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      COVID-19, antibiotics and One Health: a UK environmental risk assessment

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          Abstract

          Sir, There is growing interest in the role of secondary bacterial and fungal infections as a cause of increased morbidity and mortality in COVID-19 patients, 1 with reports of up to 95% of COVID-19 inpatients being prescribed antibiotics. 2 Concerns have been raised over the environmental implications of such a large-scale drug administration 3 and statements made about the potential impacts of COVID-19-related antibiotic prescription on antimicrobial resistance (AMR) and other toxicological effects on the environment. 4 The UK National Strategy aims for a world in which AMR is effectively contained, controlled and mitigated by 2040. 5 Taking a ‘One Health’ approach to effective stewardship in settings such as those being experienced in the current pandemic will be key to minimizing the negative impacts of antibiotic use. A large proportion of some drugs (and metabolites) are excreted by patients into wastewater treatment works (WwTW), leading to release of drug residues into effluent-receiving rivers and coastal waters. Environmental concentrations and impacts will be greatest where drugs are used in high volumes, pass through WwTW largely undegraded and are discharged into rivers with limited dilution. Since 2006, the EMA has required risk assessments of human medicines to allow standardized quantification of the environmental impact of pharmaceuticals. Consequently, the pharmaceutical industry has developed a database to provide Predicted No Effect Concentrations as Minimum Inhibitory Concentrations (PNEC-MIC) for active ingredients that may select for AMR, or levels hazardous to fish and other environmental species (PNEC-ENV). 6 Combined with Predicted Environmental Concentrations (PEC), generated using monitoring and modelling data, a risk assessment may be carried out. Should the PEC of individual drugs exceed either the PNEC-MIC or PNEC-ENV, further investigations are required. To examine the potential impact of antibiotic prescribing in COVID-19 patients in the UK, we have undertaken a risk assessment based on established principles. 7 Patient numbers were obtained for UK emergency hospitals set up temporarily around the country to receive COVID-19 patients, with one chosen for illustrative purposes, and details of WwTW capacity and river water dilution serving the emergency hospital and associated town were available from previous research. 8 Antibiotic excretion rates were obtained from the open literature. These data allowed estimation of antibiotic loads entering the WwTW, over and above the expected baseline (non-COVID-19) use for UK patients. 9 A freely available and validated wastewater process model (SimpleTreat 4.0) was used to predict removal rates, which allowed predictions of effluent concentrations for antibiotics of interest being discharged to surface waters. Based on known dilution estimates, a PEC:PNEC ratio was derived to provide a risk ratio. We illustrate here data relevant to a single UK emergency hospital (Harrogate, with 500 beds; see Figure S1, available as Supplementary data at JAC Online) in different COVID-19 scenarios, providing environmental assessments relevant to designing optimal drug use and waste management systems in a One Health context. NICE COVID-19 guidance was followed, which suggests that the first-line antibiotic should be doxycycline, with amoxicillin as second line. NICE guidelines for secondary care suggest doxycycline or a combination of clarithromycin and co-amoxiclav. Clavulanic acid does not have a PNEC value, so data presented here are for the impact of amoxicillin alone. Use of antibiotics in COVID-19 patients in hospitals will lead to the release of drug residues into UK rivers or coastal waters from any WwTW (Figure S1). Under pandemic scenarios, the use of antibiotics will obviously increase dramatically, thus increasing the overall burden on WwTW and potentially the receiving waters. Data available for the UK make it possible to carry out a risk assessment for site-specific areas. 10 To examine more focused regional impacts, we have calculated PEC data for the UK emergency hospital at Harrogate (Figure 1) based on modelling tools developed through the UK water industry-sponsored Chemical Investigation Programme and briefly described above. 7 We predict PEC:PNEC risk ratios of <1.0 for doxycycline and up to 5.70 for amoxicillin under two COVID-19 scenarios (all beds occupied and 70% or 95% of patients prescribed antibiotics, with all patients receiving either doxycycline or amoxicillin). The data for amoxicillin indicate a potential environmental concern for selection of AMR, but not toxicity to fish and other environmental organisms. Figure 1. Environmental risk assessments for amoxicillin and doxycycline for a worst-case COVID-19 scenario for patients in an emergency hospital in Harrogate with risk ratios >1 highlighted in red. PNEC-MIC, Predicted No Effect Concentration, Minimum Inhibitory Concentration; PNEC-ENV, Predicted No Effect Concentration, Environmental; PEC, Predicted Environmental Concentration. This figure appears in colour in the online version of JAC and in black and white in the printed version of JAC. We have not modelled scenarios for hospitals where different proportions of patients receive one or other antibiotic, though in future this may inform best practice for minimizing selection for AMR or causing toxic environmental effects. We recommend more extensive environmental assessments be undertaken for all antimicrobial medicines used during pandemics. This will facilitate development of a robust evidence base in order to guide antibiotic prescribing choices that are less likely to increase AMR 11 and have the least environmental impact, thus supporting the UK National Strategy. 5 Such information could also inform future decisions on the location of emergency hospitals and wider drug and waste management to ensure optimal patient and environmental outcomes during pandemics. Supplementary Material dkaa338_Supplementary_Data Click here for additional data file.

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Co-infections: potentially lethal and unexplored in COVID-19

            Respiratory viral infections predispose patients to co-infections and these lead to increased disease severity and mortality. Most fatalities in the 1918 influenza outbreak were due to subsequent bacterial infection, particularly with Streptococcus pneumoniae. 1 Poor outcomes in the 2009 H1N1 influenza pandemic were also associated with bacterial co-infections, although few studies captured these data. 2 Despite the proven importance of co-infections in the severity of respiratory diseases, they are understudied during large outbreaks of respiratory infections. Zhou and colleagues 3 showed that in the current coronavirus disease 2019 (COVID-19) pandemic, 50% of patients with COVID-19 who have died had secondary bacterial infections, and Chen and colleagues 4 have recorded both bacterial and fungal co-infections. Although 71% of the admitted patients with COVID-19 received antibiotic drugs, no information is available on the antimicrobial sensitivities of the organisms that were identified, or on the type and duration of antimicrobial treatment. Chronic obstructive pulmonary disease (COPD) is a risk factor for severe COVID-19 disease and many patients with COPD will have underlying chronic bacterial infections before severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but this important information is not being reported. More data on co-infections are urgently required to establish their importance in COVID-19 severity and mortality. Diagnosing co-infections is complex. The organism itself might be carried by the patient before the viral infection, might be part of an underlying chronic infection, or might be picked up nosocomially. In the UK, National Institute for Health and Care Excellence (NICE) treatment guidance for severe acquired pneumonia is broad-spectrum antibiotic co-amoxiclav plus a macrolide to cover atypical organisms. Currently, antibiotic use is high (74·5%) among patients with COVID-19 who are admitted to intensive care units, rendering culture-based microbiological testing less sensitive. Patients with COVID-19 are kept on invasive mechanical ventilation for a long time (mean 9·1 days [SD 5·5]), increasing chances of hospital and ventilator acquired infections. Hence, early diagnosis of co-infection is required, preferably using methods capable of detecting a broad range of potential pathogens and antimicrobial resistances, with subsequent monitoring for infection development. To accurately diagnose and study co-infection in COVID-19, patients should be recruited on admission to intensive care units and sampled longitudinally throughout the disease course using culture-independent techniques capable of identifying complex mixed infections without previous target selection, such as whole-genome metagenomics. 5 Such a study would provide valuable surveillance data on the pathogens causing co-infections and antimicrobial resistance in the intensive care setting, thereby helping inform antibiotic prescribing policy. Rapid characterisation of co-infection is essential in the management and treatment of the most severe COVID-19 cases, could help to save lives, and will improve antimicrobial stewardship throughout the course of the pandemic.
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              COVID-19 and the potential long-term impact on antimicrobial resistance

              Abstract The emergence of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has required an unprecedented response to control the spread of the infection and protect the most vulnerable within society. Whilst the pandemic has focused society on the threat of emerging infections and hand hygiene, certain infection control and antimicrobial stewardship policies may have to be relaxed. It is unclear whether the unintended consequences of these changes will have a net-positive or -negative impact on rates of antimicrobial resistance. Whilst the urgent focus must be on controlling this pandemic, sustained efforts to address the longer-term global threat of antimicrobial resistance should not be overlooked.
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                Author and article information

                Journal
                J Antimicrob Chemother
                J. Antimicrob. Chemother
                jac
                Journal of Antimicrobial Chemotherapy
                Oxford University Press
                0305-7453
                1460-2091
                12 August 2020
                : dkaa338
                Affiliations
                [d1 ] School of Geography, Earth and Environmental Sciences, University of Plymouth , Drake Circus, Plymouth PL4 8AA, UK
                [d2 ] School of Biomedical Sciences, University of Plymouth , Drake Circus, Plymouth PL4 8AA, UK
                [d3 ] Pharmacy Department, Royal Cornwall Hospital Trust , Truro TR1 3LJ, UK
                Author notes
                Corresponding author. E-mail: sean.comber@ 123456plymouth.ac.uk
                Author information
                http://orcid.org/0000-0003-4287-6396
                Article
                dkaa338
                10.1093/jac/dkaa338
                7454586
                32785691
                97fd7cd4-8363-48c0-a088-f98129c2af87
                © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 01 July 2020
                : 15 July 2020
                Page count
                Pages: 2
                Categories
                Research Letter
                AcademicSubjects/MED00740
                AcademicSubjects/MED00290
                AcademicSubjects/MED00230
                Custom metadata
                PAP

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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