Transcript Staphylococcus aureus Management of a Problematic Pathogen

Methicillin Resistant
Staphylococcus aureus (MRSA)
What is it ?
a)
b)
c)
d)
e)
A flesh-eating virus
An Ebola-like pathogen
The plague
I don’t know, but I don’t want
them !
Previously common bacteria that
have acquired resistance genes.
Evolution of Drug Resistance in S. aureus
Penicillin
S. aureus
Methicillin
Penicillin-resistant
[1950s]
S. aureus
Methicillinresistant
[1970s]
S. aureus (MRSA)
[1997]
Vancomycin
[1990s]
Vancomycin
-resistant S.
aureus
[ 2002 ]
Vancomycin
intermediateresistant
S. aureus
(VISA)
Vancomycin-resistant
enterococci (VRE)
Methicillin-Resistant
Staphylococcus aureus (MRSA)
Percent Resistance
60
50
40
30
20
10
Source: National Nosocomial Infections
Surveillance (NNIS) System
20
05
20
03
20
01
19
99
19
97
19
95
19
93
19
91
19
89
0
U.S. Non-Intensive Care
U.S. Intensive Care
The Nebraska Medical Center
Worldwide Prevalence of MRSA
Among S. aureus Isolates
Grundmann et al. Lancet 2006; 368:874-85.
5
S. aureus: A well-armed pathogen
1) Adherence and
colonization
2) Tissue destruction and
invasion
3) Toxin production and
“disease at a distance”
Virulence under tight
regulatory control
Lowy, NEJM 1998
Colonization
2/3 to 3/4 of humans are
colonized by S. aureus at
some point, 20% to 50% at
any given time, 10% - 20%
persistently colonized
 Anterior nares is most
common site of colonization
 80% to 90% of strains
causing diseases come from
endogenous flora
 Risk of Infection:
 MSSA 2% - 10%
 MRSA 5% - 30%

S. aureus Colonization
National Health and Nutrition
Examination Survey 2001-2002
• 32.4% of population (89.4
million persons) nasal
colonization by S. aureus
• 0.8% MRSA
• Burden of MRSA most likely
greatly increased since 2001
• Nashville: 2001 (0.8%); 2004
(9.2%) (Creech et al, Ped Inf Dis J,
Kuehnert MJ, et al. J Infect Dis, 2006
2005)
Beta-lactamase producing and methicillinresistant S. aureus
Hospital
Community
Hospital
Community
McDonald LC. J Infect Dis, 2006
Community-Acquired MRSA
Community MRSA Throughout the U.S. (2007)
X
X
X
X X X
X
X
X
XX
X
XX
X X
X
X
X X
X
X X X XX
X
X X
X
X
X
X
X
X
X X
X
X
X
X
X
X
Chambers HF. Personal Communication. January 19, 2007
Prevalence of CA-MRSA
Survey of 11 EDs throughout US in Aug 2004
 422 pts with skin & soft tissue infection
 320/422 (75%) caused by S. aureus
 MRSA 59% (15% - 74%), USA300 strain 97%


KC 74%; Atlanta 72%, Charlotte NC 68%, New
Orleans 67%, Albuquerque 60%, Phoenix 60%,
Philadelphia 55%, Portland OR 54%, Los Angeles
51%, Minneapolis 39%, New York 15%
CA-MRSA: What’s Going On?
SCCmec I-V, mecIV is most commonly
found in CA-MRSA; 25 KB, mobile
What’s different about CA-MRSA?
SCCmec IV (V) is mobile and in variety of
background strains
 Replicate more rapidly than HA-MRSA (23 min
vs 46 min) – More fit than HA-MRSA
 MW2 sequence vs 5 HA-MRSA reveal 19
putative virulence genes: 4 Enterotoxins, 11
exotoxins (PVL), collagen adhesin, etc. More
virulent?
 LD is 5x less than HA-MRSA (no single gene
appears responsible)

What is PVL (Panton-Valentine
Leukocidin)?
1st described in 1932
Bicomponent synergistic membrane-tropic
toxin
 Encoded by lukS-PV and lukF-PV genes
 Assembled as hetero-oligimers that
synergistically act to form pores in cell
membranes (lysis) of pmns and
monocytes/macrophages
 Associated with necrotizing skin and soft
tissue infections and pneumonia


S. aureus Today





Most common cause of endocarditis (38%)
Most common cause of nosocomial infection
(13%)
Most common cause of SSI (20%)
Most common cause of cellulitis, osteomyelitis,
septic arthritis
Common cause of bacteremia, nosocomial
pneumonia, foodborne disease, implant infection,
abscess, etc
Staphylococcal Skin & Soft Tissue Infections
Cellulitis
Staphylococcal Disease due to
Metastatic Seeding
Staphylococcal Disease due to
Metastatic Seeding
Staphylococcal Disease due to Metastatic
Seeding: Endocarditis
Staphylococcal ToxinMediated Diseases
Toxic
Shock
Syndrome
Staphylococcal
Scalded Skin
Syndrome
Staphylococcal ToxinMediated Diseases:
Food Poisoning
Clinical Presentation of CA-MRSA
Clinical Presentation of CA-MRSA
Clinical Disease due to CA-MRSA
Pyomyositis
Necrotizing
Pneumonia
Purpura fulminans,
Necrotizing fasciitis
The distinction between CA and HA is
blurring!
100%
80%
Seybold U, et al.
Clin Infect Dis,
2006
USA800
USA500
USA100
USA300
60%
40%
20%
0%
Total (n=116)


HA (n=107)
Noso (n=49)
Characterized 132 cases of MRSA BSI in Atlanta
34% of MRSA were USA 300
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28% of pts with HA BSI factors
20% of pts with nosocomial BSI
Methicillin Resistant
Staphylococcus aureus (MRSA)
Who usually gets infected with MRSA?
a)
b)
c)
d)
e)
ID Physicians
Family members of those who have
been previously diagnosed.
Hospital personnel, especially NP’s
Residents of extended care facilities
Patients hospitalized for other medical
reasons.
Treatment of CA-MRSA
Most disease is skin & soft tissue (75% 80%)
 Data suggests that many cases can be
treated with I&D without Abx


73% of pts in one study received antibiotics to
which the organisms was resistant. No difference
in number of follow-up visits, subsequent need for
I&D, or change in antibiotic therapy (Fridkin,
NEJM, 2005)
Recurrent Furunculosis
Very little data indicating long-term benefit of
decolonization regimens. Toxicity/cost/resistance
 Combination of topical, mucosal, and systemic
antibiotics:


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Oral TMP-SMX, nasal mupirocin, chlorhexidine showers
x 5d
Bleach baths (1 teaspoon of bleach per gallon of water)
x 10 minutes 2 times/wk
Environmental cleaning (bedclothes, towels, surfaces)
Close contacts? Pets? Environment?
Time-kill curves for all isolates of Methicillin
Resistant Staphylococcus Aureus (12)
10
10
Linezolid
Rifampin
SXT
SXT+Rifampin
Clindamycin
Minocycline
Control
9
Bacteria [CFU/mL]
10
8
10
7
10
Kaka, et al
IDSA, 2005
6
10
5
10
4
10
3
10
2
10
0
4
8
12 24
Time (hours)
36
48
Inducible Clindamycin Resistance
Vancomycin Treatment of MRSA
• Time-kill assays vancomycin
kills S. aureus more slowly than
beta-lactam antibiotics
• Vancomycin treatment of Rsided endocarditis is assoc with
failure in 15% - 33% vs. 5% for
nafcillin
• Bacteremia lasts a median of 7-9
days with vancomycin treatment
vs. 3-5 days with nafcillin
Small and Chambers, AAC 1990; Korzeniowski
et al, Ann Intern Med 1982;Levine et al, Ann
Intern Med 1991; Chambers et al Ann Intern Med
1988
log10 CFU
Vanc vs B-lactam for MSSA
8
7
6
5
4
3
2
1
0
0
2h
Nafcillin
4
8
12 18 24
Vancomycin
FAQ Re: Treatment of MRSA

What is role of aminoglycosides?


Gentamicin (in combination with B-lactam or
Vanc) results in more rapid killing and clearance
of blood cultures and defervescence of fever.
Goal peak of 3-5 ug/mL, 3-5 days. May be
assoc with renal toxicity (particularly in
elderly)
What is role of Rifampin?

Rifampin (in combination with B-lactam or vanc)
can result in indifference, antagonism, or
synergism. Rifampin in combination with FQ
yields synergism.
Newer Agents to Treat MRSA
Quinupristin/Dalfopristin (Synercid)
Linezolid (Zyvox)
Daptomycin (Cubicin)
Tigecycline (Tygacil)
Investigational Agents
Oxazolidinones:
Linezolid (Zyvox®, 2000)
Mechanism: Interferes with formation of protein
synthesis initiation complex
Pharmacokinetics: Essentially 100% bioavailable (IV or
oral), Peak level ~ 15, ½ life 5 hours (BID dosing)
Quinupristin/Dalfopristin

Synercid (1999)
Combination of quinupristin/dalfopristin,
cidal for susceptible strains; static for
MLSB(+) strains
 Cost
 IV route, phlebitis
 Myalgias/arthralgias
 Cytochrome p450 (CYP3A4) metabolism

Adverse Events Associated with Linezolid
Drug Warning:

Reversible myelosuppression




associated with linezolid therapy
(particularly > 2 wks)
Serotonin Syndrome
 Reported in pts on SSRI with
underlying hepatic, pulmonary, or
cardiovascular dz
 HTN, agitation, tremors, fatigue,
palpitations (Raad et al, CID 2003) Vaculated erythroblasts in
Neuropathy
subject receiving Linezolid x 4
 Peripheral and Optic (Lee, et al,
mo
CID 2003)
(Green, et al. JAMA 2001)
Resistance

Increasing reports of resistant
staphylococci and enterococci
Daptomycin (2003)
O
HO2C
NH
HN
HO
O
NH
N
H
O
O
HN
H
N
(CH2)8CH3
Streptomyces
roseosporus
N
H
O
O
N
H
O
H
N
O
CO2H
NH
HO2C
CONH2
O
O
O
OO
Lipopeptide
antibiotic
 Fermentation
product of

NH2
HN
O
HN
N
H
O
HO2C
H
N
NH2
O
Water soluble
 Stable

Baltz RH. In: Strohl WR, ed. Biotechnology of Antibiotics. 1997;415-435.
Bacteremia/Endocarditis Study Outcomes (ITT)
60
56.3 55.2
Success Rate (%)
50
43.3
37.7
40
42.1 43.8
Dapto
Comp
30
22.2
20
11.1
10
0
Uncomp
Bact
Comp
Bact
RLendocard endocard
MRSA Study Outcomes at 6 weeks (ITT)
60
60
50
Success Rate (%)
50
40
45.5
44.4
50
Dapto
Comp
45.5
32.6
27.3
30
20
10
0
0
Overall
Uncomp Bact
Comp Bact
R-Endocard
0
L-Endocard
Decreased Renal Function
26.3
30
25
Dapto
Comp
20
% 15
10
5
0
11
Tigecycline (Tygacil)

FDA Approval June
2005


Complicated skin and
skin structure
infections;
Complicated intraabdominal infections
In-vitro activity vs.
MRSA & VRE
100
90
80
70
60
50
40
30
20
10
0
Tigecycline
Vanc/Az
Clinical Cure M-ITT, SSTI, N= 1057
Investigational Anti-Staphylococcal
Antibiotics

Glycopeptides

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DHFR inhibitor

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Ortivancin (Intermune)
Dalbovancin (Vicuron)
Telavancin (Theravance)
Iclaprim (Arpida)
Novel B-lactams


Ceftobiprole
BMS-247243, RWJ 54428, CB-181963, BAL 5788,
S-3578
Other Potential AntiStaphylococcal Agents

Capsule 5/8 Vaccine (NABI): -

Staph capsule IG (NABI & Biosynexus) (Halt 11/05)
Lysostaphin (Biosynexus)
Aurexis (Inhibitex) anti-ClfA
Veronate (Inhibitex) Adhesin Ab (neonates)
Aurograb (NeuTec) Ab vs ABC transporter
Peptide deformylase inhibitors

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
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FDA fast tracked
announced 10/12/04; Halt in development 11/05
Methicillin Resistant
Staphylococcus aureus
(MRSA)
How can we protect our
patients, ourselves ?
MRSA precautions
Handwashing Compliance
Author
Clinical Setting
Rate of Compliance, %
Open ward
ICU
16
30
ICUs
ICUs
41
28
All wards
44
Donowitz
PICU
30
Graham
ICU
32
Dubbert et al
ICU
81
Pettinger et al
SICU
51
NICU/others
29
Doebbeling et al
ICUs
40
Zimakoff et al
ICUs
40
Meengs et al
Emergency department
32
All wards
48
Preston et al.
Albert et al
Larson
Larson et al
Pittet et al
Boyce JM. Clin Infect Dis. 2001;33:S135.
Infection Control:
Conflicting Approaches

“Search and Destroy”
Universal application of active surveillance
cultures and rigorous enforcement of
contact isolation
 Decolonization


Laissez-Faire

No cultures, No isolation for pts colonized
or infected with MRSA
ICHE 2003
Numerous reports of control of MRSA,
primarily in short-term outbreak setting
through application of contact isolation and
surveillance cultures
 Experience in Netherlands and Northern
Europe

Strategies to Reduce Transmission of
Antimicrobial Resistant Bacteria in the ICU
(STAR-ICU)
Huskins, et al. SHEA 2007. Prospective, clusterrandomized study of Std Precautions vs Intense
Control Strategy
 10 ICUs in ICS vs 9 ICUs in Std precautions
 All pts at admit in ICS had surveillance cx for MRSA
and VRE, In ICS unit pts placed in universal glove use
until Cx known
 5434 pts in ICS ICUs vs 3705 pts in Std ICUs
 No differences in pt populations re: comorbidity,
Severity of illness, LOS, devices, antibiotics,
 ~90% compliance with cultures

Life Goes On!