-
Parasitology Research May 2024Ivermectin mass drug administration has been used for decades to target human and veterinary ectoparasites, and is currently being considered for use against malaria... (Review)
Review
Ivermectin mass drug administration has been used for decades to target human and veterinary ectoparasites, and is currently being considered for use against malaria vectors. Although there have been few reports of resistance to date in human ectoparasites, we must anticipate the development of resistance in mosquitoes in the future. Hence, through this review, we mapped the existing evidence on ivermectin resistance mechanisms in human ectoparasites. A search was conducted on the 8th November 2023 through databases, PubMed, Web of Science, and Google Scholar, using terms related to ivermectin, human and veterinary ectoparasites, and resistance. Abstracts (5893) were screened by JFA and CK. Data on the study organism, the type of resistance, the analysis methods, and, where applicable, the gene loci of interest were extracted from the studies. Details of the methodology and results of each study were summarised narratively and in a table. Eighteen studies were identified describing ivermectin resistance in ectoparasites. Two studies described target site resistance; and 16 studies reported metabolic resistance and/or changes in efflux pump expression. The studies investigated genetic mutations in resistant organisms, detoxification, and efflux pump expression in resistant versus susceptible organisms, and the effect of synergists on mortality or detoxification enzyme/efflux pump transcription. To date, very few studies have been conducted examining the mechanisms of ivermectin resistance in ectoparasites, with only two on Anopheles spp. Of the existing studies, most examined detoxification and efflux pump gene expression, and only two studies in lice investigated target-site resistance. Further research in this field should be encouraged, to allow for close monitoring in ivermectin MDA programmes, and the development of resistance mitigation strategies.
Topics: Ivermectin; Animals; Humans; Drug Resistance; Insecticides; Ectoparasitic Infestations; Insecticide Resistance
PubMed: 38787430
DOI: 10.1007/s00436-024-08223-z -
Medical Principles and Practice :... 2024The success in determining the whole genome sequence of a bacterial pathogen was first achieved in 1995 by determining the complete nucleotide sequence of Haemophilus... (Review)
Review
The success in determining the whole genome sequence of a bacterial pathogen was first achieved in 1995 by determining the complete nucleotide sequence of Haemophilus influenzae Rd using the chain-termination method established by Sanger et al. in 1977 and automated by Hood et al. in 1987. However, this technology was laborious, costly, and time-consuming. Since 2004, high-throughput next-generation sequencing technologies have been developed, which are highly efficient, require less time, and are cost-effective for whole genome sequencing (WGS) of all organisms, including bacterial pathogens. In recent years, the data obtained using WGS technologies coupled with bioinformatics analyses of the sequenced genomes have been projected to revolutionize clinical bacteriology. WGS technologies have been used in the identification of bacterial species, strains, and genotypes from cultured organisms and directly from clinical specimens. WGS has also helped in determining resistance to antibiotics by the detection of antimicrobial resistance genes and point mutations. Furthermore, WGS data have helped in the epidemiological tracking and surveillance of pathogenic bacteria in healthcare settings as well as in communities. This review focuses on the applications of WGS in clinical bacteriology.
Topics: Humans; Whole Genome Sequencing; Genome, Bacterial; Drug Resistance, Bacterial; High-Throughput Nucleotide Sequencing
PubMed: 38402870
DOI: 10.1159/000538002 -
International Wound Journal Oct 2023To assist orthopaedic surgeons in choosing appropriate antibiotics, this study attempted to identify the common microorganisms that cause periprosthetic joint infection...
To assist orthopaedic surgeons in choosing appropriate antibiotics, this study attempted to identify the common microorganisms that cause periprosthetic joint infection (PJI) and their respective drug resistance spectrums. The clinical data of 202 patients with PJI after primary hip and knee arthroplasty between January 2017 and December 2021 were retrospectively analysed. There were 84 males and 118 females, aged (63.03 ± 13.10) years (range: 24-89 years). A total of 102 and 100 patients underwent total hip and total knee arthroplasty, respectively. Based on the time of postoperative infection, the patients were divided into acute (25 cases), delayed (91 cases), and chronic (86 cases) PJI groups. The results of pathogen species, composition ratio, and drug susceptibility tests were collected. Gram-positive bacteria were the primary causative pathogens of PJI (58.91%, 119/202), and their culture-positive rates in patients with acute, delayed, and chronic PJI were 32.00% (8/25), 62.64% (57/91), and 62.79% (54/86), respectively. Staphylococcus epidermidis and Staphylococcus aureus were the major gram-positive bacteria detected, followed by gram-negative bacteria (29/202, 14.36%), and fungi (4/202, 1.98%). Gram-positive bacteria showed higher resistance to penicillin (81.25%), oxacillin (63.33%), erythromycin (61.17%), and clindamycin (48.35%) and 100% sensitivity to linezolid, vancomycin, daptomycin, and tigecycline. In gram-negative bacteria, the drug resistance rates to cefazolin, gentamicin, furantoin, cefuroxime, ticacillin/clavulanic acid, ceftriaxone, ciprofloxacin, and tobramycin were >50%. However, no vancomycin-resistant bacteria were discovered in the current study. The drug resistance rate to carbapenems was low, ranging from 0% to 3.57%. Gram-positive bacteria are the main causative pathogens of PJI, and the resistance rate of pathogens of chronic PJI is higher than those of delayed and acute PJI. Use of cefuroxime and clindamycin in patients with PJIs should proceed with caution because of the high drug resistance rate. Vancomycin can be used as a first-line antibiotic against gram-positive bacteria. Carbapenems can be used as the first choice against gram-negative bacteria because of to their high sensitivity.
Topics: Male; Female; Humans; Retrospective Studies; Prosthesis-Related Infections; Clindamycin; Cefuroxime; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Anti-Bacterial Agents; Staphylococcus aureus; Drug Resistance; Gram-Positive Bacteria; Gram-Negative Bacteria; Carbapenems
PubMed: 37186450
DOI: 10.1111/iwj.14212 -
Nature Communications Oct 2023Approximately 10% of antimicrobials used by humans in low- and middle-income countries are estimated to be substandard or falsified. In addition to their negative impact... (Review)
Review
Approximately 10% of antimicrobials used by humans in low- and middle-income countries are estimated to be substandard or falsified. In addition to their negative impact on morbidity and mortality, they may also be important drivers of antimicrobial resistance. Despite such concerns, our understanding of this relationship remains rudimentary. Substandard and falsified medicines have the potential to either increase or decrease levels of resistance, and here we discuss a range of mechanisms that could drive these changes. Understanding these effects and their relative importance will require an improved understanding of how different drug exposures affect the emergence and spread of resistance and of how the percentage of active pharmaceutical ingredients in substandard and falsified medicines is temporally and spatially distributed.
Topics: Humans; Counterfeit Drugs; Anti-Bacterial Agents; Drug Resistance, Bacterial
PubMed: 37788991
DOI: 10.1038/s41467-023-41542-w -
Frontiers in Cellular and Infection... 2023The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies... (Review)
Review
The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies are being explored to enhance the effectiveness of antibiotics. Antibiotic adjuvants have emerged as a promising approach to combat MDR pathogens by acting synergistically with antibiotics. This review focuses on the role of antibiotic adjuvants as a synergistic tool in the fight against MDR pathogens. Adjuvants refer to compounds or agents that enhance the activity of antibiotics, either by potentiating their effects or by targeting the mechanisms of antibiotic resistance. The utilization of antibiotic adjuvants offers several advantages. Firstly, they can restore the effectiveness of existing antibiotics against resistant strains. Adjuvants can inhibit the mechanisms that confer resistance, making the pathogens susceptible to the action of antibiotics. Secondly, adjuvants can enhance the activity of antibiotics by improving their penetration into bacterial cells, increasing their stability, or inhibiting efflux pumps that expel antibiotics from bacterial cells. Various types of antibiotic adjuvants have been investigated, including efflux pump inhibitors, resistance-modifying agents, and compounds that disrupt bacterial biofilms. These adjuvants can act synergistically with antibiotics, resulting in increased antibacterial activity and overcoming resistance mechanisms. In conclusion, antibiotic adjuvants have the potential to revolutionize the treatment of MDR pathogens. By enhancing the efficacy of antibiotics, adjuvants offer a promising strategy to combat the growing threat of antibiotic resistance. Further research and development in this field are crucial to harness the full potential of antibiotic adjuvants and bring them closer to clinical application.
Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Bacteria; Adjuvants, Immunologic; Biofilms; Microbial Sensitivity Tests
PubMed: 38179424
DOI: 10.3389/fcimb.2023.1293633 -
International Journal of Molecular... Jul 2023Over the years, cancer has been affecting the lives of many people globally and it has become one of the most studied diseases. Despite the efforts to understand the... (Review)
Review
Over the years, cancer has been affecting the lives of many people globally and it has become one of the most studied diseases. Despite the efforts to understand the cell mechanisms behind this complex disease, not every patient seems to respond to targeted therapies or immunotherapies. Drug resistance in cancer is one of the limiting factors contributing to unsuccessful therapies; therefore, understanding how cancer cells acquire this resistance is essential to help cure individuals affected by cancer. Recently, the altered microbiome was observed to be an important hallmark of cancer and therefore it represents a promising topic of cancer research. Our review aims to provide a global perspective of some cancer hallmarks, for instance how genetic and epigenetic modifications may be caused by an altered human microbiome. We also provide information on how an altered human microbiome can lead to cancer development as well as how the microbiome can influence drug resistance and ultimately targeted therapies. This may be useful to develop alternatives for cancer treatment, i.e., future personalized medicine that can help in cases where traditional cancer treatment is unsuccessful.
Topics: Humans; Gastrointestinal Microbiome; Carcinogenesis; Microbiota; Neoplasms; Drug Resistance
PubMed: 37511612
DOI: 10.3390/ijms241411855 -
Journal of Molecular Cell Biology Nov 2023Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells...
Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81, two 'stemness' cell surface markers, are highly enriched in CCCs. Furthermore, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81- cells. Transcriptome profiling identified UGT1A10, shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance. From a high-content chemical screen, we identified Cymarin, which downregulates UGT1A10, eliminates TRA-1-60/TRA-1-81 expression, and increases chemosensitivity both in vitro and in vivo. Finally, TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival, which highlights their potentiality for targeted therapy. Therefore, we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance, as well as a leading drug candidate to target this pathway.
Topics: Humans; Cell Line, Tumor; Drug Resistance, Neoplasm; Pancreatic Neoplasms; Gene Expression Profiling
PubMed: 37327088
DOI: 10.1093/jmcb/mjad039 -
Biomedicine & Pharmacotherapy =... Dec 2023Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may...
Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may develop resistance to chemotherapeutics in time due to inter alia overexpression of ATP-binding cassette transporters. Using clinically-relevant resistant models of triple negative breast cancer (MDA-MB-231; TNBC) as well as non-small cell lung cancer (A549; NSCLC), we tested the efficacy of I-CBP112 - CBP/EP300 bromodomain inhibitor to overcome drug resistance by declining ABC gene transcription. I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures. This was phenocopied only by the joint effect of ABC inhibitors such as tariquidar (ABCB1 - P-glycoprotein and ABCG2) and MK-571 (ABCC), whereas single inhibition of ABCB1/ABCG2 or ABCC proteins did not affect drug accumulation, thereby implying the need of simultaneous deficiency in activity of majority of drug pumps for enhanced drug retention. I-CBP112 failed to directly inhibit activity of ABCB1, ABCG2 and ABCC subfamily members at the same time. Importantly, I-CBP112 treated cancer cells polarized human macrophages into proinflammatory phenotypes. Moreover, I-CBP112 remained non-toxic to primary cell lines, nor did it enhance anticancer drug toxicity to blood-immune cells. In silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.
Topics: Humans; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Carcinoma, Non-Small-Cell Lung; A549 Cells; Triple Negative Breast Neoplasms; Drug Resistance, Neoplasm; Lung Neoplasms; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37913733
DOI: 10.1016/j.biopha.2023.115798 -
American Journal of Veterinary Research Dec 2023To understand the comparative concerns and perceptions of veterinary and medical health professionals regarding antimicrobial resistance (AMR) and its effects on their...
OBJECTIVE
To understand the comparative concerns and perceptions of veterinary and medical health professionals regarding antimicrobial resistance (AMR) and its effects on their clinical practices.
SAMPLE
17 Doctors of medicine and veterinary medicine and 1 nurse practitioner were interviewed to collect qualitative-based data regarding their clinical experience with AMR.
METHODS
The interviews from the health professionals were transcribed and thematically coded to reveal 3 overarching themes and 7 corresponding subthemes.
RESULTS
Both veterinary and human medical health professionals share concerns about antimicrobial resistance, specifically regarding the development of "superbugs" and increased difficulty in treating disease. However, there were some unique differences in the clinical effects of AMR between the professions in relation to client demand and satisfaction, ability to track/test trends, and approaches to therapy. Both professions also discussed the possible one-health implications of AMR and its transmission.
CLINICAL RELEVANCE
There are several barriers to veterinarians that prevent them from using best-practice methods with antimicrobials that were not shared with human medical personnel, who can use antibiotic stewardship principles and readily access necessary testing. However, many veterinarians possessed a unique one-health-based understanding of how antimicrobial resistance can affect the wider community across species and globally that many human medical professionals had not previously considered. This demonstrates an increased need for one-health understanding within human medical professionals and a need for veterinarians to have access to necessary tools to comply with stewardship guidelines, such as culture and sensitivity testing and antibiograms, to have the ability to limit their contribution to antibiotic resistance.
Topics: Humans; Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Health Personnel; Anti-Infective Agents; Veterinarians
PubMed: 38041944
DOI: 10.2460/ajvr.23.06.0121 -
Scientific Reports Dec 2023The important hypothesis that organic livestock management reduces the prevalence of antimicrobial resistance is either fiercely supported or bitterly contested. Yet,...
The important hypothesis that organic livestock management reduces the prevalence of antimicrobial resistance is either fiercely supported or bitterly contested. Yet, empirical evidence supporting this view remains fragmentary, in part because relationships between antimicrobial use and drug resistance vary dramatically across contexts, hosts, pathogens, and country-specific regulations. Here, we synthesize global policies and definitions of 'organic' and ask if organic farming results in notable reductions in the prevalence of antimicrobial resistance when directly examined alongside conventional analogs. We synthesized the results of 72 studies, spanning 22 countries and five pathogens. Our results highlight substantial variations in country-specific policies on drug use and definitions of 'organic' that hinder broad-scale and generalizable patterns. Overall, conventional farms had slightly higher levels of antimicrobial resistance (28%) relative to organic counterparts (18%), although we found significant context-dependent variation in this pattern. Notably, environmental samples from organic and conventional farms often exhibited high levels of resistance to medically important drugs, underscoring the need for more stringent and consistent policies to control antimicrobial contaminants in the soil (particularly on organic farms, where the application of conventional manure could faciliate the spread antimicrobial resistance). Taken together, these results emphasize the challenges inherent in understanding links between drug use and drug resistance, the critical need for global standards governing organic policies, and greater investment in viable alternatives for managing disease in livestock.
Topics: Animals; Anti-Bacterial Agents; Farms; Drug Resistance, Bacterial; Anti-Infective Agents; Organic Agriculture; Livestock
PubMed: 38114527
DOI: 10.1038/s41598-023-47862-7