Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling.

Background: The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii. Objectives: The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii. Methods: A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices. Results: The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population. Conclusion: The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

Draft genomes of 10 Vibrio cholerae isolates collected in Sudan in 2019.

This report presents the first genomes from positive cases of cholera in Sudan. Genomic analysis of 10 Vibrio cholerae isolates, profiled as serogroup O1, reveals evidence of antimicrobial resistance genes and a 139-kb IncC plasmid with 99.74% identity to the multidrug-resistant plasmid pCNRVC190243 previously reported in Yemen and Lebanon.

Comparison of genotypic features between two groups of antibiotic resistant Klebsiella pneumoniae clinical isolates obtained before and after the COVID-19 pandemic from Egypt.

Klebsiella pneumoniae is a common pathogen capable of causing a wide range of infections. Antibiotic resistance complicates treatment of these infections significantly. We are comparing resistance levels and genotypes among two collections of K. pneumoniae clinical isolates from Alexandria Main University Hospital (AMUH). We used disc diffusion and Minimum Inhibitory Concentration (MIC) by microbroth dilution to assess resistance levels and performed whole genome sequencing (WGS) to describe multilocus sequence types (MLST) and resistance gene presence. Among a collection of 56 K. pneumoniae clinical isolates (19 from 2019 to 37 from 2021), multidrug resistance (MDR) was 33% and 10%, extended drug resistance (XDR) was 24% and 46% and pan-drug resistance (PDR) was 43% and 43%, respectively. We identified 15 MLST STs including two novel types (ST-6118 and ST-6119 ). ST-101 and ST-383 were common between the two collections; ST-101 was the most common genotype in 2019 (28.6%) and ST-147 was most common in 2021 (25%). Ampicillin/sulbactam, amikacin, cefepime, ceftriaxone and ertapenem MICs were significantly higher in 2021. Prevalence of aph(3') - Ia, aph(3')-VI, mphA was significantly higher in 2021. The increasing resistance levels and the persistence of some MDR/XDR genotypes is concerning. Understanding mechanisms of resistance will inform infection control and antimicrobial stewardship plans to prevent evolution and spread of XDR and PDR strains.

Synergistic pH-responsive MUC-1 aptamer-conjugated Ag/MSN Janus nanoparticles for targeted chemotherapy, photothermal therapy, and gene therapy in breast cancer.

Drug resistance in cancer treatment, primarily attributed to the overexpression of the multidrug resistance (MDR) gene, significantly hampers the effectiveness of chemotherapy. This mechanism, driven by the increased production of P-glycoprotein (P-gp) efflux pumps, highlights the urgent need for innovative strategies to combat drug resistance in cancer patients. This study explores the application of antisense technology to suppress MDR gene expression, while addressing the challenges of instability and limited cellular uptake associated with antisense oligonucleotides. We synthesized Janus silver-mesoporous silica nanoparticles (Ag/MSN JNPs) using a sol-gel method, characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), revealing uniformly sized, dumbbell-shaped nanoparticles with an average size of 285 ± 5.12 nm. Doxorubicin (DOX) was loaded into the porous structure of the mesoporous silica, and JNPs were functionalized with chitosan (CS) to incorporate P-gp antisense and a MUC-1 aptamer, serving as a pH-responsive gatekeeper. Our findings indicate that the Ap-As-DOX-JNPs achieved a remarkable 89 ± 0.59 % cell death in drug-resistant MCF-7/ADR cells after 48 h, alongside an 80 % reduction in P-gp expression. The combination of DOX, antisense technology, and photothermal therapy utilizing these JNPs demonstrates a promising strategy to effectively overcome drug resistance. Notably, normal MCF-7 cells exhibited reduced viability from 39.11 ± 1.12 % to 30.05 ± 1.07 % when treated with DOX-JNPs under near-infrared (NIR) irradiation. These results underscore the potential of utilizing MUC-1 aptamer-conjugated Janus nanoparticles in conjunction with chitosan as a gatekeeper to enhance the efficacy of chemotherapy, photothermal therapy, and gene therapy in overcoming multidrug resistance in cancer treatment.

In vitro and in vivo assessment of the competence of a novel lytic phage vB_EcoS_UTEC10 targeting multidrug resistant Escherichia coli with a robust biofilm eradication activity.

Escherichia coli (E. coli) is a leading cause of human infections worldwide and is considered a major cause of nosocomial infections, sepsis, meningitis and diarrhea. Lately, there has been an alarming increase in the incidence of antimicrobial resistance among clinical E. coli isolates. In the current study, a novel bacteriophage (phage) vB_EcoS_UTEC10 was isolated and characterized. The isolated phage showed high stability over wide temperature and pH ranges beside its promising bacteriolytic activity against multidrug resistant (MDR) E. coli isolates. In addition, vB_EcoS_UTEC10 showed a marked antibiofilm capability against mature E. coli biofilms. Genomic investigation revealed that vB_EcoS_UTEC10 has a double stranded DNA genome that consists of 44,772 bp comprising a total of 73 open reading frames (ORFs), out of which 35 ORFs were annotated as structural or functional proteins, and none were related to antimicrobial resistance or lysogeny. In vivo investigations revealed a promising bacteriolytic activity of vB_EcoS_UTEC10 against MDR E. coli which was further supported by a significant reduction in bacterial load in specimens collected from the phage-treated mice. Histopathology examination demonstrated minimal signs of inflammation and necrosis in the tissues of phage-treated mice compared to the degenerative tissue damage observed in untreated mice. In summary, the present findings suggest that vB_EcoS_UTEC10 has a remarkable ability to eradicate MDR E. coli infections and biofilms. These findings could be further invested for the development of targeted phage therapies that offer a viable alternative to traditional antibiotics against resistant E. coli.

Assessing antimicrobial resistance profiles of Salmonella enterica in the pork production system.

Introduction. Salmonella enterica is a significant enteric pathogen affecting human and livestock health. Pork production is a common source of Salmonella contamination, with emerging multidrug resistance (MDR) posing a global health threat.Gap statement. Salmonella contamination and antimicrobial resistance (AMR) profiles in the pig production chain are underreported.Aim. To investigate the prevalence of S. enterica in the pig production chain and characterise their AMR profiles.Methodology. We collected 485 samples from pig farms, a standard pig abattoir and retail markets in Patthalung and Songkhla provinces in southern Thailand. Antimicrobial susceptibility testing was performed on these samples, and AMR profiles were determined.Results. S. enterica was detected in 68.67% of farm samples, 45.95% of abattoir samples and 50.67% of retail market samples. Analysis of 264 isolates, representing 18 serotypes, identified S. enterica serotype Rissen as the most prevalent. The predominant resistance phenotypes included ampicillin (AMP, 91.29%), tetracycline (TET, 88.26%) and streptomycin (STR, 84.47%). Over 80% of isolates showed resistance to three or more antimicrobial classes, indicating MDR. The AMP-STR-TET resistance pattern was found in nearly 70% of all MDR isolates across the production chain.Conclusions. The high prevalence of MDR is consistent with extensive antimicrobial use in the livestock sector. The presence of extensively resistant S. enterica highlights the urgent need for antimicrobial stewardship. Strengthening preventive strategies and control measures is crucial to mitigate the risk of MDR Salmonella spreading from farm to fork.

Whole genome sequence analysis reveals high genomic diversity and potential host-driven adaptations among multidrug-resistant Escherichia coli from pre-weaned dairy calves.

Food-producing animals such as dairy cattle are potential reservoirs of antimicrobial resistance (AMR), with multidrug-resistant (MDR) organisms such as Escherichia coli observed in higher frequency in young calves compared to older cattle. In this study, we characterized the genomes of enteric MDR E. coli from pre-weaned dairy calves with and without diarrhea and evaluated the influence of host-level factors on genomic composition. Whole genome sequence comparative analysis of E. coli (n = 43) revealed substantial genomic diversity that primarily clustered by sequence type and was minimally driven by calf diarrheal disease status (healthy, diarrheic, or recovered), antimicrobial exposure, and dietary zinc supplementation. Diverse AMR genes (ARGs)-including extended-spectrum beta-lactamase genes and quinolone resistance determinants-were identified (n = 40), with unique sets of ARGs co-occurring in gene clusters with large AMR plasmids IncA/C2 and IncFIB(AP001918). Zinc supplementation was not significantly associated with the selection of individual ARGs in E. coli, however analysis of ARG and metal resistance gene pairs identified positive associations between certain aminoglycoside, beta-lactam, sulfonamide, and trimethoprim ARGs with acid, tellurium and mercury resistance genes. Although E. coli in this study lacked the typical virulence factors of diarrheagenic strains, virulence genes overlapping with those in major pathotypes were identified. Among the 103 virulence genes detected, the highest abundance and diversity of genes corresponded to iron acquisition (siderophores and heme uptake). Our findings indicate that the host-level factors evaluated in this study were not key drivers of genomic variability, but that certain accessory genes in enteric MDR E. coli may be enriched. Collectively, this work provides insight into the genomic diversity and host-microbe interface of MDR E. coli from pre-weaned dairy calves.

Reversible chemoresistance of pancreatic cancer grown as spheroids.

Better in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Recent advances and challenges of revolutionizing drug-resistant tuberculosis treatment.

Tuberculosis (TB), an infectious disease induced by Mycobacterium tuberculosis, is one of the primary public health threats all over the world. Since the prevalence of first-line anti-TB agents, the morbidity and mortality issues of TB descended obviously. Nevertheless, the emergences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the double prevalence of HIV-TB co-infection, and the insufficiency of plentiful health care have led to an increased incidence of TB. It is noted that current drugs for treating TB have proved unsustainable in the face of highly resistant strains. Fortunately, five categories of new drugs and candidates with new mechanisms of action have emerged in the field of anti-TB research after decades of stagnation in the progression of anti-TB drugs. In this paper, the research status of these promising anti-TB drugs and candidates are reviewed, emphasizing the challenges to be addressed for efficient development of future TB therapies.

Changes in the Sensitivity of MCF-7 and MCF-7/DX Breast Cancer Cells to Cytostatic in the Presence of Metformin.

Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.

Extensively and multidrug-resistant bacterial strains: case studies of antibiotics resistance.

The development of antibiotic resistance compromises the effectiveness of our most effective defenses against bacterial infections, presenting a threat to global health. To date, a large number of research articles exist in the literature describing the case reports associated with extensively drug-resistant (XDR) and multidrug-resistant (MDR) bacterial strains. However, these findings are scattered, making it time-consuming for researchers to locate promising results and there remains a need for a comparative study to compile these case reports from various geographical regions including the Kingdom of Saudi Arabia. Additionally, no study has yet been published that compares the genetic variations and case reports of MDR and XDR strains identified from Saudi Arabia, the Middle East, Central Europe, and Asian countries. This study attempts to provide a comparative analysis of several MDR and XDR case reports from Saudi Arabia alongside other countries. Furthermore, the purpose of this work is to demonstrate the genetic variations in the genes underlying the resistance mechanisms seen in MDR and XDR bacterial strains that have been reported in Saudi Arabia and other countries. To cover the gap, this comprehensive review explores the complex trends in antibiotic resistance and the growing risk posed by superbugs. We provide context on the concerning spread of drug-resistant bacteria by analyzing the fundamental mechanisms of antibiotic resistance and looking into individual case reports. In this article, we compiled various cases and stories associated with XDR and MDR strains from Saudi Arabia and various other countries including China, Egypt, India, Poland, Pakistan, and Taiwan. This review will serve as basis for highlighting the growing threat of MDR, XDR bacterial strains in Saudi Arabia, and poses the urgent need for national action plans, stewardship programs, preventive measures, and novel antibiotics research in the Kingdom.

A Systematic Review on Antimicrobial Resistance in Ghana from a One Health Perspective.

BACKGROUND: Antimicrobial resistance (AMR) poses a global health threat, with lower-middle-income countries bearing a disproportionate burden. Surveillance of AMR under a One Health framework is needed to elucidate the associations among clinical, animal, and environmental AMR. This review aimed to describe the state of AMR in Ghana, focusing on One Health. METHOD: This review utilized the PRISMA guidelines and major databases to systematically search and analyze AMR in Ghana published from 1 January 2014 to 1 May 2023. RESULTS: Out of the 48 articles that met the inclusion criteria, 28 studies were conducted on humans, 14 studies involved animals, and 6 studies focused on the environment. A total of 48 different pathogens were identified across the human, animal, and environmental sectors, with the most common being Escherichia coli (67%, n = 32), Klebsiella spp. (52%, n = 25), Pseudomonas spp. (40%, n = 19), and Salmonella spp. (38%, n = 18). Generally, a high prevalence of antibiotic resistance was observed among various bacterial species across the sectors. These bacteria exhibited resistance to commonly used antibiotics, with resistance to ampicillin and tetracycline exceeding 80%, and multidrug resistance (MDR) ranging from 17.6% in Shigella spp. to 100% in Acinetobacter spp. CONCLUSION: This review reaffirms the significant challenge of AMR in Ghana, with a high prevalence observed in the human, animal, and environmental sectors. Key pathogens (e.g., Staphylococcus aureus and Escherichia coli) found across the sectors emphasize the urgent need for a One Health approach to tackle AMR in Ghana.

Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.

Hypoxia modulates P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug transporters in brain endothelial cells of the developing human blood-brain barrier.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier (BBB). They confer fetal brain protection against harmful compounds that may be circulating in the peripheral blood. The fetus develops in low oxygen levels; however, some obstetric pathologies such as pre-eclampsia, placenta accreta/previa may result in even greater fetal hypoxic states. We investigated how hypoxia impacts MDR transporters in human fetal brain endothelial cells (hfBECs) derived from early and mid-stages of pregnancy. Hypoxia decreased BCRP protein and activity in hfBECs derived in early pregnancy. In contrast, in hfBECs derived in mid-pregnancy there was an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key physiological and pharmacological substrates of P-gp and BCRP in the developing fetal brain and potentially contribute to the pathogenesis of neurodevelopmental disorders commonly associated with in utero hypoxia.

Phenylspirodrimane with Moderate Reversal Effect of Multidrug Resistance Isolated from the Deep-Sea Fungus Stachybotrys sp. 3A00409.

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3-10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.

Recent trends and challenges to overcome Pseudomonas aeruginosa infections.

INTRODUCTION: Pseudomonas aeruginosa (PA) is a Gram-negative bacterium that can cause a wide range of severe infections in immunocompromised patients. The most difficult challenge is due to its ability to rapidly develop multi drug-resistance. New strategies are urgently required to improve the outcome of patients with PA infections. The present patent review highlights the new molecules acting on different targets involved in the antibiotic resistance. AREA COVERED: This review offers an insight into new potential PA treatment disclosed in patent literature. From a broad search of documents claiming new PA inhibitors, we selected and summarized molecules that showed in vitro and in vivo activity against PA spp. in the period 2020 and 2023. We collected the search results basing on the targets explored. EXPERT OPINION: This review examined the main patented compounds published in the last three years, with regard to the structural novelty and the identification of innovative targets. The main areas of antibiotic resistance have been explored. The compounds are structurally unrelated to earlier antibiotics, characterized by a medium-high molecular weight and the presence of heterocycle rings. Peptides and antibodies have also been reported as potential alternatives to chemical treatment, hereby expanding the therapeutic possibilities in this field.

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites.

Molecular mechanisms of tigecycline-resistance among Enterobacterales.

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

Advances in traditional herbal formulation based nano-vaccine for cancer immunotherapy: Unraveling the enigma of complex tumor environment and multidrug resistance.

Cancer is attributed to uncontrolled cell growth and is among the leading causes of death with no known effective treatment while complex tumor microenvironment (TME) and multidrug resistance (MDR) are major challenges for developing an effective therapeutic strategy. Advancement in cancer immunotherapy has been limited by the over-activation of the host immune response that ultimately affects healthy tissues or organs and leads to a feeble response of the patient's immune system against tumor cells. Besides, traditional herbal medicines (THM) have been well-known for their essential role in the treatment of cancer and are considered relatively safe due to their compatibility with the human body. Yet, poor solubility, low bio-availability, and lack of understanding about their pathophysiological mechanism halt their clinical application. Moreover, considering the complex TME and drug resistance, the most precarious and least discussed concerns for developing THM-based nano-vaccination, are identification of specific biomarkers for drug inhibitory protein and targeted delivery of bioactive ingredients of THM on the specific sites in tumor cells. The concept of THM-based nano-vaccination indicates immunomodulation of TME by THM-based bioactive adjuvants, exerting immunomodulatory effects, via targeted inhibition of key proteins involved in the metastasis of cancer. However, this concept is at its nascent stage and very few preclinical studies provided the evidence to support clinical translation. Therefore, we attempted to capsulize previously reported studies highlighting the role of THM-based nano-medicine in reducing the risk of MDR and combating complex tumor environments to provide a reference for future study design by discussing the challenges and opportunities for developing an effective and safe therapeutic strategy against cancer.

Bacterial Diversity and Antibiotic Resistance Patterns of Community-Acquired Urinary Tract Infections in Mega Size Clinical Samples of Egyptian Patients: A Cross-Sectional Study.

BACKGROUND:  Community-acquired urinary tract infection (UTI) is one of the most common infectious diseases nowadays. Alarming increased levels of antimicrobial resistance are developing globally which limit treatment options and may lead to life-threatening problems. AIM: Our study aimed to collect surveillance data on non-hospitalized Egyptian UTI cases and to develop strategies against multidrug-resistant pathogens (MDR). According to our knowledge, this is the first study to screen this high number (15,252 urine samples) in a short period (three months), providing valuable data on resistance profiles in non-hospitalized Egyptian UTI patients. METHODS: A total of 15,252 urine samples were collected from different patients. Positive cultures were identified using a semi-quantitative method. Kirby-Bauer's disc diffusion method was used for antibiotic susceptibility testing, the double disc diffusion method was used for extended-spectrum beta-lactamases-producing strains, and the Chi-square test was used for statistical data processing. RESULTS: The results showed 61% positive cultures, females accounted for 67.5%. Infants and elderly patients showed the highest positive cultures (74.4% and 69.2%, respectively). Despite Escherichia coli being the most common uropathogen (47.19%), Klebsiella species(24.42%) were the most MDR and extended-spectrum ß-lactamase (ESBL)-producing organisms. E. coli and Klebsiella spp. displayed increased resistance to cephalosporins (75% and 81%, respectively). In contrast, both organisms displayed high sensitivity to carbapenems. Unlike Klebsiella spp., E. coli was highly sensitive (92%) to first-line treatment (nitrofurantoin) for UTI. Moreover, trimethoprim/sulfamethoxazole showed higher sensitivity rates compared to other nations. CONCLUSION:  Despite Escherichia coli being the most often identified bacteria in our isolates Klebsiella spp. displayed higher resistance to the majority of tested antibiotics. Fortunately, trimethoprim/sulfamethoxazole significantly increased sensitivity, especially against E. coli. However, both species showed high rates of cephalosporin resistance. Moreover, It is important to promote Egypt's national action plan for antimicrobial resistance in collaboration with the World Health Organization, especially in the community to minimize the chance of bacterial resistance in the Egyptian community.