Broad-spectrum Drug Research Articles

Phage-displayed heptapeptide sequence conjugation significantly improves the specific targeting ability of antimicrobial peptides against Staphylococcus aureus.

Broad-spectrum antibacterial drugs often lack specificity, leading to indiscriminate bactericidal activity, which can disrupt the normal microbial balance of the host flora and cause unnecessary cytotoxicity during systemic administration. In this study, we constructed a specifically targeted antimicrobial peptide against Staphylococcus aureus by introducing a phage-displayed peptide onto a broad-spectrum antimicrobial peptide and explored its structure-function relationship through one-factor modification. SFK2 obtained by screening based on the selectivity index and the targeting index showed specific killing ability against S. aureus. Moreover, SFK2 showed excellent biocompatibility in mice and piglet, and demonstrated significant therapeutic efficacy against S. aureus infection. In conclusion, our screening of phage-derived heptapeptides effectively enhances the specific bactericidal ability of the antimicrobial peptides against S. aureus, providing a theoretical basis for developing targeted antimicrobial peptides.

Plasmonic Imaging of Multivalent NTD-Nucleic Acid Interactions for Broad-Spectrum Antiviral Drug Analysis.

The discovery and identification of broad-spectrum antiviral drugs are of great significance for blocking the spread of pathogenic viruses and corresponding variants of concern. Herein, we proposed a plasmonic imaging-based strategy for assessing the efficacy of potential broad-spectrum antiviral drugs targeting the N-terminal domain of a nucleocapsid protein (NTD) and nucleic acid (NA) interactions. With NTD and NA conjugated gold nanoparticles as core and satellite nanoprobes, respectively, we found that the multivalent binding interactions could drive the formation of core-satellite nanostructures with enhanced scattering brightness due to the plasmonic coupling effect. The core-satellite assembly can be suppressed in the presence of antiviral drugs targeting the NTD-NA interactions, allowing the drug efficacy analysis by detecting the dose-dependent changes in the scattering brightness by plasmonic imaging. By quantifying the changes in the scattering brightness of plasmonic nanoprobes, we uncovered that the constructed multivalent weak interactions displayed a 500-fold enhancement in affinity as compared with the monovalent NTD-NA interactions. We demonstrated the plasmonic imaging-based strategy for evaluating the efficacy of a potential broad-spectrum drug, PJ34, that can target the NTD-NA interactions, with the IC50 as 24.35 and 14.64 μM for SARS-CoV-2 and SARS-CoV, respectively. Moreover, we discovered that ceftazidime holds the potential as a candidate drug to inhibit the NTD-NA interactions with an IC50 of 22.08 μM from molecular docking and plasmonic imaging-based drug analysis. Finally, we validated that the potential antiviral drug, 5-benzyloxygramine, which can induce the abnormal dimerization of nucleocapsid proteins, is effective for SARS-CoV-2, but not effective against SARS-CoV. All these demonstrations indicated that the plasmonic imaging-based strategy is robust and can be used as a powerful strategy for the discovery and identification of broad-spectrum drugs targeting the evolutionarily conserved viral proteins.

Isavuconazole Induces Neurodevelopment Defects and Motor Behaviour Impairment in Zebrafish Larvae.

Isavuconazole is a broad-spectrum antifungal drug used for the treatment of serious infections caused by invasive aspergillosis and mucormycosis in adults. With the continuous use of this drug, its safety and environmental impact have received increasing attention. However, information on the adverse effects of the drug is very limited. Fish is a particularly important model for assessing environmental risks. In this study, the aquatic vertebrate zebrafish was used as a model to study the toxic effects and mechanisms of isavuconazole. We exposed zebrafish embryos to 0.25, 0.5, and 1mg/L of isavuconazole 6h after fertilization. The results showed that at 72 hpf, isavuconazole exposure reduced heart rate, body length, and survival of zebrafish embryos compared to controls. Secondly, when isavuconazole reached a certain dose level (0.25mg/L), it caused morphological changes in the Tg(elavl3:eGFP) transgenic fish line, with the head shrunk, the body bent, the fluorescence intensity becoming weaker, the abnormal motor behaviour, etc. At the same time, exposure of zebrafish embryos to isavuconazole downregulated acetylcholinesterase (AchE) and adenosine triphosphate (ATPase) activities but upregulated oxidative stress, thereby disrupting neural development and gene expression of neurotransmitter pathways. In addition, astaxanthin partially rescued the neurodevelopmental defects of zebrafish embryos by downregulating oxidative stress. Thus, our study suggests that isavuconazole exposure may induce neurodevelopment defects and behavioural disturbances in larval zebrafish.

MYCOLOGICAL ANALYSIS OF CYSTIC CONTENT IN PATIENTS WITH POLYMICROCYSTIC CHANGES OF THE MAXILLARY SINUS MUCOSA

The prevalence of mycotic infections of the paranasal sinuses is constantly increasing worldwide. Pathogens can enter the sinuses through the respiratory tract that leads to the colonization of microorganisms in both the lungs and paranasal sinuses as part of the normal microflora. The presence of filamentous fungi in the maxillary sinus may result from endodontic treatment of molars directly adjacent to the sinus, increasing the risk of fungal foci development. Fungal paranasal sinusitis manifests in invasive or non-invasive forms. While mycological culture remains the traditional gold standard for mycosis diagnosis, its sensitivity is reportedly low. Paranasal sinus cysts comprise 4-8% of general ENT pathologies and approximately 4-16% of chronic paranasal sinus diseases, with a predominant presence in the maxillary sinus. Factors that contribute to the development of sinusitis and create favorable conditions for fungal spore adhesion and growth include impaired ventilation and transport function of the sinus mucosa, inadequate use of broad-spectrum antibacterial drugs and steroid therapy, as well as household factors. Recently, there has been an increase in the number of cases of multiple small cysts in maxillary sinuses. Clinical manifestations range from asymptomatic incidental findings to varying degrees of discomfort and/or pain localized in the maxillary sinus area. The aim of this study is to identify the involvement of a fungal agent and to develop a set of therapeutic and prophylactic measures for polymicrocystic changes in the mucous membrane of the maxillary sinuses. The study enrolled 37 patients aged 18 to 65 years. Atypical cystic content was collected and cultured in Sabouraud's nutrient broth and Amies transport medium at 35-37°C for 5-7 days, with final measurements on day 21. Treatment involved a 14-day regimen of itraconazole (100 mg once daily) alongside topical miramistin (0.01% solution, 2 ml) sinus injections. The findings obtained demonstrate the following: positive fungal growth was observed in 26 cases (70.3%), predominantly Penicillium (48.6%) and Aspergillus (21.6%). Absence of growth was noted in 11 cases (29.7%). Follow-up examinations in 6 months and in a year revealed no crusts in the nasal cavity, moderate mucous discharge in the sinuses, and no polymicrocystic changes. Conclusion. The analysis has demonstrated the involvement of fungal flora in the development and recurrence of cystic changes in the maxillary sinus mucosa, advocating for mycological examination alongside bacteriological analysis. Itraconazole for systemic therapy and miramistin for topical therapy demonstrate efficacy in treatment and recurrence prevention.

Paclitaxel loaded into metformin oleate ionic liquid micelle: Preparation and synergistic antitumor

Although paclitaxel (PTX) is a broad-spectrum anticancer drug, its low water solubility, poor bioavailability, and susceptibility to drug resistance have seriously limited its application. In recent years, studies have shown that metformin has potential anti-tumor activity. This paper reports the successful loading of PTX into metformin oleate ionic liquid ([Met][Ole] IL) micelles and [Met][Ole] IL/tween 80 (T-80) micelles. The obtained PTX-IL/T-80 micelle exhibited a good particle size (5.77 nm) and stability (Zeta potential: −51.65 ± 7.73 mV) in addition to possessing in vitro and in vivo antitumor efficacy. The inhibition rate of PTX-IL/T-80 (10 ppm) on 4 T1 cells reached 93 %. Furthermore, the results of the in vivo treatment in mice revealed that the tumor inhibition rate of PTX-IL/T-80 under a small-dose treatment (0.5 mg·kg−1) was 37.7 %, which was much higher than that of the PTX prodrug group (11.7 %). Consequently, PTX-IL/T-80 has a great potential for its application in cancer therapy owing to the good synergistic antitumor effect between ([Met][Ole] ionic liquid and PTX.

Two {CuI[P4Mo6]2}-Based Coordination Polymers Incorporating In Situ Converted Tetrapyridyl Ligands for Trace Analysis of Nitrofuran Antibiotics.

Nitrofurans are important synthetic broad-spectrum antibacterial drugs with the basic structure of 5-nitrofuran. Due to their toxicity, it is essential to develop a sensitive sensor with strong anti-interference capabilities for their detection. In this work, two {P4Mo6O31}12--based compounds, [H4(HPTTP)]2{CuI[Mo12O24(OH)6(PO4)3(HPO4)(H2PO4)4]}·xH2O (x = 13 for (1), 7 for (2); HPTTP = 4,4',4″,4‴-(1H-pyrrole-2,3,4,5-tetrayl)tetrapyridine), exhibiting similar coordination but distinct stacking modes. Both compounds were synthesized and used for the electrochemical detection of nitrofuran antibiotics. The tetrapyridine-based ligand was generated in situ during assembly, and its potential mechanism was discussed. Composite electrode materials, formed by mixing graphite powder with compounds 1-2 and physically grinding them, proved to be highly effective in the electrochemical trace detection of furazolidone (FZD) and furaltadone hydrochloride (FTD·HCl) under optimal conditions. Besides, the possible electrochemical detection mechanisms of two nitro-antibiotics were studied.

Urinary tract infections in pregnant women

Urinary tract infections (UTIs) are the most common pathology among pregnant women and are associated with maternal and foetal complications. According to some authors, the incidence of UTIs increased 4 times in the last decades of the 20th century. Escherichia coli is the most predominant pathogen causing up to 80% of UTIs, Klebsiella is ranked second causing up to 8% of UTIs, and pathogenic staphylococcus and mixed microflora are ranked third. To diagnose UTIs, laboratory, physical and radiological diagnostic methods are applied. According to most authors, informative value yielded by lab tests is more than 90%. The prescription of antibacterial chemotherapy should be based on the results of urine culture and sensitivity testing. Before the test results are obtained, broad-spectrum antibacterial drugs (ABs) are usually prescribed. The most commonly used therapy regimens are third-generation cephalosporins with dose adjustments, as may be necessary, after sensitivity is determined. Some authors recommend to continue treatment with urinary tract antiseptics after AB therapy is completed. The impaired urine output should be restored before AB therapy is prescribed. This review presents an analysis of the literature that was found in the databases PubMed (the National Library of Medicine), The Cochrane Library, as well as in the research citation databases (Scopus, Web of Science). The etiological factors and features of the pathogenesis of UTIs in pregnant women, as well as diagnostic standards, are described. The current guidelines for the treatment and prevention of UTIs in pregnant women are considered and antibacterial therapy regimens with current dosage forms are presented. The benefits of using cefixime dispersible forms are described in detail.

Enrofloxacin, Effective Treatment of Pseudomonas aeruginosa and Enterococcus faecalis Infection in Oreochromis niloticus.

Enrofloxacin is a broad-spectrum synthetic antimicrobial drug widely used in veterinary medicine. The present study aimed to determine the effective enrofloxacin dose for treating Pseudomonas aeruginosa and Enterococcus faecalis infection in Oreochromis niloticus. P. aeruginosa and E. faecalis isolates were verified using selective differential media and biochemically using the Vitek 2 test. Bacterial isolates were virulent for O. niloticus with LD50 equal to 2.03 × 106 and 2.22 × 107 CFU fish-1 for P. aeruginosa and E. faecalis, respectively. Infected fish suffered from decreased feed intake followed by off-food, tail erosion, darkening of the external body surface, exophthalmia, ascites, and loss of escape reflex. Internally, congested hemorrhagic hepatopancreas with engorged distended gall bladder were dominant. The posterior kidney was congested with enlarged spleen, and empty elementary tract. Pathologically, severe degenerative changes were dominant in the hepatopancreas, posterior kidney, spleen, stomach, and gills of infected fish. Antimicrobial sensitivity test indicated the high susceptibility of P. aeruginosa and E. faecalis to enrofloxacin with MIC estimated at 1 and 0.0625 µg/mL, respectively. Enrofloxacin effectively protected O. niloticus against E. faecalis and P. aeruginosa infection when used with medicated feed at doses of 10 and 20 mg kg-1 body weight.

Pharmacological efficacy and potential of the use of nitazoxanide, a thiazolide drug with a wide spectrum of action

The article is devoted to the possibility and prospects of using nitazoxanide in a wide range of diseases. Based on literature data, the authors evaluate the pharmacological effectiveness and substantiate the potential of using nitazoxanide in bacterial, helminthic, protean, viral and oncological diseases. This information is of interest and can be used to decide on the need to conduct clinical trials of nitazoxanide in Russia. A systematic search for current information was conducted in four databases until December 1, 2023: PubMed, EMBASE, Web of Science and Cochrane Library. The work included preclinical studies in vitro and in vivo, as well as randomized clinical trials comparing the pharmacological effectiveness of nitazoxanide and placebo. The broad-spectrum thiazolide drug nitazoxanide has antibacterial, antiprotozoal, anthelmintic, antiviral and antitumor activity. This is achieved through its pharmacological properties, namely: regulation of the cell cycle, apoptosis, cell proliferation and migration; activation of innate immunity; influence on the synthesis and activation of cell proteins, some of which are links in cellular signaling pathways; binding to proteins of viruses, bacteria, protozoa and helminths with disruption of their vital functions; immunomodulating effect by regulating the activity of pro- and anti-inflammatory cytokines. The article systematizes and summarizes current information on the pharmacodynamics of nitazoxanide, as well as the results of preclinical and clinical studies of the drug, and discusses further prospects.

An RNA-hydrolyzing recombinant minibody prevents both influenza A virus and coronavirus in co-infection models

With the lifting of COVID-19 non-pharmaceutical interventions, the resurgence of common viral respiratory infections was recorded in several countries worldwide. It facilitates viral co-infection, further burdens the already over-stretched healthcare systems. Racing to find co-infection-associated efficacy therapeutic agents need to be rapidly established. However, it has encountered numerous challenges that necessitate careful investigation. Here, we introduce a potential recombinant minibody-associated treatment, 3D8 single chain variable fragment (scFv), which has been developed as a broad-spectrum antiviral drug that acts via its nucleic acid catalytic and cell penetration abilities. In this research, we demonstrated that 3D8 scFv exerted antiviral activity simultaneously against both influenza A viruses (IAVs) and coronaviruses in three established co-infection models comprising two types of coronaviruses [beta coronavirus—human coronavirus OC43 (hCoV-OC43) and alpha coronavirus—porcine epidemic diarrhea virus (PEDV)] in Vero E6 cells, two IAVs [A/Puerto Rico/8/1934 H1N1 (H1N1/PR8) and A/X-31 (H3N2/X-31)] in MDCK cells, and a combination of coronavirus and IAV (hCoV-OC43 and adapted-H1N1) in Vero E6 cells by a statistically significant reduction in viral gene expression, proteins level, and approximately around 85%, 65%, and 80% of the progeny of ‘hCoV-OC43–PEDV’, ‘H1N1/PR8–H3N2/X-31’, and ‘hCoV-OC43–adapted-H1N1’, respectively, were decimated in the presence of 3D8 scFv. Taken together, we propose that 3D8 scFv is a promising broad-spectrum drug for treatment against RNA viruses in co-infection.

Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma-en route to broad-spectrum antimycetomal drugs.

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.

Insights into solid–liquid equilibrium behavior of 2′,4′-Dichloro-5′-fluoroacetophenone

2′,4′-Dichloro-5′-fluoroacetophenone is a key intermediate in the preparation of ciprofloxacin hydrochloride, a broad-spectrum quinolone antibacterial drug. Wherein, crystallization and solid–liquid equilibrium thermodynamics play an irreplaceable role in the separation and purification of 2′,4′-Dichloro-5′-fluoroacetophenone. Therefore, in this work, the solubility of 2′,4′-Dichloro-5′-fluoroacetophenone was measured by dynamic method in eight different solvents and range from 273.15 K to 288.15 K. The results showed that the solubility of 2′,4′-Dichloro-5′-fluoroacetophenone increased with increasing temperature. Further analysis showed that the solubility of 2′,4′-Dichloro-5′-fluoroacetophenone increased with increasing carbon chain length in ester solvents. Single crystals of 2′,4′-Dichloro-5′-fluoroacetophenone were successfully prepared and the result reveals that the Cl⋯H, O⋯H, and F⋯H interactions dominated the packing and long-range order of the crystals. Then, different thermodynamic models were employed to describe the thermodynamic behavior of 2′,4′-Dichloro-5′-fluoroacetophenone. The calculated ARD% and RMSD values show that the correlation results are in good agreement with the experimental data, and the Van’t Hoff equation has the best regression performance. Finally, it is interesting to find that the contribution of entropy and enthalpy change to dissolution of 2′,4′-Dichloro-5′-fluoroacetophenone tends to be equal with increasing temperature.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos>dipterex>dibrom>paraoxon>fenthion>dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate>paraoxon>dichlorvos>dibrom>(fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

Retracted and republished from: "The current state of research on influenza antiviral drug development: drugs in clinical trial and licensed drugs".

Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the Food and Drug Administration are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These recommended antivirals are currently effective for major subtypes of IVs as the compounds target conserved domains in neuraminidase or polymerase acidic (PA) protein. However, this trend may gradually change due to the selection of antiviral drugs and the natural evolution of IVs. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.

Study of the Pharmacokinetics and Safety of Dioxidine®, Solution for Topical and External Use, 0.25 mg/ml, in Various Routes of Administration

Topical use of antibacterial drugs as part of complex therapy for purulent-inflammatory infections of the skin and oropharynx can not only eliminate the symptoms but also influence the cause of the disease. Dioxidine® is a broad-spectrum antibacterial drug, active against both gram-positive and gram-negative bacteria. The aim of this study was to investigate the bioavailability, pharmacokinetic parameters, and safety profile of Dioxidine®, solution for topical and external use, 0.25 mg/ml, in cutaneous and topical application. Another dosage form of Dioxidine® — a solution for infusion and external use, 5 mg/ml — was used as a comparison drug. The study consisted of 4 stages reflecting different routes of drug administration: rinsing the oropharynx (path A), a single irrigation of the oropharynx using a spray nozzle (path B), back skin irrigation (path C), and intravenous administration (path D — for the reference drug). The results of the study made it possible to determine the absolute dose-normalized bioavailability of the study drug in the indicated routes of administration, as well as to evaluate its safety profile.

Toxic effect of ciprofloxacin on the photosynthesis reactions in microalga Scenedesmus quadricauda (Turp.) Bréb.

Ciprofloxacin (CIP) is widely used broad-spectrum antimicrobial drug of fluoroquinolone family. The widespread use of ciprofloxacin increases its release into the environment. Ciprofloxacin is detected in aquatic ecosystems potentially harming aquatic organisms. The CIP effect on photosynthetic organisms is not fully studied. In this study we examined the CIP effect on green freshwater microalgae Scenedesmus quadricauda (Turp.) Bréb. using chlorophyll fluorescence methods (JIP test parameters and rapid light curves). A significant decrease in the cell number was observed at ≥10 mg/L of сiprofloxacin in comparison with control. Analysis of chlorophyll fluorescence parameters obtained from OJIP transients revealed the changes in photosynthetic reactions in сiprofloxacin treatment. Ciprofloxacin was found to inhibit electron transport rate in photosystem II (PSII). The decrease in the quantum yield of electron transport in photosystem II (φEo) was accompanied by the decrease in performance index (PIABS) and an increase in energy dissipation (DI0/RC). Ciprofloxacin enhanced the photosensitivity of microalgae but did not inhibit the recovery of photosynthetic activity after the photooxidative stress. In this regard the effect of CIP differs from that of the well-known antibiotic chloramphenicol that inhibits the resynthesis of plastid proteins and, accordingly, the recovery of photosynthetic activity associated with the resynthesis of PSII protein D1. Among the fluorescence parameters, PIABS was found to be the most stress-specific; therefore it can be proposed to detect an early toxic CIP effect in microalgae.

Imaging in a rare case of cerebral phaeohyphomycosis caused by Cladophialophora bantiana in a renal transplant patient: a case report and the literature review

BackgroundCerebral phaeohyphomycosis is a rare and potentially life-threatening fungal infection caused by dematiaceous fungi (Levin TP et al. in J Clin Microbiol 42(9):4374–4378, 2004). It may occur in both immunocompetent and immunodeficient individuals, with a relatively higher incidence in the former (Revankar SG et al. in J Trop Med Hyg 38(1):206–222, 2004). A search of the Pubmed and Google Scholar databases revealed seven cases of cerebral phaeohyphomycosis in renal transplant patients caused by Cladophialophora bantiana (C. bantiana).Case presentationA 35-year-old male patient who had undergone a renal transplant presented with fever, imbalance while walking, and focal seizures involving the right lower limb. Magnetic Resonance Imaging (MRI) of the brain showed two lesions in the cerebral hemispheres. Craniotomy with excision of the lesion was done. The Periodic Acid Schiff (PAS) stain and the tissue culture on the Sabouraud dextrose agar suggested C. bantiana. The broad-spectrum antifungal drugs were started. However, the patient deteriorated in the subsequent follow-ups and eventually died of the disease.ConclusionsWe present a detailed report on the imaging characteristics of a rare fungal brain abscess caused by C. bantiana, which is the first case of its kind (refer to Table 1). In immunodeficient cases, intracranial pathologies can encompass a wide range of conditions, from infections to neoplasms, which often exhibit significant imaging overlap. In such a setting, the remote possibility of phaeohyphomycosis is easy to miss clinically and imaging-wise. MRI can narrow down the differential diagnosis and raise suspicion. In every suspicious case, it is of the utmost importance to correlate with the histopathology and the culture reports to initiate the prompt targeted therapy and avoid a fatal outcome. Complete excision of the abscess and antifungal agents like Voriconazole and Posaconazole are the mainstay of management in these patients.

Brincidofovir Effectively Inhibits Proliferation of Pseudorabies Virus by Disrupting Viral Replication.

Pseudorabies is an acute and febrile infectious disease caused by pseudorabies virus (PRV), a member of the family Herpesviridae. Currently, PRV is predominantly endemoepidemic and has caused significant economic losses among domestic pigs. Other animals have been proven to be susceptible to PRV, with a mortality rate of 100%. In addition, 30 human cases of PRV infection have been reported in China since 2017, and all patients have shown severe neurological symptoms and eventually died or developed various neurological sequelae. In these cases, broad-spectrum anti-herpesvirus drugs and integrated treatments were mostly applied. However, the inhibitory effect of the commonly used anti-herpesvirus drugs (e.g., acyclovir, etc.) against PRV were evaluated and found to be limited in this study. It is therefore urgent and important to develop drugs that are clinically effective against PRV infection. Here, we constructed a high-throughput method for screening antiviral drugs based on fluorescence-tagged PRV strains and multi-modal microplate readers that detect fluorescence intensity to account for virus proliferation. A total of 2104 small molecule drugs approved by the U.S. Food and Drug Administration (FDA) were studied and validated by applying this screening model, and 104 drugs providing more than 75% inhibition of fluorescence intensity were selected. Furthermore, 10 drugs that could significantly inhibit PRV proliferation in vitro were strictly identified based on their cytopathic effects, virus titer, and viral gene expression, etc. Based on the determined 50% cytotoxic concentration (CC50) and 50% inhibitory concentration (IC50), the selectivity index (SI) was calculated to be 26.3-3937.2 for these 10 drugs, indicating excellent drugability. The antiviral effects of the 10 drugs were then assessed in a mouse model. It was found that 10 mg/kg brincidofovir administered continuously for 5 days provided 100% protection in mice challenged with lethal doses of the human-origin PRV strain hSD-1/2019. Brincidofovir significantly attenuated symptoms and pathological changes in infected mice. Additionally, time-of-addition experiments confirmed that brincidofovir inhibited the proliferation of PRV mainly by interfering with the viral replication stage. Therefore, this study confirms that brincidofovir can significantly inhibit PRV both in vitro and in vivo and is expected to be an effective drug candidate for the clinical treatment of PRV infections.

Coexistence of blaIMP−4 and blaSFO−1 in an IncHI5B plasmid harbored by tigecycline-non-susceptible Klebsiella variicola strain

BackgroundKlebsiella variicola is considered a newly emerging human pathogen. Clinical isolates of carbapenemase and broad-spectrum β-lactamase-producing K. variicola remain relatively uncommon. A strain of K. variicola 4253 was isolated from a clinical sample, and was identified to carry the blaIMP−4 and blaSFO−1 genes. This study aims to discern its antibiotic resistance phenotype and genomic characteristics.MethodsSpecies identification was conducted using MALDI-TOF/MS. PCR identification confirmed the presence of the blaIMP−4 and blaSFO−1 genes. Antibiotic resistance phenotype and genomic characteristics were detected by antimicrobial susceptibility testing and whole-genome sequencing. Plasmid characterization was carried out through S1-PFGE, conjugation experiments, Southern blot, and comparative genomic analysis.ResultsK. variicola 4253 belonged to ST347, and demonstrated resistance to broad-spectrum β-lactamase drugs and tigecycline while being insensitive to imipenem and meropenem. The blaIMP−4 and blaSFO−1 genes harbored on the plasmid p4253-imp. The replicon type of p4253-imp was identified as IncHI5B, representing a multidrug-resistant plasmid capable of horizontal transfer and mediating the dissemination of drug resistance. The blaIMP−4 gene was located on the In809-like integrative element (Intl1-blaIMP−4-aacA4-catB3), which circulates in Acinetobacter and Enterobacteriaceae.ConclusionsThis study reports the presence of a strain of K. variicola, which is insensitive to tigecycline, carrying a plasmid harboring blaIMP−4 and blaSFO−1. It is highly likely that the strain acquired this plasmid through horizontal transfer. The blaIMP−4 array (Intl1-blaIMP−4-aacA4-catB3) is also mobile in Acinetobacter and Enterobacteriaceae. So it is essential to enhance clinical awareness and conduct epidemiological surveillance on multidrug-resistant K. variicola, conjugative plasmids carrying blaIMP−4, and the In809 integrative element.

Modern approaches to the treatment of superficial pyoderma in the practice of a dermatologist

The skin, as an organ in combination with a large number of commensal bacteria that colonized its surface and hair follicles, should be considered as a full-fledged and complex ecosystem. The imbalance of the skin microbiome can lead to skin diseases. The proportion of pyoderma among all skin pathology ranges from 17 to 36% among the population of the Russian Federation. Most skin infections occur de novo, but pyoderma often occurs when exposed to predisposing factors (for example, a violation of the skin barrier, the presence of maceration, old age, diabetes mellitus, obesity, peripheral arteriovenous insufficiency, corticosteroid treatment or chemotherapy, dysglobulinemia, blood diseases, cachexia, congenital or acquired immunodeficiency). Staphylococcus aureus and Streptococcus spp. they are the cause of most pyoderma. In patients undergoing long-term hospital treatment, S. aureus, P. aeruginosa, Enterococcus spp. and Escherichia coli are often the causative agents of skin infections. In localized, uncomplicated superficial pyoderma, local therapy is most often used. Dioxidin® is a derivative of di-N-oxy quinoxaline, a synetic broad-spectrum bactericidal drug that has been actively used by otolaryngologists and surgeons since 1976 to combat various bacterial infections. The drug is produced in the form of an aqueous solution for intravenous and intracavitary administration, as well as in the form of new dosage forms for topical and external use. Dioxidin is characterized by high bactericidal activity against a wide range of microorganisms, including anaerobic ones, and also acts against Candida albicans. This drug is able to completely suppress microorganisms with acquired resistance to antimicrobial drugs of other classes, including multiresistant strains. Dioxidine® in a new dosage form (0.25 mg/ml solution for topical and external use) has shown high efficacy when applied cutaneous to superficial pyoderma.