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Journal of Global Antimicrobial... Sep 2023Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin,...
OBJECTIVES
Mycobacterium avium (M. avium) complex bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and consists of a macrolide, a rifamycin, and ethambutol, and in severe cases, amikacin. Mechanisms of antibiotic tolerance remain mostly unknown. Therefore, we studied the contribution of efflux and amikacin modification to antibiotic susceptibility.
METHODS
We characterised M. avium ABC transporters and studied their expression together with other transporters following exposure to clarithromycin, amikacin, ethambutol, and rifampicin. We determined the effect of combining the efflux pump inhibitors berberine, verapamil and CCCP (carbonyl cyanide m-chlorophenyl hydrazone), to study the role of efflux on susceptibility. Finally, we studied the modification of amikacin by M. avium using metabolomic analysis.
RESULTS
Clustering shows conservation between M. avium and M. tuberculosis and transporters from most bacterial subfamilies (2-6, 7a/b, 10-12) were found. The largest number of transporter encoding genes was up-regulated after clarithromycin exposure, and the least following amikacin exposure. Only berberine increased the susceptibility to clarithromycin. Finally, because of the limited effect of amikacin on transporter expression, we studied amikacin modification and showed that M. avium, in contrast to M. abscessus, is not able to modify amikacin.
CONCLUSION
We show that M. avium carries ABC transporters from all major families important for antibiotic efflux, including homologues shown to have affinity for drugs included in treatment. Efflux inhibition in M. avium can increase susceptibility, but this effect is efflux pump inhibitor- and antibiotic-specific. Finally, the lack of amikacin modifying activity in M. avium is important for its activity.
Topics: Humans; Amikacin; Mycobacterium avium; Clarithromycin; Ethambutol; Berberine; Anti-Bacterial Agents; Mycobacterium avium Complex; Membrane Transport Proteins; Mycobacterium tuberculosis; ATP-Binding Cassette Transporters
PubMed: 37453496
DOI: 10.1016/j.jgar.2023.07.007 -
Frontiers in Pharmacology 2024Once hailed as miraculous solutions, antibiotics no longer hold that status. The excessive use of antibiotics across human healthcare, agriculture, and animal husbandry... (Review)
Review
Once hailed as miraculous solutions, antibiotics no longer hold that status. The excessive use of antibiotics across human healthcare, agriculture, and animal husbandry has given rise to a broad array of multidrug-resistant (MDR) pathogens, posing formidable treatment challenges. Antimicrobial resistance (AMR) has evolved into a pressing global health crisis, linked to elevated mortality rates in the modern medical era. Additionally, the absence of effective antibiotics introduces substantial risks to medical and surgical procedures. The dwindling interest of pharmaceutical industries in developing new antibiotics against MDR pathogens has aggravated the scarcity issue, resulting in an exceedingly limited pipeline of new antibiotics. Given these circumstances, the imperative to devise novel strategies to combat perilous MDR pathogens has become paramount. Contemporary research has unveiled several promising avenues for addressing this challenge. The article provides a comprehensive overview of these innovative therapeutic approaches, highlighting their mechanisms of action, benefits, and drawbacks.
PubMed: 38420197
DOI: 10.3389/fphar.2024.1347750 -
Sleep Medicine Dec 2023Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and...
STUDY OBJECTIVES
Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.
METHODS
Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.
RESULTS
41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.
CONCLUSION
Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.
CLINICAL TRIAL REGISTRATION NUMBER
Clinical Trials.gov Identifier NCT05321355.
Topics: Humans; Modafinil; Quality of Life; Narcolepsy; Piperidines; Disorders of Excessive Somnolence; Benzhydryl Compounds
PubMed: 37839272
DOI: 10.1016/j.sleep.2023.10.005 -
Cancer Reports (Hoboken, N.J.) Sep 2023Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized... (Review)
Review
BACKGROUND
Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.
RECENT FINDINGS
Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed.
CONCLUSION
Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.
Topics: Humans; Neoplasms; Polymorphism, Genetic
PubMed: 37150853
DOI: 10.1002/cnr2.1830 -
Frontiers in Microbiology 2023The current opioid pandemic is a major public health crisis in the United States, affecting millions of people and imposing significant health and socioeconomic burdens.... (Review)
Review
The current opioid pandemic is a major public health crisis in the United States, affecting millions of people and imposing significant health and socioeconomic burdens. Preclinical and clinical research over the past few decades has delineated certain molecular mechanisms and identified various genetic, epigenetic, and environmental factors responsible for the pathophysiology and comorbidities associated with opioid use. Opioid use-induced epigenetic modifications have been identified as one of the important factors that mediate genetic changes in brain regions that control reward and drug-seeking behavior and are also implicated in the development of tolerance. Recently, it has been shown that opioid use results in microbial dysbiosis, leading to gut barrier disruption, which drives systemic inflammation, impacting the perception of pain, the development of analgesic tolerance, and behavioral outcomes. In this review, we highlight the potential role of microbiota and microbial metabolites in mediating the epigenetic modifications induced by opioid use.
PubMed: 37670983
DOI: 10.3389/fmicb.2023.1233194 -
Diabetes, Metabolic Syndrome and... 2023To investigate the change in hypothalamic kisspeptin-1 (Kiss1) expression during the development of polycystic ovary syndrome (PCOS) and hypoglycemic drug intervention.
BACKGROUND
To investigate the change in hypothalamic kisspeptin-1 (Kiss1) expression during the development of polycystic ovary syndrome (PCOS) and hypoglycemic drug intervention.
METHODS
Letrozole lavage was used to construct a polycystic ovary rat model. After successful modeling, we treated PCOS rats with metformin, pioglitazone, and acarbose, and we then observed changes in weight, estrus, glucose tolerance, insulin resistance, sex hormones, and hypothalamic kiss1 expression.
RESULTS
PCOS rats exhibited increased body weight, abnormal estrous cycle, impaired glucose tolerance, insulin resistance, increased testosterone level, increased luteinizing hormone level, and increased Kiss1 expression in the hypothalamus. However, intervention with metformin, pioglitazone, and acarbose improved the reproductive and metabolic disorders as well as reduced hypothalamic Kiss1 expression.
CONCLUSION
The expression of hypothalamic Kiss1 may play an important role in the pathogenesis of PCOS. Metformin, pioglitazone, and acarbose may reduce the expression of hypothalamic Kiss1 by improving insulin resistance, thereby improving reproductive and metabolic disorders in PCOS rats.
PubMed: 37701721
DOI: 10.2147/DMSO.S421911 -
EMBO Reports Aug 2023Recalcitrant infections pose a serious challenge by prolonging antibiotic therapies and contributing to the spread of antibiotic resistance, thereby threatening the... (Review)
Review
Recalcitrant infections pose a serious challenge by prolonging antibiotic therapies and contributing to the spread of antibiotic resistance, thereby threatening the successful treatment of bacterial infections. One potential contributing factor in persistent infections is antibiotic persistence, which involves the survival of transiently tolerant subpopulations of bacteria. This review summarizes the current understanding of antibiotic persistence, including its clinical significance and the environmental and evolutionary factors at play. Additionally, we discuss the emerging concept of persister regrowth and potential strategies to combat persister cells. Recent advances highlight the multifaceted nature of persistence, which is controlled by deterministic and stochastic elements and shaped by genetic and environmental factors. To translate in vitro findings to in vivo settings, it is crucial to include the heterogeneity and complexity of bacterial populations in natural environments. As researchers continue to gain a more holistic understanding of this phenomenon and develop effective treatments for persistent bacterial infections, the study of antibiotic persistence is likely to become increasingly complex.
Topics: Humans; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Biological Evolution; Environment; Drug Resistance, Bacterial
PubMed: 37395716
DOI: 10.15252/embr.202357309 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2023Desensitization therapy for iodinated contrast media (ICM) aims to induce drug tolerance in patients with a history of severe allergic reactions to ICM in a short time.... (Review)
Review
Desensitization therapy for iodinated contrast media (ICM) aims to induce drug tolerance in patients with a history of severe allergic reactions to ICM in a short time. Currently, there is no widely accepted consensus on inducing desensitization to avoid severe allergic responses to ICM. The clinically successful cases have shown that prophylactic use of antihistamines and glucocorticoids can increase the desensitization effect; repeatedly desensitizing and gradually increasing the dose can be conducive to establishing better tolerance to ICM. Most desensitization effects, including stress resistance, can endure 24-48 h. The mechanisms of desensitization therapy remain unclear, the initial dose, administration interval and dose gradient are largely based on clinical experiences and the reaction of patients. This article reviews the current research progress on ICM-related allergies, desensitization methods and related mechanisms, as well as the benefits and hazards of desensitization, to provide a reference for desensitization treatment of hypersensitivity to ICM .
Topics: Humans; Contrast Media; Consensus; Glucocorticoids; Hypersensitivity
PubMed: 37643986
DOI: 10.3724/zdxbyxb-2023-0220 -
Annals of Medicine Dec 2023More than half of the metastatic breast cancer patients with brain metastases (BCBM) are HER-2 negative, and the prognosis of HER2-negative BCBM is dismal. But few...
BACKGROUND
More than half of the metastatic breast cancer patients with brain metastases (BCBM) are HER-2 negative, and the prognosis of HER2-negative BCBM is dismal. But few clinical trials have investigated systemic therapies for this subgroup of patients.
METHODS
This real-world study included 58 HER2-negative BCBMs who received low-dose apatinib (250 mg daily) in combination with chemotherapy between 18 March 2017 and 31 December 2021. The objective response rate (ORR) of the central nervous system, clinical benefit rate (CBR), progression-free survival of central nervous system (CNS-PFS) and overall survival (OS) were analyzed. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for CNS-PFS and OS.
RESULTS
At the cut-off date, the median follow-up time was 28.2 months. Of the 58 patients, 36 patients were HR+/HER2-, and 22 patients were TNBC. The CNS-ORR was 17.2% (95%CI 9.6% to 28.9%) and the CBR was 53.4% (95%CI 40.8% to 65.7%). The median duration of CNS-PFS for the entire cohort was 6.4 months, and the median OS was 10.7 months. The median CNS-PFS and OS were not affected by hormone receptor status, disease-free survival, the number of prior lines of therapy and local treatment. The most common grade 2-3 adverse events associated with low-dose apatinib were hypertension (20.6%), elevated bilirubin (10.4%), hypothyroidism (10.3%), and hand-foot skin reaction (10.3%).
CONCLUSION
Apatinib-based chemotherapy demonstrates potential feasibility with acceptable tolerance for HER2-negative BCBM. Its clinical application in BCBM still needs further verification.
Topics: Humans; Female; Breast Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms
PubMed: 37260331
DOI: 10.1080/07853890.2023.2218647 -
Frontiers in Cellular and Infection... 2023As a probiotic, enterococcus faecium (E. faecium) has the characteristics of high temperature resistance, gastric acid resistance, bile salt resistance, etc. It can also... (Review)
Review
As a probiotic, enterococcus faecium (E. faecium) has the characteristics of high temperature resistance, gastric acid resistance, bile salt resistance, etc. It can also effectively improve animal performance and immunity and improve the animal's intestinal environment, so in recent years it has been more widely used in the livestock industry. However, due to the improper use of antibiotics and the growing environmental stress of strains, the drug resistance of enterococcus faecium has become more and more serious, and because some enterococcus faecium carry virulence genes, leading to the emergence of pathogenic strains, its safety issues have been widely concerned. This paper focuses on the biological characteristics of enterococcus faecium, the application of this bacterium in animal husbandry and the safety issues in its use, with a view to providing a reference for the application of enterococcus faecium in the development of animal husbandry.
Topics: Animals; Enterococcus faecium; Animal Husbandry; Anti-Bacterial Agents; Bile Acids and Salts; Livestock
PubMed: 37600940
DOI: 10.3389/fcimb.2023.1168189