Lecture 4 Vancomycin resistance VRE VISA / hVISA / VRSA Thursday – 1/17/2008.
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Transcript of Lecture 4 Vancomycin resistance VRE VISA / hVISA / VRSA Thursday – 1/17/2008.
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Lecture 4
Vancomycin resistance
VREVISA / hVISA / VRSA
Thursday – 1/17/2008
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Enterococcus • Gr+ Cocci (in chains).
• Two species infecting human:
E. faecium and E. faecalis.
• Initially considered harmless GI commensal.• Infection typically follows GI colonization.
• Low pathogenicity• Yet, can cause high mortality in patients with
bacteremia.
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Enterococcus infections
• E. faecalis vs. E. faecium• Nosocomial infections, mostly in debilitated
patients
• Common cause of nosocomial urinary tract infection
• Currently 3rd leading cause of bloodstream infections.
• Serious complication: endocarditis
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Nosocomial transmission
• Mode of transmission:– HCW– Environmental sources (medical devices)
• Carriage:– GI tract– Duration: months - years
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Enterococcus and antibiotic resistance
• Enterococci intrinsically resistant to various antimicrobial classes
– Low level aminoglycoside (low ability to penetrate cell wall)– Relative resistance to β-lactams (Cephalosporines + penicillin) (PBP5) – macrolides (low level)– TMP-SMX
• Acquire high level antibiotic resistance through horizontal transfer of relevant genes.
• 1980’s: emergence of beta-lactam and high gentamycin resistance.
• 1986 fist report of VRE in Europe, 1989 first report in US.
• Currently: alarming situation in US hospitals, rare in Europe
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Glycopeptidesvancomycin, teicoplanin, telavancin
• Antibiotic class used to treat Gram positive bacteria.
• Mode of action: disruption of peptidoglycan polymerization
• Bind to the amino-acids within the cell wall. (D-ala-D-ala).
• Prevent the addition of new units to the peptidoglycan.
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VRE - mechanism of resistance
1. Modifying enzymes
2. Degrading enzymes
3. Target Change
4. Efflux pumps
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Cell wall synthesis in enterococci:
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Mechanism of resistance• Operons that encode enzymes for
– synthesis of low-affinity precursors (D-ala-D-lac vs. D-ala-D-ala).– Elimination of normal high-affinity precursors (removing the
vancomycin-binding target)
• Operon encoded on a transposon
VanA operon
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Glycopeptide resistance gene operons: vanA-vanE and vanG
• Enterococci – acquisition of VanA, B, D, E and G phenotypes.
• VanC – affords intrinsic resistance, and is chromosomal (arises in less virulent enterococci).
• VanD, E, G: reported only sporadically.
• VanC and VanE: D-Ala-D-Ser
• VanA & VanD: resistant to vancomycin + teicoplanin.
• VanA & VanB: most common • The phenotype is accomplished by multiple proteins in gene
clusters.
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The vanA gene cluster
Adapted from Courvalin et al. 2006
vanA (ligase) and vanH (dehydrogenase) are responsible for the synthesis of the modified depsipeptide (D-Ala-D-Lac).
vanX (D,D-Dipeptidase) and vanY (D,D-Carboxypeptidase) cleave normal peptidoglycan substrates.
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• VanA type: inducible high levels of vanco-R and teicoplanin-R (Tn1546)– VanH - dehydrogenase (pyruvate->lactate)– VanA - ligase catalyses bond of D-Ala-D-Lac.– VanX and VanY - remove c-terminal D-Ala to
eliminate normal precursor
• VanB different in its regulation (and no vanZ, additional vanW - function unknown).
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Transformation
Plasmidtransfer
Genetic Mechanisms of Resistance Acquisition
Mutation
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Genetic Mechanisms of VRE
• Resistant genes clustered in operons
• Operons located on transposons
• Transposons transmitted– Directly to chromosome – via plasmids
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Rapid spread of VRE
Tn1546 Transposon (vanA)
• A small mobile genetic element (6625 bp)
• More mobile than a plasmid
• Plasmids that carry Tn1546 - highly efficient conjugative plasmids (~65 Kbp)
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Virulence genes associated with VRE
Enterococcal surface protein variant (esp)
hylEFM
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Variant esp gene (esp- / espEfm) enterococcal surface protein
• Enhanced adherence
• Associated with hospital infections (VREF-100% and VSEF~50%).
• Prevalent in E. faecalis strains related with infections.
• Absent in community isolates.
• Not more virulent in mouse model.
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Another virulent factor: hylEfm
• Significant identity with hyaluronidase genes
• Hyaluronidase: a virulent factor in S. aureus, S. pneumoniae, GAS
• Predominant in VREF strains
• Associated with espEfm
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Epidemiology of VRE infections
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Prevalence of VRE among enterococci in nosocomial infections
in ICU patients
Bonten et al. Lancet Infect. Dis. 2001
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Vancomycin-resistant enterococci (VRE)
E. faecium• Rare, but emerging cause
of infection (15% ->~30%)
• Most (>90%) are VRE (VREF)
• Colonization of hospitalized patients 1.5%-32%
E. faecalis• Common cause of
infection (>90% ->70%).
• But most not VRE.
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VRE: European vs. US epidemiology
• 1986 - first case.• Uncommon as nosocomial
infection (<3%) only sporadic outbreaks
• Widely prevalent in European livestock and in healthy people in the community
• Inciting factor: animal use of glycopeptides– Avoparcin as a growth factor
since 1970s, banned in 1997.
• 1989 – first case.• Epidemic spread:
– Small outbreaks– Northeast -> West coast– By 1995 – high endemicity
in ICUs.
• Community reservoir – absent.
• Inciting factor: use of oral vancomycin.
Europe USA
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VRE: European vs. US epidemiology
• Sporadic nosocomial outbreaks.
• Highly prevalent in healthy humans and livestock.
• ‘Non-epidemic strains’.
• Do not have esp gene.
• Endemic in US ICUs
• No community reservoir
• ‘Epidemic strains’.
• Contain esp gene.
Europe USA
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Vancomycin use in US vs. Europe
Bonten et al. Lancet Infect. Dis. 2001
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Bloodstream isolates of VREF SENTRY antimicrobial surveillance program
Deshpande et al. Diag. Microbiol. Infect Dis. 2007
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Genetic capitalism (the rich become richer)
The success of a highly adaptive clone.
Leavis et al. Curr. Opion. Microbiol 2006
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Emergence of CC17 in the Netherlands / Top et al. JCM 2008
Is the European epidemic following the US epidemic in a 10 y delay?
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Factors influencing VRE spread:
• Patient colonization– GI tract– Groin– Skin
• Colonization pressure– Number/density of colonized
patients– Admission/transfer of
colonized patients– Proximity of colonized
patients– Shared care givers
• Contaminated environment– Stethoscopes/ BP cuffs, etc..
• Antibiotic pressure– Vanco– Cephalosporins– Antianaerobic
• Bacterial virulence factors– esp gene
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Suggested strategies for IC of VRE / Bonten et al. Lancet Infec Dis 2001
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Infection Control and/or Ab control
• When not clonal spread, strict IC - not efficient.
• Then probably resriction of Ab classes but which?
• Studies show: RF for VRE:– Vancomycin (IV - controversial)– Extended-spectrum cephalosporin– Other B-lactam-B-lactam inhibitors (controversial which)– Anti-anaerobic regimens.
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Vancomycin resistant S. aureus (VRSA)
Vancomycin intermediate
S. aureus (VISA, hVISA)
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Vancomycin resistance in S. aureus VISA (vancomycin intermediate S. aureus)
• First case 1996
• MIC 4-8µg/ml
• Thick cell wall (reduces vanco penetration through cell wall).
• Accumulates multiple mutations that activate pathways for cell wall synthesis & change cell physiology
• High fitness cost
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hetero-VISA (hVISA)
• hVISA (hetero-VISA)– Appear to be susceptible, but
consists of subpopulations that have MIC≥4µg/ml
– Difficult to detect.
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VRSA - yet a very rare event
• 2002 Michigan – 1st case vanA mediated since then 6 more cases.
• vanA resistance in VRSA rare, most occurred in the same geographical area (Michigan)
• Only very few descriptions of vanA gene cluster in MRSA, though in lab – years ago it was demonstrated.
• Gene cluster found on a plasmid-specified transposon (Tn1546)
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Currently most worrisome:
• Concomitant carriage of VRE and MRSA is increasing.