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Latifa Patel - One of the best experts on this subject based on the ideXlab platform.
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Macrolide Antibiotics for cystic fibrosis
Cochrane Database of Systematic Reviews, 2012Co-Authors: K W Southern, P M Barker, Arturo Solismoya, Latifa PatelAbstract:Background Macrolide Antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis. Objectives To test the hypotheses that, in people with cystic fibrosis, Macrolide Antibiotics: 1. improve clinical status compared to placebo or another antibiotic; 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of Macrolide therapy. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing Macrolide Antibiotics for unpublished or follow-up data (May 2010). Latest search of the Group's Cystic Fibrosis Trials Register: 29 February 2012. Selection criteria Randomised controlled trials of Macrolide Antibiotics compared to: placebo; another class of antibiotic; another Macrolide antibiotic; or the same Macrolide antibiotic at a different dose. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review. Main results Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral Antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in Macrolide resistance. Authors' conclusions This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of Macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.
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The Cochrane Library - Macrolide Antibiotics for cystic fibrosis
Cochrane Database of Systematic Reviews, 2012Co-Authors: K W Southern, P M Barker, Arturo Solis-moya, Latifa PatelAbstract:Background Macrolide Antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis. Objectives To test the hypotheses that, in people with cystic fibrosis, Macrolide Antibiotics: 1. improve clinical status compared to placebo or another antibiotic; 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of Macrolide therapy. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing Macrolide Antibiotics for unpublished or follow-up data (May 2010). Latest search of the Group's Cystic Fibrosis Trials Register: 29 February 2012. Selection criteria Randomised controlled trials of Macrolide Antibiotics compared to: placebo; another class of antibiotic; another Macrolide antibiotic; or the same Macrolide antibiotic at a different dose. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review. Main results Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral Antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in Macrolide resistance. Authors' conclusions This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of Macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.
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Macrolide Antibiotics for cystic fibrosis.
The Cochrane database of systematic reviews, 2011Co-Authors: K W Southern, P M Barker, Arturo Solis-moya, Latifa PatelAbstract:Macrolide Antibiotics may have a modifying role in diseases which involve airway infection and inflammation, like cystic fibrosis. To test the hypotheses that, in people with cystic fibrosis, Macrolide Antibiotics: 1. improve clinical status compared to placebo or another antibiotic; 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of Macrolide therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing Macrolide Antibiotics for unpublished or follow-up data (May 2010).Latest search of the Group's Cystic Fibrosis Trials Register: 09 February 2011. Randomised controlled trials of Macrolide Antibiotics compared to: placebo; another class of antibiotic; another Macrolide antibiotic; or the same Macrolide antibiotic at a different dose. Two authors independently extracted data and assessed risk of bias. Seven groups were contacted and provided additional data which were incorporated into the review. Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral Antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in Macrolide resistance. This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of Macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.
R M Marce - One of the best experts on this subject based on the ideXlab platform.
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determination of Macrolide Antibiotics in meat and fish using pressurized liquid extraction and liquid chromatography mass spectrometry
Journal of Chromatography A, 2008Co-Authors: Houda Berrada, Francesc Borrull, G Font, R M MarceAbstract:Abstract We developed a method for determining the quantities of seven Macrolide Antibiotics in meat and fish by using pressurized liquid extraction (PLE) and liquid chromatography–mass spectrometry with electrospray ionization (LC–(ESI)MS). The PLE was optimized with regard to solvents, temperature, pressure, extraction time and number of cycles. The optimum conditions were: methanol as the extraction solvent; a temperature of 80 °C; a pressure of 1500 psi; an extraction time of 15 min; 2 cycles; a flush volume of 150% and a purge time of 300 s. All recoveries for Macrolide Antibiotics were over 77% at 200 μg/kg, except for erythromycin, which was 58%. The repeatability and reproducibility on days in between, expressed as %RSD (n = 12), were lower than 10% and 12%, respectively. The quantification limits of all compounds were 25 μg/kg of dry weight of animal muscle except for troleandomycin (50 μg/kg). The method was applied to determine the pharmaceuticals in real samples taken from 18 meat and fish samples. The results showed that PLE is quantitative short time consuming technique, with use of smaller initial sample sizes. Greater specificity and selectivity in extraction and increased potential for automation were shown.
Rodrigo B Andrade - One of the best experts on this subject based on the ideXlab platform.
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total synthesis of desmethyl Macrolide Antibiotics
Synlett, 2015Co-Authors: Rodrigo B AndradeAbstract:Macrolide Antibiotics occupy a special place in the history of organic chemistry and medicine. This account chronicles the evolution of our approach that ultimately led to the successful total syntheses of four desmethyl (i.e., Me → H) analogues of telithromycin, a semisynthetic derivative of the flagship Macrolide antibiotic, erythromycin. 1 Introduction 2 Project Rationale and Retrosynthetic Analysis 3 Lessons Learned from the Total Synthesis of 4,8,10-Tridesmethyl Telithromycin 4 Total Synthesis of 4,10-Didesmethyl Telithromycin 5 Total Synthesis of 4,8-Didesmethyl Telithromycin 6 Total Synthesis of 4-Desmethyl Telithromycin 7 Biological Evaluation of Desmethyl Telithromycin Analogues 8 Concluding Remarks
Amit X Garg - One of the best experts on this subject based on the ideXlab platform.
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Macrolide Antibiotics and the risk of ventricular arrhythmia in older adults
Canadian Medical Association Journal, 2016Co-Authors: Mai H Trac, Eric Mcarthur, Racquel Jandoc, Stephanie N Dixon, Danielle M Nash, Daniel G Hackam, Amit X GargAbstract:Background: Many respiratory tract infections are treated with Macrolide Antibiotics. Regulatory agencies warn that these Antibiotics increase the risk of ventricular arrhythmia. We examined the 30-day risk of ventricular arrhythmia and all-cause mortality associated with Macrolide Antibiotics relative to nonMacrolide Antibiotics. Methods: We conducted a population-based retrospective cohort study involving older adults (age > 65 yr) with a new prescription for an oral Macrolide antibiotic (azithromycin, clarithromycin or erythromycin) in Ontario from 2002 to 2013. Our primary outcome was a hospital encounter with ventricular arrhythmia within 30 days after a new prescription. Our secondary outcome was 30-day all-cause mortality. We matched patients 1:1 using propensity scores to patients prescribed nonMacrolide Antibiotics (amoxicillin, cefuroxime or levofloxacin). We used conditional logistic regression to measure the association between Macrolide exposure and outcomes, and repeated the analysis in 4 subgroups defined by the presence or absence of chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval. Results: Compared with nonMacrolide Antibiotics, Macrolide Antibiotics were not associated with a higher risk of ventricular arrhythmia (0.03% v. 0.03%; relative risk [RR] 1.06, 95% confidence interval [CI] 0.83–1.36) and were associated with a lower risk of all-cause mortality (0.62% v. 0.76%; RR 0.82, 95% CI 0.78–0.86). These associations were similar in all subgroups. Interpretation: Among older adults, Macrolide Antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonMacrolide Antibiotics. These findings suggest that current warnings from the US Food and Drug Administration may be overstated.
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comparing two types of Macrolide Antibiotics for the purpose of assessing population based drug interactions
BMJ Open, 2013Co-Authors: Jamie L Fleet, Danielle M Nash, Salimah Z Shariff, David G Bailey, Sonja Gandhi, David N Juurlink, Muhammad Mamdani, Tara Gomes, Amit M Patel, Amit X GargAbstract:Objective: Clarithromycin strongly inhibits enzyme cytochrome P450 3A4, preventing the metabolism of some other drugs, while azithromycin is a weak inhibitor. Accordingly, blood concentrations of other drugs increase with clarithromycin coprescription leading to adverse events. These Macrolide Antibiotics also differ on other properties that may impact outcomes. In this study, we compared outcomes in two groups of Macrolide antibiotic users in the absence of potentially interacting drugs. Design: Population-based retrospective cohort study.
Alexander S. Mankin - One of the best experts on this subject based on the ideXlab platform.
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how Macrolide Antibiotics work
Trends in Biochemical Sciences, 2018Co-Authors: Nora Vazquezlaslop, Alexander S. MankinAbstract:Macrolide Antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus, Macrolides have been viewed as ‘tunnel plugs’ that stop the synthesis of every protein. More recent evidence, however, demonstrates that Macrolides selectively inhibit the translation of a subset of cellular proteins, and that their action crucially depends on the nascent protein sequence and on the antibiotic structure. Therefore, Macrolides emerge as modulators of translation rather than as global inhibitors of protein synthesis. The context-specific action of Macrolides is the basis for regulating the expression of resistance genes. Understanding the details of the mechanism of Macrolide action may inform rational design of new drugs and unveil important principles of translation regulation.
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the general mode of translation inhibition by Macrolide Antibiotics
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Krishna Kannan, Tanel Tenson, Pinal Kanabar, David Schryer, Tanja Florin, Eugene Oh, Neil Bahroos, Jonathan S Weissman, Alexander S. MankinAbstract:Macrolides are clinically important Antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that Macrolide Antibiotics can differentially affect synthesis of individual proteins. To understand the general mechanism of Macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of Macrolide Antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of Macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5′-proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The problematic sequence motifs are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segment that contacts the antibiotic molecule in the exit tunnel. Therefore, it appears that the general mode of Macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not functioning during in vitro protein synthesis may modulate site-specific action of Macrolide Antibiotics.
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Macrolide Antibiotics in the ribosome exit tunnel species specific binding and action
Annals of the New York Academy of Sciences, 2011Co-Authors: Krishna Kannan, Alexander S. MankinAbstract:: Macrolide Antibiotics bind in the nascent peptide exit tunnel of the ribosome and inhibit protein synthesis. The majority of information on the principles of binding and action of these Antibiotics comes from studies that employed model organisms. However, there is a growing understanding that the binding of Macrolides to their target, as well as the mode of inhibition of translation, can be strongly influenced by variations in ribosome structure between bacterial species. Awareness of the existence of species-specific differences in drug action and appreciation of the extent of these differences can stimulate future work on developing better Macrolide drugs. In this review, representative cases illustrating the organism-specific binding and action of Macrolide Antibiotics, as well as species-specific mechanisms of resistance are analyzed.
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binding site of Macrolide Antibiotics on the ribosome new resistance mutation identifies a specific interaction of ketolides with rrna
Journal of Bacteriology, 2001Co-Authors: Georgina Garzaramos, Liqun Xiong, Ping Zhong, Alexander S. MankinAbstract:Macrolides represent a clinically important class of Antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The Macrolide binding site is composed primarily of rRNA. However, the mode of interaction of Macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of Macrolide Antibiotics, known as ketolides, show improved activity against organisms that have developed resistance to previously used Macrolides. The biochemical reasons for increased potency of ketolides remain unknown. Here we describe the first mutation that confers resistance to ketolide Antibiotics while leaving cells sensitive to other types of Macrolides. A transition of U to C at position 2609 of 23S rRNA rendered E. coli cells resistant to two different types of ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with Macrolide Antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the Macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of Macrolide inhibitory action and explains the dominant nature of Macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with Macrolides from those believed to participate in structure-specific interactions with ketolides provides the structural basis for the improved activity of the broader spectrum group of Macrolide Antibiotics.
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Short peptides conferring resistance to Macrolide Antibiotics
Peptides, 2001Co-Authors: Tanel Tenson, Alexander S. MankinAbstract:Abstract Translation of specific short peptides can render the ribosome resistant to Macrolide Antibiotics such as erythromycin. Peptides act in cis upon the ribosome on which they have been translated. Amino acid sequence and size are critical for peptide activity. Pentapeptides with different consensus sequences confer resistance to structurally different Macrolide Antibiotics, suggesting direct interaction between the peptide and the drug on the ribosome. Translation of resistance peptides may result in expulsion of the Macrolide Antibiotics from the ribosome. The consensus sequence of peptides conferring erythromycin resistance is similar to the sequence of the leader peptide involved in translational attenuation of erythromycin resistance genes, indicating that a similar type of interaction between the nascent peptide and Antibiotics can occur in both cases.
