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Nosocomial pneumonia is defined as pneumonia occurring ≥ 48 h after hospital admission in a patient without severe immunosuppression. It can occur in spontaneously breathing patients or with noninvasive ventilation (NIV) and mechanically ventilated patients. In patients with suspected ventilator-associated pneumonia (VAP) (semi)quantitative cultures of tracheobronchial aspirates or bronchoalveolar lavage fluid should be perfomed. The initial empirical antimicrobial treatment is determined by the risk for multidrug-resistant pathogens (MDRP). The advantage of combination treatment increases with the prevalence of MDRPs. The antibiotic treatment should be adapted when the microbiological results are available. After 72 h a standardized re-evaluation including the response to treatment and also checking of the suspected diagnosis of pneumonia in a structured form is mandatory. Treatment failure can occur as a primary or secondary failure and in the case of primary progression necessitates another comprehensive diagnostic work-up before any further antibiotic treatment. [ABSTRACT FROM AUTHOR]

Purpose: To describe the prevalence and antibiotic resistance profiles of Pseudomonasaeruginosa isolated from the Asia Cornea Society Infectious Keratitis Study (ACSIKS). Methods: All bacterial isolates from ACSIKS underwent repeat microbiological identification in a central repository in Singapore. Minimum inhibitory concentration (MIC) determination was conducted for isolates of P. aeruginosa against thirteen antibiotics from 6 different classes, and categorized based on Clinical Laboratory Standard Institutes' reference ranges. The percentage rates of resistance (non-susceptibility) to each antibiotic included isolates of both intermediate and complete resistance. Multi-drug resistance (MDR) was defined as non-susceptibility to at least one agent in three or more antimicrobial classes. Results: Of the 1493 unique bacterial specimens obtained from ACSIKS, 319 isolates were of P. aeruginosa. The majority of isolates were from centers in India (n = 118, 37%), Singapore (n = 90, 28.2%), Hong Kong (n = 31, 9.7%) and Thailand (n = 30, 9.4%). The cumulative antibiotic resistance rate was the greatest for polymyxin B (100%), ciprofloxacin (17.6%) and moxifloxacin (16.9%), and lowest for cefepime (11.6%) and amikacin (13.5%). Isolates from India demonstrated the highest antibiotic resistance rates of all the centers, and included moxifloxacin (47.5%) and ciprofloxacin (39.8%). Forty-eight of the 59 MDR isolates also originated from India. Antibiotic resistance rates were significantly lower in the other ACSIKS centers, and were typically less than 10%. Conclusions: The antibiotic resistance profiles of P. aeruginosa varied between different countries. While it was low for most countries, substantial antibiotic resistance and a significant number of multi-drug resistant isolates were noted in the centers from India. [ABSTRACT FROM AUTHOR]

Objective　To investigate the clinical features of patients with acute-on-chronic liver failure （ACLF） and bacterial infection and early warning indicators associated with multidrug-resistant infections. Methods　A retrospective analysis was performed for 130 patients with ACLF and bacterial infection who attended The Second Affiliated Hospital of Air Force Medical University from January 1, 2010 to December 31, 2021, and according to the drug susceptibility results, the patients were divided into multidrug-resistant （MDR） bacterial infection group with 80 patients and non-MDR bacterial infection group with 50 patients. General information and laboratory examination results were compared between the two groups to screen for the early warning indicators associated with MDR bacterial infection. The Student’s t-test was used for comparison of normally distributed continuous data with homogeneity of variance between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. The binary logistic regression analysis and the receiver operating characteristic （ROC） curve were used to assess the predictive value of early warning indicators. Results　Among the 130 patients with ACLF and bacterial infection， sputum （27.7%） was the most common specimen for detection， followed by blood（ 24.6%), urine（ 18.5%), and ascites（ 17.7%). Bacterial infections were dominated by Gram-negative bacteria（ 58.5%). Of all bacteria， Escherichia coli （18.5%), Klebsiella pneumoniae （14.6%), and Enterococcus faecium （13.8%） were the most common pathogens. Gram-positive bacteria had a high resistance rate to the antibacterial drugs such as erythromycin （72.2%), penicillin （57.4%), ampicillin （55.6%), and ciprofloxacin （53.7%), while Gram-negative bacteria had a high resistance rate to the antibacterial drugs such as ampicillin （73.3%), cefazolin （50.0%), and cefepime （47.4%). The patients with ACLF and bacterial infection had a relatively high rate of MDR bacterial infection （61.5%). Comparison of clinical data between the two groups showed that compared with the patients with non-MDR bacterial infection， the patients with MDR bacterial infection had significantly higher levels of alanine aminotransferase （Z=2.089， P=0.037), aspartate aminotransferase （Z=2.063， P=0.039), white blood cell count （Z=2.207， P=0.027), and monocyte count （Z=4.413， P<0.001). The binary logistic regression analysis showed that monocyte count was an independent risk factor for MDR bacterial infection （odds ratio=7.120， 95% confidence interval ［CI］： 2.478 — 20.456，P<0. 001） and had an area under the ROC curve of 0.686 （95%CI： 0.597 — 0.776） in predicting ACLF with MDR bacterial infection（P<0. 001), with the optimal cut-off value of 0.50×109/L， a sensitivity of 0.725， and a specificity of 0.400. Conclusion　ACLF combined with bacterial infections is mainly caused by Gram-negative bacteria， with the common pathogens of Escherichia coli and Klebsiella pneumoniae and a relatively high MDR rate in clinical practice. An increase in monocyte count can be used as an early warning indicator to distinguish MDR bacterial infection from non-MDR bacterial infection. [ABSTRACT FROM AUTHOR]

Introduction. Multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) is difficult to control, has high morbidity and mortality, and demands priority public health intervention. In Colombia, MDR/RR-TB has been becoming more widespread annually. Before the COVID-19 pandemic, over an 8-year period, the number of cases of multidrug-resistant tuberculosis in Colombia was close to a thousand cases. Timely identification of the different risk factors for MDR/RR-TB will contribute fundamentally to the systematic management. Objective. To determine which risk factors were associated with the presentation of MDR in Colombia between 2013 and 2018. Materials and methods. A retrospective case-control study was carried out, for which the data from the routine surveillance of MDR/events in the country were used. Results. The cases of multidrug-resistant tuberculosis were mainly in young people, Afrodescendants, and males. Of the clinical conditions, comorbidities such as malnutrition, diabetes, and HIV, presence of at least one factor, such as drug dependence, taking immunosuppressive medications, belonging to the black race, afro, and living in an area of high disease burden were risk factors. Conclusion. In addition to the diagnosis and timely provision of MDR-TB treatment, it is necessary that public health programs at the local level pay special attention to patients with the identified risk factors.

Objective To investigate the mechanism of luteolin's (Lut) reversal effect on multidrug resistance of chronic myeloid leukemia K562/ADR cells. Methods CCK-8 assay was used to detect drug resistance in K562 and K562/ADR cells 24 hours after treatment with different doses of adriamycin (ADR). CCK-8 assay was used to assess the cytotoxicity and sensitizing effect of Lut on ADR after K562/ADR cells were treated with Lut alone or in combination with ADR for 24 hours. K562/ADR cells in logarithmic growth phase were separated into three group: 0 µmol/L Lut, 2 µmol/L and 4 µmol/L Lut groups. ADR accumulation in cells was measured using flow cytometry. Nuclear factor erythroid-2-related factor 2 (Nrf2), multidrug resistance associated protein 1 (MRP1), P-glycoprotein (P-gp) and glutathione-S-transferase-PI (GST-pi) mRNA and protein expressions were identified using RT-PCR and Western blot assay. Glutathione (GSH) kit was used to detect intracellular GSH content. Results Compared with K562 cells, K562/ADR cell line was significantly resistant to ADR, and the drug resistance was 53.69 times. K562/ADR cell proliferation was decreased to variable degrees by different doses of Lut when compared to the 0 µmol/L Lut group (P＜0.05). The proliferation inhibition rates of K562/ADR cells treated with 2 and 4 µmol/L Lut were less than 10%, indicating that the concentration of Lut was non-toxic. Compared with the 0 µmol/L Lut group, the 2 µmol/L Lut group and the 4 µmol/L Lut group showed significantly increased ADR growth inhibition rate on K562/ADR and increased accumulation of ADR in cells, improved the reversal resistance fold, and decreased GSH content in cells. MRP1, P-gp, GST-pi and Nrf2 mRNA and protein expression were reduced in cells (P＜ 0.05). The effect of 4 mol/L Lut was greater than that of 2 mol/L Lut. Conclusion Lut may decrease K562/ADR cell proliferation and reverse ADR medication resistance. The mechanism could be connected to the downregulation of Nrf2, MRP1, P-gp and GST-pi expression, which leads to an increase in ADR accumulation in K562/ADR cells. [ABSTRACT FROM AUTHOR]

Objectives. To determine the proportion of Salmonella enterica in fecal samples of live pigs with suspected salmonellosis analyzed at the diagnostic unit of the University of Antioquia, Colombia between 2019 and 2021, and examine the serotypes and antimicrobial resistance patterns. Methods. This was a laboratory-based cross-sectional study of routine data on fecal samples received from pig farms in all nine subregions of Antioquia state, Colombia. Salmonella spp. detection at the university is done using enrichment, selective culture, and polymerase chain reaction. Serotypes were identified using the Kauffmann–White scheme and isolates were tested for antimicrobial susceptibility using broth microdilution. Results. Of 653 samples tested, 149 (23%) were positive for S. enterica. Nine serotypes were identified. The most common were Salmonella Typhimurium (56%) and its monophasic variant (35%). Resistance to ampicillin (70%) was most frequently observed, followed by ciprofloxacin (55%), and sulfamethoxazole–trimethoprim (52%). No isolates were resistant to amikacin and gentamicin. Multidrug resistance (resistance to ≥ 3 classes of antibiotics) was observed in 61 (44%) isolates. Multidrug resistance was highest in S. Typhimurium (57%) compared with the other serotypes. Serotype was associated with multidrug resistance (p = 0.01), but age of the pig and sub-region were not. Conclusions. The proportion of Salmonella spp. and the associated high levels of multidrug resistance are of concern and may indicate irrational use of antimicrobials and poor management practices in pig production systems in the region. Strengthened surveillance is needed to monitor and improve farm management practices and the use of antimicrobials in farms in Colombia.

Background: Colistin is the most significant last-line antibiotic for the treatment of multidrug-resistant infections caused by Gram-negative bacteria, especially the Enterobacteriaceae family. The emergence and rapid spread of the plasmid-mediated resistance gene, mcr-1 (mobilized colistin resistance), in some isolates of Escherichia coli in recent years provoked public health concerns since it has been shown that mcr-1 with other resistance genes, such as ESBLs (extended-spectrum beta-lactamases) and carbapenemases, could be carried on a single plasmid concurrently. The excessive consumption of colistin, particularly in the livestock industry, and the transmission of these resistant bacteria from livestock to humans may potentially increase the risk of the spread of resistance in humans. Therefore, this study aimed to detect the prevalence of mcr and carbapenem resistance genes among neonatal calves in Mashhad, Razavi Khorasan Province, Iran. Methods: In the current study, 200 fecal samples from healthy and diarrheic neonatal calves (≤35 days old) were collected in Mashhad (190 E. coli strains were isolated). Antibiotic susceptibility to ceftazidime, cefepime, cefixime, meropenem, colistin, and ciprofloxacin was examined. The double-disk diffusion method (ceftazidime + ceftazidime/clavulanic acid) was performed on Mueller-Hinton agar (MHA) media to phenotypically distinguish the ESBL producers. Afterward, the Multiplex polymerase chain reaction (PCR) method was used to detect colistin resistance genes (mcr-1, mcr-2, mcr-3, mcr-4, and mcr5), NDM-1 (New Delhi metallo-beta-lactamase 1), and OXA-48 as carbapenemases. Results: The results of the resistance rate to antibiotics were cefepime, ceftazidime, cefixime, meropenem, and colistin. Based on the findings, 33.7% were phenotypically ESBL producers, 4.21% harbored mcr-1, and no NDM1 or OXA-48 was detected. Among the mcr-1-positive isolates, 5 strains showed the ESBL phenotype. Conclusion: The results highlight the need for continued monitoring of antibiotic resistance in livestock and the potential for transmission to humans. The findings also underscore the importance of responsible antibiotic use in both human and animal health to mitigate the spread of antibiotic resistance. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections (LRTI) in patients in an ICU. Methods: This was an observational cohort study involving patients with nosocomial LRTI (health care-associated pneumonia, hospital-acquired pneumonia, or ventilator-associated pneumonia). Data were prospectively collected between 2015 and 2019. The multidrugresistant pathogens (MDRPs) identified in the isolates studied included resistant to extended-spectrum cephalosporin-resistant and carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus at microbiological diagnosis. Results: During the study period, 267 patients in the ICU were diagnosed with LRTI, microbiological confirmation of LRTI having been obtained in 237. Of these, 146 (62%) had at least one MDRP isolate. Patients infected with MDRP were found to have poorer outcomes than patients infected with susceptible strains, such as prolonged mechanical ventilation (18.0 days vs. 12.0 days; p < 0.001), prolonged ICU length of stay (23.0 days vs.16.0 days; p < 0.001), and higher mortality (73% vs. 53%; p < 0.001) when compared with patients infected with susceptible strains. Hospital length of stay ≥ 5 days (OR = 3.20; 95% CI: 1.39-7.39; p = 0.005) and prolonged use vasoactive drugs (OR = 3.15; 95% CI: 1.42-7.01; p = 0.004) were independent predictors of LRTI caused by MDRPs (LRTI-MDRP). The presence of LRTI-MDRP was found to be an independent predictor of death (OR = 2.311; 95% CI: 1.091-4.894; p = 0.028). Conclusions: Prolonged use of vasoactive drugs and prolonged hospital length of stay were independent predictors of LRTI-MDRP in this population of critically ill patients with very poor outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Hospital outbreaks of multidrug resistant Pseudomonas aeruginosa are often caused by Pseudomonas aeruginosa clones which produce metallo-β-lactamases, such as Verona Integron-encoded Metallo-β-lactamase (VIM). Although different sources have been identified, the exact transmission routes often remain unknown. However, quantifying the role of different transmission routes of VIM-PA is important for tailoring infection prevention and control measures. The aim of this study is to quantify the relative importance of different transmission routes by applying a mathematical transmission model using admission and discharge dates as well as surveillance culture data of patients. Methods We analyzed VIM-PA surveillance data collected between 2010 and 2018 of two intensive-care unit (ICU) wards for adult patients of the Erasmus University Medical Center Rotterdam using a mathematical transmission model. We distinguished two transmission routes: direct cross-transmission and a persistent environmental route. Based on admission, discharge dates, and surveillance cultures, we estimated the proportion of transmissions assigned to each of the routes. Results Our study shows that only 13.7% (95% CI 1.4%, 29%) of the transmissions that occurred in these two ICU wards were likely caused by cross-transmission, leaving the vast majority of transmissions (86.3%, 95% CI 71%, 98.6%) due to persistent environmental contamination. Conclusions Our results emphasize that persistent contamination of the environment may be an important driver of nosocomial transmissions of VIM-PA in ICUs. To minimize the transmission risk from the environment, potential reservoirs should be regularly and thoroughly cleaned and disinfected, or redesigned.

ABSTRACT Objective: To determine the prevalence, outcomes, and predictors of multidrug-resistant nosocomial lower respiratory tract infections (LRTI) in patients in an ICU. Methods: This was an observational cohort study involving patients with nosocomial LRTI (health care-associated pneumonia, hospital-acquired pneumonia, or ventilator-associated pneumonia). Data were prospectively collected between 2015 and 2019. The multidrug-resistant pathogens (MDRPs) identified in the isolates studied included resistant to extended-spectrum cephalosporin-resistant and carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus at microbiological diagnosis. Results: During the study period, 267 patients in the ICU were diagnosed with LRTI, microbiological confirmation of LRTI having been obtained in 237. Of these, 146 (62%) had at least one MDRP isolate. Patients infected with MDRP were found to have poorer outcomes than patients infected with susceptible strains, such as prolonged mechanical ventilation (18.0 days vs. 12.0 days; p < 0.001), prolonged ICU length of stay (23.0 days vs.16.0 days; p < 0.001), and higher mortality (73% vs. 53%; p < 0.001) when compared with patients infected with susceptible strains. Hospital length of stay ≥ 5 days (OR = 3.20; 95% CI: 1.39-7.39; p = 0.005) and prolonged use vasoactive drugs (OR = 3.15; 95% CI: 1.42-7.01; p = 0.004) were independent predictors of LRTI caused by MDRPs (LRTI-MDRP). The presence of LRTI-MDRP was found to be an independent predictor of death (OR = 2.311; 95% CI: 1.091-4.894; p = 0.028). Conclusions: Prolonged use of vasoactive drugs and prolonged hospital length of stay were independent predictors of LRTI-MDRP in this population of critically ill patients with very poor outcomes.

Copyright of Der Internist is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: There are no specific recommendations for prevention of surgical site infection (SSI) caused by multidrug resistant Gram-negative bacilli (MDR-GNB). Our objective was to systematically review the literature evaluating the efficacy and safety of measures specifically designed to prevent MDR-GNB SSI. Methods: We searched MEDLINE, EMBASE, CINAHL and LILACS databases up to February 18, 2020. Randomized trials and observational cohort studies evaluating the efficacy of preventive measures against MDR-GNB SSI in adult surgical patients were eligible. We evaluated methodological quality of studies and general quality of evidence using Newcastle-Ottawa scale, Cochrane ROBINS-I and GRADE method. Random-effects meta-analyses were performed using Review Manager V.5.3 software. Results: A total of 10,663 titles by searching databases were identified. Two retrospective observational studies, comparing surgical antibiotic prophylaxis (SAP) with or without aminoglycoside in renal transplantation recipients, and one non-randomized prospective study, evaluating ertapenem vs. cephalosporin plus metronidazole for SAP in extended spectrum beta-lactamase producing Enterobacteriales carriers undergoing colon surgery, were included. Risk of bias was high in all studies. Meta-analysis was performed for the renal transplantation studies, with 854 patients included. Combined relative risk (RR) for MDR GNB SSI was 0.57 (95%CI: 0.25-1.34), favoring SAP with aminoglycoside (GRADE: moderate). Conclusions: There are no sufficient data supporting specific measures against MDR-GNB SSI. Prospective, randomized studies are necessary to assess the efficacy and safety of SAP with aminoglycoside for MDR-GNB SSI prevention among renal transplantation recipients and other populations. PROSPERO 2018 CRD42018100845.

The management of cattle ticks, particularly Rhipicephalus microplus, poses a global challenge in subtropical regions like Ecuador due to its impact on meat and milk productivity, leading to economic losses. Misuse of acaricides has resulted in resistance and multi-resistance, diminishing their effectiveness. This study evaluated resistance to amitraz, alpha-cypermethrin, and ivermectin using the Larval Packet test, laboratory-reared tick larvae collected from cattle were tested. Data on farm management and tick control practices were gathered via a questionnaire in Northwest Pichincha and Quijos River Valley over two years. Resistance rates in the first year (2020-2021) were 67.21% for amitraz, 57.38% for ivermectin, and 67.21% for alpha-cypermethrin. One year later (2021-2022), resistance levels were 59.57% for amitraz, 57.45% for ivermectin, and 68.09% for alpha-cypermethrin, with multi-resistance rates at 67.21% and 65.96% respectively. No significant differences were found between years or locations. Analysis of larval survival data determined lethal doses for tested acaricides. The study emphasizes the association between the lack of acaricide rotation, the incorrect dosage, and the absence of non-chemical measures in tick management could be associated with the development of resistances in ticks. Likewise, this study promotes the need for collaborative efforts to improve control practices and maintain acaricide efficacy.

Background: Hospital outbreaks of multidrug resistant Pseudomonas aeruginosa are often caused by Pseudomonas aeruginosa clones which produce metallo-β-lactamases, such as Verona Integron-encoded Metallo-β-lactamase (VIM). Although different sources have been identified, the exact transmission routes often remain unknown. However, quantifying the role of different transmission routes of VIM-PA is important for tailoring infection prevention and control measures. The aim of this study is to quantify the relative importance of different transmission routes by applying a mathematical transmission model using admission and discharge dates as well as surveillance culture data of patients. Methods: We analyzed VIM-PA surveillance data collected between 2010 and 2018 of two intensive-care unit (ICU) wards for adult patients of the Erasmus University Medical Center Rotterdam using a mathematical transmission model. We distinguished two transmission routes: direct cross-transmission and a persistent environmental route. Based on admission, discharge dates, and surveillance cultures, we estimated the proportion of transmissions assigned to each of the routes. Results: Our study shows that only 13.7% (95% CI 1.4%, 29%) of the transmissions that occurred in these two ICU wards were likely caused by cross-transmission, leaving the vast majority of transmissions (86.3%, 95% CI 71%, 98.6%) due to persistent environmental contamination. Conclusions: Our results emphasize that persistent contamination of the environment may be an important driver of nosocomial transmissions of VIM-PA in ICUs. To minimize the transmission risk from the environment, potential reservoirs should be regularly and thoroughly cleaned and disinfected, or redesigned. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: We investigated the genetic diversities and lineage-specific transmission dynamics of multidrug-resistant tuberculosis (MDR-TB), with the goal of determining the potential factors driving the MDR epidemics in China., Methods: We curated a large nationwide Mycobacterium tuberculosis ( M. tuberculosis ) whole genome sequence data set, including 1313 MDR strains. We reconstructed the phylogeny and mapped the transmission networks of MDR-TB across China using Bayesian inference. To identify drug-resistance variants linked to enhanced transmissibility, we employed ordinary least-squares (OLS) regression analysis., Result: The majority of MDR-TB strains in China belong to lineage 2.2.1. Transmission chain analysis has indicated that the repeated and frequent transmission of L2.2.1 plays a central role in the establishment of MDR epidemic in China, but no occurrence of a large predominant MDR outbreak was detected. Using OLS regression, the most common single nucleotide polymorphisms (SNPs) associated with resistance to isoniazid ( katG&#95;p.Ser315Thr and katG&#95;p.Ser315Asn ) and rifampicin ( rpoB&#95;p.Ser450Leu , rpoB&#95;p.His445Tyr , rpoB&#95;p.His445Arg , rpoB&#95;p.His445Asp , and rpoB&#95;p.His445Asn ) were more likely to be found in L2 clustered strains. Several putative compensatory mutations in rpoA , rpoC , and katG were significantly associated with clustering. The eastern, central, and southern regions of China had a high level of connectivity for the migration of L2 MDR strains throughout the country. The skyline plot showed distinct population size expansion dynamics for MDR-TB lineages in China., Conclusion: MDR-TB epidemic in China is predominantly driven by the spread of highly transmissible Beijing strains. A range of drug-resistance mutations of L2 MDR-TB strains displayed minimal fitness costs and may facilitate their transmission.

Objective. To describe the resistance profile and the genetic characteristics of Escherichia coli isolates that harbor the mobilizable colistin resistance gene mcr-1 in Argentina. Methods. This was a retrospective study of 192 E. coli isolates positive for mcr-1 obtained from 69 hospitals of Buenos Aires City and 14 Argentinean provinces in 2012 – 2018. The antimicrobial susceptibility was performed by agar diffusion, broth macrodilution, and/or agar dilution. Standard polymerase chain reaction (PCR) was performed to detect resistance genes and incompatibility groups; specific PCR was applied to discriminate between blaCTX-M allelic groups and mcr-1.5 variant. The genetic relatedness among isolates was evaluated by XbaI-pulsed field gel electrophoresis and multilocus sequence typing in a subset of isolates. Results. All E. coli isolates showed minimal inhibitory concentrations to colistin ≥ 4μg/mL; nearly 50% were resistant to third-generation cephalosporins, with CTX-M-2 being the main extended-spectrum β-lactamase detected. Five E. coli were carbapenemase-producers (3 NDM, 2 KPC). The mcr-1.5 variant was detected in 13.5% of the isolates. No genetic relationship was observed among the mcr-1-positive E. coli clinical isolates, but a high proportion (164/192; 85.4%) of IncI2 plasmids was detected. Conclusions. The presence of IncI2 plasmids among highly diverse E. coli clones suggests that the mcr-1 gene’s wide distribution in Argentina may be driven by the horizontal transmission of IncI2 plasmids.

Acinetobacter baumannii is considered to be a worldwide threat to public health due to its high antimicrobial resistance rates and the severe infections it can cause. Little is known about this pathogen’s resistance in Central America. This report aims to describe the antimicrobial resistance profile of A. baumannii at a tertiary hospital in Honduras. The cross-sectional analysis was conducted at the tertiary care laboratory hospital in San Pedro Sula in 2015 – 2017. A total of 113 consecutive microbiological reports were analyzed, comprising 100 individuals from whom A. baumannii was isolated. Epidemiological and microbiological data, including the isolation setting and patient information, were recorded. Prevalence of multi-drug and extensive-drug resistance was assessed according to international standards. The median age of individuals was 22 years (2 – 35 years); female was the predominant gender (53%). The hospital’s pediatric wards had the highest number of isolates (n = 48). The most frequent specimen from which A. baumannii was isolated was skin and soft tissue (n = 39). Resistance to carbapenems was reported to be 40.7% among the isolates (n = 46); multi-drug resistant, 35.4% (n = 40); and extensively-drug resistant, 7.1% (n = 8). This report reveals the threat of this pathogen to public health in Honduras and appeals for antibiotic stewardship programs throughout Central America.

Background: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes., Methods: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis., Results: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring., Conclusions: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment., (© 2024. The Author(s).)

Multidrug-resistant organism infections are a serious health problem globally, and can result in patient mortality and morbidity. In this descriptive study, we produced the first web application for transmission prevention specific to the situation based on nursing experience, knowledge, and practice guidelines and to evaluate web application satisfaction among Thai nurses. The sample comprised 282 Thai registered nurses experienced in caring for patients with multidrug-resistant organisms in a tertiary hospital. A demographic form and knowledge test were completed anonymously online. Data were analyzed using descriptive statistics. The application emphasized crucial topics for which participants had low preliminary knowledge and included tutorial sessions, pictures, video clips, drills, and a post-test. The application was piloted with a random sample of 30 nurses, and an instrument tested their satisfaction with this. Results revealed that preliminary knowledge scores for preventing transmission were moderate, and participants were highly satisfied with the application. Findings suggest the application is suitable for Thai nurses and could be applied to nursing practice elsewhere. However, further testing is recommended before implementing it into nursing practice., (© 2024 John Wiley & Sons Australia, Ltd.)

Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA: 9.06 %). After hyaluronic acid (HA)-mediated endocytosis, the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles. Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc.; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer., Competing Interests: Declaration of competing interest All authors agree to be published and declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH 2 ) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. β-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Hongtao Song reports financial support was provided by Fujian Provincial Department of Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Overcoming multidrug resistance (MDR) is one of the major challenges in cancer therapy. In this respect, Schiff base-related compounds (bearing a R 1 R 2 CNR 3 bond) gained high interest during the past decades. Schiff bases are considered privileged ligands for various reasons, including the easiness of their preparation and the possibility to form complexes with almost all transition metal ions. Schiff bases and their metal complexes exhibit many types of biological activities and are used for the treatment and diagnosis of various diseases. Until now, 13 Schiff bases have been investigated in clinical trials for cancer treatment and hypoxia imaging. This review represents the first collection of Schiff bases and their complexes which demonstrated MDR-reversal activity. The areas of drug resistance covered in this article involve: 1) Modulation of ABC transporter function, 2) Targeting lysosomal ABCB1 overexpression, 3) Circumvention of ABC transporter-mediated drug efflux by alternative routes of drug uptake, 4) Selective activity against MDR cancer models (collateral sensitivity), 5) Targeting GSH-detoxifying systems, 6) Overcoming apoptosis resistance by inducing necrosis and paraptosis, 7) Reactivation of mutated p53, 8) Restoration of sensitivity to DNA-damaging anticancer therapy, and 9) Overcoming drug resistance through modulation of the immune system. Through this approach, we would like to draw attention to Schiff bases and their metal complexes representing highly interesting anticancer drug candidates with the ability to overcome MDR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Multidrug resistance (MDR) poses a significant impediment to the efficacy of chemotherapy in clinical settings. Despite Paclitaxel (PTX) being designated as the primary pharmaceutical agent for treating recurrent and metastatic breast cancer, the emergence of PTX resistance frequently results in therapeutic shortcomings, representing a substantial obstacle in clinical breast cancer management. In response, we developed a delivery system exhibiting dual specificity for both tumors and mitochondria. This system facilitated the sequential administration of small interfering B-cell lymphoma-2 (siBcl-2) and PTX to the tumor cytoplasm and mitochondria, respectively, with the aim of surmounting PTX resistance in tumor cells through the activation of the mitochondrial apoptosis pathway. Notably, we employed genetic engineering techniques to fabricate a recombinant ferritin containing the H-subunit (HFn), known for its tumor-targeting capabilities, for loading siBcl-2. This HFn-siBcl-2 complex was then combined with positively charged Triphenylphosphine-Liposome@PTX (TL@PTX) nanoparticles (NPs) to formulate HFn/siBcl-2@TL/PTX. Guided by HFn, these nanoparticles efficiently entered cells and released siBcl-2 through the action of triphenylphosphine (TPP)-mediated "proton sponge," thereby precisely modulating the expression of Bcl-2 protein. Simultaneously, PTX was directed to the mitochondria through the accurate targeting of TL@PTX, synergistically initiating the mitochondrial apoptosis pathway and effectively suppressing PTX resistance both in vitro and in vivo. In conclusion, the development of this dual-targeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments., Competing Interests: Competing interests statement:The authors declare no competing interest.

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.

Lamellarins are polyaromatic alkaloids isolated from marine organisms, including mollusks, tunicates, and sponges. Currently, over 60 structurally distinct natural lamellarins have been reported, and most of them exhibit promising biological activities, such as topoisomerase inhibition, mitochondrial function inhibition, multidrug resistance reversing, and anti-HIV activity. There has also been a significant progress on the synthetic study of lamellarins which has been regularly updated by numerous medicinal chemists as well. This review provides a detailed summary of the synthesis, pharmacology, and structural modification of lamellarins over the past decades., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Small multidrug resistance transporters efflux toxic compounds from bacteria and are a minimal system to understand multidrug transport. Most previous studies have focused on EmrE, the model SMR from Escherichia coli, finding that EmrE has a broader substrate profile than previously thought and that EmrE may perform multiple types of transport, resulting in substrate-dependent resistance or susceptibility. Here, we performed a broad screen to identify potential substrates of three other SMRs: PAsmr from Pseudomonas aeruginosa; FTsmr from Francisella tularensis; and SAsmr from Staphylococcus aureus. This screen tested metabolic differences in E. coli expressing each transporter versus an inactive mutant, for a clean comparison of sequence and substrate-specific differences in transporter function, and identified many substrates for each transporter. In general, resistance compounds were charged, and susceptibility substrates were uncharged, but hydrophobicity was not correlated with phenotype. Two resistance hits and two susceptibility hits were validated via growth assays and IC50 calculations. Susceptibility is proposed to occur via substrate-gated proton leak, and the addition of bicarbonate antagonizes the susceptibility phenotype, consistent with this hypothesis., (© 2024 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict to interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mexico is an important producer/exporter of cattle and cattle products. In the last decade, an increase in antibiotic resistance in E. coli pathotype strains from livestock environments has been reported. This study aimed to determine the prevalence and antibiotic resistance profiles of E. coli pathotype strains from the feces of beef or dairy cattle reared in the states of Aguascalientes (AG, central) and Nuevo Leon (NL, northeastern) in Mexico. One hundred and ten fecal samples were collected (beef cattle-AG = 30; dairy cattle-AG = 20; beef cattle-NL = 30; dairy cattle-NL = 30). From these, E. coli was isolated using selective/differential media and confirmed on chromogenic media. Multiplex PCR was used to identify diarrheagenic E. coli, and the Kirby-Bauer technique was used to determine the antimicrobial susceptibilities. All the animals harbored E. coli, and pathotypes were found in 34 animals from both, beef and dairy cattle, mainly from Aguascalientes. Of the positive samples, 31 harbored a single E. coli pathotype, whereas three samples harbored two different pathotypes; EHEC was the most prevalent, followed by EPEC, ETEC, and EIEC or the combination of two of them in some samples. Most pathotype strains (19/37) were isolated from beef cattle. Neither the animals' productive purpose (beef or dairy cattle) (r = 0.155) nor the geographic regions (Aguascalientes or Nuevo Leon) (r = -0.066) had a strong positive correlation with the number of E. coli pathotype strains. However, animals reared in Aguascalientes had up to 8.5-fold higher risk of harboring E. coli pathotype strains than those reared in Nuevo Leon. All pathotype strains were resistant to erythromycin, tetracycline, and trimethoprim/sulfamethoxazole, and all dairy cattle pathotype strains were further resistant to five β-lactams (χ 2 , P = 0.017). The existence of these pathotypes and multidrug-resistant pathogens in the food chain is a risk to public health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC 50 values ranging from 7.0 to 41.1 μM and 3.2 to 45.5 μM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Three new annonaceous acetogenins, annotemoyin L ( 1 ), annotemoyin Y ( 2 ) and annotemoyin X, ( 3 ) were isolated from the seeds of Annona squamosa Linn. Their structures were ascertained by chemical methods and spectral data. The cytotoxic activities of compounds against three multidrug-resistant cancer cell lines were evaluated, and compound 3 exerted strong cytotoxicity against SMMC 7721/ADR (IC 50 0.163 μM), A549/T (IC 50 0.064 μM) and MCF-7/ADR (IC 50 0.057 μM).

Introduction: The use of antibiotics in humans, animal husbandry and veterinary activities induces selective pressure leading to the colonization and infection by resistant strains. Objective: We evaluated water samples collected from rivers of the Guanabara Bay, which have suffered minor and major environmental degradation, and clinical samples of hospital origin to detect evidence of the presence of resistance genes to aminoglycosides, beta-lactam antibiotics and fluoroquinolones in strains of Klebsiella pneumoniae subsp. pneumoniae, K. pneumoniae subsp. ozaenae and Escherichia coli. Materials and methods: For isolation of the water strains we employed culture media containing 32 μg/ml cephalotin and 8 μg/ml gentamicin. The strains from clinical materials were selected using culture media containing 8 μg/ml gentamicin. The strains were identified and subjected to antimicrobial susceptibility testing (AST), plasmid DNA extraction and polymerase chain reaction (PCR) to detect genes encoding enzymes modifying aminoglycosides (EMA), extended-spectrum beta-lactamases (ESBL) and plasmid mechanisms of quinolone resistance (PMQR). Results: The AST of the isolates recovered from water samples showed multidrugresistance profiles similar to those found in isolates recovered from clinical materials. All isolates from water samples and 90% of the isolates from clinical samples showed at least one plasmid band. In the PCR assays, 7.4% of the isolates recovered from water samples and 20% of those from clinical materials showed amplification products for the three antimicrobial classes. Conclusion: We believe that the detection of microorganisms presenting genetic elements in environments such as water is necessary for the prevention and control of their dissemination with potential to infect humans and other animals in eventual contact with these environments.

P-glycoprotein (P-gp) imparts multi-drug resistance (MDR) on the cancers cell and malignant tumor clinical therapeutics. We report a class of newly designed and synthesized oxygen-heterocyclic-based pyran analogues (4a-l) bearing different aryl/hetaryl-substituted at the 1-postion were synthesized, aiming to impede the P-gp function. These compounds (4a-l) have been tested against cancerous PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines as well as non-cancerous HFL-1 and WI-38 cell lines to determine their anti-proliferative potency.The findings demonstrated the superior potency of 4a-c with 4-F, 2-Cl, and 3-Cl derivatives and 4h,g with 4-NO 2 , 4-MeO derivatives against PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines.Compounds 4a-c were tested for P-gp inhibition and demonstrated significant vigour against MCF-7/ADR cells with IC 50  = 5.0-10.7 μM. The Rho123 accumulation assay showed that compounds 4a-c adequately inhibited P-gp function, as predicted. Furthermore, 4a or 4b administration resulted in MCF-7/ADR cell accumulation in the S phase, while compound 4c induced apoptosis by causing cell cycle arrest at G2/M. The molecular docking was applied to understand the likely modes of action and guide us in the rational design of more potent analogs. The investigate derivatives showed their good binding potential for p-gp active site with excellent docking scores and interactions. Finally, the majority of investigated derivatives 4a-c derivatives showed high oral bioavailability, but they did not cross the blood-brain barrier. These results suggest that they have favorable pharmacokinetic properties. Therefore, these compounds could serve as leads for designing more potent and stable drugs in the future., (© 2024. The Author(s).)

Inspired by the structure of dysoxylactam A (DLA) that has been demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) effectively, 61 structurally simplified cyclolipopeptides were thus designed and synthesized via an effective method, and their reversing P-gp-mediated MDR potentials were evaluated, which provided a series of more potent analogues and allowed us to explore their structure-activity relationship (SAR). Among them, a well-simplified compound, 56 , with only two chiral centers that all derived from amino acids dramatically reversed drug resistance in KBV200 cells at 10 μM in combination with vinorelbine (VNR), paclitaxel (PTX), and adriamycin (ADR), respectively, which is more promising than DLA. The mechanism study showed that 56 reversed the MDR of tumor cells by inhibiting the transport function of P-gp rather than reducing its expression. Notably, compound 56 effectively restored the sensitivity of MDR tumors to VNR in vivo at a dosage without obvious toxicity.

Overuse of antibiotics during coronavirus disease 2019 (COVID-19) in an attempt to reduce COVID-19 mortality in the short term may have contributed to long-term mortality from antimicrobial resistance (AMR). The aim of this study was to evaluate the impact of the COVID-19 pandemic on AMR in Egypt and map the distribution of multidrug-resistant (MDR) and extensive drug-resistant (XDR) across Egypt. Through a multicenter cross-sectional study 2430 culture results were collected in 2019 and 2022 pre and post-COVID-19 pandemic in Egypt, including 400 Klebsiella pneumoniae, 760 Escherichia coli, 650 Acinetobacter baumannii, and 620 Methicillin-resistant staphylococcus aureus (MRSA) culture results. MDR and XDR culture results distribution across Egypt was highlighted through the geographic information system. Mixed effect logistic regression models and sub-group analysis were performed according to the type of specimens to test the impact of COVID-19 on resistance. Adjusted analysis demonstrated K. pneumoniae resistance has increased against quinolones and carbapenems (P < 0.001). Resistance of E. coli has increased significantly against imipenem and meropenem. While E.coli susceptibility has increased to cefoxitin, levofloxacin, and ciprofloxacin. A. baumannii resistance has increased more than double against ceftazidime, cefepime, and piperacillin-tazobactam (P < 0.001). MRSA reserved its susceptibility to vancomycin and linezolid. MDR K. pneumoniae and A. baumannii have increased post-COVID-19 from 67% to 94% and from 79% to 98%, respectively (P < 0.001). XDR K. pneumoniae and A. baumannii have increased from 6% to 46%, and from 47% to 69%, respectively (P < 0.001). COVID-19 has changed the profile of AMR in Egypt so that urgent action is required to mitigate this threat and preserve our capacity to face infections in future decades., (© 2024. The Author(s).)

Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H 2 O 2 . In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H 2 O 2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H 2 O 2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers., Aim of the Study: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells., Methods: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480 R ) to study the biological effect of annonacin, in reversing drug resistance in these cells., Results: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin., Conclusion: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

RNA polymerase II transcription elongation directs an intricate pattern of histone modifications. This pattern includes a regulatory cascade initiated by the elongation factor Rtf1, leading to monoubiquitylation of histone H2B, and subsequent methylation of histone H3 on lysine 4. Previous studies have defined the molecular basis for these regulatory relationships, but it remains unclear how they regulate gene expression. To address this question, we investigated a drug resistance phenotype that characterizes defects in this axis in the model eukaryote Schizosaccharomyces pombe (fission yeast). The mutations caused resistance to the ribonucleotide reductase inhibitor hydroxyurea (HU) that correlated with a reduced effect of HU on dNTP pools, reduced requirement for the S-phase checkpoint, and blunting of the transcriptional response to HU treatment. Mutations in the C-terminal repeat domain of the RNA polymerase II large subunit Rpb1 led to similar phenotypes. Moreover, all the HU-resistant mutants also exhibited resistance to several azole-class antifungal agents. Our results suggest a novel, shared gene regulatory function of the Rtf1-H2Bub1-H3K4me axis and the Rpb1 C-terminal repeat domain in controlling fungal drug tolerance., (© 2024 Chen et al.)

Elesclomol (ES), a copper-binding ionophore, forms an ES-Cu complex with copper ions (Cu(II)). ES-Cu has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, ES-Cu is poorly water-soluble, and its delivery to various cancer cells is a challenge. Herein, we designed a d-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS-CA)-based micellar nanoparticle for delivering the ES-Cu complex to various cancer cell lines to demonstrate its efficacy as an anticancer agent. The ES-Cu nanoparticles exerted high encapsulation efficiency and excellent serum stability. The anticancer efficacy of ES-Cu nanoparticles was evaluated in various drug-sensitive cell lines (DU145, PC3, and A549) and drug-resistant cell lines (DU145TXR, PC3TXR, and A549TXR). The results showed that ES-Cu nanoparticles exerted potent anticancer activities in both drug-sensitive and drug-resistant cell lines. The Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and molecular docking results suggested that ES-Cu is not a substrate for P glycoprotein (P-gp), which is an efflux transporter potentially causing multidrug resistance (MDR) in cancer cells. ES-Cu nanoparticles could bypass P-gp without compromising their activity, indicating that they may overcome MDR in cancer cells and provide a novel therapeutic strategy. Additionally, the extracellular matrix of ES-Cu nanoparticles-pretreated drug-resistant cells could polarize Raw 264.7 macrophages into the M1 phenotype. Therefore, our TPGS/CS-CA-based ES-Cu nanoparticles provide an effective method of delivering the ES-Cu complex, a promising strategy to overcome MDR in cancer therapy with potential immune response stimulation.