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Abstract Introduction The mortality rate of hospitalized patients with severe hospital-acquired pneumonia (SHAP) remains high. Empirical broad-spectrum antibiotic coverage and the misuse of high-grade antibiotics could lead to the emergence of multi-drug and even pandrug-resistant bacteria. In addition to metagenomic next-generation sequencing (mNGS), microbiological rapid on-site evaluation (M-ROSE) might be a useful technique to identify the pathogens in the early stage; however, the effect of M-ROSE guiding anti-infection treatment on prognostic outcomes of SHAP patients is still unclear. Methods/design This is a multicenter, single-blind, prospective, randomized controlled trial to evaluate the effect of M-ROSE guiding anti-infection treatment in SHAP patients, which will provide new strategies for the prevention and control of clinical multi-drug resistance bacteria. A total of 166 patients with SHAP, aged 18 years and over, will be recruited from seven centers in Beijing and randomly assigned to the intervention group (M-ROSE combined with mNGS) or the control group (mNGS only) in a 1:1 ratio using the central randomization system. Patients in the intervention group will accept M-ROSE and mNGS analysis, and the control group will accept mNGS analysis. Individualized anti-infective treatment and routine treatment will be selected according to the analysis results. The primary outcome is the ICU outcome (mortality). The safety of the intervention measures will be evaluated during the entire trial period. This trial will be the first randomized controlled trial to evaluate the effect of M-ROSE guiding treatment on mortality in patients with SHAP and may change the prevalence of multi-drug resistant bacteria. Ethics and dissemination This trial adheres to the Declaration of Helsinki and guidelines of Good Clinical Practice. Signed informed consent will be obtained from all participants. The trial has been approved by the Chinese PLA General Hospital (Approval Number: 20220322001). Trial registration ClinicalTrials.gov NCT05300776. Registered on 25 March 2022.

Introduction: The mortality rate of hospitalized patients with severe hospital-acquired pneumonia (SHAP) remains high. Empirical broad-spectrum antibiotic coverage and the misuse of high-grade antibiotics could lead to the emergence of multi-drug and even pandrug-resistant bacteria. In addition to metagenomic next-generation sequencing (mNGS), microbiological rapid on-site evaluation (M-ROSE) might be a useful technique to identify the pathogens in the early stage; however, the effect of M-ROSE guiding anti-infection treatment on prognostic outcomes of SHAP patients is still unclear. Methods/design: This is a multicenter, single-blind, prospective, randomized controlled trial to evaluate the effect of M-ROSE guiding anti-infection treatment in SHAP patients, which will provide new strategies for the prevention and control of clinical multi-drug resistance bacteria. A total of 166 patients with SHAP, aged 18 years and over, will be recruited from seven centers in Beijing and randomly assigned to the intervention group (M-ROSE combined with mNGS) or the control group (mNGS only) in a 1:1 ratio using the central randomization system. Patients in the intervention group will accept M-ROSE and mNGS analysis, and the control group will accept mNGS analysis. Individualized anti-infective treatment and routine treatment will be selected according to the analysis results. The primary outcome is the ICU outcome (mortality). The safety of the intervention measures will be evaluated during the entire trial period. This trial will be the first randomized controlled trial to evaluate the effect of M-ROSE guiding treatment on mortality in patients with SHAP and may change the prevalence of multi-drug resistant bacteria. Ethics and dissemination: This trial adheres to the Declaration of Helsinki and guidelines of Good Clinical Practice. Signed informed consent will be obtained from all participants. The trial has been approved by the Chinese PLA General Hospital (Approval Number: 20220322001). Trial registration: ClinicalTrials.gov NCT05300776. Registered on 25 March 2022. [ABSTRACT FROM AUTHOR]

Biofilm formation is known to promote drug resistance in methicillin-resistant Staphylococcus aureus (MRSA), which is closely related to persistent infections in hospital settings. In this study, a DNA aptamer specific to penicillin-binding protein 2a (PBP2a) with a dissociation constant (Kd) of 82.97 ± 8.86 nM was obtained after 14 cycles of systematic evolution of ligands by exponential enrichment (SELEX). Next, a bifunctional complex containing the aptamer intercalated by berberine into the double-strand region was prepared and adsorbed onto the surface of graphene oxide (GO) by π-stacking interactions. The GO-loaded aptamer/berberine bifunctional complex showed significantly higher inhibition of MRSA biofilm formation than the control. Furthermore, this study shows that the complex possesses anti-biofilm activity, which can be attributed to the ability of the aptamer to reduce cell-surface attachment by blocking the function of PBP2a and berberine to attenuate the level of the accessory gene regulator (agr) system, which plays an important role in mediating MRSA biofilm formation. Therefore, the simultaneous delivery of berberine and PBP2a-targted aptamer using GO may have potential for the treatment of chronic infections caused by MRSA biofilms. It also provides a new avenue for multitarget treatment of bacterial biofilms.

ABSTRACT Fosfomycin (FOS) has been recently reintroduced into clinical practice, but its effectiveness against multidrug-resistant (MDR) Enterobacterales is reduced due to the emergence of FOS resistance. The copresence of carbapenemases and FOS resistance could drastically limit antibiotic treatment. The aims of this study were (i) to investigate fosfomycin susceptibility profiles among carbapenem-resistant Enterobacterales (CRE) in the Czech Republic, (ii) to characterize the genetic environment of fosA genes among the collection, and (iii) to evaluate the presence of amino acid mutations in proteins involved in FOS resistance mechanisms. During the period from December 2018 to February 2022, 293 CRE isolates were collected from different hospitals in the Czech Republic. FOS MICs were assessed by the agar dilution method (ADM), FosA and FosC2 production was detected by the sodium phosphonoformate (PPF) test, and the presence of fosA-like genes was confirmed by PCR. Whole-genome sequencing was conducted with an Illumina NovaSeq 6000 system on selected strains, and the effect of point mutations in the FOS pathway was predicted using PROVEAN. Of these strains, 29% showed low susceptibility to fosfomycin (MIC, ≥16 μg/mL) by ADM. An NDM-producing Escherichia coli sequence type 648 (ST648) strain harbored a fosA10 gene on an IncK plasmid, while a VIM-producing Citrobacter freundii ST673 strain harbored a new fosA7 variant, designated fosA7.9. Analysis of mutations in the FOS pathway revealed several deleterious mutations occurring in GlpT, UhpT, UhpC, CyaA, and GlpR. Results regarding single substitutions in amino acid sequences highlighted a relationship between ST and specific mutations and an enhanced predisposition for certain STs to develop resistance. This study highlights the occurrence of several FOS resistance mechanisms in different clones spreading in the Czech Republic. IMPORTANCE Antimicrobial resistance (AMR) currently represents a concern for human health, and the reintroduction of antibiotics such as fosfomycin into clinical practice can provide further option in treatment of multidrug-resistant (MDR) bacterial infections. However, there is a global increase of fosfomycin-resistant bacteria, reducing its effectiveness. Considering this increase, it is crucial to monitor the spread of fosfomycin resistance in MDR bacteria in clinical settings and to investigate the resistance mechanism at the molecular level. Our study reports a large variety of fosfomycin resistance mechanisms among carbapenemase-producing Enterobacterales (CRE) in the Czech Republic. Our study summarizes the main achievements of our research on the use of molecular technologies, such as next-generation sequencing (NGS), to describe the heterogeneous mechanisms that reduce fosfomycin effectiveness in CRE. The results suggest that a program for widespread monitoring of fosfomycin resistance and epidemiology fosfomycin-resistant organisms can aide timely implementation of countermeasures to maintain the effectiveness of fosfomycin.

Microorganisms are closely related to the occurrence and development of common oral diseases. Due to the unique physiological and anatomical characteristics of the oral cavity, locally introduced antibacterial drugs cannot be maintained in the effective concentration range under the effect of saliva erosion. Therefore, to enhance the retention and bioavailability of antibacterial drugs in biofilms, some scholars designed pH sensitive drug delivery systems with the fact that the pH value of oral biofilm is lower than the physiological pH value. This article reviews the research reports of a pH-sensitive drug delivery system in the oral cavity and elaborates its application in oral diseases such as dental caries, endodontic disease, periapical disease, peri-implant diseases, and oral candidiasis. Literature review Results show that the pH-sensitive drug delivery system loaded with antibacterial drugs could be used for the control of oral microorganisms with excellent pH sensitivity and antibacterial properties, especially in the application of acid-producing bacteria such as Streptococcus mutans for the prevention and treatment of dental caries. However, the research of pH-sensitive drug delivery systems in the oral cavity is still limited to basic research,and in clinical applications, it still faces many challenges, such as a complex design and synthesis, difficulties with lasting effects and eliminating drug-resistance and persistent bacteria. Further optimization of pH sensitive systems, as well as animal experiments and in vivo studies will be the focus of future research.

Objective: This study was to investigate the characteristics and related factors of postoperative drug-resistant bacteria infection (DRBI) in patients with acute Stanford A aortic dissection (AD) (AAAD) based on a two-fluid numerical simulation model (TFNS model). Methods: 50 patients with AAAD admitted to our hospital from July 2018 to October 2020 were selected as the research objects. The patients were rolled into an infection group and a non-infection group according to whether DRBI occurred after surgery. There were 21 patients in the infected group and 29 patients in the non-infected group. The clinical data of the patients were collected, including preoperative, intraoperative, and postoperative conditions. A TFNS model was constructed. The construction of vascular physical model could be completed by the construction of fluid area and solid area. The blood flows through the fluid area and the blood vessel wall was located in the solid area. The model was adopted to study the characteristics of DRBI. The data of the patients were analyzed to explore the relationship of the multi-DRBI to intraoperative blood loss, postoperative complications, intensive care unit (ICU) stay time, invasive procedures, and use of antibiotics. In addition, the multi-factor postoperative multi-DRBI was performed with the regression analysis. Results: There was no significant difference between the infected group and the non-infected group in antibiotics used such as cephalosporin, penicillin, glycopeptide, and quinolones (P > 0.05). The time spent on antibiotics was greatly lower in the infected group than in the non-infected group (P

Millions of patients annually suffer life-threatening illnesses caused by bacterial infections of skin wounds. However, the treatment of wounds infected with bacteria is a thorny issue in clinical medicine, especially with drug-resistant bacteria infections. Therefore, there is an increasing interest in developing wound dressings that can efficiently fight against drug-resistant bacterial infections and promote wound healing. In this work, an anti-drug-resistant bacterial chitosan/cellulose nanofiber/tannic acid (CS/CNF/TA) hydrogel with excellent wound management ability was developed by electrospinning and fiber breakage-recombination. The hydrogel exhibited an outstanding antibacterial property exceeding 99.9 %, even for drug-resistant bacteria. This hydrogel could adhere to the tissue surface due to its abundant catechol groups, which avoided the shedding of hydrogel during the movement. Besides, it exhibited extraordinary hemostatic ability during the bleeding phase of the wound and then regulated the wound microenvironment by absorbing water and moisturizing. Moreover, the CS/CNF/TA also promoted the regrowth of vessels and follicles, accelerating the healing of infected wound tissue, with a healing rate exceeding 95 % within a 14-day timeframe. Therefore, the CS/CNF/TA hydrogel opens a new approach for the healing of drug-resistant bacterial infected wounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Many pathogenic species of bacteria are showing increasing drug resistance against clinically used antibiotics. Molecules structurally distant from known antibiotics and possessing membrane targeting bactericidal activities are more likely to display activity against drug-resistant pathogens. Mitocurcumin (MitoC) is one of such compounds, synthesized by triphenyl-phosphonium conjugation with curcumin, and has been shown recently from our laboratory to have broad-spectrum bactericidal activity (Kumari et al.2019Free Radic. Biol. Med.143 140–145). Here, we further demonstrate the antibacterial properties of MitoC against resistant strains and also its mechanism of action. It displays efficient bactericidal activity against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae (MIC values in the 1.5–12.5 µM range), and coagulase-negative Staphylococci do not show resistance development against MitoC. Liposome based studies and MIC values against TolC deletion mutant (ΔtolC; outer membrane protein) of E. coli suggest extensive membrane damage to be the primary mechanism of bactericidal activity. MitoC did not exhibit toxicity in BALB/c mice with an oral administration of 250 mg/kg body weight and was found to be totally safe without any significant effect on haematological, biochemical parameters and inflammatory responses. Its rapid bactericidal action as assessed by in vitro time-kill assay against B. subtilis, compared to ciprofloxacin, and long half-life in rodent serum, suggest that MitoC could be an excellent lead-molecule against drug-resistant pathogens. The highlights of the study are that mitocurcumin belongs to a structurally new class of bactericidal compounds. It displays activity against MDR strains of pathogenic bacteria and challenging MRSA. Liposome-based studies confirm the membrane damaging property of the molecule. Mitocurcumin does not show resistance development even after 27 bacterial generations. [ABSTRACT FROM AUTHOR]

Silver nanocomposites embedded within a polymer matrix have attracted attention in recent years. Ionic polymer hydrogels comprise networks of chemically or physically cross-linked polymers that swell considerably in an appropriate solvent. In this study, we used a solution of the carboxylic monomer acrylic acid and silver nitrate to prepare nanocomposite hydrogels through ultraviolet (UV)-light irradiation. Silver-impregnated biomaterial composed of acrylic acid contains only a monomer and no cross-linker. The formation of hydrogels and reduction of silver nanoparticles were affected by the preparation parameters, that is, the monomer concentration and silver nitrate concentration. The morphology, structure, and size of the silver nanocomposite hydrogels were evaluated through field emission scanning electron microscopy and UV–visible absorption. The antimicrobial activity of the samples was tested against fourstandard strains Candida albicans , Staphylococcus aureus , Pseudomonas aeruginosa , and Escherichia coli ; and five clinical bacterial isolates Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa , Acinetobacter baumannii , Klebsiella pneumonia . The silver nanocomposite hydrogels exhibited an interconnected porous structure and could absorb 400 to 550 g of deionized water per gram of dried hydrogel. Moreover, these hydrogels produced a strong antibacterial effect, which can be useful in developing new superabsorbent antimicrobial pharmaceutical products. [ABSTRACT FROM AUTHOR]

Bacterial infections have seriously threatened human health and the abuse of natural or artificial antibiotics leads to bacterial resistance, so development of a new generation of antibacterial agents and treatment methods is urgent. 2D molybdenum sulfide (MoS 2 ) has good biocompatibility, high specific surface area to facilitate surface modification and drug loading, adjustable energy bandgap, and high near-infrared photothermal conversion efficiency (PCE), so it is often used for antibacterial application through its photothermal or photodynamic effects. This review comprehensively summarizes and discusses the fabrication processes, structural characteristics, antibacterial performance, and the corresponding mechanisms of MoS 2 -based materials as well as their representative antibacterial applications. In addition, the outlooks on the remaining challenges that should be addressed in the field of MoS 2 are also proposed., (© 2022 Wiley-VCH GmbH.)

Developing effective therapies to fight against biofilm-associated infection is extremely urgent. The complex environment of biofilm forces the bacteria to evade the elimination of antibiotics, resulting in recalcitrant chronic infections. To address this issue, a cationic antibacterial agent based on phosphindole oxide (β-PM-PIO) is designed and prepared. The unique molecular structure endows β-PM-PIO with aggregation-induced emission feature and efficient singlet oxygen generation ability. β-PM-PIO shows excellent visual diagnostic function to planktonic bacteria and biofilm. In addition, owing to the synergistic effect of phototoxicity and dark toxicity, β-PM-PIO can achieve superb antibacterial and antibiofilm performance against Gram-positive bacteria with less potential of developing drug resistance. Notably, β-PM-PIO also holds excellent anti-infection capacity against drug-resistant bacteria in vivo with negligible side effects. This work offers a promising platform to develop advanced antibacterial agents against multidrug-resistant bacterial infection., (© 2022 Wiley-VCH GmbH.)

This study was to investigate the characteristics and related factors of postoperative drug-resistant bacteria infection (DRBI) in patients with acute Stanford A aortic dissection (AD) (AAAD) based on a two-fluid numerical simulation model (TFNS model). 50 patients with AAAD admitted to our hospital from July 2018 to October 2020 were selected as the research objects. The patients were rolled into an infection group and a non-infection group according to whether DRBI occurred after surgery. There were 21 patients in the infected group and 29 patients in the non-infected group. The clinical data of the patients were collected, including preoperative, intraoperative, and postoperative conditions. A TFNS model was constructed. The construction of vascular physical model could be completed by the construction of fluid area and solid area. The blood flows through the fluid area and the blood vessel wall was located in the solid area. The model was adopted to study the characteristics of DRBI. The data of the patients were analyzed to explore the relationship of the multi-DRBI to intraoperative blood loss, postoperative complications, intensive care unit (ICU) stay time, invasive procedures, and use of antibiotics. In addition, the multi-factor postoperative multi-DRBI was performed with the regression analysis. There was no significant difference between the infected group and the non-infected group in antibiotics used such as cephalosporin, penicillin, glycopeptide, and quinolones (P > 0.05). The time spent on antibiotics was greatly lower in the infected group than in the non-infected group (P < 0.05). The ICU stay time in the infected group was 17.78 ± 11.55, and that in the non-infected group was 6.67 ± 4.36, without notable difference between the two groups (P < 0.05). In addition, there was no significant difference between the two groups in the time to transfer to the ICU, while there was one case infected with Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter cloacae. The excessive plasma loss (odds ratio (OR) = 3.823, 95% confidential interval (CI) = 1.643–8.897), renal insufficiency (OR = 1.855, 95% CI = 1.076–3.199), ICU stay time (OR = 5.089, 95% CI = 1.507–17.187), indwelling time of nasal feeding tube (NFT) (OR = 3.225, 95% CI = 1.332–7.807), assisted ventilation (OR = 3.077, 95% CI = 1.640–5.773), tracheal intubation (OR = 5.078, 95% CI = 1.415–18.227), tracheotomy (OR = 0.073, 95% CI = 0.013–0.382), continuous renal replacement (CRR) therapy (OR = 0.111, 95% CI = 0.023–0.476), use time of antibiotics (OR = 1.089, 95% CI = 1.038–1.143) were independent risk factors for postoperative multi-DRBI. postoperative multi-DRBI was characterized by Acinetobacter baumannii infection with the largest proportion, followed by Klebsiella pneumoniae; excessive plasma loss, renal insufficiency, ICU stay time, indwelling time of NFT, assisted ventilation, tracheal intubation, tracheotomy, CRR therapy, and use time of antibiotics were all independent risk factors of postoperative multi-DRBI. In the postoperative care of AAAD patients, the inducing factors had to be informed to the patient, and relative measures should be taken to prevention and treatment, which was conductive to reducing the incidence of infection and promote the recovery of AAAD. [ABSTRACT FROM AUTHOR]