Efficacy and Safety of Oral and IV Levonadifloxacin Therapy in Management of Bacterial Infections: Findings of a Prospective, Observational, Multi-center, Post-marketing Surveillance Study.

Background Antimicrobial resistance by bacteria poses a substantial threat to morbidity and mortality worldwide, and treatment of resistant infections is a challenge for the treating clinician. Levonadifloxacin is a novel broad-spectrum agent belonging to the benzoquinolizine subclass of quinolone, which can be used by both oral and intravenous administration for the treatment of infections caused by gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). Patients and methods This prescription event monitoring study captured data from 1266 patients receiving levonadifloxacin (oral and/or IV) in a real-world setting to assess the safety and efficacy in the treatment of various bacterial infections. The duration of the study was 18 months. Study outcomes were clinical success and microbial success at the end of therapy. Global assessments were done for safety and efficacy at the end of therapy using a 5-point Likert scale (excellent, very good, good, satisfactory, and poor). Results The mean (median) duration of therapy was 7.2 (7.0) days, with a median time to clinical improvement of four days. Oral therapy was administered to 224 patients; 940 received IV, and 102 received IV followed by oral therapy. Patients were prescribed levonadifloxacin for gram-positive infections, skin and soft tissue infections, diabetic foot infections, septicemia, catheter-related blood-stream infections, bone and joint infections, febrile neutropenia, and respiratory infections, including COVID-19 pneumonia. The clinical cure on the eighth day was 95.7%, whereas the microbial success on the eighth day was 93.3% (n=60). For different types of infections, the clinical success rates ranged from 85.2% to 100%. There were only 30 treatment-emergent adverse events reported in 29 patients. Overall, about 95.6% of patients rated the efficacy as good to excellent, whereas only 3.8% of patients rated it satisfactory; for safety, 95.7% of patients rated it as good to excellent, with only 3.9% of patients rated it as satisfactory. Conclusions The excellent safety and efficacy profile of levonadifloxacin, when administered as an oral or intravenous therapy, makes it a desirable treatment modality for the management of various bacterial infections, including those caused by resistant pathogens such as MRSA and quinolone-resistant Staphylococcus aureus (QRSA). Features of levonadifloxacin, such as availability in both IV and oral form, minimal drug-drug interactions, lack of the need to adjust dosages in renal and hepatically impaired patients along with a broad spectrum of coverage, make it a suitable agent that meets several unmet clinical needs of physicians.

Native Aortic Valve Infective Endocarditis Secondary to Community-Acquired Methicillin-Resistant Staphylococcus aureus: A Case Report and Literature Review.

Infective endocarditis (IE) refers to a microbial infection affecting either a heart valve or endocardium, resulting in tissue damage and the formation of vegetation. Native aortic valve endocarditis in children is rare and is associated with serious complications related to valvular insufficiency and systemic embolizations. As reports about community-acquired methicillin-resistant Staphylococcus aureus (MRSA) native aortic valve endocarditis in children are very scarce, we report this case along with a literature review about its complications and management. Here, we report the case of a seven-month-old infant who was previously healthy and presented with signs and symptoms of shock and systemic embolizations secondary to native aortic valve IE. His blood culture showed MRSA. He developed aortic valve insufficiency heart failure and multiorgan septic emboli that progressed to fatal refractory multiorgan failure. The management of complicated aortic valve endocarditis in children is challenging and needs a multidisciplinary team approach and prompt intervention.

Automated detection of methicillin-resistant Staphylococcus aureus with the MRSA CHROM imaging application on BD Kiestra Total Lab Automation System.

The virulence of methicillin-resistant Staphylococcus aureus (MRSA) and its potentially fatal outcome necessitate rapid and accurate detection of patients colonized with MRSA in healthcare settings. Using the BD Kiestra Total Lab Automation (TLA) System in conjunction with the MRSA Application (MRSA App), an imaging application that uses artificial intelligence to interpret colorimetric information (mauve-colored colonies) indicative of MRSA pathogen presence on CHROMagar chromogenic media, anterior nares specimens from three sites were evaluated for the presence of mauve-colored colonies. Results obtained with the MRSA App were compared to manual reading of agar plate images by proficient laboratory technologists. Of 1,593 specimens evaluated, 1,545 (96.98%) were concordant between MRSA App and laboratory technologist reading for the detection of MRSA growth [sensitivity 98.15% (95% CI, 96.03, 99.32) and specificity 96.69% (95% CI, 95.55, 97.60)]. This multi-site study is the first evaluation of the MRSA App in conjunction with the BD Kiestra TLA System. Using the MRSA App, our results showed 98.15% sensitivity and 96.69% specificity for the detection of MRSA from anterior nares specimens. The MRSA App, used in conjunction with laboratory automation, provides an opportunity to improve laboratory efficiency by reducing laboratory technologists' labor associated with the review and interpretation of cultures.

Chemo-photothermal therapy of chitosan/gold nanorod clusters for antibacterial treatment against the infection of planktonic and biofilm MRSA.

Bacterial infections trigger inflammation and impede the closure of skin wounds. The misuse of antibiotics exacerbates skin infections by generating multidrug-resistant bacteria. In this study, we developed chemo-photothermal therapy (chemo-PTT) based on near-infrared (NIR)-irradiated chitosan/gold nanorod (GNR) clusters as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents. The nanocomposites exhibited an average size of 223 nm with a surface charge of 36 mV. These plasmonic nanocomposites demonstrated on-demand and rapid hyperthermal action under NIR. The combined effect of positive charge and PTT by NIR-irradiated nanocomposites resulted in a remarkable inhibition rate of 96 % against planktonic MRSA, indicating a synergistic activity compared to chitosan nanoparticles or GNR alone. The nanocomposites easily penetrated the biofilm matrix. The combination of chemical and photothermal treatments by NIR-stimulated clusters significantly damaged the biofilm structure, eradicating MRSA inside the biomass. NIR-irradiated chitosan/GNR clusters increased the skin temperature of mice by 13 °C. The plasmonic nanocomposites induced negligible skin irritation in vivo. In summary, this novel nanosystem demonstrated potent antibacterial effects against planktonic and biofilm MRSA, showcasing the possible efficacy in treating skin infections.

Early Initiation of Ceftaroline-Based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia.

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B. Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression. Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups. Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy.

HOCl-producing Electrochemical Bandage is Active in Murine Polymicrobial Wound Infection.

Wound infections, exacerbated by the prevalence of antibiotic-resistant bacterial pathogens, necessitate innovative antimicrobial approaches. Polymicrobial infections, often involving Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), present formidable challenges due to biofilm formation and antibiotic resistance. Hypochlorous acid (HOCl), a potent antimicrobial agent produced naturally by the immune system, holds promise as an alternative therapy. An electrochemical bandage (e-bandage) that generates HOCl in situ was evaluated for treatment of murine wound biofilm infections containing both MRSA and P. aeruginosa with "difficult-to-treat" resistance. Previously, the HOCl-producing e-bandage was shown to reduce wound biofilms containing P. aeruginosa alone. Compared to non-polarized e-bandage (no HOCl production) and Tegaderm only controls, the polarized e-bandages reduced bacterial loads in wounds infected with MRSA plus P. aeruginosa (MRSA: vs Tegaderm only - 1.4 log10 CFU/g, p = 0.0015, vs. non-polarized - 1.1 log10 CFU/g, p = 0.026. P. aeruginosa: vs Tegaderm only - 1.6 log10 CFU/g, p = 0.0015, vs non-polarized - 1.6 log10 CFU/g, p = 0.0032), and MRSA alone (vs Tegaderm only - 1.3 log10 CFU/g, p = 0.0048, vs. non-polarized - 1.1 log10 CFU/g, p = 0.0048), without compromising wound healing or causing tissue toxicity. Addition of systemic antibiotics did not enhance the antimicrobial efficacy of e-bandages, highlighting their potential as standalone therapies. This study provides additional evidence for the HOCl-producing e-bandage as a novel antimicrobial strategy for managing wound infections, including in the context of antibiotic resistance and polymicrobial infections.

Relapsing bronchopneumonia due to community-associated methicillin-resistant Staphylococcus aureus: a case report.

BACKGROUND: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased the incidence of community-onset MRSA infection. Respiratory tract infections caused by MRSA has been noted for their severity; however, repeated relapses that require extended antibiotic therapy are rare. CASE PRESENTATION: We report a case of relapsing bronchopneumonia caused by CA-MRSA in a 56-year-old man. The patient responded to antibiotics, but repeatedly relapsed after stopping treatment. MRSA was consistently isolated from airway specimens during each relapse. Extended oral antibiotic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) for 6 months achieved infection control. Whole-genome sequencing of the isolated strain revealed that the causative agent was sequence type (ST)1/staphylococcal cassette chromosome mec (SCCmec) type IVa, a clone that is rapidly increasing in Japan. DISCUSSION AND CONCLUSIONS: This patient had an unusual course of MRSA bronchopneumonia with repeated relapses. Although the choice of antibiotics for long-term use in MRSA respiratory tract infections has not been well established, TMP/SMX was effective and well tolerated for long-term therapy in this case. The clinical course of infections related to the rapid emerging clone, ST1/SCCmec type IVa warrants further attention.

Synergism with Shikimic Acid Restores ß-Lactam Antibiotic Activity against Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved into a dangerous pathogen resistant to beta-lactam antibiotics (BLAs) and has become a worrisome superbug. In this study, a strategy in which shikimic acid (SA), which has anti-inflammatory and antibacterial activity, is combined with BLAs to restart BLA activity was proposed for MRSA treatment. The synergistic effects of oxacillin combined with SA against oxacillin resistance in vitro and in vivo were investigated. The excellent synergistic effect of the oxacillin and SA combination was confirmed by performing the checkerboard assay, time-killing assay, live/dead bacterial cell viability assay, and assessing protein leakage. SEM showed that the cells in the control group had a regular, smooth, and intact surface. In contrast, oxacillin and SA or the combination treatment group exhibited different degrees of surface collapse. q-PCR indicated that the combination treatment group significantly inhibited the expression of the mecA gene. In vivo, we showed that the combination treatment increased the survival rate and decreased the bacterial load in mice. These results suggest that the combination of oxacillin with SA is considered an effective treatment option for MRSA, and the combination of SA with oxacillin in the treatment of MRSA is a novel strategy.

Community-Acquired Methicillin-Resistant Staphylococcus aureus Strain Positive for the Panton-Valentine Leucocidin Gene in a Middle-Aged Patient With Multiple Septic Pulmonary Emboli.

A 59-year-old man suffered from fever and chest pain for three days following an accidental bite to a lip ulcer. His lower lip showed swelling and tenderness, and chest computed tomography showed multiple bilateral nodules. He was diagnosed with septic pulmonary embolism and a lip abscess, and blood, sputum, and lip abscess cultures confirmed the presence of methicillin-resistant Staphylococcus aureus (MRSA). Despite the initiation of vancomycin, he rapidly developed respiratory failure and septic shock, necessitating intubation and noradrenaline support. Gentamicin was added on the seventh day of admission due to an insufficient effect, and vancomycin was switched to linezolid on the 14th day of admission. However, his respiratory failure persisted as bilateral pneumothorax developed. Blood culture was negative on the 14th day after admission, but the patient died on the 15th day after admission. The MRSA isolate was tested for the presence of the Panton-Valentine leukocidin (PVL) gene in conjunction with the USA300 strain. The prevalence of community-acquired (CA)-MRSA in the USA300 clone is increasing but still low in Japan, and this type of infection is commonly observed in people of all ages; this case is the first instance reported in Japan of a middle-aged patient with septic pulmonary embolism. Given the anticipated global increase in CA-MRSA infection caused by the USA300 clone and the emergence of USA300 with altered pathogenicity, it may be crucial to suspect PVL-positive CA-MRSA infections even in middle-aged or elderly patients presenting with septic pulmonary embolism as community infections.

Interaction of beauvericin in combination with antibiotics against methicillin-resistant Staphylococcus aureus and Salmonella typhimurium.

Multidrug resistance in bacteria is a major challenge worldwide, increasing both mortality by infections and costs for the health systems. Therefore, it is of utmost importance to find new drugs against resistant bacteria. Beauvericin (BEA) is a mycotoxin produced by entomopathogenic and other fungi of the genus Fusarium. Our work determines the effect of BEA combined with antibiotics, which has not been previously explored. The combination analysis included different antibiotics against non-methicillin-resistant Staphylococcus aureus (NT-MRSA), methicillin-resistant Staphylococcus aureus (MRSA), and Salmonella typhimurium. BEA showed a synergy effect with oxacillin with a fractional inhibitory concentration index (FICI) = 0.373 and an additive effect in combination with lincomycin (FICI = 0.507) against MRSA. In contrast, it was an antagonist when combined with ciprofloxacin against S. typhimurium. We propose BEA as a molecule with the potential for the development of new therapies in combination with current antibiotics against multidrug-resistant bacteria.

Prevalence and genetic characteristics of Staphylococcus aureus isolates from cell phones of medical students from Iran.

Although mobile phones as a rapid communication vehicle can lead to improved quality of healthcare, they can also facilitate the transmission of pathogens to patients. This current research focuses on genetic diversity, and genes involved in resistance and biofilm production of Staphylococcus aureus isolates from mobile phones of medical students. Antibiotic resistance profiling and polymerase chain reaction (PCR) amplification of antibiotic resistance and biofilm-related genes were investigated and statistically analyzed. Staphylococcal cassette chromosome mec (SCCmec) types were analyzed by multiplex PCR, and S. aureus protein A gene typing (spa typing) was done using PCR and sequencing. Sixty-four S. aureus isolates (16.8%) were obtained from 380 medical students' mobile phones who were working in hospitals. The findings showed that 71.9% of the isolates were MRSA and 78.1% were classified as MDR. All isolates exhibited sensitivity to vancomycin and linezolid. Overall, 7.8% of the isolates displayed an inducible clindamycin resistance phenotype, while 26.7% showed resistance to mupirocin. The results indicated that 68.8% of the isolates were biofilm producers, with 7 isolates (15.9%) classified as strong producers, 22 isolates (50%) as moderate producers, and 15 isolates (34.1%) as weak producers. The most prevalent type was CC8-MRSA III/t030 (18.7%), followed by CC8-MRSA III/t037 (12.5%), CC/ST22-MSSA/t790 (10.9%), CC1-MRSA IV-t114 (9.4%), CC1-MRSA IV-t127 (7.8%), CC8-MRSA V/t064 (7.8%), CC/ST15-MSSA-t360 (7.8%), CC30-MSSA/t021(6.3%), MRSA V-t355 (6.3%), CC8-MRSA III/t421 (4.7%), CC1-MRSA V-t267 (4.7%), and CC/ST15-MSSA-t084 (3.1%). The genetic diversity and prevalent multidrug resistance indicate that the resistance situation of S. aureus recovered from mobile phones in Tehran is severe, posing a potential threat to patients, the community, and healthcare settings.

Providing insight into the mechanism of action of cationic lipidated oligomers using metabolomics.

The increasing resistance of clinically relevant microbes against current commercially available antimicrobials underpins the urgent need for alternative and novel treatment strategies. Cationic lipidated oligomers (CLOs) are innovative alternatives to antimicrobial peptides and have reported antimicrobial potential. An understanding of their antimicrobial mechanism of action is required to rationally design future treatment strategies for CLOs, either in monotherapy or synergistic combinations. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of one CLO, C12-o-(BG-D)-10, which we have previously shown to be effective against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. The metabolomes of MRSA ATCC 43300 at 1, 3, and 6 h following treatment with C12-o-(BG-D)-10 (48 µg/mL, i.e., 3× MIC) were compared to those of the untreated controls. Our findings reveal that the studied CLO, C12-o-(BG-D)-10, disorganized the bacterial membrane as the first step toward its antimicrobial effect, as evidenced by marked perturbations in the bacterial membrane lipids and peptidoglycan biosynthesis observed at early time points, i.e., 1 and 3 h. Central carbon metabolism and the biosynthesis of DNA, RNA, and arginine were also vigorously perturbed, mainly at early time points. Moreover, bacterial cells were under osmotic and oxidative stress across all time points, as evident by perturbations of trehalose biosynthesis and pentose phosphate shunt. Overall, this metabolomics study has, for the first time, revealed that the antimicrobial action of C12-o-(BG-D)-10 may potentially stem from the dysregulation of multiple metabolic pathways.IMPORTANCEAntimicrobial resistance poses a significant challenge to healthcare systems worldwide. Novel anti-infective therapeutics are urgently needed to combat drug-resistant microorganisms. Cationic lipidated oligomers (CLOs) show promise as new antibacterial agents against Gram-positive pathogens like methicillin-resistant Staphylococcus aureus (MRSA). Understanding their molecular mechanism(s) of antimicrobial action may help design synergistic CLO treatments along with monotherapy. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of CLOs against MRSA. The results of our study indicate that the CLO, C12-o-(BG-D)-10, had a notable impact on the biosynthesis and organization of the bacterial cell envelope. C12-o-(BG-D)-10 also inhibits arginine, histidine, central carbon metabolism, and trehalose production, adding to its antibacterial characteristics. This work illuminates the unique mechanism of action of C12-o-(BG-D)-10 and opens an avenue to design innovative antibacterial oligomers/polymers for future clinical applications.

Vasculitis and infectious risk in a patient with type 2 diabetes mellitus: A case report.

The connection between vasculitis and infection is complex. The present study described a typical situation for a patient with unbalanced type 2 diabetes and chronic complications, in which a lack of adherence to the protection and care measures ultimately led to the appearance of some of the worst consequences of the condition, namely, ulceration, gangrene and amputation. In the context of an unstable condition with significant metabolic imbalance there was an impaired response to infections in the present patient, and the amputation resulted in wound persistence and ulcer development, followed by superinfection with methicillin-resistant Staphylococcus aureus according to the antibiogram performed. In this case, an episode of vasculitis was triggered without evidence of bacteraemia. The present case report highlighted the importance of proper hygiene and good metabolic control in patients with diabetes that suffer from amputations and conditions that expose them to certain complications, including vasculitis.

Community-acquired multidrug-resistant pneumonia, bacteraemia, and infective endocarditis: A case report.

BACKGROUND: The prevalence of multidrug-resistant (MDR) bacteria has increased globally, with extensive drug-resistant (XDR) bacteria posing a threat to patients. CASE SUMMARY: This case report describes a young man admitted for suspected tropical fever infections who experienced rapid deterioration in health. Despite negative results for tropical fever infections, he had neutrophilic leucocytosis, acute kidney injury, and chest imaging findings suggestive of bilateral consolidations. On day two, he was diagnosed with infective endocarditis with possible rheumatic heart disease and MDR methicillin-resistant Staphylococcus aureus bacteraemia, and community-acquired pneumonia. Despite treatment with broad-spectrum antibiotics, he did not respond and succumbed to death on day five. CONCLUSION: This case highlights that clinicians/public should be aware of MDR community-acquired pneumonia, bacteraemia, and endocarditis which ultimately culminate in high rates of morbidity and mortality. Early identification of pathogenic strain and prompt antibiotic treatment are a mainstay for the management and prevention of early fatalities. Simultaneously, route cause analysis of community-acquired MDR/XDR pathogens is a global need.

Bactericidal and biofilm eradication efficacy of a fluorinated benzimidazole derivative, TFBZ, against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major inducement of nosocomial infections and its biofilm formation render the high tolerance to conventional antibiotics, which highlights the requirement to develop new antimicrobial agents urgently. In this study, we identified a fluorinated benzimidazole derivative, TFBZ, with potent antibacterial efficacy toward planktonic MRSA (MIC = 4 µg/mL, MBC = 8 µg/mL) and its persistent biofilms (≥99%, MBEC = 8 µg/mL). TFBZ manifested significant irreversible time-dependent killing against MRSA as characterized by diminished cell viability, bacterial morphological change and protein leakage. Furthermore, the results from CBD devices, crystal violet assay in conjunction with live/dead staining and scanning electron microscopy confirmed that TFBZ was capable of eradicating preformed MRSA biofilms with high efficiency. Simultaneously, TFBZ reduced the bacterial invasiveness and exerted negligible hemolysis and cytotoxicity toward mammalian cells, which ensuring the robust therapeutic effect on mouse skin abscess model. The transcriptome profiling and quantitative RT-PCR revealed that a set of encoding genes associated with cell adhesion, biofilm formation, translation process, cell wall biosynthesis was consistently downregulated in MRSA biofilms upon exposure to TFBZ. In conclusion, TFBZ holds promise as a valuable candidate for therapeutic applications against MRSA chronic infections.

Isotretinoin self-nano-emulsifying drug delivery system: Preparation, optimization and antibacterial evaluation.

Purpose: Isotretinoin (ITN) is a poorly water-soluble drug. The objective of this study was to design a successful liquid self-nanoemulsifying drug delivery system (L-SNEDDS) for ITN to improve its solubility, dissolution rate, and antibacterial activity. Methods: According to solubility and emulsification studies, castor oil, Cremophor EL, and Transcutol HP were selected as system excipients. A pseudo ternary phase diagram was constructed to reveal the self-emulsification area. The developed SNEDDS were visually assessed, and the droplet size was measured. In vitro release studies and stability studies were conducted. The antimicrobial effectiveness against multiple bacterial strains, including Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and different accessory gene regulator (Agr) variants were investigated for the optimum ITN-loaded SNEDDS formulation. Results: Characterization studies showed emulsion homogeneity and stability (%T 95.40-99.20, A graded) with low droplet sizes (31.87 ± 1.23 nm-115.47 ± 0.36 nm). It was found that the developed ITN-SNEDDS provided significantly a higher release rate (>96 % in 1 h) as compared to the raw drug (<10 % in 1 h). The in vitro antimicrobial activities of pure ITN and ITN-loaded SNEDDS demonstrated a remarkable inhibitory effect on bacterial growth with statistically significant findings (p < 0.0001) for all tested strains when treated with ITN-SNEDDS as compared to the raw drug. Conclusion: These outcomes suggested that SNEDDS could be a potential approach for improving solubility, dissolution rates, and antibacterial activity of ITN.

Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus.

The increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of S. aureus emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of de novo drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT.

Dual elemental doping activated signaling pathway of angiogenesis and defective heterojunction engineering for effective therapy of MRSA-infected wounds.

Multi-drug resistant bacterial infections pose a significant threat to human health. Thus, the development of effective bactericidal strategies is a pressing concern. In this study, a ternary heterostructure (Zn-CN/P-GO/BiS) comprised of Zn-doped graphite phase carbon nitride (g-C3N4), phosphorous-doped graphene oxide (GO) and bismuth sulphide (Bi2S3) is constructed for efficiently treating methicillin-resistant Staphylococcus aureus (MRSA)-infected wound. Zn doping-induced defect sites in g-C3N4 results in a reduced band gap (ΔE) and a smaller energy gap (ΔEST) between the singlet state S1 and triplet state T1, which favours two-photon excitation and accelerates electron transfer. Furthermore, the formation of an internal electric field at the ternary heterogeneous interface optimizes the charge transfer pathway, inhibits the recombination of electron-hole pairs, improves the photodynamic effect of g-C3N4, and enhances its catalytic performance. Therefore, the Zn-CN/P-GO/BiS significantly augments the production of reactive oxygen species and heat under 808 nm NIR (0.67 W cm-2) irradiation, leading to the elimination of 99.60% ± 0.07% MRSA within 20 min. Additionally, the release of essential trace elements (Zn and P) promotes wound healing by activating hypoxia-inducible factor-1 (HIF-1) and peroxisome proliferator-activated receptors (PPAR) signaling pathways. This work provides unique insight into the rapid antibacterial applications of trace element doping and two-photon excitation.

An emerging zoonosis: molecular detection of multidrug-methicillin resistant Staphylococcus aureus from butchers' knives, livestock products and contact surfaces.

Methicillin-resistant Staphylococcus aureus (MRSA) transmission in livestock, community, and healthcare settings poses a significant public health concern both locally and globally. This study aimed to investigate the occurrence, molecular detection, and antibiogram of the MRSA strain in fresh beef, contact surfaces, and butchers' knives from the four major abattoirs (Karu, Gwagwalada, Deidei, and Kubwa) located in the Federal Capital Territory, Nigeria. A multi-stage sampling technique was used to collect 400 swab samples from butchers' knives (132), fresh beef (136), and contact surfaces (132). Presumptive colonies on mannitol salt agar were subjected to culture, isolation, and biotyping. The antibiogram was carried out via a Kirby-Bauer disk containing eight antibiotics. MRSA was phenotypically confirmed by oxacillin-resistant screening agar base (ORSAB) and genotypically by PCR to detect the presence of the mecA gene. Out of the 400 samples, 47.24% of fresh beef, 37% of contact surfaces, and 64.33% of butchers' knife swabs were Staphylococcus aureus positive. Thirty-two Staphylococcus aureus-positive isolates were confirmed to be MRSA, 50% fresh beef, 28.12% contact surfaces, and 21.87% butcher's knife swabs. MRSA isolates displayed multidrug-resistant traits, with a high resistance of 90.62% against cloxacillin, and a highest susceptibility of 100% to co-trimaxole. The antibiogram showed MRSA strains to be multidrug resistant. Molecular characterisation of the MRSA detected the presence of the mecA gene at a band size of 163 bp in all isolates. Strict hygiene of butchers, and working equipment in meat processing and marketing should be of top priority.