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.

Recent developments in streptogramin research.

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

The pharmacokinetics of quinupristin/dalfopristin in laboratory animals and in humans.

Abstract: The pharmacokinetics of quinupristin/dalfopristin have been studied in rats, monkeys and humans following intravenous infusion of radiolabelled and unlabelled drug. In rats and monkeys quinupristin and dalfopristin undergo rapid elimination from the blood and wide tissue distribution. Nevertheless, they do not penetrate the central nervous system or cross the placenta to any significant degree and they do not appear to be subject to significant body retention following cessation of administration. The blood elimination half-life of quinupristin was approximately 0.6 h in rats and 0.5 h in monkeys, and that of dalfopristin was approximately 0.6 h and 0.2 h, respectively. Both compounds are primarily eliminated through the bile into the faeces; quinupristin is mainly excreted unchanged whereas dalfopristin is extensively metabolized beforehand. The metabolites include the microbiologically active pristinamycin PIIA for dalfopristin and the microbiologically active glutathione- and cysteine-conjugated derivatives for quinupristin. Quinupristin and dalfopristin appear to be handled in a similar manner by humans. Following intravenous administration both compounds are rapidly cleared from the blood with elimination half-lives of approximately 1 h for quinupristin and 0.4‐0.5 h for dalfopristin. The pharmacokinetic profile of quinupristin is dose-independent and so is that of dalfopristin and RP 12536 when considered together. Extravascular diffusion of quinupristin/ dalfopristin has been assessed in human non-inflammatory interstitial flu i d .

Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci.

Abstract: The antistaphylococcal activities of four newly developed antibiotics, moxifloxacin (an 8-methoxyfluoroquinolone), trovafloxacin (a naphthyridone), quinupristin/dalfopristin (a semisynthetic streptogramin) and linezolid (an oxazolidinone), were examined and compared with those of ciprofloxacin, vancomycin and teicoplanin, using an agar dilution method. A total of 245 clinical isolates of staphylococci, including a large number of clonally different methicillin-resistant strains, were tested. The new agents tested exhibited wide-spectrum antistaphylococcal activity against both methicillin-susceptible and methicillin-resistant strains. In contrast to the quinolones, the in-vitro activities of quinupristin/dalfopristin, linezolid and the glycopeptides remained almost unchanged, irrespective of the resistance phenotype for methicillin. A number of isolates with elevated quinolone MICs were observed.

Comparative antimicrobial susceptibility of Listeria monocytogenes, L. innocua, and L. welshimeri.

Abstract: The current study compared antimicrobial susceptibility of Listeria innocua, L. welshimeri, and L. monocytogenes isolated from various sources. Antimicrobial susceptibility testing was performed using a microbroth procedure with Sensititre® minimum inhibitory concentration plates containing 18 antimicrobials. Resistant isolates were analyzed for the presence of antimicrobial resistance genes using PCR. The majority of L. monocytogenes isolates were resistant to oxacillin (99%, 89/90) and ceftriaxone (72%, 65/90), while few isolates were resistant to clindamycin (21%, 19/90) and ciprofloxacin (2%, 2/90). When selected sources of L. monocytogenes are compared, resistance to ceftriaxone, clindamycin, and oxacillin ranged from 27% to 86%, 7% to 43%, and 96% to 100%, respectively. Resistance to ciprofloxacin (6%, 2/34), quinupristin/dalfopristin (7%, 1/14), and tetracycline (7%, 1/15) was observed with L. monocytogenes isolated from food, animal, and environmental sources, respectively. All L. welshimeri isola...

In-vitro and in-vivo antibacterial activity of quinupristin/dalfopristin.

Abstract: Quinupristin/dalfopristin is a new water-soluble streptogramin antimicrobial agent comprising quinupristin and dalfopristin in a ratio of 30:70. The in-vitro spectrum of activity includes most multi-resistant Gram-positive aerobes, important Gram-negative aerobes, Gram-positive anaerobes and intracellular bacteria that are causal agents of respiratory, blood and cutaneous infections. Of particular note, quinupristin/dalfopristin is active against multidrug-resistant isolates of Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium, and against penicillin-resistant and/or erythromycin-resistant Streptococcus pneumoniae. The combination is also active against staphylococci showing both constitutive and inducible erythromycin resistance. Bactericidal activity and a prolonged post-antibiotic effect have also been noted for quinupristin/dalfopristin against Gram-positive cocci. Gram-negative bacteria susceptible to quinupristin/dalfopristin include Moraxella catarrhalis, Legionella spp. and Mycoplasma spp. Overall, the spectrum of antibacterial activity indicates a potential role for this combination in the treatment of difficult-to-treat Gram-positive infections, including those caused by multidrug-resistant organisms. Since this activity extends to Gram-negative respiratory bacteria, quinupristin/dalfopristin may also find a role in the treatment of atypical, as well as typical, pneumonia.