Search

Objective: The foodborne pathogen Salmonella enterica serovar Typhimurium causes self-limiting gastroenteritis in humans and is difficult to eliminate due to its ability to adhere to surfaces and form biofilms that exhibit high resistance to antimicrobial agents. To explore alternative strategies for biofilm treatment, it is essential to investigate novel agents that inhibit Salmonella biofilms., Method: In this study, we investigated the minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm eradication concentrations (MBECs) of nafcillin and diosmin, both previously identified as Lon protease inhibitors, against biofilms formed by S. Typhimurium. Furthermore, we examined the expression of genes associated with the type II toxin-antitoxin system to enhance our understanding of the impact of these inhibitors., Results: The findings indicated a strong antibiofilm effect of nafcillin, with MBIC and MBEC values of 8 µg/mL and 32 µg/mL, respectively. These results were confirmed by field emission scanning electron microscopy (FE-SEM), which showed that biofilm formation was reduced in the presence of nafcillin. Additionally, it revealed morphological changes in the bacteria within the nafcillin-treated biofilms. Furthermore, gene expression analyses demonstrated a significant reduction in the expression of type II TA system genes following treatment with nafcillin and diosmin., Conclusion: This study highlights the effectiveness of nafcillin in disrupting the biofilms of S. Typhimurium. These results suggest promising avenues for the development of novel therapeutic strategies targeting biofilms associated with S. Typhimurium., Competing Interests: Declarations. Ethical approval: This study was approved by the Ethics Committee of Iran University of Medical Sciences by Ethics No. (IR.IUMS.FMD.REC.1402.262). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The present study is an evaluation of Centella asiatica ethanolic extract in terms of total phenolic content, total flavonoids, total flavonols, anthocyanin, antioxidants, and antibacterial activities. Centella asiatica plants were collected from Guilan province, Iran. High-performance liquid chromatography-Diode array detector analysis demonstrated that the ethanolic extract of C. asiatica contained phenolic substances such as sinapic acid, catechin, quercetin, p-coumaric acid, hesperidin, eugenol, and hesperetin. The predominant phenolic compound in the extract was hesperetin. The antibacterial activities of the extract were highly potent against S. aureus and B. cereus. These findings suggest that C. asiatica is rich in phenolic compounds and can be utilised for future cosmetic and pharmaceutical purposes.

Objective: Persister cells are a specific subset of bacteria capable of surviving exposure to lethal doses of antibiotics, leading to antibiotic therapy failures and infection relapses. This research explores the utilization of drug repositioning to target the Lon protease in Salmonella Typhimurium., Method: In this study, FDA-approved drugs sourced from the Drug Bank database were screened to identify existing pharmaceuticals with the potential to combat the Lon protease. The formation of persister cells in the presence of antibiotics, as well as the combination of antibiotics with potential Lon protease inhibitors, was examined. Furthermore, the expression of type II toxin-antitoxin system genes was analyzed to enhance our comprehension of the inhibitors' effects., Result: Molecular docking analysis revealed that Diosmin and Nafcillin exhibited strong binding affinity to the Lon protease. Molecular dynamics simulation trajectories analysis demonstrated that the interaction of these ligands with the enzyme did not induce instability; rather, the enzyme's structure remained stable. Combinations of ceftazidime and ciprofloxacin with either Nafcillin or Diosmin led to significant reductions in bacterial cell counts. Furthermore, the effectiveness of these combinations, when compared to antibiotics alone, highlighted the substantial impact of Nafcillin and Diosmin in reducing type II TA system gene expression., Conclusion: These findings suggest promising prospects for developing novel therapeutic approaches targeting persister cells to mitigate treatment failures in Salmonella infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Narimisa, Razavi, Khoshbayan, Gharaghani and Jazi.)

Nosocomial infections, also known as healthcare-associated infections, are a significant global concern due to their strong association with high mortality and morbidity in both developed and developing countries. These infections are caused by a variety of pathogens, particularly the ESKAPE group of bacteria, which includes the six pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp . These bacteria have demonstrated noteworthy resistance to different antibiotics. Antimicrobial resistance mechanisms can manifest in various forms, including restricting drug uptake, modifying drug targets, inactivating drugs, active drug efflux, and biofilm formation. Accordingly, various strategies have been developed to combat antibiotic-resistant bacteria. These strategies encompass the development of new antibiotics, the utilization of bacteriophages that specifically target these bacteria, antimicrobial combination therapy and the use of peptides or enzymes that target the genomes or essential proteins of resistant bacteria. Among promising approaches to overcome antibiotic resistance, the CRISPR/Cas system stands out and offers many advantages. This system enables precise and efficient editing of genetic material at specific locations in the genome. Functioning as a bacterial "adaptive immune system," the CRISPR/Cas system recognizes, degrades, and remembers foreign DNA sequences through the use of spacer DNA segments that are transcribed into CRISPR RNAs (crRNA). This paper has focused on nosocomial infections, specifically the pathogens involved in hospital infections, the mechanisms underlying bacterial resistance, and the strategies currently employed to address this issue. Special emphasis has been placed on the application of CRISPR/Cas technology for overcoming antimicrobial resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review., Methods: We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243., Findings: 58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality., Interpretation: The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests MJL, DWC, LY, TEAP, and ASW declare funding from the National Institute for Health Research (NIHR) for the ARK-Hospital programme. ASW is an NIHR Senior Investigator. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Due to a high unresponsiveness to chemotherapy, biofilm formation is an important medical problem that frequently occurs during infection with many bacterial pathogens. In this study, the marine sponge-derived natural compounds 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol and 3,4,6-tribromo-2-(2',4'-dibromophenoxy)phenol were found to exhibit broad antibacterial activity against medically relevant gram-positive and gram-negative pathogens. The compounds were not only bactericidal against both replicating and stationary phase-persistent planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa; they also killed biofilm-incorporated cells of both species while not affecting biofilm structural integrity. Moreover, these compounds were active against carbapenemase-producing Enterobacter sp. This simultaneous activity of compounds against different growth forms of both gram-positive and gram-negative bacteria is rare. Genome sequencing of spontaneous resistant mutants and proteome analysis suggest that resistance is mediated by downregulation of the bacterial EIIBC phosphotransferase components scrA and mtlA in MRSA likely leading to a lower uptake of the molecules. Due to their only moderate cytotoxicity against human cell lines, phenoxyphenols provide an interesting new scaffold for development of antimicrobial agents with activity against planktonic cells, persisters and biofilm-incoporated cells of ESKAPE pathogens. KEY POINTS: • Brominated phenoxyphenols kill actively replicating and biofilm-incorporated bacteria. • Phosphotransferase systems mediate uptake of brominated phenoxyphenols. • Downregulation of phosphotransferase systems mediate resistance.

Selective chemical probes enable individual investigation of penicillin-binding proteins (PBPs) and provide critical information about their enzymatic activity with spatial and temporal resolution. To identify scaffolds for novel probes to study peptidoglycan biosynthesis in Bacillus subtilis , we evaluated the PBP inhibition profiles of 21 β-lactam antibiotics from different structural subclasses using a fluorescence-based assay. Most compounds readily labeled PBP1, PBP2a, PBP2b, or PBP4. Almost all penicillin scaffolds were coselective for all or combinations of PBP2a, 2b, and 4. Cephalosporins, on the other hand, possessed the lowest IC 50 values for PBP1 alone or along with PBP4 (ceftriaxone, cefoxitin) and 2b (cefotaxime) or 2a, 2b, and 4 (cephalothin). Overall, five selective inhibitors for PBP1 (aztreonam, faropenem, piperacillin, cefuroxime, and cefsulodin), one selective inhibitor for PBP5 (6-aminopenicillanic acid), and various coselective inhibitors for other PBPs in B. subtilis were discovered. Surprisingly, carbapenems strongly inhibited PBP3, formerly shown to have low affinity for β-lactams and speculated to be involved in β-lactam resistance in B. subtilis . To investigate the specific roles of PBP3, we developed activity-based probes based on the meropenem core and utilized them to monitor the activity of PBP3 in living cells. We showed that PBP3 activity localizes as patches in single cells and concentrates as a ring at the septum and the division site during the cell growth cycle. Our activity-based approach enabled spatial resolution of the transpeptidation activity of individual PBPs in this model microorganism, which was not possible with previous chemical and biological approaches.

Target vulnerability correlates the level of drug-target engagement required to generate a pharmacological response. High vulnerability targets are those that require only a relatively small fraction of occupancy to achieve the desired pharmacological outcome, whereas low vulnerability targets require high levels of engagement. Here, we demonstrate that the slope of the correlation between drug-target residence time and the post-antibiotic effect (PAE) can be used to define the vulnerability of bacterial targets. For macrolides, a steep slope is observed between residence time on the E. coli ribosome and the PAE, indicating that the ribosome is a highly vulnerable drug target. The analysis of the residence time-PAE data for erythromycin, azithromycin, spiramycin, and telithromycin using a mechanistic pharmacokinetic-pharmacodynamic model that integrates drug-target kinetics into predictions of drug activity lead to the successful prediction of the cellular PAE for tylosin, which has the longest residence time (7.1 h) and PAE (5.8 h). Although the macrolide data support a connection between residence time, PAE, and bactericidality, many bactericidal β-lactam antibiotics do not give a PAE, illustrating the role of factors such as protein resynthesis in the expression of target vulnerability.

The present work reports the development of nanostructured material from Cashew nut shell liquid (CNSL, an agro byproduct of cashew industry, 87% cardanol) to evaluate their potential in antibacterial applications as a substitute of petroleum feedstock via an energy-efficient method. The nanostructured material was synthesized by coordination polymerization reaction of cardanol and divalent Mn(II) salt with the aid of microwave irradiations. FTIR spectroscopy was used to confirm the proposed structure of the synthesized materials. FTIR-ATR spectroscopy was employed to verify the curing of material by comparing the spectra of the cured samples with the frequencies of uncured samples. Magnetic moment and UV-visible spectroscopy were used to confirm the proposed structure of the material further. Morphology of the synthesized material was investigated by XRD, optical microscopy, SEM and TEM and thermal behaviour by TGA/DTG/DSC technique. Agar diffusion method was utilized to investigate the antibacterial activity of the synthesized material against bacterial strains E. coli, K. pneumoniae, B. subtilis and S. aureus. N 2 adsorption-desorption was investigated to check BET specific surface area and BJH pore size distribution of the same. The results revealed that the synthesized materials were obtained as semicrystalline, porous, thermally stable and nanostructured film forming materials with moderate to good antibacterial activity against different nosocomial bacteria. They can be used as thermally stable antibacterial agents in the field of films/coatings for health care applications., Competing Interests: Declaration of competing interest The author have declared no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

As an intracellular pathogen, Listeria monocytogenes can enter host cells where it can replicate and escape detection and eradication by the host immune response making the clearance of infection very challenging. Furthermore, with the advent of antimicrobial resistance, the need for alternative targets is inevitable. Internalin proteins are crucial to this bacterium as they contribute to bacterial entry to the systemic circulation. In this study, we targeted a highly conserved region of these proteins by an antisense sequence that was covalently conjugated to the cell penetrating peptides (CPP) to overcome the challenging delivery barriers. Then, we evaluated the efficiency of this construct in vitro. We also assessed the antigenicity, cytotoxicity, and probability of apoptosis induction by this construct. The studied CPP-PNA inhibited bacterial growth and suppressed the mRNA expression of internalins in a dose-dependent manner. In addition, at all studied concentrations, CPP-PNA significantly reduced the invasion rate of L. monocytogenes in the examined cell lines. Moreover, different concentrations of CPP-PNA did not have a significant antigenic, cytotoxic, and apoptotic properties compared to the control. These results suggest the effectiveness of CPP-antisense in targeting the mRNAs of internalins for various research, therapeutic and preventive purposes. However, additional research is required to evaluate the potency, safety, and pharmacokinetics of this compound for the prevention and treatment of listeriosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

There is an increasing interest toward biodegradable active packaging because of consumer demand and environmental concerns. Despite this interest, poor thermal, mechanical, and water barrier properties of biodegradable polymers such as gelatin limit their application in food packaging. In this study, to prevail these limitations, the gelatin-based nanocomposite containing chitosan nanofiber (CHNF) and ZnO nanoparticles (ZnONPs) were fabricated and characterized by FTIR, SEM, and DSC analyses. The results showed the appropriate interactions between gelatin matrix, CHNF and ZnONPs due to their good compatibility. Additionally, the nanocomposite showed high mechanical and water barrier properties due to its high dense and less permeable structure. The incorporation of CHNF compensated the negative effect of ZnONPs on the color properties of gelatin film. In addition, the synergistic effect between CHNF and ZnONPs improved the antibacterial activity of nanocomposite. In conclusion, the fabricated bio nanocomposite indicated considerable potential for food packaging., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Despite a variety of programs developed to control inappropriate antibiotic prescribing for viral infections, antibiotics are still prescribed excessively for Respiratory Tract Infections (RTI). The patient's expectation to receive an antibiotic often influences the clinician's decision and can lead to inappropriate antibiotic prescriptions. Our objective was to investigate the changes in patient expectations over time when presenting with symptoms of a respiratory infection., Methods: We performed a systematic review of patient's expectation to receive antibiotics for RTIs. Two reviewers independently evaluated the collected studies based on inclusion and exclusion criteria. Our search initially identified 12 070 studies, of which 321 studies were eligible for full text review and 37 articles were selected for final evaluation. Meta-regression analysis was used to evaluate the association between patient expectations and different years. Heterogeneity was evaluated using the Q statistic., Results: Patient expectations (effect size) were pooled using a random effects model. The effect-equality test showed heterogeneity among studies (Q = 3304.23, df = 40, P < 0.0001, k = 40, τ 2  = 0.63). Meta-regression results revealed that there is a significant linear negative relationship (B = -1.8374, P < 0.05) between patient expectation and year of data collection, at the global level. A similar finding is observed for the subset of studies conducted outside United States (U.S.) (B = -1.2411, P < 0.1). However, there is no discernible trend for patient expectation in the U.S. or among children and adult subgroups. Also, no significant differences are observed between the patient expectations when considering different age groups., Conclusion: The trend of patient expectation for receiving antibiotics for RTIs is declining over time on a global level and also outside the U.S., (© 2019 John Wiley & Sons Ltd.)

In the current study, two series of antimicrobial dressings conjugated with silver sulfadiazine (SSD) and silver nanoparticles (AgNPs) were developed and evaluated for chronic wound healing. Highly porous polycaprolactone (PCL)/polyvinyl alcohol (PVA) nanofibers were loaded with different concentrations of SSD or AgNPs and compared comprehensively in vitro and in vivo. SSD and AgNPs indicated a strong and equal antimicrobial activity against S. aureus. However, SSD had more toxicity against fibroblast cells over one week in vitro culture. An in vivo model of wound healing on male Wistar rats was developed with a full thickness wound. All the wound dressings indicated enough flexibility and hydrophilicity, which resulted an adequate adhesion into the wound closure. After 30 days, the control group without any treatment indicated 31% wound closure while the group treated with PCL/PVA (without antimicrobial components) indicated 44% wound closure. Presence of antimicrobial components in the PCL/PVA nanofibers resulted into a lower inflammation response leading to a faster proliferation and maturation phases. In agreement with the higher biocompatibility of AgNPs than SSD, a faster angiogenesis, epithelialization and subsequently, remodeling were observed for the wound dressings loaded with AgNPs. The group treated with the highest concentration of AgNPs showed the fastest healing process leading to a final epithelialization with 96% wound closure after 30 days. This study indicated that AgNPs have higher biocompatibility and regulate wound healing process more efficiently compared to SSD. PCL/PVA nanofibers conjugated with AgNPs are promising wound dressings for full-thickness wounds., (Copyright © 2019 Elsevier B.V. All rights reserved.)

ABPP methods have been utilized for the last two decades as a means to investigate complex proteomes in all three domains of life. Extensive use in eukaryotes has provided a more fundamental understanding of the biological processes involved in numerous diseases and has driven drug discovery and treatment campaigns. However, the use of ABPP in prokaryotes has been less common, although it has gained more attention over the last decade. The urgent need for understanding bacteriophysiology and bacterial pathogenicity at a foundational level has never been more apparent, as the rise in antibiotic resistance has resulted in the inadequate and ineffective treatment of infections. This is not only a result of resistance to clinically used antibiotics, but also a lack of new drugs and equally as important, new drug targets. ABPP provides a means for which new, clinically relevant drug targets may be identified through gaining insight into biological processes. In this chapter, we place particular focus on the discussion of ABPP strategies that have been applied to study different classes of bacterial enzymes.

Cystic fibrosis (CF) patients commonly suffer from continuous and recurrent lung infections caused by Pseudomonas aeruginosa, the dominant pathogen in CF airways. This study aimed to determine the integron types, gene cassettes, virulence determinants, β-lactam resistance genes, biofilm formation and alginate production in P. aeruginosa isolated from Iranian CF patients. A total of 143 P. aeruginosa isolates were obtained from CF patients. Susceptibility of isolates to different antimicrobials was evaluated by disc diffusion method. ESBL, MBL and KPC production was assessed. Congo red agar and tissue culture plates were used for evaluation of biofilm formation. Alginate production was determined using the Carbazole assay. Integrase genes, resistance determinants (ESBLs, MBLs and KPC) and genes encoding virulence factors were evaluated by PCR. All isolates were susceptible to colistin, piperacillin-tazobactam and ticarcillin; 8.4% of isolates were considered as MDR phenotype. Out of 6.3% IPM-resistant isolates, prevalence of virulence genes was as follows: lasB (100%) and plcB (100%), plcH (96.5%). Biofilm formation and alginate production ability were found in 54.5% of isolates. The prevalence of the alginate-encoding genes was 92.3%, 86.7% and 67.1% for algD, algU and algL genes, respectively. PpyR, pslA and pelA genes were detected in 98.6%, 89.5% and 57.3% of the isolates, respectively. The high prevalence of colonization in CF lungs may increase the pathogenicity of P. aeruginosa due to their adhesion and protective properties caused by biofilm- and alginate-production. LasB, plcB, plcH, exoS, toxA, algD, ppyR and pslA genes were predominant in CF P. aeruginosa strains.

Persistence of antibacterial drugs for prolonged period in milk increases the probability of antimicrobial resistance progress. Ceftizoxime was found to be excreted in milk for a prolonged period in goats, cows and buffaloes following intravenous injection of ceftriaxone and ceftizoxime. A single dose of ceftriaxone was administered intravenously in healthy control goats (group I) and a single oral dose of the commercial mammary protective polyherbal drug (1.9 gm) was given one hour prior to intravenous ceftriaxone injection in healthy (group II) and induced mastitic (group III) goats to evaluate milk disposition of ceftizoxime following single intravenous dosing of ceftriaxone at 42.25 mg kg -1 .Ceftriaxone/ceftizoxime was analyzed by HPLC. The t 1/2 α and t 1/2 β values were 14.755 ± 2.733 and 149.079 ± 18.565 hour, respectively indicating prolonged persistence of ceftizoxime in milk. The polyherbal drug increased the milk concentration at later hours and hastened the excretion of ceftizoxime from milk compared to control group. Ceftriaxone could not be detected in milk. The study suggested that adjunct single or repeated therapy of  the polyherbal drug may cause non persistence of ceftriaxone and shorter persistence of ceftizoxime in milk.

Graphene and its derivatives have recently attracted much attention for sensing and deactivating pathogens. However, the mechanism of multivalent interactions at the graphene-pathogen interface is not fully understood. Since different physicochemical parameters of graphene play a role at this interface, control over graphene's structure is necessary to study the mechanism of these interactions. In this work, different graphene derivatives and also zwitterionic graphene nanomaterials (ZGNMs) were synthesized with defined exposure, in terms of polymer coverage and functionality, and isoelectric points. Then, the switchable interactions of these nanomaterials with E. coli and Bacillus cereus were investigated to study the validity of the generally proposed "trapping" and "nano-knives" mechanisms for inactivating bacteria by graphene derivatives. It was found that the antibacterial activity of graphene derivatives strongly depends on the accessible area, i.e. edges and basal plane of sheets and tightness of their agglomerations. Our data clearly confirm the authenticity of "trapping" and "nano-knives" mechanisms for the antibacterial activity of graphene sheets.

Background: Metronidazole (MTZ) is a synthetic derivative of nitroimidazole that has been widely used for the treatment of several bacterial and parasitic infections including trichomoniasis, amoebiasis, giardiasis, liver abscess, gingivitis, syphilis and phagedena. Scientists have evaluated its carcinogenicity in preclinical in vitro and in vivo studies., Method: Google scholar and Pubmed search engines were used to construct historic timeline after discovery of MTZ with a journey of ~3 decades of research. Similar search was conducted for its in vivo carcinogenic activities, further extended to elaborate its role in carcinogenicity in humans., Results: In addition to preclinical in vitro validation of DNA damage, MTZ has been reported to induce cancer in a variety of animal models including lung cancer, malignant lymphomas, breast cancer, hepatocellular carcinoma, pituitary tumors, testicular neoplasms and uterine cancer. Several retrospective cohort studies have reported MTZ as a potential risk factor for lung cancer (n = 771), cervical cancer (n = 2500), breast cancer (n = 2), cholangiocarcinoma (n = 1), and neuroblastoma (n = 28). So far, all the reported data have confirmed MTZ carcinogenicity in animals; however it is still controversial in humans. Based on previous observations, the oxidative metabolites from MTZ are shown to have more carcinogenic effects than the parent drug itself., Conclusion: Due to potent carcinogenic behaviour, use of MTZ for animals' treatment and its uses in animal food products is prohibited in USA and European countries; however its clinical use in human population is still increasing. Therefore, regular research studies are required to explicate its mechanism/s involved in carcinogenesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in the drug-target residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structure-kinetic relationship for 22 ethyl- or hexyl-substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a two-dimensional kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off rates, where residence times of up to ∼700 min (∼11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (∼5 h) through changes in only ground state stabilization (PT119). Structural analysis of nine enzyme:inhibitor complexes reveals that the variation in structure-kinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 from 118 min (∼2 h) to 670 min (∼11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400.

Introduction: The purpose of this study was to examine community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) carriage and infections and determine risk factors associated specifically with MRSA USA300., Methods: We conducted a case control study in a pediatric emergency department. Nasal and axillary swabs were collected, and participants were interviewed for risk factors. The primary outcome was the proportion of S. aureus carriers among those presenting with and without a skin and soft tissue infection (SSTI). We further categorized S. aureus carriers into MRSA USA300 carriers or non-MRSA USA300 carriers., Results: We found the MRSA USA300 carriage rate was higher in children less than two years of age, those with an SSTI, children with recent antibiotic use, and those with a family history of SSTI. MRSA USA300 carriers were also more likely to have lower income compared to non-MRSA USA300 carriers and no S. aureus carriers. Rates of Panton-Valentine leukocidin (PVL) genes were higher in MRSA carriage isolates with an SSTI, compared to MRSA carriage isolates of patients without an SSTI. There was an association between MRSA USA300 carriage and presence of PVL in those diagnosed with an abscess., Conclusion: Children younger than two years were at highest risk for MRSA USA300 carriage. Lower income, recent antibiotic use, and previous or family history of SSTI were risk factors for MRSA USA300 carriage. There is a high association between MRSA USA300 nasal/axillary carriage and presence of PVL in those with abscesses., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias.

Introduction: Chemomechanical caries removal (CMCR) is an effective method of caries removal especially for primary teeth as they cause less discomfort when compared with conventional caries removal. The most significant thing about caries removal is the elimination of cariogenic bacteria. This study compares the antibacterial activity of two CMCR gels., Materials and Methods: A total of 40 primary molar teeth with carious dentin were split along the long axis in a laboratory. Total viable count (TVC) was taken for the teeth before splitting as a measure of colony-forming units per milliliter (CFU/mL). Each half was treated with either Carisolv or Carie-Care CMCR gels. Clean dentin samples were evaluated for Streptococcus mutans (SM) and Lactobacillus acidophilus (LB) after removal of carious tissue using the caries removal gels using serial dilutions and incubating on specific agar plates., Results: The results showed significant reduction in mean TVC after use of both the CMCR gels. Both gels reduced the CFU/mL of SM and LB to a significant level (p < 0.05). However, there was no significant difference between the antibacterial activities of the two CMCR gels., Conclusion: The CMCR gels (Carisolv and Carie-Care) significantly reduced the residual TVC as well as SM and LB in carious primary dentin. Both CMCR gels had a similar antibacterial activity on the carious dentin of primary teeth., Clinical Significance: The CMCR gels tested have a significant antibacterial activity and can be effectively used for elimination of caries-causing bacteria in primary teeth.

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC0-24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC0-24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0-24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC0-24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC0-24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC0-24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC0-24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: To describe the management of afebrile neonatal skin and soft tissue infections (SSTIs) in the pediatric emergency department (PED)., Methods: This is a retrospective cohort study of all patients aged 0 to 28 days seen in the PED for SSTIs from 2004 to 2010. The SSTIs were identified from the International Classification of Diseases, Ninth Revision codes of pustulosis, cellulitis, and abscess. Records were reviewed to determine the absence of fever; anatomical location; cultures of blood, urine, and cerebrospinal fluid; antibiotic usage; and return visits. Data were analyzed to compare admitted versus discharged patients with SSTI subtypes., Results: Of the 136 neonates identified, 104 met inclusion criteria. Afebrile SSTIs included 8 pustulosis, 45 cellulitis, and 51 abscesses. Blood cultures were obtained in 13% of pustulosis, 96% of cellulitis, and 69% of abscesses. No serious bacterial infection was noted. Three blood cultures grew contaminants. Parenteral antibiotics for neonates with pustulosis, cellulitis, and abscesses were given in 13%, 87%, and 59%, respectively. Admission rates for neonates with pustulosis, cellulitis, and abscesses were 13%, 84%, and 55%, respectively. Cases of cellulitis were more likely to have blood cultures drawn (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.03-62.3), receive intravenous antibiotics (OR, 5.87; 95% CI, 2.16-15.0), and be admitted to the hospital (OR, 5.62; 95% CI, 2.16-14.6) as compared with the other SSTI subtypes., Conclusions: None of the neonates who had cultures drawn had serious bacterial infection. The SSTI subtype correlated with the extent of evaluation and dispositions. The findings of this study will help with management strategies for afebrile neonates with SSTIs in the PED.

Background: Temocillin, a β-lactam stable against most β-lactamases [including extended-spectrum β-lactamases (ESBLs) and derepressed AmpC cephalosporinases (dAmpC)], has been suggested as an alternative to carbapenems when Pseudomonas can be excluded. Aims To assess temocillin clinical and microbiological cure rates (CCR and MCR) in infection caused by ESBL/dAmpC-producing Enterobacteriaceae and the effects of different dosage regimens., Methods: Data were collected retrospectively from patients treated for at least 3 days with temocillin for urinary tract infection (n = 42), bloodstream infection (n = 42) or hospital-acquired pneumonia (n = 8) in six centres in the UK., Results: Data on 92 infection episodes were collected. Overall CCR and MCR were 86% and 84% respectively; ESBL/dAmpC status had no effect. Significantly higher CCR and MCR occurred in patients treated with temocillin at optimal dosage [2 g twice daily or renally adjusted equivalent (ORAE)] compared with those treated with a suboptimal dosage (<2 g twice daily ORAE) (CCR 91% and MCR 92% versus CCR 73% and MCR 63%). This difference was more pronounced in the ESBL/dAmpC-positive subset (CCR 97% and MCR 97% versus CCR 67% and MCR 50%)., Conclusions: Clinical and microbiological efficacies of temocillin are unaffected by ESBL/dAmpC production, confirming its potential application as a carbapenem-sparing agent. Both CCR and MCR are optimized by a regimen of 2 g twice daily ORAE in ESBL/dAmpC-positive infection.

Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.

Objective: To evaluate the patterns of ceftriaxone use in an urban pediatric emergency department (PED) and to determine if overuse exists based on published guidelines for management of febrile infants., Methods: We conducted a retrospective study of 229 young febrile patients who received ceftriaxone between January 1 and March 31, 1995, in a large urban PED in a teaching hospital in Atlanta. Patients younger than 3 months, patients with chronic illnesses (eg, sickle cell anemia, HIV), and those who received ceftriaxone for sexually transmitted diseases were excluded., Results: During the study period, ceftriaxone was administered 289 times to 229 patients (53% male) aged 3 months to 18 years. Sixty patients (26%) received ceftriaxone two or more times for the same illness. Data were stratified based on age, source of fever, temperature, leukocyte count, diagnosis of pneumonia, and visit order (initial or follow-up). At the time of their initial visit, 180 of 229 patients had an identifiable focus of infection (76 had pneumonia), but no source could be identified in the remaining 49. Based on temperature, leukocyte count, and the presence or absence of a focus, ceftriaxone use, as compared with practice guidelines, was justified in 40 of 229 (17.5%) patients, questionable in 43 of 229 (18.8%), and not justified in 146 of 229 (63.7%). For the 60 patients who received ceftriaxone more than once, its use was justified in only 13%. Results of blood cultures were positive in 3 of 229 (1.3%) patients. Ceftriaxone was justified according to published guidelines in two of these three patients, whereas one patient with pneumonia and pneumococcal bacteremia could have been treated with oral antibiotics. Overall, for the entire study population (289 encounters at initial and subsequent visit combined), ceftriaxone use was justified in 48 patients (16.6%), questionable in 49 patients (17%), and not justified in 192 patients (66.4%)., Conclusions: Based on published guidelines, ceftriaxone use in the PED was not justified in the majority of cases.