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Dalfopristin

About: Dalfopristin is a research topic. Over the lifetime, 696 publications have been published within this topic receiving 26621 citations. The topic is also known as: RP-54476 & Dalfopristina.


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TL;DR: Quinupristin/dalfopristin this paper is a semisynthetic derivative of the injectable streptogramin quinupricolinoyl, which has shown promising properties for treating the rising number of infections caused by multiply resistant bacteria.
Abstract: The streptogramins are a class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally, but the therapeutic use of the natural compounds is limited because they do not dissolve in water. New semisynthetic derivatives, in particular the injectable streptogramin quinupristin/dalfopristin, offer promise for treating the rising number of infections that are caused by multiply resistant bacteria. The streptogramins consist of two structurally unrelated compounds, group A and group B. The group A compounds are polyunsaturated macrolactones: the group B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, the 4-dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Semi-synthesis on this third residue led to the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Michael addition of aminothiols to the dehydroproline ring of pristinamycin IIA. Followed by oxidation of the intermediate sulfide into the sulfone derivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modified group B compounds are now also being produced by mutasynthesis, via disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIB, the group B component of the oral streptogramin RPR 106972. The streptogramins inhibit bacterial growth by disrupting the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial ribosome. The group A compounds interfere with the elongation of the polypeptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the dissociation of the peptidyl-tRNA and may also interfere with the release of the completed polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between the group A and group B compounds appears to result from an enhanced affinity of the group B compounds for the ribosome. Apparently, the group A compound induces a conformational change such that B compound binds with greater affinity. The natural streptogramins are produced as mixtures of the group A and B compounds, the combination of which is a more potent antibacterial agent than either type of compound alone. Whereas the type A or type B compound alone has, in vitro and in animal models of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfopristin range from 0.20 to 1 mg/l for Streptococcus pneumonae, from 0.25 to 2 mg/l for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal target organisms of this drug. Quinupristin/dalfopristin also has activity against mycoplasmas, Neisseria gonorrhoeae, Haemophilus influenz, Legionella spp. and Moraxella catarrhalis. Bacteria develop resistance to the streptogramms by ribosomal modification, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction that is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincosamides; hence, MLSB resistance), but group A and B compounds usually maintain their synergy and their bactericidal effect against MLSB-resistant strains. erm genes are widespread both geographically and throughout numerous bacterial genera. Several types of enzymes (acetyltransferases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so far been found only in staphylococci, particularly in coagulase-negative species

3 citations

01 Jan 2015
TL;DR: This review encompasses the most prominent knowledge on the ecology and dissemination of the multidrug resistant E. faecium (MEF) and future directions including mitigation strategies through systemic and molecular approaches are suggested.
Abstract: Currently, 80% of the antibiotics used in the United States (U.S.) are dedicated to agricultural systems, primarily to promote animal livestock growth and control microbial contaminant load at slaughter. Moreover, 87% of drug resistant microorganisms including Enterococcus faecium were detected in ground turkey products due to antibiotic agent usage namely, virginiamycin. Given that quinupristin/dalfopristin (QD), like virginiamycin (VIR), another mixture of streptogramin has been used in hospitals as a last alternative to treat immunocompromised population infected by vancomycin-resistant E. faecium (VRE). Consequently, understanding the epidemiology and the antibiotic resistance in some E. faecium strains from food animals’ to humans is a matter of great concern that urges effective strategies to intervention. This review encompasses the most prominent knowledge on the ecology and dissemination of the multidrug resistant E. faecium (MEF). Beneficial attributes of some E. faecium strains are also reviewed. Future directions including mitigation strategies through systemic and molecular approaches are suggested.

3 citations

Journal ArticleDOI
TL;DR: It is concluded that DU-6859a and trovafloxacin are very potent against enterococci, especially when combined with gentamicin.
Abstract: In a study designed to obtain data on compounds active against enterococci, the minimum inhibitory concentrations (MICs) of quinupristin/dalfopristin (RP 59500) and the novel quinolones DU-6859a, trovafloxacin, levofloxacin, and sparfloxacin were determined for 122 Enterococcus faecalis and seven Enterococcus faecium isolates. In addition, 15 Enterococcus faecalis isolates resistant to gentamicin, DU-6859a, and trovafloxacin were exposed over time to combinations of DU-6859a plus gentamicin and trovafloxacin plus gentamicin. DU-6859a and trovafloxacin were found to be the most active compounds against Enterococcus faecalis and DU-6859a and RP 59500 against Enterococcus faecium. Synergy between either DU-6859a or trovafloxacin and gentamicin was observed with 27 to 35% of the isolates. It is concluded that DU-6859a and trovafloxacin are very potent against enterococci, especially when combined with gentamicin.

3 citations

Journal ArticleDOI
TL;DR: In this paper, enterococcus spp. were isolated from PDO-cheese of Azeitao and Nisa at six cheesemaking units over four years (2016-2019).
Abstract: Enterococcus spp. were isolated from PDO-cheese of Azeitao and Nisa at six cheesemaking units (Azeitao: A1, A2, A3, A4; and Nisa: N9, N10), over four years (2016–2019). Genomic typing was performed using RAPD and distinct enterococci (n = 145) were identified at the species level by multiplex-PCR and evaluated regarding antimicrobial drug resistance (AMR). Antibiotics from nine distinct classes (aminoglycosides, macrolides, oxazolidinones, chloramphenicol, streptogramins, tetracyclines, glycopeptides, β-lactams, and quinolones) were selected for AMR surveillance and breakpoint criteria defined by EUCAST and CLSI were considered and compared. Regarding species allocation, 78 enterococci were identified as E. faecium, 37 confirmed as E. faecalis and 30 as E. durans. High levels of resistance to quinupristin-dalfopristin, tetracycline and teicoplanin were observed. Some resistances to clinically relevant antimicrobials were also detected, including β-lactams, aminoglycosides, and glycopeptides. Two isolates were considered multidrug-resistant, one according to EUCAST and the other to CLSI breakpoint criteria. Overall, considering the absence of reports regarding enterococcal-related toxinfections or infections resulting from the consumption of PDO-cheeses, traditional foods harbouring these bacteria should be considered safe. However, the possibility of horizontal gene transfer events associated with antibiotic resistance determinants further highlights the importance for AMR surveillance along the food chain.

3 citations

Journal ArticleDOI
TL;DR: Unlike the synergic activity noted against Gram-positive bacteria, the activity of quinupristin/dalfopristin against H. influenzae appears to be due almost entirely to the dalfopristsin component of the combination.
Abstract: Quinupristin/dalfopristin is an injectable streptogramin antibiotic that is constituted in a 30:70 (w/w) ratio of the two components. Quinupristin and dalfopristin are thought to act synergically by binding to two separate sites on the bacterial 50S ribosomal subunit. The in-vitro activities of the two components separately and together in different ratios were determined for a collection of 100 Haemophilus influenzae strains representing various antimicrobial resistance phenotypes. The NCCLS microdilution susceptibility testing procedure incorporating Haemophilus test medium (HTM) broth was used to determine MICs of quinupristin, dalfopristin and seven other antimicrobial agents. The MIC 50 and MIC 90 values were 4 and 8, 4 and 16, and 64 and 128 mg/L for quinupristin/dalfopristin (30:70), dalfopristin and quinupristin, respectively. MICs of quinupristin and dalfopristin were also determined in Mueller-Hinton lysed horse blood broth and by HTM agar dilution testing. Compared with HTM broth-derived results, the MICs of quinupristin/dalfopristin and its components were the same or one dilution higher in lysed horse blood and HTM agar incubated in air, and were equivalent or one dilution lower in HTM agar incubated in a CO 2 atmosphere. The MICs of quinupristin and dalfopristin separately or together were directly proportional to erythromycin MICs, but were otherwise unaffected by any of the resistance mechanisms represented in these strains. MICs of quinupristin and dalfopristin combined in ratios of 10:90, 70:30 and 90:10 did not differ significantly from those of the 30:70 ratio. Thus, unlike the synergic activity noted against Gram-positive bacteria, the activity of quinupristin/ dalfopristin against H. influenzae appears to be due almost entirely to the dalfopristin component of the combination.

3 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20237
202217
20219
202010
201913
201811