Garlic-Derived Exosome-like Nanovesicles-Based Wound Dressing for Staphylococcus aureus Infection Visualization and Treatment.

Garlic-derived exosome-like nanovesicles (GELNs) could function in interspecies communication and may serve as natural therapeutics to regulate the inflammatory response or as nanocarriers to efficiently deliver specific drugs. Staphylococcus aureus (S. aureus) is able to hide within host cells to evade immune clearance and antibiotics, leading to life-threatening infections. On-site detection and efficient treatment of intracellular S. aureus infection in wounds remain challenging. Herein, we report a thermosensitive, injectable, visible GELNs-based wound dressing, Van@GELNs/F127 hydrogel (gel Van@GELNs), which is H2O2-responsive and can slowly release vancomycin into host cells forS. aureus infection visualization and treatment in wounds. GELNs show inherent antibacterial activity, which is significantly enhanced after loading vancomycin. Both GELNs and Van@GELNs have the ability to be internalized by cells, so Van@GELNs are more effective than free vancomycin in killing S. aureus in RAW 264.7 macrophages. When applied to an S. aureus-infected wound on a mouse, the colorless HRP&ABTS/Van@GELNs/F127 solution immediately changes to a green hydrogel and shows better therapeutic effect than vancomycin. Thus, direct visualization by the naked eye and effective treatment of S. aureus infection in wounds are achieved by gel Van@GELNs. We anticipate gel Van@GELNs be applied for the theranostics of S. aureus infection diseases in the clinic in the near future.

Liquid chromatography-tandem mass spectrometry methods for quantification of total and free antibiotic concentrations in serum and exudate from patients with post-sternotomy deep sternal wound infection receiving negative pressure wound therapy.

BACKGROUND: Systemically administered antibiotics are thought to penetrate the wounds more effectively during negative pressure wound therapy (NPWT).To test this hypothesis total and free antibiotic concentrations were quantified in serum and wound exudate. METHODS: UHPLC-MS/MS methods were developed and validated for the determination of ceftazidime, cefepime, cefotaxime, cefuroxime, cefazolin, meropenem, oxacillin, piperacillin with tazobactam, clindamycin, ciprofloxacin, sulfamethoxazole/trimethoprim (cotrimoxazole), gentamicin, vancomycin, and linezolid. The unbound antibiotic fraction was obtained by ultrafiltration using a Millipore Microcon-30kda Centrifugal Filter Unit. Analysis was performed on a 1.7-µm Acquity UPLC BEH C18 2.1 × 100-mm column with a gradient elution. RESULTS: The validation was performed for serum, exudates and free fractions. For all matrices, requirements were met regarding linearity, precision, accuracy, limit of quantitation, and matrix effect. The coefficient of variation was in the range of 1.2-13.6%.and the recovery 87.6-115.6%, respectively. Among the 29 applications of antibiotics thus far, including vancomycin, clindamycin, ciprofloxacin, oxacillin, cefepime, cefotaxime, cotrimoxazole, and gentamicin, total and free antibiotic concentrations in serum and exudate were correlated. CONCLUSION: This method can accurately quantify the total and free concentrations of 16 antibiotics. Comparison of concentration ratios between serum and exudates allows for monitoring individual antibiotics' penetration capacity in patients receiving NPWT.

Host-defense piscidin peptides as antibiotic adjuvants against Clostridioides difficile.

The spore-forming intestinal pathogen Clostridioides difficile causes multidrug resistant infection with a high rate of recurrence after treatment. Piscidins 1 (p1) and 3 (p3), cationic host defense peptides with micromolar cytotoxicity against C. difficile, sensitize C. difficile to clinically relevant antibiotics tested at sublethal concentrations. Both peptides bind to Cu2+ using an amino terminal copper and nickel binding motif. Here, we investigate the two peptides in the apo and holo states as antibiotic adjuvants against an epidemic strain of C. difficile. We find that the presence of the peptides leads to lower doses of metronidazole, vancomycin, and fidaxomicin to kill C. difficile. The activity of metronidazole, which targets DNA, is enhanced by a factor of 32 when combined with p3, previously shown to bind and condense DNA. Conversely, the activity of vancomycin, which acts at bacterial cell walls, is enhanced 64-fold when combined with membrane-active p1-Cu2+. As shown through microscopy monitoring the permeabilization of membranes of C. difficile cells and vesicle mimics of their membranes, the adjuvant effect of p1 and p3 in the apo and holo states is consistent with a mechanism of action where the peptides enable greater antibiotic penetration through the cell membrane to increase their bioavailability. The variations in effects obtained with the different forms of the peptides reveal that while all piscidins generally sensitize C. difficile to antibiotics, co-treatments can be optimized in accordance with the underlying mechanism of action of the peptides and antibiotics. Overall, this study highlights the potential of antimicrobial peptides as antibiotic adjuvants to increase the lethality of currently approved antibiotic dosages, reducing the risk of incomplete treatments and ensuing drug resistance.

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy.

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP-Van@IR780 NPs). SP-Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP-Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP-Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection.

Emergence of vancomycin-resistant enterococci from vancomycin-susceptible enterococci in hospitalized patients under antimicrobial therapy.

OBJECTIVES: Enterococci are opportunistic pathogens with plastic genomes that evolve, acquire, and transmit antimicrobial-resistant determinants such as vancomycin resistance clusters. While vancomycin-resistant enterococci (VRE) have emerged as successful nosocomial pathogens, the mechanism by which vancomycin-susceptible enterococci (VSE) transform to VRE in hospitalized patients remains understudied. METHODS: Genomes of Enterococcus faecium from two critically ill hospitalized patients subjected to multiple antibiotic therapies, including broad-spectrum antibiotics, were investigated. To identify mechanisms of resistance evolution, genomes of vancomycin-susceptible and -resistant isolates were compared. RESULTS: While VSE isolates were initially identified, VRE strains emerged post-vancomycin therapy. Comparative genomics revealed horizontal transmission of mobile genetic elements containing the Tn1549 transposon, which harbours the vanB-type vancomycin resistance gene cluster. This suggests that broad-spectrum antibiotic stress promoted the transfer of resistance-conferring elements, presumably from another gut inhabitant. CONCLUSION: This is one of the first studies investigating VSE and VRE isolates from the same patient. The mechanism of transmission and the within-patient evolution of vancomycin resistance via mobile genetic elements under antibiotic stress is illustrated. Our findings serve as a foundation for future studies building on this knowledge which can further elucidate the dynamics of antibiotic stress, resistance determinant transmission, and interactions within the gut microbiota.

Structural Element of Vitamin U-Mimicking Antibacterial Polypeptide with Ultrahigh Selectivity for Effectively Treating MRSA Infections.

Antimicrobial peptides (AMPs) exhibit mighty antibacterial properties without inducing drug resistance. Achieving much higher selectivity of AMPs towards bacteria and normal cells has always been a continuous goal to be pursued. Herein, a series of sulfonium-based polypeptides with different degrees of branching and polymerization were synthesized by mimicking the structure of vitamin U. The polypeptide, G2 -PM-1H+ , shows both potent antibacterial activity and the highest selectivity index of 16000 among the reported AMPs or peptoids (e.g., the known index of 9600 for recorded peptoid in "Angew. Chem. Int. Ed., 2020, 59, 6412."), which can be attributed to the high positive charge density of sulfonium and the regulation of hydrophobic chains in the structure. The antibacterial mechanisms of G2 -PM-1H+ are primarily ascribed to the interaction with the membrane, production of reactive oxygen species (ROS), and disfunction of ribosomes. Meanwhile, altering the degree of alkylation leads to selective antibacteria against either gram-positive or gram-negative bacteria in a mixed-bacteria model. Additionally, both in vitro and in vivo experiments demonstrated that G2 -PM-1H+ exhibited superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) compared to vancomycin. Together, these results show that G2 -PM-1H+ possesses high biocompatibility and is a potential pharmaceutical candidate in combating bacteria significantly threatening human health.

Clinical study of drug-loaded calcium sulfate in the treatment of hematogenous osteomyelitis in children.

BACKGROUND: At present, good results have been obtained in the treatment of hematogenous osteomyelitis(HO) in children by the use of drug-loaded calcium sulfate, but there are few clinical studies reported. The aim of this study was to investigate the clinical efficacy of radical debridement combined with drug-laden calcium sulphate antibiotics in paediatric haematogenous osteomyelitis. METHODS: In this study, we retrospectively analyzed the clinical data of 15 cases of pediatric hematogenous osteomyelitis admitted to our hospital in recent years. A total of 15 pediatric patients with HO treated in our hospital from January 2018 to February 2022 were included for evaluation. RESULTS: All 15 patients were treated with drug-laden calcium sulfate, and the antibiotic of choice was vancomycin in 14 cases and vancomycin combined with gentamicin in 1 case. The follow-up period ranged from 12 to 36 months, with a mean follow-up time of 24.73 months, and all children were treated with drug-laden calcium sulfate with satisfactory clinical outcomes. The results of serological examination showed that the preoperative white blood cell count level, C-reactive protein and erythrocyte sedimentation rate were higher than the postoperative ones, and the differences were statistically significant (P < 0.05).After the operation, referring to the treatment standard of McKee's osteomyelitis, 15 cases were cured without recurrence; According to the Lower Extremities Functional Scale, 12 cases were excellent, 2 cases were good and 1 case was moderate, with an excellent rate of 93.33%. Children with lower limb involvement could walk with full weight bearing, and gait was basically normal. CONCLUSION: Drug-loaded calcium sulfate is a good therapeutic method for the treatment of hematogenous osteomyelitis in children, with a effect of reducing complications and reducing recurrence.

Development of dual-functional core-shell electrospun mats with controlled release of anti-inflammatory and anti-bacterial agents for the treatment of corneal alkali burn injuries.

In this study, a novel dual-drug carrier for the co-administration of an anti-inflammatory and antibiotic agent consisting of core-shell nanofibers for the treatment of cornea alkali burns was designed. The core-shell nanofibers were prepared via coaxial electrospinning of curcumin-loaded silk fibroin as the core and vancomycin-loaded chitosan/polyvinyl alcohol (PVA) as the shell. Electron microscopy (SEM and TEM) images confirmed the preparation of smooth, bead-free, and continuous fibers that formed clear core-shell structures. For further studies, nanofiber mats were cross-linked by heat treatment to avoid rapid disintegration in water and improve both mechanical properties and drug release. The release profile of curcumin and vancomycin indicated an initial burst release, continued by the extended release of both drugs within 72 hours. Rabbit corneal cells demonstrated high rates of proliferation when evaluated using a cell metabolism assay. Finally, the therapeutic efficiency of core/shell nanofibers in healing cornea alkali burn was studied by microscopic and macroscopic observation, fluorescence staining, and hematoxylin-eosin assay on rabbit eyes. The anti-inflammatory activity of fabricated fibers was evaluated by enzyme-linked immunosorbent assay and Immunofluorescence analysis. In conclusion, using a robust array of in vitro and in vivo experiments this study demonstrated the ability of the dual-drug carriers to promote corneal re-epithelialization, minimize inflammation, and inhibit corneal neovascularization. Since these parameters are critical to the healing of corneal wounds from alkali burns, we suggest that this discovery represents a promising future therapeutic agent that warrants further study in humans.

Chemical composition and antibacterial activity of bee venom against multi-drug resistant pathogens.

Bee venom with an antimicrobial effect is a powerful natural product. One of the most important areas where new antimicrobials are needed is in the prevention and control of multi-drug resistant pathogens. Today, antibacterial products used to treat multi-drug resistant pathogen infections in hospitals and healthcare facilities are insufficient to prevent colonisation and spread, and new products are needed. The aim of the study is to investigate the antibacterial effect of the bee venom (BV), a natural substance, on the species of Methicillin resistant Staphylococcus aureus, Vancomycin resistant Enterococcus faecalis, Carbapenem resistant Escherichia coli, Carbapenem resistant Klebsiella pneumoniae and Carbapenem resistant Acinetobacter baumannii. As a result of this study, it was found that MIC90 and MBC90 values ranged from 6.25 µg/mL - 12.5 µg/mL and numbers of bacteria decreased by 4-6 logs within 1-24 h for multi-drug resistant pathogens. In particular, Vancomycin resistant Enterococcus faecalis isolate decreased 6 log cfu/mL at 50 µg/mL and 100 µg/mL concentrations in the first hour. The effective bacterial inhibition rate of bee venom suggests that it could be a potential antibacterial agent for multi-drug resistant pathogens.Contribution: The treatment options of antibiotic-resistant pathogens are a major problem in both veterinary and human medicine fields. We have detected a high antibacterial effect against these agents in this bee venom study, which is a natural product. Apitherapy is a fashionable treatment method all over the world and is used in many areas of health. Bee venom is also a product that can be used as a drug or disinfectant raw material and can fill the natural product gap that can be used against resistant bacteria.

Short-Chain Fatty Acids Alleviate Vancomycin-Caused Humoral Immunity Attenuation in Rabies-Vaccinated Mice by Promoting the Generation of Plasma Cells via Akt-mTOR Pathway.

Mounting evidence suggests that gut microbial composition and its metabolites, including short-chain fatty acids (SCFAs), have beneficial effects in regulating host immunogenicity to vaccines. However, it remains unknown whether and how SCFAs improve the immunogenicity of the rabies vaccine. In this study, we investigated the effect of SCFAs on the immune response to rabies vaccine in vancomycin (Vanco)-treated mice and found that oral gavage with butyrate-producing bacteria (C. butyricum) and butyrate supplementation elevated RABV-specific IgM, IgG, and virus-neutralizing antibodies (VNAs) in Vanco-treated mice. Supplementation with butyrate expanded antigen-specific CD4+ T cells and IFN-γ-secreting cells, augmented germinal center (GC) B cell recruitment, promoted plasma cells (PCs) and RABV-specific antibody-secreting cells (ASCs) generation in Vanco-treated mice. Mechanistically, butyrate enhanced mitochondrial function and activated the Akt-mTOR pathway in primary B cells isolated from Vanco-treated mice, ultimately promoting B lymphocyte-induced maturation protein-1 (Blimp-1) expression and CD138+ PCs generation. These results highlight the important role of butyrate in alleviating Vanco-caused humoral immunity attenuation in rabies-vaccinated mice and maintaining host immune homeostasis. IMPORTANCE The gut microbiome plays many crucial roles in the maintenance of immune homeostasis. Alteration of the gut microbiome and metabolites has been shown to impact vaccine efficacy. SCFAs can act as an energy source for B-cells, thereby promoting both mucosal and systemic immunity in the host by inhibiting HDACs and activation of GPR receptors. This study investigates the impact of orally administered butyrate, an SCFA, on the immunogenicity of rabies vaccines in Vanco-treated mice. The results showed that butyrate ameliorated humoral immunity by facilitating the generation of plasma cells via the Akt-mTOR in Vanco-treated mice. These findings unveil the impact of SCFAs on the immune response of the rabies vaccine and confirm the crucial role of butyrate in regulating immunogenicity to rabies vaccines in antibiotic-treated mice. This study provides a fresh insight into the relationship of microbial metabolites and rabies vaccination.

Time for a Change: Considering Vancomycin Alternatives for Pediatric Methicillin-Resistant Staphylococcus aureus Bacteremia.

Vancomycin remains the standard of care for treating methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in pediatrics largely because no alternative antibiotic is definitively superior. Long-standing historical precedent and S. aureus' notable lack of vancomycin resistance are clear benefits, but vancomycin's use remains plagued by nephrotoxicity and the need for therapeutic drug monitoring, with inadequate consensus on how best to dose or monitor vancomycin in pediatrics. Daptomycin, ceftaroline, and linezolid are all promising alternatives, with improved safety relative to vancomycin. However, inadequate and variable efficacy data limit confidence in their use. Despite this, we contend that it is time for clinicians to reconsider vancomycin's place in clinical use. In this review, we summarize the supporting data for using vancomycin versus these other anti-MRSA antibiotics, present a framework for antibiotic decision-making that considers patient-specific factors, and discuss approaches to antibiotic selection for various etiologies of MRSA bacteremia. This review aims to help pediatric clinicians choose among the various treatment options for MRSA bacteremia, acknowledging that the optimal antibiotic choice is sometimes uncertain.

Intravitreal triple therapy with vancomycin, ceftazidime, and moxifloxacin for bacterial endophthalmitis: A Twelve-year experience.

PURPOSE: Increasing rates of antibiotic resistance in endophthalmitis have been reported. This study examines outcomes of triple therapy with intravitreal vancomycin, ceftazidime, and moxifloxacin for endophthalmitis. METHODS: Retrospective, consecutive series of all patients treated with abovementioned intravitreal antibiotics from January 2009 to June 2021. Percentages of eyes attaining greater than or equal to 20/200 and 20/50 Snellen visual acuities and adverse events were evaluated. RESULTS: 112 eyes met inclusion criteria. 63 of 112 eyes (56%) achieved a visual acuity of 20/200 during follow-up, with 39 (35%) returning to at least 20/50. In subgroup analysis, 23 of 24 (96%) eyes with post-cataract endophthalmitis obtained ≥ 20/200 acuity and 21 of 24 (88%) obtained ≥ 20/50 acuity during follow-up. There were no cases of macular infarction. CONCLUSIONS: Intravitreal moxifloxacin (160 µg/0.1 mL) was well tolerated as an adjunct to vancomycin and ceftazidime for bacterial endophthalmitis. Use of this novel combination offers several theoretical advantages compared to standard therapy with two antibiotics, including expanded gram-negative coverage and potential synergy, and may be particularly valuable in geographies where the local antibiogram supports empiric use. Further study is merited to verify the safety and efficacy profile.

In vitro evaluation of multiple antibacterial agents for the treatment of chronic staphylococcal anterior blepharitis.

OBJECTIVE: To evaluate the bactericidal efficacy of several compounds used in the treatment of chronic staphylococcal anterior blepharitis through an in vitro study. MATERIALS AND METHODS: Standard commercial strains of Staphylococcus aureus (SAu) (ATCC 25923 Culti-Loops) and coagulase-negative Staphylococcus (CoNS) (ATCC 12228 Culti-Loops) were cultured. Susceptibility tests were performed to vancomycin 30 µg, netilmicin 30 µg, hypochlorous acid (HOCl) 0.01% (Ocudox™, Brill®), Melaleuca alternifolia leaf oil (MeAl) (Navyblef® Daily Care, NOVAX®) and 1% chlorhexidine digluconate (DGCH) (Cristalmina™, Salvat®) using the agar disk diffusion method (Rosco Neo-Sensitabs®). After 24 h, the induced halos were measured with automatic calipers. The results were analyzed using the EUCAST- and CLSI potency Neo-Sensitabs® guidelines. RESULTS: Vancomycin induced a halo of 22.37 mm and 21.81 mm in SAu and CoNS, respectively. Netilmicin produced halos of 24.45 mm in SAu and 32.49 mm in CoNS. MeAl induced halos of 12.65 mm in SAu and 15.83 mm in CoNS. A 12.11 mm halo was found in SAu and an 18.38 mm halo in CoNS using HOCl. DGCH produced halos of 26.55 mm and 23.12 mm in SAu and CoNS, respectively. CONCLUSION: Netilmicin and vancomycin demonstrated antibiotic activity against both pathogens, so they can be alternative rescue therapies to treat chronic staphylococcal blepharitis. DGCH has efficacy against both comparable to antibiotics, while HOCl and MeAl show less efficacy.

Study of the effect of administration of narasin or antibiotics on in vivo selection of a narasin- and multidrug-resistant Enterococcus cecorum strain.

Enterococcus cecorum is a member of the normal poultry gut microbiota and an emerging poultry pathogen. Some strains are resistant to key antibiotics and coccidiostats. We evaluated the impact on chicken excretion and persistence of a multidrug-resistant E. cecorum of administering narasin or antibiotics. E. cecorum CIRMBP-1294 (Ec1294) is non-wild-type to many antimicrobials, including narasin, levofloxacin, oxytetracycline and glycopeptides, it has a low susceptibility to amoxicillin, and carries a chromosomal vanA operon. Six groups of 15 chicks each were orally inoculated with Ec1294 and two groups were left untreated. Amoxicillin, oxytetracycline or narasin were administered orally to one group each, either at the recommended dose for five days (amoxicillin, oxytetracycline) or continuously (narasin). Faecal samples were collected weekly and caecal samples were obtained from sacrificed birds on day 28. Ec1294 titres were evaluated by culture on vancomycin- and levofloxacin-supplemented media in 5 % CO2. For inoculated birds given narasin, oxytetracycline or no antimicrobials, vancomycin-resistant enterococci were searched by culture on vancomycin-supplemented media incubated in air, and a PCR was used to detect the vanA gene. Ec1294 persisted in inoculated chicks up to day 28. Compared to the control group, the Ec1294 titre was significantly lower in the amoxicillin- and narasin-receiving groups on days 21 and 28, but was unexpectedly higher in the oxytetracycline-receiving group before and after oxytetracycline administration, preventing a conclusion for this group. No transfer of the vanA gene to other enterococci was detected. Other trials in various experimental conditions should now be conducted to confirm this apparent absence of co-selection of the multi-drug-resistant E. cecorum by narasin or amoxicillin administration.

Pangenome profiling of novel drug target against vancomycin-resistant Enterococcus faecium.

Enterococcus faecium is a frequent causative agent of nosocomial infection mainly acquired from outgoing hospital patients (Hospital Acquired Infection-HAIs). They are largely involved in the outbreaks of bacteremia, UTI, and endocarditis with a high transmissibility rate. The recent emergence of VRE strain (i.e. vancomycin resistant enterococcus) turned it into high priority pathogen for which new drug research is of dire need. Therefore, in current study, pangenome and resistome analyses were performed for available antibiotic-resistant genomes (n = 216) of E. faecium. It resulted in the prediction of around 5,059 genes as an accessory gene, 1,076 genes as core and 1,558 genes made up a unique genome fraction. Core genes common to all strains were further used for the identification of potent drug targets by applying subtractive genomics approach. Moreover, the COG functional analysis showed that these genomes are highly enriched in metabolic pathways such as in translational, ribosomal, proteins, carbohydrates and nucleotide transport metabolism. Through subtractive genomics it was observed that 431 proteins were non-homologous to the human proteome, 166 identified as essential for pathogen survival while 26 as potential and unique therapeutic targets. Finally, 3-dehydroquinate dehydrogenase was proposed as a potent drug target for further therapeutic candidate identification. Moreover, the molecular docking and dynamic simulation technique were applied to performed a virtual screening of natural product libraries (i.e., TCM and Ayurvedic compounds) along with 3-amino-4,5-dihydroxy-cyclohex-1-enecarboxylate (DHS) as a standard compound to validate the study. Consequently, Argeloside I, Apigenin-7-O-gentiobioside (from Ayurvedic library), ZINC85571062, and ZINC85570908 (TCM library) compounds were identified as potential inhibitors of 3-dehydroquinate dehydrogenase. The study proposed new compounds as novel therapeutics, however, further experimental validation is needed as a follow-up.Communicated by Ramaswamy H. Sarma.

Antimicrobial Isoflavans and Other Metabolites of Dalea jamesii.

The phytochemical investigation of extracts of Dalea jamesii root and aerial portions led to the isolation of ten phenolic compounds. Six previously undescribed prenylated isoflavans, summarily named ormegans A - F (1 - 6: ), were characterized, along with two new arylbenzofurans (7, 8: ), a known flavone (9: ), and a known chroman (10: ). The structures of the new compounds were deduced by NMR spectroscopy, supported by HRESI mass spectrometry. The absolute configurations of 1 - 6: were determined by circular dichroism spectroscopy. Compounds 1 - 9: exhibited in vitro antimicrobial activities, causing 98% or greater growth inhibition at concentrations as low as 2.5 - 5.1 µM against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and Cryptococcus neoformans. Interestingly, the most active compound was the dimeric arylbenzofuran 8: (> 90% growth inhibition at 2.5 µM) against both methicillin-resistant S. aureus and vancomycin-resistant E. faecalis, tenfold more active than its corresponding monomer (7: ).

Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations.

Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here, we show that unsaturated fatty acids act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens, and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection.

Impact of Vancomycin Loading Doses and Dose Escalation on Glomerular Function and Kidney Injury Biomarkers in a Translational Rat Model.

Vancomycin-induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in the glomerular filtration rate (GFR) and correlations with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague-Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had low GFRs and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2 compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high-dose folic acid. Rats in both the low- and high-dose vancomycin groups had higher GFRs on all dosing days than the positive-control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFRs on days 1, 2, and 4. Compared to low-dose vancomycin, the KIM-1 was elevated among rats in the high-dose group on dosing day 3. The GFR correlated most closely with the urinary injury biomarker KIM-1 on all experimental days. Vancomycin loading doses were associated with significant losses of kidney function and elevations of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker increases corresponded to the magnitude of the vancomycin dose (i.e., a higher dose resulted in worse outcomes).

Pyrolysis of Ca/Fe-rich antibiotic fermentation residues into biochars for efficient phosphate removal/recovery from wastewater: Turning hazardous waste to phosphorous fertilizer.

Ca/Fe-rich antibiotic fermentation residues (AFRs), a type of hazardous waste, can be regarded as recyclable biomass and metal resources. However, concurrent detoxification and reutilization of biomass and metals resources from AFRs have never been reported before. In this study, Ca/Fe-rich vancomycin fermentation residues were pyrolyzed into biochar to adsorb phosphate for the first time. The residual vancomycin and antibiotic resistance genes were completely decomposed during pyrolysis. The resultant Ca/Fe-rich biochar exhibited excellent performance at adsorbing phosphate without further modifications. The process had rapid kinetics and a maximum adsorption capacity of 102 mg P/g. Ca and Fe were the active sites, whereas different mechanisms were observed under acidic and alkaline conditions. Surprisingly, HCO3- enhanced phosphate adsorption with an increase of adsorption capacity from 43.9 to 71.0 mg/g when HCO3- concentration increased from 1 to 10 mM. Furthermore, actual wastewater could be effectively treated by the biochar. The phosphate-rich spent biochar significantly promoted seed germination (germination rate: 96.7 % vs. 80.0 % in control group, p < 0.01) and seedling growth (shoot length was increased by 57.9 %, p < 0.01) due to the slow release of bioavailable phosphate, and thus could be potentially used as a phosphorous fertilizer. Consequently, the hazardous waste was turned into phosphorous fertilizer, with the additional benefits of detoxifying AFRs, reutilizing biomass and metal resources from AFRs, controlling phosphate pollution, and recovering phosphate from wastewater.

Adherence to practice guidelines for the management of febrile neutropenia in patients undergoing hematopoietic stem cell transplantation: An observational study in a referral center in Iran.

INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation (HSCT) are suspected to develop febrile neutropenia (FN) and severe infections. Therefore, appropriate prescription of antibiotics in these patients is crucial to reduce the rates of morbidity, mortality, and antimicrobial resistance. The present study aimed to evaluate the physicians' prescription and adherence to the FN clinical guidelines among patients undergoing HSCT. METHODS: This prospective observational single-center study was conducted during a 15-month period in a tertiary referral hospital in Iran. The patients with at least one episode of FN following HSCT were included in the current study. The physicians' adherence to the Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) clinical guidelines for the management of FN was evaluated using prescription data and medical record reviews. RESULTS: Two hundred and fifteen patients with 297 FN episodes were evaluated. The timing of antibiotics and the selection of the initial regimen were considered guideline-based therapy. However, antibiotic dosing and initial regimen modification were not followed in terms of the guideline recommendations in 58.1% of the patients. In particular, vancomycin was inappropriately given in 83.1% of patients. The overall adherence of physicians to the guidelines was 35.8%. CONCLUSION: Non-adherence to clinical guidelines is high particularly in initial regimen modification and administration of vancomycin, which affects hospital stay and patient's outcome. Implementation of guideline-review sessions to raise the awareness of the physicians and to improve the rational use of antimicrobial agents may be crucial.