Antimicrobial Resistance in ICUs An Update in The.2
Antimicrobial Resistance in ICUs An Update in The.2
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.
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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
1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.com
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
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
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
&&
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.
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
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&& of outstanding interest
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