Antibiotic resistance among
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"144",leadTitle:null,fullTitle:"Speech Technologies",title:"Speech Technologies",subtitle:null,reviewType:"peer-reviewed",abstract:"This book addresses different aspects of the research field and a wide range of topics in speech signal processing, speech recognition and language processing. The chapters are divided in three different sections: Speech Signal Modeling, Speech Recognition and Applications. The chapters in the first section cover some essential topics in speech signal processing used for building speech recognition as well as for speech synthesis systems: speech feature enhancement, speech feature vector dimensionality reduction, segmentation of speech frames into phonetic segments. The chapters of the second part cover speech recognition methods and techniques used to read speech from various speech databases and broadcast news recognition for English and non-English languages. 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From 1988 to 1998 he was a staff member of the Laboratory for Artificial Perception, at the Faculty of Electrical Engineering, University of Ljubljana. Since 1998\nIvo Ipšić has been a professor of computer science at the University of Rijeka, teaching computer science courses. 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Vascular dysfunction is a highly complex biological process, and cardiovascular diseases are a leading cause of morbidity and mortality in the United States [1]. It is estimated that approximately 80 million US adults (>1 in 3) have one or more types of cardiovascular (CV) disease, including hypertension, atherosclerosis, and congestive heart failure. CV disease has been estimated to account for 34.3% of all deaths in the United States in 2006 [1]. Vascular or endothelial dysfunction is caused by many interrelated factors including oxidative stress, hypertension, diabetes mellitus, renal disease, smoking, inflammation and atherosclerosis.
In this chapter we will review results from large-scale clinical trials to determine if inhibitors of the renin–angiotensin system (RAS), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin type II receptor blockers (ARBs) and calcium channel blockers (CCBs), may have beneficial effects on central aortic pressure (CAP) and the biomarkers high-sensitivity C-reactive protein (hsCRP), adiponectin, cystatin C, homeostasis model assessment of insulin resistance (HOMA-IR), procollagen, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6).
Biomarkers are playing an increasing role in the study of CV disease and we attempt to define their function in improving clinical management and outcomes [2, 3]. By definition, biomarkers are objectively measured indicators of biological processes, and to be of use, they must be relevant, predictable, accurate, and reproducible [3]. They provide readily quantifiable surrogate endpoints and allow accurate assessment of the effects of therapy on particular pathological processes, thereby allowing for prompt diagnosis and more timely initiation of appropriate treatment, improved monitoring, and treatment augmentation [4].
Some of the benefits of inhibiting RAS with ARBs and ACEIs have been shown to be independent of blood pressure (BP) reduction [5] [6]. Surrogate biomarkers are diverse, and they may provide a viable means of measuring the response to treatment. This chapter will focus on the following eight biomarkers, which have been used as predictors of vascular outcome in patients with hypertension and those with metabolic syndrome: CAP, hsCRP, adiponectin, cystatin C, HOMA-IR, procollagen, TNF-α, and IL-6.
Anti-inflammatory, anti-atherogenic, and/or improved metabolic homeostasis, independent of BP lowering, which is seen with some antihypertensives, may benefit high-risk patient populations or those who do not achieve adequate BP control. These include ethnic groups such as African Americans, obese patients, and patients with renal disease, metabolic syndrome, diabetes mellitus, and/or existing vascular disease. Improvements in inflammatory and other biomarkers has been reported with ARBs and ACEIs in obese patients with metabolic syndrome [7, 8] and in hypertensive patients with and without type 2 diabetes mellitus (T2DM) [9, 10]. Similarly, CCBs have been shown to improve markers of inflammation in patients with hypertension [11, 12], while β-blockers such as nebivolol were shown to modify markers of inflammation and obesity in obese African Americans with hypertension [13]. As a class, ARBs are known to have anti-inflammatory properties, which may contribute to their pharmacologic effects. Biomarker studies in hypertensive patients have demonstrated the effects of ARBs on inflammatory and other biomarkers [7, 14], including CAP [15, 16], hsCRP [14, 17-19], adiponectin [20], cystatin [21, 22], HOMA-IR [23-25], procollagen [26-28], TNF-α [29-31], and IL-6 [32-34].
This chapter summarizes the role of biomarkers as surrogate endpoints in the treatment of hypertensive patients and discusses the evidence for the effects of ARBs and other antihypertensive drugs on biomarkers and their correlation with clinical efficacy. The source material for this review was derived from a MEDLINE literature search, performed from 1999 to 2011, to identify published studies investigating the use of selective antihypertensive agents using at least one of the eight previously mentioned biomarkers. The agents specified in the search were amlodipine, olmesartan medoxomil, combination amlodipine plus olmesartan medoxomil, losartan, hydrochlorothiazide (HCTZ), and combination losartan plus HCTZ.
Hypertension is a strong contributor to cardiovascular disease in patients with the cardiometabolic syndrome. It has been shown to not only be an independent risk factor, but it also contributes to the development of other risk factors for cardiovascular disease. Over the last few decades, a number of classes of anti-hypertensive drugs have been used to treat hypertension, with the ultimate goal of reducing the incidence of endpoints such as heart attacks and stroke. Some of the broad categories of antihypertensives include thiazide diuretics, ARBs, ACEIs, CCBs and β-blockers.
The first step in atherosclerosis is endothelial dysfunction. It has been shown that the RAS is involved in the development of atherosclerosis through many different mechanisms including increasing oxidative stress, vasoconstriction, inflammation and reduced ability of the endothelium to regenerate itself (reviewed in [35]). The blockage of the RAS through ACEIs and ARBs, aids in slowing down the processes of endothelial dysfunction and subsequent atherosclerosis. ACEIs reduce angiotensin II production and suppress the degradation of bradykinin. This results in reduced oxidative stress, improved vasodilation and improved endothelial function [36, 37]. Some common ACEIs include ramipril, enalapril, lisinopril, perindopril and fosinopril. The Heart Outcomes Prevention Evaluation (HOPE) study evaluated the benefits of ramipril as compared to placebo [38]. Ramipril (10mg/day) resulted in a reduction of cardiovascular death (26% RR), nonfatal myocardial infarction (MI) (20% RR) and stroke (32% RR). Ramipril was shown to be beneficial in all subgroups of patients in the HOPE Study. The Efficacy of Perindopril in Reduction of Cardiovascular Events Among Patients with Stable Coronary Artery Disease (EUROPA) study, Perindopril Protection Against Recurrent Stroke (PROGRESS) study and the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) study are some other large, outcome trials which also showed a positive effect of ACEIs on cardiovascular events and mortality [39-41].
ARBs also block the RAS. This is accomplished through blocking of the angiotensin I receptor which leads to an upregulation of the angiotensin II receptor and the conversion of of angiotensin II to angiotensin (1-7) which has vasodilatory, antioxidant and pro-apoptotic properties [42, 43]. Some common ARBs include losartan, telmisartan, valsartan, olmesartan, candesartan and irbesartan. Large outcome trials such as the Renal Outcomes with Telmisartan, Ramipril, or Both, in People at High Vascular Risk (ONTARGET) study, and the Valsartan in Acute Myocardial Infarction (VALIANT) study have shown that ARBs are comparable to ACEIs in reducing cardiovascular risk, without the side effect of excess coughing that is frequently experienced by patients who are taking ACEIs [44] [45]. Combination of ARBs with β-blockers or statins have also shown positive results [46, 47].
CCBs are another class of antihypertensives which provide similar blood pressure lowering effects of ACEIs and ARBs, but they provide better protection against stroke and heart failure [48]. CCBs inhibit the flow of extracellular calcium through ion-specific channels that span the cell wall. This causes vascular smooth muscle cells to relax and thereby results in vasodilation, blood pressure lowering and reduced peripheral arterial resistance. Commonly prescribed CCBs include amlodipine, benidipine, azelnidipine and manidipine.
β-blockers are another group of antihypertensives which are divided into two main categories. Traditional (non-vasodilatory) β-blockers such as atenolol, metropolol and propanolol reduce blood pressure by reducing cardiac output [49]. These β-blockers are effective at lowering brachial blood pressure, however data from studies including the Conduit Artery Function Evaluation (CAFÉ) study suggests that these compounds do not adequately control central aortic pressure [50]. This can then lead to an increase in vascular events including stroke [51]. Additionally, these agents have been shown to increase plasma triglyceride levels [52] and the risk of new-onset diabetes by about 20-30% [53, 54]. The other group of β-blockers are the vasodilatory β-blockers which includes labetalol, carvediol and nebivolol. These drugs reduce systemic vascular resistance while maintaining cardiac output. Additionally, these agents do not negatively affect glycemic control and may even provide beneficial metabolic effects [55-57].
Diuretics include HCTZ, chlorthalidone and the loop diuretics such as furosemide. According to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, diuretics are recommended as the first line of therapy for hypertension [58]. Chlorothalidone is more potent at 25mg dosing than 50mg of HCTZ. Also, chlorothalidone has been shown to improve cardiovascular outcomes [59]. Certain subpopulations, including diabetics, the elderly and blacks have lower renin levels and they respond favorably to diuretic therapy [60]. Diuretics, particularly HCTZ, are often combined with antihypertensives from another class, such as ARBs and ACEIs, to provide enhanced therapeutic benefits [61].
The newest category of anytihypertensives include direct renin inhibitors (DRIs). Aliskiren is the most common DRI. This class of drugs works by inhibiting the first rate-limiting step in the RAS, resulting in a more complete inhibition of the RAS cascade as compared to ACEIs and ARBs [62]. Additionally, DRIs reduce the production of aldosterone, which in addition to its sodium retension effects, also is a mediator in oxidative stress and inflammation [63] [64]. The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study and the Aliskiren Observation of Heart Failure Treatment (ALOFT) trial show that aliskiren has renal and cardio protective effects in addition to blood pressure regulation [65, 66].
While brachial BP is easily measured and has been shown to be predictive of CV morbidity and mortality, it is an imperfect surrogate measure of CAP. Peripheral systolic BP (SBP) measured at the brachial artery does not accurately reflect CAP, particularly in youths, as a result of peripheral amplification of the pulse pressure wave [67-69]. This amplification difference decreases with age and arterial stiffness. Central aortic systolic pressure or pulse pressure has been shown to be a powerful and more robust predictor of end organ damage and CV mortality than brachial BP, irrespective of whether the central pressures were derived from noninvasive pulse wave analysis or measured directly during routine catheterization [68]. Although techniques have been developed to a stage where direct noninvasive measurement of CAP could be readily applied to routine clinical practice, the studies conducted to-date, assessing the predictive value of CAP, have been relatively small. Thus, additional data from large interventional studies of clinical outcomes and larger-scale longitudinal epidemiological studies of clinical outcomes are required to confirm the utility of CAP as a predictor of vascular risk before it becomes part of routine clinical practice [67-69].
Noninvasive assessment of the central pulse pressure waveform is performed by applanation tonometry, which involves applying a pressure sensor (tonometer) with mild pressure over the radial or carotid artery. The recorded waveform is then used to algorithmically derive central pressure indices from a peripheral brachial BP measurement [69]. In addition, aortic pulse wave velocity (PWV), which is usually recorded between the carotid and femoral arteries, is used to determine vessel distensibility; the velocity of the pulse wave increases with decreasing vessel distensibility (increased arterial stiffness) [67]. Increased PWV, an indication of arterial stiffness, appears to be associated with endothelial dysfunction, inflammation, and atherosclerosis, and has been shown to be an independent predictor of coronary events and CV mortality [67]. Hence, arterial stiffness is an emerging biomarker for therapeutic interventions.
C-reactive protein (CRP), an acute phase reactant predominantly produced in the liver in response to IL-6, interleukin-1β, and TNF-α, is a marker of the general inflammatory response. Current technology permits the quantification of CRP through a high-sensitivity assay, therefore this marker is referred to as hsCRP. Epidemiological studies have established that individuals with higher levels of hsCRP have increased CV risk [70]. The nature of the relationship between hsCRP and CV disease is unclear, but hsCRP provides a useful measure of risk and the effects of interventions [70, 71].
Studies have shown a continuous independent association between serum CRP levels and elevated BP [72]. In elderly, normotensive individuals, higher baseline CRP levels were associated with a higher incidence of new-onset hypertension after 2 years [73]. Moreover, in apparently healthy adults representative of the US population, a 10-mmHg increase in pulse pressure was associated with significant increases of 12%–15% in the odds of having an elevated CRP level, independent of SBP or diastolic BP (DBP), or demographic factors [74]. There are even suggestions that hsCRP may be a better marker of coronary artery disease (CAD) than low-density lipoprotein cholesterol (LDL-C) [2, 75]. Evidence suggests that inhibition of the RAS with certain agents, particularly ARBs and ACEIs, may improve CV outcomes by reducing vascular inflammation and remodeling independently of BP reductions [76].
Adiponectin is one of the adipocyte-derived hormones that has profound anti-inflammatory and anti-atherogenic properties. It is also thought to play an important role in the modulation of glucose and lipid metabolism [2, 77]. Reduced adiponectin levels have been noted in males, obese subjects, and patients with hypertension, CAD, or T2DM [78]. Reduced adiponectin levels are predictive of CAD and MI [79]. Animal studies have shown that increased adiponectin levels are protective against atherosclerosis, while clinical studies with antihypertensive drugs, including ARBs, ACEIs, and CCBs, have associated improvements in BP and insulin resistance with increased adiponectin levels [78, 80]. In obese subjects, serum adiponectin levels were inversely associated with intima-media thickness, a surrogate measure of subclinical atherosclerosis, and positively associated with arterial compliance [79]. The mechanism behind the beneficial effects of adiponectin is uncertain; one hypothesis suggests that adiponectin increases nitric oxide activity, thereby inhibiting platelet activation, while another hypothesis suggests it suppresses monocyte activation [78].
The serum cystatin C level directly correlates with the glomerular filtration rate (GFR) and is produced constantly, independent of muscle mass, age, or sex. It is therefore an easily obtained biomarker for renal dysfunction that may be more reliable than measurement of creatinine levels in certain patient populations, particularly in children [81-83]. However, there are concerns over the cost of the immunoassay, intraindividual variability, and its sensitivity in transplant patients or its suitability in patients with cancer, where cystatin C production may vary [82]. Notably, a study in patients after heart transplantation found that cystatin C was superior to creatinine as a prognostic indicator of early renal dysfunction during 4 years of follow-up [84].
Cystatin C is a predictor of CV morbidity and mortality, and it has been suggested that this association may be independent of renal function [85, 86]. In one study, cystatin C, but not creatinine or GFR, was closely associated with left ventricular (LV) mass in patients with hypertension, suggesting utility as a marker for cardiac hypertrophy [86].
HOMA-IR is a mathematical model prediction that provides an accurate quantitative assessment of insulin resistance [87], which is associated with hypertension, obesity, and diabetes, and an increased risk of CAD [88].
Many CV drugs adversely affect glucose and lipid homeostasis, and insulin resistance is an important mediator of these adverse effects on glucose metabolism [88]. Direct RAS inhibitors (ARBs and ACEIs) and some other antihypertensives provide beneficial effects in terms of glucose homeostasis [88].
Collagen fractions in the extracellular matrix are intimately involved in the atherosclerotic process and the vascular remodeling that occurs in CV disease [89]. There is evidence that altered collagen metabolism (eg, elevated serum levels of tissue inhibitor of metalloproteinase-1) is associated with hypertension [89], and that plasma markers of collagen metabolism are positively correlated with arterial stiffness measured by PWV in hypertensive patients with LV hypertrophy [90].
Therefore, measurement of serum procollagen fractions as indicators of myocardial fibrosis may be useful in the clinical assessment of CV risk [91].
TNF-α is a marker of inflammation and is believed to promote the development of insulin resistance and hyperinsulinemia, and thereby affect BP [29]. TNF-α is released from mast cells and macrophages in the myocardial endothelium during acute MI, and from cardiomyocytes during persistent ischemia. The released TNF-α contributes to ischemic and/or reperfusion injury and is believed to contribute to cardiac contractile dysfunction after MI via a local inflammatory reaction [31]. Surprisingly, low levels of TNF-α may be beneficial and display a cardioprotective effect, reducing infarct size [31]. TNF-α is also believed to play a role in the development of atherosclerosis by up-regulating cell surface receptors for advanced glycation end products that promote the release of inflammatory mediators in the endothelium [30]. The differential effects are possibly related to which of the two tumor necrosis receptor types (TNF-R1 or TNF-R2) the TNF-α molecule interacts.
IL-6 is an inflammatory cytokine that, along with TNF-α, is one of the main inducers of acute phase reactants, such as CRP. It has been positively correlated with CV risk. For instance, in elderly subjects without known CV disease, serum levels of IL-6 were significantly associated with CAD, stroke, and congestive heart failure events, and to a greater extent than CRP or TNF-α levels [92]. Similarly, in older men without CAD, IL-6 was found to be more discriminating than CRP and fibrinogen in predicting a first coronary artery ischemic event, being associated with MI/coronary death but not CAD endpoints (angina) [33]. However, not all studies have found strong correlations between IL-6 and CAD [34].
Clinical evidence that many current antihypertensive agents have a beneficial effect on putative biomarkers of CV pathology or risk continues to accumulate and indicates that not all drugs or patient subpopulations are equal.
Of the various antihypertensive drug classes, RAS inhibitors (ARBs and ACEIs) and CCBs generally appear to have greater effects on CAP than β-blockers and thiazide diuretics. Despite similar brachial BP reductions, the combination of amlodipine plus perindopril was associated with greater reductions in CAP than atenolol plus a thiazide diuretic [93]. Lisinopril also significantly reduced central SBP, central pulse pressure, and the augmentation index, while bisoprolol only significantly lowered central DBP and actually increased the augmentation index [94]. The combination of olmesartan and azelnidipine was compared to olmesartan and amlodipine [95]. While both combinations had similar brachial BP lowering effects, there was a greater reduction in CAP with the olmesartan/azelnidipine combination. Another study showed significant reductions in both brachial and central BP reductions with different drug classes in the following order: CCBs > diuretics (HCTZ) > ACEIs [96]. β-blockers did not significantly lower peripheral or central BP.
Similar brachial BP and CAP reductions were achieved with valsartan plus HCTZ versus amlodipine; however, valsartan plus HCTZ provided a greater reduction in arterial stiffness (estimated by aortic PWV) [97]. Reductions in central SBP were greater with fosinopril plus HCTZ than with indapamide or amlodipine; this correlated with 24-hour and nighttime SBP reductions, but not with seated cuff SBP [98].
Recent studies have shown that PWV is significantly reduced with candesartan or benidipine treatment, as compared to amlodipine [99, 100]. Arterial stiffness, measured through cardioankle vascular index was significantly decreased with combination of olmesartan and azelnidipine, but not with olmesartan monotheraphy [101]. However, arterial index decreased significantly with monotheraphy and combination therapy in this study. On the other hand, another recent study showed that monotheraphy with olmesartan does significantly decrease arterial stiffness [102].
The effects of antihypertensives on flow mediated dilation (FMD) has also been measured. Olmesartan has been shown to positively impact FMD and while amlodipine treatment has no effect on FMD [103], the combination of amlodipine and atorvastatin has significant improvements on this marker, even more than atorvastatin alone [104]. Another study found the same effects of amlodipine and atorvastatin combination on patients with hypertension and hyperglycemia [105]. The combination of amlodipine and valsartan was also found to improve FMD in diabetics with early hypertension, even more than the effects of the individual drugs [106].
Several antihypertensive drug classes, such as ARBs, ACEIs, and CCBs, lower serum hsCRP in addition to BP, indicating a reduction in the inflammatory processes involved in the progression of atherosclerosis. ARBs, in particular, seem to have a strong depressor effect on this marker of inflammation. Patients with chronic kidney disease (CKD), who have higher baseline levels of inflammation than control subjects with normal renal function, displayed significant reductions in hsCRP and brachial BP with olmesartan medoxomil treatment [107]. In a small study of 10 patients with mild-to-moderate hypertension, olmesartan medoxomil did not reduce BP significantly, but did produce significant reductions in hsCRP and appeared to improve myocardial function independent of BP lowering [19]. In another study, hsCRP levels significantly dropped in hypertensive patients who were treated with olmesartan for 6 month [102]. In non-diabetic patients with hypertension and the metabolic syndrome, both olmesartan medoxomil plus amlodipine and olmesartan medoxomil plus HCTZ effectively reduced BP and CRP with no differences between groups. However, olmesartan plus amlodipine produced greater reductions in all other inflammatory markers [108]. Olmesartan treatment was compared to candesartan treatment in hypertensive patients with T2DM [109]. BP and hsCRP reductions were similar in both treatment groups. In a separate study, these researchers also found that monotherapy with either losartan or ramapril is equally beneficial in lowering hsCRP [109].
In a study comparing the CCB azelnidipine or the thiazide diuretic trichlormethiazide added to an ARB, the ARB plus azelnidipine combination produced significantly greater reductions in hsCRP than the ARB plus thiazide combination; this reduction mirrored the BP-lowering effects [110]. Similar data were shown in a 4-month crossover study comparing olmesartan medoxomil plus azelnidipine or trichlormethiazide [111]. Azelnidipine was shown to be superior to amlodipine with regards to hsCRP lowering in nondiabetic hypertensive patients and the beneficial effects of azelnidipine also included improved glucose tolerance and insulin sensitivity [112]. When combined with atorvastatin, amlodipine therapy reduces plasma hsCRP significantly [104]. In the recent Effects of Manidipine and its Combination with an ACE Inhibitor on Insulin Sensitivity and Metabolic, Inflammatory and Prothrombotic Markers in Hypertensive Patients with Metabolic Syndrome: the MARCADO Study, a number of monotherapies (manidipine, amlodipine, teimisartan) and combination therapy (manidipine/lisionpril) were compared for treatment of non-diabetic, hypertensive patients with the metabolic syndrome. Levels of hsCRP reduced with all of these treatments, but the most significant reduction was with the manidipine/lisinopril combination therapy [113]. Comparison of 12 weeks of combination therapy with enalapril plus add-on losartan with higher dose enalapril monotherapy showed a significant reduction in hsCRP with combination therapy, but not with high-dose enalapril alone; BP reductions were significant and similar in both groups [114]. In another study, patients who were on olmesartan therapy received additional HCTZ or azelnidipine therapy for 24 weeks. HsCRP levels dropped significantly with the azelnidipine add-on therapy but there was no change with HCTZ therapy [115].
Evidence suggests that ARBs may differ in their anti-inflammatory effects. For instance, in patients with CAD, olmesartan medoxomil and valsartan both produced significant reductions in BP, but only olmesartan medoxomil induced a significant reduction in hsCRP [116]. Losartan has also been shown to reduce hsCRP in newly diagnosed hypertensive patients who are at CV disease risk [117]. Studies comparing the hsCRP-lowering effects of ARBs and CCBs have shown variable results. One study found no difference in hsCRP reductions after 8 weeks of therapy with losartan or amlodipine regimens [118]. The effects on hsCRP and other inflammatory markers did not explain the greater improvements in insulin sensitivity seen with ARBs over CCBs. However, in patients with hypertension and other CV risk factors, therapy with valsartan plus HCTZ was significantly more effective than amlodipine in reducing hsCRP. These biomarker results correlated with BP reductions [119]. HsCRP improvement did not correlate with endothelial function in a study comparing candesartan with amlodipine; both treatments significantly improved endothelial function (assessed by changes in forearm blood flow in reactive hyperemia), whereas significant reductions in hsCRP levels were seen only with candesartan and not amlodipine therapy [120]. The study investigators concluded that the anti-inflammatory effects observed with candesartan may be related to observed improvement in insulin sensitivity. In a study of patients with CAD, treatment with irbesartan did not lower hsCRP levels. [121] The lack of effect of irbesartan may have been due to low levels of hsCRP at study baseline. Patients were also receiving statin and aspirin therapy, which also lower levels of this marker. In a recent study, olmesartan reduced hsCRP levels in patients with essential hypertension while amlodipine had no effects on hsCRP [103].
As with ARBs, CCBs seem to differ in their ability to reduce inflammatory markers. In hypertensive patients with the metabolic syndrome, similar significant reductions in hsCRP and BP were seen with manidipine and amlodipine, but these data did not correlate with changes in other biomarkers, such as adiponectin, HOMA-IR, and TNF-α, which showed greater improvements with manidipine than with amlodipine [122]. In a different study in patients with arterial hypertension and insulin resistance who were already receiving at least two antihypertensive agents, neither moxonidine nor amlodipine showed significant changes in hsCRP, whereas both treatments resulted in significant BP lowering [123].
Adding a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (atorvastatin) to amlodipine therapy produced significantly greater reductions in BP and hsCRP than was seen with amlodipine alone [124], but losartan plus simvastatin achieved similar reductions in hsCRP compared with losartan or simvastatin alone [47]. BP reductions were significantly greater with losartan or losartan plus simvastatin than with simvastatin alone. The combination of rosuvastatin and a number of ARBs was studied as treatment in adults with the metabolic syndrome [125]. While rosuvastatin and telmisartan reduced hsCRP by 44% after 24 weeks of therapy, there was less reduction in hsCRP with the combination of rosuvastatin and irbesartan or rosuvastatin and olmesartan.
These observations suggest that RAS antagonists such as ARBs and ACEIs have a significant anti-inflammatory effect, and there may be variations within these classes. As diseases such as diabetes mellitus and atherosclerosis are inflammatory processes, the clinical benefits seen with these classes of antihypertensives may be a combination of the suppression of inflammation and the reduction of BP.
Studies assessing the effect of the selected antihypertensive drugs on the serum levels of adiponectin are discussed here. Antihypertensive agents do not uniformly influence metabolic parameters in patients with hypertension. In a comparison of telmisartan and irbesartan in obese, insulin-resistant, hypertensive patients, increases were significantly greater with telmisartan, although both treatments resulted in significant increases in adiponectin levels [126]. Adiponectin changes correlated inversely with changes in BP for telmisartan, but not for irbesartan. The investigators speculate that the differences between the two agents may be partly due to partial peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist activity exhibited by telmisartan, although a study by Kintscher et al in 14,200 patients confirmed that irbesartan also activates PPAR-γ [127]. Despite similar reductions in BP, olmesartan medoxomil plus amlodipine produced significant increases in adiponectin levels in patients with hypertension and the metabolic syndrome, whereas olmesartan medoxomil plus HCTZ did not [108]. The increase in adiponectin correlated with a lower risk for developing T2DM and paralleled reductions (improvements) in HOMA-IR index and fasting plasma insulin levels.
In nondiabetic, proteinuric patients, treatment with losartan plus HCTZ reduced BP, proteinuria, and LDL-C, and increased adiponectin, but the change in adiponectin correlated with adverse reductions in high-density lipoprotein cholesterol (HDL-C) levels [128]. In a crossover study that investigated possible factors to explain improvements in insulin sensitivity with ARB therapy compared with CCB therapy in patients with hypertension, between group differences were not noted for increases in adiponectin levels or reductions in BP after 8 weeks of therapy with losartan or amlodipine [118]. In contrast, although both telmisartan and amlodipine increased adiponectin levels in patients with hypertension and T2DM, the increases were higher with telmisartan than with amlodipine [129]. Both groups showed a similar significant decrease in BP. Similarly, in patients with prediabetes, losartan produced greater increases in adiponectin than a CCB, whereas BP reduction was similar and significant in both groups [130]. Within CCBs, candesartan, but not olmesartan therapy, over the period of a year resulted in increased adiponectin and insulin sensitivity in T2DM hypertensive patients, even though BP lowering was similar in both treatment groups [109]. When compared to the ACEI ramipril, losartan treatment significantly improved adiponectin levels and overall metabolic parameters while ramipril had no effect on adiponectin or any other metabolic markers [131]. In obese hypertensive patients, telmisartan, but not losartan raised serum adiponectin levels [132].
ARBs and statins have additive effects on adiponectin. Losartan plus simvastatin or losartan alone resulted in significantly greater increases in adiponectin levels from baseline than with simvastatin alone [47]. This correlated with BP reductions, which were greater with losartan or losartan plus simvastatin than with simvastatin alone. A correlation was also observed with LDL reductions, which were greater with simvastatin or simvastatin with losartan relative to losartan alone.
There were no changes in adiponectin levels with the aldosterone blocker spironolactone or the CCB amlodipine in patients with diabetic nephropathy or in controls. However, spironolactone, but not amlodipine, increased adiponectin in a subgroup of patients with poor baseline glycemic control, i.e. glycosylated hemoglobin (HbA1c) ≥8%. A significant decrease in SBP, but not DBP, was observed in both treatment groups [133]. This link between the renin-angiotensin cascade and aldosterone suggests a possible mechanism by which spironolactone provides an increased level of adiponectin in hyperglycemia.
In a comparison of enalapril, metoprolol, amlodipine, and indapamide, no changes in adiponectin level were seen with enalapril, amlodipine, or metoprolol, whereas a reduction in adiponectin was seen with indapamide. This reduction in adiponectin with the thiazide-like diuretic correlated with increased insulin resistance [134]. In a comparison of metoprolol, amlodipine, ramipril, doxazosin, and valsartan in hypertensive patients with the metabolic syndrome, both ramipril and valsartan resulted in significantly higher increases in adiponectin than the other regimens; adiponectin levels inversely correlated with SBP [135]. In a study comparing manidipine, amlodipine, telmisartan, and the combination therapy of manidipine and lisinopril, adiponectin levels increased with all of the treatments except amlodipine. The greatest increase in adiponectin was seen with manidipine [113]. The combination of amlodipine and atorvastatin resulted in a greater increase in adiponectin than treatment with amlodipine alone [104]. Similar results were seen in patients with hypertension and hyperglycemia that were treated with amlodipine and atorvastatin [105].
In a small study in patients with hypertension, ramipril, candesartan, and amlodipine were associated with greater increases in adiponectin levels while thiazide and atenolol were associated with a decrease in adiponectin. There were no correlations with BP lowering, which was greatest with atenolol, amlodipine, and candesartan therapies than with ramipril [136].
Unlike the situation with hypertensive, obese, or diabetic patients, where adiponectin levels are reportedly reduced, the levels of adiponectin are raised in patients with renal disease when compared with healthy controls. Thus, in patients with renal disease, a positive correlation between adiponectin and insulin resistance is seen, and increased adiponectin levels are associated with increased all-cause and CV mortality (the opposite of that seen in obese patients or those with T2DM without renal disease). Paradoxically, short-term losartan therapy in patients with T2DM nephropathy was associated with a significant decrease in adiponectin levels compared with amlodipine therapy [137].
Adiponectin, secreted by fat cells, regulates the insulin response and has a favorable effect on glucose and lipid metabolism. Insulin resistance is a hallmark for the progression of vascular disease. The quantitative changes in adiponectin provide insight into how antihypertensive agents such as ARBs may be effective in attenuating or reversing the pathogenesis of atherosclerosis and diabetes mellitus.
Only three studies have assessed the effect of the selected antihypertensive drugs on serum cystatin C levels. In one study, a significant decrease in cystatin C with olmesartan medoxomil therapy correlated with improvements in BP, LV mass index, and LV hypertrophy at 6 months [138]. Another study found that cystatin C levels decreased in patients who were on olmesartan or olmesartan with HCTZ, but in this study, there was no correlation between cyctatin C and BP levels [139]. However, the third study found no significant decrease in cystatin C with enalapril/losartan combination therapy or with high-dose enalapril, despite significant reductions in BP [114].
The use of cystatin C as an early marker for CKD may be helpful in longitudinal follow-up analyses. The findings in the above studies are preliminary but suggest that BP reduction may be associated with lower cystatin C levels. It is too early to determine whether inhibition of the RAS (in the form of ACEIs or ARBs) may have an effect on cystatin C that is superior to other antihypertensive drugs.
HOMA-IR is a model and calculation to determine quantification of insulin resistance. Antihypertensive drugs appear to have differing effects on insulin resistance, with ARBs foremost among those improving insulin sensitivity, although considerable variability has been observed and not all ARBs may be equal in this regard. RAS inhibitors generally have greater effects on glucose homeostasis than CCBs, which are usually considered to have neutral effects.
In hypertensive patients, a significantly greater reduction in HOMA-IR was seen with losartan/amlodipine therapy than with high-dose amlodipine [118]. The addition of losartan therapy to chronic heart failure patients who were on ACEIs resulted in a reduction of HOMA-IR as well as inflammatory cytokines after 24 weeks of therapy [140]. The MARCADOR Study compared the effects of manidipine, amlodipine, telmisartan, and manidipine combined with lisinopril. While BP lowering was similar with all of these treatments, HOMA-IR levels improved in all of the treatments except for amlodipine, and the greatest change in HOMA-IR was seen with manidipine treatment [113]. In contrast to previous results, both losartan and telmisartan had neutral effects on insulin resistance in 42 hypertensive patients with the metabolic syndrome, with no significant reductions in HOMA-IR in either group; BP reductions were similar for both ARBs [141]. In a more recent study, obese hypertensive patients were treated with telmisartan or olmesartan. While olmesartan improved BP levels, only telmisartan improved insulin glucose and HOMA-IR levels in addition to improving BP levels [25]. Others have also shown that telmisartan therapy helps to reduce HOMA-IR levels as compared to other ARBs and CCBs [132, 142]. Researchers studied the effects of irbesartan as compared to olmesartan in obese hypertensive females and found that while both treatments improved BP and lipid levels, only olmesartan resulted in HOMA-IR changes [143]. Olmesartan was also found to reduce HOMA-IR in hypertensive patients with sleep disordered breathing. Positive changes in BP level and left ventricular ejection fraction were also seen in these patients with olmesartan treatment [144].
Non-diabetic CKD patients have a high prevalence of insulin resistance, metabolic syndrome, and chronic inflammation. Treatment with olmesartan medoxomil for 16 weeks was associated with a significant reduction in HOMA-IR, along with reductions in markers of inflammation [107]. Losartan therapy was associated with improvements in fasting plasma insulin and HOMA-IR in patients with T2DM nephropathy, in parallel with reductions in adiponectin levels [137]. Both olmesartan medoxomil and telmisartan were shown to improve HOMA-IR in patients with nonalcoholic fatty liver disease and chronic hepatitis C, conditions with a greater incidence of insulin resistance than other liver diseases [145].
In a study investigating the effect of combination therapy with amlodipine plus olmesartan medoxomil on HOMA-IR in hypertensive patients with the metabolic syndrome, HOMA-IR was significantly reduced with olmesartan medoxomil/amlodipine, whereas no significant changes were seen with olmesartan medoxomil/HCTZ. The reductions in the HOMA-IR index strongly correlated with the increases in adiponectin level in the group treated with olmesartan medoxomil/amlodipine [108].
In a crossover study of amlodipine with or without atorvastatin therapy in obese patients with hypertension and normal lipid profiles, combination amlodipine/atorvastatin therapy produced a significantly greater reduction in HOMA-IR than amlodipine monotherapy; there was no correlation with BP reduction with either treatment [29]. The combination of rosuvastatin with telmisartan significantly lowered HOMA-IR and fasting serum insulin levels in metabolic syndrome patients, but when irbesartan or olmesartan was combined with rosuvastatin, HOMA-IR and fasting insulin levels increased [125]. In non-diabetic patients with the metabolic syndrome, manidipine, but not amlodipine, significantly reduced HOMA-IR [122].
In patients with hypertension and insulin resistance, neither moxonidine nor amlodipine produced changes in HOMA-IR. Both treatments significantly lowered BP and increased HDL-C, but only moxonidine reduced serum triglycerides. Neither drug affected serum CRP levels [123].
In patients with T2DM nephropathy, losartan, but not amlodipine, reduced HOMA-IR from baseline, but the between-group difference was not significant. However, other parameters of glucose metabolism (eg, fasting blood glucose, HbA1c, and insulin sensitivity) were improved to a greater extent with losartan than with amlodipine [146]. In patients with hypertension and T2DM, telmisartan resulted in greater improvements in HOMA-IR than amlodipine [129].
Similar results with losartan and amlodipine were seen in patients with prediabetes, with greater improvements in HOMA-IR with losartan than with amlodipine; the two agents resulted in similar BP reductions [130].
In a study in hypertensive patients, both candesartan and amlodipine significantly improved endothelial function, but significant decreases in HOMA-IR and CRP were only observed with candesartan [120].
In a comparison of losartan and amlodipine in Japanese patients with hypertension, with or without diabetes, losartan provided greater increases in adiponectin than amlodipine. These increases correlated with HOMA-IR changes [147].
In agreement with the adiponectin results discussed earlier, indapamide treatment increased HOMA-IR in patients with hypertension, whereas no changes in HOMA-IR were seen with enalapril, metoprolol, or amlodipine [134]. In patients with hypertension and the metabolic syndrome, doxazosin, amlodipine, ramipril, and valsartan produced significant reductions in HOMA-IR, whereas no changes were seen with metoprolol [135].
Insulin resistance is a central force in the pathogenesis of vascular diseases, and HOMA-IR provides a reasonable assessment of the quantification of insulin resistance. Several long-term clinical studies have demonstrated the clinical benefit of ARBs in diabetic kidney disease, both in late stage [the Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) study] and early stage [The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA-2) study]. The role of HOMA-IR may be beneficial in clinical practice, and quantitative and longitudinal analysis could provide long-term follow-up of disease management.
Several studies have assessed the effect of antihypertensive agents on procollagen fractions as a marker of atherogenesis and vascular remodeling. Valsartan and ramipril, but not amlodipine, were associated with reductions in procollagen. Despite similar BP lowering, valsartan and ramipril were more effective than amlodipine in preventing new episodes of atrial fibrillation [148].
Another study showed a significant difference in procollagen type I carboxy-terminal peptide (PICP) lowering between candesartan and amlodipine. Although BP control was similar, 24-hour SBP was significantly lower and LV mass index significantly decreased with amlodipine, while the effect of ARBs on procollagen indicate that they protect against CV fibrosis and renal injury [149].
There were no differences in procollagen markers with losartan- or atenolol-based regimens after the first year of treatment; changes in PICP during the first year of treatment were related to subsequent changes in LV mass index after 2 and 3 years of treatment in patients randomized to losartan, but not atenolol [26]. Losartan-related reduction in procollagen was shown to be greater in patients with higher baseline levels (those with hypertension and severe myocardial fibrosis) [150] and was significantly associated with symptom improvement [151].
The effects of antihypertensive drugs on the inflammatory biomarker TNF-α have been somewhat variable. In patients with hypertension, olmesartan medoxomil reduced TNF-α levels in one study [152], but in another study in Japanese patients, neither losartan nor the CCB amlodipine significantly affected TNF-α levels [147]. In obese hypertensive patients, telmisartan, but not losartan treatment, was shown to reduce serum TNF-α levels [132]. Conversely, another study showed that in newly diagnosed hypertension patients, losartan lowers TNF-α levels [117]. In chronic heart failure patients, the addition of losartan to ACEI therapy resulted in a significant reduction of TNF-α levels [140]. Amlodipine was effective in reducing TNF-α, but was significantly more effective when combined with atorvastatin [153]. Another study found no difference between losartan and amlodipine in TNF-α levels after treatment, but the investigators did not appear to perform baseline assessments in order to determine if either drug reduced TNF-α from baseline levels [118]. Manidipine and lisinopril combination therapy was shown to have a highly significant effect on TNF-α levels in non-diabetic, hypertensive patients with the metabolic syndrome [113].
Losartan therapy significantly reduced TNF-α in patients with hypertension and T2DM [154]. However, olmesartan medoxomil combined with HCTZ had no effect on TNF-α in patients with hypertension and the metabolic syndrome (without diabetes), but when olmesartan medoxomil was combined with amlodipine, the combination did significantly reduce TNF-α levels [108]. Amlodipine was shown to reduce serum TNF-α levels, as well as mRNA expression of TNF-α in hypertensives with and without diabetes [155]. Interestingly, amlodipine alone was shown in another study to have no effect on TNF-α levels in patients with hypertension and the metabolic syndrome, whereas manidipine monotherapy was effective in lowering TNF-α [122]. Olmesartan medoxomil had no effect on TNF-α levels in patients with stage 3 or 4 CKD [107], and TNF-α was unaffected by amlodipine or spironolactone in patients with diabetic nephropathy [133].
Studies investigating the effect of antihypertensive drugs on IL-6 levels are summarized here. In an open-labeled study, losartan therapy reduced IL-6 levels in recently diagnosed hypertension without other CV disease risk factors [117]. Olmesartan medoxomil reduced IL-6 levels in one study in patients with hypertension [152], but had no effect in patients with stage 3 or 4 CKD [107]. Olmesartan medoxomil was ineffective when combined with HCTZ in patients with hypertension and the metabolic syndrome, but was effective in these patients when combined with amlodipine [108]. Valsartan combined with HCTZ was more effective than amlodipine alone in reducing IL-6 [156]. Another study showed that diabetics with hypertension have higher IL-6 levels than non-diabetics with hypertension, and amlodipine reduced serum IL-6 as well as mRNA expression of IL-6 in diabetics and non-diabtetics [155]. In a crossover study with non-diabetic hypertensive patients, IL-6 levels were reduced with azelnidipine therapy, but not with amlodipine [112]. In the MARCADOR study, the greatest reduction in IL-6 was achieved with a combination of manidipine and lisinopril, while there was no change in IL-6 with amlodipine [113]. Another study found a greater reduction in IL-6 with benidipine treatment as compared to amlodipine treatment [100]. Losartan, as add-on therapy has also been shown to reduce IL-6 levels [140].
These cytokines are rather non-specific for quantification of inflammation; however, these studies do reflect the general state of inflammation in the vasculature. Clinical studies that measure the level of the cytokines demonstrate variable results. Multiple studies with antihypertensives indicate a general reduction in the levels of cytokines, suggesting a decrease in vascular inflammation. In context with the clinical situation and other risk factors, the measurement of these biomarkers may be useful.
It can be expected that biomarkers will continue to play an increasing role in the management of CV disease. Their importance or significance is likely to increase in direct proportion to the growth in our knowledge of disease pathophysiology and the mechanisms of drug action. The use of biomarkers does, however, depend upon the markers being accurate, relevant to the purpose, easy to measure, and consistently reproducible.
There is a wealth of evidence for improvement of validated biomarkers of vascular disease with most classes of antihypertensive treatment in a range of high-risk patient populations. These include obese patients, patients with diabetes, patients with renal disease and/or metabolic syndrome, existing vascular disease, and African American patients. Benefits have also been observed in those with normal BP, but with other CV risk factors. There is some evidence to suggest that at least part of the effect seen with some antihypertensives on these biomarkers may be independent of BP reduction. Different drugs may have quite different effects on biomarkers, despite very similar or equivalent effects on BP. However, with other drugs, the changes in certain biomarkers appear to parallel changes in BP. In addition, there appear to be clear associations between certain biomarkers, such as HOMA-IR and adiponectin, and the manner in which they are affected by certain antihypertensive drugs.
There is particularly compelling evidence that RAS inhibitors (ACEIs and ARBs) and CCBs may have beneficial effects beyond BP control, making them particularly attractive for either monotherapy or combination therapy. In contrast, other drugs, such as the thiazide diuretic HCTZ, appear to counter the beneficial effects on biomarkers normally observed with ARBs when they are used in combination.
Of the biomarkers selected for review in this chapter, the benefits of antihypertensive therapy on hsCRP, adiponectin, and HOMA-IR reflect a potential for quantifiable long-term vascular benefits. However, more evidence is required to elucidate the mechanisms involved and understand the variability and apparent anomalies observed. In addition, more information about any differences between specific antihypertensive agents within the same class is needed. Additional evidence is required to determine the relevance of improvements observed with antihypertensive therapy on CAP, cystatin C, procollagen, TNF-α, and IL-6 to a reduction in the risk of subsequent vascular events.
Further research is required to determine the extent to which these antihypertensive-related improvements in biomarkers contribute to the overall clinical outcome achieved in tandem with other CV risk reduction strategies and interventions. In addition, long-term studies with biomarkers are also required to show whether biomarkers correlate with long-term clinical outcomes.
Urinary tract infections (UTI) are the most common bacterial infections affecting humans (Zhanel et al. [1]). They may be simple or complicated urinary tract infections (cUTIs), with the latter occurring in patients with urinary tract anatomic or functional abnormalities or major comorbidities [2]. UTIs may be categorized as either population- or hospital-acquired. In community-acquired UTIs,
In addition to being a clinically significant pathogen,
Several studies indicate that efflux pumps can play at least four roles in biofilm formation efflux of EPSs and/or QS and quorum quenching (QQ) molecules to promote biofilm environment creation and regulate QS, correspondingly; indirect regulation of genes engagement in biofilm formation; abolition of harmful particles such as antibiotics and metabolic intermediates; and efflux of harmful molecules such as antibiotics and metabolic intermediates and by encouraging or preventing adhesion to surfaces and other cells, aggregation can be influenced [14]. Overexpression of an efflux system, which results in a decrease in antibiotic accumulation, is an effective mechanism for drug resistance [15, 16].
Efflux pumps are membrane proteins that are involved in the export of noxious substances from within the bacterial cell into the external environment. Efflux proteins are found in both Gram-negative and Gram-positive bacteria as well as in eukaryotic organisms [17]. The ATP-binding cassette (ABC) superfamily [18], the resistance-nodulation-division (RND) family [19], the small multidrug resistance (SMR) family [20], the major facilitator superfamily (MFS) [21], and the multidrug and toxic compound extrusion (MATE) [22] family. The ABC family uses ATP hydrolysis to power substrate export, while the other families depend on the proton motive force for energy. The MFS, ABC, SMR, and MATE families are found in Gram-positive and Gram-negative bacteria, respectively, while the RND superfamily is only found in Gram-negative bacteria. Members of the RND family are often found as part of a three-part complex that spans Gram-negative bacteria’s two membranes [23].
This type of pump is occupied as a tripartite complex constituting the RND protein (the inner membrane component), membrane fusion protein (the periplasmic compartment), and the outer membrane protein. These three proteins form a constitute channel crossways the Gram-negative cell envelope guaranteeing that the molecule, taken from the outer leaflet of the inner membrane bilayer, is replied directly transversely to the periplasm and the outer membrane into the exterior medium with the assistance of the proton-gradient as an energy source. RND family shows a significant role in the intrinsic resistance of Gram-negative bacteria [24, 25]. The most frequent member of RND family in enterobacteria include AcrAB-TolC, AcrAD-TolC, and AcrFE-TolC.
AcrAB-TolC, one of the efflux systems, constitutively expressed in
AcrD is a component of an efflux pump that mediates the export of aminoglycosides and a few amphiphilic compounds such as sodium dodecyl sulfate (SDS), deoxycholate, and novobiocin, AcrA is a periplasmic fusion protein that also exports aminoglycosides in association with the cytoplasmic membrane protein AcrD [30]. Despite increased acrA expression, the mutant strain showed no increase in resistance, suggesting that the deletion of acrD contributes to adaptive resistance directly, rather than indirectly via mechanisms like control of other efflux components. As a result, the previously reported adaptive cross-resistance to non-aminoglycoside antibiotics cannot be due to the development of the AcrAB-TolC complex as shown by an acrD mutant that showed significantly reduced biofilm formation and expression of key biofilm proteins encoded by csgBD, the AcrD efflux pump has an effect on biofilm formation, and appears to play a special biological function, according to Buckner et al. [32] findings. The transcriptome showed major changes, which supported this theory. The transcriptomes of the acrD mutant were compared to the transcriptome of the acrB mutant, which had previously been released AcrD is not a “backup” efflux pump, but serves a physiological function in the cell, as shown by the fact that the effect was quite distinct. This comparison found 232 major gene expression changes that were only caused by the inactivation of acrD and not by the disruption of acrB. Both the acrB and acrD mutant transcriptomes had 169 genes that were differentially expressed as compared to the acrB mutant transcriptome. Experiments have shown that the AcrB and AcrD efflux pumps have different substrate profiles when it refers to aminoglycoside antibiotics [33]. AcrEF-TolC pump is known to exhibit higher expression levels in quinolone-resistant
There is a variety of transport systems in
The MacA-MacB-TolC assembly of
In a macrolide-susceptible AcrAB deficient
Small multidrug resistance transporters (SMR) systems provide to study the minimal requirements for active transport [43]. They are also small multidrug transporters, with four transmembrane helices and no significant extra membrane domain, although they function as dimers the minimum functional unit is a bundle of eight α-helices [44]. SMR transporter exports a broad class of polyaromatic cation substrates, thus conferring resistance to drug compounds matching this chemical description. Genes encoding SMR proteins (variously annotated emrE, ynfA and tehA) are frequently found in mobile drug resistance gene arrays, and provide a broad selective advantage by conferring resistance to ubiquitous environmental pollutants with low-grade toxicity to microbes [45]. The SMR family consists of small hydrophobic proteins of about 100 amino acid residues with four transmembrane α-helical spanners [46].
SMR family includes more than 40 proteins in eubacteria, a few of which have been studied in detail. One of them, EmrE, is an
The gene, ynfA of
The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. The major facilitator transporters form a superfamily that composed a number of subfamilies; of these subfamilies, transporters of sugars and drugs are by far the most numerous [52].
These MFS transporters are typically composed of approximately 400 amino acids that are putatively arranged in 12 membrane-spanning helices, with a large cytoplasmic loop among helices six and seven [43]. The MFS family of drug transporters is made up of two domains that are centered around a central pore and two domains that transfer conformations from the cytoplasmic to the periplasmic side of the membrane in response to a Na + or H+ ion gradient [53]. The MFS drug transporters are classified into subfamilies −12-helix and 14-helix transporters (e.g., TetA(B) and TetA(K), class two and class K tetracycline transporters from
EmrAB–TolC from
EmrD is a multidrug transporter from the Major Facilitator Superfamily that expels amphipathic compounds across the inner membrane of
Export of substrates and toxins by the cell is a fundamental life process and members of the MATE family represent the last class of multidrug resistance (MDR) transporters to be structurally characterized. MATE transporters involved a variety of important biological functions across all kingdoms of life [60]. MATE transporters are very similar in size to the MFS transporters and are typically composed of approx. 450 amino acids which are putatively arranged into 12 helices however, they do not have any sequence similarity to members of the MFS transporters [61]. MdtK is one of the important MATE inner membrane transporter in
The study include antibiotic susceptibility profile (for 20 antibiotics) according to CLSI-2021 [63] and efflux pumps gene profile for (19 genes) for 50 isolates of
Antibiotic | Resistance % | |
---|---|---|
Amoxicillin | 100% | 92% |
Piperacillin | 14% | 16% |
Ceftriaxone | 54% | 92% |
Ceftazidime | 100% | 98% |
Cefepime | 58% | 80% |
Cefixime | 52% | 84% |
Cefotaxime | 100% | 92% |
Cefoxitin | 42% | 46% |
Nitrfuraniton | 38% | 58% |
streptomycin | 36% | 78% |
Gentamycin | 4% | 40% |
Kanamycin | 42% | 50% |
Tobramycin | 20% | 44% |
Amikacin | 14% | 10% |
Netlimicin | 2% | 4% |
Imipenem | 0% | 12% |
Meropenem | 6% | 8% |
Aztreonam | 20% | 58% |
Azithromycin | 10% | 24% |
Nalidixic acid | 26% | 16% |
Antibiotic resistance among
Classes of MDR | ||
---|---|---|
MDR-8 classes | 0% | 4% |
MDR-7 classes | 4% | 8% |
MDR-6 classes | 12% | 20% |
MDR-5 classes | 2% | 22% |
MDR-4 classes | 24% | 28% |
MDR-3 classes | 20% | 8% |
non-MDR | 38% | 10% |
Total | 100% | 100% |
Classes of MDR among
Biofilm Formation Pattern | ||
---|---|---|
non-biofilm former | 2% | 0% |
weak biofilm former | 60% | 40% |
moderate biofilm former | 24% | 44% |
strong biofilm former | 14% | 16% |
Total | 100% | 100% |
Biofilm formation patterns among
Efflux pumps gene | Presence % | |
---|---|---|
100 | 96 | |
86 | 88 | |
96 | 100 | |
100 | 92 | |
66 | 64 | |
100 | 92 | |
98 | 100 | |
100 | 100 | |
100 | 96 | |
100 | 98 | |
96 | 70 | |
100 | 66 | |
98 | 76 | |
100 | 76 | |
98 | 96 | |
100 | 76 | |
98 | 100 | |
100 | 100 | |
100 | 86 |
Efflux pump genes among
Concern results of coexisted pumps in the same
Genotype | No. | % |
---|---|---|
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/TehA/ MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 32 | 64 |
AcrAB-TolC/ AcrAD-TolC/ AcrFE-TolC/ MdfA/ EmrD/ EmrAB-TolC/ YnfA/ TehA/ MacAB-TolC/ MdlAB-TolC/ Mdtk/ DinF | 1 | 2 |
AcrAB-TolC/ AcrAD-TolC/ MdfA/ EmrD/ EmrAB-TolC/ EmrE/ YnfA/ TehA/ MacAB-TolC/ MdlAB-TolC/ Mdtk/ DinF | 16 | 32 |
AcrAB-TolC/ AcrAD-TolC/ MdfA/ EmrD/ EmrAB-TolC/ EmrE/ YnfA/ MacAB-TolC | 1 | 2 |
Co-existed efflux pump genes among
Genotypes | No. | % |
---|---|---|
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 8 | 16 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 3 | 6 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 2 | 4 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk | 2 | 4 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/ YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 8 | 16 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/MacAB-TolC/Mdtk/DinF | 3 | 6 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/TehA/MdlAB-TolC/Mdtk | 2 | 4 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/YnfA/TehA/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MacAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/ TehA/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/TehA/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/TehA/ MacAB- TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/TehA/ MacAB-TolC/MdlAB-TolC/Mdtk | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/TehA/ MacAB- TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/ MacAB-TolC/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/MacAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MacAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/YnfA/TehA/ MdlAB-TolC/ Mdtk/ DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/AcrFE-TolC/MdfA/EmrD/EmrE/ YnfA/MdlAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/AcrAD-TolC/MdfA/EmrD/EmrAB-TolC/MacAB-TolC/Mdtk/DinF | 1 | 2 |
AcrAB-TolC/MdfA/EmrD/EmrAB-TolC/EmrE/TehA/MacAB-TolC/Mdtk | 1 | 2 |
AcrFE-TolC/MdfA/EmrD/EmrAB-TolC/YnfA/MdlAB-TolC/Mdtk/ DinF | 1 | 2 |
Co-existed efflux pump genes among
There is a strong correlation between antibiotic resistance, especially to β-lactams, and the presence of efflux pump genes, which may be reflected in biofilm formation in both
There is no conflict of interest for this work.
Ove Odredbe i uvjeti ističu pravila i regulacije u svezi korištenja IntechOpenove stranice www.intechopen.com i svih poddomena u vlasništvu IntechOpena, tvrtke sa sjedištem u 5 Princes Gate Court, London, SW7 2QJ, Ujedinjeno Kraljevstvo.
',metaTitle:"Odredbe i uvjeti",metaDescription:"Ove Odredbe i uvjeti ističu pravila i regulacije u svezi korištenja IntechOpenove stranice www.intechopen.com i svih poddomena u vlasništvu IntechOpena, tvrtke sa sjedištem u 5 Princes Gate Court, London, SW7 2QJ, Ujedinjeno Kraljevstvo.",metaKeywords:null,canonicalURL:"/page/cro-terms-and-conditions",contentRaw:'[{"type":"htmlEditorComponent","content":"Pristupom na stranicu www.intechopen.com slažete se s ovim odredbama, sa svim primjenjivim zakonskim odredbama, te se slažete s poštovanjem svih lokalnih zakona. Korištenje i/ili pristup ovoj stranici temelji se na potpunom prihvaćanju ovih odredbi. Svi materijali na ovoj stranici zaštićeni su primjenjivim zakonima o autorskim pravima i žigu.
\\n\\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\\n\\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\\n\\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\\n\\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\\n\\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\\n\\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\\n\\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\\n\\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\\n\\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\\n\\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\\n\\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\\n\\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\\n\\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\\n\\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\\n\\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Pristupom na stranicu www.intechopen.com slažete se s ovim odredbama, sa svim primjenjivim zakonskim odredbama, te se slažete s poštovanjem svih lokalnih zakona. Korištenje i/ili pristup ovoj stranici temelji se na potpunom prihvaćanju ovih odredbi. Svi materijali na ovoj stranici zaštićeni su primjenjivim zakonima o autorskim pravima i žigu.
\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\n\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\n\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\n\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\n\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\n\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\n\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\n\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\n\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\n\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\n\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\n\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\n\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\n\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. 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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. 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