MRSA Infection Research Articles

Recombination-mediated dissemination of Methicillin-resistant S. aureus clonal complex 1 in the Egyptian health care settings

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a rapidly evolving pathogen that is frequently associated with outbreaks and sustained epidemics. This study investigated the population structure, resistome, virulome, and the correlation between antimicrobial resistance determinants with phenotypic resistance profiles of 36 representative hospital-acquired MRSA isolates recovered from hospital settings in Egypt.ResultsThe community-acquired MRSA lineage, clonal complex 1 (CC1) was the most frequently detected clone, followed by three other globally disseminated clones, CC121, CC8, and CC22. Most isolates carried SCCmec type V and more than half of isolates demonstrated multi-drug resistant phenotypes. Resistance to linezolid, a last resort antibiotic for treating multidrug resistant MRSA, was observed in 11.11% of the isolates belonging to different genetic backgrounds. Virulome analysis indicated that most isolates harboured a large pool of virulence factors and toxins. Genes encoding aureolysin, gamma hemolysins, and serine proteases were the most frequently detected virulence encoding genes. CC1 was observed to have a high pool of AMR resistance determinants including cfr, qacA, and qacB genes, which are involved in linezolid and quaternary ammonium compounds resistance, as well as high content of virulence-related genes, including both of the PVL toxin genes. Molecular clock analysis revealed that CC1 had the greatest frequency of recombination (compared to mutation) among the four major clones, supporting the role of horizontal gene transfer in modulating AMR and hypervirulence in this clone.ConclusionsThis pilot study provided evidence on the dissemination success of CA-MRSA clone CC1 among Egyptian hospitals. Co-detection of multiple AMR and virulence genes in this lineage pose a broad public health risk, with implications for successful treatment. The results of this study, together with other surveillance studies in Egypt, should be used to develop strategies for controlling MRSA infections in Egyptian health-care settings.

741. Assessing the Concordance of MRSA Carriage Screening with MRSA Infections

Abstract Background There is a lack of research on MRSA surveillance in children. This study focused on children with confirmed MRSA infections to determine the utility of MRSA screens in guiding empiric anti-MRSA treatment for children without history of MRSA infection. We examined the concordance of screens to assess for differences by infection type, and used statistical analysis to determine significant contributors to concordance. Methods Pediatric hospital patients admitted from 2002-2022 were included. Subjects had MRSA infections subsequent to a MRSA surveillance screen performed in the preceding year. Statistical analysis, namely multivariable and binomial regression, identified associations between MRSA screens and infections. Number needed to treat analysis calculated the utility of re-screening. Results Among 246 subjects, 39.0% had concordant screens. 151 (61.4%) screens were obtained in the two weeks preceding infection. Sensitivity for bacteremia was 50.0% (n=42), for ET/respiratory 44.4% (n=81), for SSTI 29.4% (n=102). For children under 6 months of age, sensitivity was 35.9% (n=78). Multivariable analysis significantly associated days since MRSA screening and decreasing likelihood of concordance. Binomial regression modeled the probability of concordance to drop below 50.0% for all infections after four days, after six days for bacteremia specifically, and twelve days for ET/respiratory infections. Probability of Concordance Over Time The probability of MRSA screening concordance over time based upon binomial prediction modeling. Each line represents the probability of concordance on a given day subsequent to MRSA screening. Number Needed to Treat (test) Analysis A theoretical control arm of patients receiving no re-screening is compared to a theoretical treatment arm receiving re-screening. Each column represents the number needed to re-screen (for a given number of days) to predict one MRSA infection. Absolute risk reduction is overlaid. Conclusion The concordance of screens was far lower than NPV found in past studies. Bacteremia concorded at 50.0%, ET/respiratory infections 44.4%, SSTI 29.4%. The number of days elapsed since MRSA screening proved the only significant covariate. When that covariate modeled the probability of screening concordance with infection, 7 days represented when the probability of concordance fell to or dropped below 50.0% for infection types. Only patients with a known MRSA infection were included in our study, and concordance of screens was far lower than NPV found in past studies; previous results may have been impacted by low prevalence to inform high NPV. We suggest that negative MRSA screens should not invalidate reasonable suspicion for MRSA infection in patients with high pre-test probabilities for infection. Re-screening patients may optimize concordance. Disclosures All Authors: No reported disclosures

329. Vancomycin area under the concentration-time curve monitoring from Bayesian modeling in outpatient parenteral antimicrobial therapy

Abstract Background Current vancomycin monitoring guidelines recommend area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) monitoring for patients with serious MRSA infections. Most AUC monitoring studies have included hospitalized patients only; however, many patients complete vancomycin therapy in the outpatient setting. While traditional two-level AUC calculations are logistically challenging for outpatients, Bayesian modeling software can allow for single level AUC estimations. There are sparse data on the feasibility, safety, and efficacy of vancomycin AUC monitoring in OPAT. Methods We conducted a single-center, quasi-experimental, interrupted time series study of adult patients enrolled in the OPAT program at our institution for vancomycin management. Our institution implemented a pharmacist-driven vancomycin monitoring program using AUC targets from September 8th, 2019 to February 25th, 2020, and again from September 25th, 2022 to March 16th, 2023. Patients enrolled in the monitoring program underwent vancomycin monitoring using an AUC goal of 400-600 mg*hr/L, estimated using Bayesian modeling. A cohort comprising all patients enrolled in the OPAT program from July 4th, 2021 through August 27th, 2022 for trough only vancomycin monitoring was used for comparison. Patients were excluded from analysis if they were undergoing renal replacement therapy at baseline, enrolled in OPAT for ≤ 72 hours, or did not have vancomycin levels drawn for ≥ 14 days. The primary outcome was nephrotoxicity defined as a serum creatinine increase by ≥ 0.5 mg/dL or ≥ 50% during outpatient vancomycin therapy. Results There were 63 patients in the AUC arm, and 60 patients in the trough-only arm. The incidence of nephrotoxicity was lower in the AUC cohort (6.3% vs 23.3%, p=0.01). There was no difference in other vancomycin-related adverse event rates (1.6% vs 10.0%, p=0.06). Vancomycin discontinuation due to adverse event was lower in the AUC arm (6.3% vs 20.0%, p=0.03). Conclusion Patients undergoing AUC monitoring were significantly less likely to develop nephrotoxicity during outpatient vancomycin treatment. Bayesian modeling represents a viable and safe option for vancomycin AUC monitoring in OPAT. Disclosures David W. Kubiak, PharmD, BCPS, BCIDP, FIDSA, Astellas Pharma, Inc.: Advisor/Consultant|AVIR Pharma Inc: Advisor/Consultant|Cidara Therapeutics: Advisor/Consultant|Shionogi Inc: Grant/Research Support

982. A Comparison of Decolonization Methods and Impact on MRSA Infection in a Neonatal Intensive Care Unit

Abstract Background Infection due to methicillin-resistant Staphylococcus aureus (MRSA) causes morbidity and mortality in premature hospitalized neonates. MRSA colonization is a risk factor for transmission and outbreaks within neonatal intensive care units. Decolonization aims to stop MRSA transmission and infection. National guidelines lack recommendations for which decolonization practices are the most effective in neonates. We hypothesize that both topical mupirocin and chlorhexidine (CHG) is more effective than mupirocin alone at preventing MRSA infection in neonates. Methods In this retrospective study, we compared the rates of MRSA infection among all colonized neonates admitted to a 42 bed NICU at Texas Children’s Hospital from 2012 to 2020. Our surveillance and decolonization protocol (Figure 1) was introduced in October 2016. The MRSA screening methodology initially consisted of culture, then was changed to PCR (reflexed to culture if MRSA was detected). We grouped colonized neonates as those who underwent no decolonization, partial decolonization (mupirocin only), and full decolonization (CHG+ mupirocin) and compared the rates of infection in each. Infection was defined by isolation of MRSA from any specimen in the context of illness. This study was approved through the Baylor College of Medicine Institutional Review Board. Figure 1 MRSA surveillance and decolonization protocol Results 7,980 neonates were admitted to the NICU from 2012-2020. Of those screened, 128 were MRSA-colonized. Eighteen were fully decolonized, 76 partially decolonized and 34 received neither (Table 1). Zero infants who underwent full decolonization had MRSA infection. Decolonized infants were less likely to develop infection (OR 0.56, 95% C.I. 0.2-1.58) compared to infants who did not undergo any decolonization. Neonates who received only mupirocin (due to age) were less likely to develop infection (OR 0.72, 95% C.I. 0.26-2.04), however this reduction was not as impactful as with the combination of CHG and mupirocin (Figure 2). Table 1 MRSA infection rates by category of decolonization Figure 2 Comparison of MRSA infection between decolonized vs not decolonized and mupirocin vs no mupirocin with odds ratio and relative risk Conclusion Neonates who received CHG and mupirocin did not develop MRSA infection, and decolonization with mupirocin alone provides some but not as much protection from MRSA disease as does both mupirocin and CHG. Further studies should evaluate the safety of CHG wipes in neonates less than 36 weeks gestation/4 weeks chronologic age. Disclosures All Authors: No reported disclosures

1266. Refining Antimicrobial Stewardship by De-escalating Vancomycin Using MRSA (Methicillin Resistant Staphylococcus aureus) Nasal Screening in a Community Hospital Setting

Abstract Background Our institution has prioritized appropriate use of anti-Methicillin-resistant Staphylococcus aureus (MRSA) drugs such as vancomycin. The overuse of anti-MRSA drugs contributes to drug toxicities and development of resistant organisms such as vancomycin-resistant enterococcus (VRE). Recent studies show that MRSA nasal surveillance screening has a high negative predictive value of 96.5% in all types of pneumonia. At our community hospital a decentralized pharmacist-driven MRSA nares screening protocol was novel. We report the results of implementing a MRSA nares screening protocol for vancomycin de-escalation in pneumonia patients. Methods A decentralized pharmacist reviewed patients with a diagnosis of pneumonia and prescribed vancomycin. The pharmacist ensured that a culture-based MRSA nares screen was performed within 48 hours of admission, if not already ordered. If the nares screen returned negative and respiratory cultures did not grow MRSA at 48 hours, the decentralized pharmacist contacted the medical team to recommend discontinuing vancomycin. Reasons for exclusion included a positive respiratory culture for MRSA within the prior 7 days, septic shock, alternative site of MRSA infection, and greater than 48 hours of anti-MRSA therapy at time of swab collection. Results 164 patients were reviewed by pharmacy between 6/16/22 and 4/25/23. 98% of MRSA nares screening had been performed within 48 hours of admission. MRSA screen was ordered by the decentralized pharmacist in 44% of patients. 89% of patients screened were negative for MRSA and reviewed for de-escalation of vancomycin. In 40% of patients, vancomycin was discontinued after recommendations by the decentralized pharmacist, with 95% of the recommendations accepted by the primary hospitalist physician. 37% of patients' vancomycin was discontinued by the attending physician. Overall, 77% of patients with negative MRSA nasal screen results were successfully de-escalated. Conclusion Our data highlights the effectiveness of close physician-pharmacy collaboration. Most nares cultures were negative for MRSA allowing for de-escalation of antibiotics. Pharmacist recommendations were accepted majority of the time. Given the data, we plan to apply this approach for other ongoing stewardship initiatives. Disclosures All Authors: No reported disclosures

Different evolution of S. aureus methicillin-resistant and methicillin-susceptible infections, Argentina

Staphylococcus aureus-(SA) is widespread among healthcare-associated-(HA) and the community-associated-(CA) infections. However, the contributions of MRSA and MSSA to the SA overall burden remain unclear.In a nationally-representative-survey conducted in Argentina, 668 SA clinical isolates from 61 hospitals were examined in a prospective, cross-sectional, multicenter study in April 2015. The study aimed to analyze MRSA molecular epidemiology, estimate overall SA infection incidence (MSSA, MRSA, and genotypes) in community-onset (CO: HACO, Healthcare-Associated-CO and CACO, Community-Associated-CO) and healthcare-onset (HO: HAHO, Healthcare-associated-HO) infections, stratified by age groups. Additionally temporal evolution was estimated by comparing this study's (2015) incidence values with a previous study (2009) in the same region. Erythromycin-resistant-MSSA and all MRSA strains were genetically typed.The SA total-infections (TI) overall-incidence was 49.1/100,000 monthly-visits, 25.1 and 24.0 for MRSA and MSSA respectively (P = 0.5889), in April 2015. In adults with invasive-infections (INVI), MSSA was 15.7 and MRSA was 11.8 (P = 0.0288), 1.3-fold higher. HA SA infections, both MSSA and MRSA, surpassed CA infections by over threefold.During 2009–2015, there was a significant 23.4 % increase in the SA infections overall-incidence, mainly driven by MSSA, notably a 54.2 % increase in INVI among adults, while MRSA infection rates remained stable. The MSSA rise was accompanied by increased antimicrobial resistance, particularly to erythromycin, linked to MSSA-CC398-t1451-ermT + -IEC+-pvl- emergence. The SA-infections rise was primarily attributed to community-onset-infections (37.3 % and 62.4 % increase for TI and INVI, respectively), particularly HACO-MSSA and HACO-MRSA in adults, as well as CACO-MSSA. The main CA-MRSA-PFGE-typeN-ST30-SCCmecIVc-PVL+/− clone along with other clones (USA300-ST8-IV-LV-PVL+/−, PFGE-typeDD-ST97-IV- PVL−) added to rather than replaced CA-MRSA-PFGE-typeI-ST5-SCCmecIVa-PVL+/− clone in HA invasive-infections. They also displaced clone HA-MRSA-PFGE-typeA-ST5-SCCmecI, mainly in HAHO infections.The overall-burden of SA infections is rising in Argentina, driven primarily by community-onset MSSA, particularly in adults, linked to increased erythromycin-resistance and MSSA-CC398-t1451-ermT + -IEC+-pvl- emergence. Novel knowledge and transmission-control strategies are required for MSSA.

Effect of Resveratrol and Curcumin on Gene Expression of Methicillin-Resistant Staphylococcus aureus (MRSA) Toxins.

Staphylococcus aureus is an opportunistic pathogen that can lead to a number of potentially terrible community- and hospital-acquired illnesses. Among the diverse set of virulence factors that S. aureus possesses, secreted toxins play a particularly preeminent role in defining its virulence. In this work, we aimed to facilitate the development of novel strategies utilizing natural compounds to lower S. aureus's toxin production and consequently enhance therapeutic approaches. Two natural polyphenols, resveratrol (RSV) and curcumin (CUR), were tested for their effect on reducing toxin gene production of MRSA isolates. Fifty clinical MRSA isolates were gathered from Riyadh and Jeddah. Molecular screening of toxin genes (sea, seb, sec, sed, seh, lukF, and lukS) harbored by MRSA was performed. Sub-inhibitory concentrations of RSV (50 μg/ml) and CUR (20 μg/ml) were determined to study their effect on the gene expression MRSA's toxin genes. Our findings revealed the presence of the tested genes in MRSA isolates, with lukF being the most prevalent gene and seh the least detected gene. We found that RSV reduced the relative expression of toxin genes, sea, seb, lukF, and lukS, respectively, while CUR decreased the relative expression of sea and seb genes in the examined isolates. Regarding lukF and lukS, CUR downregulated the expression of both genes in some isolates and upregulated the expression in other isolates. From these results, we concluded that RSV and CUR could be used as alternative therapeutic approaches to treat MRSA infections through reducing toxin production.

Discovery of new quaternized norharmane dimers as potential anti-MRSA agents

IntroductionMethicillin-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. ObjectivesThis study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. MethodsA 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. ResultsCompound 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. ConclusionsThese 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.

Evaluation of the Effect and Mechanism of Sanhuang Ointment on MRSA Infection in the Skin and Soft Tissue via Network Pharmacology.

Skin and soft tissue infection (SSTI) is a frequently encountered clinical disease, and Sanhuang ointment, a traditional Chinese medicine, is used to treat it. However, the pharmacological effect of Sanhuang ointment on SSTI and its underlying mechanism remains unclear. Here, we investigate the protective effect of Sanhuang ointment on Methicillin-resistant Staphylococcus aureus (MRSA) infection in the skin and soft tissues and the underlying mechanism by network pharmacological analysis, followed by in vivo experimental validation. Via network pharmacology, the active components and disease targets of Sanhuang ointment were screened and intersected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A rat model of skin and soft tissue infection was established, and pathological features were observed. Large, medium, and small-dose groups (1 g, 0.5 g, and 0.25 g/animal, with the total amount of Vaseline, dispensed 1 g/animal) of Sanhuang ointment were prepared and Mupirocin ointment was used as a positive control (0.5 g/animal, with the total amount of Vaseline, dispensed 1 g/animal). The expressions of key proteins of the IL-17/NF-κB signaling pathway and downstream inflammatory factors were analyzed by histomorphological analysis, enzyme-linked immunosorbent assay, polymerase chain reaction, and Western blotting. In all, 119 active components and 275 target genes of Sanhuang ointment were identified and intersected with MRSA infection-related genes via network pharmacology analysis, and 34 target genes of Sanhuang ointment were found to be involved in skin and soft tissue infections with MRSA. Sanhuang ointment (1 g/mouse) could effectively ameliorate histopathological changes and significantly inhibit the expression of key proteins involved in the IL-17/NF-κB signaling pathway and downstream inflammatory factors (p < 0.05). Sanhuang ointment has a protective effect on MRSA infection and inhibits inflammation by inhibiting the IL-17/NF-κB signaling pathway. Our findings are important for the secondary development and new drug development of Sanhuang ointment.

Discontinuation of contact precautions in patients with hospital-acquired MRSA and VRE infections during the COVID-19 pandemic: A multi-center experience.

Variations in the literature support the benefit of contact precautions for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) infections in the hospital setting. During personal protective equipment shortages throughout the COVID-19 pandemic, contact precautions were discontinued for MRSA and VRE-infected patients. Rates of hospital-acquired MRSA and VRE infections were compared before and after this intervention, along with hand hygiene proportions. Contact precaution discontinuation did not lead to an increase in hospital-acquired MRSA or VRE infections.

Natural antibacterial agent-based nanoparticles for effective treatment of intracellular MRSA infection.

Intracellular MRSA is extremely difficult to eradicate by traditional antibiotics, leading to infection dissemination and drug resistance. A general lack of facile and long-term strategies to effectively eliminate intracellular MRSA. In this study, glabridin (GLA)-loaded pH-responsive nanoparticles (NPs) were constructed using cinnamaldehyde (CA)-dextran conjugates as carriers. These NPs targeted infected macrophages/MRSA via dextran mediation and effectively accumulated at the MRSA infection site. The NPs were then destabilized in response to the low pH of the lysosomes, which triggered the release of CA and GLA. The released CA downregulated the expression of cytotoxic pore-forming toxins, thereby decreasing the damage of macrophage and risk of the intracellular bacterial dissemination. Meanwhile, GLA could rapidly kill intracellularly entrapped MRSA with a low possibility of developing resistance. Using a specific combination of the natural antibacterial agents CA and GLA, NPs effectively eradicated intracellular MRSA with low toxicity to normal tissues in a MRSA-induced peritonitis model. This strategy presents a potential alternative for enhancing intracellular MRSA therapy, particularly for repeated and long-term clinical applications. STATEMENT OF SIGNIFICANCE: Intracellular MRSA infections are a growing threat to public health, and there is a general lack of a facile strategy for efficiently eliminating intracellular MRSA while reducing the ever-increasing drug resistance. In this study, pH-responsive and macrophage/MRSA-targeting nanoparticles were prepared by conjugating the phytochemical cinnamaldehyde to dextran to encapsulate the natural antibacterial agent glabridin. Using a combination of traditional Chinese medicine, the NPs significantly increased drug accumulation in MRSA and showed superior intracellular and extracellular bactericidal activity. Importantly, the NPs can inhibit potential intracellular bacteria dissemination and reduce the development of drug resistance, thus allowing for repeated treatment. Natural antibacterial agent-based drug delivery systems are an attractive alternative for facilitating the clinical treatment of intracellular MRSA infections.

Methicillin-resistant Staphylococcus aureus (MRSA) clusters in neonatal intensive care units (NICUs) and other neonatal units in New York State (NYS), 2001 to 2017

New York State (NYS) mandates reporting of all hospital-associated communicable disease outbreaks. We describe trends in NYS surveillance for neonatal unit methicillin-resistant Staphylococcus aureus (MRSA) outbreaks, the evolution of national MRSA infection prevention and control (IPC) recommendations, and IPC measures taken by NYS neonatal units. We evaluated trends of reported neonatal unit MRSA outbreaks by etiology from 2001 to 2017. We reviewed all reports and the use of IPC recommendations over time. From 2001 to 2017, 124 MRSA outbreaks were reported in 47 hospital neonatal units, with a total of 1,055 laboratory-confirmed infant cases, 18 infant deaths, and 52 laboratory-confirmed staff cases. The number of outbreaks increased with the level of care. During the study period, a higher proportion of hospitals reported implementing IPC measures, including reinforcing hand hygiene compliance (increased from 79.2% to 95.1%) and enhancing environmental cleaning and disinfection (increased from 4.2% to 78.0%) as well as performing active surveillance testing (AST) on exposed neonates (increased from 4.2% to 51.2%) and molecular testing on MRSA-positive isolates (increased from 5.3% to 18.9%). From 2001 to 2017, IPC measures in neonatal units increased in parallel with expanded national IPC recommendations. However, MRSA outbreaks in neonatal units continued to be frequent occurrences in NYS.

Immunoinformatics design of B-cell multi-epitope peptide for the diagnosis of Methicillin Resistant Staphylococcus aureus (MRSA) infection

Background: Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) remains a significant clinical and epidemiological pathogen in hospital settings and in the community world-wide. The resistance to methicillin in Staphylococcus aureus is mediated by the mecA gene, which encodes penicillin-binding protein 2a (PBP2A). Rapid patient screening for MRSA is essential for infection control procedures in order to possibly enhance the outcomes of infected patients. In this study, we utilized PBP2A to predict and create a novel synthetic protein with multiple immunodominant B cell epitopes for rapid diagnosis of MRSA using an in-silico approach. Methods: Seven putative PBP2A peptides were used to analyze the protein’s primary, secondary, and tertiary structures (BepiPred). The B cell construct was then evaluated using I-TASSER server, and physicochemical properties, and homology modeling of the 3 D structure of the protein were obtained. Results: In silico analyses revealed regions with high immunogenicity. Altogether, 19 consented epitopes were selected for the in-silico succession; three consented epitopes from ALJ10988.1, three from ORN56903.1, three from AFJ06714.1, one from AEO00772.1, three from WP_000721309.1, three from WP_057521704.1, and three from WP_063851348.1. The constructs have an average length of 503 amino acids, molecular weight of 55,151.78, instability index of 41.44, theoretical PI of 9.28 and a C score −1.50. In addition, the parameters that were examined indicated the newly multi-epitope construct could potentially serve as a theoretical framework for the development of a MRSA diagnostic kit. Conclusions: Overall, we have developed an antigen-based multi-epitope peptide for the rapid and accurate diagnosis of MRSA infection through an in-silico approach, acceptable in terms of antigenicity, physicochemical properties, structural stability and strong immunogenicity.

Comparison of the predictive accuracy of the physiologically based pharmacokinetic (PBPK) model and population pharmacokinetic (PPK) model of vancomycin in Japanese patients with MRSA infection

IntroductionThe latest therapeutic drug monitoring guidelines for vancomycin (VCM) recommend that area under the concentration-time curve is estimated based on model-informed precision dosing and used to evaluate efficacy and safety. Therefore, we predicted VCM concentrations in individual methicillin-resistant Staphylococcus aureus-infected patients using existing a physiologically based pharmacokinetic (PBPK) model and 1- and 2-compartment population pharmacokinetic (PPK) models and confirmed and verified the accuracy of the PBPK model in estimating VCM concentrations with the PPK model. MethodsThe subjects of the study are 20 patients, and the predicted concentrations were evaluated by comparing the observed and predicted trough and peak values of VCM concentrations for individual patients. ResultsThe results showed good correlation between the observed and predicted trough and peak concentrations of VCM was observed generally in the PBPK model, R2 values of 0.72, 0.62, and 0.40 with trough values of 0.49, 0.40, and 0.34 with peak values for PBPK model, 1-compartment, and 2-compartment model, respectively. ConclusionsAlthough the performance of the PBPK model is not as predictive as the PPK model, generally similar predictive trends were obtained, suggesting that it may be a valuable tool for rapid and accurate prediction of AUC for VCM.

MRSA infections in horses

MRSA infections in horses

Retrospective Study on Staphylococcus aureus Resistance Profile and Antibiotic Use in a Pediatric Population.

The growing phenomenon of antibiotic resistance and the presence of limited data concerning the pediatric area prompted us to focus on Staphylococcus aureus infection in this study, its antibiotic resistance profile, and the therapeutic management of affected children. We conducted a retrospective study by collecting clinical data on infants and children with antibiogram-associated S. aureus infection. We enrolled 1210 patients with a mean age of 0.9 years. We analyzed the resistance patterns and found 61.5% resistance to oxacillin, 58.4% resistance to cephalosporins, 41.6% resistance to aminoglycosides, and 38.3% resistance to fluoroquinolones. Importantly, we found no resistance to glycopeptides, a key antibiotic for MRSA infections whose resistance is increasing worldwide. We also found that the main risk factors associated with antibiotic resistance are being aged between 0 and 28 days, the presence of devices, and comorbidities. Antibiotic resistance is a growing concern; knowing the resistance profiles makes it possible to better target the therapy; however, it is important to use antibiotics according to the principles of antibiotic stewardship to limit their spread.

CNP-miR146a Decreases Inflammation in Murine Acute Infectious Lung Injury.

Acute respiratory distress syndrome (ARDS) has approximately 40% in-hospital mortality, and treatment is limited to supportive care. Pneumonia is the underlying etiology in many cases with unrestrained inflammation central to the pathophysiology. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA(miR)-146a, reduces bleomycin- and endotoxin-induced acute lung injury (ALI) by decreasing inflammation. We therefore hypothesized that CNP-miR146a would decrease inflammation in murine infectious ALI. Mice were injured with intratracheal (IT) MRSA or saline followed by treatment with IT CNP-miR146a or saline control. Twenty-four hours post-infection, bronchoalveolar lavage fluid (BALF) and whole lungs were analyzed for various markers of inflammation. Compared to controls, MRSA infection significantly increased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β; p < 0.05), BALF proinflammatory cytokines (IL-6, IL-8, TNFα, IL-1β; p < 0.01), and inflammatory cell infiltrate (p = 0.03). CNP-miR146a treatment significantly decreased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β; p < 0.05), bronchoalveolar proinflammatory protein leak (IL-6, IL-8, TNFα; p < 0.05), and inflammatory infiltrate (p = 0.01). CNP-miR146a decreases inflammation and improves alveolar-capillary barrier integrity in the MRSA-infected lung and has significant promise as a potential therapeutic for ARDS.

Infective Endocarditis at a Referral Children's Hospital During 19-Year Period: Trends and Outcomes.

We noted a recent increase in cases of infective endocarditis (IE) at our institution. The purpose of the study is to examine the incidence, risk factors, microbiology and outcome of IE in our pediatric population. Retrospective review of IE cases during 2002-2020 at Children's Hospital of Michigan, Detroit. 68 patients with IE were identified. There was a 2-fold increase in incidence during the 2012-2020 (late period) compared to the 2002-2011 (early period). The most common predisposing conditions were congenital heart disease (CHD) in 39 (57.4%) and central venous catheter (CVC) in 19 (27.9%). CHD was more frequent in the late period (29/43, 67.4%) compared to early period (10/25, 40.0%) (p = 0.042). In CHD patients, palliative or corrective cardiac surgery was performed prior to IE diagnosis in 4/25 (16%) in early period and 23/43 (53.5%) in the late period (p = 0.004). S. aureus was the most common causative organism (35.3%) followed by streptococci (22.1%). Valve replacement or valvuloplasty was performed in 22.1% of patients. Complications occurred in 20 (29.4%). Mortality occurred in 7 (10.3%): 3 had CHD, 3 had CVC and underlying conditions and 1 had fulminant MRSA infection. The higher incidence of IE during the late period is likely due to an increase in patients with CHD who had undergone prior cardiac surgery. S. aureus was the predominant pathogen in all patients including those with CHD, followed by streptococci. IE in children continues to be associated with high rates of morbidity and mortality.

Design of a chimeric glycosyltransferase OleD for the site-specific O-monoglycosylation of 3-hydroxypyridine in nosiheptide.

To identify the potential role of the 3-hydroxyl group of the pyridine ring in nosiheptide (NOS) for its antibacterial activity against Gram-positive pathogens, enzymatic glycosylation was utilized to regio-selectively create a monoglycosyl NOS derivative, NOS-G. For this purpose, we selected OleD, a UDP glycosyltransferase from Streptomyces antibioticus that has a low productivity for NOS-G. Activity of the enzyme was increased by swapping domains derived from OleI, both single and in combination. Activity enhancement was best in mutant OleD-10 that contained four OleI domains. This chimer was engineered by site-directed mutagenesis (single and in combination) to increase its activity further, whereby variants were screened using a newly-established colorimetric assay. OleD-10 with I117F and T118G substitutions (FG) had an increased NOS-G productivity of 56%, approximately 70 times higher than that of wild-type OleD. The reason for improved activity of FG towards NOS was structurally attributed to a closer distance (<3 Å) between NOS/sugar donor and the catalytic amino acid H25. The engineered enzyme allowed sufficient activity to demonstrate that the produced NOS-G had enhanced stability and aqueous solubility compared to NOS. Using a murine MRSA infection model, it was established that NOS-G resulted in partial protection within 20 h of administration and delayed the death of infected mice. We conclude that 3-hydroxypyridine is a promising site for structural modification of NOS, which may pave the way for producing nosiheptide derivatives as a potential antibiotic for application in clinical treatment.

A Photomodulable Bacteriophage‐Spike Nanozyme Enables Dually Enhanced Biofilm Penetration and Bacterial Capture for Photothermal‐Boosted Catalytic Therapy of MRSA Infections (Adv. Sci. 24/2023)

A Photomodulable Bacteriophage‐Spike Nanozyme Enables Dually Enhanced Biofilm Penetration and Bacterial Capture for Photothermal‐Boosted Catalytic Therapy of MRSA Infections (Adv. Sci. 24/2023)