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Resistance to oxazolidinones

in Gram-positive bacteria

Dr. Ian Morrissey

Chief Executive Officer

G.R. Micro Ltd.

London, UK.


Oxazolidinones - linezolid


Linezolid – mechanism of action I.

• Exact

mechanism(s)

still elusive

• Bind to the 50S

ribosomal

subunit.


Bacterial Ribosome large subunit (50S)

Animated by David S. Goodsell at the RSCB PDB data bank

http://www.rcsb.org/pdb/explore.do?structureId=1ffk


Linezolid – mechanism of action II.

From http://www.chm.bris.ac.uk/motm/linezolid/linezolid.htm


Prevalence of linezolid resistance

CLSI breakpoints (mg/L)

S I R

Enterococci ≤2 4 ≥8

Staphylococci ≤4 - -

Streptococci ≤2 - -

From Ross et al (2007) Int. J.

Antimicrob. Agents 29:295


USA Enterococci 2004

From Draghi et al. 2005 Antimicrob Agents Chemother 49:5024


Linezolid resistance in Enterococci

• 23S rRNA mutation

– G2576U

Early compassionate use

– E. faecium in 2 patients (Zurenko ICAAC 1999 Abst 848).

• During clinical use.

– USA (Gonzales 2001 Lancet 357:1179)

– UK (Auckland 2002 JAC 50:743)

– Greece (Bersos 2004 JAC 53:685)

– Poland (Krawczyk 2004 Pol J Micro 53:194)

– Italy (Schulte 2005 Int J Hyg Env Hlth 208:477)

– Spain (Sanchez-Gomes 2006 J Chem 18:440)

• Where patients have never been exposed to linezolid.


Linezolid resistance in S. aureus

• First found in 2001 in USA during therapy

– Tsiodras 2001 Lancet 358:207

– UK (Wilson 2003 JAC 51:186)

– Brazil (Gales et al 2006 IJAA 27:300)

– USA (Paterson ICAAC 2003 abst. K-1405)

ALL G2576U MUTATION

• One report of T2500A mutation

– Meka 2004 JID 190:311


Multiple copies of rRNA operons

• Most bacteria have more than 1 copy of the 23S rRNA genes

– E. faecium = 6 copies

– E. faecalis = 4 copies

– S. aureus = 5-6 copies

– S. pneumoniae = 4 copies


Sinclair et al. 2003 AAC 47:3620


2

5

23S rRNA Domain V G2576U

Wilson et al. 2003 JAC 51:186


RNA mutations can also revert in vitro

Meka 2004 JAC 54:818


…and in clinical isolates

Meka 2004 JID 190:311


PhLOPS A phenotype in Staphylococci

• Cfr RNA methyltransferase

– Methylates A2503 of domain V of 23S rRNA

– Raises LZD MIC from 0.5 to 4/8 mg/L.

– Found on various plasmids in veterinary strains including S.

aureus

– Overlaps binding sites for:

– Phenicols

– Lincosamides

– Oxazolidinones

– Pleuromutilins

– Streptogramin A

• Although not found in clinical strains it is of future concern.

Long 2006 AAC 50:2500


Domain V of 23S rRNA

T2500A

G2576U

Enterococci

S. aureus

Cfr

methylase

S. aureus

Modified from Sander et al. 2002 Mol. Microbiol. 46:1295.


Resistance in S. pneumoniae

• Ribosomal protein L4 deletion

• Extremely rare

Volter 2005 AAC 49:3554


L4 deletions sometimes have a fitness cost

Volter 2005 AAC 49:3554


G2576U in S. aureus is not a burden

Pillai 2002 JID 186:1603


Summary

• Oxazolidinone resistance is not widespread

– Up and coming in Enterococci?

• Resistance due to 23S domain V mutations in Enterococci &

Staphylococci.

• L4 deletions in pneumococci

• Transferrable resistance (cfr on plasmids from vet staphs) is a

real future possibility.

• It is important that laboratories determine linezolid

susceptibility as full susceptibility can no longer be assumed.

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