key: cord-0703282-b0bhq024
authors: Amarsy, Rishma; Trystram, David; Cambau, Emmanuelle; Monteil, Catherine; Fournier, Sandra; Oliary, Juliette; Junot, Helga; Sabatier, Pierre; Porcher, Raphaël; Robert, Jérôme; Jarlier, Vincent
title: Surging bloodstream infections and antimicrobial resistance during the first wave of COVID-19: a study in a large multihospital institution in the Paris region
date: 2021-10-22
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.10.034
sha: 11ee737fda314ac1be27271f0f86a8bed1a6b723
doc_id: 703282
cord_uid: b0bhq024

Objectives We measured the impact of the first wave of COVID-19 (March-April 2020) on the incidence of bloodstream infections (BSIs) during at the Assistance Publique - Hôpitaux de Paris (APHP), the largest multisite public healthcare institution in France. Methods The number of patient admissions blood cultures (BCs) collected, positive BCs as well as antibiotic resistance and consumption was retrospectively analyzed for the first quarter of 2020, and of 2019 for comparison, in 25 APHP hospitals (ca. 14,000 beds). Results Up to a fourth on patients admitted in March-April 2020 in these hospitals had COVID-19. BSI rate per 100 admissions increased globally, by 24% in March and 115% in April 2020, and separately for the major pathogens (Escherichia coli, Klebsiella pneumoniae, enterococci, Staphylococcus aureus, Pseudomonas aeruginosa, yeasts). A sharp increase in the rate of BSIs caused by microorganisms resistant to 3rd generation cephalosporins (3GC) was also observed in March-April 2020, particularly in K.pneumoniae, in enterobacterial species naturally producing inducible AmpC (Enterobacter cloacae...) and P.aeruginosa. A concomitant increase occurred in 3GC consumption. Conclusions COVID-19 pandemic had a strong impact on hospital management and also unfavorable effects on severe infections, antimicrobial resistance and laboratory work diagnostics.

Since the beginning of the coronavirus disease pandemic in 2019, the world has been faced with an unprecedented surge of acute respiratory infections that often require intensive care and have a high case fatality rate. (Khalili et al., 2020) While the demographics, clinical characteristics and overall survival rate (Fried et al., 2020; Guan et al., 2020; Lippi et al., 2020) of hospitalized patients with COVID-19 have been already characterized in extensive reports from several parts of the word, little is known about the bacterial complications contributing to the morbidity or mortality of inpatients.

In general, it has been widely reported that patients receiving intensive care are at higher risk for hospital-acquired infections. This is due to invasive monitoring and support, exposure to multiple antibiotics and colonization with resistant microorganisms. (Maki et al., 2008) Among these nosocomial infections, bloodstream infections (BSIs) and respiratory tract infections are the most common and life threatening. (Prowle et al., 2011) Hence, we sought to analyze the impact of the first wave of the COVID-19 pandemic and the subsequent high demand for intensive care on the epidemiology of bloodstream infections in a large public multihospital institution in the Paris region.

The research was conducted at Assistance Publique -Hôpitaux de Paris (APHP), a multihospital institution covering the Paris region (the 12 million inhabitants of the city of Paris, its suburbs and the surrounding counties). APHP is the largest hospital institution in

France. It provides a total of approximately 20,000 beds and admits around 1.4 million patients per year. Approximately 14,000 (70%) of these beds are distributed among 25 hospitals, including 18 acute care hospitals and seven rehabilitation/long-term care hospitals (see list in the supplementary material). These hospitals are served by laboratories of Bacteriology that all use the same laboratory information system (LIS), allowing standardized data extraction and combined analysis. The research was conducted in these 25 hospitals.

The study covers the four-month period from January to the end of April 2020 and, as control, the same four-month period in 2019. The March-April 2020 period that corresponds to the rise and the development of the first COVID-19 epidemic wave in the Paris region was referred as the "COVID-19 period".

The number of patients admitted to the 25 hospitals during the two four-month periods (January-April), as well as the number of patients present each day in these hospitals in March and April 2020 with a virologically proven COVID-19 (based on a positive RT-PCR), were obtained from the central APHP administration.

Data on blood cultures were extracted from the LIS of the laboratories serving these 25 hospitals and merged in a relational SQL-queryable database. A blood culture set (BC set) was defined as the combination of one aerobic and one anaerobic blood culture bottle drawn through the same puncture. A positive BC sets, defined as microbial growth in at least one of the two bottles.

A clinically significant episode of BSI was defined as a positive BC set growing a recognized pathogen.

(https://www.ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/healthcareassociated-infections-HAI-ICU-protocol.pdf) BC sets growing bacteria belonging to commensal skin microbiota (coagulase-negative staphylococci, corynebacteria and propionibacteria) are generally defined as contaminants, except in specific individual patient clinical situations. (Beekmann et al., 2005;  https://www.ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/healthcareassociated-infections-HAI-ICU-protocol.pdf) These BC were not included in the study since clinical data were not available in the LIS. To remove duplicates, only one BSI episode was counted when several BC sets were positive with the same microorganism for a given patient.

Antimicrobial resistance was extracted from the LIS, as explained above. All of the involved laboratories participate in the national accreditation process (COFRAC), including internal and external quality assessment programs, and use the EUCAST European quality standards for antimicrobial susceptibility testing (https://eucast.org/clinical_breakpoints/).

The consumption of third-generation cephalosporins (3GC, including cefotaxime, ceftriaxone and ceftazidime), a group of antibiotics largely used for treating serious bacterial infections in hospital settings, was recorded for the four-month periods of January-April 2019 and 2020 by the central APHP pharmacy and converted into defined daily doses (DDDs) using the WHO definitions. (https://www.whocc.no/ddd/definition_and_general_considera/)

Rate ratios and their confidence intervals were computed using Poisson models, with a linear time trend to account for possible changes in rate over time, independent of the COVID-19

pandemic. To account for multiple analyses, 99% confidence intervals were used.

The rise of the COVID-19 pandemic was observed at the beginning of March 2020 in the Paris region. It peaked at the beginning of April and declined until the end of that month APHP. To deal with the massive influx of adult COVID-19 patients, the organization of the APHP hospitals was extensively modified. Some medical units were dedicated entirely to the admission of COVID-19 patients who did not require intensive care. The capacity of ICU beds for adults was multiplied by 2.6 by converting post-surgery recovery rooms, operating theaters and even some pediatric ICUs. Other beds were closed, particularly in surgery since non-urgent surgical procedures were largely postponed. In these cases, the corresponding personnel was redeployed to take care of the COVID-19 patients. Consequently, the overall number of patients admitted to the 25 hospitals decreased during the COVID-19 period (Table   1 ).

Data on the 185,132 BC sets taken during the periods of January-April 2019 and 2020 in the 25 hospitals were reviewed. There was a dramatic increase in the number of blood cultures collected during the COVID-19 period, i.e. 42.9 BCs per 100 admissions during March-April 2020 vs 23.6 during January-April 2019 (Table 1) . This increase was more precisely assessed by computing the rate ratios of BCs per 100 admissions, which was 1. 

When considering only clinically significant microorganisms recovered from positive BCs, the rate ratios of BSIs per 100 admissions increased by 24% (99% CI: 11 to 38) in March and 115% (99% CI: 94 to 139) in April 2020 in comparison with the rates in January-April 2019

and January-February 2020 ( Figure 2 ).

When computed according to bacterial species, the increase in the rate of BSIs per 100 admissions in April 2020 ranged between 46% (Escherichia coli and anaerobes) and 254%

(enterococci) ( 1) . This increase also concerned organisms that are naturally resistant to 3GC, e.g., enterococci (3.5 fold) and yeasts (3.3 fold).

A sharp increase (DDDs per 100 admissions) in the consumption of 3GC, mostly of cefotaxime, occurred in the 25 hospitals during the COVID-19 period. In March, the increase was 131% and in April it was 148%, as compared with baseline consumption during the periods between January-April 2019 and January-February 2020 ( Figure 3 ). During the first wave of the COVID-19 pandemic, the rate ratios s of blood culture collection per 100 admissions increased in the 25 hospitals by 60% in March and 137% in April 2020.

The same trend was observed when using rates of 1,000 patient days as an indicator (data not shown). A sharp increase in blood culturing during the COVID-19 pandemic was also reported in January through March 2020 in five hospitals in New York city, overwhelming local laboratory capacity and leading to a decrease in the duration of bottle incubation in order to free space in the automated systems. (Sepulveda et al., 2020) In contrast, no variation in BCs was observed during the first wave of COVID-19 in five London hospitals. (Denny et al., 2021) Concomitantly Finally, concomitantly to the rise of BSI and resistance, a sharp increase in 3GC consumption was observed. Similar increases of broad spectrum beta-lactams, and particularly 3GC, have been reported during the COVID-19 pandemic in different countries but always in a single facility that may not be representative. (Abelenda-Alonso et al., 2020; Bork et al., 2020; Giacomelli et al., 2021; Nestler et al., 2020) Intensive use of 3GC is known to exert a selective pressure on enterobacteria with acquired resistance to these antibiotics, either through ESBL production or cephalosporinase overproduction (Mizrahi et al., 2020; Padmini et al., 2017) as well as on naturally resistant organisms such as yeasts (Arendrup, 2010) the lack of individual data on indwelling catheters or other invasive procedures made the identification of "true" BSIs due to skin commensal species (coagulase negative staphylococci, etc.) impossible. Third, we did not evaluate other factors such as nursing staff ratios or staff expertise that could have affected BSIs rates in a more complex context. (Amarsy et al., 2020; Robert et al., 2000) Upheaval in hospital organization has been reported in many countries where the health system has been overwhelmed by the spread of the COVID-19. (Grasselli et al., 2020; https://www.health.org.uk/news-and-comment/blogs/covid-19-five-dimensions-of-impact) Health care systems can be rapidly compromised in cases of explosive outbreaks of emerging infections (Crawford et al., 2016; Elston et al., 2017; Nuzzo et al., 2019) or in the case of conflicts and natural disasters. (López Tagle and Santana Nazarit, 2011; Roberts et al., 2003) The collateral effects of the COVID-19 crisis on BSIs, antimicrobial resistance (AMR) and

antibiotic consumption have not been reported simultaneously and at the scale of a large region. Comprehensive studies in more focused populations will be needed to assess the respective contributions of risk factors to BSIs and increases in antibiotic resistance during the pandemic. A combination of responsible use of antimicrobials and adequate hygiene measures should be used in order to minimize the risk of unfavorable outcomes following another sudden crisis of a similar magnitude.

None.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

This study did not require any specific ethical approval, as it uses data that were extracted 

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