key: cord-0931415-9igb9wh0
authors: Seaton, Ronald A.; Gibbons, Cheryl L.; Cooper, Lesley; Malcolm, William; McKinney, Rachel; Dundas, Stephanie; Griffith, David; Jeffreys, Danielle; Hamilton, Kayleigh; Choo-Kang, Brian; Brittain, Suzanne; Guthrie, Debbie; Sneddon, Jacqueline
title: Survey of antibiotic and antifungal prescribing in patients with suspected and confirmed COVID-19 in Scottish hospitals
date: 2020-09-26
journal: J Infect
DOI: 10.1016/j.jinf.2020.09.024
sha: d2789f4c5ab24d1c48620dd10fc7bae2a92aeacd
doc_id: 931415
cord_uid: 9igb9wh0

BACKGROUND: Concern regarding bacterial co-infection complicating SARS-CoV-2 has created a challenge for antimicrobial stewardship. Following introduction of national antibiotic recommendations for suspected bacterial respiratory tract infection complicating COVID-19, a point prevalence survey of prescribing was conducted across acute hospitals in Scotland. METHODS: Patients in designated COVID-19 units were included and demographic, clinical and antimicrobial data were collected from 15 hospitals on a single day between 20(th) and 30(th) April 2020. Comparisons were made between SARS-CoV-2 positive and negative patients and patients on non-critical care and critical care units. Factors associated with antibiotic prescribing in SARS-CoV-2 positive patients were examined using Univariable and multivariable regression analyses. FINDINGS: There were 820 patients were included, 64.8% were SARS-CoV-2 positive and 14.9% were managed in critical care, and 22.1% of SARS-CoV-2 infections were considered probable or definite nosocomial infections. On the survey day, antibiotic prevalence was 45.0% and 73.9% were prescribed for suspected respiratory tract infection. Amoxicillin, doxycycline and co-amoxiclav accounted for over half of all antibiotics in non-critical care wards and meropenem, piperacillin-tazobactam and co-amoxiclav accounted for approximately half prescribed in critical care. Of all SARS-CoV-2 patients, 38.3% were prescribed antibiotics. In a multivariable logistic regression analysis, COPD/chronic lung disease and CRP ≥ 100 mg/l were associated with higher odds and probable or confirmed nosocomial COVID-19, diabetes and management on an elderly care ward had lower odds of an antibiotic prescription. Systemic antifungals were prescribed in 9.8% of critical care patients and commenced a median of 18 days after critical care admission. INTERPRETATION: A relatively low prevalence of antibiotic prescribing in SARS-CoV-2 hospitalised patients and low proportion of broad spectrum antibiotics in non-critical care settings was observed potentially reflecting national antimicrobial stewardship initiatives. Broad spectrum antibiotic and antifungal prescribing in critical care units was observed indicating the importance of infection prevention and control and stewardship initiatives in this setting. FUNDING: The Scottish Antibiotic Prescribing Group is funded by Scottish Government

There is concern that the COVID-19 pandemic will lead to unnecessary antibiotic use which will further drive antimicrobial resistance. Published evidence indicates high rates of antibiotic prescribing in relation to SARS-CoV-2 infection without supporting evidence of bacterial co-infection. As limiting unnecessary antibiotic use in viral infections is a key focus for antimicrobial stewardship initiatives, the Scottish Antimicrobial Prescribing Group developed recommendations for prudent use of antibiotics in hospital in the context of suspected SARS-CoV-2 in March 2020. A national point prevalence antimicrobial survey was then performed across designated COVID-19 units in acute hospitals to assess antimicrobial prescribing.

This is the first national survey of antibiotic prescribing in suspected COVID- 19 

There were 820 patients were included, 64.8% were SARS-CoV-2 positive and 14.9% were managed in critical care, and 22.1% of SARS-CoV-2 infections were considered probable or definite nosocomial infections. On the survey day, antibiotic prevalence was 45.0% and 73.9% were prescribed for suspected respiratory tract infection. Amoxicillin, doxycycline and co-amoxiclav accounted for over half of all antibiotics in non-critical care wards and meropenem, piperacillin-tazobactam and co-amoxiclav accounted for approximately half

The nature and rationale for antibiotic prescribing in patients with suspected COVID-19 is not well characterised. Unnecessary antibiotic prescribing is of concern for the individual in view of the risk of antibiotic-related adverse events 1 and to the wider public health due to the impact on antimicrobial resistance 2 . Limiting prescribing when viral respiratory tract infection (RTI) is suspected is an important target for antimicrobial stewardship interventions 3 and particularly in the context of SARS-CoV-2 infection 4 .

When first reported in Wuhan in December 2019, more than 90% of hospitalised patients with COVID-19 received antibiotics with little supporting evidence of associated bacterial infection 5 . The International Severe Acute Respiratory Infection Consortium (ISARIC) study subsequently reported prescribing in 72% of those hospitalised 6 . The World Health Organisation recommends prompt antibiotic therapy (as per local guidance) against likely pathogens causing severe acute respiratory infection or sepsis for those hospitalised with suspected COVID-19 7 . A recent meta-analysis of published reports has estimated community-acquired bacterial co-infection in COVID-19 to be low at approx. 3.5% 8 however prolonged ventilatory and multi-organ support in a proportion of hospitalised patients with severe COVID-19 raises concern for nosocomial bacterial and fungal infection risk 9 .

With clinical overlap between COVID-19 and bacterial lower RTIs and with emerging global COVID-19-related prescribing; COVID-19 Antimicrobial Stewardship advice was issued by the Scottish Antimicrobial Prescribing Group (SAPG) cautioning against routine antibiotic use in suspected COVID-19, and promoting the judicious use of short duration (5 day), narrow spectrum antibiotics when there is clinical suspicion of pneumonia or purulent bronchitis 10 .

In order to better understand reasons for, and dynamics of, antibiotic prescribing and identify opportunities for improved prescribing an antimicrobial point prevalence survey (PPS) was conducted to coincide with high clinical activity in Scottish hospitals.

Here, results from a PPS of antibiotic and antifungal prescribing in patients with suspected and proven COVID-19 infection in acute hospitals are summarised. 

Data were collected from written and electronic medical notes and prescription charts. A data collection tool based on one currently used in Glasgow hospitals 11 , the global PPS tool 12 and bespoke PPS 13, 14 was used. Data collection was carried out by medical staff, antimicrobial and ward pharmacists and antimicrobial nurses. Where necessary, staff were trained by local clinicians experienced in PPS.

Clinical records were reviewed for SARS-CoV-2 test status. Probable nosocomial COVID-19 and definite nosocomial COVID-19 were defined as a compatible clinical illness with a new positive test 8 to 14 days and more the 14 days following admission, respectively 15 .

Antibiotic prescribing in the two weeks prior to admission and on the day of admission was recorded as detailed in the medical records. Detailed information on antibiotics and systemic antifungals prescribed on the survey day including start date, route and indication as per anatomical source (e.g. respiratory tract, urinary tract etc) of the suspected infection was recorded 12 . Microbiological investigations were not recorded however prescribing was recorded as empirical (prior to microbiological confirmation) or directed (following microbiological confirmation).

Potential factors influencing antibiotic prescribing were collected including: demographics, care home residency and co-morbidities (Table 1 ). Immunocompromised was defined by immunosuppressant therapy including regular corticosteroids, organ or bone marrow transplant, HIV infection, renal replacement therapy, asplenia or recently completed therapy for malignancy.

Descriptive clinical data included presence and nature of sputum production (grouped as 'purulent/bloody' if recorded as green, brown or bloody sputum), CRP (C-reactive protein value) and chest X-ray responses were grouped as normal or abnormal (included COVID-19 compatible, indeterminant, pneumonia or other abnormal).

Other clinical management data included use of oxygen, respiratory support and use of investigational therapeutic agents as part of a clinical trial. Presence of treatment escalation plans and 'do not attempt cardiopulmonary resuscitation' documentation (DNACPR) was recorded where available.

Following completion of data collection, anonymised data were sent to the core survey team for curation, validation and analysis.

Analyses included patients with a SARS-CoV-2 RT-PCR test result. Prevalence estimates with 95% confidence intervals (95% CI) were calculated and frequency tables of survey population and prescribing characteristics were produced. Patients with missing data were excluded from denominators. Data were examined for the whole patient population and comparisons were made between SARS-CoV-2 RT-PCR positive and negative patients, and those on medical or elderly care wards were compared to those on high dependency and intensive care units (combined as 'critical care'). Pearson's Chi square tests with a continuity correction or Fisher's Exact tests were used to compare percentages between two groups and determine if significantly different. A Mann-Whitney U test compared median ages between groups. Median durations were presented with range (minimum to maximum) and

inter-quartile ranges (IQR). Statistical significance was set at p<0.05. All analyses were carried out using R (version 3.5.1).

The average daily number of hospitalised patients in NHS Scotland with confirmed COVID-19 infection (positive SARS-CoV-2 RT-PCR test) during the study period was used to estimate the proportion of hospitalised COVID-19 patients in Scotland included in this survey 15 .

Univariable and multivariable regression analyses were conducted to identify factors associated with prescribing of at least one antibiotic on the survey day in patients with confirmed COVID-19 infection. A survey weighted binomial model was used (which accounted for clustering of beds within wards) and analyses were conducted in R version

Univariable factors were screened and those with p-values below 0.3 were included in a backward elimination and forward stepwise approach to select the most parsimonious multivariate model. Statistical significance was set at p<0.05. A category-level p-value (using the Wald test), odds ratios (OR) and 95% CI were calculated for each factor in the final model.

Local governance processes for audit/survey of clinical practice were followed. No patient identifiers were collected and there were no interventions or patient contact during the survey.

Eight of the 15 Scottish NHS boards participated with data collected from 15 of the 22 acute hospitals (ranging from 400 to 1400 inpatient beds). Of these hospitals, 112 (84.8%) of all 132 designated COVID-19 wards and critical care units were surveyed. In total, 1,061 patients were screened and 820 patients tested for SARS-CoV-2 were included. Of the 820, 666 (81.4%) were suspected of having COVID-19 on admission, and 531 (64.8%) tested positive for SARS-CoV-2 up to and including the day of the survey (Table 1 ). There was a daily average of 1,403 (range 1,324 to 1,520) SARS-CoV-2 positive patients in all hospitals nationally during the survey period suggesting that the SARS-CoV-2 positive population studied here represented approximately two fifths of the total inpatient SARS-CoV-2 positive population at this time.

Over half (51.8%) were male and median age was 71 years (range 17 to 104, IQR 59 to 81).

The majority (65.9%) were managed on medical wards, 19.3% on elderly care wards and 14.9% in critical care. There were 11.1% mechanically ventilated, 2.1% were receiving noninvasive ventilation, 0.6% high flow nasal oxygen and 40.8% supplementary oxygen. Six hundred and eighty five patients (83.5%) had a treatment escalation plan recorded, 44.2% of whom were for critical care referral or discussion at an escalation multidisciplinary team (MDT) meeting if required. More than half of surveyed patients (54.4%) had a DNACPR instruction recorded and 13.1% patients were enrolled in a clinical therapeutic trial.

When compared to SARS-CoV-2 negative patients, SARS-CoV-2 positive patients were older (median age 72 versus 69 years, p=0.005), more likely admitted from a care home (11.9% versus 4.2%, p<0.001), had a DNACPR order recorded (57.7% versus 48.3%, p=0.01), and less likely to have COPD/chronic respiratory disease (excluding asthma) (13.6% versus 26.5%, p<0.001) or another suspected infection (37.5% versus 58.5%, p<0.001). SARS-CoV-2 positive patients were also more likely to have an abnormal chest X-ray (77.3% versus 59.9%, p<0.001) and to have a CRP ≥ 100 mg/l (45.1% versus 30.7%, p<0.001) ( Table 1 ).

Of those who tested SARS-CoV-2 positive and for whom the admission and test dates were recorded; 9.5% were diagnosed prior to admission, 59.8% within 3 days of admission, 8.6% between 3 and 7 days post-admission, 6.7% between 8 and 14 days and 15.4% more than 14 days post-admission. Therefore, approximately one fifth (22.1%) of COVID-19 infections in this population were considered to have a COVID-19 infection of probable or definite hospital-onset.

Prevalence of antibiotic prescribing in the two weeks prior to admission was 29.2% (95%CI:

26.1 to 32.5) and 62.4% (95%CI: 58.9 to 65.7) on the day of admission. Of all patients receiving an antibiotic on the day of admission and for whom a route was recorded; 59.9% received intravenous (IV) therapy (with or without oral antibiotic therapy) and the majority (92.5%) was empirical ( Table 2 ). The most common prescribing indication was RTI (59.8%) followed by urinary tract infection (8.7%), skin and soft tissue (3.7%), systemic (3.0%), gastrointestinal (1.6%), and other sites (2.4%) with no indication was recorded for 102 patients receiving an antibiotic on admission (20.7%).

Prevalence of antibiotic prescribing on the survey day was 45.0% (95%CI: 41.6 to 48.4) and a total of 490 antibiotics were prescribed to 368 patients (Table 3) Median time from admission to prescribing was 2 days (range 1 to 344, IQR 1 to 10). This was 2 days (range 1 to 344, IQR 1 to 7) on medical and elderly wards and 14 days (range 1 to 28, IQR 1.75 to 18.25 in critical care). More than half of all antibiotics that patients were still receiving on the survey day (52.7%) were prescribed on the day of admission or day two (56.4% for patients on medical and elderly wards and 38.9% in critical care). were receiving antibiotics compared with 36.3% of those on medical and elderly wards (Table 2) .

Clinical variables examined by Univariable logistic regression analysis for an association with antibiotic prescribing on the survey day in patients who were SARS-CoV-2 RT-PCR positive are shown in Table 4 . In a multivariable logistic regression analysis, COPD/chronic lung disease and a CRP≥100 mg/l were associated with higher odds of receiving at least one antibiotic, and patients with probable or confirmed nosocomial COVID-19, diabetes and patients receiving care on an elderly ward had lower odds of receiving at least one antibiotic on the survey day (Table 5) .

Systemic antifungals were prescribed in 13 patients (prevalence: 1.6%, 95% CI: 0.9 to 2.7) on the survey day (Table 3) 

To our knowledge, this is the first national PPS of antibiotic and antifungal prescribing in hospitalised adults with suspected and confirmed COVID-19 infection. The prevalence of antibiotic prescribing on the survey day was 45.0% which, while not directly comparable, is higher than reported prevalence estimates from two Scottish PPS of antibiotic prescribing in acute adult inpatients (35.7% in 2016 and 33.2% in 2011) 16 . This was not unexpected as the present PPS was restricted to patients cared for in hospital units designated for suspected and confirmed COVID-19 cases in the midst of the pandemic. In the 2016 national PPS, higher prevalence estimates were also seen in specialties with more acutely unwell patients, e.g. ICU medical (48.1%) and respiratory medicine (56.6%) 16 There were clear differences in antibiotic choice between those managed on medical and elderly wards compared with critical care. Narrow spectrum antibiotics amoxicillin and doxycycline, promoted within Scottish guidance for suspected mild and moderate severity lower RTI, were prescribed most frequently followed by co-amoxiclav which is recommended for severe lower RTI 10 Note: *Patients may have received more than one antibiotic. The name of one antimicrobial was not recorded for one patient (COVID-19 positive and in critical care) receiving an antibiotic on the day of the survey for a respiratory indication. Note: COPD-Chronic obstructive pulmonary disease and other chronic lung disease. Modelling excludes records with unknown antimicrobial status, COPD/ Chronic lung disease, Morbid obesity, Treatment for HBP, Cardiovascular disease, Immuno-compromised as per HPS/SG advice, Other chronic illness and DNACPR. This left 694 rows for inclusion in the analysis of factors associated with antimicrobial prescribing for a respiratory indication, and 511 rows for inclusion in analysis of factors associated with antimicrobial prescribing in patients who had confirmed COVID-19.

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The authors would like to thank health board Antimicrobial Management Teams and clinicians in the participating hospitals who coordinated the survey and collected data: