Quinolones in 2005: an update
TL;DR: Overall, it is concluded that these important agents should be used in an educated fashion, based on a careful balance between their ease of use and efficacy vs. the risk of emerging resistance and toxicity.
About: This article is published in Clinical Microbiology and Infection.The article was published on 2005-04-01 and is currently open access. It has received 342 citations till now. The article focuses on the topics: Antibacterial agent & Drug resistance.
Citations
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TL;DR: Among broad-spectrum antibiotics in development, ceftobiprole, sitafloxacin and doripenem show interesting in-vitro activity, although the first two molecules have been evaluated in clinics only against Gram-positive organisms.
563 citations
TL;DR: This work reviews selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa.
Abstract: Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.
487 citations
TL;DR: This review focuses on the use of fluoroquinolones within veterinary medicine, providing an overview of the structure-activity relationship of the various members of the group, the clinical uses offluoroquolones in veterinary Medicine, their pharmacokinetics and potential interspecies differences, and a summary of toxicities associated with this class of compounds.
Abstract: The fluoroquinolones are a class of compounds that comprise a large and expanding group of synthetic antimicrobial agents. Structurally, all fluoroquinolones contain a fluorine molecule at the 6-position of the basic quinolone nucleus. Despite the basic similarity in the core structure of these molecules, their physicochemical properties, pharmacokinetic characteristics and microbial activities can vary markedly across compounds. The first of the fluoroquinolones approved for use in animals, enrofloxacin, was approved in the late 1980s. Since then, five other fluoroquinolones have been marketed for use in animals in the United States, with others currently under investigation. This review focuses on the use of fluoroquinolones within veterinary medicine, providing an overview of the structure-activity relationship of the various members of the group, the clinical uses of fluoroquinolones in veterinary medicine, their pharmacokinetics and potential interspecies differences, an overview of the current understanding of the pharmacokinetic/pharmacodynamic relationships associated with fluoroquinolones, a summary of toxicities that have been associated with this class of compounds, their use in both in human and veterinary species, mechanisms associated with the development of microbial resistance to the fluoroquinolones, and a discussion of fluoroquinolone dose optimization. Although the review contains a large body of basic research information, it is intended that the contents of this review have relevance to both the research scientist and the veterinary medical practitioner.
336 citations
TL;DR: Although plasmid-mediated resistance mechanisms cause only low-level resistance, they favor and complement the selection of other resistance mechanisms.
263 citations
Cites background from "Quinolones in 2005: an update"
...Quinolone antimicrobial agents Classification Quinolones are synthetic antimicrobial agents derived from the 4-quinolone structure [6, 14]....
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TL;DR: The recent observations suggest that the aquatic environment might constitute the original source of PMQR genes, that would secondly spread among animal or human isolates.
Abstract: Resistance to quinolones and fluoroquinolones is being increasingly reported among human but also veterinary isolates during the last two to three decades, very likely as a consequence of the large clinical usage of those antibiotics. Even if the principle mechanisms of resistance to quinolones are chromosome-encoded, due to modifications of molecular targets (DNA gyrase and topoisomerase IV), decreased outer-membrane permeability (porin defect) and overexpression of naturally-occurring efflux, the emergence of plasmid-mediated quinolone resistance (PMQR) has been reported since 1998. Although these PMQR determinants confer low-level resistance to quinolones and/or fluoroquinolones, they are a favorable background for selection of additional chromosome-encoded quinolone resistance mechanisms. Different transferable mechanisms have been identified, corresponding to the production of Qnr proteins, of the aminoglycoside acetyltransferase AAC(6’)-Ib-cr, or of the QepA-type or OqxAB-type efflux pumps. Qnr proteins protect target enzymes (DNA gyrase and type IV topoisomerase) from quinolone inhibition (mostly nalidixic acid). The AAC(6’)-Ib-cr determinant acetylates several fluoroquinolones, such as norfloxacin and ciprofloxacin. Finally, the QepA and OqxAB efflux pumps extrude fluoroquinolones from the bacterial cell. A series of studies have identified the environment to be a reservoir of PMQR genes, with farm animals and aquatic habitats being significantly involved. In addition, the origin of the qnr genes has been identified, corresponding to the waterborne species Shewanella sp. Altogether, the recent observations suggest that the aquatic environment might constitute the original source of PMQR genes, that would secondly spread among animal or human isolates.
243 citations
Cites background from "Quinolones in 2005: an update"
...…developed and presented increased activity toward Gram-positive bacteria, in particularly to Streptococcus pneumoniae (e.g., sparfloxacin, levofloxacin, or moxifloxacin), and potent activity against anaerobic bacteria (e.g., trovafloxacin, gatifloxacin, or gemifloxacin; Van Bambeke et al., 2005)....
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...Newer FQ (third generation quinolones) were subsequently developed and presented increased activity toward Gram-positive bacteria, in particularly to Streptococcus pneumoniae (e.g., sparfloxacin, levofloxacin, or moxifloxacin), and potent activity against anaerobic bacteria (e.g., trovafloxacin, gatifloxacin, or gemifloxacin; Van Bambeke et al., 2005)....
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References
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TL;DR: Quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.
Abstract: For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.
1,436 citations
"Quinolones in 2005: an update" refers background in this paper
...The rapid bactericidal effect of fluoroquinolones is thought to result from the release of DNA ends, which are thought to induce bacterial apoptosis [35]....
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TL;DR: Although resistance was low in wild-type strains, higher levels of quinolone resistance arose readily by mutation, suggesting that a multiresistance plasmid can speed the development and spread of resistance to these valuable antimicrobial agents.
1,081 citations
TL;DR: The rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities are provided and shown to be more precise than current guidelines.
Abstract: Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.
1,071 citations
"Quinolones in 2005: an update" refers background or result in this paper
...This led to the first, large-scale clinical study aimed at defining the PD parameters which were predictors of efficacy [100]....
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...[100] and most other clinical studies, the lack of variability in dosing schedules made Cmax and AUC covariates, so that their relative roles could not be distinguished....
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TL;DR: The prevalence of pneumococci with reduced susceptibility to fluoroquinolones is increasing in Canada, probably as a result of selective pressure from the increased use of fluoroquolones.
Abstract: Background Fluoroquinolones are now recommended for the treatment of respiratory tract infections due to Streptococcus pneumoniae, particularly when the isolates are resistant to β-lactam antibiotics. Although pneumococci with reduced susceptibility to fluoroquinolones have been identified, their prevalence has not been determined in a defined population. Methods We performed susceptibility testing on 7551 isolates of S. pneumoniae obtained from surveillance in Canada in 1988 and from 1993 to 1998. Pneumococci with reduced susceptibility to fluoroquinolones (defined as a minimal inhibitory concentration of ciprofloxacin of at least 4 μg per milliliter) were further characterized. We also examined antibiotic prescriptions dispensed in Canadian retail pharmacies. Results Between 1988 and 1997, fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100 persons per year. The prevalence of pneumococci with reduced susceptibility to fluoroquinolones increased from 0 percent in 1993 to 1.7 percent in 1997 a...
1,011 citations
TL;DR: Nucleotide sequence analysis disclosed that all nine spontaneous quinolone-resistant gyrB mutants of Escherichia coli KL16 had a point mutation from aspartic acid to asparagine at amino acid 426 and that all four type 2 mutants had apoint mutation from lysine to glutamic acid at amino acids 447.
Abstract: Thirteen spontaneous quinolone-resistant gyrB mutants of Escherichia coli KL16, including two that were examined previously, were divided into two types according to their quinolone resistance patterns. Type 1 mutants were resistant to all the quinolones tested, while type 2 mutants were resistant to acidic quinolones and were hypersusceptible to amphoteric quinolones. Nucleotide sequence analysis disclosed that all nine type 1 mutants had a point mutation from aspartic acid to asparagine at amino acid 426 and that all four type 2 mutants had a point mutation from lysine to glutamic acid at amino acid 447.
766 citations