Resistance mechanisms

During the past decade, there has been extensive investigation of bacterial resistance mechanisms.The interplay of genetic and antibiotic factors on antibiotic resistance are multiple and complex. Antibiotic resistance is the clinical expression of these factors. This article reviews the most studied and understood mechanisms of resistance in bacterial species in which resistance problems have clinical significance. Besides plasmid mediated resistance some resistance problems among respiratory pathogens are clonal resistance. The precise cause of this actual genetic event causing bacterial mutation recombination and selection is not always clear. Although resistance mechanisms may be identical within an antibiotic class, expression of resistance often varies among antibiotics of the same class.     

Antibiotics and Resistance of Uropathogens

This article shall give an overview of the commonly used antibiotics in urological practice, their resistance rates and the resistance mechanisms of uropathogens. The bacterial spectrum of urinary tract infections and the resistance rates of uncomplicated community acquired and complicated, nosocomially acquired uropathogens can differ substantially from region to region and over time. The results from different surveillance studies are evaluated and exemplary the resistance rates of uropathogens in the last ten years of our institution are reflected. Especially the increasing resistance of enterobacteria to fluoroquinolones is notable. Antibiotics are widely used in urological practice for the need of modern medicine and therefore antibiotic resistance is of increasing importance for the urologist. Knowledge of resistance rates is paramount for empirical antimicrobial therapy. A basic understanding of the resistance mechanisms is of great help in this respect.     

Resistance to vitamin K antagonists. 6 cases

Haemorrhage is the most frequent complication of oral anticoagulant therapy (OAT) and a resistance to these drugs is rarely reported. The following classification of OAT resistance is proposed: primary or secondary resistance according to the delay of onset (at the initiation of therapy or later); selective or generalized according to the number of drugs involved (only one or several); absolute or relative as judged by the prolongation of the prothrombin time (absent or moderate). Six cases are reported and the mechanisms of resistance are discussed: no intake, variations in the vitamin K availability (diet, intestinal absorption and synthesis of vitamin K), variations in the pharmacokinetics of oral anticoagulants (drug interactions, abnormal hepatic metabolism) and variations in the receptor affinity (hereditary resistance). Resistance is often overcome by progressive increase of the doses of oral coagulant, or by changing drugs, to warfarin or coumadin (long acting drugs).     

氯吡格雷抵抗研究现状

氯吡格雷对血小板的抑制作用具有个体差异性。氯吡格雷抵抗是指那些接受了标准的抗血小板治疗的病人仍然发生不良的心血管事件。导致氯吡格雷抵抗的原因是多方面的,主要有P2Y12受体及CYP3A的基因多态性、药物吸收及活性代谢物清除的个体差异、血小板高反应性等。目前对氯吡格雷抵抗仍然缺乏统一的标准,正确认识、发现、解决氯吡格雷抵抗需要更深入的研究。     

Resistance to the organophosphate temephos: Mechanisms, evolution and reversion in an Aedes aegypti laboratory strain from Brazil

Insecticide resistance is one of the main problems in vector control programs. Because insects have developed resistance to all classes of available chemical insecticides, a proper surveillance and management of resistance in areas where these compounds are being utilized is crucial for the success of control programs. Since the mechanisms and molecular bases of resistance are various, they must be characterized to allow efficient monitoring strategies. Here we report the establishment of an Aedes aegypti strain resistant to temephos, named RecR, selected under laboratory conditions. The parental A. aegypti population was obtained from eggs collected in an area where temephos had been used for 8 years, and presented a baseline resistance ratio (RR) of 7. After 17 generations under selective pressure, the RR has increased to 180. Biochemical assays indicate that metabolic mechanisms are involved on temephos resistance in the selected strain. These experiments showed that, compared to the susceptible colony Rockefeller, RecR present higher activity of glutathione S-transferases (GSTs), α- and β-esterases, and, to a lesser degree, mixed function oxidases (MFO). At the 14th or 17th generations, there was no cross resistance of these insects to deltamethrin, cypermethrin and malathion, while a low resistance level (RR = 3) was observed for pyriproxyfen, a juvenile hormone analogue. Experiments on resistance reversal, performed through three different field simulated schemes using the resistant strain, showed that temephos susceptibility can be recovered. The establishment of an A. aegypti colony resistant to temephos is extremely valuable for a deeper understanding of resistance mechanisms and thus for further improvements in control strategies against this vector. With the urgent need on improving methodologies to monitor resistance, molecular studies such as microarrays, and resistant colonies such as RecR will certainly hasten such studies.     

Possible Mechanisms of Aspirin Resistance

Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F₂-isoprostane 8-iso-prostaglandin (PGF₂), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.     

Mechanisms of Insulin Resistance in Hypertensive Rats

Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. Recent evidence indicates that these impairments in glucose metabolism may play a role not only in the development of type 2 diabetes, but also in the onset and persistence of hypertension, dyslipidemia, and abdominal obesity. The accumulation of these risk factors constitutes a high-risk group of cardiovascular diseases, the so-called metabolic syndrome. Insulin resistance has also been reported in several animal models for hypertension, including the spontaneously hypertensive rat (SHR) and the fructose-fed rat (FFR). SHRs and FFRs have been employed in many studies to investigate the mechanisms and pathophysiology of insulin resistance and hypertension, but the precise mechanism of insulin resistance remains to be clarified. In this review, the possible mechanisms of insulin resistance in SHRs and FFRs are summarized.     

Resistance to aspirin and clopidogrel therapy

Introduction: Despite increasing evidence on the roles of aspirin and clopidogrel in decreasing morbidity and mortality from cardiovascular disease, resistance to therapy remains an emerging clinical entity. The aim of this review was to revisit current knowledge of the mechanisms, laboratory evaluation, clinical impact and management of resistance to aspirin and clopidogrel therapy. Methods: Potentially relevant studies were identified from an electronic search of MEDLINE and PubMed databases. There were no language or publication year restrictions. References in published articles were also reviewed. Results: Several definitions for resistance have been set, and various laboratory testing modalities are available. The pathophysiological mechanisms remain poorly understood; yet, several extrinsic, intrinsic and genetic factors are described. The clinical implications of this phenomenon are alarming and warrant concern. Management is currently limited to dosing alteration and introduction of other antiplatelet agents. Conclusion: Data from ongoing and future studies are awaited to better understand this entity and to highlight the most appropriate treatment strategies.     

Antimicrobial Use and Resistance

As antimicrobial use continues to rise, we are experiencing a concomitant rise in the prevalence of antimicrobial resistance. The precise relationship between use and resistance, however, has been challenging to define. Although the selection pressure exerted by antibiotic therapy appears to be the primary force promoting resistance, it is clear that the pathway to resistance is different for various organisms and antimicrobial agents. By understanding the mechanisms by which resistance emerges and spreads, it should be possible to design intervention strategies to slow or halt the process. This review summarizes some of our current understandings about the development and transmission of antibioticresistant bacteria, some of the control measures designed to interrupt the process, and how mathematical modeling can help us to better understand these complex pathways.     

氯吡格雷抵抗的现状与展望

氯吡格雷是一种广泛用于冠心病患者的抗血小板药物。但是氯吡格雷不是对所有病人都有同样效果。有些病人尽管进行了氯吡格雷治疗,依然发生了不良事件。这可以被氯吡格雷的抗血小板凝集能力下降所部分解释。一个离体研究定义这一现象为氯吡格雷无应答或抵抗。然而不管是流行病学资料还是和冠心病风险的相关性都不明朗。现对氯吡格雷抵抗的定义、影响因子、临床意义及解决的途径和问题做一综述。     

Resistance test welcomed, with caution

Murex Technologies has launched an HIV drug resistance test, LiPA HIV-1 RT, that is causing both confusion and excitement. Researchers warn that resistance testing is still in its infancy and urge that the test be used with caution. Researchers are concerned with the number of patients who are failing drug therapy after only one year. Drug failure can be caused by a number of reasons, including patient noncompliance and the ineffectiveness of the treatment. Resistance tests are being developed for both genotypic and phenotypic resistance. The mechanisms of how resistance develops, and the benefits and advantages of each type of test are discussed.     

Resistance to host antimicrobial peptides is necessary for Salmonella virulence.

The production of antibacterial peptides is a host defense strategy used by various species, including mammals, amphibians, and insects. Successful pathogens, such as the facultative intracellular bacterium Salmonella typhimurium, have evolved resistance mechanisms to this ubiquitous type of host defense. To identify the genes required for resistance to host peptides, we isolated a library of 20,000 MudJ transposon insertion mutants of a virulent peptide-resistant S. typhimurium strain and screened it for hypersensitivity to the antimicrobial peptide protamine. Eighteen mutants had heightened susceptibility to protamine and 12 of them were characterized in detail. Eleven mutants were attenuated for virulence in vivo when inoculated into BALB/c mice by the intragastric route, and 8 of them were also avirulent following intraperitoneal inoculation. The mutants fell into different phenotypic classes with respect to their susceptibility to rabbit defensin NP-1, frog magainin 2, pig cecropin P1, and the insect venom-derived peptides mastoparan and melittin. The resistance loci mapped to eight distinct locations in the genome. Characterization of the mutants showed that one had a defective lipopolysaccharide and another mutant harbored a mutation in phoP, a locus previously shown to control expression of Salmonella virulence genes. Our data indicate that the ability to resist the killing effect of host antimicrobial peptides is a virulence property and that several resistance mechanisms operate in S. typhimurium.     

胰岛素抵抗与代谢综合征

胰岛素对糖脂代谢、血压调控、血管收缩反应都有影响,胰岛素抵抗和/或代偿性高胰岛素血症可导致糖耐量异常、血脂异常、高血压、血管功能失调。随着胰岛素抵抗的出现,一些心血管危险因子往往聚集在一起形成代谢综合征,由于此综合征具有预测心血管疾病的内在价值,因此最近提出将代谢综合征提升为“疾病”。这些心血管危险因子的病理生理改变与胰岛素抵抗和代偿性高胰岛素血症密切相关,现对此进行综述。     

氯吡格雷抵抗研究进展

氯吡格雷的抗血小板聚集作用在急性冠脉综合征和经皮冠状动脉介入术患者中得到广泛应用,但氯吡格雷抵抗的出现影响了其临床疗效。现就氯吡格雷抵抗的定义、临床意义、血小板聚集检测方法、发生机制及防治策略分别加以阐述。     

Current Clinical Practice: Application of Resistance Reversal Agents in Hematologic Malignancies

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.     

HIV Drug Resistance and the Advent of Integrase Inhibitors

This review focuses on the topic of HIV integrase inhibitors that are potent antiretroviral drugs that efficiently decrease viral load in patients. However, emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy. Here, we provide new information about the most recent mutations identified and other mutations that confer resistance to several integrase inhibitors, such as new resistance mutations—for example, G118R, R263K, and S153Y—that have been identified through in vitro selection studies with second-generation integrase strand transfer inhibitors (INSTIs). These add to the three main resistance pathways involving mutations at positions Y143, N155, and Q148. Deep sequencing, structural modeling, and biochemical analyses are methods that currently help in the understanding of the mechanisms of resistance conferred by these mutations. Although the new resistance mutations appear to confer only low levels of cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all drugs of the INSTI family of compounds.     

阿司匹林抵抗的研究进展

阿司匹林能够有效预防心血管疾病病人血栓栓塞事件的发生,但其抗血小板作用有个体差异性.现对阿司匹林抵抗的生物学机制、流行病学资料以及研究进展进行探讨.     

Chronic Kidney Disease-Induced Insulin Resistance: Current State of the Field

Purpose of Review

Insulin resistance is an early complication of chronic kidney disease (CKD) associated with worsening cardiovascular outcomes. This review will evaluate mechanisms responsible for CKD-induced insulin resistance and therapies currently available.

Recent Findings

Recent mechanisms have been identified including SIRPα and specific E3 ubiquitin ligases causing insulin resistance in CKD. The hallmark finding in these mechanisms is degradation of the insulin receptor substrate 1 (IRS1) which impairs intracellular insulin signaling and ultimately metabolism. The mechanisms responsible for insulin resistance in CKD include inflammation, oxidative stress, elevations in aldosterone, angiotensin II, uremic toxins, and metabolic acidosis. Potential treatments currently available for CKD-induced insulin resistance include lifestyle modification and metformin. Potential future treatments may include glucagon-like peptide agonists, SGLT2 inhibitors, and thiazolidinediones.

Summary

Investigations into molecular mechanisms responsible for insulin resistance in CKD may provide new therapeutic targets while current therapies may prevent the catabolic sequelae of CKD and ameliorate its cardiovascular consequences.

     

Resistance to clopidogrel: a review of the evidence

Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y(12) receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel's antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.