Laponite/lactoferrin hydrogel loaded with eugenol for methicillin-resistant Staphylococcus aureus-infected chronic skin wound healing.

Severe bacterial infections can give rise to protracted wound healing processes, thereby posing a significant risk to a patient's well-being. Consequently, the development of a versatile hydrogel dressing possessing robust bioactivity becomes imperative, as it holds the potential to expedite wound healing and yield enhanced clinical therapeutic outcomes. In this context, the present study involves the formulation of an injectable multifunctional hydrogel utilizing laponite (LAP) and lactoferrin (LF) as foundational components and loaded with eugenol (EG). This hydrogel is fabricated employing a straightforward one-pot mixing approach that leverages the principle of electrostatic interaction. The resulting LAP/LF/EG2% composite hydrogel can be conveniently injected to address irregular wound geometries effectively. Once administered, the hydrogel continually releases lactoferrin and eugenol, mitigating unwarranted oxidative stress and eradicating bacterial infections. This orchestrated action culminates in the acceleration of wound healing specifically in the context of MRSA-infected wounds. Importantly, the LAP/LF/EG2% hydrogel exhibits commendable qualities including exceptional injectability, potent antioxidant attributes, and proficient hemostatic functionality. Furthermore, the hydrogel composition notably encourages cellular migration while maintaining favorable cytocompatibility. Additionally, the hydrogel manifests noteworthy bactericidal efficacy against the formidable multidrug-resistant MRSA bacterium. Most significantly, this hydrogel formulation distinctly expedites the healing of MRSA-infected wounds by promptly inducing hemostasis, curbing bacterial proliferation, and fostering angiogenesis, collagen deposition, and re-epithelialization processes. As such, the innovative hydrogel material introduced in this investigation emerges as a promising dressing for the facilitation of bacterial-infected wound healing and consequent tissue regeneration.

Machine Learning To Stratify Methicillin-Resistant Staphylococcus aureus Risk among Hospitalized Patients with Community-Acquired Pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) is an uncommon but serious cause of community-acquired pneumonia (CAP). A lack of validated MRSA CAP risk factors can result in overuse of empirical broad-spectrum antibiotics. We sought to develop robust models predicting the risk of MRSA CAP using machine learning using a population-based sample of hospitalized patients with CAP admitted to either a tertiary academic center or a community teaching hospital. Data were evaluated using a machine learning approach. Cases were CAP patients with MRSA isolated from blood or respiratory cultures within 72 h of admission; controls did not have MRSA CAP. The Classification Tree Analysis algorithm was used for model development. Model predictions were evaluated in sensitivity analyses. A total of 21 of 1,823 patients (1.2%) developed MRSA within 72 h of admission. MRSA risk was higher among patients admitted to the intensive care unit (ICU) in the first 24 h who required mechanical ventilation than among ICU patients who did not require ventilatory support (odds ratio [OR], 8.3; 95% confidence interval [CI], 2.4 to 32). MRSA risk was lower among patients admitted to ward units than among those admitted to the ICU (OR, 0.21; 95% CI, 0.07 to 0.56) and lower among ICU patients without a history of antibiotic use in the last 90 days than among ICU patients with antibiotic use in the last 90 days (OR, 0.03; 95% CI, 0.002 to 0.59). The final machine learning model was highly accurate (receiver operating characteristic [ROC] area = 0.775) in training and jackknife validity analyses. We identified a relatively simple machine learning model that predicted MRSA risk in hospitalized patients with CAP within 72 h postadmission.

Population Pharmacokinetic Modeling and Probability of Target Attainment of Ceftaroline in Brain and Soft Tissues.

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT>MIC) to treat MRSA infections. Healthy subjects' plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients' plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CLin] and CLout). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CLin,CSF. Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT>MIC of 28.8%. Using the same target, patients with inflamed meninges (0.5 < GLUC ≤ 2 mmol/L) would reach PTAs of 99.8% and 97.2% for 600 mg q8h and q12h, respectively. For brain infection with mild inflammation (2 < GLUC ≤ 3.5 mmol/L), the PTAs would be reduced to 34.3% and 9.1%, respectively. Ceftaroline's penetration enhanced by meningeal inflammation suggests that the drug could be a candidate to treat MRSA CNS infections.

Toxin-Enabled "On-Demand" Liposomes for Enhanced Phototherapy to Treat and Protect against Methicillin-Resistant Staphylococcus aureus Infection.

An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.

Phloroglucinol Derivative Carbomer Hydrogel Accelerates MRSA-Infected Wounds' Healing.

Globally, wound infection is considered to be one of the major healthcare problems, with bacterial infections being the most critical threat, leading to poor and delayed wound healing, and even death. As a superbug, methicillin-resistant Staphylococcus aureus (MRSA) causes a profound hazard to public health safety, prompting us to search for alternative treatment approaches. Herein, the MTT test and Hoechst/propidium iodide (PI) staining demonstrated that PD was slightly less toxic to human fibroblasts including Human keratinocytes (HaCaT) cell line than Silver sulfadiazine (SSD), and Vancomycin (Van). In the MRSA-infected wound model, PD hydrogel (1%, 2.5%) was applied with for 14 days. The wound healing of PD hydrogel groups was superior to the SSD, Van, and control groups. Remarkably, the experimental results showed that PD reduced the number of skin bacteria, reduced inflammation, and upregulated the expression of PCNA (keratinocyte proliferation marker) and CD31 (angiogenesis manufacturer) at the wound site by histology (including hematoxylin-eosin (HE) staining, Masson staining) and immunohistochemistry. Additionally, no toxicity, hemocompatibility or histopathological changes to organs were observed. Altogether, these results suggested the potential of PD hydrogel as a safe, effective, and low toxicity hydrogel for the future clinical treatment of MRSA-infected wounds.

Orchestrating Nitric Oxide and Carbon Monoxide Signaling Molecules for Synergistic Treatment of MRSA Infections.

The local delivery of gaseous signaling molecules (GSMs) has shown promising therapeutic potential. However, although GSMs have a subtle interplay in physiological and pathological conditions, the co-delivery of different GSMs for therapeutic purposes remains unexplored. Herein, we covalently graft a nitric oxide (NO)-releasing N-nitrosamine moiety onto the carbon monoxide (CO)-releasing 3-hydroxyflavone (3-HF) antenna, resulting in the first NO/CO-releasing donor. Under visible light irradiation, photo-mediated co-release of NO and CO reveals a superior antimicrobial effect toward Gram-positive bacteria with a combination index of 0.053. The synergy of NO and CO hyperpolarizes and permeabilizes bacterial membranes, which, however, shows negligible hemolysis and no evident toxicity toward normal mammalian cells. Moreover, the co-release of NO and CO can efficiently treat MRSA infection in a murine skin wound model, showing a better therapeutic capacity than vancomycin.

Biomimetic Nanosponges Suppress In Vivo Lethality Induced by the Whole Secreted Proteins of Pathogenic Bacteria.

Polymeric nanoparticles coated with membrane of intact red blood cells have emerged as biomimetic toxin nanosponges (RBC-NS) that absorb and neutralize bacterial virulence factors associated with numerous bacterial infections. Despite its promise, a clear correlation between in vitro neutralization of complex bacterial toxins and in vivo therapeutic efficacy remains elusive. In this study, the whole secreted proteins (wSP) of methicillin-resistant Staphylococcus aureus (MRSA) are collected to induce lethality in mice. The wSP preserve the complexity of bacterial virulence profile while avoiding the intricacy and dynamics of infections by live bacteria. RBC-NS are first quantified for their neutralization capacity against the hemolytic activity of MRSA wSP in vitro. Using a mouse model, in vivo studies further demonstrate that, by neutralizing the hemolytic activity, RBC-NS confer significant survival benefits against wSP-induced lethality. Furthermore, when mice are challenged with a sublethal dosage of MRSA supernatant, RBC-NS reduce lung damages and inhibit the activation of nuclear factor kappa B in the spleen. These results provide a systematic evaluation of RBC-NS toward the treatment of severe MRSA infections such as MRSA bacteremia and MRSA-induced sepsis.

Purified citritin in combination with vancomycin inhibits VRE in vitro and in vivo.

Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) have been frequently associated with bacterial resistance mechanisms. These mechanisms, in turn, restrict a range of therapeutic opportunities for the treatment of infections caused by these micro-organisms. Faced with this problem, the present study aims to isolate and characterize molecules with antimicrobial activity derived from the fungus Penicillium citrinum isolated from Cerrado soil. Furthermore, we also tested possible antibacterial potential alone and in combination with commercial antimicrobial agents. In this context, citrinin was isolated and characterized by nuclear magnetic resonance and electrospray ionization. Functional analyses showed MIC of 128 µg ml-1 against S. aureus ATCC 25923, E. faecalis ATCC 29212 and a clinical isolate of vancomycin-resistant E. faecium (VRE01). However, for a clinical strain of methicillin-resistant S. aureus (MRSA01), the MIC was 256 µg ml-1. In order to avoid such high concentrations and reduce the collateral effects, additive effects were evidenced by combining citrinin with cefoxitin against MRSA01 (FIC index=0.5) and also citrinin with vancomycin toward VRE01 (FIC index=0.5). In vivo studies with BALB/c-tipe mice (MRSA assay) demonstrated a clinical ineffectiveness of cefoxitin associated with citrinin (9.8 mg kg-1 of cefoxitin +0.2 mg kg-1 of citrinin), with this combination being inefficient to increase animal survival. However, the combination used in the treatment of VRE (23.5 mg kg-1 of citrinin +1.5 mg kg-1 of vancomycin) sepsis model was extremely promising, leading to an animal survival rate of 80 percent. In summary, our data show, for the first time, the possible successful use of citrinin associated with vancomycin for pathogenic bacteria control.

Nanoparticle-Based Antivirulence Vaccine for the Management of Methicillin-Resistant Staphylococcus aureus Skin Infection.

With the rising threat of antibiotic-resistant bacteria, vaccination is becoming an increasingly important strategy to prevent and manage bacterial infections. Made from deactivated bacterial toxins, toxoid vaccines are widely used in the clinic as they help to combat the virulence mechanisms employed by different pathogens. Herein, the efficacy of a biomimetic nanoparticle-based anti-virulence vaccine is examined in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) skin infection. Vaccination with nanoparticle-detained staphylococcal α-hemolysin (Hla) effectively triggers the formation of germinal centers and induces high anti-Hla titers. Compared to mice vaccinated with control samples, those vaccinated with the nanoparticle toxoid show superior protective immunity against MRSA skin infection. The vaccination not only inhibits lesion formation at the site of bacterial challenge, but also reduces the invasiveness of MRSA, preventing dissemination into other organs. Overall, this biomimetic nanoparticle-based toxin detainment strategy is a promising method for the design of potent anti-virulence vaccines for managing bacterial infections.

Association between vitamin D deficiency and methicillin-resistant Staphylococcus aureus infection.

PURPOSE: Given that vitamin D (25(OH)D) contributes to immune defense, we sought to determine if deficiency of 25(OH)D was significantly associated with methicillin-resistant Staphylococcus aureus (MRSA) infection. METHODS: All patients with 25(OH)D determinations at the Atlanta VAMC from 2007 to 2010 were included in the analyses. These patients were cross-referenced with a prospectively collected MRSA infection database at the AVAMC (2006-2010). Patients with one or more MRSA infections during the study period were considered MRSA-infected patients. Multivariate logistic regression was used to determine the association between 25(OH)D status [deficient (<20 ng/mL) vs. non-deficient (≥20 ng/mL)] and MRSA infection. RESULTS: A total of 6405 patients with 25(OH)D determinations were included in the analyses, of which 401 (6.3 %) were MRSA-infected patients. Mean (SD) vitamin D levels, in ng/mL, were 21.1 (12.4) and 24.0 (12.6) for MRSA-infected patients and non-MRSA infected patients, respectively (p < 0.0001). The multivariate logistic regression model confirmed associations between MRSA infection and sex, race, BMI, HIV status, and 25(OH)D [odds ratio for 25(OH)D: 1.94; 95 % confidence interval: 1.51-2.49]. CONCLUSION: MRSA-infected patients had significantly lower serum vitamin D levels than non-MRSA infected patients, even when controlling for potential confounding variables.

A Smart Stimulation-Deadhesion and Antimicrobial Hydrogel for Repairing Diabetic Wounds Infected with Methicillin-Resistant Staphylococcus aureus.

The healing of chronic diabetic wounds is a common and significant challenge in the medical field. Despite extensive efforts, the development of hydrogel dressings with satisfactory functionality remains an ongoing concern. In this study, a multifunctional hydrogel wound dressing (PAN/Ag-PLG) with adhesion, antibacterial, hemostatic, and other properties, which can effectively repair diabetic wounds infected with methicillin-resistant Staphylococcus aureus (MRSA), is presented. The hydrogel dressing is composed of gallic acid (GA)-functionalized polylysine (PL)-reduced silver nanoparticles (Ag-PLG), oxidized hyaluronic acid (OHA), and cross-linked polyacrylic acid grafted with N-hydrosuccinimide ester. Notably, compared to most conventional wound dressing that lack adhesion or are difficult to remove, the prepared hydrogels exhibit excellent adhesion and mild stimulation-triggered detachment. In vitro and in vivo experiments reveal that the PAN/Ag-PLG hydrogel exhibits outstanding biocompatibility and antibacterial properties and promotes diabetic wound repair by reducing oxidative damage and promoting cell migration and angiogenesis. The smart PAN/Ag-PLG hydrogel reported in this study provides an approach for the potential clinical development of painless antibacterial dressings.

Fabrication of photo-induced molecular superoxide radical generator for highly efficient therapy against bacterial wound infection.

The pressing need for highly efficient antibacterial strategies arises from the prevalence of microbial biofilm infections and the emergence of rapidly evolving antibiotic-resistant strains of pathogenic bacteria. Photodynamic therapy represents a highly efficient and compelling antibacterial approach, offering promising prospects for effective control of the development of bacterial resistance. However, the effectiveness of many photosensitizers is limited due to the reduced generation of reactive oxygen species (ROS) in hypoxic microenvironment, which commonly occur in pathological conditions such as inflammatory and bacteria-infected wounds. Herein, we designed and prepared two phenothiazine-derived photosensitizers (NB-1 and NB-2), which can effectively generate superoxide anion radicals (O2●-) through the type I process. Both photosensitizers demonstrate significant efficacy in vitro for the eradication of broad-spectrum bacteria. Moreover, NB-2 possesses distinct advantages including strong membrane binding and strong generation of O2●-, rendering it an exceptionally efficient antibacterial agent against mature biofilms. In addition, laser activated NB-2 could be applied to treat MRSA-infected wound in vivo, which offers new opportunities for potential practical applications.

Fractional order model of MRSA bacterial infection with real data fitting: Computational Analysis and Modeling.

Bacterial infections in the health-care sector and social environments have been linked to the Methicillin-Resistant Staphylococcus aureus (MRSA) infection, a type of bacteria that has remained an international health risk since the 1960s. From mild colonization to a deadly invasive disease with an elevated mortality rate, the illness can present in many different forms. A fractional-order dynamic model of MRSA infection developed using real data for computational and modeling analysis on the north side of Cyprus is presented in this paper. Initially, we tested that the suggested model had a positively invariant region, bounded solutions, and uniqueness for the biological feasibility of the model. We study the equilibria of the model and assess the expression for the most significant threshold parameter, called the basic reproduction number (ℛ0). The reproductive number's parameters are also subjected to sensitivity analysis through mathematical methods and simulations. Additionally, utilizing the power law kernel and the fixed-point approach, the existence, uniqueness, and generalized Ulam-Hyers-Rassias stability are presented. Chaos Control was used to regulate the linear responses approach to bring the system to stabilize according to its points of equilibrium, taking into account a fractional-order system with a managed design where solutions are bound in the feasible domain. Finally, numerical simulations demonstrating the effects of different parameters on MRSA infection are used to investigate the impact of the fractional operator on the generalized form of the power law kernel through a two-step Newton polynomial method. The impact of fractional orders is emphasized in the study so that the numerical solutions support the importance of these orders on MRSA infection. With the application of fractional order, the significance of cognizant antibiotic usage for MRSA infection is verified.

Ca-doping interfacial engineering and glycolysis enable rapid charge separation for efficient phototherapy of MRSA-infected wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is the primary pathogenic agent responsible for epidermal wound infection and suppuration, seriously threatening the life and health of human beings. To address this fundamental challenge, we propose a heterojunction nanocomposite (Ca-CN/MnS) comprised of Ca-doped g-C3N4 and MnS for the therapy of MRSA-accompanied wounds. The Ca doping leads to a reduction in both the bandgap and the singlet state S1-triplet state T2 energy gap (ΔEST). The Ca doping also facilitates the two-photon excitation, thus remarkably promoting the separation and transfer of 808 nm near-infrared (NIR) light-triggered electron-hole pairs together with the built-in electric field. Thereby, the production of reactive oxygen species and heat are substantially augmented nearby the nanocomposite under 808 nm NIR light irradiation. Consequently, an impressive photocatalytic MRSA bactericidal efficiency of 99.98 ± 0.02 % is achieved following exposure to NIR light for 20 min. The introduction of biologically functional elements (Ca and Mn) can up-regulate proteins such as pyruvate kinase (PKM), L-lactate dehydrogenase (LDHA), and calcium/calmodulin-dependent protein kinase (CAMKII), trigger the glycolysis and calcium signaling pathway, promote cell proliferation, cellular metabolism, and angiogenesis, thereby expediting the wound-healing process. This heterojunction nanocomposite, with its precise charge-transfer pathway, represents a highly effective bactericidal and bioactive system for treating multidrug-resistant bacterial infections and accelerating tissue repair. STATEMENT OF SIGNIFICANCE: Due to the bacterial resistance, developing an antibiotic-free and highly effective bactericidal strategy to treat bacteria-infected wounds is critical. We have designed a heterojunction consisting of calcium doped g-C3N4 and MnS (Ca-CN/MnS) that can rapidly kill methicillin-resistant Staphylococcus aureus (MRSA) without damaging normal tissue through a synergistic effect of two-photon stimulated photothermal and photodynamic therapy. In addition, the release of trace amounts of biofunctional elements Mn and Ca triggers glycolysis and calcium signaling pathways that promote cellular metabolism and cell proliferation, contributing to tissue repair and wound healing.

Phage therapy in prosthetic joint infections caused by Staphylococcus aureus - A literature review.

Prosthetic joint infections (PJIs) are dreaded arthroplasty complications often caused by Staphylococcus aureus. Due to methicillin-resistant S. aureus (MRSA) strains or biofilm formation, successful treatment remains difficult. Currently, two-stage revision surgery constitutes the gold standard therapy of PJIs, sometimes replaced or supplemented by debridement, antibiotics, and implant retention (DAIR). Given the dire consequences of therapeutic failure, bacteriophage therapy might be another treatment option. Here we provide a comprehensive literature review addressing the efficacy of phages applied against S. aureus as causative agent of PJIs. The included 17 publications had in common that the applied phages proved to be effective against various S. aureus isolates including MRSA even in biofilms. Experiments with mice, rats, rabbits, and moth larvae confirmed favorable features of phage preparations in PJI treatment in vivo; including its synergistic with antibiotics. Case reports of PJI patients unanimously described the bacterial eradication following, alongside other measures, intravenous and intra-articular phage administration. Generally, no major side effects occurred, but in some cases elevated liver transaminases were observed. To conclude, our review compiled promising evidence suggesting the safety and suitability of phage therapy as an adjuvant to DAIR in S. aureus PJIs, and thus, underscores the significance of further research.

Methicillin-resistant Staphylococcus aureus nasal carriage among patients on haemodialysis with newly inserted central venous catheters.

BACKGROUND: Although methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization is common among end-stage kidney disease patients undergoing haemodialysis, few studies were focused on MRSA nasal carriers among haemodialysis patients with central venous catheters (CVCs). The aim of this study is to evaluate the risk factors, various clinical outcomes and effect of decolonization for MRSA nasal colonization among patients on haemodialysis via CVCs. METHODS: This was a single-centre non-concurrent cohort study of 676 patients who had new haemodialysis CVCs inserted. They were all screened for MRSA colonization via nasal swabs and were categorized into two groups: MRSA carriers and MRSA noncarriers. Potential risk factors and clinical outcomes were analysed in both groups. All MRSA carriers were given decolonization therapy and the effect of decolonization on subsequent MRSA infection was also performed. RESULTS: Eighty-two patients (12.1%) were MRSA carriers. Multivariate analysis showed that MRSA carrier (OR 5.44; 95% CI 3.02-9.79), long-term care facility resident (OR 4.08; 95% CI 2.07-8.05), history of Staphylococcus aureus infection (OR 3.20; 95% CI 1.42-7.20) and CVC in situ > 21 days (OR 2.12; 95% CI 1.15-3.93) were independent risk factors for MRSA infection. There was no significant difference in all-cause mortality between MRSA carriers and noncarriers. The MRSA infection rates were similar between MRSA carriers with successful decolonization and those who had failed/incomplete decolonization in our subgroup analysis. CONCLUSION: MRSA nasal colonization is an important cause of MRSA infection among haemodialysis patients with CVCs. However, decolonization therapy may not be effective in reducing MRSA infection.

Gellan gum spongy-like hydrogel-based dual antibiotic therapy for infected diabetic wounds.

Diabetic foot infection (DFI) is an important cause of morbidity and mortality. Antibiotics are fundamental for treating DFI, although bacterial biofilm formation and associated pathophysiology can reduce their effectiveness. Additionally, antibiotics are often associated with adverse reactions. Hence, improved antibiotic therapies are required for safer and effective DFI management. On this regard, drug delivery systems (DDSs) constitute a promising strategy. We propose a gellan gum (GG)-based spongy-like hydrogel as a topical and controlled DDS of vancomycin and clindamycin, for an improved dual antibiotic therapy against methicillin-resistant Staphylococcus aureus (MRSA) in DFI. The developed DDS presents suitable features for topical application, while promoting the controlled release of both antibiotics, resulting in a significant reduction of in vitro antibiotic-associated cytotoxicity without compromising antibacterial activity. The therapeutic potential of this DDS was further corroborated in vivo, in a diabetic mouse model of MRSA-infected wounds. A single DDS administration allowed a significant bacterial burden reduction in a short period of time, without exacerbating host inflammatory response. Taken together, these results suggest that the proposed DDS represents a promising strategy for the topical treatment of DFI, potentially overcoming limitations associated with systemic antibiotic administration and minimizing the frequency of administration.

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Integration of terpesomes loaded Levocetrizine dihydrochloride gel as a repurposed cure for Methicillin-Resistant Staphylococcus aureus (MRSA)-Induced skin infection; D-optimal optimization, ex-vivo, in-silico, and in-vivo studies.

The intention of this work is to assess the repurposed antimicrobial impact of Levocetirizine dihydrochloride (LVC), which is a well-known antihistaminic drug, in addition, to augment the antimicrobial effect by using terpene-enriched vesicles (TPs). To investigate how various parameters affect TPs aspects, TPs were made employing the ethanol-injection-method and optimized d-optimal design. The TPs were characterized based on their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum TP was submitted to more examinations. The optimum TP (TP12) showed a spherical vesicle having an EE% of 66.39 ± 0.12%, PS of 243.3 ± 4.60 nm, PDI of 0.458 ± 0.003, and ZP of 24.2 ± 0.55 mV. The in-vitro release study results demonstrated that LVC is sustainedly liberated from the optimum TP compared to LVC-solution. The ex-vivo assessment showed that LVC was released in a more sustained manner from TPs-gel related to LVC solution, optimum TP, and LVC gel. Ex-vivo visualization by confocal laser scanning microscopy showed good deposition of the fluorescein-labeled TP. Further, the in-vitro anti-bacterial effect and biofilm inhibition and detachment assessment confirmed the potency of LVC against Methicillin-resistant-Staphylococcus-aureus (MRSA). The in-silico study demonstrated that the LVC has excellent stability with other ingredients combined with it in the TPs, further, it proved that LVC is a potential candidate for treating MRSA. In-vivo assessments revealed a good antimicrobial effect toward MRSA infection. Moreover, the histopathological evaluation confirmed the safety of using TPs-gel topically. In conclusion, MRSA-related skin infections may be treated using the LVC loaded TPs-gel as a promising system.

Single-Component Self-Healing Antibacterial Anti-Inflammatory Intracellular-Antioxidative Poly(itaconic acid-pluronic) Hydrogel for Rapid Repair of MRSA-Impaired Wound.

The rapid healing and repair of multidrug-resistant bacteria infected wound is still a challenge in the field of wound surgery. It is an effective strategy to develop multifunctional bioactive biomaterials with anti-infection therapy and promoting tissue regeneration. However, most of conventional multifunctional wound healing biomaterials possess the complicated composition and fabrication procedure, which may limit their clinical transformation. Herein, we report a single-component multifunctional bioactive self-healing scaffold (itaconic acid-pluronic-itaconic acid) (FIA) with robust antibacterial antioxidant anti-inflammatory bioactivity for treating methicillin-resistant Staphylococcus aureus (MRSA) impaired wound. FIA scaffolds exhibited the temperature-responsive sol-gel behavior, good injectability, and broad-spectrum antibacterial activity (100% inhibition rate against S. aureus, E. coli, and MRSA). FIA possessed favorable hemocompatibility and cell compatibility and even stimulated the cellular proliferation. FIA could efficiently scavenge the intracellular reactive oxygen species (ROS), decrease the inflammation factors expression, promote endotheliocyte migration and blood tube formation, and reduce the M1 phenotype of macrophages in vitro. FIA could significantly clear the MRSA infection, speed up the MRSA-infected wound healing and rapid formation of the normal epithelial layer and skin appendages. This work may provide a simple and efficient multifunctional bioactive biomaterial strategy for overcoming the challenge of the MRSA-impaired wound.