Title: The epidemiology and impact of bacterial secondary infections and antimicrobial resistance on Intensive Care during the SARS-CoV-2 pandemic
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Antimicrobial resistance (AMR) remains a global public health threat and priority for governments and health authorities (1-3). AMR bacterial infections pose a risk to the most critically ill and vulnerable patients. On intensive care units (ICUs), antimicrobial stewardship (AS), surveillance of pathogens, alongside infection prevention and control (IPC) precautions, are important components of strategies to limit spread of AMR and optimise patient management (4-7). The COVID-19 (Coronavirus Disease 2019) pandemic presents a challenge in combating AMR on ICUs but also an opportunity to evaluate the impact of changes in antimicrobial prescribing, IPC, patient mix, staff-patient ratios on bacterial ecology in ICU patients (6,7). Clinical experience in Wales and international literature suggests that most patients receive early broad-spectrum antibiotics despite limited evidence that COVID-19 patients have high rates of bacterial co-infections (6-10). Additionally, management of COVID means many of these patients also receive drugs which suppress the host immune system (11,12), increasing vulnerability to secondary infection. Reports of secondary infections are more common and associated with additional mortality later in hospital stays (6,7,9). This research will characterise the epidemiology of bacterial pathogens in ICU patients in Cardiff and Swansea during the COVID pandemic. The focus will be changes over time in predominant bacterial strains, AMR and genetic determinants of resistance. These will be related to changing prescribing and IPC practices and staff-patient ratios from the November 2020 until March 2022. Comparison will also be between patients with and without COVID at time of bacteriological sampling. Blood culture isolates from ICU patients collected pre-pandemic (2017-19) and during pandemic will be compared to establish if the multifactorial changes introduced in response to COVID-19 have affected AMR indicators and predominant causes of systemic infection. Target pathogenic bacterial isolates from routinely collected sputum, BAL, blood, stool, rectal swabs, urine and Methicillin Resistant Staphylococcus Aureus (MRSA) screens will undergo “gold standard” antimicrobial susceptibility testing (AST), with next generation sequencing (NGS) of key pathogens. NGS will allow detailed typing of strains and assessment of the distribution, type and change over time of genetic determinants of AMR including markers of key AMR pathogens of concerns such as MRSA and carbapenemase producing organisms (CPO). Typing by NGS will help identify infection transmission events and whether there are shifts in dominant strains, possibly to those associated with greater potential for both nosocomial spread and AMR. Secondary objectives are: Influence policies and surveillance to support IPC of healthcare associated infections (HAIs) Enhance understanding of the role of pathogen NGS and typing in elucidating the spread of bacterial HAIs and AMR Support existing research on the pathogen immune response in patients with sepsis, with and without COVID Inform the management of patients with sepsis, with and without SARS-CoV-2 infection

Lay abstract: Bacterial infections acquired in hospital are an important cause of illness, increased hospital stay, extended treatment and death. Such infections are preventable and more frequent in severely ill patients, especially on Intensive Care Units (ICUs). These patients are vulnerable due to severity of illness, the body’s reduced ability to fight infection and use of medical devices. Bacterial infections are treated with antibiotics, but treatment failure occurs if the bacteria are antibiotic resistant, a globally increasing trend. Antibiotic resistant bacteria commonly cause hospital acquired infections especially in the sickest patients. Bacteria can spread between patients on hands of carers, medical devices and by contamination from the hospital environment. Certain bacteria can survive for extended periods in hospital environments despite cleaning and decontamination. During the current pandemic patients admitted to ICU often require support due to COVID related lung damage. These patients are vulnerable to further infections, but it is difficult to identify which patients fail to improve due to their body's response to the virus, or further infections. As a result, patients often receive powerful broad-spectrum antibiotics (covering the broadest range of bacteria) early in their admission. Overuse of these can drive up rates of antibiotic resistance, leading to future treatment failure. This can be a direct consequence to an individual patient, now more likely to be infected with resistant bacteria, or from secondary spread of more resistant bacteria within hospital. Other changes to ICU management during the pandemic could have an impact on antibiotic resistance through a change in type of bacteria colonising (present on or within the patient’s body without causing infection) or infecting (causing disease). These include: -type of patients admitted (eg more with COVID) -use of infection control precautions (more personal protective equipment e.g. masks, gowns) -increased patient numbers -use of drugs which suppress the immune system. Surveillance (sampling to understand bacteria present on units) and clinical sampling (analysing samples to establish cause of infection) is performed routinely, and antibiotic prescribing guidance and infection control is co-ordinated through specialist doctors/nurses. However, surveillance sampling is limited, and routine clinical sample analysis does not include detailed antibiotic testing or use genetic testing to understand the causes of antibiotic resistance, factors that help bacteria cause infection plus how closely related bacteria are. This information can help identify which bacteria are successful at causing infection and predict what factors are influencing resistance. Currently, clinicians/researchers are working to better understand clinical/ immune responses to bacterial infections, including as a complication of COVID-19. They are developing tests that can better identify when a bacterial infection is present. A detailed understanding of the bacteria present in these patients will support this work. The work will help support policies and procedures, such as infection prevention and antibiotic prescribing guidelines in ICUs, for patients with and without COVID-19. It may demonstrate the benefits of detailed analysis of bacteria capable of causing infections on ICU and support increased surveillance using these techniques in Wales.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION