Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult ...to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL-positive bacterial infection in conjunction with existing carbapenems.
To describe the infection control preparedness measures undertaken for coronavirus disease (COVID-19) due to SARS-CoV-2 (previously known as 2019 novel coronavirus) in the first 42 days after ...announcement of a cluster of pneumonia in China, on December 31, 2019 (day 1) in Hong Kong.
A bundled approach of active and enhanced laboratory surveillance, early airborne infection isolation, rapid molecular diagnostic testing, and contact tracing for healthcare workers (HCWs) with unprotected exposure in the hospitals was implemented. Epidemiological characteristics of confirmed cases, environmental samples, and air samples were collected and analyzed.
From day 1 to day 42, 42 of 1,275 patients (3.3%) fulfilling active (n = 29) and enhanced laboratory surveillance (n = 13) were confirmed to have the SARS-CoV-2 infection. The number of locally acquired case significantly increased from 1 of 13 confirmed cases (7.7%, day 22 to day 32) to 27 of 29 confirmed cases (93.1%, day 33 to day 42; P < .001). Among them, 28 patients (66.6%) came from 8 family clusters. Of 413 HCWs caring for these confirmed cases, 11 (2.7%) had unprotected exposure requiring quarantine for 14 days. None of these was infected, and nosocomial transmission of SARS-CoV-2 was not observed. Environmental surveillance was performed in the room of a patient with viral load of 3.3 × 106 copies/mL (pooled nasopharyngeal and throat swabs) and 5.9 × 106 copies/mL (saliva), respectively. SARS-CoV-2 was identified in 1 of 13 environmental samples (7.7%) but not in 8 air samples collected at a distance of 10 cm from the patient's chin with or without wearing a surgical mask.
Appropriate hospital infection control measures was able to prevent nosocomial transmission of SARS-CoV-2.
Face mask usage by the healthy population in the community to reduce risk of transmission of respiratory viruses remains controversial. We assessed the effect of community-wide mask usage to control ...coronavirus disease 2019 (COVID-19) in Hong Kong Special Administrative Region (HKSAR).
Patients presenting with respiratory symptoms at outpatient clinics or hospital wards were screened for COVID-19 per protocol. Epidemiological analysis was performed for confirmed cases, especially persons acquiring COVID-19 during mask-off and mask-on settings. The incidence of COVID-19 per million population in HKSAR with community-wide masking was compared to that of non-mask-wearing countries which are comparable with HKSAR in terms of population density, healthcare system, BCG vaccination and social distancing measures but not community-wide masking. Compliance of face mask usage in the HKSAR community was monitored.
Within first 100 days (31 December 2019 to 8 April 2020), 961 COVID-19 patients were diagnosed in HKSAR. The COVID-19 incidence in HKSAR (129.0 per million population) was significantly lower (p<0.001) than that of Spain (2983.2), Italy (2250.8), Germany (1241.5), France (1151.6), U.S. (1102.8), U.K. (831.5), Singapore (259.8), and South Korea (200.5). The compliance of face mask usage by HKSAR general public was 96.6% (range: 95.7% to 97.2%). We observed 11 COVID-19 clusters in recreational ‘mask-off’ settings compared to only 3 in workplace ‘mask-on’ settings (p = 0.036 by Chi square test of goodness-of-fit).
Community-wide mask wearing may contribute to the control of COVID-19 by reducing the amount of emission of infected saliva and respiratory droplets from individuals with subclinical or mild COVID-19.
Ka Hung Chan and colleagues argue that monitoring influenza-like illness could be a complementary approach to assessing the effectiveness of general infection control measures against covid-19
The role of severe respiratory coronavirus virus 2 (SARS-CoV-2)-laden aerosols in the transmission of coronavirus disease 2019 (COVID-19) remains uncertain. Discordant findings of SARS-CoV-2 RNA in ...air samples were noted in early reports.
Sampling of air close to 6 asymptomatic and symptomatic COVID-19 patients with and without surgical masks was performed with sampling devices using sterile gelatin filters. Frequently touched environmental surfaces near 21 patients were swabbed before daily environmental disinfection. The correlation between the viral loads of patients' clinical samples and environmental samples was analyzed.
All air samples were negative for SARS-CoV-2 RNA in the 6 patients singly isolated inside airborne infection isolation rooms (AIIRs) with 12 air changes per hour. Of 377 environmental samples near 21 patients, 19 (5.0%) were positive by reverse-transcription polymerase chain reaction (RT-PCR) assay, with a median viral load of 9.2 × 102 copies/mL (range, 1.1 × 102 to 9.4 × 104 copies/mL). The contamination rate was highest on patients' mobile phones (6 of 77, 7.8%), followed by bed rails (4 of 74, 5.4%) and toilet door handles (4 of 76, 5.3%). We detected a significant correlation between viral load ranges in clinical samples and positivity rate of environmental samples (P < .001).
SARS-CoV-2 RNA was not detectable by air samplers, which suggests that the airborne route is not the predominant mode of transmission of SARS-CoV-2. Wearing a surgical mask, appropriate hand hygiene, and thorough environmental disinfection are sufficient infection control measures for COVID-19 patients isolated singly in AIIRs. However, this conclusion may not apply during aerosol-generating procedures or in cohort wards with large numbers of COVID-19 patients.
Abstract
Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes,
bla
MBL
and
mcr
, raises a significant challenge to the treatment of life-threatening infections by ...the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by
Escherichia coli
co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs.
A cruise ship is a closed-off environment that simulates the basic functioning of a city in terms of living conditions and interpersonal interactions. Thus, the Diamond Princess cruise ship, which ...was quarantined because of an onboard outbreak of COVID-19 in February, 2020, provides an opportunity to define the shedding pattern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient antibody responses before and after the onset of symptoms.
We recruited adult (≥18 years) passengers from Hong Kong who had been on board the Diamond Princess cruise ship docked in Yokohama, Japan in February, 2020. All participants had been found to be negative for SARS-CoV-2 by RT-PCR 4 days before disembarking and were transferred to further quarantine in a public estate in Hong Kong, where they were recruited. Participants were prospectively screened by quantitative RT-PCR (RT-qPCR) of nasopharyngeal and throat swabs, and serum IgG and IgM against internal nucleoprotein and the surface spike receptor-binding protein (RBD) of SARS-CoV-2 at baseline (upon entering quarantine) and on days 4, 8, and 12 of quarantine.
On Feb 22, 2020, 215 adults were recruited, of whom nine (4%; 95% CI 2–8) were positive for SARS-CoV-2 by RT-qPCR or serology and were hospitalised. Of these nine patients, nasopharyngeal swab RT-qPCR was positive in eight patients (89%; 57–99) at baseline. All nine patients were positive for anti-RBD IgG by day 8. Eight (89%; 57–99) were simultaneously positive for nasopharyngeal swab RT-PCR and anti-RBD IgG. One patient who was positive for anti-RBD IgG and had a negative viral load had multifocal peripheral ground-glass changes on high-resolution CT that were typical of COVID-19. Five patients (56%; 27–81) with ground-glass changes on high-resolution CT were found to have higher anti-nucleoprotein-IgG OD values on day 8 and 12 and anti-RBD IgG OD value on day 12 than patients without ground-glass changes. Six (67%; 35–88) patients remained asymptomatic throughout the 14-day quarantine period.
Patients with COVID-19 can develop asymptomatic lung infection with viral shedding and those with evidence of pneumonia on imaging tend to have an increased antibody response. Positive IgG or IgM confirmed infection of COVID-19 in both symptomatic and asymptomatic patients. A combination of RT-PCR and serology should be implemented for case finding and contact tracing to facilitate early diagnosis, prompt isolation, and treatment.
Shaw Foundation Hong Kong; Sanming-Project of Medicine (Shenzhen); High Level-Hospital Program (Guangdong Health Commission).
The spread of antibiotic resistance has become one of the most urgent threats to global health, which is estimated to cause 700,000 deaths each year globally. Its surrogates, antibiotic resistance ...genes (ARGs), are highly transmittable between food, water, animal, and human to mitigate the efficacy of antibiotics. Accurately identifying ARGs is thus an indispensable step to understanding the ecology, and transmission of ARGs between environmental and human-associated reservoirs. Unfortunately, the previous computational methods for identifying ARGs are mostly based on sequence alignment, which cannot identify novel ARGs, and their applications are limited by currently incomplete knowledge about ARGs.
Here, we propose an end-to-end Hierarchical Multi-task Deep learning framework for ARG annotation (HMD-ARG). Taking raw sequence encoding as input, HMD-ARG can identify, without querying against existing sequence databases, multiple ARG properties simultaneously, including if the input protein sequence is an ARG, and if so, what antibiotic family it is resistant to, what resistant mechanism the ARG takes, and if the ARG is an intrinsic one or acquired one. In addition, if the predicted antibiotic family is beta-lactamase, HMD-ARG further predicts the subclass of beta-lactamase that the ARG is resistant to. Comprehensive experiments, including cross-fold validation, third-party dataset validation in human gut microbiota, wet-experimental functional validation, and structural investigation of predicted conserved sites, demonstrate not only the superior performance of our method over the state-of-art methods, but also the effectiveness and robustness of the proposed method.
We propose a hierarchical multi-task method, HMD-ARG, which is based on deep learning and can provide detailed annotations of ARGs from three important aspects: resistant antibiotic class, resistant mechanism, and gene mobility. We believe that HMD-ARG can serve as a powerful tool to identify antibiotic resistance genes and, therefore mitigate their global threat. Our method and the constructed database are available at http://www.cbrc.kaust.edu.sa/HMDARG/ . Video abstract (MP4 50984 kb).
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