Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0348321 (Haemophilus)
 15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 micrograms/ml and 0.5 to 2 micrograms/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC90, < or = 0.5 microgram/ml) and quinupristin/dalfopristin (MIC90, < or = 0.25 microgram/ml). Against all streptococcal strains tested (including penicillin-resistant pneumococcus), RPR 106972 was highly active with MIC results at < or = 1 microgram/ml. RPR 106972 inhibited Corynebacterium jeikeium (MIC90, 0.5 microgram/ml). Moraxella catarrhalis (MIC90, 0.25 microgram/ml), and some Haemophilus influenzae (MIC50, 2 micrograms/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC90s, 4 to 32 micrograms/ml) as compared to Enterococcus faecium (MIC90s, 0.5 to 1 microgram/ml) and other Enterococcus ssp. (MIC90s, 1 microgram/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 micrograms/ml; for S. aureus ATCC 29213, 0.25 to 1 microgram/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 microgram/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics.
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PMID:In vitro antimicrobial activity and MIC quality control guidelines of RPR 106972 (RPR 112808/RPR106950): a novel orally administered streptogramin combination. The Quality Control Study Group. 929 4

Quinupristin/dalfopristin and RPR 106972 were active in vitro against a wide range of aerobic Gram-positive organisms including Enterococcus faecium. However, most isolates of Enterococcus faecalis were resistant or of intermediate sensitivity. Against Staphylococcus aureus quinupristin/dalfopristin was more active but for all other species the range of activity of the two drugs was the same or RPR 106972 was more active. RPR 106972 was also more active against the respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis. Quinupristin/dalfopristin MICs for isolates of H. influenzae (1-8 mg/L) clustered around the breakpoint. There were differences in the quality of growth, but little difference in MICs or zone diameters was obtained on three different media: Mueller-Hinton (MHA), Iso-Sensitest (ISA), and Diagnostic Sensitivity Test (DST) agars. The addition of blood to the medium increased MICs 2- to 4-fold, with MHA showing the greatest increase, and reduced zone diameters around quinupristin/dalfopristin discs by 3-4 mm, with the greatest effect on ISA.
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PMID:Comparative activity of quinupristin/dalfopristin and RPR 106972 and the effect of medium on in-vitro test results. 1005 93

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
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PMID:Recent developments in streptogramin research. 1019 38

In response to conflicting reports on the chemical stability of quinupristin/dalfopristin, a study was designed to assess the in vitro longevity and effects of media and storage conditions on this streptogramin combination. Broth microdilution trays containing parenteral (quinupristin/dalfopristin) and oral (RPR 106972) streptogramin combinations as well as pristinomycin components (P-I and P-II) were preincubated at 35 degrees C for 12-72 h before inoculation with control strains (Streptococcus pneumoniae ATCC 49619, Haemophilus influenzae ATCC 49247, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213) and five clinical isolates with various drug resistance phenotypes. Overall, the mean quinupristin/dalfopristin activity loss was 24%/12 h, 41%/18 h, 43%/24 h, 69%/48 h and 79%/72 h with no detected loss of potency when measured by E. faecalis until 18 h. RPR 106972 mean activity loss was 6%/12 h, 19%/18 h, 19%/24 h, 56%/48 h and 71%/72 h with no loss of potency as measured by S. aureus until 48 h. Overall, P-I components had greater stability as compared with P-II for both drug combinations. Bioassays showed similar trends in decreased activity. Bioassay differences among media types were only significant (> 3 mm; greater loss of potency) for haemophilus test media for both P-II components at 72 h. The presence of an organism in the medium had no effect on stability assay results. The effect of storage temperature (4, 25 degrees C) on quinupristin/dalfopristin and RPR 106972 stability was also detrimental to drug potency indicating the requirement for rigid quality assurance for streptogramin diagnostic reagents when determining activity by reference or standardized susceptibility tests.
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PMID:Evaluation of quinupristin/dalfopristin (Synercid) and RPR 106972 stability in susceptibility testing media. 1092 79

MIC methodology was used to test the antibacterial activity of XRP 2868, a new oral combination of two semisynthetic streptogramins, RPR 132552A and RPR 202868, compared to activities of other antibacterial agents against pneumococci, Haemophilus influenzae, and Haemophilus parainfluenzae. For 261 pneumococci, XRP 2868 and pristinamycin MICs were similar, irrespective of penicillin G and erythromycin A susceptibilities (MIC at which 50% of isolates were inhibited [MIC(50)], 0.25 micro g/ml; MIC(90), 0.5 micro g/ml), while quinupristin/dalfopristin had MICs which were 1 to 2 dilutions higher. Single components of both XRP 2868 and quinupristin/dalfopristin had higher MICs. Erythromycin A, azithromycin, clarithromycin, and clindamycin MICs were higher for penicillin G-intermediate and -resistant than -susceptible pneumococci. Against 150 H. influenzae strains, all compounds tested had unimodal MIC distributions. XRP 2868 had an overall MIC(50) of 0.25 micro g/ml and an MIC(90) of 1.0 micro g/ml, with no differences between beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant strains. Of note was the similarly low activity of one of its components, RPR 132552A. Pristinamycin and quinupristin/dalfopristin had MICs of 0.125 to 8.0 micro g/ml; quinupristin alone had MICs of 8.0 to >64.0 micro g/ml, and dalfopristin had MICs of 1.0 to >64.0 micro g/ml. Erythromycin A, azithromycin, and clarithromycin had modal MICs of 4.0, 1.0, and 8.0 micro g/ml, respectively. MICs of all compounds against H. parainfluenzae were 1 to 2 dilutions higher than against H. influenzae. XRP 2868 showed potent activity against pneumococci and Haemophilus strains irrespective of their susceptibility to other agents.
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PMID:Activities of a new oral streptogramin, XRP 2868, compared to those of other agents against Streptococcus pneumoniae and haemophilus species. 1450 40