, several
studies analyzing the population structure of carba-
penemase producing Enterobacterales or MDR/XDR
MULTIDRUG-RESISTANT HIGH-RISK P. aeruginosa revealed that these resistant organisms
CLONES IN THE ICU are concentrated in a few clones when compared
Molecular epidemiology studies have shown that with the susceptible population. Several HiRCs
within a bacterial population certain clusters or exemplify the importance of these populations in
lineages are over-represented among MDR isolates the ICU ecology, which are frequently involved
recovered from infected or colonized patients [22]. in cross-transmission events and multiresistance
In this context, the concept of HiRCs has been used (Table 1).
to address the importance of successful populations Within the Gram-negatives, the ST131 E. coli is a
within bacterial pathogenic species [22]. These recognized HiRC mostly associated with the global

436 www.co-criticalcare.com Volume 26  Number 5  October 2020

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

 Antimicrobial resistance in ICUs Cantón et al.

Table 1. Summary of high-risk clones of Gram-negative pathogens involved in the emergence and maintenance of
antimicrobial resistance in ICU environment
Specie Clon Mechanism of antimicrobial resistance
Coresistance

Escherichia coli ST131 ESBL (CTX-M-15, -14, -27) Fluoroquinolones [topoisomerase mutations, qnr, aac(60 )-Ib-
cr. . .]; plasmidic AmpC beta-lactamases, carbapenemases;
colistin resistance (mcr-1)
Klebsiella ST11 ESBL (CTX-M-15, . . .) Fluoroquinolones [topoisomerases mutations, qnr, aac(60 )-Ib-
pneumoniae ST15 Carbapenemases (KPC, cr. . .]; plasmidic AmpC beta-lactamases (DHA-1),
ST101 VIM, NDM, OXA-48) aminoglycoside resistance (ArmA, RmtB methylases)
ST147
ST258 Carbapenemases (KPC) Colistin resistance (mutations in pmrB), ceftazidime-avibactam
resistance
ST307 Carbapenemases (KPC-like, NDM) Ceftazidime-avibactam resistance
ST405 Carbapenemases (OXA-48) ESBL (CTX-M-15)
Pseudomonas ST101 Multiresistance Carbapenemases (VIM-2, GES-7, VEB-1, IMP-1, KPC-2, PER-1)
aeruginosa ST175
ST235
ST244
Acinetobacter ST2 Carbapenemases (OXA-23) Carbapenemases (OXA-24, OXA-58, NDM-1);
baumannii aminoglycosides [AAC(3)-Ia, AADA, ANT(200 )-I, APH(30 )-VI,
. . . and methylases (ArmA)]

CTX-M, Active on cefotaxime, first isolated at Munich; ESBL, extended-spectrum beta-lactamases; GES, Guiana-extended spectrum; IMP, active on imipenem; KPC,
Klebsiella pneumoniae carbapenemase; NDM, New Dehli metallo-beta-lactamase; OXA, Active on oxacillin; PER, Pseudomonas extended resistant; VEB,
Vietnamese extended-spectrum b-lactamase; VIM, Verona integron encoded metallo-beta-lactamases.

expansion of ESBL, especially CTX-M-15 [24]. A have been documented among ICU patients [29].
recent study conducted in Canada described a sig- Other K. pneumoniae HiRCs such as ST11, ST15,
nificant increase in the proportion of ESBL-produc- ST101, ST147 or the emerging ST307 clone have
ing E. coli in bloodstream infections among ICU also been associated with the global dissemination
patients, with a prevalence of 11% in 2006 com- of KPC, NDM or OXA-48-like enzymes and they
pared with 26% in 2016 [25]. Moreover, the mole- have also affected the critical ill patient population
&
cular analysis showed that the rising frequency of [30–33,34 ,35]. Currently, it is important to high-
the clonal group ST131 is responsible for this light that the emergence of ceftazidime–avibactam
increase [25]. Currently, it has also been shown that resistance mainly due to the selection of KPC-2/3-
ST131 E. coli produces carbapenemases, and other derived mutant b-lactamases, is closely related to
&&
resistance genes, but to a lesser extent than K. pneu- those HiRCs like ST258 or ST307 [36,37 ]. Never-
moniae which is the most important Enterobacterales theless, an outbreak caused by a ceftazidime–avi-
species associated with the carbapenemase dissemi- bactam-resistant KPC-2-producing K. pneumoniae-
nation worldwide [26]. In a recent work, the genome ST147 with a novel transferable ceftazidime–avibac-
sequences and epidemiological data of more than tam-resistant mechanism due to a Vietnamese
1700 K. pneumoniae clinical isolates recovered from extended-spectrum b-lactamase variant (VEB), has
244 hospitals in 32 countries, during the European recently been reported in two ICUs of a Greek gen-
&
survey of carbapenemase-producing Enterobacteria- eral hospital [34 ,38]. This finding emphasizes the
&
ceae were analyzed [27 ]. Almost 70% of carbapene- importance of HiRC in the development of resis-
mase-producing isolates were concentrated in four tance, even against last-line antibiotics such as cef-
clonal lineages (ST11, ST15, ST101 and ST258/512) tazidime–avibactam.
demonstrating a high degree of intra and interhos- In addition to E. coli or K. pneumoniae, the epi-
&
pital spread of these clones across Europe [27 ]. The demiology of P. aeruginosa is also characterized by
ST258 clone is responsible for the global dissemina- the presence of HiRCs. The ST111, ST175, ST235 and
tion of KPC and is endemic in USA (where it ST244 clones have been described as successful P.
emerged in the 1990s), Israel and in some south aeruginosa HiRCs, grouping the majority of MDR/
European countries, especially in Italy and Greece XDR and/or carbapenemase producing strains,
[22]. K. pneumoniae-ST258 has been described as a including those recovered from ICU patients
&&
cause of prolonged ICU outbreaks [28] and even the [12 ,39]. The ST111, ST235 and ST244 clones show
transmission of colistin-resistant ST258-KPC isolates a world-wide distribution, whereas the ST175 clone

1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 437

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections

&&
is confined to European countries [12 ]. Different It has been documented that up to 50% of these
carbapenemases enzymes have been detected in patients might have had secondary bacterial infec-
these HiRCs with geographic variations. For tions or superinfections, mainly bacteremia and
instance, a multicenter study carried out in Spain urinary tract infections [47,48]. These infections
described the interregional dissemination of HiRC are more prevalent in terminal patients and are
&&
ST175 and ST244 producing Verona Integron- mainly due to MDR microorganisms [49 ]. Risk
encoded Metallo-betalactamase and Active on imi- factors for infections have been demonstrated in
penem enzymes in Spanish hospitals [40]. Finally, it these patients, including those associated with
is important to point out the role of the ICU envi- MDR microorganisms, such as antibiotic use [in
ronment as a reservoir of P. aeruginosa HiRCs, as it these patients a high use of antibacterials (80–
may be involved in cross-transmission events [41]. 100% of patients) and antifungals (7.5–15% of
Lastly, A. baumannii infections are an increasing patients) has been shown], the presence of previous
concern in ICUs worldwide. In A. baumannii, the chronic pulmonary disease (18%), mechanical ven-
spread of MDR and carbapenem-resistant isolates is tilation (21%) as well as a prolonged hospital stay
&
associated with three international clonal lineages, [45 ,50].
CC1 (European clone 1 comprising ST1, ST7, ST8, During the first months of the pandemic, the
ST19 and ST20), CC2 (European clone 2 comprising principal effort with COVID-19 patients in the ICU
ST2, ST45 and ST47) and CC3 (European clone 3 was aimed at improving their clinical situation asso-
comprising ST3 and ST14). CC1 is prevalent world- ciated with the respiratory disease and the so-called
wide, whereas CC2 and CC3 are highly prevalent in cytokine storm. On the contrary, less attention was
&&
Europe and North America [23 ]. These HiRCs have directed at secondary or supra-bacterial infections.
been described as a cause of outbreaks and have been As a consequence, different articles have been pub-
isolated for prolonged periods of time in ICUs world- lished warning to the risk of these infections and the
wide [42,43]. higher development of resistance in COVID-19
patients when compared with non-COVID-19
patient, although the contrary has been also
ANTIMICROBIAL RESISTANCE, COVID-19 &
claimed [2 ,51–53]. Figure 2 summarize for and
PATIENTS AND ICUS against reasons of the increase of antimicrobial
The COVID-19 pandemic was declared by WHO on resistance in the ICU environment associated with
12 March 2020 (https://www.euro.who.int/en/ COVID-19. More reasons related with an increase in
health-topics/health-emergencies/coronavirus- antimicrobial resistance can be cited when com-
covid-19/news/news/2020/3/who-announces- pared with the arguments for the decrease in the
covid-19-outbreak-a-pandemic). At that time, the resistance rates. Reasons for a major impact of the
disease was quickly spreading since the first detec- SARS-CoV-2 infection in the increase in antimicro-
tion of SARS-CoV-2 coronavirus in Wuhan, China, bial resistance are mainly related with the rise of
&&
in December 2019 [44 ]. According to different empiric antimicrobial use, overcrowding of the
series, up to 5% of patients infected with SARS- healthcare systems, disappearance of stewardship
&
CoV-2 needed to be admitted in the ICU [45 ,46]. measures and decrease in the rhythm of laboratories

FIGURE 2. Pro and con reasons of the potential increase of antimicrobial resistance in ICUs due to the COVID-19 pandemics.

438 www.co-criticalcare.com Volume 26  Number 5  October 2020

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

 Antimicrobial resistance in ICUs Cantón et al.

activity on surveillance cultures and diagnostic tests do not include specific recommendation of antibi-
to detect antimicrobial resistant organisms. On the otic use or special control measures to avoid noso-
other hand, a minor impact on antimicrobial resis- comial infections in these patients [56]. At present,
tance development could be associated with the there are not publications of the COVID-19 pan-
increase of infection control measures adopted to demic impact in antimicrobial consumption nor
avoid healthcare personnel contamination with those related with the follow-up of surveillance
SARS-CoV-2, including hand hygiene, the use of cultures in SARS-CoV-2-infected patients admitted
personal protective equipment and devices to in ICUs. These studies are needed to clarify the
decontaminate air and surfaces. Also, early antibi- impact of antimicrobial use on resistance. In sum-
otic prescription has been indicated as a protective mary, this review highlights the importance of mon-
effect of COVID-19 patients but this might also have itoring local epidemiology, which might be relevant
played a role in the positive trend of antimicrobial for antimicrobial use and stewardship programs.
resistance.
A systematic review and meta-analysis of coin- Acknowledgements
fections in patients with COVID-19 concluded that
We thank Mary Harper for correction of the English used
only 7% of hospitalized patients presented a bacte-
in the article.
rial coinfection, but this increased to 14% in studies
&&
that only included ICU patients [48,49 ]. Overall,
Financial support and sponsorship
the specific coinfecting bacterial pathogens were
Research of R.C. and P.R.-G. are funded by the European
Mycoplasma pneumoniae (42%) followed by P. aeru-
Commission, Seven Framework Program (grants R-GNO-
ginosa (12%), Haemophilus influenzae (12%) and K.
SIS-FP7-HEALTH-F3-2011-282512) and the Instituto
pneumoniae. Other pathogens were Enterobacter spp.
de Salud Carlos III of Spain, Plan Estatal DE IþDþI
and A. baumannii and less represented was Entero-
2013–2016 (REIPI RD12/0015/0004 and RD16/0016/
coccus faecium and interestingly MRSA. The presence
0011, Spanish Network for Research in Infectious Dis-
of a specific resistance mechanism in the infecting
pathogen has been scarcely investigated and, in two eases) and cofinanced by the European Development
studies, the isolation of ESBL-producing microor- Regional Fund, ‘A Way to Achieve Europe’ (FEDER).
D.G. is funded through a research contract within the
ganisms or carbapenem resistant pathogens in
Spanish Network for Research in Infectious Diseases
COVID-19 patients was reported [48,54]. Most of
(RD16/0016/0011).
the data included in the systematic review and meta-
analysis came from China and studies could have
Conflicts of interest
been biased from local epidemiology. However, a
retrospective cohort study in a UK secondary There are no conflicts of interest.
care setting revealed similar data resulting in low
&
bacterial coinfections [55 ]. S. aureus was the most
REFERENCES AND RECOMMENDED
common respiratory pathogen isolated in commu-
READING
nity-acquired coinfection (16.7%) with P. aeruginosa Papers of particular interest, published within the annual period of review, have
and yeast identified in late-onset infections. been highlighted as:
& of special interest
&& of outstanding interest

CONCLUSION 1. Cantón R, Ruiz-Garbajosa P. Co-resistance: an opportunity for the bacteria

and resistance genes. Curr Opin Pharmacol 2011; 11:477–485.
In the last decades, a significant increase in resis- 2. Rawson TM, Ming D, Ahmad R, et al. Antimicrobial use, drug-resistant
infections and COVID-19. Nat Rev Microbiol 2020; 2:1–2.
tance to first-line antimicrobial agents has been &

A commentary on the potential impact of antimicrobial use on COVID-19 patients.

observed in Enterobacterales, P. aeruginosa and A. 3. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively
drug-resistant and pandrug-resistant bacteria: an international expert propo-
baumannii. ESBL and carbepenamase enzymes are sal for interim standard definitions for acquired resistance. Clin Microbiol
the main resistance mechanisms affecting beta-lac- Infect 2012; 18:268–281.
4. Strich JR, Kadri SS. Difficult-to-treat antibiotic-resistant Gram-negative patho-
tam agents, although there are important geo- && gens in the intensive care unit: epidemiology, outcomes and treatment. Semin
graphic variations in the resistance rates and Respir Crit Care Med 2019; 40:419–434.
The review discusses the global epidemiology, risk factors, burden and treatment
enzymes distribution. The increase of antimicrobial of highly resistant Gram-negative infections as they apply to the intensive care
resistance in ICUs is mainly due to the spread of population. Moreover, the new term ‘difficult-to-treat resistance’ is also discussed.
5. Kadri SS, Lai YLE, Ricotta EE, et al. External validation of difficult-to-treat
HiRCs, which have played an important role in resistance prevalence and mortality risk in Gram-negative bloodstream in-
the global emergence of MDR bacteria, even against fection using electronic health record data from 140 US hospitals. Open
Forum Infect Dis 2019; 6:ofz110.
last-line antibiotics such as ceftazidime–avibactam. 6. Lepape A, Jean A, De Waele J, et al. European intensive care physicians’
During the last year, the COVID-19 pandemic has & experience of infections due to antibiotic-resistant bacteria. Antimicrob Resist
Infect Control 2020; 9:1.
generated an overuse of antimicrobials in critical ill The survey assesses the intensive care physicians’ perception of the infections due to
patients. Current guidelines of COVID-19 patients antibiotic-resistant bacteria and the use of last-line antibiotics in the European Union.

1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 439

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections

7. Castanheira M, Deshpande LM, Mendes RE, et al. Variations in the occur- 27. David S, Reuter S, Harris SR, et al. Epidemic of carbapenem-resistant
rence of resistance phenotypes and carbapenemase genes among Enter- & Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nat
obacteriaceae isolates in 20 years of the SENTRY Antimicrobial Surveillance Microbiol 2019; 4:1919–1929.
Program. Open Forum Infect Dis 2019; 6(Suppl 1):S23–S3315. The work applies genome sequencing to elucidate the population structure of
8. Paterson DL, Rossi F, Baquero F, et al. In vitro susceptibilities of aerobic and carbapenem-resistant Klebsiella pneumoniae across European countries. High-
facultative Gram-negative bacilli isolated from patients with intra-abdominal risk clones (HiRCs) are transmitted predominantly via nosocomial routes.
infections worldwide: the 2003 Study for Monitoring Antimicrobial Resistance 28. Marsh JW, Mustapha MM, Griffith MP, et al. Evolution of outbreak-causing
Trends (SMART). J Antimicrob Chemother 2005; 55:965–973. carbapenem-resistant Klebsiella pneumoniae ST258 at a tertiary care hos-
9. Koksal I, Yilmaz G, Unal S, et al. Epidemiology and susceptibility of pathogens pital over 8 years. mBio 2019; 3(10):e01945–19.
from SMART 2011-12 Turkey: evaluation of hospital-acquired versus com- 29. Mavroidi A, Katsiari M, Likousi S, et al. Characterization of ST258 colistin-
munity-acquired urinary tract infections and ICU- versus non-ICU-associated resistant, blaKPC-producing Klebsiella pneumoniae in a Greek hospital.
intra-abdominal infections. J Antimicrob Chemother 2017; 72:1364–1372. Microb Drug Resist 2016; 22:392–398.
10. Karlowsky JA, Lob SH, Kazmierczak KM, et al. In-vitro activity of imipenem/ 30. Gijón D, Tedim AP, Valverde A, et al. Early OXA-48-producing Enterobacter-
relebactam and key b-lactam agents against Gram-negative bacilli isolated ales isolates recovered in a Spanish hospital reveal a complex introduction
from lower respiratory tract infection samples of intensive care unit patients – dominated by sequence type 11 (ST11) and ST405 Klebsiella pneumoniae
SMART Surveillance United States. Int J Antimicrob Agents 2020; Clones. mSphere 2020; 8(5):e00080–20.
55:105841. 31. Politi L, Gartzonika K, Spanakis N, et al. Emergence of NDM-1-producing
11. Shortridge D, Gales AC, Streit JM, et al. Geographic and temporal patterns of Klebsiella pneumoniae in Greece: evidence of a widespread clonal outbreak.
antimicrobial resistance in Pseudomonas aeruginosa over 20 years from the J Antimicrob Chemother 2019; 74:2197–2202.
SENTRY antimicrobial surveillance program, 1997–2016. Open Forum 32. Sánchez-Romero I, Asensio A, Oteo J, et al. Nosocomial outbreak of VIM-1-
Infect Dis 2019; 6(Suppl 1):S63–S68. producing Klebsiella pneumoniae isolates of multilocus sequence type 15:
12. Horcajada JP, Montero M, Oliver A, et al. Epidemiology and treatment of molecular basis, clinical risk factors, and outcome. Antimicrob Agents Che-
&& multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa mother 2012; 56:420–427.
infections. Clin Microbiol Rev 2019; 28(32):e00031–19. 33. Haller S, Kramer R, Becker K, et al. Extensively drug-resistant Klebsiella
A comprehensive literature of mechanisms of resistance, epidemiology, clinical pneumoniae ST307 outbreak, north-eastern Germany, June to October. Euro
impact and current and upcoming therapeutic options in multidrug resistant/ Surveill 2019; 24:1900734.
extensive-drug resistant Pseudomonas aeruginosa. 34. Galani I, Karaiskos I, Souli M, et al. Outbreak of KPC-2-producing Klebsiella
13. Gales AC, Seifert H, Gur D, et al. Antimicrobial susceptibility of Acinetobacter & pneumoniae endowed with ceftazidime-avibactam resistance mediated
calcoaceticus–Acinetobacter baumannii complex and Stenotrophomonas through a VEB-1-mutant (VEB-25), Greece, September to October 2019.
maltophilia clinical isolates: results from the SENTRY antimicrobial surveil- Euro Surveill 2020; 25:2000028.
lance program. Open Forum Infect Dis 2019; 6(Suppl 1):S34–S4615. The description of an outbreak in two Greek ICUs caused by a ceftazidime –
14. Ayobami O, Willrich N, Suwono B, et al. The epidemiology of carbapenem- avibactam resistant K. pneumoniae carbapenemase (KPC)-2 producing K. pneu-
nonsusceptible Acinetobacter species in Europe: analysis of EARS-Net data moniae isolate coproducing a new Vietnamese extended-spectrum b-lactamase-1
from 2013 to 2017. Antimicrob Resist Infect Control 2020; 19:89. variant.
15. European Centre for Disease Prevention and Control (ECDC). Healthcare- 35. Strydom KA, Chen L, Kock MM, et al. Klebsiella pneumoniae ST307 with
& associated infections acquired in intensive care units. ECDC annual epide- OXA-181: threat of a high-risk clone and promiscuous plasmid in a resource-
miological report for 2017. Stockholm, Sweden: ECDC; 2019 . https:// constrained healthcare setting. J Antimicrob Chemother 2020; 75:
www.ecdc.europa.eu/en/publications-data/healthcare-associated-infec- 896–902.
tions-intensive-care-units-annual-epidemiological-1 (Accessed July 2, 2002). 36. Galani I, Antoniadou A, Karaiskos I, et al. Genomic characterization of a
Last published report of the European Center for Disease Prevention and Control KPC-23-producing Klebsiella pneumoniae ST258 clinical isolate resis-
on antibiotic resistance in ESKAPE pathogens recovered in ICU in Europe. tant to ceftazidime-avibactam. Clin Microbiol Infect 2019; 25:763.
16. European Centre for Disease Prevention and Control. Healthcare-associated e5 – 763.e8.
infections acquired in intensive care units. In: Annual epidemiological report 37. Giddins MJ, Macesic N, Annavajhala MK, et al. Successive emergence of
for 2016. Stockholm: ECDC; 2018:. https://www.ecdc.europa.eu/sites/de- && ceftazidime-avibactam resistance through distinct genomic adaptations in
fault/files/documents/AER_for_2016-HAI_0.pdf (Accessed July 2, 2002). blaKPC-2-harboring Klebsiella pneumoniae sequence type 307 isolates. Anti-
17. European Centre for Disease Prevention and Control. Healthcare-associated microb Agents Chemother 2018; 23(62):e02101–17.
infections acquired in intensive care units. In: Annual epidemiological report Description of the evolution of a ceftazidime–avibactam susceptible K. pneumo-
for 2015. Stockholm: ECDC; 2017:. https://www.ecdc.europa.eu/sites/de- niae isolate to a resistant one due to the emergence of a KPC variant associated
fault/files/documents/AER_for_2015-healthcare-associated-infections_0.pdf with the HiRC ST307.
(Accessed July 2, 2002). 38. Voulgari E, Kotsakis SD, Giannopoulou P, et al. Detection in two hospitals of
18. European Centre for Disease Prevention and Control. Annual epidemiological transferable ceftazidime-avibactam resistance in Klebsiella pneumoniae due
report 2014 – healthcare-associated infections acquired in intensive care to a novel VEB b-lactamase variant with a Lys234Arg substitution, Greece
units. Stockholm: ECDC; 2016. https://www.ecdc.europa.eu/sites/default/ 2019. Euro Surveill 2020; 25:1900766.
files/documents/AER-HCAI_ICU_3_0.pdf (Accessed July 2, 2002). 39. Slekovec C, Robert J, van der Mee-Marquet N, et al. Molecular epidemiology
19. Garcı́a-Fernández S, Garcı́a-Castillo M, Bou G, et al. Activity of ceftolozane/ of Pseudomonas aeruginosa isolated from infected ICU patients: a French
tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates multicenter 2012–2013 study. Eur J Clin Microbiol Infect Dis 2019;
recovered from intensive care unit patients in Spain: the SUPERIOR multi- 38:921–926.
centre study. Int J Antimicrob Agents 2019; 53:682–688. 40. Pérez-Vázquez M, Sola-Campoy PJ, Zurita ÁM, et al. Carbapenemase-produ-
20. Asempa TE, Nicolau DP, Kuti JL. Carbapenem-non susceptible Pseudomo- cing Pseudomonas aeruginosa in Spain: interregional dissemination of the
nas aeruginosa isolates from intensive care units in the United States: a high-risk clones ST175 and ST244 carrying blaVIM-2, blaVIM-1, blaIMP-8, blaVIM-
potential role for new b-lactam combination agents. J Clin Microbiol 2019; 20 and blaKPC-2. Int J Antimicrob Agents 2020; 22:106026.
26(57):e00535–19. 41. Pelegrin AC, Saharman YR, Griffon A, et al. High-risk international clones of
21. Liao CH, Lee NY, Tang HJ, et al. Antimicrobial activities of ceftazidime– carbapenem-non susceptible Pseudomonas aeruginosa endemic in Indone-
avibactam, ceftolozane–tazobactam, and other agents against Escherichia sian intensive care units: impact of a multifaceted infection control intervention
coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolated from analyzed at the genomic level. mBio 2019; 12(10):e02384–19.
intensive care units in Taiwan: results from the Surveillance of Multicenter 42. Zhao Y, Hu K, Zhang J, et al. Outbreak of carbapenem-resistant Acinetobacter
Antimicrobial Resistance in Taiwan in 2016. Infect Drug Resist 2019; baumannii carrying the carbapenemase OXA-23 in ICU of the eastern
12:545–552. Heilongjiang Province, China. BMC Infect Dis 2019; 19:452.
22. Mathers AJ, Peirano G, Pitout JD. The role of epidemic resistance plasmids 43. Piana A, Palmieri A, Deidda S, et al. Molecular typing of XDR Acinetobacter
and international high-risk clones in the spread of multidrug-resistant Enter- baumannii strains in an Italian ICU. Epidemiol Prev 2015; 39(4 Suppl
obacteriaceae. Clin Microbiol Rev 2015; 28:565–591. 1):129–133.
23. De Oliveira DMP, Forde BM, Kidd TJ, et al. Antimicrobial resistance in 44. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with
&& ESKAPE pathogens. Clin Microbiol Rev 2020; 13(33):e00181–19. && pneumonia in China. N Engl J Med 2020; 382:727–733.
A recent review of the current state of antimicrobial resistance in ESKAPE Early description of the COVID-19 pandemics in China and patient’s clinical
pathogens, with a focus on new and emerging drug development. features.
24. Pitout JDD, Finn TJ. The evolutionary puzzle of Escherichia coli ST131. Infect 45. Clancy CJ, Nguyen MH. COVID-19, superinfections and antimicrobial devel-
Genet Evol 2020; 81:104265. & opment: what can we expect? Clin Infect Dis 2020; 1:ciaa524.
25. Mineau S, Kozak R, Kissoon M, et al. Emerging antimicrobial resistance Overview of the risk for bacterial infections and superinfections of SARS-CoV2
among Escherichia coli strains in bloodstream infections in Toronto, infected patients.
2006–2016: a retrospective cohort study. CMAJ Open 2018; 46. Bengoechea JA, Bamford CGG. SARS-CoV-2, bacterial co-infections, and
6:E580–E586. AMR: the deadly trio in COVID-19? EMBO Mol Med 2020; 26:e12560.
26. Ellaby N, Doumith M, Hopkins KL, et al. Emergence of diversity in carbape- 47. Rawson TM, Moore LSP, Zhu N, et al. Bacterial and fungal co-infection in
nemase-producing Escherichia coli ST131, England, January 2014 to individuals with coronavirus: a rapid review to support COVID-19 antimicro-
June 2016. Euro Surveill 2019; 24:1800627. bial prescribing. Clin Infect Dis 2020; 2:ciaa530.

440 www.co-criticalcare.com Volume 26  Number 5  October 2020

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

 Antimicrobial resistance in ICUs Cantón et al.

48. Fu Y, Yang Q, Xu M, et al. Secondary bacterial infections in critical ill patients with 53. Spernovasilis NA, Kofteridis DP. COVID-19 and antimicrobial stewardship:
coronavirus disease 2019. Version 2. Open Forum Infect Dis 2020; 5:ofaa220. what is the interplay? Infect Control Hosp Epidemiol 2020; 15:1–2.
49. Lansbury L, Lim B, Baskaran V, et al. Co-infections in people with COVID-19: 54. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients
&& a systematic review and meta-analysis. J Infect 2020; 27:. S0163- with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retro-
4453(20)30323-6. spective, observational study. Lancet Respir Med 2020; 8:475–481.
A complete systematic review and meta-analysis evaluating the burden of bacterial 55. Hughes S, Troise O, Donaldson H, et al. Bacterial and fungal coinfection
coinfections in patients with COVID-19. & among hospitalised patients with COVID-19: a retrospective cohort study in a
50. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in UK secondary care setting. Clin Microbiol Infect 2020; 27:. S1198-
hospital with COVID-19 using the ISARIC WHO clinical characterisation 743X(20)30369-4.
protocol: prospective observational cohort study. BMJ 2020; 369:m1985522. A retrospective cohort study in a UK secondary care setting revealing low bacterial
51. Huttner BD, Catho G, Pano-Pardo JR, et al. COVID-19: don’t neglect anti- coinfections in patients with COVID-19 and presenting community-acquired and
microbial stewardship principles! Clin Microbiol Infect 2020; 26:808–810. late-onset coinfections.
52. Rawson TM, Moore LSP, Castro-Sanchez E, et al. COVID-19 and the 56. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious diseases society of
potential long-term impact on antimicrobial resistance. J Antimicrob Che- America guidelines on the treatment and management of patients with
mother 2020; 75:1681–1684. COVID-19. Clin Infect Dis 2020; 27:ciaa478.

1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com 441

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.