Community antibiotic prescribing in patients with COVID-19 across three pandemic waves: a population-based study in Scotland, UK.

OBJECTIVES: This study aims to examine community antibiotic prescribing across a complete geographical area for people with a positive COVID-19 test across three pandemic waves, and to examine health and demographic factors associated with antibiotic prescribing. DESIGN: A population-based study using administrative data. SETTING: A complete geographical region within Scotland, UK. PARTICIPANTS: Residents of two National Health Service Scotland health boards with SARS-CoV-2 virus test results from 1 February 2020 to 31 March 2022 (n=184 954). Individuals with a positive test result (n=16 025) had data linked to prescription and hospital admission data ±28 days of the test, general practice data for high-risk comorbidities and demographic data. OUTCOME MEASURES: The associations between patient factors and the odds of antibiotic prescription in COVID-19 episodes across three pandemic waves from multivariate binary logistic regression. RESULTS: Data included 768 206 tests for 184 954 individuals, identifying 16 240 COVID-19 episodes involving 16 025 individuals. There were 3263 antibiotic prescriptions ±28 days for 2395 episodes. 35.6% of episodes had a prescription only before the test date, 52.3% of episodes after and 12.1% before and after. Antibiotic prescribing reduced over time: 20.4% of episodes in wave 1, 17.7% in wave 2 and 12.0% in wave 3. In multivariate logistic regression, being female (OR 1.31, 95% CI 1.19 to 1.45), older (OR 3.02, 95% CI 2.50 to 3.68 75+ vs <25 years), having a high-risk comorbidity (OR 1.45, 95% CI 1.31 to 1.61), a hospital admission ±28 days of an episode (OR 1.58, 95% CI 1.42 to 1.77) and health board region (OR 1.14, 95% CI 1.03 to 1.25, board B vs A) increased the odds of receiving an antibiotic. CONCLUSION: Community antibiotic prescriptions in COVID-19 episodes were uncommon in this population and likelihood was associated with patient factors. The reduction over pandemic waves may represent increased knowledge regarding COVID-19 treatment and/or evolving symptomatology.

Repurposing Mitomycin C in Combination with Pentamidine or Gentamicin to Treat Infections with Multi-Drug-Resistant (MDR) Pseudomonas aeruginosa.

The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR P. aeruginosa in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of P. aeruginosa, a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance. These results imply that mitomycin C is a substrate of the RND efflux pumps. Mitomycin C monotherapy successfully treated infected Galleria mellonella larvae, albeit at doses too high for human administration. Checkerboard and time-kill assays showed that the combination of mitomycin C with pentamidine, or the antibiotic gentamicin, resulted in synergistic inhibition of most P. aeruginosa strains in vitro. In vivo, administration of a combination therapy of mitomycin C with pentamidine, or gentamicin, to G. mellonella larvae infected with P. aeruginosa resulted in enhanced efficacy compared with monotherapies for the majority of MDR clinical isolates. Notably, the therapeutic benefit conferred by the combination therapy occurred with doses of mitomycin C close to those used in human medicine. Thus, repurposing mitomycin C in combination therapies to target MDR P. aeruginosa infections merits further investigation.

Rapid determination of antimicrobial susceptibility of Gram-negative bacteria from clinical blood cultures using a scattered light-integrated collection device.

Background. A bloodstream infection (BSI) presents a complex and serious health problem, a problem that is being exacerbated by increasing antimicrobial resistance (AMR).Gap Statement. The current turnaround times (TATs) for most antimicrobial susceptibility testing (AST) methods offer results retrospective of treatment decisions, and this limits the impact AST can have on antibiotic prescribing and patient care. Progress must be made towards rapid BSI diagnosis and AST to improve antimicrobial stewardship and reduce preventable deaths from BSIs. To support the successful implementation of rapid AST (rAST) in hospital settings, a rAST method that is affordable, is sustainable and offers comprehensive AMR detection is needed.Aim. To evaluate a scattered light-integrated collection (SLIC) device against standard of care (SOC) to determine whether SLIC could accelerate the current TATs with actionable, accurate rAST results for Gram-negative BSIs.Methods. Positive blood cultures from a tertiary referral hospital were studied prospectively. Flagged positive Gram-negative blood cultures were confirmed by Gram staining and analysed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Vitek 2, disc diffusion (ceftriaxone susceptibility only) and an SLIC device. Susceptibility to a panel of five antibiotics, as defined by European Committee on Antimicrobial Susceptibility Testing breakpoints, was examined using SLIC.Results. A total of 505 bacterial-antimicrobial combinations were analysed. A categorical agreement of 95.5 % (482/505) was achieved between SLIC and SOC. The 23 discrepancies that occurred were further investigated by the broth microdilution method, with 10 AST results in agreement with SLIC and 13 in agreement with SOC. The mean time for AST was 10.53±0.46 h and 1.94±0.02 h for Vitek 2 and SLIC, respectively. SLIC saved 23.96±1.47 h from positive blood culture to AST result.Conclusion. SLIC has the capacity to provide accurate AST 1 day earlier from flagged positive blood cultures than SOC. This significant time saving could accelerate time to optimal antimicrobial therapy, improving antimicrobial stewardship and management of BSIs.

Modulation of multidrug-resistant clone success in Escherichia coli populations: a longitudinal, multi-country, genomic and antibiotic usage cohort study.

BACKGROUND: The effect of antibiotic usage on the success of multidrug-resistant (MDR) clones in a population remains unclear. With this genomics-based molecular epidemiology study, we aimed to investigate the contribution of antibiotic use to Escherichia coli clone success, relative to intra-strain competition for colonisation and infection. METHODS: We sequenced all the available E coli bloodstream infection isolates provided by the British Society for Antimicrobial Chemotherapy (BSAC) from 2012 to 2017 (n=718) and combined these with published data from the UK (2001-11; n=1090) and Norway (2002-17; n=3254). Defined daily dose (DDD) data from the European Centre for Disease Prevention and Control (retrieved on Sept 21, 2021) for major antibiotic classes (ß-lactam, tetracycline, macrolide, sulfonamide, quinolone, and non-penicillin ß-lactam) were used together with sequence typing, resistance profiling, regression analysis, and non-neutral Wright-Fisher simulation-based modelling to enable systematic comparison of resistance levels, clone success, and antibiotic usage between the UK and Norway. FINDINGS: Sequence type (ST)73, ST131, ST95, and ST69 accounted for 892 (49·3%) of 1808 isolates in the BSAC collection. In the UK, the proportion of ST69 increased between 2001-10 and 2011-17 (p=0·0004), whereas the proportions of ST73 and ST95 did not vary between periods. ST131 expanded quickly after its emergence in 2003 and its prevalence remained consistent throughout the study period (apart from a brief decrease in 2009-10). The extended-spectrum ß-lactamase (ESBL)-carrying, globally disseminated MDR clone ST131-C2 showed overall greater success in the UK (154 [56·8%] of 271 isolates in 2003-17) compared with Norway (51 [18·3%] of 278 isolates in 2002-17; p<0·0001). DDD data indicated higher total use of antimicrobials in the UK, driven mainly by the class of non-penicillin ß-lactams, which were used between 2·7-times and 5·1-times more in the UK per annum (ratio mean 3·7 [SD 0·8]). This difference was associated with the higher success of the MDR clone ST131-C2 (pseudo-R2 69·1%). A non-neutral Wright-Fisher model replicated the observed expansion of non-MDR and MDR sequence types under higher DDD regimes. INTERPRETATION: Our study indicates that resistance profiles of contemporaneously successful clones can vary substantially, warranting caution in the interpretation of correlations between aggregate measures of resistance and antibiotic usage. Our study further suggests that in countries with low-to-moderate use of antibiotics, such as the UK and Norway, the extent of non-penicillin ß-lactam use modulates rather than determines the success of widely disseminated MDR ESBL-carrying E coli clones. Detailed understanding of underlying causal drivers of success is important for improved control of resistant pathogens. FUNDING: Trond Mohn Foundation, Marie Sklodowska-Curie Actions, European Research Council, Royal Society, and Wellcome Trust.

Combination Therapy with Ciprofloxacin and Pentamidine against Multidrug-Resistant Pseudomonas aeruginosa: Assessment of In Vitro and In Vivo Efficacy and the Role of Resistance-Nodulation-Division (RND) Efflux Pumps.

The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against Galleria mellonella larvae infected with an MDR strain of P. aeruginosa and (ii) determine if pentamidine acts as an efflux-pump inhibitor. Resistant clinical isolates, mutant strains overexpressing one of three RND efflux pumps (MexAB-OprM, MexCD-OprJ, and MexEF-OprN), and a strain with the same three pumps deleted were used. MIC assays confirmed that the clinical isolates and the mutants overexpressing efflux pumps were resistant to ciprofloxacin and pentamidine. The deletion of the three efflux pumps induced sensitivity to both compounds. Exposure to pentamidine and ciprofloxacin in combination resulted in the synergistic inhibition of all resistant strains in vitro, but no synergy was observed versus the efflux-pump deletion strain. The treatment of infected G. mellonella larvae with the combination of pentamidine and ciprofloxacin resulted in enhanced efficacy compared with the monotherapies and significantly reduced the number of proliferating bacteria. Our measurement of efflux activity from cells revealed that pentamidine had a specific inhibitory effect on the MexCD-OprJ and MexEF-OprN efflux pumps. However, the efflux activity and membrane permeability assays revealed that pentamidine also disrupted the membrane of all cells. In conclusion, pentamidine does possess some efflux-pump inhibitory activity, in addition to a more general disruptive effect on membrane integrity that accounts for its ability to potentiate ciprofloxacin activity. Notably, the enhanced efficacy of combination therapy with pentamidine and ciprofloxacin versus MDR P. aeruginosa strains in vivo merits further investigation into its potential to treat infections via this pathogen in patients.

Clinical and Genomic Evolution of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections over Two Time Periods at a Tertiary Care Hospital in South India: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the evolution of carbapenem-resistant Klebsiella pneumoniae (CRKp) infections and their impact at a tertiary care hospital in South India. METHODS: A comparative analysis of clinical data from two prospective cohorts of patients with CRKp bacteremia (C1, 2014-2015; C2, 2021-2022) was carried out. Antimicrobial susceptibilities and whole genome sequencing (WGS) data of selected isolates were also analyzed. RESULTS: A total of 181 patients were enrolled in the study, 56 from C1 and 125 from C2. CRKp bacteremia shifted from critically ill patients with neutropenia to others (ICU stay: C1, 73%; C2, 54%; p = 0.02). The overall mortality rate was 50% and the introduction of ceftazidime-avibactam did not change mortality significantly (54% versus 48%; p = 0.49). Oxacillinases (OXA) 232 and 181 were the most common mechanisms of resistance. WGS showed the introduction of New Delhi metallo-ß-lactamase-5 (NDM-5), higher genetic diversity, accessory genome content, and plasmid burden, as well as increased convergence of hypervirulence and carbapenem resistance in C2. CONCLUSIONS: CRKp continues to pose a significant clinical threat, despite the introduction of new antibiotics. The study highlights the evolution of resistance and virulence in this pathogen and the impact on patient outcomes in South India, providing valuable information for clinicians and researchers.

In Vitro Activity of Two Cefepime-Based Novel Combinations, Cefepime/Taniborbactam and Cefepime/Zidebactam, against Carbapenemase-Expressing Enterobacterales Collected in India.

In recent times, discovery efforts for novel antibiotics have mostly targeted carbapenemase-producing Gram-negative organisms. Two different combination approaches are pertinent: ß-lactam-ß-lactamase inhibitor (BL/BLI) or ß-lactam-ß-lactam enhancer (BL/BLE). Cefepime combined with a BLI, taniborbactam, or with a BLE, zidebactam, has been shown to be promising. In this study, we determined the in vitro activity of both these agents along with comparators against multicentric carbapenemase-producing Enterobacterales (CPE). Nonduplicate CPE isolates of Escherichia coli (n = 270) and Klebsiella pneumoniae (n = 300), collected from nine different tertiary-care hospitals across India during 2019 to 2021, were included in the study. Carbapenemases in these isolates were detected by PCR. E. coli isolates were also screened for the presence of the 4-amino-acid insert in penicillin binding protein 3 (PBP3). MICs were determined by reference broth microdilution. Higher MICs of cefepime/taniborbactam (>8 mg/L) were linked to NDM, both in K. pneumoniae and in E. coli. In particular, such higher MICs were observed in 88 to 90% of E. coli isolates producing NDM and OXA-48-like or NDM alone. On the other hand, OXA-48-like-producing E. coli or K. pneumoniae isolates were nearly 100% susceptible to cefepime/taniborbactam. Regardless of the carbapenemase types and the pathogens, cefepime/zidebactam showed potent activity (>99% inhibited at ≤8 mg/L). It seems that the 4-amino-acid insert in PBP3 (present universally in the study E. coli isolates) along with NDM adversely impact the activity of cefepime/taniborbactam. Thus, the limitations of the BL/BLI approach in tackling the complex interplay of enzymatic and nonenzymatic resistance mechanisms were better revealed in whole-cell studies where the activity observed was a net effect of ß-lactamase inhibition, cellular uptake, and target affinity of the combination. IMPORTANCE The study revealed the differential ability of cefepime/taniborbactam and cefepime/zidebactam in tackling carbapenemase-producing Indian clinical isolates that also harbored additional mechanisms of resistance. NDM-expressing E. coli with 4-amino-acid insert in PBP3 are predominately resistant to cefepime/taniborbactam, while the ß-lactam enhancer mechanism-based cefepime/zidebactam showed consistent activity against single- or dual-carbapenemase-producing isolates including E. coli with PBP3 inserts.

Carbapenem-Only Combination Therapy against Multi-Drug Resistant Pseudomonas aeruginosa: Assessment of In Vitro and In Vivo Efficacy and Mode of Action.

The aim of the study was to determine the efficacy of carbapenem-only combination treatments derived from four approved drugs (meropenem, doripenem, ertapenem and imipenem) against a MDR strain of P. aeruginosa in a Galleria mellonella larvae infection model. G. mellonella larvae were infected with P. aeruginosa NCTC 13437 (carrying the VIM 10 carbapenamase) and the efficacy of the six possible dual, four triple, and one quadruple carbapenem combination(s) were compared to their constituent monotherapies. Four of these combinations showed significantly enhanced survival compared to monotherapies and reduced the bacterial burden inside infected larvae but without complete elimination. Bacteria that survived combination therapy were slower growing, less virulent but with unchanged carbapenem MICs-observations that are consistent with a persister phenotype. In vitro time-kill assays confirmed that the combinations were bactericidal and confirmed that a low number of bacteria survived exposure. Mass spectrometry was used to quantify changes in the concentration of carbapenems in the presence of carbapenemase-carrying P. aeruginosa. The rate of degradation of individual carbapenems was altered, and often significantly reduced, when the drugs were in combinations compared with the drugs alone. These differences may account for the enhanced inhibitory effects of the combinations against carbapenem-resistant P. aeruginosa and are consistent with a 'shielding' hypothesis. In conclusion, carbapenem combinations show promise in combating MDR P. aeruginosa and are worthy of additional study and development.

Epidemiology, Outcomes and Resource Utilisation in Patients with Carbapenem Non-susceptible Gram-Negative Bacteria in the UK: A Retrospective, Observational Study (CARBAR UK).

INTRODUCTION: Antimicrobial resistance is an urgent medical challenge. In this two-part study, we investigated the epidemiology and management of carbapenem non-susceptible (Carb-NS) Gram-negative bacteria (GNB) in the UK. METHODS: We conducted a retrospective review of data from UK hospitals (ten in part 1, nine in part 2). In part 1, epidemiological data were collected from patients hospitalised between April 2017 and March 2018 with any laboratory detection of Carb-NS GNB, encompassing both colonisation and infection. In part 2, diagnosis and management pathways in a randomly selected population of adults from part 1 with confirmed Carb-NS GNB infection were assessed. Data were obtained from a detailed medical chart review for ≥ 3 months from index (collection date of first positive Carb-NS GNB sample). RESULTS: Of 42,340 GNB isolates from 36,098 patients colonised/infected with GNB in part 1, 7% were Carb-NS. In 157 patients included in part 2, 234 GNB index samples were collected, of which 197 (82%) were Carb-NS (median number of Carb-NS pathogens per patient, 1; range 1-3). The most frequent Carb-NS isolates were Pseudomonas aeruginosa (36%), Stenotrophomonas maltophilia (29%) and Klebsiella pneumoniae (10%). Median length of hospitalisation was 34 days. Median time from index to appropriate therapy was 3 days, with empirical therapy initiated a median of 1 day before index. Carb-NS infection was believed to contribute to 21 (28%) of 76 deaths during the study. CONCLUSIONS: This study highlights the high incidence of Carb-NS GNB colonisation and infection in the UK and the need for improved management of patients with Carb-NS GNB infection.

A computational investigation of COVID-19 transmission inside hospital wards and associated costs.

The COVID-19 pandemic has placed a particular burden on hospitals: from intra-hospital transmission of the infections to reduced admissions of non-COVID-19 patients. There are also high costs associated with the treatment of hospitalised COVID-19 patients, as well as reductions in revenues due to delayed and cancelled treatments. In this study we investigate computationally the transmission of COVID-19 inside a hospital ward that contains multiple-bed bays (with 4 or 6 beds) and multiple single-bed side rooms (that can accommodate the contacts of COVID-19-positive patients). The aim of this study is to investigate the role of 4-bed bays vs. 6-bed bays on the spread of infections and the hospital costs. We show that 4-bed bays are associated with lower infections only when we reduce the discharge time of some patients from 10 days to 5 days. This also leads to lower costs for the treatment of COVID-19 patients. In contrast, 6-bed bays are associated with reduced hospital waiting lists (especially when there are also multiple side rooms available to accommodate the contacts of COVID-19-positive patients identified inside the 6-bed bays).

Presence of optrA-mediated linezolid resistance in multiple lineages and plasmids of Enterococcus faecalis revealed by long read sequencing.

Transferable linezolid resistance due to optrA, poxtA, cfr and cfr-like genes is increasingly detected in enterococci associated with animals and humans globally. We aimed to characterize the genetic environment of optrA in linezolid-resistant Enterococcus faecalis isolates from Scotland. Six linezolid-resistant E. faecalis isolated from urogenital samples were confirmed to carry the optrA gene by PCR. Short read (Illumina) sequencing showed the isolates were genetically distinct (>13900 core SNPs) and belonged to different MLST sequence types. Plasmid contents were examined using hybrid assembly of short and long read (Oxford Nanopore MinION) sequencing technologies. The optrA gene was located on distinct plasmids in each isolate, suggesting that transfer of a single plasmid did not contribute to optrA dissemination in this collection. pTM6294-2, BX5936-1 and pWE0438-1 were similar to optrA-positive plasmids from China and Japan, while the remaining three plasmids had limited similarity to other published examples. We identified the novel Tn6993 transposon in pWE0254-1 carrying linezolid (optrA), macrolide (ermB) and spectinomycin [ANT(9)-Ia] resistance genes. OptrA amino acid sequences differed by 0-20 residues. We report multiple variants of optrA on distinct plasmids in diverse strains of E. faecalis. It is important to identify the selection pressures driving the emergence and maintenance of resistance against linezolid to retain the clinical utility of this antibiotic.

Probabilistic microsimulation to examine the cost-effectiveness of hospital admission screening strategies for carbapenemase-producing enterobacteriaceae (CPE) in the United Kingdom.

BACKGROUND: Antimicrobial resistance has been recognised as a global threat with carbapenemase- producing-Enterobacteriaceae (CPE) as a prime example. CPE has similarities to COVID-19 where asymptomatic patients may be colonised representing a source for onward transmission. There are limited treatment options for CPE infection leading to poor outcomes and increased costs. Admission screening can prevent cross-transmission by pre-emptively isolating colonised patients. OBJECTIVE: We assess the relative cost-effectiveness of screening programmes compared with no- screening. METHODS: A microsimulation parameterised with NHS Scotland date was used to model scenarios of the prevalence of CPE colonised patients on admission. Screening strategies were (a) two-step screening involving a clinical risk assessment (CRA) checklist followed by microbiological testing of high-risk patients; and (b) universal screening. Strategies were considered with either culture or polymerase chain reaction (PCR) tests. All costs were reported in 2019 UK pounds with a healthcare system perspective. RESULTS: In the low prevalence scenario, no screening had the highest probability of cost-effectiveness. Among screening strategies, the two CRA screening options were the most likely to be cost-effective. Screening was more likely to be cost-effective than no screening in the prevalence of 1 CPE colonised in 500 admitted patients or more. There was substantial uncertainty with the probabilities rarely exceeding 40% and similar results between strategies. Screening reduced non-isolated bed-days and CPE colonisation. The cost of screening was low in relation to total costs. CONCLUSION: The specificity of the CRA checklist was the parameter with the highest impact on the cost-effectiveness. Further primary data collection is needed to build models with less uncertainty in the parameters.

The protective effect of SARS-CoV-2 antibodies in Scottish healthcare workers.

BACKGROUND: Healthcare workers (HCWs) are believed to be at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection. METHODS: A prospective observational study of HCWs in Scotland (UK) from May to September 2020 was performed. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general local population, were studied for comparison. New infections (up to 2 December 2020) post antibody testing were recorded to determine whether the presence of SARS-CoV-2 antibodies protects against re-infection. RESULTS: A total of 2063 health and social care workers were recruited for this study. At enrolment, 300 HCWs had a positive antibody test (14.5%). 11 out of 231 control sera tested positive (4.8%). HCWs therefore had an increased likelihood of a positive test (OR 3.4, 95% CI 1.85-6.16; p<0.0001). Dentists were most likely to test positive. 97.3% of patients who had previously tested positive for SARS-CoV-2 by reverse transcriptase (RT)-PCR had positive antibodies. 18.7% had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCWs who were previously antibody negative, and one symptomatic RT-PCR-positive re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (hazard ratio 0.15, 95% CI 0.06-0.35; p=0.026). CONCLUSION: HCWs were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all infected individuals developed an antibody response, which was 85% effective in protecting against re-infection with SARS-CoV-2.

Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland.

Coronavirus disease 2019 (COVID-19) was first diagnosed in Scotland on 1 March 2020. During the first month of the outbreak, 2,641 cases of COVID-19 led to 1,832 hospital admissions, 207 intensive care admissions and 126 deaths. We aimed to identify the source and number of introductions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into Scotland using a combined phylogenetic and epidemiological approach. Sequencing of 1,314 SARS-CoV-2 viral genomes from available patient samples enabled us to estimate that SARS-CoV-2 was introduced to Scotland on at least 283 occasions during February and March 2020. Epidemiological analysis confirmed that early introductions of SARS-CoV-2 originated from mainland Europe (the majority from Italy and Spain). We identified subsequent early outbreaks in the community, within healthcare facilities and at an international conference. Community transmission occurred after 2 March, 3 weeks before control measures were introduced. Earlier travel restrictions or quarantine measures, both locally and internationally, would have reduced the number of COVID-19 cases in Scotland. The risk of multiple reintroduction events in future waves of infection remains high in the absence of population immunity.

Modelling the transmission of infectious diseases inside hospital bays: implications for COVID-19.

Healthcare associated transmission of viral infections is a major problem that has significant economic costs and can lead to loss of life. Infections with the highly contagious SARS-CoV-2 virus have been shown to have a high prevalence in hospitals around the world. The spread of this virus might be impacted by the density of patients inside hospital bays. To investigate this aspect, in this study we consider a mathematical modelling and computational approach to describe the spread of SARS-CoV-2 among hospitalised patients. We focus on 4-bed bays and 6-bed bays, which are commonly used to accommodate various non-COVID-19 patients in many hospitals across the United Kingdom (UK). We investigate the spread of SARS-CoV-2 infections among patients in non-COVID bays, in the context of various scenarios: placing the initially-exposed individual in different beds, varying the recovery and incubation periods, having symptomatic vs. asymptomatic patients, removing infected individuals from these hospital bays once they are known to be infected, and the role of periodic testing of hospitalised patients. Our results show that 4-bed bays reduce the spread of SARS-CoV-2 compared to 6-bed bays. Moreover, we show that the position of a new (not infected) patient in specific beds in a 6-bed bay might also slow the spread of the disease. Finally, we propose that regular SARS-CoV-2 testing of hospitalised patients would allow appropriate placement of infected patients in specific (COVID-only) hospital bays.

Repurposing the anti-viral drug zidovudine (AZT) in combination with meropenem as an effective treatment for infections with multi-drug resistant, carbapenemase-producing strains of Klebsiella pneumoniae.

Multi-drug resistant (MDR) Klebsiella pneumoniae represent a global threat to healthcare due to lack of effective treatments and high mortality rates. The aim of this research was to explore the potential of administering zidovudine (AZT) in combination with an existing antibiotic to treat resistant K. pneumoniae infections. Two MDR K. pneumoniae strains were employed, producing either the NDM-1 or KPC-3 carbapenemase. Efficacy of combinations of AZT with meropenem were compared with monotherapies against infections in Galleria mellonella larvae by measuring larval mortality and bacterial burden. The effect of the same combinations in vitro was determined via checkerboard and time-kill assays. In vitro, both K. pneumoniae strains were resistant to meropenem but were susceptible to AZT. In G. mellonella, treatment with either AZT or meropenem alone offered minimal therapeutic benefit against infections with either strain. In contrast, combination therapy of AZT with meropenem presented significantly enhanced efficacy compared to monotherapies. This was correlated with prevention of bacterial proliferation within the larvae but not elimination. Checkerboard assays showed that the interaction between AZT and meropenem was not synergistic but indifferent. In summary, combination therapy of AZT with meropenem represents a potential treatment for carbapenemase-producing MDR K. pneumoniae and merits further investigation.

Drive-through testing for SARS-CoV-2 in symptomatic health and social care workers and household members: an observational cohort study.

The requirement for health and social care workers to self-isolate when they or their household contacts develop symptoms consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to critical staff shortages in the context of a pandemic. In this report, we describe the implementation of a drive-through testing service in a single National Health Service region in Scotland. From 17 March 2020 to 11 April 2020, 1890 SARS-CoV-2 reverse transcription PCR assay (RT-PCR) tests were performed. 22% of tests were positive. Allowing the remaining 78% of staff to return to work within 24 hours was estimated to save over 8000 working days during the peak pandemic period.