key: cord-0976943-pvasecj6
authors: d'Humieres, C.; Patrier, J.; Lortat-Jacob, B.; Tran-dinh, A.; Chemali, L.; Maataoui, N.; Rondinaud, E.; Ruppe, E.; Burdet, C.; Ruckly, S.; Montravers, P.; Timsit, J.-F.; Armand-Lefevre, L.
title: Two original observations concerning bacterial infections in COVID-19 patients hospitalized in intensive care units during the first wave of the epidemic in France
date: 2021-01-26
journal: nan
DOI: 10.1101/2021.01.22.21250287
sha: 4e7ef9f3f5a0fc7acb5f4fff057777e53330fe83
doc_id: 976943
cord_uid: pvasecj6

Among 197 COVID-19 patients hospitalized in ICU, 88 (44.7%) experienced at least one bacterial infection, with pneumonia (39.1%) and bloodstream infections (15,7%) being the most frequent. Unusual findings include frequent suspicion of bacterial translocations originating from the digestive tract as well as bacterial persistence in the lungs despite adequate therapy

Since December 2019, the world has been facing a pandemic due to the spread of SARS-CoV-2 coronavirus, which may lead to acute respiratory failure. In 6% of cases, patients are hospitalized [1] , and 20% of whom develop acute respiratory distress syndrome for which they are admitted to intensive care unit (ICU) [1] . Hospitalization in ICU is highly associated with health-care infections, particularly ventilator-associated pneumonia (VAP) and bloodstream infections (BSI). In France, the first COVID-19 patients, all from Wuhan (China), were hospitalized at the end of January 2020 [2] . One of them, admitted to the medical ICU of our hospital, was surprisingly co-infected upon arrival with an unexpected antibiotic susceptible Acinetobacter baumannii. Two meta-analyses reported bacterial infection rates in COVID-19 ICU patients of 8.1% [3] and 14% [4] . But data on bacterial infections in COVID-19 patients are still sparse and not always consistent. Moreover, several studies highlight the over-prescription of antibiotics in COVID-19 patients and the risk of a global increase of antimicrobial resistance [5, 6] . It is thus essential to know the incidence and epidemiology of bacterial infections in such patients, in order to manage antibiotic prescriptions.

Our study describes bacterial infections in COVID-19 patients hospitalized in two ICUs of a French referral center hospital. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

This retrospective study was conducted on COVID-19 patients hospitalized in ICUs of Bichat Claude Bernard University Hospital (Paris, France) between January 29 th (first patient admission) and May 31 st 2020. Demographic data, comorbidities and microbiological data have been retrospectively collected.

A COVID-19 confirmed case was defined by a positive result for SARS-CoV-2 virus, based on a reverse transcriptase-polymerase-chain-reaction (RT-PCR) test on a nasopharyngeal swab or respiratory specimen and/or typical parenchyma infiltrates on a chest CT scan.

Bacterial pneumonia was diagnosed according to clinical IDSA guidelines [7] and the presence of bacteria in a respiratory sample (broncho-alveolar lavage (BAL), plugged telescoping catheter (PTC), tracheal aspiration or sputum). Early-and late-onset VAP or BSI were established using a breakpoint of 5 days of mechanical ventilation for VAP and of ICU stay for BSI [8] .

The Committee for Research Ethics in Anesthesia and Critical care (CERAR) authorized the study (IRB 00010254-2020-168).

For univariate analysis, categorical data were analyzed using Pearson's chi-squared analysis or Fisher test, and continuous data were analyzed using non-parametric Wilcoxon test.

All statistical analyses were 2-tailed with a significance level of 5%, and were performed with scipy.stat package from Python. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ;

Overall, 197 COVID-19 patients were admitted to ICU. Median age was 59 years (IQR 50-68) and sex ratio (M/F) was 3. At admission the median SAPS II was 34 (IQR 25-50).

Among patients, 116 (58.9%) had at least one co-morbidity and 81 (41.1%) were overweight (body mass index (BMI) ≥ 25 kg/m²). In all, 179 patients (91.0 %) received antibiotics (122/179 introduced before ICU and 57/179 during ICU stay) (table S1). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint and Escherichia coli (8/65, 12.3%). No difference was observed in the distribution of bacteria between early-and late-onset VAP (data not shown). Among Enterobacterales, 11/37 (29.7%) were resistant to third-generation cephalosporins but susceptible to carbapenems (8 extended-spectrum beta-lactamase and 3 high-level expression of cephalosporinase) and 5/37 (13.5%) were resistant to carbapenems (all harboring an NDMtype carbapenemase).

Strikingly, we observed an unusual persistence of bacteria in the respiratory samples of patients with VAP despite an adequate antibiotic therapy. Among patients still hospitalized 7 days following the initial VAP, the responsible bacteria was still detected in culture in 57.4% (27/47) of cases. Presence of the bacteria, was 23.1% (6/26) among those who were still hospitalized 16 days following initial VAP (figure S1). The comparison of patients with (27/47) or without (20/47) persistent VAP at D7 shows a lower age (52y vs 60.6y, p<0.01) and a higher BMI (31.5 vs 27.8, p=0.018) among those with persistent VAP (Table S2) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ;

Here, we showed that almost half of COVID-19 ICU patients developed a bacterial infection. Our study highlights two bacteriological peculiarities in these patients (i) an epidemiology of BSI that may suggest digestive or oropharyngeal translocations and (ii) a persistence of bacteria in the lungs of patients adequately treated for VAP.

We observed a higher rate (33.5%) of positive blood cultures than reported in the literature (3.8% to 12%) [9, 10] and by the same ICUs last year (12.8%, personal data). More than half of these were considered as contaminants that may be due to changes in guidelines and safety equipment of nursing staff due to the COVID-19 crisis. Bacteria causing BSI were mainly Enterococci (35.5%), Staphylococci (32.2%) and Streptococci (12.9%) which is unusual in ICU patients. Indeed, the bacteria causing BSI in the same ICUs last year were rather Enterobacterales (33.3%), then Staphylococci (30.3%) and Enterococci (18%), (personal data). Interestingly, in 54.8% of episodes, no origin of the BSI could be determined and translocation of bacteria from digestive or oropharyngeal microbiota was suspected. One hypothesis is that the hyper-inflammatory status of COVID-19 patients may increase the permeability of the intestinal or oropharyngeal barriers and thus bacterial translocations. The description of the composition of the intestinal and oropharyngeal microbiota would be helpful to understand the origin of these unusual BSIs [11] .

We also observed that 50.4% of COVID-19 ICU intubated patients developed a VAP, a rate much higher than observed in the literature (ranging from 0% in USA [12] , 7.5% [13] in Spain, and to 30.6% in France) [14] . The distribution of bacteria causing VAP did not show any particularity, however, we observed a high rate of multi-drug resistant bacteria (MDRB). This could be explained by an increased use of antibiotics in COVID-19 patients (91%), associated with an increase of MDRB dissemination in the ICUs. Surprisingly, we observed that VAP bacteria clearance from the lungs was exceptionally slow despite adequate antibiotic therapy. The cause of antimicrobial failures remains speculative. The main reasons advocated by experts are (i) pharmacodynamic alterations due to frequent glomerular hyperfiltration, even though in our study we did not find any difference in renal function between the patients, (ii) pharmacodynamic alterations due to a high BMI, which seems to be the case in this study, (iii) a probable decrease in the antimicrobial lung is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ;

concentration associated with pulmonary emboli and obstruction of the pulmonary vasculature frequently observed in ICU COVID-19 patients [15] , and/or (iv) an impaired immune response. To our knowledge, these observations have not previously been described in the literature.

This retrospective observational study was conducted in a single center, comprising two ICUs and with a small sample size and our observations should be confirmed by a multicenter case-control study and experimental confirmation.

In conclusion, this work is the first of its kind to describe bacterial persistence in the lungs despite adequate therapy, as well as frequent suspicion of bacterial translocations originating from the digestive or oropharyngeal microbiota, in COVID-19 ICU patients. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ; https://doi.org/10.1101/2021.01.22.21250287 doi: medRxiv preprint Table S2 : Description of patients and bacteria of patient with or without a persistent ventilatorassociated pneumonia (VAP) at day 7 post initial VAP diagnosis . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ; https://doi.org/10.1101/2021.01.22.21250287 doi: medRxiv preprint Figure S1 : Persistence of bacteria in respiratory samples of COVID-19 patients with VAP is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 26, 2021. ; https://doi.org/10.1101/2021.01.22.21250287 doi: medRxiv preprint

Coronavirus: chiffres clés et évolution de la COVID-19 en France

Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists

Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis

Co-infections in people with COVID-19: a systematic review and meta-analysis

COVID-19 and the potential long-term impact on antimicrobial resistance

COVID-19: don't neglect antimicrobial stewardship principles!

Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the

Hospital-acquired pneumonia, health care-associated pneumonia, ventilator-associated pneumonia, and ventilator-associated tracheobronchitis: definitions and challenges in trial design

Clinical Characteristics of Covid-19 in New York City

Bacteremia and Blood Culture Utilization During COVID-19 Surge in New York City

Relationship between the composition of the intestinal microbiota and the tracheal and intestinal colonization by opportunistic pathogens in intensive care patients

Covid-19 in Critically Ill Patients in the Seattle Region -Case Series

Incidence of co-infections and superinfections in hospitalised patients with COVID-19: a retrospective cohort study