Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 29, Number 8—August 2023
Research

Multidrug-Resistant Bacterial Colonization and Infections in Large Retrospective Cohort of Mechanically Ventilated COVID-19 Patients1

On This Page
Methods
Results
Discussion
Cite This Article
Figures
Figure 1
Figure 2
Figure 3
Tables
Table 1
Table 2
Table 3
Downloads
Article
Appendix
RIS [TXT - 2 KB]
Article Metrics
Metric Details
Related Articles
Sporadic Occurrence of Ensitrelvir-Resistant SARS-CoV-2, Japan
Detection of OXA-181 Carbapenemase in Shigella flexneri
Antimicrobial Resistance after Bacteremia
More articles on Antimicrobial Resistance
Author affiliations: Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy (D. Mangioni, E. Palomba, M. Bolis, N. Bottino, G. Breda, G. Massobrio, C. Matinato, A. Muscatello, G. Zuglian, G. Grasselli, A. Gori, N. Stocchetti, A. Bandera); University of Milan, Milan (D. Mangioni, E. Palomba, G. Grasselli, A. Gori, N. Stocchetti, A, Bandera); Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan (L. Chatenoud, M.V. Chiaruttini); Harvard Medical School, Boston, Massachusetts, USA (J. Colombo); ASST Grande Ospedale Metropolitano Niguarda, Milan (J. Colombo, F.A. Guerrero, G. Fior, M. Marotta, P. Previtali, S. Santambrogio, F. Tardini, R. Fumagalli, G. Monti); ULSS 3 Serenissima, Venice, Italy (G. Zuglian); University of Milano-Bicocca, Milan (R. Fumagalli)

Cite This Article

Abstract

Few data are available on incidence of multidrug-resistant organism (MDRO) colonization and infections in mechanically ventilated patients, particularly during the COVID-19 pandemic. We retrospectively evaluated all patients admitted to the COVID-19 intensive care unit (ICU) of Hub Hospital in Milan, Italy, during October 2020‒May 2021. Microbiologic surveillance was standardized with active screening at admission and weekly during ICU stay. Of 435 patients, 88 (20.2%) had MDROs isolated ≤48 h after admission. Of the remaining patients, MDRO colonization was diagnosed in 173 (51.2%), MDRO infections in 95 (28.1%), and non-MDRO infections in 212 (62.7%). Non-MDRO infections occurred earlier than MDRO infections (6 days vs. 10 days; p<0.001). Previous exposure to antimicrobial drugs within the ICU was higher in MDRO patients than in non-MDRO patients (116/197 [58.9%] vs. 18/140 [12.9%]; p<0.001). Our findings might serve as warnings for future respiratory viral pandemics and call for increased measures of antimicrobial stewardship and infection control.

Bacterial superinfections represent a major threat for patients in intensive care units (ICUs), severely affecting clinical course and length of hospital stay. The COVID-19 pandemic caused an unprecedented rate of ICU admissions and drastically changed ICU care itself, in terms of infection control measures and therapeutic usage of steroids and immunomodulating drugs. The percentages of hospital-acquired infections (HAIs) in COVID-19 patients vary widely, ranging from 7% to 13% in nonintensive hospital wards and up to 45% in ICUs (1–3).

Several studies have assessed the burden of multidrug-resistant organisms (MDROs) in COVID-19 patients admitted to ICUs, reporting heterogeneous results with prevalence ranging from 11% to 50% and incidence rate from 4.5 cases/1,000 patient-days to 30 cases/1,000 patient-days (4–21). However, studies published so far have relevant limitations, often not clearly discriminating between colonization and infection (8,9,11,12), and either including small populations or showing heterogeneity in clinical settings and microbiologic surveillance procedures when describing larger pool of persons, such as in multicentric studies (18–20).

Our study was conducted to address the need for further evidence on incidence and etiology of MDRO colonization and infections in mechanically ventilated COVID-19 patients. We analyzed clinical and microbiologic data systematically collected in a large ICU in northern Italy.

Methods

Study Design and Setting

We conducted a retrospective cohort study on routinely collected data of COVID-19 patients admitted to the Milano Fiera ICU during October 23, 2020‒May 31, 2021. This ICU was a large COVID-19 ICU developed in Milan, Italy, to face the effect of the pandemic. It admitted patients who had SARS-CoV-2 infection requiring mechanical ventilation from different healthcare settings: emergency department, nonintensive hospital wards, and other ICUs. This ICU could accommodate up to 100 patients divided into distinct units (modules) managed by ICU staff from different hospitals. Microbiologic surveillance was standardized and consisted of perineal and nasal swab specimens for MDROs and endotracheal aspirate cultures obtained at ICU admission and then once (perineal and nasal swab specimens) or twice (endotracheal aspirate) a week. All modules referred to the IRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation for laboratory and microbiologic analyses and for infectious diseases specialist consultation.

Study Participants and Data Collection

All consecutive patients who had laboratory-confirmed SARS-CoV-2 infection and were admitted to the ICU were considered for inclusion. Exclusion criteria were age <18 years, length of mechanical ventilation <48 h, and lack of comprehensive clinical documentation. We collected demographic, clinical, laboratory, and outcome data from clinical records and microbiologic and therapeutic data from dedicated hospital databases (Appendix). The study was registered by the Milan Area 2 Ethical Committee (#701_2021) and was conducted in accordance with standards of the Helsinki Declaration. Written informed consent was waived because of the retrospective nature of the analysis. The study was retrospectively registered at clinicaltrials.gov on March 24, 2022 (identifier: NCT05293418).

Microbiologic Data Processing

For each patient, we retrieved bacterial isolates from a microbiology database, which were independently reviewed by dedicated intensivists and infectious disease specialists and classified as contamination, colonization, or infection, according to international guidelines (Appendix) (22,23). In brief, infections were defined by the presence of a major bacterial load associated with clinical manifestations within the infection window period (±3 days from specimen collection) (22,23), Isolates were classified as colonization when no adverse clinical signs or symptoms were documented. We defined contamination as all microbiologic isolates that did not meet the criteria of infection or colonization and that were listed in the US Centers for Disease Control and Prevention National Healthcare Safety Network (https://www.cdc.gov/nhsn/index.html) list of common commensals. We retained only the first species-specific MDRO colonization of each patient for further analysis.

We distinguished new infectious episodes from persistent infections according to the European Centre for Disease Prevention and Control definitions (23). We stratified infection episodes as infection without sepsis, sepsis or septic shock according to Sepsis-3 criteria (24). We defined secondary bloodstream infections (BSIs) by using the secondary BSI attribution period according to the Centers for Diseases Control and Prevention National Healthcare Safety Network (22). We also defined isolates as MDROs when they were nonsusceptible to >1 agents in >3 antimicrobial drug categories (25) or when harboring specific antimicrobial drug resistance mechanisms (e.g., methicillin-resistant Staphylococcus spp., vancomycin-resistant Enterococcus spp., extended-spectrum β-lactamase/AmpC/carbapenemases‒producing Enterobacterales) by using rapid detection methods (4).

Statistical Analysis

We reported patient characteristics overall and for selected groups of interest, such as MDROs acquired before/after ICU admittance and MDRO infection/colonization. Medians (interquartile range [IQRs]) are reported for continuous variables and numbers (percentages) for categorical variables. We calculated crude incidence rates (IRs) per 1,000 patient-days and relative 95% CIs, considering for each patient any first species-specific MDRO colonization or each new MDRO/non-MDRO HAI (26). We used SAS version 9.4 software (SAS Institute, https://www.sas.com) for statistical analysis (Appendix).

Results

Population Description

Figure 1

Study flowchart showing patient selection process for multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May 2021. ICU, intensive care unit; MDR, multidrug resistant. Asterisks indicate subgroups. *Patients are grouped on the basis of the worst MDR event diagnosed in MDR colonization or MDR infection, irrespective of the presence of previous or later MDR colonization. †At ICU admission, there were 78 colonizations and 10 infections. During ICU stay, 35/78 (44.9%) colonized patients had MDR infections develop.

Figure 1. Study flowchart showing patient selection process for multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May 2021....

A total of 451 patients from 46 different hospitals were admitted to ICUs during October 2020‒May 2021. Of those, 435 were included in the analysis. We provide details of the patient selection process (Figure 1) and trends of patient admission by referring hospital per month (Appendix Figure 1).

Only 12/435 patients (2.7%) were reported to have MDRO colonization/infection before ICU admission. In 88/435 patients (20.2%), MDRO were isolated within 48 h upon entry to the ICU (MDR≤48h), and those patients were similarly distributed between referring hospitals (Appendix Figure 2). This group was composed of 78 colonizations and 10 infections; 35/78 (44.9%) colonized patients subsequently had MDRO infections develop. Compared with the 347 patients who had no evidence of MDRO during the first 48 hours of ICU stay (no-MDR+MDR>48h), the MDR≤48h group was characterized by higher admittance from other ICUs and lower admittances from emergency departments (ICU 31/88 [35.2%] in MDR≤48h vs. 86/347 [24.8%]) in no-MDR+MDR>48h; emergency department 15/88 [17.1%] in MDR≤48h vs. 102/347 [29.4%] in no-MDR+MDR>48h). The MDR≤48h group showed slightly longer (although not significantly) length of stay in the ICU of origin than patients who developed MDRO events later during their stay and to no-MDR patients (medians 11.5, 9, and 7 days, respectively; p = 0.09). The MDR≤48h group was also characterized by a larger amount of antimicrobial drug intake before ICU admission (no antimicrobial drug in 25/88 [28%] of MDR≤48h vs. 126/327 [36.3%] of no-MDR+MDR>48h; >3 classes of antimicrobial drugs in 12/88 [13.6%] of MDR≤48h vs. 23/347 [6.6%] of no-MDR+MDR>48h). We compiled demographic and clinical characteristics by groups (Appendix Table 1) and duration between hospitalization and transfer to the ICU on the basis of patients’ setting of provenance (Appendix Table 2).

Of the 347 patients who had no MDRO isolates within the first 48 hours from ICU admission, 207 (67.5%) had >1 MDRO event (MDR>48h); 107 (30.8%) patients had MDRO colonization only (MDRCOL>48h) and 100 (28.8%) had >1 MDRO infection (MDRINF>48h) (Figure 1). We compiled patient characteristics and outcomes (Table 1) overall and for no-MDR and MDR>48h patients, further stratified as MDRCOL>48h and MDRINF>48h. Median age was 65 years (IQR 59–71 years); 95/347 (27.4%) patients were female. More than 80% of patients had >1 concurrent condition, and hypertension was the most common (181/347, 52.2%). Patients who had ever smoked were more frequent in the MDRINF>48h group (26/100, 26%) than in the MDRCOL>48h group (11/107, 10.3%; p = 0.003). Transfer to the ICU occurred mostly from nonintensive hospital wards (159/347, 45.8%), but relevant proportions were transferred directly from the emergency department (102/347, 29.4%) or from other ICUs (86/347, 24.8%). Patients were transferred to ICU early during hospitalization, a median time of 5 days from first hospital admittance.

Groups did not differ for steroid use or antimicrobial drug therapies received before ICU admission. According to clinical practice, steroids had been administered for SARS-CoV-2 infection management in 252/347 (72.6%) patients, mostly (228/347, 65.7%) with only a standard dose (dexamethasone 6 mg/d). Most patients (221/347, 63.7%) had previously received antimicrobial drugs before ICU admission. MDRO events before ICU admission were reported in only 4 patients (1.2%). During ICU stay, 118 patients (34%) died, but there were no significant differences between groups. When compared with no-MDR patients, we found that MDR>48h patients had a longer duration of mechanical ventilation (median 18 vs. 14 days; p = 0.001) and of ICU stay (median 25 vs. 15.5 days; p = 0.001). Those differences were largely caused by the MDRINF>48h group (Table 1).

Bacterial Isolate Description and Incidence

Figure 2

Study flowchart showing microbial isolates selection process for multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May 2021. ETA, emergency treatment area; ICU, intensive care unit; MDR, multidrug resistant; MDRO, multidrug-resistant organism. *Of 338 patients, 159 (47.0%) had either MDRO or non-MDRO infections; 74/338 (21.9%) had both MDRO and non-MDRO infections.

Figure 2. Study flowchart showing microbial isolates selection process for multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May...

Complete microbiologic reports were available for 426/435 patients, including 338/347 patients (97.4%) with no MDRO isolates within the first 48 hours of ICU admission. We describe the selection process conducted to assess incidences of HAIs and of MDRO events distinguishing between colonization and infection (Figure 2). We identified 801 bacterial isolates from 271 patients that correspond to first MDRO colonization (255 isolates in 173/338 patients, 51.2%) and new episodes of bacterial superinfections, either by MDRO (130 isolates in 95/338 patients, 28.1%) or antimicrobial drug‒susceptible bacteria (non-MDRO, 416 isolates in 212/338 patients, 62.7%). A total of 73 (21.6%) patients had both MDRO colonization and MDRO infection develop during ICU stay, and infections were caused by the same colonizing bacterial species in nearly one third of them (24/73, 32.9%) (Appendix Table 3). Clinical interpretation of bacterial isolates as colonization/infection by attending physicians at the time of arrival of microbiologic results was found to be highly concordant with the retrospective evaluation conducted according to international guidelines (κ coefficient 0.902, 95% CI 0.890–0.913) (Appendix Table 4).

Overall, 546 bacterial HAIs were recorded, 130 (23.8%) caused by MDRO. Gram-negative bacteria accounted for 59.7% (326/546) of all HAIs and for 60% (78/130) of infections caused by MDROs. Bacterial species responsible for HAIs varied by infection site and severity of infection (Appendix Tables 5, 6). Ventilator-associated lower respiratory tract infections (VALRTIs) represented most infectious episodes (359/546, 65.7%), followed by BSI (141, 25.8%) and urinary tract infections (40, 7.3%). Among BSIs, 31/141 (22%) were associated with a central line, 43 (30.5%) were secondary to VALRTI or urinary tract infections, and the remaining 67 (47.5%) were classified as primary BSI without a known bacteremic focus (Appendix Figure 3).

Among MDRO colonization, Enterococcus faecium (112/255 isolates, 43.9%) was the most frequent isolate, followed by Klebsiella spp. (34, 13.3%), Escherichia coli (26, 10.2%), Staphylococcus aureus (25, 9.8%), Pseudomonas aeruginosa (15, 5.9%) and Acinetobacter baumannii (13, 5.1%). We compiled the percentages of MDRO colonization, MDRO HAIs, and non-MDRO HAIs for the most frequently isolated bacteria of the World Health Organization priority pathogens list (27) (Appendix Figure 4).

Figure 3

Multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May 2021. Kernel density plot (violin plot) shows healthcare-associated infections by onset time comparing MDRO with non-MDRO. Red lines indicate mean and green lines median onset times; medium blue shading indicates interquartile ranges, and the light blue shading indicates 95% CIs of the mean (p<0.001 by Wilcoxon rank-sum test). ICU, intensive care unit; MDRO, multidrug-resistant organism.

Figure 3. Multidrug-resistant bacterial colonization and infections in large retrospective cohort of COVID-19 mechanically ventilated patients admitted to ICU in Milan, Italy, October 2020–May 2021. Kernel density plot (violin plot) shows healthcare-associated...

First MDRO colonization occurred at a median time of 13 (IQR 8–12) days after ICU admission. HAIs caused by antimicrobial drug‒susceptible bacteria occurred earlier than in those caused by MDROs at 6 (IQR 3–10) and 10 (IQR 6–17) days from admission (p<0.001) (Figure 3). The incidence rates for MDRO colonization was 29.97 cases/1,000 patient-days (95% CI 26.34–34.10), for MDRO infection was 14.99 cases/1,000 patient-days (95% CI 12.36–18.19), and for non-MDRO infection, was 50.12 cases/1,000 patient-days (95% CI 44.59–56.32). Infection rates varied substantially by infection site (Table 2).

Association of Antimicrobial Drugs and Steroids to MDRO Events

We investigated possible associations between MDRO events and previous steroid and antimicrobial drug therapies (Appendix Tables 7, 8). Because steroids were included in the management of COVID-19 pneumonia from the early stage of the disease, we evaluated their intake before and during ICU stay. Almost the entire population had received steroid therapy (313/338, 92.6%), without major differences between no-MDR (132/140, 94.3%), MDRCOL>48h (98/103, 95.1%) and MDRINF>48h (83/95, 87.4%) (Appendix Table 7).

To assess possible association between MDRO events and previous antimicrobial drug use, we focused on therapies administered during the first 10 days of ICU stay. This timeline was set to balance observation time between no-MDR and MDR>48h groups because three fourths of MDRO events occurred within this timeframe. Also, three fourths of patients in no-MDR group stayed in ICU >10 days (Appendix Table 8). Previous exposure to antimicrobial drugs was notably higher in patients who developed MDRO events than in patients who did not (116/197 [58.9%] in MDR>48h vs 18/140 [12.9%] in no-MDR; p<0.001) (Appendix Table 8).

Discussion

We describe incidences and clinical characteristics of HAIs and MDRO events, distinguishing between colonization and infection, in a large cohort of ICU COVID-19 patients from a country with high prevalence of MDRO (28). Despite being composed of patients admitted from >45 different hospitals, our cohort is homogeneous for concurrent conditions and risk factors for MDRO acquisition, clinical severity of COVID-19, management of antimicrobial drug therapy, and infection prevention and control strategies within the ICU, including surveillance sampling.

Antimicrobial drug resistance represents a major challenge in the ICU. Its occurrence is the result of the influx of previously colonized patients and acquisition of MDROs during ICU stay, as a consequence of antimicrobial drug overexposure and interpatient transmission, as well as contact with colonized healthcare workers, fomites, or the environment. The incidence of MDROs is strongly influenced by pandemic periods, such as during COVID-19, when unprecedented patient loads in ICUs resulted in breaches in IPC, such as gaps in microbiologic surveillance, lack of communication between clinicians, and reduced attention to environmental measures and contact precautions among healthcare workers (29). In addition, ICU admissions caused by viral pandemics place a strain on ICU resources, requiring the reallocation of non-ICU beds, along with the use of non-ICU staff to meet the urgent demand. In this setting, strengthening measures, such as active surveillance with prompt recognition of outbreaks, staff training, increased environmental disinfection and cohorting, become essential to reducing MDRO circulation (30).

In the pre–COVID-19 pandemic era, the prevalence of infections caused by MDROs in ICU patients varied from a reported rate of 14.1% in VALRTIs acquired in ICUs in North America (31) to an average of >40% in 2 large multicentric worldwide studies of nosocomial BSIs (32,33). Variability exists between participating countries, ranging from 8% (Australia) to >75%–80% in Asia, eastern Europe, and southern Europe. Carbapenem resistance was present in more than one third of gram-negative bacteria, and 36% of all gram-positive bacteria were MDR (32,33).

Several studies have been published on MDRO incidence, etiology and source of HAIs in ICU COVID-19 patients (4–21) (Table 3). Most of those studies evaluated overall MDRO infections or specific HAIs, such as BSI or VALRTIs (7,15–17,19,21), whereas colonization events were assessed in only a few studies (8–12,14). Incidence measures of MDRO events varied widely; cumulative incidence of the first MDRO event was 5%–57% (7,17) and incidence rate 2.6–31.48 cases/1,000 patient-days (11,16). The percentage of MDRO was 27%–100% for all recorded events (15,17). Compared with the amount of literature evaluating MDRO events during ICU stay, we found that few data are available on MDRO proportions among COVID-19 patients at ICU admission. In recent work of the multicenter HAI-ICU surveillance network in France, the percentage of MDR gram-negative bacteria among >4,000 COVID-19 patients admitted was 11.7% (34).

In our cohort, 20% of patients had MDRO isolation within the first 48 hours, indicating acquisition before ICU admittance. We found that patients who had MDROs isolated during the first 48 hours were more frequently transferred from other ICUs and exposed to a higher number of antimicrobial drugs before ICU admission. Both of those factors are well known to be associated with development of infections by antimicrobial drug‒resistant pathogens (6). Only 2.7% of our cohort had MDRO colonization/infection before ICU admission. The marked difference between expected and observed MDRO prevalence at ICU admission probably reflects the major issues in IPC during the emergency situation of the pandemic mentioned beforehand.

Considering patients without MDRO isolation within the first 48 hours, we observed no differences in demographic characteristics or in clinical severity at admission between patients who showed or not showed development of MDRO events during ICU stay, underlying consistency between groups at ICU admission. In our cohort, we did not find direct association between MDRO infection and in-ICU deaths. However, length of ICU stay and duration of mechanical ventilation were longer for patients with MDRO events and, among them, longer for patients who had infections than for colonized patients. No causative effect can be drawn from these results because occurrence of MDRO events could be either responsible for longer ICU stay or its direct consequence because of longer exposure time (35,36).

Active surveillance screening coupled with the evaluation of all microbial isolates enabled us to precisely identify patients who had with MDRO events. Two thirds of the cohort showed development of MDRO colonization or infection during ICU stay. Half of our patients were given diagnoses of MDRO colonization during ICU stay, compared with 21% observed in a recent study analyzing a smaller population (10). Our results can be, in part, explained by strict routine microbiologic surveillance, which enabled prompt and precise recognition of such cases. Data from previous studies on bacterial superinfections in COVID-19 ICU patients are heterogenous and describe MDRO HAIs in 11%–50% of the population (6,13). Our results confirm the substantial risk for mechanically ventilated COVID-19 patients to have MDRO infections develop; such infections affected almost 30% of our cohort during ICU stays. Also, more than twice as many patients had antimicrobial drug‒susceptible HAIs.

We found high concordance between clinical diagnosis and retrospective evaluation of HAIs according to literature criteria. We believe this result well demonstrates how implementation of structured antimicrobial stewardship and IPC measures, with collaboration of infectious disease consultants and intensivists, can strongly effect management of critically ill patients, favoring accurate diagnosis and therapeutic choices, according to international guidelines.

Patients who had MDRO events had greater exposure to antimicrobial drugs the first 10 days of ICU stay than patients who had no MDRO findings. This observation is consistent with results of recent studies conducted on large population of patients, which showed major associations between exposure to specific antimicrobial drug classes and drug resistance, and a decreasing pattern over time (37,38). However, accurate analysis of the association between antimicrobial drug exposure and MDRO events was beyond the scope of this study because other variables, such as average intake time of each antimicrobial drug class and infections with antimicrobial drug‒susceptible bacteria during the observation time, should be considered.

The first limitation of this study is that it was a retrospective monocentric cohort and, therefore, had intrinsic risks of limited accuracy and generalizability. However, interpretation of all microbiologic findings has been conducted ex post on the basis of standardized literature criteria and independent from the physicians’ view. Also, even though the study was monocentric, patients were admitted from >45 hospitals and assisted by different hospital staff. Advantages to this study design derive from the standardized microbiologic surveillance, both in terms of timing and laboratory method, as well as from homogeneous antimicrobial stewardship and IPC strategies among ICU modules. This factor enabled us to provide precise and consistent data in terms of incidence of HAIs and MDRO events, not only infections but also colonization.

Second, this study was not conducted for evaluation of the effect of antimicrobial drugs on development of MDRO or the effect of MDRO events on ICU deaths and length of stay; the sample size was probably inadequate for these issues. Therefore, our findings on this issue should be interpreted with caution.

Third, patients’ data before ICU admission were retrieved from information registered at ICU entry and not from hospital databases of the single referring centers. Accuracy of previous MDRO events and steroids and antimicrobial drug treatments might be limited, although these factors play a major role in routine management of ICU patients, and we do not expect major gaps in data acquisition.

In conclusion, our in-depth analysis of incidence measures of HAIs and MDRO events contributes to increase knowledge of MDRO colonization and infections in ICU COVID-19 patients. These findings should be a priority in contributing toward IPC and antimicrobial stewardship policies for ensuring the best clinical care.

Dr. Mangioni is an assistant professor at the University of Milan and Consultant in Infectious Diseases at the Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy. His primary research interests are infections in critically ill patients and infections caused by multidrug-resistant organisms.

MDR in FIERA study group: Valeria Pastore, Mara Tomasello, Lisa Cariani, Anna Grancini, Anna Maraschini (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy); Teresio Arazzi (Rho Hospital, Rho, Italy); Alessandro Protti (Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy); Virginia Porta (Legnano Hospital, Legnano, Italy); Marco Dei Poli (San Donato Hospital, Milano, Italy); Paolo Severgnini (Varese Hospital, Varese, Italy); Egle Rondelli (San Gerardo Hospital, Monza, Italy).

Top

Acknowledgments

This study was partially supported by the Italian Ministry of Health and projects STOP-COVID and PREP-COVID.

Deidentified patient data used for the results reported in this article, including data in text, tables, figures, and appendixes, will be available to researchers who provide a methodologically sound proposal to achieve their aims. Proposals should be addressed to andrea.gori@unimi.it and davide.mangioni@policlinico.mi.it. To gain access, data applicants will need to sign a data access agreement.

D.M., J.C., G.Ma., and A.B. designed the study; L.C. and M.C.V. performed methods and formal analysis; D.M., J.C., E.P., F.A.G., M.B., B.B., M.C., G.F., M.M., G.Mo, P.P., S.S., F.T., and G.Z. performed investigations; D.M. and E.P. wrote the original draft of the paper, wrote, reviewed, and edited the paper, and performed a literature review; L.C., J.C., F.A.G., M.B., N.B., B.B., M.C., G.F., M.M., G.Ma., C.M., A.M., P.P., S.S., F.T., G.Z., G.G., R.F., A.G., N.S., G.Mo., and A.B. wrote, reviewed, and edited the paper; and N.B., N,S., G.Ma., and A.B. supervised the study. All authors have read and agreed to the published version of the manuscript.

Top

References

  1. Lansbury  L, Lim  B, Baskaran  V, Lim  WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020;81:266–75. DOIPubMedGoogle Scholar
  2. Pasero  D, Cossu  AP, Terragni  P. Multi-drug resistance bacterial infections in critically ill patients admitted with COVID-19. Microorganisms. 2021;9:1773. DOIPubMedGoogle Scholar
  3. Russell  CD, Fairfield  CJ, Drake  TM, Turtle  L, Seaton  RA, Wootton  DG, et al.; ISARIC4C investigators. Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study. Lancet Microbe. 2021;2:e354–65. DOIPubMedGoogle Scholar
  4. Grasselli  G, Scaravilli  V, Mangioni  D, Scudeller  L, Alagna  L, Bartoletti  M, et al. Hospital-acquired infections in critically ill patients with COVID-19. Chest. 2021;160:454–65. DOIPubMedGoogle Scholar
  5. Ramos  R, de la Villa  S, García-Ramos  S, Padilla  B, García-Olivares  P, Piñero  P, et al. COVID-19 associated infections in the ICU setting: a retrospective analysis in a tertiary-care hospital. Enferm Infecc Microbiol Clin. 2021.PubMedGoogle Scholar
  6. Karruli  A, Boccia  F, Gagliardi  M, Patauner  F, Ursi  MP, Sommese  P, et al. Multidrug-resistant infections and outcome of critically ill patients with coronavirus disease 2019: a single center experience. Microb Drug Resist. 2021;27:1167–75. DOIPubMedGoogle Scholar
  7. Palanisamy  N, Vihari  N, Meena  DS, Kumar  D, Midha  N, Tak  V, et al. Clinical profile of bloodstream infections in COVID-19 patients: a retrospective cohort study. BMC Infect Dis. 2021;21:933. DOIPubMedGoogle Scholar
  8. Baiou  A, Elbuzidi  AA, Bakdach  D, Zaqout  A, Alarbi  KM, Bintaher  AA, et al. Clinical characteristics and risk factors for the isolation of multi-drug-resistant Gram-negative bacteria from critically ill patients with COVID-19. J Hosp Infect. 2021;110:165–71. DOIPubMedGoogle Scholar
  9. Bogossian  EG, Taccone  FS, Izzi  A, Yin  N, Garufi  A, Hublet  S, et al. The acquisition of multidrug-resistant bacteria in patients admitted to COVID-19 intensive care units: a monocentric retrospective case‒control study. Microorganisms. 2020;8:1–11. DOIPubMedGoogle Scholar
  10. Fernández  P, Moreno  L, Yagüe  G, Andreu  E, Jara  R, Segovia  M. Colonization by multidrug-resistant microorganisms in ICU patients during the COVID-19 pandemic. [English Ed]. Med Intensiva. 2021;45:313–5.
  11. Pascale  R, Bussini  L, Gaibani  P, Bovo  F, Fornaro  G, Lombardo  D, et al. Carbapenem-resistant bacteria in an intensive care unit during the coronavirus disease 2019 (COVID-19) pandemic: A multicenter before-and-after cross-sectional study. Infect Control Hosp Epidemiol. 2022;43:461–6. DOIPubMedGoogle Scholar
  12. Temperoni  C, Caiazzo  L, Barchiesi  F. High prevalence of antibiotic resistance among opportunistic pathogens isolated from patients with COVID-19 under mechanical ventilation: results of a single-center study. Antibiotics (Basel). 2021;10:1080. DOIPubMedGoogle Scholar
  13. Pourajam  S, Kalantari  E, Talebzadeh  H, Mellali  H, Sami  R, Soltaninejad  F, et al. Secondary bacterial infection and clinical characteristics in patients with COVID-19 admitted to two intensive care units of an academic hospital in Iran during the first wave of the pandemic. Front Cell Infect Microbiol. 2022;12:784130. DOIPubMedGoogle Scholar
  14. Sathitakorn  O, Jantarathaneewat  K, Weber  DJ, Warren  DK, Nanthapisal  S, Rutjanawech  S, et al. The feasibility of procalcitonin and CPIS score to reduce inappropriate antibiotics use among severe-critically ill COVID-19 pneumonia patients: A pilot study. Am J Infect Control. 2022;50:581–4. DOIPubMedGoogle Scholar
  15. Bonazzetti  C, Morena  V, Giacomelli  A, Oreni  L, Casalini  G, Galimberti  LR, et al. Unexpectedly high frequency of enterococcal bloodstream infections in coronavirus disease 2019 patients admitted to an Italian ICU: an observational study. Crit Care Med. 2021;49:e31–40. DOIPubMedGoogle Scholar
  16. Scaravilli  V, Guzzardella  A, Madotto  F, Beltrama  V, Muscatello  A, Bellani  G, et al. Impact of dexamethasone on the incidence of ventilator-associated pneumonia in mechanically ventilated COVID-19 patients: a propensity-matched cohort study. Crit Care. 2022;26:176. DOIPubMedGoogle Scholar
  17. Mantzarlis  K, Deskata  K, Papaspyrou  D, Leontopoulou  V, Tsolaki  V, Zakynthinos  E, et al. Incidence and risk factors for blood stream infection in mechanically ventilated COVID-19 patients. Antibiotics (Basel). 2022;11:1053. DOIPubMedGoogle Scholar
  18. Falcone  M, Suardi  LR, Tiseo  G, Galfo  V, Occhineri  S, Verdenelli  S, et al. Superinfections caused by carbapenem-resistant Enterobacterales in hospitalized patient with COVID-19: a multicentre observational study from Italy (CREVID study). JAC Antimicrobial Resist. 2022;4:dlac064.
  19. Yohannes  S, Ahmed  Z, Schelling  R, Perinkulam Sathyanarayanan  S, Pratt  A, Schreiber  MP. Incidence and impact of ventilator associated multidrug resistant pneumonia in patients with SARS-COV2. Crit Care Res Pract. 2022;2022:9730895. DOIPubMedGoogle Scholar
  20. Menekşe  Ş, Deniz  S. Secondary infections in COVID-19 patients: A two-centre retrospective observational study. J Infect Dev Ctries. 2022;16:1294–301. DOIPubMedGoogle Scholar
  21. Bansal  S, Kalpakam  H, Kumar  A, Varsha  A, Thorbole  A, Mehta  RM. Lower respiratory tract sampling in COVID-19 acute respiratory distress syndrome: A focus on microbiology, cellular morphology, cytology, and management impact. Lung India. 2022;39:139–44. DOIPubMedGoogle Scholar
  22. Centers for Disease Control and Prevention. National Healthcare Safety Network (NHSN) Patient safety component manual; 2021.
  23. European Centre for Disease Prevention and Control. Surveillance of healthcare-associated infections and prevention indicators in European intensive care units; 2017.
  24. Singer  M, Deutschman  CS, Seymour  CW, Shankar-Hari  M, Annane  D, Bauer  M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801–10. DOIPubMedGoogle Scholar
  25. Magiorakos  AP, Srinivasan  A, Carey  RB, Carmeli  Y, Falagas  ME, Giske  CG, 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;18:268–81. DOIPubMedGoogle Scholar
  26. Glynn  RJ, Buring  JE. Ways of measuring rates of recurrent events. BMJ. 1996;312:364–7. DOIPubMedGoogle Scholar
  27. World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. 2017 [cited 2023 Jun 21]. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed
  28. European Centre for Disease Prevention and Control. Antimicrobial resistance in the EU/EEA (EARS-Net). Annual epidemiological report 2020. Solna (Sweden): The Centre; 2022.
  29. Witt  LS, Howard-Anderson  JR, Jacob  JT, Gottlieb  LB. The impact of COVID-19 on multidrug-resistant organisms causing healthcare-associated infections: a narrative review. JAC Antimicrob Resist. 2022;5:2dlac130.
  30. Mangioni  D, Fox  V, Chatenoud  L, Bolis  M, Bottino  N, Cariani  L, et al. Genomic characterization of carbapenem-resistant Acinetobacter baumannii (CRAB) in mechanically ventilated COVID-19 patients and impact of infection control measures on reducing CRAB circulation during the second wave of the SARS-CoV-2 pandemic in Milan, Italy. Microbiol Spectr. 2023;11:e0020923. DOIPubMedGoogle Scholar
  31. Lat  I, Daley  MJ, Shewale  A, Pangrazzi  MH, Hammond  D, Olsen  KM, et al. DEFINE study group and the Discovery Research Network. A multicenter, prospective, observational study to determine predictive factors for multidrug-resistant pneumonia in critically ill adults: the DEFINEsStudy. Pharmacotherapy. 2019;39:253–60. DOIPubMedGoogle Scholar
  32. Tabah  A, Koulenti  D, Laupland  K, Misset  B, Valles  J, Bruzzi de Carvalho  F, et al. Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med. 2012;38:1930–45. DOIPubMedGoogle Scholar
  33. Tabah  A, Buetti  N, Staiquly  Q, Ruckly  S, Akova  M, Aslan  AT, et al.; EUROBACT-2 Study Group, ESICM, ESCMID ESGCIP and the OUTCOMEREA Network. Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study. Intensive Care Med. 2023;49:178–90. DOIPubMedGoogle Scholar
  34. Lepape  A, Machut  A, Bretonnière  C, Friggeri  A, Vacheron  CH, Savey  A; REA-REZO network. Effect of SARS-CoV-2 infection and pandemic period on healthcare-associated infections acquired in intensive care units. Clin Microbiol Infect. 2023;29:530–6. DOIPubMedGoogle Scholar
  35. Martin-Loeches  I, Torres  A, Rinaudo  M, Terraneo  S, de Rosa  F, Ramirez  P, et al. Resistance patterns and outcomes in intensive care unit (ICU)-acquired pneumonia. Validation of European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) classification of multidrug resistant organisms. J Infect. 2015;70:213–22. DOIPubMedGoogle Scholar
  36. Liu  P, Li  X, Luo  M, Xu  X, Su  K, Chen  S, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection: a meta-analysis. Microb Drug Resist. 2018;24:190–8. DOIPubMedGoogle Scholar
  37. Baraz  A, Chowers  M, Nevo  D, Obolski  U. The time-varying association between previous antibiotic use and antibiotic resistance. Clin Microbiol Infect. 2022;0.
  38. Tacconelli  E, Górska  A, De Angelis  G, Lammens  C, Restuccia  G, Schrenzel  J, et al. Estimating the association between antibiotic exposure and colonization with extended-spectrum β-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study. Clin Microbiol Infect. 2020;26:87–94. DOIPubMedGoogle Scholar

Top

Figures
Tables

Top

Cite This Article

DOI: 10.3201/eid2908.230115

1Preliminary results were presented at the European Congress of Clinical Microbiology and Infectious Diseases, 2022, Lisbon, Portugal, April 23‒26, 2022 (abstract no. 02641).

2These senior authors contributed equally to this article.

3Study group members are listed at the end of this article.

Table of Contents – Volume 29, Number 8—August 2023

EID Search Options
presentation_01 Advanced Article Search – Search articles by author and/or keyword.
presentation_01 Articles by Country Search – Search articles by the topic country.
presentation_01 Article Type Search – Search articles by article type and issue.

Top

Page created: June 22, 2023
Page updated: July 20, 2023
Page reviewed: July 20, 2023
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external