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

Abstract

Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.

Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.

Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59-84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives.

Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist.

Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.

Figure 1

Study flowchart A complete admission was considered an outcome recorded at 28 days or earlier, and could either be a final outcome (eg, death or discharged alive) or documentation the patient remained in hospital. Relevant microbiological investigations were blood cultures, sputum, deep respiratory (endotracheal aspirates, bronchoalveolar lavage, and pleural fluid), urine, abdominopelvic, or pus samples from abscesses. *Some patients had both a COVID-19 related and unrelated infection.

Figure 2

Cause of microbiologically confirmed respiratory and bloodstream infections The ten most identified pathogens from sputum, deep respiratory, and blood cultures, as a percentage of all positive samples of that type. The number at the end of each bar represents the total number of positive samples for the pathogen. Numbers annotated on the plots indicate the total number of organisms for each subgroup. Deep respiratory samples are endotracheal aspirates, bronchoalveolar lavage, and pleural fluid. Pathogen identification is stratified into sample obtained <2 days (co-infection) or >2 days (secondary infection) from admission to hospital (A); sample obtained <1 day or >1 day after admission to critical care (B); presence or absence of chronic pulmonary disease (C); and presence or absence of immunocompromise (D). S aureus=Staphylococcus aureus. H influenzae=Haemophilus influenzae. P aeruginosa=Pseudomonas aeruginosa. E coli=Escherichia coli. S marcescens=Serratia marcescens. S pneumoniae=Streptococcus pneumoniae. K pneumoniae=Klebsiella pneumoniae. M catarrhalis=Moraxella catarrhalis. K aerogenes=Klebsiella aerogenes. C koseri=Citrobacter koseri. E cloacae=Enterobacter cloacae. K oxytoca=Klebsiella oxytoca. M morganii=Morganella morganii. C freundii=Citrobacter freundii. P mirabilis=Proteus mirabilis. S maltophilia=Stenotrophomonas maltophilia. E faecalis=Enterococcus faecalis. E faecium=Enterococcus faecium. A fumigatus=Aspergillus fumigatus. B fragilis=Bacteroides fragilis. E kobei=Enterobacter kobei. S oralis=Streptococcus oralis.

Figure 2

Cause of microbiologically confirmed respiratory and bloodstream infections The ten most identified pathogens from sputum, deep respiratory, and blood cultures, as a percentage of all positive samples of that type. The number at the end of each bar represents the total number of positive samples for the pathogen. Numbers annotated on the plots indicate the total number of organisms for each subgroup. Deep respiratory samples are endotracheal aspirates, bronchoalveolar lavage, and pleural fluid. Pathogen identification is stratified into sample obtained <2 days (co-infection) or >2 days (secondary infection) from admission to hospital (A); sample obtained <1 day or >1 day after admission to critical care (B); presence or absence of chronic pulmonary disease (C); and presence or absence of immunocompromise (D). S aureus=Staphylococcus aureus. H influenzae=Haemophilus influenzae. P aeruginosa=Pseudomonas aeruginosa. E coli=Escherichia coli. S marcescens=Serratia marcescens. S pneumoniae=Streptococcus pneumoniae. K pneumoniae=Klebsiella pneumoniae. M catarrhalis=Moraxella catarrhalis. K aerogenes=Klebsiella aerogenes. C koseri=Citrobacter koseri. E cloacae=Enterobacter cloacae. K oxytoca=Klebsiella oxytoca. M morganii=Morganella morganii. C freundii=Citrobacter freundii. P mirabilis=Proteus mirabilis. S maltophilia=Stenotrophomonas maltophilia. E faecalis=Enterococcus faecalis. E faecium=Enterococcus faecium. A fumigatus=Aspergillus fumigatus. B fragilis=Bacteroides fragilis. E kobei=Enterobacter kobei. S oralis=Streptococcus oralis.

Figure 3

Frequency and nature of antimicrobial use (A) The proportion of inpatients receiving antimicrobials between March and June, 2020, stratified by level of care. Data show rolling mean over a window of 14 days. Dotted lines represent 95% CIs. (B) Specific antimicrobials used, stratified by level of care or critical care. Co-use of specific antimicrobials in patients receiving ward-level care (C) and patients admitted to critical care (D), highlighting antimicrobials used for lower respiratory tract infection (blue box and shading), a signature of prescribing in response to penicillin allergy (green box and shading), carbapenem and glycopeptide usage in critical care (D only; blue box) and piperacillin–tazobactam and carbapenem in critical care (D only; orange box). The greater the intensity of red shading, the greater the correlation of antimicrobial use measured by Jaccard distance. Dendrograms show the result of hierarchical clustering. Data available for 46 061 patients.

Figure 4

Geographical variation in antimicrobial use over time Maps are divided into Scotland, Wales, and regions of England (northeast and Yorkshire, northwest, midlands, east, southeast, southwest, and London). Purple shading of regions represents the percentage of patients who received antimicrobial therapy during their hospital admission, stratified by month of admission (March, April, and May) and by level of care (ward-level or critical care). Data available for 46 061 patients.