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Linezolid
• Approved in 2000 in the USA.• Community-acquired and nosocomial pneumonia.• Complicated and uncomplicated skin and soft-tissue
infections.• Methicillin-resistant Staphylococcus aureus and
vancomycin-resistant enterococci. • Protein synthesis inhibitor• Bacteriostatic agent• Oral and parenteral formulations.
Linezolid susceptibility
• Non-susceptibility is rare– Some development signs in Enterococci esp. E. faecium.– Occasional cases in S. aureus.– Very rare in S. pneumoniae.
Linezolid MIC Breakpointsmg/L (≤S/>R)
Zone diameters, 10 µg disc (mm)
≥S I ≤R
Staphylococcus 4/4 19 - 20
Enterococcus 4/4 19 - 20
Streptococcus A,B,C,G 4/4 19 - 20
S.pneumoniae 2/4 19 - 20
Non-species related 2/4 - - -
CLSI modified guidelines• QC ranges changed from 27-31 mm to 25-32 mm after 4-5
yrs of use.• Bacteriostatic agents may be more problematical when
measuring zones or MICs by Etest.
Biedenbach & Jones 2003 CMI 9:1035
Tigecycline
• Launched 2005 in USA for SSTI.• First glycylcycline
– Derivative of minocycline– Evades Tet A-E & K efflux pumps– But not those of Proteae or Pseudomonas
• Unique amongst newer agents having activity against Gram-negative bacteria.– But is active against MRSA and VRE.– Acinetobacter baumannii
• Parenteral administration only.• Bacteriostatic.
Tigecycline susceptibility
• High against Gram-positive bacteria, E. coli & K. oxytoca.
• Some resistance found in Gram-negs– K. pneumoniae (92-95% susceptibility)– E. aerogenes (96% susceptibility)– E. cloacae (93% susceptibility)– S. marcescens (97% susceptibility)
Waites et al 2006 AAC 50: 3479
Tigecycline breakpoints
Tigecycline MIC Breakpoints Zone diameters, 15 µg disc (mm)
mg/L (≤S/>R) ≥S I ≤R
Enterobacteriaceae 1/2 19 20-23 24
Staphylococcus 0.5/0.5 25 - 26
Enterococcus 0.25/0.5 20 - 21
Streptococcus 0.25/0.5 19 - 20
Non-species related 0.25/0.5 - - -
Medium batch & Tigecycline activity
• Inconsistencies were noticed in QC data.– Linked to medium batch variation.
• Tetracyclines are prone to inactivation by oxidation.• Studies carried out to investigate.
– Petersen & Bradford 2005 AAC 49:3910– Bradford et al 2005 AAC 49:3903.
Medium effect
• Important for agar dilution or broth dilution.– Media >12h old affected.
• Does not effect disc diffusion or Etest methods.• If using broth microdilution frozen panels are also not
affected.• Solved by boiling or addition of oxyrase.
Daptomycin
• First glycolipopeptide• Launched in 2003 in the USA – 2006 in Europe
– SSTI– Endocarditis in the USA
• Gram-positives only• Parenteral application only• Rapidly bactericidal
Daptomycin Susceptibility
• Non-susceptibility rare.– Some reports but case studies only.
Daptomycin MIC Breakpoints Zone diameters (mm)
mg/L (≤S/>R) ≥S I ≤R
Staphylococcus 1/1 - - -
[Enterococcus 4/4] - - -
Streptococcus 1/1 - - -
[CLSI only]
Daptomycin diffusion assays
• Daptomycin discs supplemented with 50 mg/L Ca++ have been developed.– Only for CLSI methodology (i.e. MHB)– Discontinued in 2005
• Isosensitest discs have proved problemmatical and have never been available.
Why are dapto & Ca++ discs no longer available even for CLSI?
Dalbavancin
• New lipoglycopeptide– Derived from teicoplanin
• Extended half-life– Once weekly dosing
• Bactericidal• 8-16-fold more active than vancomycin• No resistance found to date
– Except for cross-resistance to vanA Enterococci.• Not clinically available but has ‘FDA Approval’
Dalbavancin Susceptibility
• Breakpoints not currently set.• Broth microdilution requires addition of polysorbate-80
into wells for accurate and reproducible results.• Agar diluton has not been proposed as a standard
method– Fritsche et al 2006 JCM 44:2988
• Problems with disc development– Poor agar diffusion– Jones et al 2006 JCM 44:2622
• Etest is available.– Correct interpretation is essential.
BSAC agar dilution method
• BSAC method compares well with CLSI (NCCLS)– Mustaq et al 2004 JAC
54:617.• Agar dilution commonly 1
dilution higher
Summary
• Linezolid– Continued use has ironed-out previous QC issues
• Tigecycline– For broth: fresh medium or oxyrase is essential
• Daptomycin– Discs not available – but Etests work.– Ca++ supplement required
• Dalbavancin– Some question over agar dilution but BSAC seems
OK.– Polysorbate-80 supplement in broth.– No disc but Etest is available.