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antibacterial agent vs. gram-positive bacteria

New antibiotics, C21. Oxazolidinones: structure / activity. . . N. O. O. . . . N. H. C. . . . . O. CH3. . . . . F. . . N. O. . H. 5. Morpholino enhances pharmacokinetics

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antibacterial agent vs. gram-positive bacteria

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    1. Antibacterial agent vs. gram-positive bacteria DAVID M LIVERMORE Health Protection Agency, Colindale

    3. Oxazolidinones: structure / activity

    4. Linezolid : mode of action

    5. MICs of linezolid Unimodal Narrow distributions Mostly 0.5-4 mg/L

    6. Linezolid in skin & soft tissue, Phase III

    7. Time to discharge, SSTI infections

    8. Linezolid 600 mg bds oral or iv: Pneumonia, phase III

    9. Linezolid in S. aureus pneumonia

    10. Linezolid resistance in therapy Enterococci Scatter of reports Under-dosage, difficult sites, long Rx One report of spread in a unit MRSA 3 reports: peritoneal dialysis one empyema

    11. 23S Ribosomal RNA Mutations in Linezolid-Resistant Bacteria

    12. Risk factors for resistance Under-dosage- 200 mg bds in one trial Protracted therapy- 3-4 weeks Un-removed lines / devices Sequestered sites Usual suspects.....

    13. Quinupristin/dalfopristin (Synercid) Unrelated streptogramin A (dalfopristin) and B (quinupristin) mixture Act synergistically on the ribosome MICs 0.5 -2 mg/L for most Gram+ve E. faecalis R : efflux G-ves R : impermeability

    14. Synercid in vivo Licensed for nosocomial pneumonia, skin & soft tissue infection, E. faecium infection Extensive named patient trials: impressive vs. MRSA bone & joint infections Need central line to avoid venous side-effects c. 10% rates of myalgia & arthralgia

    15. Acquired Synercid Resistance vatA-E (staphs & E. faecium)- dalfopristin acetyltransferases vgb (staphs & E. faecium) Quinupristin lyase vga (staphs) efflux of dalfopristin 6% emergence of resistance in E. faecium in Rx Resistance v. rare in human isolates in UK; high but falling in livestock in Denmark

    17. Daptomycin in vitro Disrupts cytoplasmic membrane function & cell wall synthesis MICs 1-2 mg/L for G+ve cocci Bactericidal at 1-2 x MIC Mutational resistance difficult…..

    18. Daptomycin in vivo Lilly, 1980’s- skeletal muscle weakness @ bds Cubist, 2000- no toxicity @ ods Phase III trials- Skin, soft tissue- equal to oxacillins, vancomycin CAP- inferior to ceftriaxone… Bacteraemia/endocarditis- in progress

    19. Long half life glycopeptides

    20. Glycopeptide resistance

    21. Oritavancin, activity

    22. Why a b-lactam vs. MRSA? Mortality in bacteraemic pneumonia due to MSSA: vancomycin Rx 47% cloxacillin Rx 0%

    23. ?-Lactams binding PBP2’ of MRSA Penicillin BRL44154; MIC 4-8 mg/L for MRSA, 0.25-1 mg/L for MSSA worked in mice; metabolised in man Many cephs presented @ past ICAACs Carbapenem L695,256; MIC 2 mg/L for MRSA, 0.2 mg/L for MSSA cured endocarditis in rabbits formed insoluble crystals Now under dept RWJ-52248 & BAL9141

    24. RWJ-52248: anti-MRSA ceph

    25. Glycylcycline, GAR-936

    26. MIC90s of tigecycline

    27. MICs of tetracyclines, mg/L

    28. Iclaprim (AR-100), Arpida Dihydrofolate reductase inhibitor Anti G +ve & G-ve 8 x more active than trim vs. G+ve’s, inc. pneumococci Overcomes low level trim R in most G+ve’s not G-ve’s

    29. New agents for respiratory tract infection Key pathogens Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Mycoplasma, Chlymydia and, ahem, viruses!

    30. Ketolides Like macrolides; but multiple ribosomal binding sites in streptococci Active vs. erythromycin S strains Active vs. most ery-R streptococci; not staphylococci or enterococci Telithromycin not marketed in UK

    31. New quinolones, 1997-2003 Casualties Grepafloxacin Sparfloxacin Trovafloxacin Clinafloxacin Gemifloxacin

    32. Quinolones vs. pneumococci MIC90 (mg/L)

    34. Community acq’d pneumonia trial 502 patients, 1 g ertapenem or ceftriaxone i.v. ods Switch to co-amoxiclav p.o. @ >3 days Median 4 days i.v.therapy; 90 switched to oral Favourable: 92.3% ertapenem; 91% ceftriaxone Pen I/R pneumococci responded: 11/11

    35. New vs. G+ves Already Linezolid, Synercid Telithromycin, quinolones & ertapenem vs. respiratory pathogens, including pneumococci Future, Daptomycin, oritavancin,, tigecycline, anti MRSA cephs Very little vs. problem G-ve’s

    36. Imipenem-resistant Acinetobacter Jan ’96- Sept ‘01, USA

    37. Some problem G-ve's

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