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David C. Hooper - One of the best experts on this subject based on the ideXlab platform.
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MECHANISMS OF QUINOLONE RESISTANCE
Gram-Positive Pathogens, 2014Co-Authors: David C. HooperAbstract:With the increasing use of Quinolones for the treatment of gram-positive bacterial infections, an understanding of the mechanisms of quinolone resistance in gram-positive bacteria is of considerable importance. This chapter summarizes the current understanding of established mechanisms of resistance to this class of antimicrobial agents in gram-positive bacteria. There are important differences between gram-positive and gram negative bacteria both in target enzyme sensitivity and in the means by which efflux resistance mechanisms operate that are of clinical and fundamental importance. Quinolones interact with both of the two type 2 topoisomerases in eubacteria, DNA gyrase and topoisomerase IV, which are essential for bacterial DNA replication. Quinolone-resistant clinical and laboratory strains of Streptococcus pneumoniae have been shown to have reduced accumulation of Quinolones that is reversible with reserpine, suggesting the involvement of an efflux system(s) in quinolone resistance. Quinolone-resistant clinical isolates of viridans streptococci have been shown to have an efflux phenotype defined as lower MICs of Quinolones in the presence of reserpine. DNA from such strains of S. mitis and S. oralis was able to transform S. pneumoniae to efflux phenotype in the laboratory. Overexpression of norA and genes for topoisomerases from plasmids are known, however, to have toxic effects on the cell that may limit the fitness of resistant bacteria containing them. Thus, at present quinolone resistance in gram-positive bacteria is attributable exclusively to chromosomal mutations that affect quinolone targets or quinolone permeation to these targets.
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Mechanisms of Quinolone Action
Quinolone Antimicrobial Agents, 2014Co-Authors: Karl Drlica, David C. HooperAbstract:This chapter introduces the Quinolones with a brief consideration of DNA topoisomerases and quinolone target preference. Throughout the chapter attention is given to fluoroquinolone structure. Recently discovered examples include the relaxation of supercoils associated with infection of cultured macrophages by Salmonella enterica serovar Typhimurium and with hydrogen peroxide treatment of Escherichia coli. The bacterial topoisomerases are divided into three groups: type I (topoisomerases I and III), type II (gyrase and topoisomerase IV), and specialized topoisomerases (enzymes that catalyze transposition or integration/excision of bacteriophage DNA from the bacterial chromosome). A function of topoisomerase I is the topological destabilization of transcription-mediated R loops. Another is likely to be control of global supercoiling, since a topA defect that raises supercoiling also suppresses a mukB mutation, a defect that has a global effect on chromosome condensation. Quinolone binding to these mutant gyrase-DNA complexes induces a conformational change that can be detected in the GyrB subunit by limited proteolysis. The location of the quinolone-gyrase-DNA complexes on the bacterial chromosome is likely to influence the potential damage that Quinolones can cause. The bacteriostatic effects of the Quinolones are now understood at a level sufficient to allow structure-function interpretations. From a clinical perspective, there is a need to identify safe compounds that rapidly kill bacteria, especially resistant mutants. However, further refinement could become an academic exercise if ways are not developed to slow the emergence of fluoroquinolone-resistant pathogens.
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plasmid mediated quinolone resistance a multifaceted threat
Clinical Microbiology Reviews, 2009Co-Authors: Jacob Strahilevitz, George A. Jacoby, David C. Hooper, Ari RobicsekAbstract:Summary: Although plasmid-mediated quinolone resistance (PMQR) was thought not to exist before its discovery in 1998, the past decade has seen an explosion of research characterizing this phenomenon. The best-described form of PMQR is determined by the qnr group of genes. These genes, likely originating in aquatic organisms, code for pentapeptide repeat proteins. These proteins reduce susceptibility to Quinolones by protecting the complex of DNA and DNA gyrase or topoisomerase IV enzymes from the inhibitory effect of Quinolones. Two additional PMQR mechanisms were recently described. aac(6′)-Ib-cr encodes a variant aminoglycoside acetyltransferase with two amino acid alterations allowing it to inactivate ciprofloxacin through the acetylation of its piperazinyl substituent. oqxAB and qepA encode efflux pumps that extrude Quinolones. All of these genes determine relatively small increases in the MICs of Quinolones, but these changes are sufficient to facilitate the selection of mutants with higher levels of resistance. The contribution of these genes to the emergence of quinolone resistance is being actively investigated. Several factors suggest their importance in this process, including their increasing ubiquity, their association with other resistance elements, and their emergence simultaneous with the expansion of clinical quinolone resistance. Of concern, these genes are not yet being taken into account in resistance screening by clinical microbiology laboratories.
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the worldwide emergence of plasmid mediated quinolone resistance
Lancet Infectious Diseases, 2006Co-Authors: George A. Jacoby, Ari Robicsek, David C. HooperAbstract:Summary Fluoroquinolone resistance is emerging in Gram-negative pathogens worldwide. The traditional understanding that quinolone resistance is acquired only through mutation and transmitted only vertically does not entirely account for the relative ease with which resistance develops in exquisitely susceptible organisms, or for the very strong association between resistance to Quinolones and to other agents. The recent discovery of plasmid-mediated horizontally transferable genes encoding quinolone resistance might shed light on these phenomena. The Qnr proteins, capable of protecting DNA gyrase from Quinolones, have homologues in water-dwelling bacteria, and seem to have been in circulation for some time, having achieved global distribution in a variety of plasmid environments and bacterial genera. AAC(6′)-Ib-cr, a variant aminoglycoside acetyltransferase capable of modifying ciprofloxacin and reducing its activity, seems to have emerged more recently, but might be even more prevalent than the Qnr proteins. Both mechanisms provide low-level quinolone resistance that facilitates the emergence of higher-level resistance in the presence of Quinolones at therapeutic levels. Much remains to be understood about these genes, but their insidious promotion of substantial resistance, their horizontal spread, and their co-selection with other resistance elements indicate that a more cautious approach to quinolone use and a reconsideration of clinical breakpoints are needed.
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Mode of Action of FluoroQuinolones
Drugs, 1999Co-Authors: David C. HooperAbstract:The mode of action of Quinolones involves interactions with both DNA gyrase, the originally recognised drug target, and topoisomerase IV, a related type II topoisomerase. In a given bacterium these 2 enzymes often differ in their relative sensitivities to many Quinolones, and commonly DNA gyrase is more sensitive in Gram-negative bacteria and topoisomerase IV more sensitive in Gram-positive bacteria. Usually the more sensitive enzyme represents the primary drug target determined by genetic tests, but poorly understood exceptions have been documented. The formation of the ternary complex of quinolone, DNA, and either DNA gyrase or topoisomerase IV occurs through interactions in which quinolone binding appears to induce changes in both DNA and the topoisomerase that occur separately from the DNA cleavage that is the hallmark of quinolone action. X-ray crystallographic studies of a fragment of the gyrase A subunit, as well as of yeast topoisomerase IV, which has homology to the subunits of both DNA gyrase and topoisomerase IV, have revealed domains that are likely to constitute quinolone binding sites, but no topoisomerase crystal structures that include DNA and quinolone have been reported to date. Inhibition of DNA synthesis by Quinolones requires the targeted topoisomerase to have DNA cleavage capability, and collisions of the replication fork with reversible quinolone-DNA-topoisomerase complexes convert them to an irreversible form. However, the molecular factors that subsequently generate DNA double-strand breaks from the irreversible complexes and that probably initiate cell death have yet to be defined.
George A. Jacoby - One of the best experts on this subject based on the ideXlab platform.
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Study of Plasmid-Mediated Quinolone Resistance in Bacteria.
Methods in Molecular Biology, 2017Co-Authors: George A. JacobyAbstract:Plasmid-mediated quinolone resistance (PMQR) involves genes for proteins that protect the quinolone targets, an enzyme that inactivates certain Quinolones as well as aminoglycosides, and pumps that efflux Quinolones. Quinolone susceptibility is reduced by these mechanisms but not to the level of clinical resistance unless chromosomal mutations are also present. PCR primers and conditions for PMQR gene detection are described as well as how to establish a plasmid location.
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plasmid mediated quinolone resistance a multifaceted threat
Clinical Microbiology Reviews, 2009Co-Authors: Jacob Strahilevitz, George A. Jacoby, David C. Hooper, Ari RobicsekAbstract:Summary: Although plasmid-mediated quinolone resistance (PMQR) was thought not to exist before its discovery in 1998, the past decade has seen an explosion of research characterizing this phenomenon. The best-described form of PMQR is determined by the qnr group of genes. These genes, likely originating in aquatic organisms, code for pentapeptide repeat proteins. These proteins reduce susceptibility to Quinolones by protecting the complex of DNA and DNA gyrase or topoisomerase IV enzymes from the inhibitory effect of Quinolones. Two additional PMQR mechanisms were recently described. aac(6′)-Ib-cr encodes a variant aminoglycoside acetyltransferase with two amino acid alterations allowing it to inactivate ciprofloxacin through the acetylation of its piperazinyl substituent. oqxAB and qepA encode efflux pumps that extrude Quinolones. All of these genes determine relatively small increases in the MICs of Quinolones, but these changes are sufficient to facilitate the selection of mutants with higher levels of resistance. The contribution of these genes to the emergence of quinolone resistance is being actively investigated. Several factors suggest their importance in this process, including their increasing ubiquity, their association with other resistance elements, and their emergence simultaneous with the expansion of clinical quinolone resistance. Of concern, these genes are not yet being taken into account in resistance screening by clinical microbiology laboratories.
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the worldwide emergence of plasmid mediated quinolone resistance
Lancet Infectious Diseases, 2006Co-Authors: George A. Jacoby, Ari Robicsek, David C. HooperAbstract:Summary Fluoroquinolone resistance is emerging in Gram-negative pathogens worldwide. The traditional understanding that quinolone resistance is acquired only through mutation and transmitted only vertically does not entirely account for the relative ease with which resistance develops in exquisitely susceptible organisms, or for the very strong association between resistance to Quinolones and to other agents. The recent discovery of plasmid-mediated horizontally transferable genes encoding quinolone resistance might shed light on these phenomena. The Qnr proteins, capable of protecting DNA gyrase from Quinolones, have homologues in water-dwelling bacteria, and seem to have been in circulation for some time, having achieved global distribution in a variety of plasmid environments and bacterial genera. AAC(6′)-Ib-cr, a variant aminoglycoside acetyltransferase capable of modifying ciprofloxacin and reducing its activity, seems to have emerged more recently, but might be even more prevalent than the Qnr proteins. Both mechanisms provide low-level quinolone resistance that facilitates the emergence of higher-level resistance in the presence of Quinolones at therapeutic levels. Much remains to be understood about these genes, but their insidious promotion of substantial resistance, their horizontal spread, and their co-selection with other resistance elements indicate that a more cautious approach to quinolone use and a reconsideration of clinical breakpoints are needed.
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mechanism of plasmid mediated quinolone resistance
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: John H Tran, George A. JacobyAbstract:Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to Quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-like environment upstream from qacEΔ1 and sulI. The gene product Qnr was a 218-aa protein belonging to the pentapeptide repeat family and shared sequence homology with the immunity protein McbG, which is thought to protect DNA gyrase from the action of microcin B17. Qnr had pentapeptide repeat domains of 11 and 28 tandem copies, separated by a single glycine with a consensus sequence of A/C D/N L/F X X. Because the primary target of Quinolones is DNA gyrase in Gram-negative strains, we tested the ability of Qnr to reverse the inhibition of gyrase activity by Quinolones. Purified Qnr-His6 protected Escherichia coli DNA gyrase from inhibition by ciprofloxacin. Gyrase protection was proportional to the concentration of Qnr-His6 and inversely proportional to the concentration of ciprofloxacin. The protective activity of Qnr-His6 was lost by boiling the protein and involved neither quinolone inactivation nor independent gyrase activity. Protection of topoisomerase IV, a secondary target of quinolone action in E. coli, was not evident. How Qnr protects DNA gyrase and the prevalence of this resistance mechanism in clinical isolates remains to be determined.
Ari Robicsek - One of the best experts on this subject based on the ideXlab platform.
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plasmid mediated quinolone resistance a multifaceted threat
Clinical Microbiology Reviews, 2009Co-Authors: Jacob Strahilevitz, George A. Jacoby, David C. Hooper, Ari RobicsekAbstract:Summary: Although plasmid-mediated quinolone resistance (PMQR) was thought not to exist before its discovery in 1998, the past decade has seen an explosion of research characterizing this phenomenon. The best-described form of PMQR is determined by the qnr group of genes. These genes, likely originating in aquatic organisms, code for pentapeptide repeat proteins. These proteins reduce susceptibility to Quinolones by protecting the complex of DNA and DNA gyrase or topoisomerase IV enzymes from the inhibitory effect of Quinolones. Two additional PMQR mechanisms were recently described. aac(6′)-Ib-cr encodes a variant aminoglycoside acetyltransferase with two amino acid alterations allowing it to inactivate ciprofloxacin through the acetylation of its piperazinyl substituent. oqxAB and qepA encode efflux pumps that extrude Quinolones. All of these genes determine relatively small increases in the MICs of Quinolones, but these changes are sufficient to facilitate the selection of mutants with higher levels of resistance. The contribution of these genes to the emergence of quinolone resistance is being actively investigated. Several factors suggest their importance in this process, including their increasing ubiquity, their association with other resistance elements, and their emergence simultaneous with the expansion of clinical quinolone resistance. Of concern, these genes are not yet being taken into account in resistance screening by clinical microbiology laboratories.
-
the worldwide emergence of plasmid mediated quinolone resistance
Lancet Infectious Diseases, 2006Co-Authors: George A. Jacoby, Ari Robicsek, David C. HooperAbstract:Summary Fluoroquinolone resistance is emerging in Gram-negative pathogens worldwide. The traditional understanding that quinolone resistance is acquired only through mutation and transmitted only vertically does not entirely account for the relative ease with which resistance develops in exquisitely susceptible organisms, or for the very strong association between resistance to Quinolones and to other agents. The recent discovery of plasmid-mediated horizontally transferable genes encoding quinolone resistance might shed light on these phenomena. The Qnr proteins, capable of protecting DNA gyrase from Quinolones, have homologues in water-dwelling bacteria, and seem to have been in circulation for some time, having achieved global distribution in a variety of plasmid environments and bacterial genera. AAC(6′)-Ib-cr, a variant aminoglycoside acetyltransferase capable of modifying ciprofloxacin and reducing its activity, seems to have emerged more recently, but might be even more prevalent than the Qnr proteins. Both mechanisms provide low-level quinolone resistance that facilitates the emergence of higher-level resistance in the presence of Quinolones at therapeutic levels. Much remains to be understood about these genes, but their insidious promotion of substantial resistance, their horizontal spread, and their co-selection with other resistance elements indicate that a more cautious approach to quinolone use and a reconsideration of clinical breakpoints are needed.
Pedro Giavina-bianchi - One of the best experts on this subject based on the ideXlab platform.
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Quinolone-Induced Anaphylaxis
Current Treatment Options in Allergy, 2020Co-Authors: Nathalia Coelho Portilho, Jorge Kalil, Pedro Giavina-bianchiAbstract:Purpose of review Quinolones are the second most common antibiotic class that may induce IgE and non-IgE-mediated immediate hypersensitivity reactions. The prevalence of true quinolone allergy still remains unknown, but its incidence has increased in recent years, probably due to the extensive utilization of this antibiotic class and the introduction of moxifloxacin. Recent findings Quinolones may also induce nonallergic reactions through the MRGPRX2 receptor. The diagnosis of hypersensitivity reactions to Quinolones is complex, since clinical history is often doubtful, skin tests can induce false-positive results, and in vitro tests are not well validated. Therefore, in many cases, the only way to confirm or rule out the diagnosis is drug provocation test, a procedure that carries some risks. Quinolones present a variable degree of cross-reactivity that is undetermined and difficult to predict, and desensitization may be required in patients with no other antibiotic options. Summary This review critically analyzed the existing data on quinolone allergy, highlighting the recent advances in its diagnosis and management. Further studies are needed to increase the knowledge in the field and to improve patients’ care.
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Quinolone-Induced Anaphylaxis
Current Treatment Options in Allergy, 2020Co-Authors: Nathalia Coelho Portilho, Jorge Kalil, Marcelo Vivolo Aun, Pedro Giavina-bianchiAbstract:Quinolones are the second most common antibiotic class that may induce IgE and non-IgE-mediated immediate hypersensitivity reactions. The prevalence of true quinolone allergy still remains unknown, but its incidence has increased in recent years, probably due to the extensive utilization of this antibiotic class and the introduction of moxifloxacin. Quinolones may also induce nonallergic reactions through the MRGPRX2 receptor. The diagnosis of hypersensitivity reactions to Quinolones is complex, since clinical history is often doubtful, skin tests can induce false-positive results, and in vitro tests are not well validated. Therefore, in many cases, the only way to confirm or rule out the diagnosis is drug provocation test, a procedure that carries some risks. Quinolones present a variable degree of cross-reactivity that is undetermined and difficult to predict, and desensitization may be required in patients with no other antibiotic options. This review critically analyzed the existing data on quinolone allergy, highlighting the recent advances in its diagnosis and management. Further studies are needed to increase the knowledge in the field and to improve patients’ care.
Augusto Filipe - One of the best experts on this subject based on the ideXlab platform.
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Quinolones
Drug Safety, 2011Co-Authors: Ana Maria Tomé, Augusto FilipeAbstract:Quinolones are a class of antibacterial agents for the treatment of several infectious diseases (e.g. urinary and respiratory tract infections). They are used worldwide due to their broad spectrum of activity, high bioavailability and good safety profile. The safety profile varies from quinolone to quinolone. The aim of this article was to review the neurological and psychiatric adverse drug reaction (ADR) profile of Quinolones, using a literature search strategy designed to identify case reports and case series. A literature search using PubMed/MEDLINE (from inception to 31 October 2010) was performed to identify case reports and case series related to quinolone-associated neurological and psychiatric ADRs. The search was conducted in two phases: the first phase was the literature search and in the second phase relevant articles were identified through review of the references of the selected articles. Relevant articles were defined as articles referring to adverse events/ reactions associated with the use of any quinolone. Abstracts referring to animal studies, clinical trials and observational studies were excluded. Identified case reports were analysed by age group, sex, active substances, dosage, concomitant medication, ambulatory or hospital-based event and seriousness, after Medical Dictionary for Regulatory Activities (MedDRA®) coding. From a total of 828 articles, 83 were identified as referring to nervous system and/or psychiatric disorders induced by Quinolones. 145 individual case reports were extracted from the 83 articles. 40.7% of the individual case reports belonged to psychiatric disorders only, whereas 46.9% related to neurological disorders only. Eight (5.5%) individual case reports presented both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pefloxacin were the Quinolones with more neurological and psychiatric ADRs reported in the literature. Ciprofloxacin has been extensively used worldwide, which may explain the higher number of reports, while for ofloxacin and pefloxacin, the number of reports may be over-representative. A total of 232 ADRs were identified from the selected articles, with 206 of these related to psychiatric and/or neurological ADRs. The other 26 were related to other body systems but were reported together with the reactions of interest. Mania, insomnia, acute psychosis and delirium were the most frequently reported psychiatric adverse events; grand mal convulsion, confusional state, convulsions and myoclonus were the most frequently reported neurological adverse events. Several aspects should be taken into account in the development of CNS adverse effects, such as the pharmacokinetics of Quinolones, chemical structure and quinolone uptake in the brain. These events may affect not only susceptible patients but also ’healthy’ patients.
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Quinolones review of psychiatric and neurological adverse reactions
Drug Safety, 2011Co-Authors: Ana Maria Tomé, Augusto FilipeAbstract:Quinolones are a class of antibacterial agents for the treatment of several infectious diseases (e.g. urinary and respiratory tract infections). They are used worldwide due to their broad spectrum of activity, high bioavailability and good safety profile. The safety profile varies from quinolone to quinolone. The aim of this article was to review the neurological and psychiatric adverse drug reaction (ADR) profile of Quinolones, using a literature search strategy designed to identify case reports and case series. A literature search using PubMed/MEDLINE (from inception to 31 October 2010) was performed to identify case reports and case series related to quinolone-associated neurological and psychiatric ADRs. The search was conducted in two phases: the first phase was the literature search and in the second phase relevant articles were identified through review of the references of the selected articles. Relevant articles were defined as articles referring to adverse events/reactions associated with the use of any quinolone. Abstracts referring to animal studies, clinical trials and observational studies were excluded. Identified case reports were analysed by age group, sex, active substances, dosage, concomitant medication, ambulatory or hospital-based event and seriousness, after Medical Dictionary for Regulatory Activities (MedDRA®) coding. From a total of 828 articles, 83 were identified as referring to nervous system and/or psychiatric disorders induced by Quinolones. 145 individual case reports were extracted from the 83 articles. 40.7% of the individual case reports belonged to psychiatric disorders only, whereas 46.9% related to neurological disorders only. Eight (5.5%) individual case reports presented both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pefloxacin were the Quinolones with more neurological and psychiatric ADRs reported in the literature. Ciprofloxacin has been extensively used worldwide, which may explain the higher number of reports, while for ofloxacin and pefloxacin, the number of reports may be over-representative. A total of 232 ADRs were identified from the selected articles, with 206 of these related to psychiatric and/or neurological ADRs. The other 26 were related to other body systems but were reported together with the reactions of interest. Mania, insomnia, acute psychosis and delirium were the most frequently reported psychiatric adverse events; grand mal convulsion, confusional state, convulsions and myoclonus were the most frequently reported neurological adverse events. Several aspects should be taken into account in the development of CNS adverse effects, such as the pharmacokinetics of Quinolones, chemical structure and quinolone uptake in the brain. These events may affect not only susceptible patients but also 'healthy' patients.
