anti-MRSA Agents Research Articles

MIC trends of vancomycin and teicoplanin among methicillin resistant CoNS isolates from new born blood cultures in a tertiary care centre in Southern India

Background and Objectives: Coagulase-negative-Staphylococci (CoNS) are important etiological agent of bacteraemia in newborn babies. Methicillin resistant CoNS infections have only limited treatment options. The antimicrobial susceptibility pattern of Methicillin Resistant CoNS isolates from newborn blood cultures was studied with special reference to MICs of Vancomycin and Teicoplanin. Materials and Methods: The study population included Methicillin Resistant Coagulase Negative Staphylococcal isolates (MRCoNS) from newborn blood cultures, during a one-year period. Minimum inhibitory concentration (MIC) of Vanco- mycin and Teicoplanin in Methicillin resistant CoNS isolates was determined by macrobroth dilution method as per CLSI guidelines and by automated methods. Results: Coagulase Negative Staphylococci were the etiological agent in 73.7% (n=56) cases of neonatal bacteremia. Meth- icillin resistance in newborn CoNS was found to be 58.9%. All the MRCoNS isolates had vancomycin and teicoplanin MICs in the susceptible range. There were MRCoNS isolates with MICs in the upper limit of susceptible range for both vancomy- cin and teicoplanin, which can result in poor clinical response. Conclusion: Continuous large scale multi-centre surveillance studies with special attention to study the MIC pattern of the high-end anti-MRSA agents like vancomycin, teicoplanin, linezolid are to be carried out. This will help the clinicians to judiciously prescribe the antibiotics, which is very essential for antimicrobial stewardship.

Phytoconstituent and In silico Screening of Active Compounds from Red Ginger (Zingiber officinale var. rubrum Theilade) Rhizome and Avocado (Persea americana Mill.) Leaves Extracts as Novel Inhibitors of MRSA

Red ginger rhizome (Zingiber officinale var. Rubrum) and avocado leaves (Persea americana Mill.) are empirically known as one of the medicinal plants used in Taro Village, Gianyar Regency, Bali which have great potential in treating infectious diseases caused by antibiotic resistance, such as MRSA. This study aims to analyze the phytoconstituents and anti-MRSA potential contained in red ginger rhizome and avocado leaves extracts by assessing their inhibitory effects on three proteins related to MRSA resistance and virulence (PBAP2a, transglycosylase, and glycosyltransferase). Phytoconstituents of avocado leaf and red ginger extracts were analyzed using GC-MS. Molecular docking was performed in silico to determine the similarity properties of predicted drugs, bioactivity, toxicity, identification of active sites and validation of protein structures, and docking simulations were performed between compounds found in the extract and their target proteins. Phytoconstituent analysis revealed that avocado leaves and red ginger extracts as a whole have 43 types of compounds and 10 bioactive compounds each with beneficial drug-like properties. The compound 6,11-hexadecadien-1-ol from avocado leaves extracts was predicted to have hepatotoxic properties. There were at least 3 compounds, namely beta-bisabolene from avocado leaves extract, zingiberenol and gamma-curcumene from red ginger rhizome extract, showing the lowest binding affinity for the target protein. Red ginger rhizome and avocado leaves extracts showed valuable potential as anti-MRSA agents through the mechanism of inhibition of three resistance-related proteins, as predicted by in silico analysis.

Novel Tricyclic Flavonoids as Promising Anti-MRSA Agents

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is considered the main cause of nosocomial and community-associated infections. Because of antimicrobial resistance, MRSA infections are difficult or impossible to treat, leading to high mortality rates and significant economic and societal costs. In view of the MRSA challenge to public health all over the world, the identification of new and effective anti-MRSA agents is a high medical priority. Objectives: A new series of tricyclic flavonoids with a methyl substituent on ring A of the flavonoid skeleton was synthesized to assess their antimicrobial properties. Methods: The structures of novel synthetic tricyclic flavonoids and their 3-dithiocarbamic flavanones were proven by X-ray structural analyses. Minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentration (MBC/MFC) were used to evaluate antimicrobial activity. Growth kinetic and time–kill assays were employed to confirm the antibacterial effectiveness. The mechanism of action was investigated using fluorescence microscopy. Results: Our results show that the tricyclic flavonoids exhibited important antibacterial and antifungal activities, with MIC and MBC values as low as 1.95 µg/mL and 3.90 µg/mL recorded for compound 5e against a multidrug-resistant MRSA strain. Flavonoid 5e induced a more important bacteriostatic effect compared with chloramphenicol, inhibiting the bacterial growth for up to 24 h at concentrations equivalent to 2 × MIC. Also, 5e exhibited a significant bactericidal activity, with no viable cells evidenced after 6 h of incubation in the presence of MBC and a total kill effect recorded up to 24 h. The anti-MRSA activity may be explained by the cell membrane impairment induced by 5e. Conclusions: All the data support the idea that flavonoid 5e is a reliable candidate to develop effective anti-MRSA agents, but further studies are necessary.

Diterpenoids of Caryopteris trichosphaera W. W. Sm. inhibiting MRSA and VRE in vitro and in vivo

Ethnopharmacological relevanceCaryopteris trichosphaera W. W. Sm., a traditional ethnic medicine, was recorded in the Compendium of Materia Medica for treating wound infection by pathogenic infection. However, its antibacterial potential and bioactive compositions against drug-resistant bacteria need to be validated. Aim of the studyTo investigate the chemical constituents of C. trichosphaera and explore its anti-MRSA component in vitro and in vivo, together with the antibacterial mechanism. Materials and methodsBioactive constituents investigation was carried out by phytochemical method and antibacterial screening. The antibacterial mechanism was predicted by network pharmacology, which was further validated by time-kill analysis, membrane function tests, multigenerational resistance induction assay and biofilm test, and metabolomics analysis in vitro. In addition, MRSA-induced epidermal infection in mice was selected to evaluate its pharmacological effect in vivo. ResultsSix antibacterial diterpenoids against MRSA and VRE with MIC values 4–32 μg/mL from C. trichosphaera were reported for the first time, in which the major compound cativic acid (1) disrupted MRSA cell membranes by modulating permeability, depolarization, and fluidity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It also displayed remarkable anti-biofilm activity without inducing bacterial resistance or cytotoxicity. Moreover, cativic acid affected MRSA biosynthesis of cofactors, amino acid biosynthesis, nucleotide metabolism by metabolomics analysis. Furthermore, cativic acid accelerated wound healing in MRSA-infected mouse skin wounds, even better than vancomycin. ConclusionsThe results supported the traditional use of C. trichosphaera, and presented unreported anti-MRSA agent, cativic acid, as a plant-derived bactericide in vitro and in vivo for the first time.

In vitro identification of underutilized β-lactam combinations against methicillin-resistant Staphylococcus aureus bacteremia isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC95) for all isolates tested and lowered daptomycin IC95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC95s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC95s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC95. These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.

In silico studies on 3-substituted halogenated phenazines as anti-MRSA agents

Antibiotic resistance has become a more serious threat in past decades. Among them, MRSA appears to be a more versatile pathogen causing serious infections like skin infection, pneumonia, etc. and developing resistance among many antibiotics including mainly β-lactams, fluoroquinolones, tetracyclines, macrolides, and aminoglycosides. To encounter this problem among newly coming heterocycles, phenazine derivatives are the one showing antibacterial activity against MRSA with biofilm-eradicating property due to its redox active nature. This present study deals with the study of interactions of novel halogenated phenazines currently reported as MRSA biofilm eradicating agents with Penicillin-binding protein, an integral part of the cell wall of MRSA by molecular docking studies and assessment of pharmacokinetic related properties.

Rhodomyrtone: a new anti-Staphylococcus aureus agent against resistant strains.

Rhodomyrtone is a novel plant-derived antibiotic compound originally isolated from Rhodomyrtus tomentosa leaf extract. To evaluate the activity of rhodomyrtone against a group of MRSA strains, including isolates with reduced susceptibility or resistance to vancomycin, daptomycin, linezolid and ceftaroline. Broth microdilution testing was used to determine the MICs and MBCs of rhodomyrtone, fosfomycin, vancomycin, daptomycin, linezolid and ceftaroline. ROM had an MIC90 of 1 mg/L against 110 strains of MRSA from blood isolates as well as for all other isolates that were daptomycin resistant, VISA, VRSA or LRSA. The MBC90 were 4 mg/L across all groups tested. Among all S. aureus groups tested the ROM MBC did not exceed 8 mg/L. Rhodomyrtone demonstrated excellent activity against MRSA as well as isolates with resistance or reduced activity to other anti-MRSA drugs including vancomycin, daptomycin and linezolid. Rhodomyrtone may have potential clinical utility when treating patients with infections caused by MRSA including those with reduced susceptibility to first-line anti-MRSA antimicrobial agents.

Design and synthesis of unique indole-benzosulfonamide oleanolic acid derivatives as potent antibacterial agents against MRSA

The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents.

Trends in Empiric Broad-Spectrum Antibiotic Use for Suspected Community-Onset Sepsis in US Hospitals

Little is known about the degree to which suspected sepsis drives broad-spectrum antibiotic use in hospitals, what proportion of antibiotic courses are unnecessarily broad in retrospect, and whether these patterns are changing over time. To describe trends in empiric broad-spectrum antibiotic use for suspected community-onset sepsis. This cross-sectional study used clinical data from adults admitted to 241 US hospitals in the PINC AI Healthcare Database. Eligible participants were aged 18 years or more and were admitted between 2017 and 2021 with suspected community-onset sepsis, defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration on admission. Empiric anti-methicillin-resistant Staphylococcus aureus (MRSA) and/or antipseudomonal β-lactam agent use. Annual rates of empiric anti-MRSA and/or antipseudomonal β-lactam agent use and the proportion that were likely unnecessary in retrospect based on the absence of β-lactam resistant gram-positive or ceftriaxone-resistant gram-negative pathogens from clinical cultures obtained through hospital day 4. Annual trends were calculated using mixed-effects logistic regression models, adjusting for patient and hospital characteristics. Among 6 272 538 hospitalizations (median [IQR] age, 66 [53-78] years; 443 465 male [49.6%]; 106 095 Black [11.9%], 65 763 Hispanic [7.4%], 653 907 White [73.1%]), 894 724 (14.3%) had suspected community-onset sepsis, of whom 582 585 (65.1%) received either empiric anti-MRSA (379 987 [42.5%]) or antipseudomonal β-lactam therapy (513 811 [57.4%]); 311 213 (34.8%) received both. Patients with suspected community-onset sepsis accounted for 1 573 673 of 3 141 300 (50.1%) of total inpatient anti-MRSA antibiotic days and 2 569 518 of 5 211 745 (49.3%) of total antipseudomonal β-lactam days. Between 2017 and 2021, the proportion of patients with suspected sepsis administered anti-MRSA or antipseudomonal therapy increased from 63.0% (82 731 of 131 275 patients) to 66.7% (101 003 of 151 435 patients) (adjusted OR [aOR] per year, 1.03; 95% CI, 1.03-1.04). However, resistant organisms were isolated in only 65 434 cases (7.3%) (30 617 gram-positive [3.4%], 38 844 gram-negative [4.3%]) and the proportion of patients who had any resistant organism decreased from 9.6% to 7.3% (aOR per year, 0.87; 95% CI, 0.87-0.88). Most patients with suspected sepsis treated with empiric anti-MRSA and/or antipseudomonal therapy had no resistant organisms (527 356 of 582 585 patients [90.5%]); this proportion increased from 88.0% in 2017 to 91.6% in 2021 (aOR per year, 1.12; 95% CI, 1.11-1.13). In this cross-sectional study of adults admitted to 241 US hospitals, empiric broad-spectrum antibiotic use for suspected community-onset sepsis accounted for half of all anti-MRSA or antipseudomonal therapy; the use of these types of antibiotics increased between 2017 and 2021 despite resistant organisms being isolated in less than 10% of patients treated with broad-spectrum agents.

A membrane-targeting magnolol derivative for the treatment of methicillin-resistant Staphylococcus aureus infections.

Multidrug-resistant bacterial infections are a major global health challenge, especially the emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) urgently require alternative treatment options. Our study has identified that a magnolol derivative 6i as a promising agent with significant antibacterial activity against S. aureus and clinical MRSA isolates (MIC = 2-8 μg/mL), showing high membrane selectivity. Unlike traditional antibiotics, 6i demonstrated rapid bactericidal efficiency and a lower propensity for inducing bacterial resistance. Compound 6i also could inhibit biofilm formation and eradicate bacteria within biofilms. Mechanistic studies further revealed that 6i could target bacterial cell membranes, disrupting the integrity of the cell membrane and leading to increased DNA leakage, resulting in potent antibacterial effects. Meanwhile, 6i also showed good plasma stability and excellent biosafety. Notably, 6i displayed good in vivo antibacterial activity in a mouse skin abscess model of MRSA-16 infection, which was comparable to the positive control vancomycin. These findings indicated that the magnolol derivative 6i possessed the potential to be a novel anti-MRSA infection agent.

Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 μg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.

Effects of Phomopsidione on the Viability, Virulence, and Metabolites Profile of Methicillin-Resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) infections have become one of the most threatening multidrug-resistant pathogens. Thus, an ongoing search for anti-MRSA compounds remains an urgent need to effectively treating MRSA infections. Phomopsidione, a novel antibiotic isolated from Diaporthe fraxini, has previously demonstrated potent anti-candidal activity. The present study aimed to investigate the effects of phomopsidione on the viability, virulence, and metabolites profile of MRSA. MRSA was sensitive to phomopsidione in a concentration-dependent manner. Phomopsidione exhibited minimum inhibitory concentration and minimum bactericidal concentration of 62.5 and 500.00µg/mL against MRSA on broth microdilution assay. The compound showed significant reduction in virulence factors production including extracellular polymeric substances quantification, catalase, and lipase. An untargeted metabolomics analysis using liquid chromatography-high resolution mass spectrometry revealed a significant difference in the metabolites profile of MRSA with 13 putatively identified discriminant metabolites. The present study suggested the potential of phomopsidione as a promising anti-MRSA agent.

Antimicrobial therapy and outcome of methicillin-resistant Staphylococcus aureus endocarditis: A retrospective multicenter study in Japan

BackgroundMRSA (methicillin-resistant Staphylococcus aureus)-infective endocarditis (IE) is associated with high morbidity and mortality. This study aimed to assess data from patients with MRSA-IE across multiple facilities in Japan, with a specific focus on antimicrobial therapy and prognosis. MethodsThis retrospective study enrolled patients with a confirmed diagnosis of IE attributed to MRSA, spanning the period from January 2015 to April 2019. ResultsSixty-four patients from 19 centers were included, with a median age of 67 years. The overall mortality rate was 28.1% at 30 days, with an in-hospital mortality of 45.3%. The most frequently chosen initial anti-MRSA agents were glycopeptide in 67.2% of cases. Daptomycin and linezolid were selected as initial therapy in 23.4% and 17.2% of cases, respectively. Approximately 40% of all patients underwent medication changes due to difficulty in controlling infection or drug-related side effects. Significant prognostic factors by multivariable analysis were DIC for 30-day mortality and surgical treatment for 30-day and in-hospital mortality. For vancomycin as initial monotherapy, there was a trend toward a worse prognosis for 30-day and in-hospital mortality (OR, 6.29; 95%CI, 1.00–39.65; p = 0.050, OR, 3.61; 95%CI, 0.93–14.00; p = 0.064). Regarding the choice of initial antibiotic therapy, statistical analysis did not show significant differences in prognosis. ConclusionGlycopeptide and daptomycin were the preferred antibiotics for the initial therapy of MRSA-IE. Antimicrobial regimens were changed for various reasons. Prognosis was not significantly affected by choice of antibiotic therapy (glycopeptide, daptomycin, linezolid), but further studies are needed to determine which antimicrobials are optimal as first-line agents.

In vitro effects of anti-MRSA agent adsorption onto the AN69ST hemofilter

BackgroundBlood purification therapy with a sulfonated polyacrylonitrile surface treated (AN69ST) hemofilter is used to treat sepsis. However, the AN69ST hemofilter has been reported to adsorb and remove therapeutic drugs; warranting further investigation. In this study, we evaluated the adsorption effects of AN69ST membranes and hemofilters connected to a dialysis circuit model on anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents, such as arbekacin sulfate (ABK), linezolid (LZD), vancomycin hydrochloride (VCM), teicoplanin (TEIC), and daptomycin (DAP), in in vitro experiments.MethodsDrug solutions were exposed to AN69ST membranes. The absorbance of the drug solution was measured over time, and the drug content was calculated. Additionally, we calculated the drug content over time by circulating the drug solution through a dialysis circuit model. The clearance of each drug was determined at 5 and 60 min.ResultsThe content of ABK, TEIC, DAP, and VCM decreased substantially after the addition of AN69ST membranes compared to those of the standard reagent. However, the LZD content did not decrease. In the dialysis circuit model, the content of ABK, TEIC, DAP, and VCM were 3.7%, 25.7%, 43.8%, and 44.5%, respectively, at 20 min, which were clearly lower than those of the standard reagent (62–64%). However, the LZD content remained unchanged. The clearance of ABK, TEIC, DAP, and VCM increased after 5 min.ConclusionsThe in vitro adsorption of anti-MRSA agents onto the AN69ST hemofilter was confirmed for ABK, TEIC, DAP, and VCM. Positively charged ABK was particularly susceptible to adsorption and should be avoided during blood purification using the AN69ST hemofilter. In addition, we concluded that TEIC, DAP, and VCM should be used for therapeutic drug monitoring because the adsorption rate of each drug is believed to vary depending on its protein binding rate.

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.

Hematological adverse events associated with anti-MRSA agents: a real-world analysis based on FAERS

ABSTRACT This study investigated the patterns of hematological adverse events related to daptomycin (DAP), tigecycline (TIG), vancomycin (VAN) and linezolid (LIN) in the FDA Adverse Event Reporting System (FAERS). Adverse event associations were analyzed through calculating reporting odds ratio (ROR), proportional reporting ratio (PRR), multiple gamma Poisson shrinkage (MGPS), and Bayesian confidence propagation neural network (BCPNN). A comprehensive descriptive analysis was also conducted considering factors such as age, gender, daily dose, cumulative dose, and time to onset. The leading hematologic adverse events were eosinophilia for daptomycin, coagulation abnormalities and thrombocytopenia for tigecycline, thrombocytopenia, neutropenia, and anemia for linezolid, and thrombocytopenia, eosinophilia, and neutropenia for vancomycin. Most of the affected patients were over 55 years old. Daily doses for the tigecycline and daptomycin groups exceeded the standard daily dose. The times to onset were 14.00 days for daptomycin (interquartile range [IQR], 4.00–21.00), 6.00 days for tigecycline (IQR, 2.00–9.00), 10.00 days for linezolid (IQR, 4.00–16.5), and 10.00 days for vancomycin (IQR,5.00–20.00). It is essential to intensify early monitoring and identification of these adverse events, especially in the context of off-label dosages and for elderly patients and individuals taking medication for over one week.

Evaluation of the potential of endophytic Trichoderma sp. isolated from medicinal plant Ampelopsis japonica against MRSA and bioassay-guided separation of the anti-MRSA compound.

Endophytic fungi have been recognized as a valuable source for the production of biologically active compounds with potential applications in various domains. This study aimed to isolate endophytic fungi from Ampelopsis japonica (Thunb.) Makino and assess their anti-MRSA activity. Meanwhile, chromatographic separation techniques were applied to analyze the constituents of endophytic fungal secondary metabolites. The isolate BLR24, which exhibited strong inhibition activity against MRSA, was identified as Trichoderma virens based on morphological characteristics and ITS sequence analyses. The ethyl acetate extract of BLR24 (EA-BLR24) showed good anti-MRSA activity with the MIC and MBC values of 25 μg/mL and 50 μg/mL, separately. The inhibition of biofilm formation was up to 34.67% under MIC concentration treatment. Meanwhile, EA-BLR24 could significantly reduce the expression of biofilm-related genes (icaA, sarA, and agrA) of MRSA. Based on LC-MS/MS analysis, twenty compounds in EA-BLR24 could be annotated using the GNPS platform, mainly diketopiperazines. The anti-MRSA compound (Fr.1.1) was obtained from EA-BLR24 by bioassay-guided fractionation and determined as gliotoxin. The results indicated that endophytic Trichoderma virens BLR24 isolated from the medical plant A. japonica roots could be a promising source of natural anti-MRSA agents. Endophytic fungal secondary metabolites are abundant in biologically active compounds. Endophytic fungi from medicinal plants could be a source yielding bioactive metabolites of pharmaceutical importance.

Antimicrobial activity and mechanism of anti-MRSA of phloroglucinol derivatives.

In previous studies, authors have completed the total synthesis of several phloroglucinol natural products and synthesized a series of their derivatives, which were tested with good biological activities. To discover anti-MRSA lead compound and study their mechanism of action. Phloroglucinol derivatives were tested to investigate their activities against several gram-positive strains including Methicillin-resistant Staphylococcus aureus (MRSA). The mechanism study was conducted by determining extracellular potassium ion concentration, intracellular NADPH oxidase content, SOD activity, ROS amount in MRSA and MRSA survival rate under A5 treatment. The in vitro cytotoxicity test of A5 was conducted. The activity of monocyclic compounds was stronger than that of bicyclic compounds, and compound A5 showed the best MIC value of 0.98μg/mL and MBC value of 1.95μg/mL, which were 4-8 times lower than that of vancomycin. The mechanism study of A5 showed that it achieved anti-MRSA effect through membrane damage, which is proved by increased concentration of extracellular potassium ion after A5 treatment. Another possible mechanism is the over ROS production induced cell death, which is suggested by observed alternation of several reactive oxygen species (ROS) related indicators including NADPH concentration, superoxide dismutase (SOD) activity, ROS content and bacterial survival rate after A5 treatment. The cytotoxicity results in vitro showed that A5 was basically non-toxic to cells. Acylphloroglucinol derivative A5 showed good anti-MRSA activity, possibly via membrane damage and ROS-mediated oxidative stress mechanism. It deserves further exploration to be a potential lead for the development of new anti-MRSA agent.

Antimicrobial activity of nature-inspired molecules against multidrug-resistant bacteria.

Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram-negative drug-resistant bacterial pathogens. The lead compound SIMR 2404 had a minimal inhibitory concentration (MIC) of 2 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA). The MIC values against Gram-negative bacteria such as Escherichia coli and Actinobacteria baumannii were between 8-32 μg/mL. Time-kill experiments show that compound SIMR 2404 can rapidly kill tested bacteria. Compound SIMR 2404 was also found to rapidly kill MRSA persisters which display high levels of tolerance to conventional antibiotics. In antibiotic evolution experiments, MRSA quickly developed resistance to ciprofloxacin but failed to develop resistance to compound SIMR 2404 even after 24 serial passages. Compound SIMR 2404 was not toxic to normal human fibroblast at a concentration of 4 μg/mL which is twice the MIC concentration against MRSA. However, at a concentration of 8 μg/mL or higher, it showed cytotoxic activity indicating that it is not ideal as a candidate against Gram-negative bacteria. The acceptable toxicity profile and rapid antibacterial activity against MRSA highlight the potential of these molecules for further studies as anti-MRSA agents.

The impact of implementation of rapid blood culture identification panels on antimicrobial optimization: a retrospective cohort study.

Determine the impact of limited implementation of a rapid blood culture identification (BCID) panel. Retrospective cohort study. From February to April 2022, positive blood cultures identified via e-Plex BCID (Roche, Carlsbad, CA) were compared to those identified using standard microbial identification techniques. The primary outcomes assessed were time to optimal therapy, time to de-escalation of anti-MRSA (methicillin-resistant Staphylococcus aureus) agents, and time to de-escalation of anti-pseudomonal agents. Additional analysis investigated the impact of the availability of antimicrobial stewardship program support. This study was conducted at Grady Health System, a large metropolitan safety-net hospital in the southeastern United States. A total of 253 blood cultures were included in this study (153 BCID and 100 standard). Blood culture identification use was associated with a reduction in median time to optimal antimicrobial therapy (43.4 vs 72.1 h, P < .001) and median time to de-escalation of anti-MRSA agents (27.7 vs 46.7 h, P = .006), and a trend towards reduction of median time to de-escalation of anti-pseudomonal agents (38.8 vs 54.8 h, P = .07). These reductions persisted when controlling for patient age, sex, intensive care unit status, Charlson Comorbidity Index, and antimicrobial stewardship program availability. Despite restricted use and lack of 24/7 antimicrobial stewardship program availability, BCID panel utilization was associated with earlier initiation of optimal therapy and pathogen identification with subsequent de-escalation of broad-spectrum antimicrobials, as compared to standard antimicrobial techniques. This suggests the potential for benefit from adopting novel diagnostic technologies outside of idealized fully-resourced settings.