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 . 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.
MULTIDRUG-RESISTANT AND DIFFICULT-TO-TREAT ANTIMICROBIAL-RESISTANT GRAM-NEGATIVE MICROORGANISMS
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) . 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.
ANTIMICROBIAL RESISTANCE TRENDS IN ESKAPE GRAM-NEGATIVE ORGANISMS IN THE ICU
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%) . 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 . 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 . 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. 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].
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. 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. 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. 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▪].
MULTIDRUG-RESISTANT HIGH-RISK CLONES IN THE ICU
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 . In this context, the concept of HiRCs has been used to address the importance of successful populations within bacterial pathogenic species . 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).
Within the Gram-negatives, the ST131 E. coli is a recognized HiRC mostly associated with the global expansion of ESBL, especially CTX-M-15 . 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 . Moreover, the molecular analysis showed that the rising frequency of the clonal group ST131 is responsible for this increase . 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 . 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 . K. pneumoniae-ST258 has been described as a cause of prolonged ICU outbreaks  and even the transmission of colistin-resistant ST258-KPC isolates have been documented among ICU patients . 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 . 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 .
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].
ANTIMICROBIAL RESISTANCE, COVID-19 PATIENTS AND ICUS
The COVID-19 pandemic was declared by WHO on 12 March 2020 (https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic). 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.
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 . 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.
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