Methicillin-resistant Staphylococcus Aureus Pneumonia Research Articles

Insect Cuticle Protein Nanoassemblies without Nonspecific Immune Response for Acute Methicillin-Resistant Staphylococcus aureus Pneumonia Remission.

The emergence and proliferation of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia poses a significant global public health threat. Herein, the significant remission effect against acute MRSA pneumonia was realized through the insect cuticle protein (OfCPH-2) nanoassemblies without nonspecific immune response. The lung repair results could be attributed to the transforming of M1-type to M2-type macrophage polarization and the repression of Th17 cell differentiation in mice spleens through the intervention of OfCPH-2 nanoassemblies. These findings offer a valuable insight into the application of insect protein-based materials as effective antidrug resistant strain agents as well as a powerful strategy for acute MRSA pneumonia.

Myristic Acid Solid Lipid Nanoparticles Enhance the Oral Bioavailability and Therapeutic Efficacy of Rifaximin against MRSA Pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is one of the leading causes of death and an immense financial burden on healthcare systems. Rifaximin (RFX) has good antibacterial activity against MRSA, but its clinical application is limited due to its poor oral absorption. Solid lipid nanoparticles have good biocompatibility, high drug loading, sustained release performance, and the inertia of lipids in gastric acid, which facilitates oral drug delivery. In order to improve the oral bioavailability of rifaximin and expand the clinical application of RFX for MRSA pneumonia, this study developed RFX-loaded myristic acid solid lipid nanoparticles (RFX-SLNs). This study first prepared RFX-SLNs through hot melt emulsification and ultrasonic methods and selected the optimal formula of RFX-SLNs through single-factor screening. Afterward, the particle size, zeta potential, and polydispersity index (PDI) of the RFX-SLNs were measured, the morphology of RFX-SLNs was observed by transmission electron microscopy, and the encapsulation efficiency (EE) and drug loading capacity (LC) of RFX-SLNs were detected by high-performance liquid chromatography. Then, the sustained release ability and oral bioavailability of RFX-SLNs were studied through in vitro release and pharmacokinetics. Finally, the therapeutic effect of RFX-SLNs on MRSA pneumonia infection was studied by using a mouse MRSA pneumonia infection model. The optimal formulation of RFX-SLNs was 1% RFX with water (3% PVA) and oil (myristic acid) ratio of 1:19. RFX-SLNs were spherical in shape with a smooth surface and uniform size. The EE and LC of three different batches of RFX-SLNs were 89.35±2.47%, 90.45±3.69%, 88.72±1.18%, and 9.50 ± 0.01%, 10.09±0.01%, and 9.68±0.00%, respectively. In vitro release and pharmacokinetic studies showed that the myristic acid solid lipid nanoparticles showed excellent sustained release as expected and increased the oral bioavailability of RFX by 2.18 times. This indicates that RFX-SLNs can be used for the oral treatment of bacterial infections. Compared to RFX, RFX-SLNs showed good therapeutic effects in a mouse MRSA pneumonia infection model. This study indicates that the myristic acid solid lipid nanoparticles might be an effective way to enhance the oral absorption and therapy effects of RFX and other insoluble drugs. This not only opens up avenues for the clinical application of RFX but also provides a way for the development of new dosage forms of water-soluble drugs and the expansion of their clinical application scope.

Nordalbergin Synergizes with Novel β-Lactam Antibiotics against MRSA Infection.

The synergetic strategy has created tremendous advantages in drug-resistance bacterial infection treatment, whereas challenges related to novel compound discovery and identifying drug-binding targets still remain. The mechanisms of antimicrobial resistance involving β-lactamase catalysis and the degradation of β-lactam antibiotics are being revealed, with relevant therapies promising to improve the efficacy of existing major classes of antibiotics in the foreseeable future. In this study, it is demonstrated that nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, efficiently potentiated the activities of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) by suppressing β-lactamase performance and improving the bacterial biofilm susceptibility to antibiotics. Nordalbergin was found to destabilize the cell membrane and promote its permeabilization. Moreover, nordalbergin efficiently improved the therapeutic efficacy of amoxicillin against MRSA pneumonia in mice, as supported by the lower bacterial load, attenuated pathological damage, and decreased inflammation level. These results demonstrate that nordalbergin might be a promising synergist of amoxicillin against MRSA infections. This study provided a new approach for developing potentiators for β-lactam antibiotics against MRSA infections.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

Laurocapram, a transdermal enhancer, boosts cephalosporin’s antibacterial activity against Methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA), a notorious bacterium with high drug resistance and easy recurrence after surgery, has posed significant clinical treatment challenges. In the current scarcity of new antibiotics, the identification of adjuvants to existing antibiotics is a promising approach to combat infections caused by multidrug-resistant Gram-positive bacteria. The in vitro synergy test, which included a MIC assay, time-kill curve, antimicrobial susceptibility testing, and live/dead bacteria staining assay, revealed that laurocapram, a widely used chemical transdermal enhancer, could potentiate the antibacterial activity of cephalosporins against MRSA. In vitro, laurocapram combined with cefixime showed an excellent synergistic activity against MRSA (FICI = 0.28 ± 0.00). In addition, the combination of laurocapram and cefixime may inhibited the formation of MRSA biofilm and caused cell membrane damage. Following that, we discovered that combining laurocapram with cefixime could alleviate the symptoms of mice in the MRSA skin infection model and the MRSA pneumonia model. In conclusion, laurocapram is a promising and low-cost antibacterial adjuvant, providing a new strategy for further exploring the use of lower doses of cephalosporins to combat MRSA infection.

Utility of Methicillin-Resistant Staphylococcus aureus Nasal PCR Testing in Pediatric Patients With Suspected Respiratory Infections.

Observational studies in adults suggest nasal methicillin-resistant Staphylococcus aureus (MRSA) swabs have a high negative predictive value (NPV) for ruling out MRSA pneumonia, however, pediatric data are limited. This retrospective study of 505 pediatric patients found a 99.8% NPV among children with suspected respiratory infections.

Inhibiting Peptidoglycan Hydrolase Alleviates MRSA Pneumonia Through Autolysin-Mediated MDP-NOD2 Pathway.

Methicillin-resistant Staphylococcus aureus (MRSA) is a cause of staph infection that is difficult to treat because of resistance to some antibiotics. A recent study indicated that diarylurea ZJ-2 is a novel antibacterial agent against multi-drug resistant Enterococcus faecium. In this work, we refined the bactericidal mechanism of ZJ-2 as a peptidoglycan (PG) hydrolase by affecting AtlA-mediated PG homeostasis. A wild-type strain (WT) and a mutant strain (ΔatlA) were used to investigate the effects of ZJ-2 on the cell wall, PG, and autolysin regulatory system by antimicrobial susceptibility testing, hemolytic toxin assay, microanalysis, autolysis assay, qRT-PCR, ELISA and mouse model of pneumonia. The results revealed that ZJ-2 down-regulated the expression of genes related to peptidoglycan hydrolase (PGH) (sprX, walR, atlA, and lytM), and reduced the levels of PG, muramyl dipeptide (MDP), cytokines, and hemolytic toxin, while ΔatlA interfered with the genes regulation and PG homeostasis. In the mouse MRSA pneumonia model, the same trend was observed in the nucleotide oligomerization domain protein 2 (NOD2) and relative proinflammatory factors. ZJ-2 may act as a novel inhibitor of PG hydrolyse, disrupting autolysin-mediated PG homeostasis, and reducing inflammation by down-regulating the MDP-NOD2 pathway.

Effects of low-frequency ultrasound combined with anti-MRSA agents on the mouse model of pulmonary infection.

The treatment of methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia with antibiotics alone poses considerable challenges. To address these challenges, low-frequency ultrasound (LFU) emerges as a promising approach. In this study, a mouse pneumonia model was established through intratracheal injection of MRSA to investigate the therapeutic efficacy of LFU in combination with antibiotics. Minimal inhibitory concentration was assessed, and the distribution of antibiotics in the lung and plasma was determined using liquid chromatography coupled with mass spectrometry. Various parameters, including the survival rate, histopathology, lung bacterial clearance, and the expressions of cytokines and inflammation-related genes, were evaluated before and after treatment. Compared with the infection group, both the antibiotic-alone groups [vancomycin (VCM), linezolid, and contezolid (CZD)] and the groups in combination with LFU demonstrated an improvement in the survival status of mice. The average colony-forming units of lung tissue in the LFU combination groups were lower compared with the antibiotic-alone groups. While no significant changes in C-reactive protein and procalcitonin in plasma and bronchoalveolar lavage fluid were observed, histopathological results revealed reduced inflammatory damage in LFU combination groups. The secretion of interleukin-6 and tumor necrosis factor-alpha was decreased by the combination treatment, particularly in the VCM + LFU group. Furthermore, the expressions of MRSA virulence factors (hla and agrA) and inflammation-related genes (Saa3, Cxcl9, and Orm1) were further reduced by the combinations of LFU and antibiotics. Additionally, LFU treatment facilitated the distribution of VCM and CZD in mouse lung tissue at 30 and 45 min, respectively, after dosage.IMPORTANCETreating pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) with antibiotics alone poses significant challenges. In this in vivo study, we present compelling evidence supporting the efficacy of low-frequency ultrasound (LFU) as a promising approach to overcome these obstacles. Our findings demonstrated that LFU enhanced the effectiveness of vancomycin, linezolid, and contezolid in an MRSA pneumonia model. The combination of LFU with anti-MRSA agents markedly improved the survival rate of mice, accelerated the clearance of pulmonary bacteria, reduced inflammatory injury, inhibited the production of MRSA endotoxin, and enhanced the distribution of antibiotics in lung tissue. The application of LFU in the treatment of pulmonary infections held substantial significance. We believe that readers of your journal will find this topic of considerable interest.

Green Synthesis and Characterization of Silver Nanoparticles from Ficus palmata Forssk. and Evaluation of their Antibacterial Activity Against Resistant Bacteria

In the present study, the synthesis and characterization of silver nanoparticles were carried out through a green chemistry approach. The purpose was to determine the antibacterial potential of environmentally safe nanoparticles against commonly reported resistant bacteria. The nanoparticles were synthesized using the aqueous extract of Ficus palmata Forssk. leaves. The active components present in the leaf extract acted as reducing and capping agents. The method used was easy, cost-effective, eco-friendly, and less time-consuming. To determine the shape, size, and crystalline nature, the nanoparticles underwent X-ray diffraction, and scanning electron microscopy. The synthesized nanoparticles were found to be crystalline in nature and spherical in shape, with an average diameter of about 30 nm. The antibacterial activity of the silver nanoparticles (20 µl) was evaluated against a range of antibiotic-resistant bacteria using standard microbiological procedures. They were found to be effective against MRSA, Bacillus subtilis, Staphylococcus aureus, and Klebsiella pneumonia.

Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.

Bacterial pneumonia is a common clinical syndrome leading to significant morbidity and mortality worldwide. In the current study, we investigate a novel, multidirectional relationship between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Using an in vivo pneumonia model, we demonstrate that highly sulfated heparan sulfate (HS) oligosaccharides are shed into the airspaces in response to MRSA pneumonia. In vitro, these HS oligosaccharides do not directly alter MRSA growth or gene transcription. However, in the presence of an antimicrobial peptide (cathelicidin), increasing concentrations of HS inhibit the bactericidal activity of cathelicidin against MRSA as well as other nosocomial pneumonia pathogens (Klebsiella pneumoniae and Pseudomonas aeruginosa) in a dose-dependent manner. Surface plasmon resonance shows avid binding between HS and cathelicidin with a dissociation constant of 0.13 μM. These findings highlight a complex relationship in which shedding of airspace HS may hamper host defenses against nosocomial infection via neutralization of antimicrobial peptides. These findings may inform future investigation into novel therapeutic targets designed to restore local innate immune function in patients suffering from primary bacterial pneumonia.NEW & NOTEWORTHY Primary Staphylococcus aureus pneumonia causes pulmonary epithelial heparan sulfate (HS) shedding into the airspace. These highly sulfated HS fragments do not alter bacterial growth or transcription, but directly bind with host antimicrobial peptides and inhibit the bactericidal activity of these cationic polypeptides. These findings highlight a complex local interaction between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of bacterial pneumonia.

Recent Trends in the Prevalence of Antibiotic-Resistant Organism Infections (AROI) in Acute Leukemia Patients

Introduction:Infections and related complications are a major cause of morbidity and mortality in acute leukemia patients. There is a growing concern for increased antibiotic-resistant organism infections (AROI), including methicillin resistant Staphylococcus aureus pneumonia (MRSA) with the widespread use of antibiotics. Risk factors include older age, prior use of antibiotics, duration of use and type of antibiotics. The role of race, gender, income and insurance status has not been studied. We aimed to study the trends in the prevalence of AROI from 2016 to 2020. Methods: The National Inpatient Sample (NIS) database was queried to identify adult patients admitted with a principal diagnosis of acute lymphoblastic or myeloid leukemia using the International Classification of Disease (ICD-10) codes. Total leukemia admissions were then analyzed using secondary diagnoses codes for resistance to antimicrobial agents and MRSA pneumonia to assess trends for AROI prevalence and demographic characteristics. Statistics were performed using STATA, and multivariate linear and logistic regression analysis was used to adjust for confounders. Results:There were a total of 144,385 admissions for acute leukemia in the study period. The leukemia admission rate increased steadily from 2016 to 2020 (p=0.003). A higher proportion of patients belonged to the elderly group (>65 years, 45.2%) compared to middle-aged (45-65 years, 31.9%) and young adults (18-45 years, 22.8%), [p=0.018]. Most of the study population was White (60.9%), followed by Hispanics (15.7%) and African Americans (9.4%). The study population's predominant types of insurance were Medicare (37.5%) and private insurance (38.9%) followed by Medicaid (20.5%). Admissions related to AROI constituted only a small percentage of total leukemia admissions but the proportion of AROI increased from 1.16% in 2016 to 1.90% in 2020 [Adjusted Odds ratio (AOR): 1.12, 95% Confidence Interval (CI)-1.02-1.24; p=0.021]. Woman had a higher prevalence of AROI than men (AOR: 1.39, 95% CI-1.11-1.76; p=0.004). Elderly patients (> 65 years) have nearly similar odds of getting AROI (AOR 1.01) as younger patients (< = 65 years). Compared to Whites, the prevalence trend of AROI is higher in African Americans (AOR: 1.87, 95% CI-1.32-2.66; p<0.01) and Hispanic populations (AOR: 1.99, 95% CI-1.46-2.74; p<0.01). Higher-income population had increased odds of antibiotic resistance infections than the lower-income population (AOR: 1.36, 95% CI-1.01-1.85; p=0.046). Compared to patients with Medicare, those with Medicaid (AOR: 1.63, 95% CI-1.05-2.52; p=0.027) and Private insurance (AOR: 1.85, 95% CI-1.33-2.57; p=<0.01) had higher AROI, and there was no statistically significant difference with uninsured population. Over the study years, those admitted to larger hospitals (AOR: 1.82; p=0.007) and teaching hospitals (AOR: 2.07; p=0.006) had higher AROI trends than smaller hospitals and non-teaching hospitals respectively. When stratified by Charlson comorbidity index, there was statistically significant trend with increased rates of AROI in patients with lower index points (< = 4) but not in those with higher index points (> 4). Conclusion:There was a statistically significant rise in the prevalence of AROI across the study years. Racial and economic disparities exist in the prevalence of these resistant infections. Further studies are needed to assess the underlying reasons and steps to address these.

Predictive value of methicillin-resistant staphylococcus aureus nasal swab in patients with COVID-19 pneumonia and secondary bacterial pneumonia

ObjectiveTo determine the performance measures of admission methicillin-resistant Staphylococcus aureus (MRSA) nasal swabs for MRSA bacterial pneumonia in patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MethodsThe study included patients admitted with SARS-CoV-2-positive nasopharyngeal specimens, MRSA nasal screens, and bacterial cultures to assess secondary MRSA pneumonia. Results293 patients and 662 microbiological cultures evaluated. Overall, the specificity (91.8% [95% CI 88.6% to 95%]) and negative predictive value (NPV 97.4% [95% CI 95.4% – 99.3%]) of MRSA nasal swabs was high. However, the sensitivity (46.2%; 95% CI 19.1% to 73.3%) and positive predictive value (PPV 20.7%; 95% CI 59.5 – 35.4%) were low. Those patients in the MRSA nasal swab negative group had a shorter median duration of linezolid therapy. ConclusionsSARS-CoV-2 infection doesn't reduce the specificity or negative predictive value of MRSA nasal swabs for secondary MRSA pneumonia.

SAT391 Supratherapeutic Estrogen Levels in Transgender Women Likely From Sublingual Estradiol

Abstract Disclosure: E. Jalal: None. C. Baldwin: None. Transgender medicine is typically managed in the outpatient setting. We report a case where the patient’s hospitalization provided unique insight into hormone management to achieve cis-female range estrogen and testosterone levels in a monitored environment.A 38-year-old transgender woman with HIV (on antiretroviral therapy) complicated by neurocognitive disorder, polysubstance use, mood disorder with previous suicidal ideation, and polytrauma (currently wheelchair bound) was admitted for respiratory failure from MRSA pneumonia. She completed 14 days of antibiotics with resolution of acute medical problems, but ability to secure a safe discharge plan prolonged her hospitalization. Endocrinology was consulted to aid in oral estradiol (E2) management.Prior to admission, patient reported taking 10mg of oral E2 daily. While hospitalized, she was given 6mg E2 daily, but requested resumption of her home dose. Initial total estrogen and testosterone levels were 913 pg/mL (56-213 pg/mL) and 105 ng/dL (264-916 ng/dL), respectively. She denied estrogen pellets, implants, or consumption of additional E2 beyond 6mg daily, nor did she have visitors who provided supplemental hormone; however, she admitted that she does not swallow the E2 pills immediately.Endocrinology initiated intramuscular leuprolide to suppress her total testosterone production to the female range of 0-50 ng/dL, allow for decreased dosing of E2 to maintain female range estrogen levels, and minimize venous thromboembolism (VTE) risk given reduced patient mobility. Her E2 was held for 5 days, with a subsequent total estrogen level of 398 pg/mL (56-213 pg/mL). She was restarted on oral E2 2mg, with total estrogen levels of 238 pg/mL and 517 pg/mL (56-213 pg/mL) at three and six days respectively. Oral E2 was again held for an additional four days, leading to total estrogen level of 119 pg/mL (56-213 pg/mL) and total testosterone of 18 ng/dL (264-916 ng/dL). Her final regimen is now oral E2 1mg daily. She did not develop VTE while hospitalized.Research into the pharmacokinetics of oral versus sublingual E2 is scarce. Differences in absorption explain this patient’s supratherapeutic estrogen level of 913 pg/mL and insufficiently suppressed total testosterone of 105 ng/dL. Sublingual E2 achieves higher peak levels but multi-daily dosing is required to fully suppress testosterone production when compared to its oral counterpart, which corresponds to this patient’s initial laboratory findings. Sublingual E2 also has a lower risk of VTE since it avoids first-pass metabolism. Future research should target alternative routes of estrogen therapy that may potentially be safer than current modalities. Presentation: Saturday, June 17, 2023

Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization.

Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to carry a high burden in terms of mortality. With the roles of gut microbiota in mediating lung diseases being gradually uncovered, the details of the molecular mechanism of the "gut-lung axis" mediated by beneficial microorganisms and small-molecule metabolites have gradually attracted the attention of researchers. However, further studies are still necessary to determine the efficacy of microbial-based interventions. Our findings indicate that sodium butyrate (NaB) alleviates MRSA-induced pulmonary inflammation by improving gut-lung microbiota and promoting M2 polarization of alveolar macrophages. Therefore, the preventive administration of NaB might be explored as an effective strategy to control MRSA pneumonia.

Using Methicillin-Resistant Staphylococcus aureus Nasal Screens to Rule Out Methicillin-Resistant S aureus Pneumonia in Surgical Intensive Care Units

IntroductionThe methicillin-resistant Staphylococcus aureus (MRSA) polymerase chain reaction (PCR) has a high negative predictive value (NPV). We aimed to understand if there was a difference in the NPV of the MRSA screen in surgical intensive care units (ICUs) and to determine its role in antibiotic de-escalation. MethodsWe performed a single-center, retrospective cohort study of adults with a positive respiratory culture and MRSA nasal PCR admitted to a surgical ICU from 2016 to 2019. Patients were stratified by surgical ICU: cardiothoracic/cardiovascular intensive care unit (CVICU) or transplant/acute care surgery intensive care unit (ACS-ICU). Our primary outcome was the NPV of MRSA screen. Secondary outcome was the duration of empiric MRSA-targeted therapy. ResultsWe analyzed 61 patients: 42.6% (n = 26) ACS-ICU and 57.4% (n = 35) CVICU. There were no differences in age, comorbidities, prior MRSA infection, recent antibiotic use, immunocompromised status, or renal replacement therapy. At pneumonia diagnosis, more patients in the ACS-ICU were hospitalized ≥5 d (65.4% versus 8.6%, P < 0.0001) and more patients in the CVICU were in septic shock (88.6% versus 34.5%, P < 0.0001) and thrombocytopenic (40% versus 11.5%, P = 0.02). NPV of the PCR was similar (ACS-ICU: 0.92 [0.75-0.98], CV-ICU 0.89 [0.73-0.96]). On multivariable linear regression, the CVICU was associated with longer empiric therapy (β 1.5, 95% CI 0.8-2.3, P < 0.0001), as was hospitalization for ≥5 d (β 0.73, 95% CI 0.06-1.39, P = 0.03). ConclusionsThe MRSA nasal PCR screen has a high NPV for ruling out MRSA pneumonia in critically ill surgical patients. However, patients in the CVICU and patients hospitalized ≥5 d had a longer time to de-escalation of MRSA-targeted therapy, potentially due to higher clinical risk profile.

Simulation of optimal dose regimens of photoactivated curcumin for antimicrobial resistance pneumonia in COVID-19 patients: A modeling approach.

Secondary antimicrobial resistance bacterial (AMR) pneumonia could lead to an increase in mortality in COVID-19 patients, particularly of geriatric patients with underlying diseases. The comedication of current medicines for AMR pneumonia with corticosteroids may lead to suboptimal treatment or toxicities due to drug-drug interactions (DDIs). This study aimed to propose new promising dosage regimens of photoactivated curcumin when co-administered with corticosteroids for the treatment of antimicrobial resistance (AMR) pneumonia in COVID-19 patients. A whole-body physiologically-based pharmacokinetic (PBPK) with the simplified lung compartments model was built and verified following standard model verification (absolute average-folding error or AAFEs). The pharmacokinetic properties of photoactivated were assumed to be similar to curcumin due to minor changes in physiochemical properties of compound by photoactivation. The acceptable AAFEs values were within 2-fold. The verified model was used to simulate new regimens for different formulations of photoactivated curcumin. The AAFEs was 1.12-fold. Original formulation (120 mg once-daily dose) or new intramuscular nano-formulation (100 mg with a release rate of 10/h given every 7 days) is suitable for outpatients with MRSA pneumonia to improve patient adherence. New intravenous formulation (2000 mg twice-daily doses) is for hospitalized patients with both MRSA and VRSA pneumonia. The PBPK models, in conjunction with MIC and applied physiological changes in COVID-19 patients, is a potential tool to predict optimal dosage regimens of photoactivated curcumin for the treatment of co-infected AMR pneumonia in COVID-19 patients. Each formulation is appropriate for different patient conditions and pathogens.

Hybrid Biomimetic Membrane Coated Particles-Mediated Bacterial Ferroptosis for Acute MRSA Pneumonia.

Acute methicillin resistant Staphylococcus aureus (MRSA) pneumonia is one of the most frequently seen lung infection diseases with high morbidity and mortality. It is urgent to explore an efficient antibacterial strategy owing to the increase of drug resistance, virulence, and pathogenicity of MRSA. It was found that Fe3O4 can induce ferroptosis in MRSA, but its effect was inhibited by glutathione (GSH) to a certain extent, while cinnamaldehyde (CA) can enhance ferroptosis by consuming GSH. As a bacterial quorum sensing (QS) inhibitor, CA can suppress the QS system and further exert its antibacterial and antibiofilm effects. Here, we developed an Fe3O4-based ferroptosis inducer to promote ferroptosis in MRSA, interrupt the QS, destroy biofilm, and thus effectively treat acute MRSA pneumonia. We used sodium alginate (SA) to wrap Fe3O4 and CA to form particles, and then coated the surface with a hybrid biomimetic membrane composed of an erythrocyte membrane and platelet membrane to obtain lung targeted antibacterial particles (mFe-CA). Under ultrasonic (US) stimulation, mFe-CA can efficiently release Fe3O4 and CA, thereby synergically inducing MRSA death with the characteristics of ferroptosis, including mass ROS production, lipid peroxidation, GSH depletion, and respiratory chain suppression. Furthermore, mFe-CA + US can inhibit the QS system, remove biofilms, and reduce strain virulence. In the mouse model of MRSA pneumonia, mFe-CA + US treatment markedly advanced the survival rate of the mice, reduced the bacterial load in the lungs, and alleviated the inflammatory damage, but there was no obvious toxicity. This study proposes an antibacterial substitute to induce ferroptosis of MRSA, which may provide a foreground for overcoming microbial drug resistance and fighting biofilm-associated infections and also provides a target and theoretical basis for clinical treatment of acute MRSA pneumonia.

Assessing the impact of the early COVID-19 era on antibiotic-resistant threats in inpatient settings: A mixed Poisson regression approach

During the COVID-19 pandemic, increased antibiotic prescribing and infection prevention challenges coincided with antibiotic-resistant (AR) infection increases. Clostridioides difficile (C difficile) and methicillin-resistant Staphylococcus aureus (MRSA) are serious, costly AR threats. Health inequities in pandemic-era AR infections are not well-characterized. North Carolina statewide inpatient admissions were used to determine monthly admission rates and admission rate ratios (RRs) for C difficile and MRSA infections comparing 2017-2019 (prepandemic) to 2020 (pandemic exposure) using mixed-model Poisson regression adjusted for age, sex, comorbidities, and COVID-19. We assessed effect measure modification by admissions' community-level income, county rurality, and race and ethnicity. Mean total costs by infection type were compared. With pandemic exposure, C difficile (adjusted RR=0.90 [95% confidence interval [CI] 0.86, 0.94]) and MRSA pneumonia (adjusted RR=0.97 [95% CI 0.91, 1.05]) decreased, while MRSA septicemia (adjusted RR=1.13 [95% CI 1.07, 1.19]) increased. Effect measure modification was not detected. C difficile or MRSA coinfection nearly doubled mean costs among COVID-19 admissions. Despite decreases in C difficile and most MRSA infections, the early COVID-19 pandemic period saw continued increases in MRSA septicemia admissions in North Carolina. Equitable interventions to curb increases and reduce health care costs should be developed.

GENDER-RELATED VARIATIONS IN PATHOPHYSIOLOGICAL RESPONSES TO METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PNEUMONIA AND SEPSIS.

In preclinical studies, the protective effects of female sex hormones and the immunosuppressive effects of male sex hormones were demonstrated. However, gender-related differences in multiorgan failure and mortality in clinical trials have not been consistently explained. This study aims to investigate gender-related differences in the development and progression of sepsis using a clinically relevant ovine model of sepsis. Adult Merino male (n=7) and female (n=7) sheep were surgically prepared with multiple catheters before the study. To induce sepsis, bronchoscopy instilled methicillin-resistant Staphylococcus aureus into sheep's lungs. The time from the bacterial inoculation until the modified Quick Sequential Organ Failure Assessment (q-SOFA) score became positive was measured and analyzed primarily. We also compared the SOFA score between these male and female sheep over time. Survival, hemodynamic changes, the severity of pulmonary dysfunction, and microvascular hyperpermeability were also compared. The time from the onset of bacterial inoculation to the positive q-SOFA in male sheep was significantly shorter than in female sheep. Mortality was not different between these sheep (14% vs. 14%). There were no significant differences in hemodynamic changes and pulmonary function between the two groups at any time point. Similar changes in hematocrit, urine output, and fluid balance were observed between females and males. The present data indicate that the onset of multiple organ failure and progression of sepsis is faster in male sheep than in female sheep, even though the severity of cardiopulmonary function is comparable over time. Further studies are warranted to validate the above results.

Time-Course Transcriptome Analysis of the Lungs of Mice Challenged with Aerosols of Methicillin-Resistant Staphylococcus aureus USA300 Clone Reveals Inflammatory Balance.

USA300, a dominant clone of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), is circulating globally and can cause necrotizing pneumonia with high morbidity and mortality. To further reveal the host anti-MRSA infection immune response, we established a mouse model of acute primary MRSA pneumonia challenged with aerosols of the USA300 clone. A time-course transcriptome analysis of the lungs collected at 0, 12, 24, 48 and 96 h post-infection (hpi) was conducted using RNA sequencing (RNA-seq) and multiple bioinformatic analysis methods. The change trend of histopathology and five innate immune cell (neutrophils, mononuclear cells, eosinophils, macrophages, DC cells) proportions in the lungs after infection was also examined. We observed a distinct acute pulmonary recovery process. A rapid initiation period of inflammation was present at 12 hpi, during which the IL-17 pathway dominantly mediated inflammation and immune defense. The main stages of host inflammatory response occurred at 24 and 48 hpi, and the regulation of interferon activation and macrophage polarization played an important role in the control of inflammatory balance at this stage. At 96 hpi, cellular proliferation processes associated with host repair were observed, as well as adaptive immunity and complement system responses involving C1q molecules. More importantly, the data provide new insight into and identify potential functional genes involved in the checks and balances occurring between host anti-inflammatory and proinflammatory responses. To the best of our knowledge, this is the first study to investigate transcriptional responses throughout the inflammatory recovery process in the lungs after MRSA infection. Our study uncovers valuable research targets for key regulatory mechanisms underlying the pathogenesis of MRSA lung infections, which may help to develop novel treatment strategies for MRSA pneumonia.