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Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

UNLABELLED: Infections caused by Staphylococcus aureus are a leading cause of mortality worldwide. S. aureus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are particularly difficult to treat due to their resistance to next-generation β-lactams (NGBs) such as methicillin, nafcillin, and oxacillin. Resistance to NGBs, which is alternatively known as broad-spectrum β-lactam resistance, is classically mediated by PBP2a, a penicillin-binding protein encoded by mecA (or mecC) in MRSA. Thus, presence of mec genes among S. aureus spp. serves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated, mecA-deficient S. aureus strains can also exhibit NGB resistance. These strains, which are collectively termed as methicillin-resistant lacking mec (MRLM), are currently being identified in increasing numbers among natural resistant isolates of S. aureus. The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs, can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance toward NGBs at levels comparable to those of MRSAs. Our study provides a fresh new perspective about alternative mechanisms of NGB resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance in S. aureus. It thus suggests reconsideration of the current approach toward diagnosis and treatment of β-lactam-resistant S. aureus infections. IMPORTANCE: In Staphylococcus aureus, high-level, broad-spectrum resistance to β-lactams such as methicillin, also referred to as methicillin resistance, is largely attributed to mecA. This study demonstrates that S. aureus strains that lack mecA but contain mutations that functionally alter PBP4 and GdpP can also mediate high-level, broad-spectrum resistance to β-lactams. Resistance brought about by the synergistic action of functionally altered PBP4 and GdpP was phenotypically comparable to that displayed by mecA, as seen by increased bacterial survival in the presence of β-lactams. An analysis of mutations detected in naturally isolated strains of S. aureus revealed that a significant proportion of them had similar pbp4 and GGDEF domain protein containing phosphodiesterase (gdpP) mutations, making this study clinically significant. This study not only identifies important players of non-classical mechanisms of β-lactam resistance but also indicates reconsideration of current clinical diagnosis and treatment protocols of S. aureus infections.

The development of new antibiotics has stalled, and novel strategies are needed as we enter the age of antibiotic resistance. Certain naturally occurring clays have been shown to be effective in killing antibiotic resistant bacteria. However, these natural clays are too variable to be used in clinical settings. Our study shows that synthetic antibacterial minerals exhibit potent antibacterial activity against topical MRSA infections and increase the rate of wound closure relative to controls. The antibacterial minerals maintain a redox cycle between Fe2+/Fe3+ and the surfaces of pyrite minerals, which act as a semiconductor and produce reactive oxygen species (ROS), while smectite minerals act as a cation exchange reservoir. Acidic conditions are maintained throughout the application of the hydrated minerals and can mitigate the alkaline pH conditions observed in chronic non-healing wounds. These results provide evidence for the strategy of iron overload to combat antibiotic resistant infections through the maintained release of Fe2+ and generation of ROS via distinct geochemical reactions that can break the chronic wound damage cycle.

The failure of the Staphylococcus aureus (SA) IsdB vaccine trial can be explained by the recall of non-protective immune imprints from prior SA exposure. Here, we investigate natural human SA humoral imprints to understand their broader impact on SA immunizations. We show that antibody responses against SA cell-wall-associated antigens (CWAs) are non-opsonic, while antibodies against SA toxins are neutralizing. Importantly, the protective characteristics of the antibody imprints accurately predict the failure of corresponding vaccines against CWAs and support vaccination against toxins. In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics.

BACKGROUND: Community-acquired Staphylococcus aureus (CA-Sa) skin and soft tissue infections (SSTIs) are historically associated with densely populated urban areas experiencing high poverty rates, intravenous drug use, and homelessness. However, the epidemiology of CA-Sa SSTIs in the United States has been poorly understood since the plateau of the Community-acquired Methicillin-resistant Staphylococcus aureus epidemic in 2010. This study examines the spatial variation of CA-Sa SSTIs in a large, geographically heterogeneous population and identifies neighborhood characteristics associated with increased infection risk. METHODS: Using a unique neighborhood boundary, California Medical Service Study Areas, a hotspot analysis, and estimates of neighborhood infection risk ratios were conducted for all CA-Sa SSTIs presented in non-Federal California emergency departments between 2016 and 2019. A Bayesian Poisson regression model evaluated the association between neighborhood-level infection risk and population structure, neighborhood poverty rates, and being a healthcare shortage area. RESULTS: Emergency departments in more rural and mountainous parts of California experienced a higher burden of CA-Sa SSTIs between 2016 and 2019. Neighborhoods with high infection rates were more likely to have a high percentage of adults living below the federal poverty level and be a designated healthcare shortage area. Measures of population structure were not associated with infection risk in California neighborhoods. CONCLUSIONS: Our results highlight a potential change in the epidemiology of CA-Sa SSTIs in California emergency departments. Future studies should investigate the CA-Sa burden in other geographies to identify whether this shift in epidemiology holds across other states and populations. Further, a more thorough evaluation of potential mechanisms for the clustering of infections seen across California neighborhoods is needed.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen associated with a wide range of infections in humans and animals. Thus, the emergence of MRSA clones poses an important threat to human and animal health. This study is aimed at elucidating the genomics insights of a strong biofilm-producing and multidrug-resistant (MDR) S. aureus MTR_BAU_H1 strain through whole-genome sequencing (WGS). The S. aureus MTR_BAU_H1 strain was isolated from food handlers hand swabs in Bangladesh and phenotypically assessed for antimicrobial susceptibility and biofilm production assays. The isolate was further undergone to high throughput WGS and analysed using different bioinformatics tools to elucidate the genetic diversity, molecular epidemiology, sequence type (ST), antimicrobial resistance, and virulence gene distribution. Phenotypic analyses revealed that the S. aureus MTR_BAU_H1 strain is a strong biofilm-former and carries both antimicrobial resistance (e.g., methicillin resistance; mecA, beta-lactam resistance; blaZ and tetracycline resistance; tetC) and virulence (e.g., sea, tsst, and PVL) genes. The genome of the S. aureus MTR_BAU_H1 belonged to ST1930 that possessed three plasmid replicons (e.g., rep16, rep7c, and rep19), seven prophages, and two clustered regularly interspaced short palindromic repeat (CRISPR) arrays of varying sizes. Phylogenetic analysis showed a close evolutionary relationship between the MTR_BAU_H1 genome and other MRSA clones of diverse hosts and demographics. The MTR_BAU_H1 genome harbours 42 antimicrobial resistance genes (ARGs), 128 virulence genes, and 273 SEED subsystems coding for the metabolism of amino acids, carbohydrates, proteins, cofactors, vitamins, minerals, and lipids. This is the first-ever WGS-based study of a strong biofilm-producing and MDR S. aureus strain isolated from human hand swabs in Bangladesh that unveils new information on the resistomes (ARGs and correlated mechanisms) and virulence potentials that might be linked to staphylococcal pathogenesis in both humans and animals.

INTRODUCTION: Staphylococcus aureus bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant S. aureus (MRSA). In contrast to resolving MRSA bacteremia (RB), persistent MRSA bacteremia (PB) blood cultures remain positive despite appropriate antibiotic treatment. Host immune responses distinguishing PB vs. RB outcomes are poorly understood. Here, integrated transcriptomic, IL-10 cytokine levels, and genomic analyses sought to identify signatures differentiating PB vs. RB outcomes. METHODS: Whole-blood transcriptomes of propensity-matched PB (n=28) versus RB (n=30) patients treated with vancomycin were compared in one independent training patient cohort. Gene expression (GE) modules were analyzed and prioritized relative to host IL-10 cytokine levels and DNA methyltransferase-3A (DNMT3A) genotype. RESULTS: Differential expression of T and B lymphocyte gene expression early in MRSA bacteremia discriminated RB from PB outcomes. Significant increases in effector T and B cell signaling pathways correlated with RB, lower IL-10 cytokine levels and DNMT3A heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures. DISCUSSION: Collectively, the present findings indicate that human PB involves dysregulated immunity characterized by impaired T and B cell responses associated with excessive IL-10 expression in context of the DNMT3A A/A genotype. These findings reveal distinct immunologic programs in PB vs. RB outcomes, enable future studies to define mechanisms by which host and/or pathogen drive differential signatures and may accelerate prediction of PB outcomes. Such prognostic assessment of host risk could significantly enhance early anti-infective interventions to avert PB and improve patient outcomes.

The purpose of the present study was to create resorbable nanoparticles (NPs) using poly(lactic-co-glycolic acid) (PLGA) to develop novel antibacterial therapeutics for the treatment of chronic wound infections that are susceptible to recurrent infections. By first performing a release study, it was possible to predict the behavior of the different PLGA NP formulations and assess the efficacy of the nanocomposite drug delivery system. These PLGA NP formulations consisted of varying ratios of PLGA without polyvinyl alcohol (PVA) and PLGA with PVA (PLGA-PVA) (i.e. 25:75[PLGA25], 50:50[PLGA50], and 75:25[PLGA75]). Then, different antibiotics (i.e. ciprofloxacin and gentamicin) were incorporated into the PLGA NP formulations to test the antibacterial efficacy of these antimicrobial NPs against different pathogens (i.e. methicillin-resistant Staphylococcus aureus USA300 [MRSA], Pseudomonas aeruginosa FRD1, and Acinetobacter baumannii BAA1605). Of particular interest was testing against the MRSA strain USA300 and the P. aeruginosa strain FRD1. This was possible by measuring the zone of inhibition. A 3-day period was used to monitor the antibacterial efficacy of the different PLGA NP formulations (i.e. PLGA25, PLGA50, and a 1:1 combination of PLGA25:PLGA50) against A. baumannii BAA1605 , MRSA, and P aeruginosa FRD1. Throughout the study, A. baumannii was a negative control and was resistant to all the PLGA NP formulations loaded with ciprofloxacin and gentamicin. At the end of the 3-day period, the PLGA and PLGA50 ciprofloxacin-loaded formulations produced zones of inhibition of 27 mm and 23 mm, respectively, against P. aeruginosa FRD1. This indicated that P. aeruginosa FRD1 was susceptible to both formulations. The mixed formulations with equal parts PLGA25:PLGA50 loaded with ciprofloxacin produced a zone of inhibition (i.e. 25 mm). This again indicated that P. aeruginosa FRD1 was susceptible to ciprofloxacin. The formulations tested against MRSA showed that only gentamicin-loaded formulations produced intermediate results, and that ciprofloxacin-loaded formulations were ineffective. The PLGA25 and the PLGA50 NP formulations loaded with gentamicin both produced zones of inhibition of 13 mm. This indicated that MRSA was intermediate to both the formulations. The PLGA25:PLGA50 loaded with gentamicin produced a zone of inhibition of 14 mm, which again showed that MRSA was intermediate to this formulation. Overall, these PLGA NP formulations showed the sustained antibacterial potential of a burst release, followed by a sustained release of antibiotics from antibiotics loaded PLGA NPs in a controlled manner. In the future, this can help prevent the emergence of recurrent infections in the treatment of chronic wounds and reduce the number of medical dressing changes. [ABSTRACT FROM AUTHOR]

The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and synthesis of quaternization or dimerization norharmane analogues are described. • Their anti-MRSA activities are evaluated, and SARs are summarized. • Compound 5a exhibits potent bactericidal activity in vitro and in vivo with low toxicity. • Compound 5a could disrupt bacterial biofilm and damage the membrane. • Metabolomics analysis is used to systematically investigate the mechanisms. Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo , low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics. [ABSTRACT FROM AUTHOR]

There is scarcity in the data about MRSA prevalence and risk factors among the pediatric population. This research explores the global prevalence and risk factors of MRSA among the pediatric population. PubMed, Scopus, Web of Sciences, and the Cochrane Central Register of Controlled Trials were systematically searched. Our primary goal was to assess the prevalence of MRSA colonization and its related risk factors in the general pediatric population. A total of 124 studies encompassing 44 million participants were included in this meta-analysis, and the overall pooled estimated global prevalence of MRSA colonization in pediatric was 5% [95% CI 4–5%]. Female sex (OR = 4.17; 95% CI, 3.31–5.27), recent surgery (OR = 3.79; 95% CI, 2.20–6.52), recent hospitalization (OR = 2.63; 95% CI, 1.78–3.86), and antibiotic use (OR = 2.42; 95% CI, 1.58–3.72) were significantly associated with higher odds of MRSA colonization. Conclusion: Future research should build on these findings by emphasizing ongoing efforts to combat MRSA in pediatric settings and implementing targeted interventions. What Is Known: • Methicillin-resistant Staphylococcus aureus (MRSA) is considered a threat to public health. It is noteworthy to mention that the prevalence of MRSA strains has not been adequately quantified in many countries, especially in the pediatric population. The pediatric population is a pivotal source of MRSA and may play a central role in its distribution in both community and healthcare settings. A notable study underscores the gravity of the situation, estimating a tenfold increase in the incidence of MRSA infection among children in the USA between 1999 and 2008. What Is New: • Here we present the first global systematic review and meta-analysis to investigate the prevalence and risk factors of MRSA among the pediatric population. A total of 124 studies encompassing 44 million participants were included in this analysis. The overall pooled estimated global prevalence of MRSA colonization in the pediatric population was 5% [95% CI 4–5%]. The prevalence was the highest in Asia and lowest in Europe. Female sex, recent surgery, recent hospitalization, and antibiotic use were significantly associated with higher odds of MRSA colonization. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy of topical vancomycin and povidone iodine (PI) application on methicillin-resistant Staphylococcus aureus (MRSA) keratitis model in rabbits. MRSA keratitis was induced by injecting 0.1 mL MRSA containing 1000 colony-forming units (CFU) into central cornea of right eyes of 24 New Zealand White rabbits. Animals were divided into four groups (n = 6): control (treated with balanced salt solution), 50 mg/mL topical vancomycin, 5% topical PI, and combination; examined before and after treatment, and corneal tissues were harvested for analysis at 9th hour of treatment. Bacterial load was determined as: 7.63 ± 0.82 log10 CFU/g in control group, 6.95 ± 1.66 log10 CFU/g in PI group, 4.67 ± 0.77 log10 CFU/g in combination group, and 4.33 ± 0.71 log10 CFU/g in vancomycin group (p = 0.001). Median of total clinical score increased significantly from 7 [range: 5–8] to 11.5 [range: 11–15] (p = 0.001) in control group, did not change (6 [range: 5–8] to 7 [range: 5–7]; p = 0.695) in vancomycin group, increased significantly from 7 [range: 5–8] to 12.5 [range: 10–14] (p < 0.001) in PI group, increased significantly from 6.5 [range: 5–7] to 8 [range: 7–9] in combination group (p = 0.002). Post-treatment clinical scores for chemosis, conjunctival injection, iritis, hypopyon, epithelial erosion, and corneal infiltrate were significantly lower in vancomycin-treated groups compared to others (p < 0.05). In PI-treated groups, especially scores for chemosis, conjunctival injection, epithelial erosion and corneal infiltrate were significantly higher than vancomycin (p < 0.05). Topical vancomycin significantly inhibited bacterial growth in MRSA keratitis. However, PI was ineffective in controlling this growth; additionally, exerted toxic effect on ocular surface. When vancomycin was combined with PI, no additional increase in efficacy of treatment was detected compared to only vancomycin. [ABSTRACT FROM AUTHOR]

The use of antibiotic-loaded bone cement (ALBC) as a mean for preventing deep surgical site infections (SSI) after total joint replacement is controversial. Therefore, we have conducted a meta-analysis to evaluate the prophylactic effect of ALBC for SSI prevention in patients undergoing arthroplasty. This study was conducted to revise treatment guidelines for MRSA infections in Japan. PubMed (Medline), Scopus, Embase, Web of Science and Cochrane library were searched for relevant articles comparing preventive effect of ALBC for patients undergoing primary total joint arthroplasty by August 2022. Primary outcome was the incidence of deep SSI. Subgroup analyses by type of surgery (total hip (THA) or knee (TKA) arthroplasty) and by causative pathogen (methicillin-resistant Staphylococcus aureus (MRSA)) were performed. Of the 3379 studies identified for screening, six studies involving 5745 patients were included. The use of ALBC significantly reduced the incidence of deep SSI in overall patients (risk ratio [RR] 0.60, 95% confidential interval [CI] 0.39–0.92), but the evidence level was very low. There was no significant preventive effect for ALBC compared with non-ALBC in both THA and TKA (THA, RR 0.52, 95% CI 0.23–1.16; TKA, RR 0.64, 95% CI 0.38–1.06), and for preventing MRSA-SSI (RR 0.27, 95% CI 0.03–2.41). Although the overall preventive effect of ALBC was significant, the evidence level was very low. Thus, the routine use of ALBC as a mean to prevent SSI in arthroplasty may not be suggested. [ABSTRACT FROM AUTHOR]

Phylogenetic analysis based on single-nucleotide polymorphism (SNP)-based through whole-genome sequencing is recognized as the standard method for probing nosocomial transmission. However, the application of WGS is constrained by the high cost of equipment and the need for diverse analysis tools, which limits its widespread use in clinical laboratory settings. In Japan, the prevalent use of PCR-based open reading frame typing (POT) for tracing methicillin-resistant Staphylococcus aureus (MRSA) transmission routes is attributed to its simplicity and ease of use. Although POT's discriminatory power is considered insufficient for nosocomial transmission analysis, conclusive data supporting this notion is lacking. This study assessed the discriminatory capabilities of SNP analysis and POT across 64 clinical MRSA strains. All 21 MRSA strains of ST5/SCC mec IIa, having more than 16 SNPs, demonstrated distinct clones. Conversely, two strains shared the same POT number and were identified as group A. Among the 12 MRSA strains of ST8/SCC mec IVl with over nine SNPs, five fell into POT group B, and five into POT group C. All four MRSA strains of ST8/SCC mec IVa were classified into POT group D, although they included strains with more than 30 SNPs. Among the 27 MRSA strains of ST1/SCC mec IVa, 14 were classified into POT group E. However, except for two clusters (each comprising two or three strains), all had SNP counts >10 (Fig. 1-D). SNP analysis of MRSA in CC1/SCCmec IV showed that several strains had the same number of SNPs in POT number (106-183-37), even among bacteria with >100 SNPs, indicating POT's limited use in detailed nosocomial transmission analysis. [ABSTRACT FROM AUTHOR]

MRSA (methicillin-resistant Staphylococcus aureus)-infective endocarditis (IE) is associated with high morbidity and mortality. This study aimed to assess data from patients with MRSA-IE across multiple facilities in Japan, with a specific focus on antimicrobial therapy and prognosis. This retrospective study enrolled patients with a confirmed diagnosis of IE attributed to MRSA, spanning the period from January 2015 to April 2019. Sixty-four patients from 19 centers were included, with a median age of 67 years. The overall mortality rate was 28.1% at 30 days, with an in-hospital mortality of 45.3%. The most frequently chosen initial anti-MRSA agents were glycopeptide in 67.2% of cases. Daptomycin and linezolid were selected as initial therapy in 23.4% and 17.2% of cases, respectively. Approximately 40% of all patients underwent medication changes due to difficulty in controlling infection or drug-related side effects. Significant prognostic factors by multivariable analysis were DIC for 30-day mortality and surgical treatment for 30-day and in-hospital mortality. For vancomycin as initial monotherapy, there was a trend toward a worse prognosis for 30-day and in-hospital mortality (OR, 6.29; 95%CI, 1.00–39.65; p = 0.050, OR, 3.61; 95%CI, 0.93–14.00; p = 0.064). Regarding the choice of initial antibiotic therapy, statistical analysis did not show significant differences in prognosis. Glycopeptide and daptomycin were the preferred antibiotics for the initial therapy of MRSA-IE. Antimicrobial regimens were changed for various reasons. Prognosis was not significantly affected by choice of antibiotic therapy (glycopeptide, daptomycin, linezolid), but further studies are needed to determine which antimicrobials are optimal as first-line agents. [ABSTRACT FROM AUTHOR]

Using existing adrentimicrobials with essential oil components to prevent antimicrobial resistance is an alternative strategy. This study aimed to evaluate the resistance status, synergistic combinations, and in vitro biofilm formation activities of clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), Stenotrophomonas maltophilia and Candida albicans against antimicrobial agents and cinnamaldehyde, carvacrol, eugenol, limonene and eucalyptol. Antimicrobial activities were evaluated by microdilution, cytotoxicity by XTT, synergy by checkerboard and time-kill, and biofilm inhibition by microplate methods. Cinnamaldehyde and carvacrol showed strong antimicrobial activity. Synergistic effects were observed when using all essential oils with antimicrobials. Only two C. albicans isolates showed antagonism with cinnamaldehyde and fluconazole. The constituents showed cytotoxic effects in the L929 cell line (except limonene). A time-kill analysis revealed a bacteriostatic effect on S. maltophilia and MRSA isolates and a fungicidal effect on C. albicans isolates. These results are important for further research to improve antimicrobial efficacy or to develop new agents. [ABSTRACT FROM AUTHOR]

Influenza infections result in a significant number of severe illnesses annually, many of which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the host immune response, leading to significant immunopathology. Type III interferons (IFNs), or IFNλs, have gained traction as potential antiviral therapeutics due to their restriction of viral replication without damaging inflammation. The role of IFNλ in regulating epithelial biology in super-infection has recently been established; however, the impact of IFNλ on immune cells is less defined. In this study, we infected wild-type and IFNLR1-/- mice with influenza A/PR/8/34 followed by S. aureus USA300. We demonstrated that global IFNLR1-/- mice have enhanced bacterial clearance through increased uptake by phagocytes, which was shown to be cell-intrinsic specifically in myeloid cells in mixed bone marrow chimeras. We also showed that depletion of IFNLR1 on CX3CR1 expressing myeloid immune cells, but not neutrophils, was sufficient to significantly reduce bacterial burden compared to mice with intact IFNLR1. These findings provide insight into how IFNλ in an influenza-infected lung impedes bacterial clearance during super-infection and show a direct cell intrinsic role for IFNλ signaling on myeloid cells. Author summary: Influenza virus infects millions of people each year and is characterized by a mostly self-resolving mild to moderate illness. However, severe disease is observed in a subset of patients and is often characterized by bacterial super-infection, which occurs following influenza virus infection. In this setting, there can be a lethal synergy between the virus and bacteria that results in severe lung injury. In recent years, the field has determined that type III interferon (IFNλ), induced by influenza virus as part of the anti-viral response, may play a detrimental role during super-infection. This has been attributed to IFNλ impacting structural cells of the airways. In this study, we define a novel role for IFNλ impacting bacterial clearance during super-infection via directly altering lung phagocytes responsible for bacterial host-defense. We use three distinct mouse models to define this new role of IFNλ in regulating phagocyte function in the lung. This study is important because it defines a new mechanism by which anti-viral IFNλ leads to increased susceptibility to bacterial super-infection. This has implications for potential use of IFNλ as an anti-viral therapeutic and identifies a new biologic function of IFNλ in the lung. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) colonizes humans asymptomatically but can also cause opportunistic infections, ranging from mild skin infections to severe life-threatening conditions. Resistance and tolerance are two ways a host can survive an infection. Resistance is limiting the pathogen burden, while tolerance is limiting the health impact of a given pathogen burden. In previous work, we established that collaborative cross (CC) mouse line CC061 is highly susceptible to Methicillin-resistant S. aureus infection (MRSA, USA300), while CC024 is tolerant. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice to generate F1 and F2 populations. Survival after MRSA infection in the F1 and F2 generations was 65% and 55% and followed a complex dominant inheritance pattern for the CC024 increased survival phenotype. Colonization in F2 animals was more extreme than in their parents, suggesting successful segregation of genetic factors. We identified a Quantitative Trait Locus (QTL) peak on chromosome 7 for survival and weight change after infection. In this QTL, the WSB/EiJ (WSB) allele was present in CC024 mice and contributed to their MRSA tolerant phenotype. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. C5ar1 and C5ar2 are receptors for the complement factor C5a, an anaphylatoxin that can trigger a massive immune response by binding to these receptors. We hypothesize that C5a may have altered binding to variant receptors in CC024 mice, reducing damage caused by the cytokine storm and resulting in the ability to tolerate a higher pathogen burden and longer survival. Author summary: Staphylococcus aureus causes a wide range of life-threatening diseases in humans. Resistance and tolerance are two ways a host can survive an infection. Resistance is limiting the pathogen burden, while tolerance is limiting the health impact of a given pathogen burden. Tolerance mechanisms are poorly understood in context of host-pathogen interaction. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice. The genetic factors controlling tolerance were well segregated in the F2 population. Using QTL mapping, we identified a significant peak on chromosome 7 for survival and weight change after infection. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. We hypothesize that C5a may have altered binding to variant receptors in CC024 mice, reducing damage caused by the cytokine storm and resulting in the ability to tolerate a higher pathogen burden and longer survival. [ABSTRACT FROM AUTHOR]

In response to the pressing global challenge of antibiotic resistance, time efficient design and synthesis of novel antibiotics are of immense need. Polycyclic polyprenylated acylphloroglucinols (PPAP) were previously reported to effectively combat a range of gram‐positive bacteria. Although the exact mode of action is still not clear, we conceptualized a late‐stage divergent synthesis approach to expand our natural product‐based PPAP library by 30 additional entities to perform SAR studies against methicillin‐resistant Staphylococcus aureus (MRSA). Although at this point only data from cellular assays are available and understanding of molecular drug‐target interactions are lacking, the experimental data were used to generate 3D‐QSAR models via an artificial intelligence training and to identify a common pharmacophore model. The experimentally validated QSAR model enabled the estimation of anti‐MRSA activities of a virtual compound library consisting of more than 100,000 in‐silico generated B PPAPs, out of which the 20 most promising candidates were synthesized. These novel PPAPs revealed significantly improved cellular activities against MRSA with growth inhibition down to concentrations less than 1 μm. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus (S. aureus) often colonizes the human skin, upper respiratory and genital tracts. In the female genital tract, it can be passed on to the newborn during vaginal delivery leading to either ordinary colonization, or neonatal infections notably umbilical stump sepsis, scalded skin syndrome, arthritis, or bacteraemia/sepsis. These infections are mediated by staphylococcal virulence factors such as (i) Staphylococcal Enterotoxins A, B, C, D, and E encoded by the sea, seb, sec, sed, see genes, (ii) Exfoliative Toxins A and B encoded by the eta and etb genes, (iii) Toxic Shock Syndrome Toxin 1 (TSST-1) encoded by the tst gene, (iv) Panton-Valentine Leukocidin (PVL) encoded by the pvl gene, and (v) Hemolysins alpha and delta encoded by the hla and hld genes, respectively. We determined the prevalence of S. aureus possessing one or more virulence factor genes and of methicillin resistant Staphylococcus aureus (MRSA) in this population. Methods: This was a cross-sectional study, which used 85 S. aureus isolates from the Chlorohexidine (CHX) clinical trial study in Uganda. The isolates had been obtained by culturing vaginal swabs (VS) from 1472 women in labour, frozen at minus 80oC, then thawed, sub-cultured, and tested for the selected virulence genes sea, seb, sec, sed, see eta, etb, tst, pvl, hla and hld, and for the methicillin resistance determining gene (mecA). Data were analyzed using SPSS version 20. Results: Of the 85 S. aureus isolates 13 (15.3%) were positive for one or more virulence factor genes, as follows: pvl 9/85 (10.6%), hld 5/85 (5.9%), sea 1/85 (1.2%) and seb genes 1/85 (1.2%). The other virulence genes (sec, sed, see, eta, etb, hla and tst) were not detected in any of the isolates. MRSA was detected in 55.3% (47/85) of the isolates, but only two of these carried the pvl virulence gene. Conclusion: This study demonstrated that 15% of the S. aureus colonizing the female lower genital tract of mothers in labour in central Uganda carried one or more virulence genes, mostly pvl, indicating potential for newborn infection with S. aureus acquired in the maternal birth canal. More than half of the isolates were MRSA. [ABSTRACT FROM AUTHOR]

Background: Community-acquired Methicillin-resistant Staphylococcus aureus (CA-MRSA) usually emerges after a viral infection and causes severe disease in immunocompetent individuals. Concurrent infection with tuberculosis (TB) is generally very rare in immunocompetent patients. Our case is the first report of the coexistence of CA-MRSA and TB in an immunocompetent patient. Case presentation: A 24-year-old male patient of African origin, who has been living in Turkey for a year, was admitted to our hospital 3 months ago with fever, cough, and sputum complaints, which developed following symptoms of influenza infection. More intense bilateral infiltration and cavitary appearance were observed on the left in the chest radiography of the patient who did not respond to amoxicillin and gemifloxacin treatments. The patient's sputum culture showed MRSA growth, and his sputum acid-resistant bacteria (ARB) was reported as three positive. Vancomycin, isoniazid, rifampicin, pyrazinamide, and ethambutol treatments were started. Subsequently, Mycobacterium Tuberculosis growth was also detected in the mycobacteria culture. Vancomycin treatment was completed in 14 days. There was no growth in the control sputum culture. When the patient, who gave clinical and laboratory response, was admitted with increased shortness of breath complaint two months after discharge, it was observed that minimal spontaneous pneumothorax developed in the left lung, and it was decided to follow up without intervention. In the second month of tuberculosis treatment, sputum ARB and mycobacteria culture became negative, and the patient was switched to dual antituberculosis treatment (isoniazid, rifampicin), and his treatment is still ongoing. Conclusions: Mixed infections should be considered in case of non-response to treatment in patients with pneumonia. Mixed infections should also be followed closely as they may be more complicated. [ABSTRACT FROM AUTHOR]

Summary: ESKAPE pathogens are responsible for complicated nosocomial infections worldwide and are often resistant to commonly used antibiotics in clinical settings. Among ESKAPE, vancomycin-resistant Enterococcus faecium (VREfm) and methicillin-resistant Staphylococcus aureus (MRSA) are two important Gram-positive pathogens for which non-antibiotic alternatives are urgently needed. We previously showed that the lipoprotein AdcA of E. faecium elicits opsonic and protective antibodies against E. faecium and E. faecalis. Prompted by our observation, reported here, that AdcA also elicits opsonic antibodies against MRSA and other clinically relevant Gram-positive pathogens, we identified the dominant epitope responsible for AdcA cross-reactive activity and designed a hyper-thermostable and multi-presenting antigen, Sc(EH)3. We demonstrate that antibodies raised against Sc(EH)3 mediate opsonic killing of a wide-spectrum of Gram-positive pathogens, including VREfm and MRSA, and confer protection both in passive and active immunisation models. Our data indicate that Sc(EH)3 is a promising antigen for the development of vaccines against different Gram-positive pathogens. [ABSTRACT FROM AUTHOR]

The design of eco‐friendly active food packaging systems based on biobased polymeric materials is a growing field of research because of the pressing concern for sustainable development. Herein, monolayer ternary thermoplastic films composed of poly(lactic acid) (PLA), gallic acid (GA, 2.5% w/w relative to PLA), and a plasticizer (poly(ethylene glycol) [PEG] or epoxidized linseed oil [ELO], 5.0 and 7.5% w/w relative to PLA) are prepared via melt‐mixing followed by compression molding. The ensuing plasticized and self‐standing PLA/GA films are translucent and have good mechanical properties (Young's modulus ~2 GPa) and welding performance. The incorporation of GA yields films with ultraviolet‐light barrier properties (transmittance below 40%, 200–400 nm), antioxidant capacity (radical scavenging activity above 94%), and antibacterial activity against the methicillin‐resistant strain of Staphylococcus aureus (minimum of 3‐log reduction colony forming units mL−1). These thermoplastic films are easily degradable via enzymatic degradation with proteinase K from Tritirachium album, reaching weight loss values of 100% after 9 days. The films plasticized with PEG present slightly better antibacterial action and enzymatic degradation, whereas those plasticized with ELO exhibit marginally higher surface hydrophobicity and thermal stability. Thus, the combination between PLA and GA yielded biobased films with bioactive properties that have potential for application in active food packaging. [ABSTRACT FROM AUTHOR]

Background: The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing in recent years, becoming a cause of community-acquired infection. Interestingly, its role in malignancy recently started to be considered after a noticed increase in reported cases and studies discussing the potential association. Case Report: In the present case, the patient had known and uncontrolled diabetes mellitus and a history of multiple abscesses that were previously treated by incision and drainage. The patient received a diagnosis of severe pneumonia, and MRSA was found in blood cultures. Further tests for HIV, hemagglutinin type 1, and neuraminidase type 1 (H1N1) were negative. The D test was also performed for macrolide-inducible resistance and was negative, indicating the need for intravenous administration of clindamycin. An echocardiogram ruled out endocarditis. Subsequently, the patient experienced progressive back pain and weakness involving the lower limbs. A pathological fracture was discovered, along with nerve root compression. An urgent posterior spine fixation was then performed by a neurosurgeon. A biopsy was collected at the site of the pathological fracture, and histopathological tests indicated a plasma cell neoplasm. Conclusions: MRSA is known to cause serious and dangerous infections, including necrotizing pneumonia. Furthermore, a link between MRSA and plasma cell dyscrasia has been considered in several reports. This necessitates the need for further studies to clarify this hidden association, which may help in the course and prognosis of these patients. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has demonstrated significant potential in addressing multidrug‐resistant bacterial infections due to its noninvasive nature and independence from antibiotics and light sources. However, the majority of current sonosensitizers exhibit aggregation‐caused quenching (ACQ), leading to low reactive oxygen species (ROS) generation efficiency. Herein, a novel nonplanar structured sonodynamic (4,4‐difluoro‐4‐boron‐3a,4‐diaza‐indandiene) BODIPY derivative, BODN, with aggregation‐induced emission (AIE) properties, and rapid generation of substantial ROS by ultrasound is introduced. The BODN is co‐assembled with the commercial amphiphilic polymer, mDSPE‐PEG2000, forming BODN nanoparticles (BODN‐NP). Under ultrasound conditions, BODN‐NP demonstrates potent antimicrobial activity and improves the inflammatory response to promote healing wounds infected by both Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus. This work expands the use of AIE sonodynamic materials in antimicrobial therapy and provides new perspectives for innovative solutions against multidrug‐resistant bacterial infections. [ABSTRACT FROM AUTHOR]

Background: Methicillin-resistant Staphylococcus aureus (MRSA) colonization increases the risk of subsequent infection by MRSA strain complex interlinking between hospital and community-acquired MRSA which increases the chance of drug resistance and severity of the disease. Objective: Genomic characterization of Staphylococcus aures strains isolated from patients attending regional referral hospitals in Tanzania. Methodology: A laboratory-based cross-sectional study using short read-based sequencing technology, (Nextseq550,Illumina, Inc. San diego, California, USA). The samples used were collected from patients attending selected regional referral hospitals in Tanzania under the SeqAfrica project. Sequences were analyzed using tools available in the center for genomic and epidemiology server, and visualization of the phylogenetic tree was performed in ITOL 6.0. SPSS 28.0 was used for statistical analysis. Results: Among 103 sequences of S. aureus, 48.5% (50/103) carry the mecA gene for MRSA. High proportions of MRSA were observed among participants aged between 18 and 34 years (52.4%), in females (54.3%), and among outpatients (60.5%). The majority of observed MRSA carried plasmids rep5a (92.0%), rep16 (90.0%), rep7c (90.0%), rep15 (82.0%), rep19 (80.0%) and rep10 (72.0%). Among all plasmids observed rep5a, rep16, rep20, and repUS70 carried the blaZ gene, rep10 carried the erm(C) gene and rep7a carried the tet(K) gene. MLST and phylogeny analysis reveal high diversity among MRSA. Six different clones were observed circulating at selected regional hospitals and MRSA with ST8 was dominant. Conclusion: The study reveals a significant presence of MRSA in Staphylococcus aureus strains from Tanzanian regional hospitals, with nearly half carrying the mecA gene. MRSA is notably prevalent among young adults, females, and outpatients, showing high genetic diversity and dominance of ST8. Various plasmids carrying resistance genes indicate a complex resistance profile, highlighting the need for targeted interventions to manage MRSA infections in Tanzania. [ABSTRACT FROM AUTHOR]

The number of Methicillin-resistant Staphylococcus aureus (MRSA) cases in communities and hospitals is on the rise worldwide. In this work, a nonlinear deterministic model for the dynamics of MRSA infection in society was developed to visualize the significance of awareness in interventions that could be applied in the prevention of transmission with and without optimal control. Positivity and uniqueness were verified for the proposed corruption model to identify the level of resolution of infection factors in society. Furthermore, how various parameters affect the reproductive number R 0 and sensitivity analysis of the proposed model was explored through mathematical techniques and figures. The global stability of model equilibria analysis was established by using Lyapunov functions with the first derivative test. A total of seven years of data gathered from a private hospital consisting of inpatients and outpatients of MRSA were used in this model for numerical simulations and for observing the dynamics of infection by using a non-standard finite difference (NSFD) scheme. When optimal control was applied as a second model, it was determined that increasing awareness of hand hygiene and wearing a mask were the key controlling measures to prevent the spread of community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA). Lastly, it was concluded that both CA-MRSA and HA-MRSA cases are on the rise in the community, and increasing awareness concerning transmission is extremely significant in preventing further spread. [ABSTRACT FROM AUTHOR]

We synthesised a sequence of structurally related copper(II) complexes of Schiff base ligands, 2-[(2-benzylamino-ethylimino)-methyl]-phenol [L1(H)], 2-[(2-benzylamino-ethylimino)-methyl]-4-methyl-phenol [L2(H)], and 2-[(2-benzylamino-ethylimino)-methyl]-4-bromo-phenol [L3(H)]. The complexes were characterized by ATR, UV-vis, EPR, ESI-MS, single crystal XRD, and elemental analyses. Based on the crystal structure, the ligand was coordinated to the copper(II) centre in a tridentate mode through phenolate(oxygen), imine nitrogen and amine nitrogen in an NNO fashion and the azide moiety served as an auxiliary ligand. Furthermore, we have investigated the antimicrobial activities of copper(II) complexes against clinically relevant fungal strains, including Candida albicans, Candida glabrata, and Candida tropicalis, as well as bacteria such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), representing Gram-negative and Gram-positive pathogenic strains. Comparing the activity of complex 2 (128–512 μg mL−1) to complex 3 (64–128 μg mL−1), the latter demonstrated more potent effectiveness against all of the tested fungal strains. The activity of the complexes against MRSA reveals the inhibitory concentrations of 1024 μg mL−1 for 1, 128 μg mL−1 for 2, and 256 μg mL−1 for 3. It is worth mentioning that, at their minimum inhibitory concentrations (MICs), the complexes are not toxic to Galleria mellonella. Furthermore, the spot and broth microdilution assay results were in good agreement with the actual metabolic viability of bacterial and fungal strains, in which the complexes were active while having no effect on the metabolite resazurin. Additionally, in silico studies have been employed to elucidate both non-bonding interactions and the mode of action across protein sequences of experimentally studied microbes. The performance of complexes closely mirrored the reactivity order determined in in vitro studies. The impeding properties of complexes can be due to the dysfunctioning of virulent genes and signalling proteins and also affect the activities of transferase and transcriptase proteins. Overall, the complexes are promising candidates for antimicrobial drug development. We anticipate utilising these molecules for clinical purposes. [ABSTRACT FROM AUTHOR]

Biofilm development significantly enhances the virulence of methicillin-resistant Staphylococcus aureus (MRSA), leading to severe infections and decreased susceptibility to antibiotics, especially in strains associated with hospital environments. This study examined the occurrence of MRSA, their ability to form biofilms, agr typing, and the antibiotic resistance profiles of biofilm-forming MRSA strains isolated from environmental surfaces at Mymensingh Medical College Hospital (MMCH). From 120 swab samples, 86 (71.67%) tested positive for S. aureus. MRSA was identified in 86 isolates using the disk diffusion technique, and by polymerase chain reaction (PCR), 56 (65.1%) isolates were confirmed to carry the mecA gene. The Crystal Violet Microtiter Plate (CVMP) test revealed that 80.35% (45 isolates) were biofilm-forming and 19.6% (11 isolates) were non-biofilm-forming. Out of 45 biofilm producer isolates 37.5% and 42.9% isolates exhibited strong and intermediate biofilm-forming characteristics, respectively. Molecular analysis revealed that 17.78% of MRSA isolates carried at least one gene related to biofilm formation, specifically icaA, icaB, and icaD genes were discovered in 13.33%, 8.89%, 6.67% of the MRSA isolates, respectively. In agr typing, the most prevalent group was agr I (71.11%), followed by group III (17.78%) and group II (11.11%). Group IV was not detected. The distribution of agr gene groups showed a significant difference among biofilm-forming isolates (p < 0.05). In agr group I, 18.75% of isolates carried the icaA gene, 12.5% carried the icaB gene, and 9.37% carried the icaD gene. Biofilm-forming genes were not detected in any of the isolates from agr groups II or III. There are no statistically significant differences between agr groups and the presence of these genes (p > 0.05). Antibiotic resistance varied significantly among agr groups, with agr group I displaying the highest resistance, agr group II, and agr group III exhibiting the least resistance (p < 0.05). Seventy-three (73.3%) of the isolates were multi-drug resistant, with agr group I displaying nineteen MDR patterns. The occurrence of MRSA in hospital environments and their capacity to form biofilm raises concerns for public health. These findings support the importance of further research focused on agr quorum sensing systems as a basis for developing novel antibacterial agents. [ABSTRACT FROM AUTHOR]

Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be a cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed to overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics with enhanced antibacterial activities and improved safety profiles are still necessary. We describe the development of a class of highly potent semisynthetic glycopeptide antibiotics, the guanidino lipoglycopeptides, which contain a positively charged guanidino moiety bearing a variable lipid group. These glycopeptides exhibited enhanced in vitro activity against a panel of Gram-positive bacteria including clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains, showed minimal toxicity toward eukaryotic cells, and had a low propensity for resistance selection. Mechanistically, guanidino lipoglycopeptides engaged with bacterial cell wall precursor lipid II with a higher binding affinity than vancomycin. Binding to both wild-type d-Ala-d-Ala lipid II and the vancomycin-resistant d-Ala-d-Lac variant was confirmed, providing insight into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant isolates. The in vivo efficacy of guanidino lipoglycopeptide EVG7 was evaluated in a S. aureus murine thigh infection model and a 7-day sepsis survival study, both of which demonstrated superiority to vancomycin. Moreover, the minimal to mild kidney effects at supratherapeutic doses of EVG7 indicate an improved therapeutic safety profile compared with vancomycin. These findings position guanidino lipoglycopeptides as candidates for further development as antibacterial agents for the treatment of clinically relevant multidrug-resistant Gram-positive infections. Editor's summary: Vancomycin and its second-generation lipoglycopeptide derivatives work mainly by binding the peptidoglycan precursor lipid II to inhibit cell wall synthesis in Gram-positive bacteria. However, antibiotic resistance and safety concerns remain, and improved antibiotics are still needed. Van Groesen et al. report the optimization of a series of vancomycin-derived antibiotic compounds: lipoglycopeptides that bear a guanidino lipid group. This modification promoted stronger binding to the cell wall precursor lipid II, resulting in potent antibacterial activity while also showing less toxicity to mammalian cells than second-generation vancomycin derivatives. The lead candidate compound outperformed vancomycin in improving therapeutic outcome in mouse models of S. aureus thigh infection and sepsis, suggesting that guanidino lipoglycopeptides may benefit from further development. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Data are limited on the clinical impact of nasal methicillin-resistant Staphylococcus aureus (MRSA) polymerase chain reaction testing for orbital cellulitis. This 2-center, retrospective study demonstrated a negative predictive value of 98.0% and an overall lower use of anti-MRSA antibiotics, without a concomitant increase in hospital readmission. [ABSTRACT FROM AUTHOR]

Background and Objectives: Staphylococcal infections are one of the major infectious diseases affecting globally in spite of advances in development of antimicrobial agents. Knowledge and awareness about the local pattern and prevalence of MRSA infections plays a key role in treatment. The aim of this study was to identify MRSA strains by phenotypic and genotypic methods and to analyze the antibiotic susceptibility pattern of MRSA strains from patients attending a tertiary care hospital. Materials and Methods: This study was conducted over a period of 1 year, where 296 isolates of Staphylococcus aureus were isolated from various clinical specimens. The isolated strains were examined for antibiotic susceptibility by the modified Kirby Bauer disc diffusion method. Methicillin resistance was detected by cefoxitin disk diffusion test. Results: A total of 104 isolates were found to be MRSA and 192 were found to be MSSA. Among the 104 MRSA isolates, 10 strains that were multidrug resistant were subjected to 16S rRNA gene sequencing analysis. All the 10 strains had a 99% match with S. aureus strains that were responsible for causing some serious biofilm mediated clinical manifestations like cystic fibrosis and device mediated infections. The biofilms were quantified using crystal violet staining and their ability to produce biofilms was analyzed using scanning electron microscopy and matched with the Genbank. Conclusion: Hence these phylogenetic analysis aid in treating the patients and combating resistance to antibiotics. [ABSTRACT FROM AUTHOR]

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6–12, were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5, 6, 7 and 9 were reported for the first time, with IC50 values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 μM, as compared with acarbose (IC50 = 671.5 ± 0.2 μM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimum inhibitory concentration (MIC) values of 16 μg/mL. These results indicate that 5, together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase. [ABSTRACT FROM AUTHOR]

Background: Urban areas are unique ecosystems with stark differences in species abundance and composition compared with natural ecosystems. These differences can affect pathogen transmission dynamics, thereby altering zoonotic pathogen prevalence and diversity. In this study, we screened small mammals from natural and urban areas in the Netherlands for up to 19 zoonotic pathogens, including viruses, bacteria, and protozoan parasites. Materials and Methods: In total, 578 small mammals were captured, including wood mice (Apodemus sylvaticus), bank voles (Myodes glareolus), yellow-necked mice (Apodemus flavicollis), house mice (Mus musculus), common voles (Microtus arvalis), and greater white-toothed shrews (Crocidura russula). We detected a wide variety of zoonotic pathogens in small mammals from both urban and natural areas. For a subset of these pathogens, in wood mice and bank voles, we then tested whether pathogen prevalence and diversity were associated with habitat type (i.e., natural versus urban), degree of greenness, and various host characteristics. Results: The prevalence of tick-borne zoonotic pathogens (Borrelia spp. and Neoehrlichia mikurensis) was significantly higher in wood mice from natural areas. In contrast, the prevalence of Bartonella spp. was higher in wood mice from urban areas, but this difference was not statistically significant. Pathogen diversity was higher in bank voles from natural habitats and increased with body weight for both rodent species, although this relationship depended on sex for bank voles. In addition, we detected methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase/AmpC-producing Escherichia coli, and lymphocytic choriomeningitis virus for the first time in rodents in the Netherlands. Discussion: The differences between natural and urban areas are likely related to differences in the abundance and diversity of arthropod vectors and vertebrate community composition. With increasing environmental encroachment and changes in urban land use (e.g., urban greening), it is important to better understand transmission dynamics of zoonotic pathogens in urban environments to reduce potential disease risks for public health. [ABSTRACT FROM AUTHOR]

Necrotizing skin and soft-tissue infections (NSTIs) are the most frequent and severe cases admitted to the intensive care unit (ICU). Timely and adequate surgical and medical care are crucial for managing these infections. The heterogeneity of patients and the varying comorbidities, clinical presentations, causative microbes, and treatments require a multidisciplinary team approach. Early diagnosis, imaging techniques, and early source control are essential. Empirical antibiotic therapy should have a broad spectrum, and adjuvant therapies such as hyperbaric oxygen therapy and intravenous immunoglobulin may be considered. Multidisciplinary management has shown benefits in optimizing therapy. [Extracted from the article]

The objective of the study was to detect the presence of Helicobacter pylori in adenotonsillar tissue and to assess the association between the presence of H pylori with Chronic Tonsillitis or Adenotonsillitis. This was a cross sectional study conducted among 60 patients diagnosed with chronic tonsillitis and adeno tonsillitis undergoing tonsillectomy or adeno tonsillectomy meeting the paradise criteria in a tertiary care hospital, Pondicherry. Rapid urease test was done in the intraoperative period immediately after the specimens were taken.The rapid urease test kit was observed for color change from yellow to pink within 4 h. The tissue was sent for histopathological examination for staining with H&E and Giemsa stain to detect the presence of helicobacter pylori. The mean age of the study participants was 15.75 ± 8.46 and majority of the study participants were females. (61.7%). 66.7% and 33.3% of the study participants had chronic tonsillitis and adeno tonsillitis respectively. Oral swab showed normal flora, yeast and methicillin resistant Staphylococcus aureus in 96.6%, 1.7% and 1.7% respectively. 1.7% (1),13.3% (8) and 20% (12) of the study participants showed positive in card test immediate, at 15 min and 1 h respectively. Giemsa stain showed that 11.7% was positive for H.pylori. Out of the 7 patients with positive Giemsa stain, 4 had chronic tonsillitis and 3 had adenotonsillitis. Colonisation of adenoids and tonsils by H. pylori is a novel forefront with contradictory results dependent on the precision of the detective techniques used and population studied. Further research may be warranted to establish the varied colonisation depending on the geographical locations. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo compare the effect of different doses of vancomycin on a rabbit model of MRSA keratitis.Twenty-four eyes of 24 New-Zealand White rabbits were included in the study. MRSA keratitis was applied to 24 left eyes of 24 New Zealand rabbits. Twenty-four hours after MRSA inoculation; 0.5 mg/0.1 mL, 1 mg/0.1 mL, and 2 mg/0.1 mL and balanced salt solution were administered to 6 rabbits in 4 groups, respectively.The effect of different doses of vancomycin on reducing bacterial load was found to be statistically significant when each was compared to the control group (p = 0.006). When comparing the dosages with each other, no superiority was shown (p = 0.297, p = 0.749, p = 0.262 respectively). There was a significant increase in the posttreatment total clinical score in the control and 2 mg/0.1 mL groups compared to the pretreatment score (p = 0.001, p = 0.001 respectively).It is emphasized that necessary treatment can be achieved by administering less antibiotic (0.5 mg/0.1 mL) to the corneal intrastromal area. [ABSTRACT FROM AUTHOR]

Bacterial infections account for countless deaths globally. Antibiotics are the primary countermeasure; however, the alarming spread of antibiotic‐resistant strains necessitates alternative solutions. Silver and silver compounds have emerged as promising antibacterial agents. However, issues related to cytotoxicity and genotoxicity of silver remain concern. To overcome these challenges, this proposes an easy‐to‐control and straightforward method to synthesize novel Silver─gallium (Ag─Ga) nano‐amalgamated particles. Gallium liquid metal (GaLM) is used to facilitate the galvanic deposition of silver nanocrystals (Ag) on oxide layer. The GaLM not only serves as a carrier for silver through the galvanic replacement process, but also provides a controlled‐release mechanism for silver, in this way improving biocompatibility, reducing inflammation, and stimulating bone growth. Notably, Ag─Ga suspensions can be conveniently deposited by spray‐coating on a range of devices and material surfaces, effectively eliminating pathogenic bacteria with efficacy comparable to that of silver ions. In vivo studies in rat models affirm the antibacterial capabilities, especially against methicillin‐resistant Staphylococcus aureus and Escherichia coli, when placed on implants such as titanium rods and magnesium discs. Furthermore, Ag─Ga promotes bone matrix formation and collagen growth without eliciting an inflammatory response, indicating a major promise for coatings on a wide variety of biomedical devices and materials. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the trends in infectious spondylitis over the past two decades. Methods: We included 157 cases, from 2000 to 2020, of infectious spondylitis. The cases were divided into two groups: 00 (cases during 2000–2009; 82 cases:) and 10 (cases during 2010–2020; 75 cases) groups. Patients' age, sex, causative organism, and localization were examined and compared between the two groups. Results: The proportions of women in the 00 and 10 groups were 30.5% and 38.7%, respectively, with no significant difference (P = 0.28). The average age was significantly higher in the 10 group (72.6 years) than in the 00 group (68.8 years; P < 0.01). A compromised host was the cause of infection in 52.4% and 36.0% of the patients in the 00 and 10 groups, respectively, showing a significant difference. The bacterial identification rates were 70.1% and 77.3% in the 00 and 10 groups, respectively (P < 0.01), and the genus Staphylococcus was the most common bacteria. The proportions of resistant bacteria such as methicillin-resistant Staphylococcus aureus in the 00 and 10 groups were 27.3% and 6.7%, respectively (P < 0.01). Conversely, infectious diseases caused by indigenous bacteria in the oral cavity and intestines were more common in the 10group (37.8%) than in the 00 group (13.0%), showing a significant difference (P < 0.01). Conclusion: Recently, infections caused by indigenous bacteria in the oral cavity and intestines have increased more than those caused by resistant bacteria over the past two decade. [ABSTRACT FROM AUTHOR]

Septic pelvic thrombophlebitis (SPT) is a rare condition that forms thrombosis in the pelvic veins, typically the ovarian veins, with subsequent infection and inflammation. We present a case of right ovarian vein thrombosis (ROVT), methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia, and delayed onset of SPT symptoms, requiring tissue‐plasminogen activator. A 40‐year‐old woman, G3P2, at 38 weeks' gestation, was admitted with a fever of 39°C. She had cervical insufficiency and had been often on bed rest. Blood culture revealed MRSA and computed tomography revealed a large ROVT. She received vancomycin and direct oral anticoagulant, and her fever resolved by day 3. On day 16, fever recurred with severe pain over the ROVT. Second computed tomography showed thickening of venous wall with enhancement around ROVT, consistent with SPT. Since pain and fever gradually exacerbated despite treatment with DOAC and antimicrobials, she was started on heparin and tissue plasminogen activator on days 23 and 25, respectively. Along with recanalization on the thrombosis by day 29, fever and abdominal pain resolved. We experienced a case of delayed onset SPT associated with MRSA bacteremia and a large ROVT. MRSA bacteremia might cause the originally existing ROVT to become an infection source, resulting in SPT with recurrent symptoms and long‐term treatment. Early and strict anticoagulation is crucial in cases with a large thrombosis and bacteremia, due to the high risk of progression to SPT. This case highlights the importance of recanalization for the treatment of SPT and usefulness of administration of tissue‐plasminogen activator for the massive thrombosis. [ABSTRACT FROM AUTHOR]

Objectives To characterize the mobile genetic elements and genetic localization of ileS2 in high-level mupirocin-resistant (Hi-MupR) methicillin-resistant Staphylococcus pseudintermedius (MRSP) and MRSA isolates recovered from canine and feline clinical samples. Methods The identification of bacterial species and presence of mecA and ileS2 genes in MRSP and MRSA isolates were performed using MALDI-TOF MS and PCR, respectively. Antimicrobial resistance (AMR) phenotypes were determined by broth microdilution assays. The genome characteristics, ileS2 -containing elements and staphylococcal cassette chromosome mec (SCC mec) were illustrated using complete circular genomes obtained from hybrid assembly of Illumina short-reads and Oxford Nanopore Technologies long-reads. These were analysed through phylogenetic and bioinformatics approaches. Results A total of 18 MRSP clinical isolates and four MRSA clinical isolates exhibited the Hi-MupR phenotype and carried multiple AMR genes, including mecA and ileS2 genes. MRSP ST182-SCC mec V (n  = 6) and ST282-ΨSCC mec 57395-t10 (n  = 4) contained the ileS2 transposable unit associated with IS 257 on the chromosome. Three MRSA ST398-SCC mec V-t034/t4652 isolates carried ∼42 kb pSK41-like ileS2 plasmids, whereas similar ileS2 plasmids lacking tra genes were found in MRSP ST282-ΨSCC mec 57395-t72/t21 isolates. Furthermore, a new group of ileS2 plasmids, carried by MRSP ST45-ΨSCC mec 57395, ST433-ΨSCC mec KW21-t05 and ST2165-SCC mec IV-t06, and by one MRSA ST398-SCC mec V-t034 strain, shared the plasmid backbone with the cfr / fexA -carrying plasmid pM084526_1 in MRSA ST398. Conclusions This study provides the first evidence of ileS2 integration into the S. pseudintermedius chromosome, which is a rare occurrence in staphylococcal species, and plasmids played a pivotal role in dissemination of ileS2 in both staphylococcal species. [ABSTRACT FROM AUTHOR]

In Israel, prevalence of sequence type 913, staphylococcal cassette chromosome mecIVa, spa type t991 methicillin-resistant Staphylococcus aureus lineage has surged among pediatric populations, predominantly in Arab and Orthodox Jewish communities. Antimicrobial resistance patterns vary by demographics. This lineage's spread and microevolution in the Middle East underscore the need for ongoing surveillance. [ABSTRACT FROM AUTHOR]

Purpose: Vancomycin is commonly prescribed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, including patients with end stage renal disease (ESRD) receiving intermittent hemodialysis (IHD). Infection is the second-leading cause of mortality in this patient population; therefore, optimizing vancomycin dosing is essential. New guidelines recommend using the ratio of area under the curve (AUC)/minimal inhibitory concentration (MIC) dosing with a target of 400-600 to maximize efficacy and minimize vancomycin nephrotoxicity. Summary: A retrospective chart review was performed to assess the current protocol for vancomycin dosing in ESRD patients on IHD at a community hospital in North Mississippi. A protocol was developed for dosing vancomycin utilizing AUC/MIC targets in this patient population. The study included all inpatient adults with ESRD receiving IHD at least 3 times weekly and receiving vancomycin. Data collection occurred in two phases. The first phase of data collection occurred before implementation of the new protocol and assessed the current vancomycin protocol effectiveness. In phase II of data collection, an assessment of the newly developed protocol utilizing similar data collected in phase I was conducted. Conclusions: It is thought that the difference in treatment outcomes and AUC/MIC targets is due to decreased immune function in this population. For this reason, we set our goal pre-dialysis level at 20-25 mg/dL, rather than 17-25 mg/dL, which correlates with an AUC/MIC of 480-600. It is important to quickly achieve therapeutic levels for the patients that do have MRSA to improve outcomes, to sustain these levels, and to reduce adverse events and costs. [ABSTRACT FROM AUTHOR]

Introduction: Autologous platelet-rich plasma (PRP) therapy has emerged as a promising regenerative treatment modality, offering potential improvements in healing outcomes through its rich content of growth factors and cytokines. We evaluated the effectiveness of PRP therapy in the management of complex wounds, using a decade-long retrospective analysis of treatments conducted at a tertiary care center from 2010 to 2020. The study introduces and assesses the efficacy of the Sandeep's Technique for Assisted Regeneration of Skin (STARS) in enhancing wound healing and quality of life for patients with complex wounds. Materials and methods: A prospective interventional study was conducted, involving two phases: the development and initial testing of PRP therapy (2010–2015) and the application and evaluation of the STARS protocol (2015–2020). The study included patients with complex wounds, utilizing autologous PRP prepared through a double spin centrifuge technique. Outcome measures included wound-healing rates, infection management, and complication rates, compared to conventional treatment methods. Results: The study treated 500 wounds in 432 patients with autologous PRP, noting significant improvements in wound-healing rates, 97.7% had infection control without antibiotics (even in MRSA cases), and all had a good pain control. Histopathological examinations confirmed collagen-rich healing with minimal scarring. The STARS protocol demonstrated the potential of PRP therapy in accelerating wound healing, reducing the need for additional surgical interventions, and enhancing patient outcomes. Conclusion: PRP therapy, particularly when administered following the STARS protocol, represents a safe, effective, and patient-friendly approach for the management of complex wounds. This study supports the integration of PRP therapy into regenerative care strategies, suggesting a shift toward more innovative and efficacious treatments in wound management. [ABSTRACT FROM AUTHOR]

The goal of this study was to isolate endophytic fungi from Ocimum sanctum L. and to evaluate their biological potential, including antibacterial, antioxidant, and enzymatic activities and further characterization of the bioactive compounds. Nine endophytic fungi were isolated from the leaves and stem tissues of O. sanctum collected from the botanical garden of Banaras Hindu University, Varanasi, India. All isolates were identified based on their microscopic structures and molecular sequencing of the ITS rDNA. Aspergillus clavatonanicus (SS7) and Cochliobolus hawaiiensis (SL3) showed the highest colonization frequencies in the stem and leaves (16 and 14%, respectively). All fungal isolates were tested for extracellular enzymatic activities of amylase, cellulase, and pectinase. Of the nine fungal isolates, 60% tested positive for amylase and cellulase, whereas 50% showed pectinase activity. Using a disc diffusion assay, the extracted secondary metabolites were checked for antibacterial activity against three human pathogenic bacteria. Two isolates, SL2 and SS7, exhibited the highest antibacterial activity against all pathogens, including Enterococcus faecalis, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus (MRSA). Crude extracts of the six fungal isolates showed positive antioxidant activity. The crude extract of Aspergillus allahabadii (isolate SL2) showed strong antibacterial and antioxidant activities and crystallized during purification. X-ray crystallography confirmed the identity of the crystal as citrinin, which also exhibited strong anticancer activity against Dalton's lymphoma cells. The results of this study suggest that endophytic fungi isolated from the leaf and stem tissues of Ocimum sanctum are potential sources of antibacterial, antioxidant, and anticancer compounds. [ABSTRACT FROM AUTHOR]

Biofilms, particularly those formed by multiple bacterial species, pose significant economic and environmental challenges, especially in the context of medical implants. Addressing the urgent need for effective treatment strategies that do not exacerbate drug resistance, we developed a novel nanoformulation, Ce6&PMb@BPN, based on black phosphorus nanosheets (BPN) for targeted treatment of mixed-species biofilms formed by Acinetobacter baumannii (A. baumannii) and methicillin-resistant Staphylococcus aureus (MRSA).The formulation leverages polymyxin B (PMb) for bacterial targeting and chlorin e6 (Ce6) for photodynamic action. Upon near-infrared (NIR) irradiation, Ce6&PMb@BPN efficiently eliminates biofilms by combining chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), reducing biofilm biomass significantly within 30 min. In vivo studies on mice infected with mixed-species biofilm-coated catheters demonstrated the formulation's potent antibacterial and biofilm ablation effects. Moreover, comprehensive biosafety evaluations confirmed the excellent biocompatibility of Ce6&PMb@BPN. Taken together, this intelligently designed nanoformulation holds potential for effectively treating biofilm-associated infections, addressing the urgent need for strategies to combat antibiotic-resistant biofilms, particularly mixed-species biofilm, in medical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20–35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0–24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0–24 following a VAN LD of 20 mg/kg. Methods: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0–24. Therapeutic AUC0–24 was defined as 400–600 mg/l*h. Results: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0–24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0–24, patients with subtherapeutic AUC0–24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0–24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0–24. Conclusions: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations. [ABSTRACT FROM AUTHOR]