# Ventilator-associated pneumonia related to extended-spectrum beta-lactamase producing Enterobacterales during severe acute respiratory syndrome coronavirus 2 infection: risk factors and prognosis

Keyvan Razazi, Charles Edouard Luyt, Guillaume Voiriot, Anahita Rouzé, Marc Garnier, Alexis Ferré, Laurent Camous, Nicholas Heming, Nathanaël Lapidus, Anais Charles-Nelson, et al.

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## To cite this version:

Keyvan Razazi, Charles Edouard Luyt, Guillaume Voiriot, Anahita Rouzé, Marc Garnier, et al. Ventilator-associated pneumonia related to extended-spectrum beta-lactamase producing Enterobacterales during severe acute respiratory syndrome coronavirus 2 infection: risk factors and prognosis. Critical Care, 2024, 28 (1), pp.131. 10.1186/s13054-024-04906-2. hal-04724606

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# Ventilator-associated pneumonia related to extended-spectrum beta-lactamase producing Enterobacterales during severe acute respiratory syndrome coronavirus 2 infection: risk factors and prognosis

Keyvan Razazi¹,¹⁵,²*, Charles-Edouard Luyt³†, Guillaume Voiriot⁴†, Anahita Rouzé⁵†, Marc Garnier⁶, Alexis Ferré⁷, Laurent Camous⁸, Nicholas Heming¹⁰,¹¹,⁹, Nathanaël Lapidus¹², Anais Charles-Nelson¹³†, Armand Mekontso-Dessap¹,¹⁴,²† and COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators

## Abstract

**Background** Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator associated pneumonia (VAP), mainly related to Enterobacterales. Data regarding extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) VAP are scarce. We aimed to investigate risk factors and outcomes of ESBL-E related VAP among critically ill coronavirus infectious disease-19 (COVID-19) patients who developed Enterobacterales related VAP.

**Patients and methods** We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU) that included 4929 COVID-19 critically ill patients. For the present analysis, only patients with complete data regarding resistance status of the first episode of Enterobacterales related VAP (ESBL-E and/or carbapenem-resistant Enterobacterales, CRE) and outcome were included.

**Results** We included 591 patients with Enterobacterales related VAP. The main causative species were *Enterobacter* sp (n = 224), *E. coli* (n = 111) and *K. pneumoniae* (n = 104). One hundred and fifteen patients (19%), developed a first ESBL-E related VAP, mostly related to *Enterobacter* sp (n = 40), *K. pneumoniae* (n = 36), and *E. coli* (n = 31). Eight patients (1%) developed CRE related VAP. In a multivariable analysis, African origin (North Africa or Sub-Saharan Africa) (OR 1.7 [1.07–2.71], *p* = 0.02), time between intubation and VAP (OR 1.06 [1.02–1.09], *p* = 0.002), PaO₂/FiO₂ ratio on the day of VAP (OR 0.997 [0.994–0.999], *p* = 0.04) and trimethoprim-sulfamethoxazole exposure (OR 3.77 [1.15–12.4], *p* = 0.03)

<footnote>†Charles Edouard Luyt, Guillaume Voiriot and Anahita Rouzé have contributed equally and should be both considered as second authors</footnote>

<footnote>‡Anais Charles-Nelson and Armand Mekontso-Dessap contributed equally and should be both considered as senior authors</footnote>

<footnote>*Correspondence:
Keyvan Razazi
keyvan.razazi@aphp.fr
Full list of author information is available at the end of the article</footnote>
were associated with ESBL-E related VAP. Weaning from mechanical ventilation and mortality did not significantly differ between ESBL-E and non ESBL-E VAP.

**Conclusion** ESBL-related VAP in COVID-19 critically-ill patients was not infrequent. Several risk factors were identified, among which some are modifiable and deserve further investigation. There was no impact of resistance of the first Enterobacterales related episode of VAP on outcome.

**Keywords** COVID-19, ARDS, Nosocomial pneumonia, Ventilator-associated pneumonia, ESBL

## Introduction

Antimicrobial resistance is a leading global health issue. Lower respiratory tract infections alone accounted for more than 400,000 attributable deaths and 1.5 million associated deaths in 2019, worldwide [1]. Among critically ill patients, ventilator associated pneumonia is frequent. The incidence of ventilator-associated pneumonia (VAP) in COVID-19 patients ranges from 30 to 84% [2–4]. Potential explanations for the high incidence of VAP in COVID-19 patients include prolonged invasive mechanical ventilation, the high incidence of acute respiratory distress syndrome (ARDS), lung microbiota alteration, COVID-19-related specific lesions, neuromuscular blocking and administration of treatments which depress the immune system. Additionally, COVID-19 patients were often treated empirically by broad-spectrum antibacterial therapy at ICU admission [5]. The main microbial species involved in VAP were Enterobacterales [3, 4]. Recent studies have reported an increase in the frequency of healthcare-associated infections and antibiotic resistance during the COVID-19 pandemic [6]. VAP-attributable mortality was higher for patients with COVID-19 than non COVID-19, with more than 9% of the overall mortality related to VAP [7].

Data regarding the outcome of VAP related to Enterobacterales according to resistance in a homogeneous group of mechanically ventilated COVID-19 patients are scare. We conducted this study to assess risk factors and prognosis of extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) related VAP in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and who developed a first episode of enterobacterales-related VAP.

## Methods, study design and patients

We performed an ancillary analysis of the COVID-ICU study. COVID-ICU was a multi-center, observational, prospective cohort study conducted in 149 ICUs from 138 centers, across three countries (France, Switzerland, and Belgium) which has been previously been described [8]. Ethical committees in Switzerland (BASEC # 2020-00704), France (French intensive care Society CE-SRLF 20-23) and Belgium (2020-294) approved this study and

all patients or relatives were informed that their data were included in the COVID-ICU cohort. In case of refusal, the data were withheld accordingly. This manuscript follows the STROBE statement for reporting cohort studies.

## Study population and data collection

All consecutive patients over 16 years of age admitted to participating ICUs between February 25, 2020, and May 4, 2020, with laboratory-confirmed SARS-CoV-2 infection were included. Patients who had been invasively ventilated for more than 24 h before transfer to one of the participating centers were excluded. Details of the data collected daily over the first 14 days from admission and then on Days 28, 45, 60, and 90 have been described elsewhere [8] and are briefly summarized below. We recorded baseline demographics [age, sex, body mass index (BMI), active smoking, treated hypertension, diabetes], long-term corticosteroids, immunodeficiency, Clinical Frailty Scale, and clinical information and ICU severity scores [Simplified Acute Physiology Score (SAPS) II and Sequential Organ Failure Assessment (SOFA)]. The study investigators recorded time-updated information, respiratory support, arterial blood gas, standard laboratory parameters, use of adjuvant therapies for ARDS, microbiological results of respiratory samples and antibiotics use. Patient vital status (with the exact date of death) was collected by study investigators 90 days after ICU admission, with a phone call to patients or their relatives if they were discharged from hospital before Day 90. Data describing the participating centers, including the number of ICU physicians, nurses, and number of beds, were also collected.

## VAP definition

VAP diagnosis was based on: (1) clinical and radiological suspicion based on criteria established by the European Center of Disease Control [9]; (2) confirmed by at least one positive quantitative microbiological sample defined when culture recovered ≥ 10⁶ CFU/mL for tracheal aspirate, ≥ 10⁴ CFU/mL for broncho-alveolar lavage (BAL), and ≥ 10³ CFU/mL for distal protected specimen brush or aspirate [9]; and (3) leading the attending physician to initiate antimicrobial therapy. In addition, pneumonia must have occurred at least 48 h after mechanical
ventilation onset. For each positive respiratory sample culture, investigators could identify the micro-organism responsible of the infection within a restricted list: Enterobactérales, *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, *Streptococcus pneumonia*, Group A or B *Streptococcus*, *Enterococcus spp.*, methicillin-susceptible *Staphylococcus aureus*, methicillin resistant *Staphylococcus aureus*, *Haemophilus influenzae*, anaerobes or other. Therefore, "other" denotes all micro-organisms not present in the preceding list and were not specified. Since respiratory cultures may identify multiple microorganisms, investigators could identify several micro-organisms within a single respiratory sample.

For this report, we restricted our analysis to patients who presented VAP related to *Enterobactérales* in whom resistance status (including ESBL-E and CRE) were known. Additional data were requested from participating centers, including involved species and coinfection with other micro-organisms. Only the first episode of VAP was considered. ESBL-E phenotype were determined by disk diffusion. Double-disk diffusion testing of clinical specimens detected production of ESBL by a synergistic effect between clavulanic acid/amoxicillin or clavulanic acid/ticarcillin and cefotaxime, ceftazidime, aztreonam or cefepime.

## Statistical analysis

Categorical variables were expressed as number (percentage) and continuous variables as median and interquartile range [IQR]. When appropriate, chi square and Fisher's exact tests were used to compare categorical variables. The Mann-Whitney U test and the Wilcoxon test were used to compare continuous variables when applicable. To identify patients' characteristics associated with ESBL-E VAP, we used multivariable logistic regression. Non-redundant variables selected by bivariate analysis (*p* < 0.10) or considered clinically relevant were entered into a logistic regression model. Multiple imputations were used to replace missing values using chained equations method and five imputations. Overall survival curves were estimated using the Kaplan-Meier method and a Cox model to assess the effect of Enterobactérales on overall survival. Results were expressed as hazard ratio and 95% confidence interval. We used a Fine and Gray model (cumulative incidence function of the Gray model) to properly estimate the effect of Enterobactérales related VAP on weaning, while considering death as a competing event using cmprsk package developed by Gray in R software (http://biowww.dfci.harvard.edu/~gray/cmprsk_2.1-4.tar.gz). Results were expressed as subdistribution hasard ratio associated to its 95% confidence interval. Two-sided *p*-values < 0.05 were considered significant.

## Results

Among the 4929 patients included in the COVID-ICU database, 1087 had VAP with Enterobactérales or "other" microorganism in the database. After additional data requested from participating centers, 494 patients were excluded because respiratory sample found no microorganism (n=154), no Enterobactérales but another microorganism (n=177), or no response of the center (n=165). 591 had all data available on Enterobactérales related VAP and were included in the current analysis (see flow chart Fig. 1). Characteristics of patients and their clinical and biological data at ICU admission are available in Tables 1 and 2. Median age was 63 [55-69] years. Four hundred and sixty-eight (79%) patients were male. Two hundred and thirty-eight (42%) patients were obese (BMI ≥ 30 kg/m²). The most frequent comorbidities were hypertension (298/586, 51%) and diabetes (156/588, 27.5%). There were 46/588 (8%) immunocompromised patients. Median SAPS II and SOFA scores at ICU admission were 37 [28-49] and 5 [3-8], respectively.

## ESBL-E VAP

Among the 591 patients with a first episode of VAP related to Enterobactérales, the main species were *Enterobacter sp* (n=224), *E. coli* (n=111) and *K. pneumoniae* (n=104). One hundred and ninety (32%) patients had polymicrobial VAP involving the following species: several Enterobactérales without other species (n=64, 11%), *Staphylococcus aureus* (n=31, 5%), *Streptococcus sp.* (n=20, 3%), *Haemophilus influenzae* (n=12, 2%), *P. aeruginosa* (n=42, 7%), or other non-fermenting gram negative bacteria (n=17; 3%). One hundred and fifteen patients (19%), developed a first episode of VAP with ESBL-E, mostly caused by *Enterobacter sp* (n=40), *K. pneumoniae* (n=36), and *E. coli* (n=31). Eight patients (1%) developed CRE related VAP. All but one CRE VAP were also ESBL-E and were therefore analyzed within the ESBL-E VAP group. There was no significant association between ICU characteristics and ESBL-E VAP, except for a higher number of ICU beds in the ESBL-E group (Additional file 1: Table E1). Risk factors for developing ESBL-E VAP were tested by univariate analysis (Tables 1, 2). African origin (North Africa or Sub-Saharan Africa), time from intubation, immunodeficiency, lower oxygenation, and higher positive end expiratory pressure level, were associated with ESBL-E VAP. Concerning antibiotic exposure, risk factors for ESBL-E VAP included exposure to fluoroquinolone, trimethoprim-sulfamethoxazole or glycopeptid. By multivariable analysis (Table 3), African origin (OR 1.7 [1.07-2.71], *p* = 0.02), time between intubation and VAP (OR 1.06 [1.02-1.09], *p* = 0.002), PaO₂/FiO₂ ratio on the day of VAP (OR 0.997 [0.994-0.999], *p* = 0.04) and Trimethoprim-sulfamethoxazole exposure
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Flow chart of the study</figcaption></figure>

(OR 3.77 [1.15–12.4], *p*=0.03), were associated with ESBL-E VAP. Risk factors did not differ after excluding the eight patients with CRE VAP, excepted for PaO₂/FiO₂ ratio on the day of VAP which felt short of statistical significance [OR=0.99 (0.99–1.00), *p*=0.07] (Additional file 1: Table E2). During the 24 h following VAP onset, patients with ESBL-E VAP received more frequently carbapenem [26/115 (23%) vs 49/476 (10%), *p*<0.001] and less frequently penicillins [27/115(23%) vs 164/476 (34%), *p*=0.02], as compared to their counterparts (Additional file 1: Table E3).

## Outcome

The number of VAP episodes after the first episode was lower in patients with VAP due to ESBL-E or CRE as compared to patients with non-ESBL-E VAP (1 [0–1] vs 1 [0–2], *p*=0.04). ESBL-E VAP was not associated with a worse outcome as compared to non-ESBL-E VAP. Weaning from mechanical ventilation (Fig. 2), as well as mortality at ICU discharge, in hospital, at 28 days and at

90 days (Additional file 1: Table E4, Fig. 3) did not differ between ESBL-E and non ESBL-E VAP. Mortality was not influenced by species, chromosomally-encoded AmpC-producing Enterobacterales, or polymicrobial VAP (Additional file 1: Table E5). Results on mortality were similar after excluding the eight patients with CRE VAP (HR 0.94 [0.62–1.41], *p*=0.75), after excluding polymicrobial VAP with *Staphylococcus aureus* or *Pseudomonas aeruginosa* (HR 0.91 [0.61–1.36], *p*=0.64), after excluding polymicrobial VAP with other species than Enterobacterales (HR 0.94 [0.62–1.41], *p*=0.75), in 220 patients sampled with BAL or protected distal sample (HR 1.07 [0.62–1.86], *p*=0.81), or after adjusting for the use of corticosteroids in the first week (HR 0.89 [0.61–1.3], *p*=0.54).

## Discussion

The main findings of this prospective multicenter study of patients with a first episode of Enterobacterales related VAP, during the first COVID wave are: (i) 19% of VAPs
<table><caption>**Table 1** Demographic, clinical, biological and ventilatory support characteristics of patients with VAP according to the occurrence of ESBL-E VAP</caption><thead><tr><th></th><th>Number with missing data</th><th>No ESBL-E VAP (n=476)</th><th>ESBL-E VAP (n=115)</th><th>P value</th></tr></thead><tbody><tr><td>Age, years</td><td>0</td><td>63 [56-70]</td><td>63 [53-68]</td><td>0.22</td></tr><tr><td>Male gender</td><td>3</td><td>375 (79%)</td><td>93 (81%)</td><td>0.71</td></tr><tr><td>Body mass index, kg/m<sup>2</sup></td><td>30</td><td>29 [25-33]</td><td>29 [25-33]</td><td>0.65</td></tr><tr><td>Ethnic origin</td><td>111</td><td></td><td></td><td>0.03</td></tr><tr><td>Caucasian</td><td></td><td>218 (57%)</td><td>43 (43%)</td><td></td></tr><tr><td>African</td><td></td><td>111 (29%)</td><td>42 (42%)</td><td></td></tr><tr><td>Other</td><td></td><td>52 (14%)</td><td>14 (14%)</td><td></td></tr><tr><td>Clinical frailty scale</td><td>53</td><td>2 [2-3]</td><td>2 [2-3]</td><td>0.66</td></tr><tr><td>Comorbidities</td><td></td><td></td><td></td><td></td></tr><tr><td>No comorbidities</td><td>2</td><td>81 (17%)</td><td>16 (14%)</td><td>0.41</td></tr><tr><td>Alcohol consumption</td><td>15</td><td>22 (5%)</td><td>5 (5%)</td><td>0.92</td></tr><tr><td>Tabaco consumption</td><td>14</td><td>19 (4%)</td><td>4 (4%)</td><td>0.99</td></tr><tr><td>Chronic respiratory disease</td><td>5</td><td>103 (22%)</td><td>28 (25%)</td><td>0.49</td></tr><tr><td>Cardiovascular co-morbidities</td><td>8</td><td>306 (65%)</td><td>70 (61%)</td><td>0.53</td></tr><tr><td>Treated hypertension</td><td>5</td><td>241 (51%)</td><td>57 (50%)</td><td>0.84</td></tr><tr><td>Coronary artery disease</td><td>4</td><td>52 (11%)</td><td>9 (8%)</td><td>0.33</td></tr><tr><td>Chronic heart failure</td><td>8</td><td>15 (3%)</td><td>4 (4%)</td><td>0.77</td></tr><tr><td>Known Diabetes</td><td>3</td><td>127 (27%)</td><td>29 (25%)</td><td>0.77</td></tr><tr><td>Chronic renal failure</td><td>3</td><td>40 (8%)</td><td>16 (14%)</td><td>0.07</td></tr><tr><td>Cirrhosis</td><td>3</td><td>3 (1%)</td><td>0 (0%)</td><td>0.99</td></tr><tr><td>Immunodeficiency</td><td>3</td><td>31 (7%)</td><td>15 (13%)</td><td>0.02</td></tr><tr><td>Hematological malignancies</td><td>3</td><td>13 (3%)</td><td>3 (3%)</td><td>0.99</td></tr><tr><td>Active solid tumor</td><td>3</td><td>5 (1%)</td><td>0 (0%)</td><td>0.59</td></tr><tr><td>Solid organ transplant</td><td>3</td><td>9 (2%)</td><td>6 (5%)</td><td>0.04</td></tr><tr><td>Human Immunodeficiency Virus</td><td>3</td><td>6 (1%)</td><td>2 (2%)</td><td>0.66</td></tr><tr><td>Home treatment</td><td></td><td></td><td></td><td></td></tr><tr><td>Immunosuppressive therapy<sup>a</sup></td><td>101</td><td>17 (4%)</td><td>11 (11%)</td><td>0.009</td></tr><tr><td>Long-term corticosteroids</td><td>102</td><td>16 (4%)</td><td>8 (8%)</td><td>0.09</td></tr><tr><td>Treatment with NSAID before ICU admission</td><td>91</td><td>34 (9%)</td><td>7 (7%)</td><td>0.63</td></tr><tr><td>In another country during 3 weeks before ICU admission</td><td>89</td><td>15 (4%)</td><td>4 (4%)</td><td>0.99</td></tr><tr><td>Living place: home</td><td>3</td><td>454 (96%)</td><td>114 (99%)</td><td>0.15</td></tr><tr><td>At ICU admission</td><td></td><td></td><td></td><td></td></tr><tr><td>SAPS II score</td><td>27</td><td>37 [29-51]</td><td>41 [32-49]</td><td>0.25</td></tr><tr><td>SOFA score at ICU admission</td><td>72</td><td>6 [3-9]</td><td>7 [4-9]</td><td>0.13</td></tr><tr><td>Patient origin</td><td></td><td></td><td></td><td></td></tr><tr><td>Emergency room Direct admission from home/emergency medical ambulance</td><td>1</td><td>300 (63%)</td><td>67 (58%)</td><td></td></tr><tr><td>Medical wards</td><td>1</td><td>130 (27%)</td><td>38 (33%)</td><td></td></tr><tr><td>Other ICU or Operating theatre</td><td>1</td><td>45 (9%)</td><td>10 (9%)</td><td></td></tr><tr><td>Concomitant bacterial pneumonia</td><td>11</td><td>47 (10%)</td><td>9 (8%)</td><td>0.49</td></tr><tr><td>Invasive mechanical ventilation</td><td>3</td><td>369 (78%)</td><td>89 (77%)</td><td>0.89</td></tr><tr><td>Biology<sup>c</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>White blood count, ×10<sup>6</sup>/L</td><td>44</td><td>8600 [6200-11700]</td><td>9000 [5300-9800]</td><td>0.50</td></tr><tr><td>C-reactive protein, mg/L</td><td>274</td><td>160 [110-248]</td><td>169 [113-267]</td><td>0.46</td></tr><tr><td>Procalcitonin, ng/mL</td><td>386</td><td>0.46 [0.23-1.37]</td><td>0.64 [0.38-2.48]</td><td>0.08</td></tr><tr><td>During the first 48 h following ICU admission</td><td></td><td></td><td></td><td></td></tr><tr><td>Prone position</td><td>42</td><td>215 (48%)</td><td>60 (57%)</td><td>0.11</td></tr><tr><td>Neuromuscular blockade</td><td>42</td><td>385 (86%)</td><td>96 (91%)</td><td>0.19</td></tr></tbody></table>
<table><caption>**Table 1 (continued)**</caption><thead><tr><th></th><th>Number with missing data</th><th>No ESBL-E VAP (n=476)</th><th>ESBL-E VAP (n=115)</th><th>P value</th></tr></thead><tbody><tr><td>ECMO</td><td>2</td><td>24 (5%)</td><td>3 (3%)</td><td>0.33</td></tr><tr><td>Dialysis</td><td>2</td><td>33 (7%)</td><td>14 (12%)</td><td>0.06</td></tr><tr><td>Antibiotics</td><td>1</td><td>435 (92%)</td><td>109 (95%)</td><td>0.25</td></tr><tr><td>CT scan</td><td>51</td><td>113 (26%)</td><td>25 (25%)</td><td>0.89</td></tr><tr><td>Corticosteroids</td><td>3</td><td>81 (17%)</td><td>17 (15%)</td><td>0.61</td></tr><tr><td>Corticosteroids the first week</td><td>0</td><td>126 (27%)</td><td>31 (27%)</td><td>0.98</td></tr><tr><td>On the day of VAP</td><td></td><td></td><td></td><td></td></tr><tr><td>Time between admission and VAP</td><td>0</td><td>10 [7–15]</td><td>12 [9–21]</td><td>0.001</td></tr><tr><td>Time between intubation and VAP</td><td>0</td><td>8 [5–12]</td><td>10 [7–18]</td><td>0.003</td></tr><tr><td>SOFA score</td><td>194</td><td>9 [7–11]</td><td>10 [7–13]</td><td>0.15</td></tr><tr><td>Non respiratory SOFA</td><td>194</td><td>7 [7, 8]</td><td>7 [4–9]</td><td>0.21</td></tr><tr><td>Catecholamine</td><td>94</td><td>153 (37%)</td><td>34 (39%)</td><td>0.76</td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>110</td><td>150 [115–220]</td><td>138 [103–184]</td><td>0.02</td></tr><tr><td>PEEP</td><td>107</td><td>11 [8–13]</td><td>12 [10–14]</td><td>0.03</td></tr><tr><td>Neuromuscular blockade</td><td>93</td><td>193(47%)</td><td>47 (53%)</td><td>0.28</td></tr><tr><td>Prone position</td><td>92</td><td>105 (26%)</td><td>28 (32%)</td><td>0.23</td></tr><tr><td>ECMO</td><td>85</td><td>28 (7%)</td><td>8 (9%)</td><td>0.43</td></tr><tr><td>Dialysis</td><td>80</td><td>51 (12%)</td><td>15 (17%)</td><td>0.24</td></tr><tr><td>Antibiotics</td><td>81</td><td>237 (56%)</td><td>56 (62%)</td><td>0.30</td></tr></tbody></table>

Categorical variables are expressed as n (%) and continuous variables as median [interquartile range]

<table><caption>**Table 2 Antibiotics in ICU before VAP related enterobacterales according to ESBL-E**</caption><thead><tr><th>Variables</th><th>No ESBL-E VAP (n=476)</th><th>ESBL-E VAP (n=115)</th><th>P value</th></tr></thead><tbody><tr><td>Ab in ICU before VAP</td><td>443 (93%)</td><td>112 (97%)</td><td>0.086</td></tr><tr><td>Penicillins</td><td>207 (44%)</td><td>49 (43%)</td><td>0.86</td></tr><tr><td>Cephalosporin</td><td>340 (71%)</td><td>90 (78%)</td><td>0.14</td></tr><tr><td>Fluoroquinolone</td><td>6 (1%)</td><td>6 (5%)</td><td>0.02</td></tr><tr><td>Carbapenem</td><td>23 (5%)</td><td>9 (8%)</td><td>0.20</td></tr><tr><td>Aminoglycoside</td><td>42 (9%)</td><td>13 (11%)</td><td>0.41</td></tr><tr><td>Co-trimoxazole</td><td>7 (1%)</td><td>8 (7%)</td><td>0.001</td></tr><tr><td>Glycopeptides</td><td>12 (3%)</td><td>8 (7%)</td><td>0.02</td></tr><tr><td>Linezolid</td><td>30 (6%)</td><td>6 (5%)</td><td>0.66</td></tr><tr><td>Macrolides</td><td>278 (58%)</td><td>67 (58%)</td><td>0.98</td></tr></tbody></table>

were related to ESBL-E; (ii) African origin, duration of mechanical ventilation, PaO2/FiO2 ratio the day of VAP and trimethoprim-sulfamethoxazole exposure were associated with ESBL-E VAP; (iii) ESBL-E VAP was not associated with a worse outcomes, including mortality, as compared to other Enterobacterales VAP.

Resistance patterns of Enterobacterales related VAP were heterogeneous across studies in COVID-19 patients. Our finding of 19% ESBL-E among Enterobacterales

<table><caption>**Table 3 Multivariable analysis of risk factors of ESBL-E related VAP**</caption><thead><tr><th>Variables</th><th>OR</th><th>95% CI</th><th>p-value</th></tr></thead><tbody><tr><td>SAPS II at ICU admission</td><td>1.00</td><td>0.98–1.01</td><td>0.90</td></tr><tr><td>African origin</td><td><strong>1.70</strong></td><td><strong>1.07–2.71</strong></td><td><strong>0.02</strong></td></tr><tr><td>Chronic renal failure</td><td>1.31</td><td>0.61–2.78</td><td>0.48</td></tr><tr><td>Immunodeficiency</td><td>1.38</td><td>0.62–3.09</td><td>0.42</td></tr><tr><td>Time between intubation and VAP</td><td><strong>1.06</strong></td><td><strong>1.02–1.09</strong></td><td><strong>0.002</strong></td></tr><tr><td>Non respiratory SOFA*</td><td>1.05</td><td>0.92–1.20</td><td>0.48</td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub>*</td><td><strong>0.997</strong></td><td><strong>0.994–0.999</strong></td><td><strong>0.04</strong></td></tr><tr><td>ECMO*</td><td>0.69</td><td>0.29–1.64</td><td>0.41</td></tr><tr><td>Antibiotics in ICU before VAP</td><td>2.23</td><td>0.63–7.90</td><td>0.21</td></tr><tr><td>Fluoroquinolone before VAP</td><td>2.59</td><td>0.71–9.43</td><td>0.14</td></tr><tr><td>Co-trimoxazole</td><td><strong>3.77</strong></td><td><strong>1.15–12.4</strong></td><td><strong>0.03</strong></td></tr><tr><td>Glycopeptides</td><td>1.65</td><td>0.58–4.67</td><td>0.35</td></tr></tbody></table>

Bold value indicates *p* < 0.05

African origin denotes North Africa or Sub-Saharan Africa origin; SAPS II Simplified Acute Physiology Score II, SOFA: Sequential Organ Failure Assessment; ECMO extracorporeal membrane oxygenation; VAP ventilator associated pneumonia, ICU intensive care unit *on the day of VAP

VAP is in accordance with findings from Vacheron et al., describing a frequency of ESBL-E VAP in COVID-19 or non-COVID-19 patients of about 13% in France [10]. Prevalence of ESBL-E ICU acquired infection were

<footnote>ª Except corticosteroids; NSAID: non-steroidal anti-inflammatory drug; SAPS II Simplified Acute Physiology Score II, SOFA: Sequential Organ Failure Assessment; ECMO extracorporeal membrane oxygenation; VAP ventilator associated pneumonia</footnote>
<figure><img src="image_5.png" /><figcaption>**Fig. 2** Cumulative probability of weaning in ESBL-E related VAP (red) and non ESBL-E related VAP (black) patients. For analysis purpose, time from intubation to weaning (continuous line) to death (dotted line) were handled as competing risks</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 3** Ninety-day survival in patients with ESBL-E related VAP and non ESBL-E related VAP</figcaption></figure>

reported as heterogeneous in France [11]. Most patients in our study were recruited in regions with higher ESBL-E prevalence (58% of the patients were recruited in the Paris or Greater Paris area).

ESBL-E infection is usually associated with previous colonization and invasive procedures [12]. Thus, it was not surprising that time between intubation and VAP was one of the main risk factor of ESBL-E VAP, as previously shown [13]. A previous study also showed that

the prevalence of ESBL increased during the second or third episode of VAP [2]. In our study, microbiological details were only available for the first episode of VAP [2]. In our cohort, most patients received antibiotics before VAP occurrence and the use of trimethoprim/sulfamethoxazole before VAP onset was independently associated with ESBL-E VAP. Exposure to trimethoprim/sulfamethoxazole was associated with ESBL-E organisms in previous reports [13–16]. The third risk factor identified by multivariable analysis was an African origin. This is in accordance with a previous French study reporting that a country of birth outside of Europe was a risk factor for ESBL-E infection [17]. In the USA, an African American origin was reported as a risk factor for ESBL-E infection [14, 18]. The role of a patient's origin may be driven by diet, food habits and/or travel abroad over the previous years [19]. We could only assess travels over a 3 week period preceding ICU admission. A lower PaO₂/FiO₂ ratio on the day of VAP was also a risk factor for ESBL-E VAP identified in this cohort. These results are in accordance with previous studies showing that ARDS was a risk factor for multidrug resistant bacteria VAP [20].

VAP was associated with significantly increased 28-day mortality in SARS-CoV-2 patients [21]. VAP-attributable mortality was higher for patients with COVID-19, with more than 9% of the overall mortality related to VAP [7]. Current evidence of the clinical burden of infections caused by ESBL-producing bacteria is highly heterogeneous and based mainly on unadjusted estimates derived from retrospective studies [22]. Lambert et al. showed that the risk of death associated with antimicrobial resistance (i.e., additional risk of death to that of the infection) was 1.2 (1.1–1.4) for pneumonia but this effect was mainly driven by *S. aureus* and *P. aeruginosa* [23]. We herein did not find different outcomes between ESBL-E and non ESBL-E VAP. Additionally, a sensitivity analysis in patients infected only with Enterobacterales excluded the hypothesis that co-infecting microorganisms could have influenced the results. Several studies with fewer ESBL-E episodes also showed no difference in outcome between ESBL-E and non ESBL-E VAP [24, 25]. Our study with a homogeneous population of COVID-19 patients strengthens these findings. Multi-drug resistant related VAP was associated with increased mortality when empiric antibiotherapy was inadequate [26, 27]. Information on early adequate regimen was unavailable but could be similar between ESBL-E and non ESBL-E VAP, explaining the absence of difference in outcome in this study. Given the poor accuracy of chest radiograph to detect new infiltrates, the diagnosis of VAP in patients with ARDS is challenging [28]. In a restrictive antibiotic policy, physician may have started antibiotic therapy after culture results. We cannot formally exclude that patients
developed ventilator associated tracheobronchitis and not VAP, but the number of patients requiring catecholamine (more than 1/3) was higher than reported in recent VAP cohorts [29]. In addition, mortality was similar in ESBL-E and non ESBL-E VAP among patients with distal quantitative samples. Lastly, mortality in COVID-19 critically was mainly altered by age, comorbidities, corticosteroids and organ failure [30, 31].

Strengths of our study include the large number of patients assessed and data recorded prospectively, and the absence of case-mix with only COVID-19 patients. We acknowledge several limitations to our study. First, all patients were included during the first epidemic wave of SARS-CoV-2 affecting Europe in the spring of 2020, a unique period when ICUs were overwhelmed. It cannot be excluded that antibiotic stewardship in COVID-19 patients with less antibiotic administration at ICU admission may change ESBL-E prevalence. Moreover, the acquisition of immunity following subsequent epidemic waves or vaccination, and/or the emergence of new SARS-CoV-2 variants, may change some of our results. Second, although this study was conducted in 149 ICUs from 138 centers, across three countries, our results were obtained from a west European population, a region of the world with relatively low prevalence of ESBL-E colonization or infection.

## Conclusions

In this prospective multicenter study of patients with a first episode of VAP related to Enterobacterales, almost a fifth were ESBL-E. African origin, duration of mechanical ventilation, a lower PaO₂/FiO₂ ratio and trimethoprim-sulfamethoxazole exposure were associated with ESBL-E VAP. ESBL-E VAP was not associated with a worse outcome as compared to other Enterobacterales-related VAP.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13054-024-04906-2.

**Additional file 1. Table E1.** Centers informations; **Table E2.** Multivariable analysis of risk factors of ESBL-E related VAP after exclusion of the 8 patients with CRE related VAP; **Table E3.** Antibiotics administered in the 24 hours following VAP according to ESBL-E; **Table E4.** Outcome according to the occurrence of ESBL-E VAP; **Table E5.** Risk factors for death in patients with VAP related to enterobacterales according to species.

## Acknowledgements

We thank all investigators from the COVID-ICU VAP Study Group, who were involved in the development of this study: S Nseir, M Fartoukh, G Voiriot, A Rouzé, CE Luyt. We gratefully acknowledge all the French, Belgian, and Swiss clinical research centers, COVID-ICU investigators, the medical students, Polytechnic University students, and patients involved in the study. Participating sites and COVID-ICU investigators: CHU Angers, Angers, France (Alain Mercat, Pierre Asfar, François Beloncle, Julien Demiselle), APHP—Hôpital

Bicêtre, Le Kremlin-Bicêtre, France (Tai Pham, Arthur Pavot, Xavier Monnet, Christian Richard), APHP—Hôpital Pitié Salpêtrière, Paris, France (Alexandre Demoule, Martin Dres, Julien Mayaux, Alexandra Beurton), CHU Caen Normandie—Hôpital Côte de Nacre, Caen, France, (Cédric Daubin, Richard Descamps, Aurélie Joret, Damien Du Cheyron), APHP—Hôpital Cochin, Paris, France (Frédéric Pene, Jean-Daniel Chiche, Mathieu Jozwiak, Paul Jaubert), APHP—Hôpital Tenon, Paris (France, Guillaume Voiriot, Muriel Fartoukh, Marion Teulier, Carisse Blayau), CHRU de Brest—La Cavale Blanche, Brest, France (Erwen L'Her, Cécile Aubron, Laetitia Bodenes, Nicolas Ferriere), Centre Hospitalier de Cholet, Cholet, France (Johann Auchabie, Anthony Le Meur, Sylvain Pignal, Thierry Mazzoni), CHU Dijon Bourgogne, Dijon, France (Jean-Pierre Quenot, Pascal Andreu, Jean-Baptiste Roudau, Marie Labruyère), CHU Lille—Hôpital Roger Salengero, Lille, France (Saad Nseir, Sébastien Preau, Julien Poissy, Daniel Mathieu), Groupe Hospitalier Nord Essonne, Longjumeau, France (Sarah Benhamida, Rémi Paulet, Nicolas Roucaud, Martial Thyrault), APHM—Hopital Nord, Marseille, France (Florence Daviet, Sami Hraiech, Gabriel Parzy, Aude Sylvestre), Hôpital de Melun-Sénart, Melun, France (Sébastien Jochmans, Anne-Laure Bouilland, Mehran Monchi), Élément Militaire de Réanimation du SSA, Mulhouse, France (Marc Danguy des Déserts, Quentin Mathais, Gwendoline Rager, Pierre Pasquier), CHU Nantes—Hôpital Hotel Dieu, Nantes, France (Jean Reignier, Amélie Seguin, Charlotte Garret, Emmanuel Canet), CHU Nice—Hôpital Archet, Nice, France (Jean Dellamonica, Clément Saccheri, Romain Lombardi, Yanis Kouchit), Centre Hospitalier d'Orléans, Orléans, France (Sophie Jacquier, Armelle Mathonnet, Mai-Ahn Nay, Isabelle Runge), Centre Hospitalier Universitaire de la Guadeloupe, Pointe-à-Pitre, France (Frédéric Martino, Laure Flurin, Amélie Rolle, Michel Carles), Hôpital de la Milétrie, Poitiers, France (Rémi Coudroy, Arnaud W Thille, Jean-Pierre Frat, Maeva Rodriguez), Centre Hospitalier Roanne, Roanne, France (Pascal Beuret, Audrey Tientcheu, Arthur Vincent, Florian Michelin), CHU Rouen—Hôpital Charles Nicolle, Rouen, France (Fabienne Tamion, Dorothée Carpentier, Déborah Boyer, Christophe Girault), CHRU Tours—Hôpital Bretonneau, Tours, France (Valérie Gissot, Stéphan Ehrmann, Charlotte Salmon Gandonnière, Djali Elaroussi), Centre Hospitalier Bretagne Atlantique, Vannes, France (Agathe Delbove, Yannick Fedun, Julien Huntzinger, Eddy Lebas), CHU Liège, Liège, Belgique (Grâce Kisoka, Céline Grégoire, Stella Marchetta, Bernard Lambermont), Hospices Civils de Lyon—Hôpital Edouard Herriot, Lyon, France (Laurent Argaud, Thomas Baudry, Pierre-Jean Bertrand, Auguste Dargent), Centre Hospitalier Du Mans, Le Mans, France (Christophe Guitton, Nicolas Chudeau, Mickaël Landais, Cédric Darreau), Centre Hospitalier de Versailles, Le Chesnay, France (Alexis Ferré, Antoine Gros, Guillaume Lacave, Fabrice Bruneel), Hôpital Foch, Suresnes, France (Mathilde Neuville, Jérôme Devaquet, Guillaume Tachon, Richard Gallot), Hôpital Claude Galien, Quincy sous Senart, France (Riad Chelha, Arnaud Galbois, Anne Jallot, Ludivine Chalumeau Lemoine), GHR Mulhouse Sud-Alsace, Mulhouse, France (Khaldoun Kuteifan, Valentin Pointurier, Louise-Marie Jandeaux, Joy Mootien), APHP—Hôpital Antoine Béclère, Clamart, France (Charles Damoisel, Benjamin Sztrymf), APHP—Hôpital Pitié-Salpêtrière, Paris, France (Mathieu Schmidt, Alain Combes, Juliette Chommeloux, Charles Edouard Luyt), Hôpital Intercommunal de Créteil, Créteil, France (Frédérique Schortgen, Leon Rusel, Camille Jung), Hospices Civils de Lyon—Hôpital Neurologique, Lyon, France (Florent Gobert), APHP—Hôpital Necker, Paris, France (Damien Vimpere, Lionel Lamhaut), Centre Hospitalier Public du Cotentin—Hôpital Pasteur, Cherbourg-en-coton tin, France (Bertrand Sauneuf, Liliane Charrirer, Julien Calus, Isabelle Desmeules), CHU Rennes—Hôpital du Pontchaillou, Rennes, France (Benoît Painvin, Jean-Marc Tadie), CHU Strasbourg—Hôpital Hautepierre, Strasbourg, France (Vincent Castelain, Baptiste Michard, Jean-Etienne Herbrecht, Mathieu Baldacini), APHP—Hôpital Pitié Salpêtrière, Paris, France (Nicolas Weiss, Sophie Demeret, Clémence Marois, Benjamin Rohaut), Centre Hospitalier Territorial Gaston-Bourret, Nouméa, France (Pierre-Henri Moury, Anne-Charlotte Savida, Emmanuel Couadau, Mathieu Série), Centre Hospitalier Compiègne-Noyon, Compiègne, France (Nica Alexandru), Groupe Hospitalier Saint-Joseph, Paris, France (Cédric Bruel, Candice Fontaine, Sonia Garrigou, Juliette Courtiade Mahler), Centre hospitalier mémorial de Saint-Lô, Saint-Lô, France (Maxime Leclerc, Michel Ramakers), Grand Hôpital de l'Est Francilien, Jossigny, France (Pierre Garçon, Nicole Massou, Ly Van Vong, Juliane Sen), Gustave Roussy, Villejuif, France (Nolwenn Lucas, Franck Chemouni, Annabelle Stoclin), Centre Hospitalier Intercommunal Robert Ballanger, Aulnay-sous-Bois, France (Alexandre Avenel, Henri Faure, Angélie Gentilhomme, Sylvie Ricome), Hospices Civiles de Lyon—Hôpital Edouard Herriot, Lyon, France (Paul Abraham, Céline Monard, Julien Textoris, Thomas Rimmele), Centre Hospitalier d'Avignon, Avignon, France (Florent Montini), Groupe Hospitalier
Diacon- esses—Croix Saint Simon, Paris, France (Gabriel Lejour, Thierry Lazard, Isabelle Etienney, Younes Kerroumi), CHU Clermont-Ferrand—Hôpital Gabriel Mont pied, Clermont Ferrand, France (Claire Dupuis, Marine Bereiziat, Elisabeth Coupez, François Thouy), Hôpital d'Instruction des Armées Percy, Clamart, France (Clément Hofmann, Nicolas Donat, Anne Chrisment, Rose-Marie Blot), CHU Nancy—Hôpital Brabois, Vandoeuvre-les-Nancy, France (Antoine Kimmoun, Audrey Jacquot, Matthieu Mattei, Bruno Levy), Centre Hospitalier de Vichy, Vichy, France (Ramin Ravan, Loïc Dopeux, Jean-Mathias Lumaudon, Delphine Roux), Hôpital Pierre Bérégovoy, Nevers, France (Brice Rey, Radu Anghel, Deborah Schenesse, Vincent Gevrey), Centre Hospitalier de Tarbes, Tarbes, France (Jermy Castanera, Philippe Petua, Benjamin Madeux), Hôpitaux Civils de Colmar—Hôpital Louis pasteur, Colmar, France (Otto Hartman), CHU Charleroi—Hôpital Marie Curie, Bruxelles, Belgique (Michael Piagnerelli, Anne Joosten, Cinderella Noel, Patrick Biston), Centre hospitalier de Verdun Saint Mihiel, Saint Mihiel, France (Thibaut Noel), CH Eure-Seine—Hôpital d'Evreux-Vernon, Evreux, France (Gurvan LE Bouar, Messabi Boukhanza, Elsa Demarest, Marie-France Bajolet), Hôpital René Dubos, Pontoise, France (Nathanaël Charrier, Audrey Quenet, Cécile Zylberfajn, Nicolas Dufour), APHP—Hôpital Lariboisière, Paris, France (Bruno Mégarbane, Sébastien Voicu, Nicolas Deye, Isabelle Malissin), Centre Hospitalier de Saint-Brieuc, Saint-Brieuc, France (François Legay, Matthieu Debarre, Nicolas Barbarot, Pierre Fillatre), Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France (Bertrand Delord, Thomas Laterrade, Tahar Saghi, Wilfried Pujol), HIA Sainte Anne, Toulon, France (Pierre Julien Cungi, Pierre Esnault, Mickael Cardinale), Grand Hôpital de l'Est Francilien, Meaux, France (Vivien Hong Tuan Ha, Grégory Fleury, Marie-Ange Brou, Daniel Zafmahazo), HIA Robert Picqué, Villenave de Ornon, France (David Tran-Van, Patrick Avargues, Lisa Carenco), Centre Hospitalier Fontainebleau, Fontainebleau, France (Nicolas Robin, Alexandre Ouali, Lucie Houdou), Hôpital Universitaire de Genève, Genève, Suisse (Christophe Le Terrier, Noémie Suh, Steve Primmaz, Jéréme Pugin), APHP—Hôpital Beaujon, Clichy, France (Emmanuel Weiss, Tobias Gauss, Jean-Denis Moyer, Catherine Paugam Burtz), Groupe Hospitalier Bretagne Sud, Lorient, France (Béatrice La Combe, Rolland Smonig, Jade Violleau, Pauline Cailliez), Centre Hospitalier Intercommunal Toulon, La Seyne sur Mer, France (Jonathan Chelly), Centre Hospitalier de Dieppe, Dieppe, France (Antoine Marchalot, Cécile Saladin, Christelle Bigot), CHU de Martinique, Fort-de-France, France (Pierre-Marie Fayolle, Jules Fatséas, Amr Ibrahim, Dabor Resiere), Hôpital Fondation Adolphe de Rothchild, Paris, France (Rabih Hage, Clémentine Cholet, Marie Cantier, Pierre Roulier), APHP—Bichat Claude Bernard, Paris, France (Philippe Montravers, Brice Lortat-Jacob, Sebastien Tanaka, Alexy Tran Dinh), APHP—Hôpital Universitaire Paris Sud, Bicêtre, France (Jacques Duranteo, Anatole Harrois, Guillaume Dubreuil, Marie Werner), APHP—Hôpital Européen Georges Pompidou, Paris, France (Anne Godier, Sophie Hamada, Diane Zlotnik, Hélène Nougue), APHP, GHU Henri Mondor, Créteil, France (Armand Mekontso-Dessap, Guillaume Carteaux, Keyvan Razazi, Nicolas De Prost), APHP—Hôpitaux Universitaires Henri Mondor, Créteil, France (Nicolas Mongardon, Nicolas Mongar- don, Meriam Lamraoui, Claire Alessandri, Quentin de Roux), APHP—Hôpital Lariboisière, Paris, France (Charles de Roquetaillade, Benjamin G. Chousterman, Alexandre Mebazaa, Etienne Gayat), APHP—Hôpital Saint-Antoine, Paris, (Marc Garnier, Emmanuel Pardo, Lea Satre-Buisson, Christophe Gutton), APHP Hôpital Saint-Louis, Paris, France (Elise Yvin, Clémence Marcault, Elie Azoulay, Michael Darmon), APHP—Hôpital Saint-Antoine, Paris, France (Hafd Ait Oufella, Geофroy Hariri, Tomas Urbina, Sandie Mazerat), APHP—Hôpital Raymond Pointcarré, Garches, France (Nicholas Heming, Francesca Santi, Pierre Moine, Djillali Annane), APHP—Hôpital Pitié Salpétrière, Paris, France (Adrien Bouglé, Edris Omar, Aymeric Lancelot, Emmanuel Begot), Centre Hospitalier Victor Dupouy, Argenteuil, France (Gaétan Planteveve, Damien Contou, Hervé Mentec, Olivier Pajot), CHU Toulouse—Hôpital Rangueil, Toulouse, France (Stanislas Faguer, Olivier Cointault, Laurence Lavayssiere, Marie-Béatrice Nogier), Centre Hospitalier de Poissy, Poissy, France (Matthieu Jamme, Claire Pichereau, Jan Hayon, Hervé Outin), APHP—Hôpital Saint-Louis, Paris, France (François Dépret, Maxime Coutrot, Maité Chaussard, Lucie Guillemet), Clinique du MontLégia, CHC Groupe-Santé, Liège, Belgique (Pierre Gofn, Romain Thouny, Julien Guntz, Laurent Jadot), CHU Saint-Denis, La Réunion, France (Romain Persichini), Centre Hospitalier de Tourcoing, Tourcoing, France (Vanessa Jean-Michel, Hugues Georges, Thomas Caulier), Centre Hospitalier Henri Mondor d'Aurillac, Aurillac, France (Gaël Pradel, Marie-Hélène Hausermann, Thi My Hue Nguyen-Valat, Michel Boudinau), Centre Hospitalier Saint Joseph Saint Luc, Lyon, France (Emmanuel Vivier, Sylvène Rosseli, Gaël Bourdin, Christian Pommier) Centre Hospitalier de Polynésie Française, Polynésie, France (Marc Vinclair, Simon Poignant, Sandrine Mons), Ramsay

Générale de Santé, Hôpital Privé Jacques Cartier, Massy, France (Wulfran Bougouin), Centre Hospitalier Alpes Léman, Contamine sur Arve, France (Franklin Bruna, Quentin Maestraggi, Christian Roth), Hospices Civils de Lyon—Hôpital de la Croix Rousse, Lyon, France (Laurent Bitker, François Dhelft, Justine Bonnet-Chateau, Mathilde Filippelli), Centre Cardiologique du Nord, Saint-Denis, France (Tristan Morichau-Beauchant, Stéphane Thierry, Charlotte Le Roy, Mélanie Saint Jouan), GHU—Hôpital Saint-Anne, Paris, France (Bruno Gr CALVES, Aurélien Mazeraud, Matthieu Daniel, Tarek Sharshar) CHR Metz—Hôpital Mercy, Metz, France (Cyril Cadoz, Rostane Gaci, Sébastien Gette, Guillaume Louis), APHP—Hôpital Paul Brousse, Villejuif, France (Sophie-Caroline Sacleux, Marie-Amélie Ordan), CHRU Nancy—Hôpital Central, Nancy, France (Aurélie Cravoisy, Marie Conrad, Guilhem Courte, Sébastien Gibot), Centre Hospitalier d'Ajaccio, Ajaccio, France (Younès Benzidi, Claudia Casella, Laurent Serpin, Jean-Lou Setti), Centre Hospitalier de Bourges, Bourges, France (Marie-Catherine Besse, Anna Bourreau), Centre hospitalier de la Côte Basque, Bayonne, France (Jérôme Pillot, Caroline Rivera, Camille Vinclair, Marie-Aline Robaux), Hospices Civils de Lyon—Hôpital de la Croix Rousse, Lyon, France (Chloé Achino, Marie-Charlotte Delignette, Tessa Mazard, Frédéric Aubrun), CH Saint-Malo, Saint-Malo, France (Bruno Bouchet, Aurélien Frélin, Laura Muller, Charlotte Quentin), Centre hospitalier de Mulhouse, Mulhouse, France (Samuel Degoul), Centre Hospitalier de Briançon, Briançon, France (Xavier Stihle, Claude Sumian, Nicoletta Bergero, Bernard Lasan spre), CHU Nice, Hôpital Pasteur 2, Nice, France (Hervé Quintard, Eve Marie Maizière), Centre Hospitalier des Pays de Morlaix, Morlaix, France (Pierre-Yves Egreteau, Guillaume Leloup, Florin Berteau, Marjolaine Cottrel), Centre Hospitalier Valence, Valence, France (Marie Bouteloup, Matthieu Jeillet, Quentin Blanc, Julien Saison), Centre Hospitalier Niort, Niort, France (Isabelle Geneau, Romaric Grenot, Abdel Ouchike, Pascal Hazera), APHP—Hôpital Pitié Salpétrière, Paris, France (Anne-Lyse Masse, Suela Demiri, Corinéez Veizinet, Eodie Baron, Deborah Benchetrit, Antoine Monsel), Clinique du Val d'Or, Saint Cloud, France (Grégoire Trebbia, Emmanuelle Schaack, Raphaël Lepecq, Mathieu Bobet), Centre Hospitalier de Béthune, Béthune, France (Christophe Vinsonneau, Thibault Dekeyser, Quentin Delforge, Imen Rahmani), Groupe Hospitalier Intercommunal de la Haute-Saône, Vesoul, France (Bréngère Vivet, Jonathan Paillot, Lucie Hierle, Claire Chaignat, Sarah Vlette), Clinique du-Saint-Martin, Caen, France (Benoît Her, Jennifer Brunet), Ramsay Générale de Santé, Clinique Convert, Bourg en Bresse, France (Mathieu Page, Fabienne Boiste, Anthony Paillot, Victor Jousselin, Dreux, France)(Florent Bavoizet, Aude Garin, Mohamed Dlala, Kais Mhamdi), Centre Hospitalier de Troye, Troye, France, (Bassem Beilouny, Alexandra Lavalard, Severine Perez), CHU de ROUEN-Hôpital Charles Nicolle, Rouen, France (Benoit Veber, Pierre-Gildas Guitard, Philippe Gouin, Anna Lamacz), Centre Hospitalier Agen-Nérac, Agen, France (Fabienne Plouvier, Bertrand Delaborde, Aïssa Kherchache, Amina Chaalal), APHP—Hôpital Louis Mourrier, Colombes, France (Jean-Damien Ricard, Marc Amouretti, Santiago Freita-Ramos, Damien Roux), APHP—Hôpital Pitié-Salpétrière, Paris, France (Jean-Michel Constantin, Mona Assef, Marine Lecore, Agathe Selves), Institut Mutualiste Montsouris, Paris, France (Florian Prevost, Christian Lamer, Ruiying Shi, Lyes Knani), CHU Besançon—Hôpital Jean Minjoz, Besançon, France, (Sébastien Pili Floury, Lucie Vettoretti), APHP—Hôpital Universitaire Robert-Debré, Paris, France (Michael Levy, Lucile Marsac, Stéphane Dauger, Sophie Guilmin-Crépon), CHU Besançon—Hôpital Jean Minjoz, Besançon, France, (Hadrien Winiszewski, Gael Piton, Thibaud Soumagne, Gilles Capellier); Médipôle Lyon-Villeurbanne, Villeurbanne, France, (Jean-Baptiste Putegnat, Frédérique Bayle, Maya Perrou, Ghyslaine Thao), APHP—Ambroise Paré, Boulogne-Billancourt, France (Guillaume Géri, Cyril Charron, Xavier Repessé, Antoine Vieillard-Baron), CHU Amiens Picardie, Amiens, France (Mathieu Guilbart, Pierre-Alexandre Roger, Sébastien Hinard, Pierre-Yves Macq), Hôpital Nord-Ouest, Villefranche-sur-Saône, France (Kevin Chaulier, Sylvie Goutte), CH de Châlons en Champagne, Châlons en Champagne, France (Patrick Chillet, Anaïs Pitta, Barbara Darjent, Amandine Bruneau), CHU Angers, Angers, France (Sigismond Lasocki, Maxime Leger, Soizic Gergaud, Pierre Lemarie), CHU Grenoble Alpes, Grenoble, France (Nicolas Terzi, Carole Schwebel, Anaïs Dartevel, Louis-Marie Galerneau), APHP—Hôpital Européen Georges Pompidou, Paris, France (Jean-Luc Diehl, Caroline Hauw-Berlemont, Nicolas Péron, Emmanuel Guérot), Hôpital Privé d'Antony, Antony, France (Abolfazl Mohebbi Amoli, Michel Benhamou, Jean-Pierre Deyme, Olivier Andremont), Institut Arnault Tzanck, Saint Laurent du Var, France (Diane Lena, Julien Cady, Arnaud Causaret, Arnaud De la Chapelle); Centre Hospitalier d'Angoulême, Angoulême, France (Christophe Cracco, Stéphane Rouleau, David Schnell); Centre Hospitalier de Cahors, Cahors, France (Camille Foucault), Centre hospitalier de Carcassonne,
Carcassonne, France (Cécile Lory); CHU Nice—Hôpital L'Archet 2, Nice, France (Thibault Chapelle, Vincent Bruckert, Julie Garcia, Abdilazize Sahraoui); Hôpital Privé du Vert Galant, Tremblay-en-France, France (Nathalie Abbosh, Caroline Bornstain, Pierre Pernet); Centre Hospitalier de Rambouillet, Rambouillet, France (Florent Poirson, Ahmed Pasem, Philippe Karoubi); Hopitaux du Léman, Thonon les Bains, France (Virginie Poupinel, Caroline Gauthier, François Bouniol, Philippe Feuchere), Centre Hospitalier Victor Jousselin, Dreux, France (Florent Bavozet, Anne Heron), Hôpital Sainte Camille, Brie sur Marne, France (Serge Carreira, Malo Emery, Anne Sophie Le Floch, Luana Giovannangeli), Hôpital d'instruction des armées Clermont-Tonnerre, Brest, France (Nicolas Herzog, Christophe Giacardi, Thibaut Baudic, Chloé Thill), APHP—Hôpital Pitié Salpêtrière, Paris, France (Said Lebbah, Jessica Palmyre, Florence Tubach, David Hajage); APHP—Hôpital Avicenne, Bobigny, France (Nicolas Bonnet, Nathan Ebstein, Stéphane Gaudry, Yves Cohen); Groupement Hospitalier la Rochelle Ré Amis, La Rochelle, France (Julie Noublanche, Olivier Lesieur); Centre Hospitalier Intercommunal de Mont de Marsan et du Pays des Sources, Mont de Marsan, France (Arnaud Sément, Isabel Roca-Cerezo, Michel Pascal, Nesrine Sma); Centre Hospitalier Départemental de Vendée, La-Roche-Sur-Yon, France (Gwenhaël Colin, Jean-Claude Lacherade, Gauthier Bionz, Natacha Maquignneau); Pôle Anesthésie-Réanimation, CHU Grenoble (Pierre Bouzat, Michel Durand, Marie-Christine Hérault, Jean-François Payen).

## Author contributions

KR, AMD designed the study, interpreted the data and wrote the manuscript. KR and ACN performed statistical analysis. All authors made significant intellectual concept. All authors read and approved the final manuscript.

## Funding

This study was funded by the Fondation APHP and its donators through the program « Alliance Tous Unis Contre le Virus», the Direction de la Recherche Clinique et du Développement, and the French Ministry of Health and the foundation of the University hospitals of Geneva, Geneva, Switzerland. The funder had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. This study was funded by Ministère des Affaires Sociales, de la Santé et des Droits des Femmes.

## Availability of data and materials

The data sets generated during the current study are available from the corresponding author on reasonable request.

## Declarations

### Ethics approval and consent to participate

Human research ethics committee approval for the study was the ethical committee of the French Intensive Care Society (CE-SRLF 20-23) following our local regulations.

### Competing interests

CEL: AdvanzPharma and Merck for lecture. Grant from AdvanzPharma. Travel reimbursement for congress from Pfizer. AF reports honoraria by Fisher & Paykel for a lecture during SFMU Congress 2022, outside the submitted work. MG reports personal fees as a speaker received from Medtronic outside the submitted work. AMD reports grants from Fischer Paykel, Baxter, Philips, Ferring and GSK, personal fees from Air Liquide, Baxter, Amomed, Getingue and Addmedica, outside the submitted work.

### Author details

¹Hôpitaux Universitaires Henri Mondor, DMU Médecine, Service de Médecine Intensive Réanimation, Assistance Publique-Hôpitaux de Paris (AP-HP), 94010 Créteil, France. ²IMRB, GRC CARMAS, Faculté de Santé de Créteil, Université Paris Est Créteil (UPEC), 94010 Créteil, France. ³Service de Médecine Intensive Réanimation, Institut de Cardiologie, Sorbonne-Université, Hôpital Pitié-Salpêtrière, and Sorbonne Université, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris (APHP), 47-83, Boulevard de L'Hôpital, 75651 Paris, France. ⁴Service de Médecine Intensive Réanimation, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France. ⁵Inserm U1285, CHU Lille, Service de Médecine Intensive - Réanimation, CNRS, UMR 8576 - UGSF - Unité

de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, 59000 Lille, France. ⁶GRC29, DMU DREAM, Anesthesiology and Critical Care Medicine Department, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France. ⁷Intensive Care Unit, Versailles Hospital, Le Chesnay, France. ⁸Medical and Surgical Intensive Care Unit, Guadeloupe Teaching Hospital, Antilles-Guyane University, Les Abymes, France. ⁹Department of Intensive Care, Hôpital Raymond Poincaré, APHP University Versailles Saint Quentin - University Paris Saclay, Paris, France. ¹⁰Laboratory of Infection and Inflammation - U1173, School of Medicine Simone Veil, INSERM, University Versailles Saint Quentin - University Paris Saclay, Garches, France. ¹¹FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to Personalize Interventions for Sepsis), Garches, France. ¹²INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Saint-Antoine Hospital, Public Health Department, Sorbonne University, 75012 Paris, France. ¹³Hôpital Européen Georges Pompidou, Unité d'Epidémiologie et de Recherche Clinique, INSERM, Centre d'Investigation Clinique1418, Module Épidémiologie Clinique, AP-HP (Assistance Publique Hôpitaux de Paris), Paris, France. ¹⁴INSERM, Unité U955, Université Paris Est, 94010 Créteil, France. ¹⁵Service de Médecine Intensive Réanimation, CHU Henri Mondor, 51, Av de Lattre de Tassigny, 94000 Créteil Cedex, France.

Received: 16 October 2023 Accepted: 8 April 2024

Published online: 20 April 2024

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