Epidemiology and clinical significance of carbapenemases in Australia: a narrative review.

Carbapenemase-producing gram-negative bacteria (CP-GNB) infections threaten public health with high mortality, morbidity and treatment costs. Although frequencies remain low in Australia (total number of CP-GNB infections reported was 907 in 2022), blaIMP-4 has established low levels of endemicity in many states. Imipenemase metallo-ß-lactamase types alone accounted for more than half of all carbapenemases in carbapenemase-producing Enterobacterales isolates in Australia, particularly in Enterobacter cloacae complex. New Delhi metallo-ß-lactamase constitutes almost 25% of all carbapenemases in Australia and was identified predominantly in Escherichia coli. The OXA-48-like carbapenemases include almost 10% of all carbapenemases and are mainly seen in Klebsiella pneumoniae and E. coli. Although K. pneumoniae carbapenemase-type carbapenemases are rare in Australia, some local outbreaks have occurred. Most carbapenem-resistant (CR) Pseudomonas aeruginosa strains in Australia do not produce carbapenemases. Finally, OXA-23-like carbapenemases are overwhelmingly positive in CR-Acinetobacter baumannii strains in Australia. Treatment of CR-GNB infections challenges physicians. Of 10 new antibiotics active against at least some CR-GNB infections that are approved by the US Food and Drug Administration, just three are approved for use in Australia. In this context, there is still an unmet need for novel antibacterials that can be used for the treatment of CR-GNB infections in Australia, as well as a pressing requirement for new mechanisms to 'de-link' antibiotic sales from their availability. In this narrative review, we aim to overview the epidemiology and clinical significance of carbapenem resistance in Australia as it pertains to Enterobacterales, P. aeruginosa and A. baumannii.

The role of centre and country factors on process and outcome indicators in critically ill patients with hospital-acquired bloodstream infections.

PURPOSE: The primary objective of this study was to evaluate the associations between centre/country-based factors and two important process and outcome indicators in patients with hospital-acquired bloodstream infections (HABSI). METHODS: We used data on HABSI from the prospective EUROBACT-2 study to evaluate the associations between centre/country factors on a process or an outcome indicator: adequacy of antimicrobial therapy within the first 24 h or 28-day mortality, respectively. Mixed logistical models with clustering by centre identified factors associated with both indicators. RESULTS: Two thousand two hundred nine patients from two hundred one intensive care units (ICUs) were included in forty-seven countries. Overall, 51% (n = 1128) of patients received an adequate antimicrobial therapy and the 28-day mortality was 38% (n = 839). The availability of therapeutic drug monitoring (TDM) for aminoglycosides everyday [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.03-2.14] or within a few hours (OR 1.79, 95% CI 1.34-2.38), surveillance cultures for multidrug-resistant organism carriage performed weekly (OR 1.45, 95% CI 1.09-1.93), and increasing Human Development Index (HDI) values were associated with adequate antimicrobial therapy. The presence of intermediate care beds (OR 0.63, 95% CI 0.47-0.84), TDM for aminoglycoside available everyday (OR 0.66, 95% CI 0.44-1.00) or within a few hours (OR 0.51, 95% CI 0.37-0.70), 24/7 consultation of clinical pharmacists (OR 0.67, 95% CI 0.47-0.95), percentage of vancomycin-resistant enterococci (VRE) between 10% and 25% in the ICU (OR 1.67, 95% CI 1.00-2.80), and decreasing HDI values were associated with 28-day mortality. CONCLUSION: Centre/country factors should be targeted for future interventions to improve management strategies and outcome of HABSI in ICU patients.

Scoping review of risk-scoring tools for early prediction of bloodstream infections caused by carbapenem-resistant Enterobacterales: do we really have a reliable risk-scoring tool?

Background: Bloodstream infections (BSIs) caused by carbapenem-resistant Enterobacterales (CRE) are a global health concern. Rapid identification of CRE may improve patient outcomes and reduce inappropriate antibiotic prescription. The use of risk-scoring tools (RSTs) can be valuable for optimizing the decision-making process for empirical antibiotic therapy of suspected CRE bacteraemia. These tools can also be used to triage use of expensive rapid diagnostic methods. Methods: We systematically reviewed the relevant literature in PubMed/MEDLINE, CINAHL, Cochrane, Web of Science, Embase and Scopus up to 1 November 2022 to identify RSTs that predict CRE BSIs. The literature review and analysis of the articles were performed by two researchers; any inconsistencies were resolved through discussion. Results: We identified 9 RSTs developed for early prediction of CRE BSIs and only logistic regression was used for most studies. These RSTs were quite different from each other in terms of their performance and the variables they included. They also had notable limitations and very few of them were externally validated. Conclusions: RSTs for early prediction of CRE BSIs have limitations and lack of external validity outside the local setting in which they were developed. Future studies to identify optimal RSTs in high and low CRE-endemic settings are warranted. Approaches based on rapid diagnostics and RSTs should be compared with a treatment approach using both methods in a randomized controlled trial.

The global epidemiology of ventilator-associated pneumonia caused by multi-drug resistant Pseudomonas aeruginosa: A systematic review and meta-analysis.

OBJECTIVES: The objective of this systematic review and meta-analysis was to estimate the global prevalence of multi-drug resistant (MDR) Pseudomonas aeruginosa causing ventilator-associated pneumonia (VAP). METHODS: The systematic search was conducted in four databases. Original studies describing MDR P. aeruginosa VAP prevalence in adults from 2012- 2022 were included. A meta-analysis, using the random effects model, was conducted for overall, subgroups (country, published year, study duration, and study design), and European data, respectively. Univariate meta-regression based on pooled estimates was also conducted. Systematic review registered in International Prospective Register of Systematic Review (CRD42022384035). RESULTS: In total of 31 studies, containing a total of 7951 cases from 16 countries, were included. The overall pooled prevalence of MDR among P. aeruginosa causing VAP was 33% (95% confidence interval [CI] 27.7-38.3%). The highest prevalence was for Iran at 87.5% (95% CI 69-95.7%), and the lowest was for the USA at 19.7% (95% CI 18.6-20.7%). The European prevalence was 29.9% (95% CI 23.2-36.7%). CONCLUSIONS: This review indicates that the prevalence of MDR P. aeruginosa in patients with VAP is generally high and varies significantly between countries; however, data are insufficient for many countries. The data in this study can provide a reference for VAP management and drug customisation strategies.

Fullerene C60 protects against 7,12-dimethylbenz [a] anthracene (DMBA) induced-pancreatic damage via NF-κB and Nrf-2/HO-1 axis in rats.

The objective of this investigation was to investigate the protective effects of fullerene C60 nanoparticle against pancreatic damage experimentally induced by 7,12-dimethylbenz [a] anthracene (DMBA) in female rats. Fullerene C60 nanoparticle was administered to rats 5 times a week by oral gavage (o.g) at 1.7 mg/kg bw 7 days after DMBA administration. 60 Wistar albino female rats divided to four groups; Groups: (1) Control group: Fed with standard diet; (2) Fullerene C60 group: Fullerene C60 (1.7 mg/kg bw); (3) DMBA group: DMBA (45 mg/kg bw); (4) Fullerene C60 + DMBA group: Fullerene C60 (1.7 mg/kg bw) and DMBA (45 mg/kg bw). Lipid peroxidation malondialdehyde (MDA), catalase activity (CAT) and glutathione (GSH) levels in pancreatic tissue were determined by spectrophotometer. Protein expression levels of p53, HO-1, p38-α (MAPK), Nrf-2, NF-κB and COX-2 in pancreatic tissue were determined by western blotting technique. In our findings, compared to the group given DMBA, MDA levels and p38-α, NF-κB and COX-2 levels decreased, CAT activity, GSH level, total protein density and p53, HO-1, Nrf-2 levels in the groups given fullerene C60 nanoparticle an increase in expression levels was observed. Our results showed that fullerene C60 nanoparticle may be more beneficial in preventing pancreatic damage.

Effects of grape seed proanthocyanidin extract on side effects of high-dose methylprednisolone administration in male rats.

In this study, we investigated the effects of grape seed proanthocyanidin extract (GSPE) against the side effects of high-dose administration of methylprednisolone (MP) in male rats. A total of 32 adult Wistar male albino rats were divided into four groups: (1) control (CON), received standard food only; (2) MP, received standard food + intraperitoneal injection of 60 mg/kg MP on day 7; (3) GSPE, received standard food + 200 mg/kg/day GSPE; and (4) MP + GSPE, received standard food + 200 mg/kg/day of GSPE + intraperitoneal injection of 60 mg/kg MP on day 7. All animals in the GSPE and GSPE + MP groups were treated once a day by oral gavage for 14 consecutive days. The feed intake of rats in the MP and MP + GSPE groups decreased significantly by 24.14% and 13.52%, respectively (p < 0.05). Administration of MP resulted in significant increases in serum concentrations of blood urea nitrogen (p < 0.001), glucose (p < 0.01), alkaline phosphatase, and adrenocorticotropic hormone (p < 0.05). High-dose MP administration significantly reduced catalase (p < 0.001) and glutathione peroxidase (p < 0.05) concentrations in the liver and kidney tissues of rats, while glutathione concentrations were only reduced in liver tissue (p < 0.05). The expression levels of Bcl-2 and TNF-α in liver, kidney, and testicular tissue were significantly increased, while the expression levels of caspase-3 were reduced (p < 0.001). Furthermore, sperm concentration was significantly affected by GSPE in rats induced by high-dose MP, and sperm loss was significantly reduced in MP + GSPE (p < 0.05). These findings suggest that GSPE could be useful as a supplement to alleviate MP-induced toxicity in rats.

In vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam monotherapy with ceftazidime-avibactam-containing combination regimens against carbapenem-resistant Enterobacterales and multidrug-resistant Pseudomonas aeruginosa isolates or infections: a scoping review.

Introduction: Carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections are associated with a high risk of morbidity, mortality, and treatment costs. We aimed to evaluate in vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam (CZA) combination regimens with CZA alone against CRE and/or MDR-PA isolates or infections. Methods: We systematically reviewed the relevant literature in CINAHL/MEDLINE, Pubmed, Cochrane, Web of Science, Embase, and Scopus until December 1, 2022. Review articles, grey literature, abstracts, comments, editorials, non-peer reviewed articles, non-English articles, and in vitro synergy studies conducted on single isolates were excluded. Results: 22 in vitro, 7 in vivo and 20 clinical studies were evaluated. In vitro studies showed reliable synergy between CZA and aztreonam against metallo-ß-lactamase (MBL)-producing isolates. Some studies indicated good in vitro synergy between CZA and amikacin, meropenem, fosfomycin and polymyxins against CRE isolates. For MDR-PA isolates, there are comparatively fewer in vitro or in vivo studies. In observational clinical studies, mortality, clinical cure, adverse events, and development of CZA resistance after exposure were generally similar in monotherapy and combination therapy groups. However, antibiotic-related nephrotoxicity and infection relapses were higher in patients receiving CZA combination therapies. Discussion: The benefit, if any, of CZA combination regimens in MDR-PA infections is elusive, as very few clinical studies have included these infections. There is no currently documented clinical benefit for the use of CZA combination regimens rather than CZA monotherapy. CZA combined with aztreonam for serious infections due to MBL producers should be evaluated by randomized controlled trials. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278552, CRD42021278552.

Fullerene C60 reduces acute lung injury by suppressing oxidative stress-mediated DMBA-induced apoptosis and autophagy by regulation of cytochrome-C/caspase-3/beclin-1/IL-1α/HO-1/p53 signaling pathways in rats.

The objective of this study was to evaluate the effect of fullerene C60 nanoparticles against 7,12-dimethylbenz[a]anthracene (DMBA)-induced lung tissue damage in rats. 60 Wistar albino (8 weeks old) female rats were assigned into four groups: Control Group (C), Fullerene C60, DMBA, and Fullerene C60+DMBA. The rats in the DMBA and Fullerene C60+DMBA groups were administered DMBA (45 mg/kg bw, oral gavage). The rats in Fullerene C60, and Fullerene C60+DMBA groups were administered with Fullerene C60 (1.7 mg/kg bw, oral gavage). Expression levels of cytochrome-C, caspase-3, beclin-1, IL-1α, HO-1 and p53 proteins in lung tissue were determined by western blotting, lipid peroxidation malondialdehyde (MDA) analyzes, glutathione (GSH), glutathione peroxidase (GSH-Px), catalase activity (CAT) and total protein levels were determined by spectrophotometer. In addition, lung tissues were evaluated by histopathologically. Fullerene C60 reduced the increasing of MDA and IL-1α protein expression levels and attenuated histopathological changes in lung. Moreover, fullerene C60 enhanced the protein expression of cytochrome-C, caspase-3, beclin-1, HO-1, and p53, which were decreased in the DMBA group. Fullerene C60 has strong biological activity that it might be an effective approach for lung damage.

Higher rates of cefiderocol resistance among NDM producing Klebsiella bloodstream isolates applying EUCAST over CLSI breakpoints.

BACKGROUND: Cefiderocol is generally active against carbapenem-resistant Klebsiella spp. (CRK) with higher MICs against metallo-beta-lactamase producers. There is a variation in cefiderocol interpretive criteria determined by EUCAST and CLSI. Our objective was to test CRK isolates against cefiderocol and compare cefiderocol susceptibilities using EUCAST and CLSI interpretive criteria. METHODS: A unique collection (n = 254) of mainly OXA-48-like- or NDM-producing CRK bloodstream isolates were tested against cefiderocol with disc diffusion (Mast Diagnostics, UK). Beta-lactam resistance genes and multilocus sequence types were identified using bioinformatics analyses on complete bacterial genomes. RESULTS: Median cefiderocol inhibition zone diameter was 24 mm (interquartile range [IQR] 24-26 mm) for all isolates and 18 mm (IQR 15-21 mm) for NDM producers. We observed significant variability between cefiderocol susceptibilities using EUCAST and CLSI breakpoints, such that 26% and 2% of all isolates, and 81% and 12% of the NDM producers were resistant to cefiderocol using EUCAST and CLSI interpretive criteria, respectively. CONCLUSIONS: Cefiderocol resistance rates among NDM producers are high using EUCAST criteria. Breakpoint variability may have significant implications on patient outcomes. Until more clinical outcome data are available, we suggest using EUCAST interpretive criteria for cefiderocol susceptibility testing.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Epidemiology and risk factors of 28-day mortality of hospital-acquired bloodstream infection in Turkish intensive care units: a prospective observational cohort study.

OBJECTIVES: To uncover clinical epidemiology, microbiological characteristics and outcome determinants of hospital-acquired bloodstream infections (HA-BSIs) in Turkish ICU patients. METHODS: The EUROBACT II was a prospective observational multicontinental cohort study. We performed a subanalysis of patients from 24 Turkish ICUs included in this study. Risk factors for mortality were identified using multivariable Cox frailty models. RESULTS: Of 547 patients, 58.7% were male with a median [IQR] age of 68 [55-78]. Most frequent sources of HA-BSIs were intravascular catheter [182, (33.3%)] and lower respiratory tract [175, (32.0%)]. Among isolated pathogens (n = 599), 67.1% were Gram-negative, 21.5% Gram-positive and 11.2% due to fungi. Carbapenem resistance was present in 90.4% of Acinetobacter spp., 53.1% of Klebsiella spp. and 48.8% of Pseudomonas spp. In monobacterial Gram-negative HA-BSIs (n = 329), SOFA score (aHR 1.20, 95% CI 1.14-1.27), carbapenem resistance (aHR 2.46, 95% CI 1.58-3.84), previous myocardial infarction (aHR 1.86, 95% CI 1.12-3.08), COVID-19 admission diagnosis (aHR 2.95, 95% CI 1.25-6.95) and not achieving source control (aHR 2.02, 95% CI 1.15-3.54) were associated with mortality. However, availability of clinical pharmacists (aHR 0.23, 95% CI 0.06-0.90) and source control (aHR 0.46, 95% CI 0.28-0.77) were associated with survival. In monobacterial Gram-positive HA-BSIs (n = 93), SOFA score (aHR 1.29, 95% CI 1.17-1.43) and age (aHR 1.05, 95% CI 1.03-1.08) were associated with mortality, whereas source control (aHR 0.41, 95% CI 0.20-0.87) was associated with survival. CONCLUSIONS: Considering high antimicrobial resistance rate, importance of source control and availability of clinical pharmacists, a multifaceted management programme should be adopted in Turkish ICUs.

Activation of Nrf-2 Transcription Factor and Caspase Pathway with Royal Jelly Reduces Fluoride Induced Testicular Damage and Infertility in Rats.

This study was carried out to investigate the protective properties of royal jelly on the testicular tissue of rats with testicular damage by giving fluoride. Sperm motility, epididymal sperm density and abnormal sperm ratios were examined and visualized with a light microscope. Expression levels of Caspase-3, Bcl-2, Nrf-2, NF-κB, COX-2, TNF-α and IL1-α proteins in testis tissue were determined by western blot technique. As a result of the study, MDA level, expression level of Bcl-2, NFÒ¡B, COX-2, TNF-α and IL1-α proteins, abnormal sperm rates were found higher in Fluoride-50 and Fluoride100 groups compared to other groups. In addition GSH, Catalase enzyme levels, expression levels of Caspase-3 and Nrf-2 proteins were found to be higher in Fluoride + Royal Jelly groups compared to Fluoride-50 and Fluoride-100 groups. In addition, lower degeneration of testicular tissue was found in the histological evaluation in the Fluoride + Royal Jelly groups compared to the other groups. When the data are evaluated royal jelly provides effective protection against testicular damage. From this point of view, we hope that similar results will be obtained when royal jelly is tested on humans.

Duration of antibiotic treatment and timing of oral switching for bloodstream infections: a survey on the practices of infectious diseases and intensive care physicians.

AIM: To understand current practice in terms of duration of antibiotic treatment and timing of intravenous (IV) to oral switching for common bacteraemic conditions amongst infectious diseases (ID) and intensive care unit (ICU) physicians. METHODS: An online survey consisting of 18 questions comprising five common clinical bacteraemia scenarios [adapted from the original survey designed by the University of Toronto (Toronto, Ontario, Canada)] was conducted amongst Turkish ID and ICU physicians between November 2020 and November 2021. RESULTS: In total, 236 physicians (76.5% ID and 17.5% ICU) responded. The most commonly recommended duration of antibiotic treatment for bacteraemia was 14 days (42%), followed by 10 (27%) and 7 (18%) days. The median recommended treatment durations were 10 [interquartile range (IQR) 10-14] days for central-venous-catheter-associated bloodstream infection, 10 (IQR 7-14) days for bacteraemic pneumonia, 14 (IQR 10-14) days for bacteraemic urinary tract and intra-abdominal infections, and 14 (IQR 7-14) days for bacteraemic skin and soft tissue infection. Carbapenem resistance influenced the recommendations, but pathogen type did not. No significant difference in responses for most scenarios was found between ID and ICU physicians. Switching to oral antibiotics after a median duration of 7 (IQR 5-7) days of IV treatment was considered by 80% of respondents. CONCLUSION: Prolonged treatment was recommended for most clinical scenarios. Extended IV durations were recommended before oral switching. A presumption that resistant bacterial infections require longer therapy may be responsible for prolonged treatment durations.

Epidemiology and outcomes of hospital-acquired bloodstream infections in intensive care unit patients: the EUROBACT-2 international cohort study.

PURPOSE: In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials. METHODS: We carried out a prospective international cohort study of adult patients (≥ 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021. RESULTS: 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28. CONCLUSIONS: HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes.

Royal jelly protects brain tissue against fluoride-induced damage by activating Bcl-2/NF-κB/caspase-3/caspase-6/Bax and Erk signaling pathways in rats.

This study is aimed at determining whether royal jelly (RJ) which has a powerful antioxidant property prevents fluoride-induced brain tissue damage and exploring whether Bcl-2/NF-κB/ and caspase-3/caspase-6/Bax/Erk pathways play a critical role in the neuroprotective effect of RJ. Wistar albino rats were chosen for the study, and they were randomly distributed into six groups: (i) control; (ii) royal jelly; (iii) fluoride-50; (iv) fluoride-100; (v) fluoride-50 + royal jelly; (vi) fluoride-100 + royal jelly. We established fluoride-induced brain tissue damage with 8-week-old male Wistar albino rats by administration of fluoride exposure (either 50 mg/kg or 100 mg/kg bw) through drinking water for 8 weeks. Then, the study duration is for 56 days where the rats were treated with or without RJ (100 mg/kg bw) through oral gavage. The effects of RJ on glutathione (GSH), catalase activity (CAT), and malondialdehyde (MDA) levels were determined via spectrophotometer. Western blot analysis was performed to investigate the effects of royal jelly on the protein expression levels of Bax, caspase-3, caspase-6, Bcl-2, NF-κB, COX-2, and Erk. It was also studied the effects of RJ on histopathological alterations in fluoride-induced damage to the rat brain. As a result, the Bcl-2, NF-κB, and COX-2 protein expression levels were increased in the fluoride-treated (50 and 100 mg/kg) groups but they were decreased significantly by RJ treatment in the brain tissue. Additionally, the protein expression of caspase-3, caspase-6, Bax, and Erk were decreased in fluoride-treated groups and they were significantly increased by RJ treatment compared to the un-treated rats. Our results suggested that RJ prevented fluoride-induced brain tissue damage through anti-antioxidant activities.

Risk factors for Gram-negative bacterial infection of cardiovascular implantable electronic devices: multicentre observational study (CarDINe Study).

BACKGROUND: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. METHODS: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. RESULTS: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). CONCLUSIONS: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Fullerene C60 Attenuates Heart Tissue Inflammation by Modulating COX-2 and TNF-Alpha Signaling Pathways in DMBA Induced Breast Cancer in Rats.

The present study aimed to investigate the therapeutic effect of fullerene C60 nanoparticle against heart tissue damage caused by 7,12-dimethylbenz [a] anthracene (DMBA) in female rats. Female Wistar albino rats, 8 weeks old (n = 60) weighing around (150 ± 10 g) were used for the study. These rats were divided into 4 groups and each group included 15 rats. Groups: (i) Control Group: Fed with standard diet; (ii) C60 Group: C60 (1.7 mg/kg bw, oral gavage); (iii) DMBA Group: DMBA (45 mg/kg bw, oral gavage); (iv) C60 and DMBA Group: C60 (1.7 mg/kg bw, oral gavage) and DMBA (45 mg/kg bw, oral gavage) group. Malondialdehyde (MDA) analysis, catalase activity (CAT), and glutathione (GSH) in heart tissue were determined by spectrophotometer. In addition, heart tissue DNA damage was investigated. Caspase-3, p53, HO-1, COX-2, and TNF-α protein expression levels in heart tissue were determined by western blotting. As a result, Caspase-3, p53, HO-1 protein expression, GSH levels and CAT activity increased, COX-2, TNF-α protein expression, and MDA levels were significantly decreased in the C60 + DMBA group compared to the DMBA group. Therefore, the fullerene C60 nanoparticle may be a promising and effective therapy for the treatment of heart diseases associated with inflammation.

Royal jelly arranges apoptotic and oxidative stress pathways and reduces damage to liver tissues of rats by down-regulation of Bcl-2, GSK3 and NF-κB and up-regulation of caspase and Nrf-2 protein signalling pathways.

IntroductionRoyal jelly (RJ) from the honey bee, Apis mellifera, is a traditional product that is widely used as a food supplement to support the medical treatment of various diseases.Material and methodsOur study continued for 8 weeks. 42 Wistar albino (8 weeks old) male rats were used in the study. The study included 6 groups; Group 1: Control group (fed with standard diet), Group 2: RJ (100 mg/kg, bw), Group 3: F-50 (50 mg/kg, bw), group 4: F-100 (100 mg/kg, bw) group 5: F-50 (50 mg/kg, bw) + RJ (100 mg/kg, bw) Group 6: F-100 (100 mg/kg, bw) + RJ (100 mg/kg, bw). Malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) activities in liver tissue were determined by spectrophotometer. Liver tissue samples were examined histopathologically and various protein levels were determined by Western blotting technique.ResultsRJ caused a significant decrease in MDA level, Bcl-2, GSK3 and NF-κB protein expression levels, whereas induced a significant increase in GSH level, CAT activities and Bax, BDNF, caspase-6, caspase-3, Nrf-2 protein expression levels.ConclusionOur findings suggest RJ to be used as a hepatoprotective agent in the clinic to modulate the toxic effects of fluoride and other chemicals in the future.

Next-Generation Polymyxin Class of Antibiotics: A Ray of Hope Illuminating a Dark Road.

Although new-generation antimicrobials, in particular ß-lactam/ß-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review.