Antimicrobial resistance (AMR) in COVID-19 patients: a systematic review and meta-analysis (November 2019-June 2021).

BACKGROUND: Pneumonia from SARS-CoV-2 is difficult to distinguish from other viral and bacterial etiologies. Broad-spectrum antimicrobials are frequently prescribed to patients hospitalized with COVID-19 which potentially acts as a catalyst for the development of antimicrobial resistance (AMR). OBJECTIVES: We conducted a systematic review and meta-analysis during the first 18 months of the pandemic to quantify the prevalence and types of resistant co-infecting organisms in patients with COVID-19 and explore differences across hospital and geographic settings. METHODS: We searched MEDLINE, Embase, Web of Science (BioSIS), and Scopus from November 1, 2019 to May 28, 2021 to identify relevant articles pertaining to resistant co-infections in patients with laboratory confirmed SARS-CoV-2. Patient- and study-level analyses were conducted. We calculated pooled prevalence estimates of co-infection with resistant bacterial or fungal organisms using random effects models. Stratified meta-analysis by hospital and geographic setting was also performed to elucidate any differences. RESULTS: Of 1331 articles identified, 38 met inclusion criteria. A total of 1959 unique isolates were identified with 29% (569) resistant organisms identified. Co-infection with resistant bacterial or fungal organisms ranged from 0.2 to 100% among included studies. Pooled prevalence of co-infection with resistant bacterial and fungal organisms was 24% (95% CI 8-40%; n = 25 studies: I2 = 99%) and 0.3% (95% CI 0.1-0.6%; n = 8 studies: I2 = 78%), respectively. Among multi-drug resistant organisms, methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and multi-drug resistant Candida auris were most commonly reported. Stratified analyses found higher proportions of AMR outside of Europe and in ICU settings, though these results were not statistically significant. Patient-level analysis demonstrated > 50% (n = 58) mortality, whereby all but 6 patients were infected with a resistant organism. CONCLUSIONS: During the first 18 months of the pandemic, AMR prevalence was high in COVID-19 patients and varied by hospital and geography although there was substantial heterogeneity. Given the variation in patient populations within these studies, clinical settings, practice patterns, and definitions of AMR, further research is warranted to quantify AMR in COVID-19 patients to improve surveillance programs, infection prevention and control practices and antimicrobial stewardship programs globally.

Bhimamycin J, a Rare Benzo[f]isoindole-dione Alkaloid from the Marine-Derived Actinomycete Streptomyces sp. MS180069.

Chemical investigation on a Streptomyces sp. strain MS180069 isolated from a sediment sample collected from the South China Sea, yielded the new benzo[f]isoindole-dione alkaloid, bhimamycin J (1). The structure was determined by extensive spectroscopic analysis, including HRMS, 1D, 2D NMR, and X-ray diffraction techniques. A molecular docking study revealed 1 as a new molecular motif that binds with human angiotensin converting enzyme2 (ACE2), recently described as the cell surface receptor responsible for uptake of 2019-CoV-2. Using enzyme assays we confirm that 1 inhibits human ACE2 79.7 % at 25 µg/mL.

Emerging Fungal Infections: New Species, New Names, and Antifungal Resistance.

BACKGROUND: Infections caused by fungi can be important causes of morbidity and mortality in certain patient populations, including those who are highly immunocompromised or critically ill. Invasive mycoses can be caused by well-known species, as well as emerging pathogens, including those that are resistant to clinically available antifungals. CONTENT: This review highlights emerging fungal infections, including newly described species, such as Candida auris, and those that having undergone taxonomic classification and were previously known by other names, including Blastomyces and Emergomyces species, members of the Rasamsonia argillacea species complex, Sporothrix brasiliensis, and Trichophyton indotinae. Antifungal resistance also is highlighted in several of these emerging species, as well as in the well-known opportunistic pathogen Aspergillus fumigatus. Finally, the increased recognition and importance of fungal co-infections with respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is discussed. SUMMARY: Both clinicians and clinical microbiology laboratories should remain vigilant regarding emerging fungal infections. These may be difficult both to diagnose and treat due to the lack of experience of clinicians and laboratory personnel with these organisms and the infections they may cause. Many of these fungal infections have been associated with poor clinical outcomes, either due to inappropriate therapy or the development of antifungal resistance.

Photodynamic disinfection and its role in controlling infectious diseases.

Photodynamic therapy is witnessing a revival of its origins as a response to the rise of multi-drug resistant infections and the shortage of new classes of antibiotics. Photodynamic disinfection (PDDI) of microorganisms is making progresses in preclinical models and in clinical cases, and the perception of its role in the clinical armamentarium for the management of infectious diseases is changing. We review the positioning of PDDI from the perspective of its ability to respond to clinical needs. Emphasis is placed on the pipeline of photosensitizers that proved effective to inactivate biofilms, showed efficacy in animal models of infectious diseases or reached clinical trials. Novel opportunities resulting from the COVID-19 pandemic are briefly discussed. The molecular features of promising photosensitizers are emphasized and contrasted with those of photosensitizers used in the treatment of solid tumors. The development of photosensitizers has been accompanied by the fabrication of a variety of affordable and customizable light sources. We critically discuss the combination between photosensitizer and light source properties that may leverage PDDI and expand its applications to wider markets. The success of PDDI in the management of infectious diseases will ultimately depend on the efficacy of photosensitizers, affordability of the light sources, simplicity of the procedures, and availability of fast and efficient treatments.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin.

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

Organic Photo-antimicrobials: Principles, Molecule Design, and Applications.

The emergence of multi-drug-resistant pathogens threatens the healthcare systems world-wide. Recent advances in phototherapy (PT) approaches mediated by photo-antimicrobials (PAMs) provide new opportunities for the current serious antibiotic resistance. During the PT treatment, reactive oxygen species or heat produced by PAMs would react with the cell membrane, consequently leaking cytoplasm components and effectively eradicating different pathogens like bacteria, fungi, viruses, and even parasites. This Perspective will concentrate on the development of different organic photo-antimicrobials (OPAMs) and their application as practical therapeutic agents into therapy for local infections, wound dressings, and removal of biofilms from medical devices. We also discuss how to design highly efficient OPAMs by modifying the chemical structure or conjugating with a targeting component. Moreover, this Perspective provides a discussion of the general challenges and direction for OPAMs and what further needs to be done. It is hoped that through this overview, OPAMs can prosper and will be more widely used for microbial infections in the future, especially at a time when the global COVID-19 epidemic is getting more serious.

Impact of SARS-CoV-2 Epidemic on Antimicrobial Resistance: A Literature Review.

Antimicrobial resistance is an urgent threat to public health and global development; in this scenario, the SARS-CoV2 pandemic has caused a major disruption of healthcare systems and practices. A narrative review was conducted on articles focusing on the impact of COVID-19 on multidrug-resistant gram-negative, gram-positive bacteria, and fungi. We found that, worldwide, multiple studies reported an unexpected high incidence of infections due to methicillin-resistant S. aureus, carbapenem-resistant A. baumannii, carbapenem-resistant Enterobacteriaceae, and C. auris among COVID-19 patients admitted to the intensive care unit. In this setting, inappropriate antimicrobial exposure, environmental contamination, and discontinuation of infection control measures may have driven selection and diffusion of drug-resistant pathogens.

Sintered and 3D-Printed Bulks of MgB2-Based Materials with Antimicrobial Properties.

Pristine high-density bulk disks of MgB2 with added hexagonal BN (10 wt.%) were prepared using spark plasma sintering. The BN-added samples are machinable by chipping them into desired geometries. Complex shapes of different sizes can also be obtained by the 3D printing of polylactic acid filaments embedded with MgB2 powder particles (10 wt.%). Our present work aims to assess antimicrobial activity quantified as viable cells (CFU/mL) vs. time of sintered and 3D-printed materials. In vitro antimicrobial tests were performed against the bacterial strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus faecium DSM 13590, and Enterococcus faecalis ATCC 29212; and the yeast strain Candida parapsilosis ATCC 22019. The antimicrobial effects were found to depend on the tested samples and microbes, with E. faecium being the most resistant and E. coli the most susceptible.

Bacterial and fungal growth in sputum cultures from 165 COVID-19 pneumonia patients requiring intubation: evidence for antimicrobial resistance development and analysis of risk factors.

BACKGROUND: Coronavirus SARS-CoV-2 causes COVID-19 illness which can progress to severe pneumonia. Empiric antibacterials are often employed though frequency of bacterial coinfection superinfection is debated and concerns raised about selection of bacterial antimicrobial resistance. We evaluated sputum bacterial and fungal growth from 165 intubated COVID-19 pneumonia patients. Objectives were to determine frequency of culture positivity, risk factors for and outcomes of positive cultures, and timing of antimicrobial resistance development. METHODS: Retrospective reviews were conducted of COVID-19 pneumonia patients requiring intubation admitted to a 1058-bed four community hospital system on the east coast United States, March 1 to May 1, 2020. Length of stay (LOS) was expressed as mean (standard deviation); 95% confidence interval (95% CI) was computed for overall mortality rate using the exact binomial method, and overall mortality was compared across each level of a potential risk factor using a Chi-Square Test of Independence. All tests were two-sided, and significance level was set to 0.05. RESULTS: Average patient age was 68.7 years and LOS 19.9 days. Eighty-three patients (50.3% of total) originated from home, 10 from group homes (6.1% of total), and 72 from nursing facilities (43.6% of total). Mortality was 62.4%, highest for nursing home residents (80.6%). Findings from 253 sputum cultures overall did not suggest acute bacterial or fungal infection in 73 (45%) of 165 individuals sampled within 24 h of intubation. Cultures ≥ 1 week following intubation did grow potential pathogens in 72 (64.9%) of 111 cases with 70.8% consistent with late pneumonia and 29.2% suggesting colonization. Twelve (10.8% of total) of these late post-intubation cultures revealed worsened antimicrobial resistance predominantly in Pseudomonas, Enterobacter, or Staphylococcus aureus. CONCLUSIONS: In severe COVID-19 pneumonia, a radiographic ground glass interstitial pattern and lack of purulent sputum prior to/around the time of intubation correlated with no culture growth or recovery of normal oral flora ± yeast. Discontinuation of empiric antibacterials should be considered in these patients aided by other clinical findings, history of prior antimicrobials, laboratory testing, and overall clinical course. Continuing longterm hospitalisation and antibiotics are associated with sputum cultures reflective of hospital-acquired microbes and increasing antimicrobial resistance. TRIAL REGISTRATION: Not applicable as this was a retrospective chart review study without interventional arm.

Simple and Rapid Method for Wogonin Preparation and Its Biotransformation.

Wogonin is one of the most active flavonoids from Scutellaria baicalensis Georgi (baikal skullcap), widely used in traditional Chinese medicine. It exhibits a broad spectrum of health-promoting and therapeutic activities. Together with baicalein, it is considered to be the one of main active ingredients of Chinese medicines for the management of COVID-19. However, therapeutic use of wogonin may be limited due to low market availability connected with its low content in baikal skullcap and lack of efficient preparative methods for obtaining this compound. Although the amount of wogonin in skullcap root often does not exceed 0.5%, this material is rich in wogonin glucuronide, which may be used as a substrate for wogonin production. In the present study, a rapid, simple, cheap and effective method of wogonin and baicalein preparation, which provides gram quantities of both flavonoids, is proposed. The obtained wogonin was used as a substrate for biotransformation. Thirty-six microorganisms were tested in screening studies. The most efficient were used in enlarged scale transformations to determine metabolism of this xenobiotic. The major phase I metabolism product was 4'-hydroxywogonin-a rare flavonoid which exhibits anticancer activity-whereas phase II metabolism products were glucosides of wogonin. The present studies complement and extend the knowledge on the effect of substitution of A- and B-ring on the regioselective glycosylation of flavonoids catalyzed by microorganisms.

Discovery of metal-based complexes as promising antimicrobial agents.

The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.

Preparation of cellulose-based wipes treated with antimicrobial and antiviral silver nanoparticles as novel effective high-performance coronavirus fighter.

Coronaviruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). We succeeded in preparing disinfectant cellulose-based wipes treated with antimicrobial and antiviral silver nanoparticles to be used for prevention of contamination and transmission of several pathogenic viruses and microbes to human in critical areas such as hospitals and healthcare centers especially coronavirus. In this work, the antimicrobial and antiviral activities of silver nanoparticles (AgNPs) prepared with four different techniques were investigated for the utilization as a disinfectant for cellulose-based wipes. These four methods are namely; 1) trisodium citrate with cotton yarn as a reducing agent, 2) preparing AgNP's using aqueous solution of PVA in the presence of glucose, 3) trisodium citrate with cotton fabric as a reducing agent, and 4) photochemical reaction of polyacrylic acid and silver nitrate solution. Polyester/viscose blended spunlace nonwoven fabrics as cellulose based fabrics were treated with the prepared silver nanoparticles to be used as surfaces disinfection wipes. The properties of the nonwoven fabrics were examined including thickness, tensile strength in dry and wet conditions in both machine direction (MD) and cross-machine direction (CMD), bursting strength, air permeability, water permeability and surface wettability. Characterization of the AgNPs was carried out in terms of UV-VIS spectroscopy, TEM, SEM, and Zeta potential analysis. The assessment of AgNPs active solutions for antimicrobial and antiviral activities was evaluated. The results obtained from the analyses of the AgNPs samples prepared with different techniques showed good uniformity and stability of the particles, as well uniform coating of the AgNPs on the fibers. Additionally, there is a significant effect of the AgNPs preparation method on their disinfectant performance that proved its effectiveness against coronavirus (MERS-CoV), S. aureus and B. subtilis as Gram-positive bacteria, E. coli and P. mirabilis as Gram-negative bacteria, A. niger and C. albicans fungi.

Increased antimicrobial resistance during the COVID-19 pandemic.

In addition to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection itself, an increase in the incidence of antimicrobial resistance poses collateral damage to the current status of the COVID-19 (coronavirus disease 2019) pandemic. There has been a rapid increase in multidrug-resistant organisms (MDROs), including extended-spectrum ß-lactamase (ESBL)-producing Klebsiella pneumoniae, carbapenem-resistant New Delhi metallo-ß-lactamase (NDM)-producing Enterobacterales, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA), pan-echinocandin-resistant Candida glabrata and multi-triazole-resistant Aspergillus fumigatus. The cause is multifactorial and is particularly related to high rates of antimicrobial agent utilisation in COVID-19 patients with a relatively low rate of co- or secondary infection. Appropriate prescription and optimised use of antimicrobials according to the principles of antimicrobial stewardship as well as quality diagnosis and aggressive infection control measures may help prevent the occurrence of MDROs during this pandemic.

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming.

Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule's tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a "taming" strategy), we found that by covalently attaching one or more facial amphiphiles ("floats") to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such "monomer control" and "taming" strategies to other membrane-disrupting antimicrobial agents is briefly discussed.

Did granny know best? Evaluating the antibacterial, antifungal and antiviral efficacy of acetic acid for home care procedures.

BACKGROUND: Acetic acid has been used to clean and disinfect surfaces in the household for many decades. The antimicrobial efficacy of cleaning procedures can be considered particularly important for young, old, pregnant, immunocompromised people, but may also concern other groups, particularly with regards to the COVID-19 pandemics. This study aimed to show that acetic acid exhibit an antibacterial and antifungal activity when used for cleaning purposes and is able to destroy certain viruses. Furthermore, a disinfecting effect of laundry in a simulated washing cycle has been investigated. RESULTS: At a concentration of 10% and in presence of 1.5% citric acid, acetic acid showed a reduction of > 5-log steps according to the specifications of DIN EN 1040 and DIN EN 1275 for the following microorganisms: P. aeruginosa, E. coli, S. aureus, L. monocytogenes, K. pneumoniae, E. hirae and A. brasiliensis. For MRSA a logarithmic reduction of 3.19 was obtained. Tests on surfaces according to DIN EN 13697 showed a complete reduction (> 5-log steps) for P. aeruginosa, E. coli, S. aureus, E. hirae, A. brasiliensis and C. albicans at an acetic acid concentration of already 5%. Virucidal efficacy tests according to DIN EN 14476 and DIN EN 16777 showed a reduction of ≥4-log-steps against the Modified Vaccinia virus Ankara (MVA) for acetic acid concentrations of 5% or higher. The results suggest that acetic acid does not have a disinfecting effect on microorganisms in a dosage that is commonly used for cleaning. However, this can be achieved by increasing the concentration of acetic acid used, especially when combined with citric acid. CONCLUSIONS: Our results show a disinfecting effect of acetic acid in a concentration of 10% and in presence of 1.5% citric acid against a variety of microorganisms. A virucidal effect against enveloped viruses could also be proven. Furthermore, the results showed a considerable antimicrobial effect of acetic acid when used in domestic laundry procedures.