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.
Lecture 4
Vancomycin resistance
VREVISA / hVISA / VRSA
Thursday – 1/17/2008
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.
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
Nosocomial transmission
• Mode of transmission:– HCW– Environmental sources (medical devices)
• Carriage:– GI tract– Duration: months - years
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
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.
VRE - mechanism of resistance
1. Modifying enzymes
2. Degrading enzymes
3. Target Change
4. Efflux pumps
Cell wall synthesis in enterococci:
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
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.
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.
• 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).
Transformation
Plasmidtransfer
Genetic Mechanisms of Resistance Acquisition
Mutation
Genetic Mechanisms of VRE
• Resistant genes clustered in operons
• Operons located on transposons
• Transposons transmitted– Directly to chromosome – via plasmids
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)
Virulence genes associated with VRE
Enterococcal surface protein variant (esp)
hylEFM
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.
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
Epidemiology of VRE infections
Prevalence of VRE among enterococci in nosocomial infections
in ICU patients
Bonten et al. Lancet Infect. Dis. 2001
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.
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
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
Vancomycin use in US vs. Europe
Bonten et al. Lancet Infect. Dis. 2001
Bloodstream isolates of VREF SENTRY antimicrobial surveillance program
Deshpande et al. Diag. Microbiol. Infect Dis. 2007
Genetic capitalism (the rich become richer)
The success of a highly adaptive clone.
Leavis et al. Curr. Opion. Microbiol 2006
Emergence of CC17 in the Netherlands / Top et al. JCM 2008
Is the European epidemic following the US epidemic in a 10 y delay?
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
Suggested strategies for IC of VRE / Bonten et al. Lancet Infec Dis 2001
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.
Vancomycin resistant S. aureus (VRSA)
Vancomycin intermediate
S. aureus (VISA, hVISA)
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
hetero-VISA (hVISA)
• hVISA (hetero-VISA)– Appear to be susceptible, but
consists of subpopulations that have MIC≥4µg/ml
– Difficult to detect.
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)
Currently most worrisome:
• Concomitant carriage of VRE and MRSA is increasing.