Secondary Logo

Journal Logo

SEVERE INFECTIONS: Edited by Jean-François Timsit

Antimicrobial resistance in ICUs: an update in the light of the COVID-19 pandemic

Cantón, Rafaela,b; Gijón, Desirèea,b; Ruiz-Garbajosa, Patriciaa,b

Author Information
Current Opinion in Critical Care: October 2020 - Volume 26 - Issue 5 - p 433-441
doi: 10.1097/MCC.0000000000000755
  • Free



Currently, healthcare-related infections are a major public health problem worldwide, and infections caused by multidrug resistant (MDR) bacteria are becoming more relevant. It has been demonstrated that indiscriminate use of antibiotics favors the appearance and rapid dissemination of these microorganisms. The problem is emphasized in ICUs where patients present higher risk factors for nosocomial infections, mainly due to MDR microorganisms. Moreover, the cost of antimicrobial resistance in these infections is very high since infections caused by these pathogens have worse clinical outcomes, prolonged hospital stays and high mortality rates.

Surveillance of antimicrobial resistance is recognized as an important tool at local, national and global levels for establishing better guidelines for empiric antimicrobial therapy and preventing the dissemination of antimicrobial resistance. Moreover, during the last years, the relevance of the so-called high-risk clones (HiRCs), including emerging ones, in the spread of antimicrobial resistance has been emphasized [1]. In this review, we present the current situation of resistance trends in Gram-negative ESKAPE microorganisms (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) in ICUs, and the implication of the HiRCs in the spread of antimicrobial resistance. Moreover, due to the emergence of SARS-CoV-2 during the last year and heavy antibiotic use in these patients [2▪], we review different aspects of the potential implication of COVID-19 patients admitted in ICUs in the spread of MDR pathogens. 

Box 1
Box 1:
no caption available


During the last decade and according to a joint panel of the European Center for Disease Prevention and Control (ECDC) and the US Centers for Diseases Control and Prevention (CDC), bacterial pathogens related to antimicrobial resistance have been classified as MDR, extensive-drug resistant (XDR) and pan-drug resistance (PDR) [3]. This classification reflects the increasing number of antimicrobial agents affected by the presence of different resistance mechanisms in the same pathogen. MDR is defined as nonsusceptible to at least one antimicrobial in three or more antimicrobial categories; XDR is defined as nonsusceptible to at least one antimicrobial in all but two or fewer antimicrobial categories; and lastly PDR is defined as nonsusceptible to all antimicrobial agents. Recently and for the better understanding of the implications of antimicrobial resistance in the selection of antimicrobial therapy and in the prevention of the spread of antimicrobial resistance pathogen, a new designation has been proposed and named as ‘difficult-to-treat antimicrobial resistant pathogens’ [4▪▪]. This concept implies that the microorganism is resistant to all first-line high efficacy, low-toxicity agents, whereas it is susceptible to ‘reserve agents’, including colistin, aminoglycosides and tigecycline. From a practical point of view, it is roughly defined as in-vitro resistance to all beta-lactams (including carbapenems) and fluoroquinolones. This classification has been used by the CDC to classify bloodstream pathogens in patients requiring an ICU stay and also to establish mortality risk in patients infected by these microorganisms [4▪▪,5]. Future surveillance studies in ICUs should adopt this new definition for the presentation of antimicrobial resistance data.

On the other hand, a recent publication reported a 2017 survey carried out among physicians working in European ICUs to determinate their perception of infections caused by antibiotic-resistant bacteria and the use of last-line antibiotics [6▪]. Overall, infections due to MDR bacteria were considered a major (24.2%) or moderate (33.9%) problem. Third-generation cephalosporin-resistant Enterobacterales were the most frequently reported MDR bacteria followed by methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacterales and P. aeruginosa, and vancomycin-resistant enterococci. Regarding the use of last-line antibiotics, linezolid, colistin, tigecycline and daptomycin were the most commonly prescribed, however, not all of them were available in all European ICUs. This survey indicates that infections with bacteria resistant to almost all available antibiotics are a reality in ICUs and that the access to last-line antibiotics is sometimes limited. Moreover, differences between subregions emphasize the need for a national and worldwide uniform analysis of the antimicrobial resistance trend. The newly defined ‘difficult-to-treat antimicrobial resistant pathogen’ concept might be an opportunity for this approach. Also, the survey illustrates the need for actions for monitoring local epidemiology to address the problem of antimicrobial resistance in ICUs.


Several surveillance studies have exemplified the increase of resistance trends over the last year. Within these studies, the SENTRY Antimicrobial Surveillance Program and the Study for Monitoring Antimicrobial Resistance Trends (SMART) programs have collected and recently published data on the global and regional resistance levels of the main ESKAPE organisms causing relevant bacterial infections for over 20 years [7,8]. These programs have demonstrated increasing resistance trends to specific antimicrobial classes among the main species. With regard to expanded spectrum cephalosporin-resistance [extended-spectrum beta-lactamase (ESBL) phenotype], a dramatic increase in Escherichia coli after the 2005–2008 period (4.6–10.4% in 2009–2012) was demonstrated. This increase has been related with the worldwide spread of the E. coli sequence type (ST)131 lineage that carries the ESBL Active on cefotaxime, first isolated at Munich (CTX-M)-15. With regard to K. pneumoniae isolates, the increase in resistance to carbapenems occurred exponentially, and the ESBL-phenotype rates increased almost 15% from 1997–2000 to 2013–2016 (21.7–36.1%) [7]. An additional significant finding in this program was the overall increase in carbapenem resistance and dominantly among K. pneumoniae. Not only was a significant increase in carbapenem resistant rates (0.6–2.9%) observed worldwide, but a remarkable change in the epidemiology of the different type of carbapenemase enzymes was reported. Overall, K. pneumoniae carbapenemase (KPC) producing Enterobacterales continue to predominate in several geographic areas but other carbapenemases such as New Delhi Metallo-beta-lactamase (NDM) and Active on oxacillin (OXA)-48 enzymes have contributed significantly to the increasing carbapenem resistant rates after 2012. The presence of KPC producing Enterobacterales was confirmed in the SMART surveillance study in the United States, whereas in other geographical areas like Turkey the most common carbapenemase was OXA-48 [9,10]. These results highlight the importance of monitoring local epidemiology, which might be relevant for antimicrobial use and stewardship programs.

On the other hand, the SENTRY Program has also reviewed geographic and temporal trends in resistant phenotypes of P. aeruginosa over the 20 years of the study [11]. Usually, MDR P. aeruginosa isolates are resistant to carbapenems and other β-lactams, which is mediated through multiple resistance mechanisms [12▪▪]. This study revealed that colistin was the most active agent overall (99.4% susceptible with CLSI/EUCAST criteria) and against isolates with MDR and XDR phenotypes. MDR isolates were most frequently found in Latin America (41.1%), followed by Europe (28.4%), North America (18.9%) and Asia-Pacific (18.8%). In addition, the rates of MDR and other resistant phenotypes for P. aeruginosa were highest in 2005–2008 and decreased in the most recent period of the study.

Finally, A. baumannii complex frequently causes nosocomial infections, particularly in ICUs where the incidence has increased over time. The SENTRY program evaluated the frequency of cases and antimicrobial susceptibility profiles of the A. baumannii collection from medical centers registered in this program [13]. This study showed that these isolates were recovered mainly from patients with pneumonia and bloodstream infections and evidenced reduced susceptibility to most antimicrobials tested. In all regions, colistin was the most active agent followed by minocycline. Imipenem and meropenem showed poor activity against these isolates. On the other hand, because of the limited therapeutic options and the high morbi-mortality associated with infections caused by Acinetobacter spp. Ayobami et al.[14] investigated epidemiological trends of carbapenem-resistant Acinetobacter spp. isolated from patients with invasive infections using EARS-net data. This study showed that most carbapenem-resistant Acinetobacter spp. isolates also revealed nonsusceptibility to ciprofloxacin and gentamicin. It is of note that coresistances to ciprofloxacin and gentamicin were especially high in south and east European areas, where antibiotic use is higher than in north European countries.

Rates of resistant bacteria in ICUs vary between country, hospitals and even hospital settings. Surveillance reports from the ECDC roughly give an idea of the problem of antimicrobial resistance in ICUs from Europe: ceftazidime resistance was found in 26.5% of P. aeruginosa and carbapenem resistance in 15.2 and 25.9% of Klebsiella spp. and P. aeruginosa isolates, respectively [15▪]. Resistance trends in ESKAPE Gram-negative pathogens in the ECDC reports regarding ICUs are shown in Fig. 1[15▪,16–18].

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].

Because patients infected by MDR bacteria are increasingly being reported in the ICUs, it is necessary to assess the in-vitro activity of new antibiotics against these microorganisms. As an example, García-Fernández et al.[19] evaluated the new combination ceftolozane–tazobactam against Enterobacterales and P. aeruginosa clinical isolates collected from ICU patients with urinary tract and complicated intra-abdominal infections in Spain. This study revealed that 23.0 and 26.4% of P. aeruginosa isolates were resistant to third-generation cephalosporins and carbapenems, respectively, whereas ceftolozane–tazobactam resistance was less than 5%. Moreover, 21.0% of E. coli and 24.6% of K. pneumoniae isolates were resistant to fluoroquinolones. Concerning third-generation cephalosporins, 12.4% of E. coli and 25.7% of K. pneumoniae isolates were resistant. Resistance to ceftolozane–tazobactam in ESBL-producing E. coli isolates was 19.3% with higher rates in ESBL-producing K. pneumoniae isolates (40.9%) (EUCAST breakpoints). No activity of ceftolozane–tazobactam was observed in carbapenemase-producing isolates. The activity of ceftazidime–avibactam as well as imipenem–relebactam has also been evaluated in isolates recovered from ICUs. Asempa et al.[20] study the role of this new combination in nonsusceptible P. aeruginosa isolates recovered from patients admitted to the ICU in different US hospitals. Carbapenem nonsusceptibility was observed in 35% of tested isolates, whereas ceftazidime–avibactam and imipenem–relebactam nonsusceptibility were just 7.2 and 8.5%, respectively. The activity of ceftazidime–avibactam was also studied in Taiwan by Liao et al.[21] observing that 99, 100 and 91% of the E. coli, K. pneumoniae and P. aeruginosa, respectively, were susceptible to this combination. All these results highlight the need to research and develop new antibiotics. However, in recent years, only a few new antibiotics have been marketed and are not always available for use in different ICUs [6▪].


Molecular epidemiology studies have shown that within a bacterial population certain clusters or lineages are over-represented among MDR isolates recovered from infected or colonized patients [22]. In this context, the concept of HiRCs has been used to address the importance of successful populations within bacterial pathogenic species [22]. These HiRCs have the ability to accumulate resistant determinants and have played an important role in the global emergence of MDR bacteria such as ESKAPE pathogens [23▪▪] (Table 1). For instance, several studies analyzing the population structure of carbapenemase producing Enterobacterales or MDR/XDR P. aeruginosa revealed that these resistant organisms are concentrated in a few clones when compared with the susceptible population. Several HiRCs exemplify the importance of these populations in the ICU ecology, which are frequently involved in cross-transmission events and multiresistance (Table 1).

Table 1
Table 1:
Summary of high-risk clones of Gram-negative pathogens involved in the emergence and maintenance of antimicrobial resistance in ICU environment

Within the Gram-negatives, the ST131 E. coli is a recognized HiRC mostly associated with the global expansion of ESBL, especially CTX-M-15 [24]. A recent study conducted in Canada described a significant increase in the proportion of ESBL-producing E. coli in bloodstream infections among ICU patients, with a prevalence of 11% in 2006 compared with 26% in 2016 [25]. Moreover, the molecular analysis showed that the rising frequency of the clonal group ST131 is responsible for this increase [25]. Currently, it has also been shown that ST131 E. coli produces carbapenemases, and other resistance genes, but to a lesser extent than K. pneumoniae which is the most important Enterobacterales species associated with the carbapenemase dissemination worldwide [26]. In a recent work, the genome sequences and epidemiological data of more than 1700 K. pneumoniae clinical isolates recovered from 244 hospitals in 32 countries, during the European survey of carbapenemase-producing Enterobacteriaceae were analyzed [27▪]. Almost 70% of carbapenemase-producing isolates were concentrated in four clonal lineages (ST11, ST15, ST101 and ST258/512) demonstrating a high degree of intra and interhospital spread of these clones across Europe [27▪]. The ST258 clone is responsible for the global dissemination of KPC and is endemic in USA (where it emerged in the 1990s), Israel and in some south European countries, especially in Italy and Greece [22]. K. pneumoniae-ST258 has been described as a cause of prolonged ICU outbreaks [28] and even the transmission of colistin-resistant ST258-KPC isolates have been documented among ICU patients [29]. Other K. pneumoniae HiRCs such as ST11, ST15, ST101, ST147 or the emerging ST307 clone have also been associated with the global dissemination of KPC, NDM or OXA-48-like enzymes and they have also affected the critical ill patient population [30–33,34▪,35]. Currently, it is important to highlight that the emergence of ceftazidime–avibactam resistance mainly due to the selection of KPC-2/3-derived mutant β-lactamases, is closely related to those HiRCs like ST258 or ST307 [36,37▪▪]. Nevertheless, an outbreak caused by a ceftazidime–avibactam-resistant KPC-2-producing K. pneumoniae-ST147 with a novel transferable ceftazidime–avibactam-resistant mechanism due to a Vietnamese extended-spectrum β-lactamase variant (VEB), has recently been reported in two ICUs of a Greek general hospital [34▪,38]. This finding emphasizes the importance of HiRC in the development of resistance, even against last-line antibiotics such as ceftazidime–avibactam.

In addition to E. coli or K. pneumoniae, the epidemiology of P. aeruginosa is also characterized by the presence of HiRCs. The ST111, ST175, ST235 and ST244 clones have been described as successful P. aeruginosa HiRCs, grouping the majority of MDR/XDR and/or carbapenemase producing strains, including those recovered from ICU patients [12▪▪,39]. The ST111, ST235 and ST244 clones show a world-wide distribution, whereas the ST175 clone is confined to European countries [12▪▪]. Different carbapenemases enzymes have been detected in these HiRCs with geographic variations. For instance, a multicenter study carried out in Spain described the interregional dissemination of HiRC ST175 and ST244 producing Verona Integron-encoded Metallo-betalactamase and Active on imipenem enzymes in Spanish hospitals [40]. Finally, it is important to point out the role of the ICU environment as a reservoir of P. aeruginosa HiRCs, as it may be involved in cross-transmission events [41].

Lastly, A. baumannii infections are an increasing concern in ICUs worldwide. In A. baumannii, the spread of MDR and carbapenem-resistant isolates is associated with three international clonal lineages, CC1 (European clone 1 comprising ST1, ST7, ST8, ST19 and ST20), CC2 (European clone 2 comprising ST2, ST45 and ST47) and CC3 (European clone 3 comprising ST3 and ST14). CC1 is prevalent worldwide, whereas CC2 and CC3 are highly prevalent in Europe and North America [23▪▪]. These HiRCs have been described as a cause of outbreaks and have been isolated for prolonged periods of time in ICUs worldwide [42,43].


The COVID-19 pandemic was declared by WHO on 12 March 2020 ( At that time, the disease was quickly spreading since the first detection of SARS-CoV-2 coronavirus in Wuhan, China, in December 2019 [44▪▪]. According to different series, up to 5% of patients infected with SARS-CoV-2 needed to be admitted in the ICU [45▪,46]. It has been documented that up to 50% of these patients might have had secondary bacterial infections or superinfections, mainly bacteremia and urinary tract infections [47,48]. These infections are more prevalent in terminal patients and are mainly due to MDR microorganisms [49▪▪]. Risk factors for infections have been demonstrated in these patients, including those associated with MDR microorganisms, such as antibiotic use [in these patients a high use of antibacterials (80–100% of patients) and antifungals (7.5–15% of patients) has been shown], the presence of previous chronic pulmonary disease (18%), mechanical ventilation (21%) as well as a prolonged hospital stay [45▪,50].

During the first months of the pandemic, the principal effort with COVID-19 patients in the ICU was aimed at improving their clinical situation associated with the respiratory disease and the so-called cytokine storm. On the contrary, less attention was directed at secondary or supra-bacterial infections. As a consequence, different articles have been published warning to the risk of these infections and the higher development of resistance in COVID-19 patients when compared with non-COVID-19 patient, although the contrary has been also claimed [2▪,51–53]. Figure 2 summarize for and against reasons of the increase of antimicrobial resistance in the ICU environment associated with COVID-19. More reasons related with an increase in antimicrobial resistance can be cited when compared with the arguments for the decrease in the resistance rates. Reasons for a major impact of the SARS-CoV-2 infection in the increase in antimicrobial resistance are mainly related with the rise of empiric antimicrobial use, overcrowding of the healthcare systems, disappearance of stewardship measures and decrease in the rhythm of laboratories activity on surveillance cultures and diagnostic tests to detect antimicrobial resistant organisms. On the other hand, a minor impact on antimicrobial resistance development could be associated with the increase of infection control measures adopted to avoid healthcare personnel contamination with SARS-CoV-2, including hand hygiene, the use of personal protective equipment and devices to decontaminate air and surfaces. Also, early antibiotic prescription has been indicated as a protective effect of COVID-19 patients but this might also have played a role in the positive trend of antimicrobial resistance.

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

A systematic review and meta-analysis of coinfections in patients with COVID-19 concluded that only 7% of hospitalized patients presented a bacterial coinfection, but this increased to 14% in studies that only included ICU patients [48,49▪▪]. Overall, the specific coinfecting bacterial pathogens were Mycoplasma pneumoniae (42%) followed by P. aeruginosa (12%), Haemophilus influenzae (12%) and K. pneumoniae. Other pathogens were Enterobacter spp. and A. baumannii and less represented was Enterococcus faecium and interestingly MRSA. The presence of a specific resistance mechanism in the infecting pathogen has been scarcely investigated and, in two studies, the isolation of ESBL-producing microorganisms or carbapenem resistant pathogens in COVID-19 patients was reported [48,54]. Most of the data included in the systematic review and meta-analysis came from China and studies could have been biased from local epidemiology. However, a retrospective cohort study in a UK secondary care setting revealed similar data resulting in low bacterial coinfections [55▪]. S. aureus was the most common respiratory pathogen isolated in community-acquired coinfection (16.7%) with P. aeruginosa and yeast identified in late-onset infections.


In the last decades, a significant increase in resistance to first-line antimicrobial agents has been observed in Enterobacterales, P. aeruginosa and A. baumannii. ESBL and carbepenamase enzymes are the main resistance mechanisms affecting beta-lactam agents, although there are important geographic variations in the resistance rates and enzymes distribution. The increase of antimicrobial resistance in ICUs is mainly due to the spread of HiRCs, which have played an important role in the global emergence of MDR bacteria, even against last-line antibiotics such as ceftazidime–avibactam. During the last year, the COVID-19 pandemic has generated an overuse of antimicrobials in critical ill patients. Current guidelines of COVID-19 patients do not include specific recommendation of antibiotic use or special control measures to avoid nosocomial infections in these patients [56]. At present, there are not publications of the COVID-19 pandemic impact in antimicrobial consumption nor those related with the follow-up of surveillance cultures in SARS-CoV-2-infected patients admitted in ICUs. These studies are needed to clarify the impact of antimicrobial use on resistance. In summary, this review highlights the importance of monitoring local epidemiology, which might be relevant for antimicrobial use and stewardship programs.


We thank Mary Harper for correction of the English used in the article.

Financial support and sponsorship

Research of R.C. and P.R.-G. are funded by the European Commission, Seven Framework Program (grants R-GNOSIS-FP7-HEALTH-F3-2011-282512) and the Instituto de Salud Carlos III of Spain, Plan Estatal DE I+D+I 2013–2016 (REIPI RD12/0015/0004 and RD16/0016/0011, Spanish Network for Research in Infectious Diseases) and cofinanced by the European Development Regional Fund, ‘A Way to Achieve Europe’ (FEDER). D.G. is funded through a research contract within the Spanish Network for Research in Infectious Diseases (RD16/0016/0011).

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest


1. Cantón R, Ruiz-Garbajosa P. Co-resistance: an opportunity for the bacteria and resistance genes. Curr Opin Pharmacol 2011; 11:477485.
2▪. Rawson TM, Ming D, Ahmad R, et al. Antimicrobial use, drug-resistant infections and COVID-19. Nat Rev Microbiol 2020; 2:12.
3. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268281.
4▪▪. Strich JR, Kadri SS. Difficult-to-treat antibiotic-resistant Gram-negative pathogens in the intensive care unit: epidemiology, outcomes and treatment. Semin Respir Crit Care Med 2019; 40:419434.
5. Kadri SS, Lai YLE, Ricotta EE, et al. External validation of difficult-to-treat resistance prevalence and mortality risk in Gram-negative bloodstream infection using electronic health record data from 140 US hospitals. Open Forum Infect Dis 2019; 6:ofz110.
6▪. Lepape A, Jean A, De Waele J, et al. European intensive care physicians’ experience of infections due to antibiotic-resistant bacteria. Antimicrob Resist Infect Control 2020; 9:1.
7. Castanheira M, Deshpande LM, Mendes RE, et al. Variations in the occurrence of resistance phenotypes and carbapenemase genes among Enterobacteriaceae isolates in 20 years of the SENTRY Antimicrobial Surveillance Program. Open Forum Infect Dis 2019; 6: (Suppl 1): S23S33. 15.
8. Paterson DL, Rossi F, Baquero F, et al. In vitro susceptibilities of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2003 Study for Monitoring Antimicrobial Resistance Trends (SMART). J Antimicrob Chemother 2005; 55:965973.
9. Koksal I, Yilmaz G, Unal S, et al. Epidemiology and susceptibility of pathogens from SMART 2011-12 Turkey: evaluation of hospital-acquired versus community-acquired urinary tract infections and ICU- versus non-ICU-associated intra-abdominal infections. J Antimicrob Chemother 2017; 72:13641372.
10. Karlowsky JA, Lob SH, Kazmierczak KM, et al. In-vitro activity of imipenem/relebactam and key β-lactam agents against Gram-negative bacilli isolated from lower respiratory tract infection samples of intensive care unit patients – SMART Surveillance United States. Int J Antimicrob Agents 2020; 55:105841.
11. Shortridge D, Gales AC, Streit JM, et al. Geographic and temporal patterns of antimicrobial resistance in Pseudomonas aeruginosa over 20 years from the SENTRY antimicrobial surveillance program, 1997–2016. Open Forum Infect Dis 2019; 6: (Suppl 1): S63S68.
12▪▪. Horcajada JP, Montero M, Oliver A, et al. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin Microbiol Rev 2019; 28 (32):e0003119.
13. Gales AC, Seifert H, Gur D, et al. Antimicrobial susceptibility of Acinetobacter calcoaceticusAcinetobacter baumannii complex and Stenotrophomonas maltophilia clinical isolates: results from the SENTRY antimicrobial surveillance program. Open Forum Infect Dis 2019; 6: (Suppl 1): S34S46. 15.
14. Ayobami O, Willrich N, Suwono B, et al. The epidemiology of carbapenem-nonsusceptible Acinetobacter species in Europe: analysis of EARS-Net data from 2013 to 2017. Antimicrob Resist Infect Control 2020; 19:89.
15▪. European Centre for Disease Prevention and Control (ECDC). Healthcare-associated infections acquired in intensive care units. ECDC annual epidemiological report for 2017. 2019; Stockholm, Sweden: ECDC, (Accessed July 2, 2002).
16. European Centre for Disease Prevention and Control. Healthcare-associated infections acquired in intensive care units. Annual epidemiological report for 2016 2018; Stockholm: ECDC, (Accessed July 2, 2002).
17. European Centre for Disease Prevention and Control. Healthcare-associated infections acquired in intensive care units. Annual epidemiological report for 2015 2017; Stockholm: ECDC, (Accessed July 2, 2002).
18. European Centre for Disease Prevention and Control. Annual epidemiological report 2014 – healthcare-associated infections acquired in intensive care units. 2016; Stockholm: ECDC, (Accessed July 2, 2002).
19. García-Fernández S, García-Castillo M, Bou G, et al. Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: the SUPERIOR multicentre study. Int J Antimicrob Agents 2019; 53:682688.
20. Asempa TE, Nicolau DP, Kuti JL. Carbapenem-non susceptible Pseudomonas aeruginosa isolates from intensive care units in the United States: a potential role for new β-lactam combination agents. J Clin Microbiol 2019; 26 (57):e0053519.
21. Liao CH, Lee NY, Tang HJ, et al. Antimicrobial activities of ceftazidime–avibactam, ceftolozane–tazobactam, and other agents against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolated from intensive care units in Taiwan: results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan in 2016. Infect Drug Resist 2019; 12:545552.
22. Mathers AJ, Peirano G, Pitout JD. The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae. Clin Microbiol Rev 2015; 28:565591.
23▪▪. De Oliveira DMP, Forde BM, Kidd TJ, et al. Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev 2020; 13 (33):e0018119.
24. Pitout JDD, Finn TJ. The evolutionary puzzle of Escherichia coli ST131. Infect Genet Evol 2020; 81:104265.
25. Mineau S, Kozak R, Kissoon M, et al. Emerging antimicrobial resistance among Escherichia coli strains in bloodstream infections in Toronto, 2006–2016: a retrospective cohort study. CMAJ Open 2018; 6:E580E586.
26. Ellaby N, Doumith M, Hopkins KL, et al. Emergence of diversity in carbapenemase-producing Escherichia coli ST131, England, January 2014 to June 2016. Euro Surveill 2019; 24:1800627.
27▪. David S, Reuter S, Harris SR, et al. Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nat Microbiol 2019; 4:19191929.
28. Marsh JW, Mustapha MM, Griffith MP, et al. Evolution of outbreak-causing carbapenem-resistant Klebsiella pneumoniae ST258 at a tertiary care hospital over 8 years. mBio 2019; 3 (10):e0194519.
29. Mavroidi A, Katsiari M, Likousi S, et al. Characterization of ST258 colistin-resistant, blaKPC-producing Klebsiella pneumoniae in a Greek hospital. Microb Drug Resist 2016; 22:392398.
30. Gijón D, Tedim AP, Valverde A, et al. Early OXA-48-producing Enterobacterales isolates recovered in a Spanish hospital reveal a complex introduction dominated by sequence type 11 (ST11) and ST405 Klebsiella pneumoniae Clones. mSphere 2020; 8 (5):e0008020.
31. Politi L, Gartzonika K, Spanakis N, et al. Emergence of NDM-1-producing Klebsiella pneumoniae in Greece: evidence of a widespread clonal outbreak. J Antimicrob Chemother 2019; 74:21972202.
32. Sánchez-Romero I, Asensio A, Oteo J, et al. Nosocomial outbreak of VIM-1-producing Klebsiella pneumoniae isolates of multilocus sequence type 15: molecular basis, clinical risk factors, and outcome. Antimicrob Agents Chemother 2012; 56:420427.
33. Haller S, Kramer R, Becker K, et al. Extensively drug-resistant Klebsiella pneumoniae ST307 outbreak, north-eastern Germany, June to October. Euro Surveill 2019; 24:1900734.
34▪. Galani I, Karaiskos I, Souli M, et al. Outbreak of KPC-2-producing Klebsiella pneumoniae endowed with ceftazidime-avibactam resistance mediated through a VEB-1-mutant (VEB-25), Greece, September to October 2019. Euro Surveill 2020; 25:2000028.
35. Strydom KA, Chen L, Kock MM, et al. Klebsiella pneumoniae ST307 with OXA-181: threat of a high-risk clone and promiscuous plasmid in a resource-constrained healthcare setting. J Antimicrob Chemother 2020; 75:896902.
36. Galani I, Antoniadou A, Karaiskos I, et al. Genomic characterization of a KPC-23-producing Klebsiella pneumoniae ST258 clinical isolate resistant to ceftazidime-avibactam. Clin Microbiol Infect 2019; 25:763.e5763.e8.
37▪▪. Giddins MJ, Macesic N, Annavajhala MK, et al. Successive emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in blaKPC-2-harboring Klebsiella pneumoniae sequence type 307 isolates. Antimicrob Agents Chemother 2018; 23 (62):e0210117.
38. Voulgari E, Kotsakis SD, Giannopoulou P, et al. Detection in two hospitals of transferable ceftazidime-avibactam resistance in Klebsiella pneumoniae due to a novel VEB β-lactamase variant with a Lys234Arg substitution, Greece 2019. Euro Surveill 2020; 25:1900766.
39. Slekovec C, Robert J, van der Mee-Marquet N, et al. Molecular epidemiology of Pseudomonas aeruginosa isolated from infected ICU patients: a French multicenter 2012–2013 study. Eur J Clin Microbiol Infect Dis 2019; 38:921926.
40. Pérez-Vázquez M, Sola-Campoy PJ, Zurita ÁM, et al. Int J Antimicrob Agents 2020; 22:106026.
41. Pelegrin AC, Saharman YR, Griffon A, et al. High-risk international clones of carbapenem-non susceptible Pseudomonas aeruginosa endemic in Indonesian intensive care units: impact of a multifaceted infection control intervention analyzed at the genomic level. mBio 2019; 12 (10):e0238419.
42. Zhao Y, Hu K, Zhang J, et al. Outbreak of carbapenem-resistant Acinetobacter baumannii carrying the carbapenemase OXA-23 in ICU of the eastern Heilongjiang Province, China. BMC Infect Dis 2019; 19:452.
43. Piana A, Palmieri A, Deidda S, et al. Molecular typing of XDR Acinetobacter baumannii strains in an Italian ICU. Epidemiol Prev 2015; 39: (4 Suppl 1): 129133.
44▪▪. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China. N Engl J Med 2020; 382:727733.
45▪. Clancy CJ, Nguyen MH. COVID-19, superinfections and antimicrobial development: what can we expect? Clin Infect Dis 2020; 1:ciaa524.
46. Bengoechea JA, Bamford CGG. SARS-CoV-2, bacterial co-infections, and AMR: the deadly trio in COVID-19? EMBO Mol Med 2020; 26:e12560.
47. Rawson TM, Moore LSP, Zhu N, et al. Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020; 2:ciaa530.
48. Fu Y, Yang Q, Xu M, et al. Secondary bacterial infections in critical ill patients with coronavirus disease 2019. Version 2. Open Forum Infect Dis 2020; 5:ofaa220.
49▪▪. Lansbury L, Lim B, Baskaran V, et al. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 2020; 27: S0163-4453(20)30323-6.
50. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study. BMJ 2020; 369:m1985522.
51. Huttner BD, Catho G, Pano-Pardo JR, et al. COVID-19: don’t neglect antimicrobial stewardship principles!. Clin Microbiol Infect 2020; 26:808810.
52. Rawson TM, Moore LSP, Castro-Sanchez E, et al. COVID-19 and the potential long-term impact on antimicrobial resistance. J Antimicrob Chemother 2020; 75:16811684.
53. Spernovasilis NA, Kofteridis DP. COVID-19 and antimicrobial stewardship: what is the interplay? Infect Control Hosp Epidemiol 2020; 15:12.
54. Yang X, Yu Y, Xu J, 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; 8:475481.
55▪. Hughes S, Troise O, Donaldson H, et al. Bacterial and fungal coinfection among hospitalised patients with COVID-19: a retrospective cohort study in a UK secondary care setting. Clin Microbiol Infect 2020; 27: S1198-743X(20)30369-4.
56. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious diseases society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis 2020; 27:ciaa478.

antimicrobial resistance surveillance; COVID-19 pandemics; ESKAPE Gram-negative pathogens; high-risk clones; ICUs

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