A carrier-free, injectable, and self-assembling hydrogel based on carvacrol and glycyrrhizin exhibits high antibacterial activity and enhances healing of MRSA-infected wounds.

Inspired by glycyrrhizin's strong pharmacological activities and the directed self-assembly into hydrogels, we created a novel carrier-free, injectable hydrogel (CAR@glycygel) by combining glycyrrhizin with carvacrol (CAR), without any other chemical crosslinkers, to promote wound healing on bacteria-infected skin. CAR appeared to readily dissolve and load into CAR@glycygel. CAR@glycygel had a dense, porous, sponge structure and strong antioxidant characteristics. In vitro, it showed better antibacterial ability than free CAR. For methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Escherichia coli, the diameter of inhibition zone values of CAR@glycygel were 3.80 ± 0.04, 3.31 ± 0.20 and 3.12 ± 0.24 times greater, respectively, than those of free CAR. The MICs for CAR@glycygel was 156.25 µg/mL while it was 1250.00 µg/mL for free CAR to these three bacteria. Its antibacterial mechanism appeared to involve destruction of the integrity of the bacterial cell wall and biomembrane, leading to a leakage of AKP and inhibition of biofilm formation. In vivo, CAR@glycygel effectively stopped bleeding. When applied to skin wounds on rats infected with MRSA, CAR@glycygel had strong bactericidal activity and improved wound healing. The wound healing rates for CAR@glycygel were 49.59 ± 15.78 %, 93.02 ± 3.09 % and 99.02 ± 0.55 % on day 3, day 7, and day 11, respectively, which were much better than blank control and positive control groups. Mechanisms of CAR@glycygel accelerating wound healing involved facilitating epidermis remolding, promoting the growth of hair follicles, stimulating collagen deposition, mitigating inflammation, and promoting angiogenesis. Overall, CAR@glycygel showed great potential as wound dressing for infected skin wounds.

Biofilm-producing ability of methicillin-resistant Staphylococcus aureus clinically isolated in China.

BACKGROUND: Staphylococcus aureus, a commensal bacterium, colonizes the skin and mucous membranes of approximately 30% of the human population. Apart from conventional resistance mechanisms, one of the pathogenic features of S. aureus is its ability to survive in a biofilm state on both biotic and abiotic surfaces. Due to this characteristic, S. aureus is a major cause of human infections, with Methicillin-Resistant Staphylococcus aureus (MRSA) being a significant contributor to both community-acquired and hospital-acquired infections. RESULTS: Analyzing non-repetitive clinical isolates of MRSA collected from seven provinces and cities in China between 2014 and 2020, it was observed that 53.2% of the MRSA isolates exhibited varying degrees of ability to produce biofilm. The biofilm positivity rate was notably high in MRSA isolates from Guangdong, Jiangxi, and Hubei. The predominant MRSA strains collected in this study were of sequence types ST59, ST5, and ST239, with the biofilm-producing capability mainly distributed among moderate and weak biofilm producers within these ST types. Notably, certain sequence types, such as ST88, exhibited a high prevalence of strong biofilm-producing strains. The study found that SCCmec IV was the predominant type among biofilm-positive MRSA, followed by SCCmec II. Comparing strains with weak and strong biofilm production capabilities, the positive rates of the sdrD and sdrE were higher in strong biofilm producers. The genetic determinants ebp, icaA, icaB, icaC, icaD, icaR, and sdrE were associated with strong biofilm production in MRSA. Additionally, biofilm-negative MRSA isolates showed higher sensitivity rates to cefalotin (94.8%), daptomycin (94.5%), mupirocin (86.5%), teicoplanin (94.5%), fusidic acid (81.0%), and dalbavancin (94.5%) compared to biofilm-positive MRSA isolates. The biofilm positivity rate was consistently above 50% in all collected specimen types. CONCLUSIONS: MRSA strains with biofilm production capability warrant increased vigilance.

Pharmacotherapies for multidrug-resistant gram-positive infections: current options and beyond.

INTRODUCTION: Infections due to multidrug-resistant organisms (MDRO) are a serious concern for public health with high morbidity and mortality. Though many antibiotics have been introduced to manage these infections, there are remaining concerns regarding the optimal management of Gram-positive MDROs. AREAS COVERED: A literature search on the PubMed/Medline database was conducted. We applied no language and time limits for the search strategy. In this narrative review, we discuss the current options for managing Gram-positive MDROs as well as non-traditional antibacterial agents in development. EXPERT OPINION: Despite their introduction more than 70 years ago, glycopeptides are still the cornerstone in treating Gram-positive infections: all registrative studies of new antibiotics have glycopeptides as control; these studies are designed as not inferior studies, therefore it is almost impossible to give recommendations other than the use of glycopeptides in the treatment of Gram-positive infections. The best evidence on treatments different from glycopeptides comes from post-hoc analysis and meta-analysis. Non-traditional antibacterial agents are being studied to aid in short and effective antibiotic therapies. The use of non-traditional antibacterial agents is not restricted to replacing traditional antibacterial agents with alternative therapies; instead, they should be used in combination with antibiotic therapies.

Temporal trends of skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus in Gabon.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of mortality due to bacterial antimicrobial resistance. While S. aureus is common in skin and soft tissue infections (SSTI) in Africa, data on MRSA rates are scarce and reports vary widely across the continent (5%-80%). In this study, we describe the proportion of MRSA causing SSTI in Lambaréné, Gabon, over an 11-year period. METHODS: We retrospectively analyzed data from 953 bacterial specimens collected from inpatients and outpatients with SSTI at the Albert Schweitzer Hospital, Lambaréné, Gabon, between 2009 and 2019. We determined temporal changes in the prevalence of MRSA and identified risk factors for SSTI with MRSA. RESULTS: 68% of all specimens with bacterial growth yielded S. aureus (n = 499/731), of which 7% (36/497) with antimicrobial susceptibility testing were identified as MRSA. Age above 18 years, admission to the surgical ward, and deep-seated infections were significantly associated with MRSA as the causative agent. After an initial decline from 7% in 2009, there was a marked increase in the proportion of MRSA among all S. aureus from SSTI from 3 to 20% between 2012 and 2019. The resistance rate to erythromycin was significantly higher in MRSA than in methicillin-susceptible S. aureus (73% vs. 10%), and clindamycin resistance was detected exclusively in MRSA isolates (8%). CONCLUSION: The increasing proportion of MRSA causing SSTI over the 11-year period contrasts with many European countries where MRSA is on decline. Continuous surveillance of MRSA lineages in the hospital and community along with antibiotic stewardship programs could address the increasing trend of MRSA.

The Clinical Characteristics and Antimicrobial Resistance of Staphylococcus aureus Isolated from Patients with Staphylococcal Scalded Skin Syndrome (SSSS) in Southwestern China.

Staphylococcal scalded skin syndrome (SSSS) is a rare, toxin-mediated, desquamating bacterial infectious dermatosis. So far, data from Southwestern China is scarce. This study aimed to investigate the clinical characteristics of SSSS patients in our hospital, the relative proportion of methicillin-resistant Staphylococcus aureus (MRSA) in skin and soft tissue secretions, and the drug sensitivity of S. aureus to better assist dermatologists in the diagnosis and treatment of SSSS. We reviewed the demographic characteristics, clinical manifestations, treatment regimens, therapeutic efficacy, laboratory test results, drug sensitivity, and outcome data of 79 SSSS patients from January 2012 to December 2021. Statistical analysis was performed using t tests and chi-square tests. Among the 79 SSSS patients, MRSA was detected in 35 (44.3%) isolates: 34 community-acquired (CA)-MRSA (97.1%) and 1 hospital-acquired (HA)-MRSA. The SSSS incidence increased annually from 2012 to 2014 and then decreased gradually after peaking in 2015. All the isolates were sensitive to vancomycin, tigecycline, linezolid, moxifloxacin, levofloxacin, and ciprofloxacin; were completely resistant to penicillin; and had low sensitivity to clindamycin and erythromycin. Interestingly, the sensitivity of MRSA to tetracycline increased annually after 2015. The resistance rates to common drugs previously used to treat SSSS increased. These findings may accelerate diagnosis and improve empirical antibiotic use, suggesting that clinicians should prescribe drugs according to antimicrobial susceptibility.

The Evolving Challenge of Appropriate Antibiotics Use in Hospitalized COVID-19 Patients: A Systematic Literature Review.

The issue of bacterial infections in COVID-19 patients has received increasing attention. Scant data are available on the impact of bacterial superinfection and antibiotic administration on the outcome of hospitalized COVID-19 patients. We conducted a literature review from 1 January 2022 to 31 March 2024 to assess the current burden of bacterial infection and the evidence for antibiotic use in hospitalized COVID-19 patients. Published articles providing data on antibiotic use in COVID-19 patients were identified through computerized literature searches with the search terms [(antibiotic) AND (COVID-19)] or [(antibiotic treatment) AND (COVID-19)]. PubMed and SCOPUS databases were searched from 1 January 2022 to 31 March 2024. No attempt was made to obtain information about unpublished studies. English language restriction was applied. The quality of the included studies was evaluated by the tool recommended by the Joanna Briggs Institute. Both quantitative and qualitative information were summarized by means of textual descriptions. Five hundred fifty-one studies were identified, and twenty-nine studies were included in this systematic review. Of the 29 included studies, 18 studies were on the prevalence of bacterial infection and antibiotic use in hospitalized COVID-19 patients; 4 studies reported on the efficacy of early antibiotic use in COVID-19; 4 studies were on the use of sepsis biomarkers to improve antibiotic use; 3 studies were on the efficacy of antimicrobial stewardship programs and predictive models among COVID-19-hospitalized patients. The quality of included studies was high in 35% and medium in 62%. High rates of hospital-acquired infections were reported among COVID-19 patients, ranging between 7.5 and 37.7%. A high antibiotic resistance rate was reported among COVID-19 patients developing hospital-acquired infections, with a high in-hospital mortality rate. The studies evaluating multi-faceted antimicrobial stewardship interventions reported efficacy in decreasing antibiotic consumption and lower in-hospital mortality.

Clinical characteristics and analysis of prognostic factors in methicillin-resistant Staphylococcus aureus endocarditis: A retrospective multicenter study in Japan.

BACKGROUND: Infective endocarditis (IE) caused by MRSA (methicillin-resistant Staphylococcus aureus) is associated with a high mortality rate. This study aimed to elucidate the characteristics of patients with MRSA-IE in Japan and identify the factors associated with prognosis. METHODS: This retrospective study included patients with a confirmed diagnosis of IE caused by MRSA, between January 2015 and April 2019. RESULTS: A total of 65 patients from 19 centers were included, with a mean age of 67 years and 26 % were female. Fifty percent of the patients with IE were had nosocomial infections and 25 % had prosthetic valve involvement. The most common comorbidities were hemodialysis (20 %) and diabetes (20 %). Congestive heart failure was present in 86 % of patients (NYHA class I, II: 48 %; III, IV: 38 %). The 30-day and in-hospital mortality rates were 29 % and 46 %, respectively. Multi-organ failure was the primary cause of death, accounting for 43 % of all causes of death. Prognostic factors for in-hospital mortality were age, disseminated intravascular coagulation, daptomycin and/or linezolid as initial antibiotic therapy, and surgery. Surgical treatment was associated with a lower mortality rate (odds ratio [OR], 0.026; 95 % confidence interval [CI], 0.002-0.382; p = 0.008 for 30-day mortality and OR, 0.130; 95 % CI; 0.029-0.584; p = 0.008 for in-hospital mortality). CONCLUSION: Mortality due to MRSA-IE remains high. Surgical treatment is a significant prognostic predictor of MRSA-IE.

Community-acquired pneumonia: The importance of the early detection of drug-resistant organisms.

Pneumonia is a disease associated with significant healthcare burden with over 1.5 million hospitalizations annually and is the eighth leading cause of death in the United States. While community-acquired pneumonia (CAP) is generally considered an acute time-limited illness, it is associated with high long-term mortality, with nearly one-third of patients requiring hospitalization dying within one year. An increasing trend of detecting multidrug-resistant (MDR) organisms causing CAP has been observed, especially in the Western world. In this editorial, we discuss about a publication by Jatteppanavar et al which reported that a case of a MDR organism was the culprit in developing pneumonia, bacteremia, and infective endocarditis that led to the patient's death. The early detection of these resistant organisms helps improve patient outcomes. Significant advances have been made in the biotechnological and research space, but preventive measures, diagnostic techniques, and treatment strategies need to be developed.

Improving Risk Prediction of Methicillin-Resistant Staphylococcus aureus Using Machine Learning Methods With Network Features: Retrospective Development Study.

BACKGROUND: Health care-associated infections due to multidrug-resistant organisms (MDROs), such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridioides difficile (CDI), place a significant burden on our health care infrastructure. OBJECTIVE: Screening for MDROs is an important mechanism for preventing spread but is resource intensive. The objective of this study was to develop automated tools that can predict colonization or infection risk using electronic health record (EHR) data, provide useful information to aid infection control, and guide empiric antibiotic coverage. METHODS: We retrospectively developed a machine learning model to detect MRSA colonization and infection in undifferentiated patients at the time of sample collection from hospitalized patients at the University of Virginia Hospital. We used clinical and nonclinical features derived from on-admission and throughout-stay information from the patient's EHR data to build the model. In addition, we used a class of features derived from contact networks in EHR data; these network features can capture patients' contacts with providers and other patients, improving model interpretability and accuracy for predicting the outcome of surveillance tests for MRSA. Finally, we explored heterogeneous models for different patient subpopulations, for example, those admitted to an intensive care unit or emergency department or those with specific testing histories, which perform better. RESULTS: We found that the penalized logistic regression performs better than other methods, and this model's performance measured in terms of its receiver operating characteristics-area under the curve score improves by nearly 11% when we use polynomial (second-degree) transformation of the features. Some significant features in predicting MDRO risk include antibiotic use, surgery, use of devices, dialysis, patient's comorbidity conditions, and network features. Among these, network features add the most value and improve the model's performance by at least 15%. The penalized logistic regression model with the same transformation of features also performs better than other models for specific patient subpopulations. CONCLUSIONS: Our study shows that MRSA risk prediction can be conducted quite effectively by machine learning methods using clinical and nonclinical features derived from EHR data. Network features are the most predictive and provide significant improvement over prior methods. Furthermore, heterogeneous prediction models for different patient subpopulations enhance the model's performance.

Methicillin-Sensitive Staphylococcus aureus-Associated Leukocytoclastic Vasculitis: A Case Report and Literature Review.

The association of Staphylococcus aureus with vasculitis remains relatively rare and poorly understood. In this report, we present a case of Methicillin-sensitive Staphylococcus aureus (MSSA)-associated leukocytoclastic vasculitis (LCV) following a surgical site infection, adding to the limited body of knowledge on this intriguing clinical entity. A 52-year-old male with a medical history significant for type 2 diabetes mellitus, hypertension, hyperlipidemia, and coronary artery disease presented with progressively worsening generalized petechial rash and migratory joint pains with associated joint swelling. The patient's symptoms began following surgical repair for a rectus abdominis incisional hernia with mesh placement that was complicated by an abdominal wall abscess at the surgical site, prompting drain placement. Cultures from the abscess aspirate revealed Methicillin-sensitive Staphylococcus aureus infection. A punch biopsy of the petechial lesions revealed findings consistent with leukocytoclastic vasculitis. The rash and joint pains resolved approximately one week after initiation of treatment with antibiotics and steroids. This case sheds light on the rare but clinically significant association between Methicillin-sensitive Staphylococcus aureus infection and leukocytoclastic vasculitis, particularly following surgical site infections. The prompt recognition and treatment of underlying MSSA infection, along with the targeted management of LCV, resulted in the resolution of symptoms in our patient. This case emphasizes the importance of a comprehensive diagnostic approach and highlights the efficacy of antibiotic therapy in mitigating MSSA-associated vasculitic manifestations.

Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning.

Drug repurposing (repositioning) is a dynamically-developing area in the search for effective therapy of infectious diseases. Repositioning existing drugs with a well-known pharmacological and toxicological profile is an attractive method for quickly discovering new therapeutic indications. The off-label use of drugs for infectious diseases requires much less capital and time, and can hasten progress in the development of new antimicrobial drugs, including antibiotics. The use of drug repositioning in searching for new therapeutic options has brought promising results for many viral infectious diseases, such as Ebola, ZIKA, Dengue, and HCV. This review describes the most favorable results for repositioned drugs for the treatment of bacterial infections. It comprises publications from various databases including PubMed and Web of Science published from 2015 to 2023. The following search keywords/strings were used: drug repositioning and/or repurposing and/or antibacterial activity and/or infectious diseases. Treatment options for infections caused by multidrug-resistant bacteria were taken into account, including methicillin-resistant staphylococci, multidrug-resistant Mycobacterium tuberculosis, or carbapenem-resistant bacteria from the Enterobacteriaceae family. It analyses the safety profiles of the included drugs and their synergistic combinations with antibiotics and discusses the potential of antibacterial drugs with antiparasitic, anticancer, antipsychotic effects, and those used in metabolic diseases. Drug repositioning may be an effective response to public health threats related to the spread of multidrug-resistant bacterial strains and the growing antibiotic resistance of microorganisms.

Predictive Value of Vancomycin AUC24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.

BACKGROUND: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

Different Bacteria and their Antibiotic Sensitivity Patterns in Patients of Chronic Otitis Media-Active Mucosal Disease at a Secondary Care Centre in Delhi.

Chronic Otitis Media is characterized by distinct bacteriology compared with Acute Otitis Media, with COM being highly likely to harbor multiple bacteria of anaerobic and aerobic types of organisms (Cameron and Hussam K. El-Kashlan, xxx). In some patients, chronic infection with otorrhea will persist despite aggressive medical therapy. With the large number of cases of COM which presents to Sanjay Gandhi Memorial Hospital, and a majority being resistant to the common medications, we decided to undertake this study to have a better understanding of the bacterial epidemiology, the resistance, and what antibiotic to use in such cases. To determine the prevalence of different bacteriological agents and their antibiotic sensitivity pattern in patients of Chronic Otitis Media-Active Mucosal Disease presenting to ENT OPD at Sanjay Gandhi Memorial Hospital, Mangolpuri, Delhi. An observational cross-sectional study of 200 patients. After an initial examination, two sterile cotton swab sticks were introduced to collect pus samples from the medial part of the external auditory canal. The swabs were sent to the microbiology lab for Gram Staining, Culture, and Biochemical Tests, for identification of the different bacteriological agents and their antibiotic sensitivity patterns. Most common organism seen was Pseudomonas aeruginosa, followed by Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis, mixed bacterial growth, and Candida spp. If regular monitoring of bacteriological profile is done in each hospital, this will help us to choose the antibiotics in a better manner and hence prevent the appearance of newer resistant strains.

Propolis Alleviates Acute Lung Injury Induced by Heat-Inactivated Methicillin-Resistant Staphylococcus aureus via Regulating Inflammatory Mediators, Gut Microbiota and Serum Metabolites.

Propolis has potential anti-inflammatory properties, but little is known about its efficacy against inflammatory reactions caused by drug-resistant bacteria, and the difference in efficacy between propolis and tree gum is also unclear. Here, an in vivo study was performed to study the effects of ethanol extract from poplar propolis (EEP) and poplar tree gum (EEG) against heat-inactivated methicillin-resistant Staphylococcus aureus (MRSA)-induced acute lung injury (ALI) in mice. Pre-treatment with EEP and EEG (100 mg/kg, p.o.) resulted in significant protective effects on ALI in mice, and EEP exerted stronger activity to alleviate lung tissue lesions and ALI scores compared with that of EEG. Furthermore, EEP significantly suppressed the levels of pro-inflammatory mediators in the lung, including TNF-α, IL-1ß, IL-6, and IFN-γ. Gut microbiota analysis revealed that both EEP and EEG could modulate the composition of the gut microbiota, enhance the abundance of beneficial microbiota and reduce the harmful ones, and partly restore the levels of short-chain fatty acids. EEP could modulate more serum metabolites and showed a more robust correlation between serum metabolites and gut microbiota. Overall, these results support the anti-inflammatory effects of propolis in the treatment of ALI, and the necessity of the quality control of propolis.

Epidemiological and microbiological characteristics of S. aureus pediatric infections in Colombia 2018-2021, a national multicenter study (Staphylored Colombia).

Background: Staphylococcus aureus infections are a significant cause of morbidity and mortality in pediatric populations worldwide. The Staphylo Research Network conducted an extensive study on pediatric patients across Colombia from 2018 to 2021. The aim of this study was to describe the epidemiological and microbiological characteristics of S. aureus in this patient group. Methods: We analyzed S. aureus isolates from WHONET-reporting centers. An "event" was a positive culture isolation in a previously negative individual after 2 weeks. We studied center characteristics, age distribution, infection type, and antibiotic susceptibilities, comparing methicillin sensitive (MSSA) and resistant S. aureus (MRSA) isolates. Results: Isolates from 20 centers across 7 Colombian cities were included. Most centers (80%) served both adults and children, with 55% offering oncology services and 85% having a PICU. We registered 8,157 S. aureus culture isolations from 5,384 events (3,345 MSSA and 1,961 MRSA) in 4,821 patients, with a median age of 5 years. Blood (26.2%) and skin/soft tissue (18.6%) were the most common infection sources. Most isolates per event remained susceptible to oxacillin (63.2%), clindamycin (94.3%), and TMP-SMX (98.3%). MRSA prevalence varied by city (<0.001), with slightly higher rates observed in exclusively pediatric hospitals. In contrast, the MRSA rate was somewhat lower in centers with Antimicrobial Stewardship Program (ASP). MRSA was predominantly isolated from osteoarticular infections and multiple foci, while MSSA was more frequently associated with recurrent infections compared to MRSA. Conclusions: This is the largest study of pediatric S. aureus infections in Colombia. We found MSSA predominance, but resistance have important regional variations. S. aureus remains susceptible to other commonly used antibiotics such as TMP-SMX and clindamycin. Ongoing monitoring of S. aureus infections is vital for understanding their behavior in children. Prospective studies within the Staphylored LATAM are underway for a more comprehensive clinical and genetic characterization.

miR-155 promotes Th17 differentiation by targeting FOXP3 to aggravate inflammation in MRSA pneumonia.

BACKGROUND: Previous researches have clarified that miR-155 is increased in methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, and modulates Th9 differentiation. Like Th9 cells, Th17 cells were also a subset of CD4+ T cells and involved in MRSA pneumonia progression. This work aimed to investigate the role and mechanism of miR-155 in Th17 differentiation. METHODS: Bronchoalveolar lavage fluid (BALF) was collected from children with MRSA pneumonia and bronchial foreign bodies. MRSA-infected murine model was established followed by collecting BALF and lung tissues. qRT-PCR, ELISA and flow cytometry were performed to examine the mRNA expression and concentration of IL-17 and the number of Th17 cells in above samples. HE and ELISA were used to evaluate inflammatory responses in lung. Furthermore, CD4+ T cells were isolated from BALF of children for in vitro experiments. After treatments with miR-155 mimic/inhibitor, the roles of miR-155 in Th17/IL-17 regulation were determined. The downstream of miR-155 was explored by qRT-PCR, western blotting, dual luciferase reporter analysis and RIP assay. RESULTS: The levels of IL-17 and the proportion of Th17 cells were increased in children with MRSA pneumonia. A similar pattern was observed in MRSA-infected mice. On the contrary, IL-17 neutralization abolished the activation of Th17/IL-17 induced by MRSA infection. Furthermore, IL-17 blockade diminished the inflammation caused by MRSA. In vitro experiments demonstrated miR-155 positively regulated IL-17 expression and Th17 differentiation. Mechanistically, FOXP3 was a direct target of miR-155. miR-155 inhibited FOXP3 level via binding between FOXP3 and Argonaute 2 (AGO2), the key component of RNA-induced silencing complex (RISC). FOXP3 overexpression reversed elevated IL-17 levels and Th17 differentiation induced by miR-155. CONCLUSIONS: miR-155 facilitates Th17 differentiation by reducing FOXP3 through interaction of AGO2 and FOXP3 to promote the pathogenesis of MRSA pneumonia. IL-17 blockade weakens the inflammation due to MRSA, which provides a nonantibiotic treatment strategy for MRSA pneumonia.

Assessing the Diagnostic Performance and Clinical Utility of Nasal Methicillin Resistant Staphylococcus aureus PCR Testing in Pediatric Orbital Cellulitis.

Data are limited on the clinical impact of nasal methicillin-resistant Staphylococcus aureus (MRSA) polymerase chain reaction (PCR) testing (nMRSA-PCR) for orbital cellulitis. This two-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.

New Synergistic Combination Therapy of Mupirocin and α-Pinene Against Multidrug-Resistant Clinical Strains of Methicillin-Resistant Staphylococcus aureus.

OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. ("rosemary", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients. METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation. RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits. CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

Unraveling the efficacy of verbascoside in thwarting MRSA pathogenicity by targeting sortase A.

In the fight against hospital-acquired infections, the challenge posed by methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of novel treatment methods. This study focused on undermining the virulence of S. aureus, especially by targeting surface proteins crucial for bacterial adherence and evasion of the immune system. A primary aspect of our approach involves inhibiting sortase A (SrtA), a vital enzyme for attaching microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) to the bacterial cell wall, thereby reducing the pathogenicity of S. aureus. Verbascoside, a phenylethanoid glycoside, was found to be an effective SrtA inhibitor in our research. Advanced fluorescence quenching and molecular docking studies revealed a specific interaction between verbascoside and SrtA, pinpointing the critical active sites involved in this interaction. This molecular interaction significantly impedes the SrtA-mediated attachment of MSCRAMMs, resulting in a substantial reduction in bacterial adhesion, invasion, and biofilm formation. The effectiveness of verbascoside has also been demonstrated in vivo, as shown by its considerable protective effects on pneumonia and Galleria mellonella (wax moth) infection models. These findings underscore the potential of verbascoside as a promising component in new antivirulence therapies for S. aureus infections. By targeting crucial virulence factors such as SrtA, agents such as verbascoside constitute a strategic and potent approach for tackling antibiotic resistance worldwide. KEY POINTS: • Verbascoside inhibits SrtA, reducing S. aureus adhesion and biofilm formation. • In vivo studies demonstrated the efficacy of verbascoside against S. aureus infections. • Targeting virulence factors such as SrtA offers new avenues against antibiotic resistance.

Prussian blue-decorated indocyanine green-loaded mesoporous silica nanohybrid for synergistic photothermal-photodynamic-chemodynamic therapy against methicillin-resistant Staphylococcus aureus.

Nanomaterial-based synergistic antibacterial agents are considered as promising tools to combat infections caused by antibiotic-resistant bacteria. Herein, multifunctional mesoporous silica nanoparticle (MSN)-based nanocomposites were fabricated for synergistic photothermal/photodynamic/chemodynamic therapy against methicillin-resistant Staphylococcus aureus (MRSA). MSN loaded with indocyanine green (ICG) as a core, while Prussian blue (PB) nanostructure was decorated on MSN surface via in situ growth method to form a core-shell nanohybrid (MSN-ICG@PB). Upon a near infrared (NIR) laser excitation, MSN-ICG@PB (200 µg mL-1) exhibited highly efficient singlet oxygen (1O2) generation and hyperthermia effect (48.7℃). In the presence of exogenous H2O2, PB with peroxidase-like activity promoted the generation of toxic hydroxyl radicals (•OH) to achieve chemodynamic therapy (CDT). PTT can greatly increase the permeability of bacterial lipid membrane, facilitating the generated 1O2 and •OH to kill bacteria more efficiently. Under NIR irradiation and exogenous H2O2, MSN-ICG@PB (200 µg mL-1) with good biocompatibility exhibited a synergistic antibacterial effect against MRSA with high bacterial killing efficiency (>98 %). Moreover, due to the synergistic bactericidal mechanism, MSN-ICG@PB with satisfactory biosafety makes it a promising antimicrobial agent to fight against MRSA.