MRSA:
Beyond Butt Boils
Jeffrey S. Bennett, M.D.
Assistant Professor of Pediatrics/Infectious Disease
Director, Section of Inpatient Pediatrics
University of Kentucky
Educational Goals
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History of current MRSA epidemic
Describe CA-MRSA, resistance patterns, and
virulence factors
Antimicrobial Selection
Review invasive and toxin mediated MRSA
diseases and their initial treatment
Managing the epidemic – media relations and
talking points
Disclosures

Dr. Bennett has no relevant financial
relationships with the manufacturer(s) of any
commercial product(s) and/or provider of
commercial services discussed in this CME
activity, and does not intend to discuss an
unapproved/investigative use of a commercial
product/device in this presentation
Epidemic!!
“Ripped from the Headlines”
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Jan 13, 2005 ABC News:
'Superbug' MRSA Worries Doctors, Athletes Drug-Resistant Germ Found
in Locker Rooms; Can Kill Within Days
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October 17, 2007 Dallas Morning News:
U.S. deaths from staph 'superbug' may surpass AIDS deaths
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October 19, 2007 Chicago Tribune:
Superbug alert at high school; Infection struck 2 football players
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October 23, 2007 Wall Street Journal:
Putting Superbugs on the Defensive
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October 28, 2007 China View News:
U.S. county to close all schools amid "superbug" fears (Pike County,
Kentucky)
Staphylococcus aureus Basics
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Gram’s stain characteristics: spherical, Gram positive
cocci in pairs and groups/clusters
Colonize anterior nares, skin of humans and warmblooded animals (40% of normal population, 50-90%
of health care workers); throat colonization increasingly
recognized as a potentially important reservoir
Produce a large array of Virulence Factors
Cause a broad spectrum of human disease
Spread most commonly by skin-to-skin contact
Able to survive for extended periods on clothing,
surfaces, other fomites
CA-MRSA Basics
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CA-MRSA are genetically distinct from hospitalassociated strains of MRSA (HA-MRSA)
Major virulence factor 1: antibiotic resistance
mec-A gene: decreased penicillin binding protein
affinity (PBP 2a), ß-lactam resistance
 erm gene: ribosomal subunit methylation,
macrolide/lincosamide/streptogramin resistance
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Major virulence factor 2: Panton-Valentine
Leukocidin (PVL)
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Creates lytic pores in WBC membranes, leads to
focal tissue necrosis and rapid abscess (boil)
formation
CA-MRSA vs. HA-MRSA*:
Same Exterior, but Very Different
Under the Hood
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Infection Types: CA-MRSA more often associated with skin and
soft tissue infection (75%) vs. HA-MRSA (37%)
Age Distribution: CA-MRSA found to be much more common in
younger individuals (median age 23 years) vs. HA-MRSA (median
age 68 years)
Pulse-Field Gel Electrophoresis Typing: CA-MRSA belong to very
different PFGE clonal groups compared to HA-MRSA (genetically
different)
Exotoxin Gene Profiles: CA-MRSA commonly carry genes for
Panton-Valentine leukocidin (PVL), while HA-MRSA do not
Antibiotic Susceptibility Profiles: CA-MRSA are more likely to be
susceptible to a broader range of antibiotics than are HA-MRSA
*CA-MRSA: Community-Associated MRSA
*HA-MRSA: Healthcare-Associated MRSA
Naimi TS, et al. JAMA Dec 10, 2003;290: 2976-2984
Historical Resistance Timeline
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1941: introduction of penicillin
1944: first reports of penicillin-resistant S. aureus
1956: discovery of Vancomycin
1960: introduction of penicillinase-resistant drugs such as
Methicillin
1975: first reports of nosocomial methicillin-resistant S.
aureus (MRSA)
1983: reports of community-acquired MRSA in children
from Ohio, Nebraska, Missouri, Hawaii, New Zealand
(majority Clindamycin susceptible)
Resistance Timeline: MRSA
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1996: first report of Vancomycin intermediate resistant S.
aureus (VISA) from Japan
1998 JAMA: 70% of cases of S. aureus disease in a
Chicago pediatric hospital are community-acquired
MRSA (CA-MRSA, most susc. to clinda, TMP/SMX)
1999 MMWR: 4 cases of serious, invasive CA-MRSA in
children (majority susc. to clindamycin, TMP/SMX.)
2002 PIDJ: 67% of cases of S. aureus disease in children
in Texas Children’s Hospital, Houston, are CA-MRSA
2010 Infect Control Hosp Epidemiol: 73% of hospitalacquired MRSA at Texas Children’s are CA-MRSA
isolates!
Percent of methicillin-resistant Staphylococcus aureus cases
classified as community-associated, 2000–2005*
*n = total number of community-associated methicillin-resistant Staphylococcus aureus cases per year
Como-Sabetti K, Harriman KH, Buck JM, et al.
Public Health Reports. May-June 2009; 124: 427-35
Percent of community-associated methicillin-resistant Staphylococcus aureus
isolates by pulsed-field type and inducible clindamycin resistance by year, 2000–
2005
ICR 5 inducible clindamycin resistance
Como-Sabetti K, Harriman KH, Buck JM, et al.
Public Health Reports. May-June 2009; 124: 427-35
MRSA Infections at 25 Children’s Hospitals, 1999-2008
Herigan JC, Hersh AL, Gerber JS, et al. Pediatr 2010; 125:e1294-e1300
S. aureus at University of
Kentucky
P
e
r
c
e
n
t
(n=1000) (n=1219) (n=1374) (n=1326) (n=1558) (n=1772) (n=2084) (n=2240) (n=2253)
Data from Clinical Microbiology Lab, Chandler Medical Center, University of Kentucky
Interpretation of Microbiology Lab
Susceptibility Reports
Typical Susceptibility Report for CA-MRSA:
 Oxacillin
R
 Tetracycline
S
 Gentamicin
S
 Ciprofloxacin
S
 Vancomycin
S
 Trimethoprim- Sulfamethoxazole
S
 Erythromycin
R
 Clindamycin
S
Clindamycin D-Test
Erythromycin resistant
Clindamycin susceptible
(eflux mechanism)
Erythromycin resistant
Clindamycin inducibly
resistant (MLSB)
Antimicrobial susceptibility and inducible clindamycin resistance trends of
CA-MRSA isolates, Minnesota Dept of Health, 2000–2005
2000
(n=106)
Percent
45
80
83
94
93
97
2001
(n=145)
Percent
43
77
83
97
94
100
2002
(n=200)
Percent
40
78
86
98
91
99
2003
(n=279)
Percent
28
68
8
99
91
99
2004
(n=434)
Percent
22
68
86
99
94
99
Characteristic
Erythromycin
Ciprofloxacin
Clindamycinc
Gentamicin
Tetracycline
Rifampin
Trimethoprimsulfamethoxazole
95
100
99
100
100
Vancomycin
100
100
100
100
100
ER-CS
30
35
44
56
64
ICR
93
82
50
36
16
Clindamycin total
58
56
64
64
76
CA-MRSA = community-associated methicillin-resistant Staphylococcus aureus
NS = not significant
ER-CS = erythromycin resistant/clindamycin susceptible
ICR = inducible clindamycin resistance
2005
(n=301)
Percent
13
59
88
99
92
100
Chi-square
for trend
(p-value)
92.8 (p<0.01)
26.9 (p<0.01)
NS
21.9 (p<0.01)
NS
NS
99
100
75
14
77
14.6 (p<0.01)
NS
118.4 (p<0.01)
155.9 (p<0.01)
38.0 (p<0.01)
Como-Sabetti K, Harriman KH, Buck JM, et al.
Public Health Reports. May-June 2009; 124: 427-35
Antimicrobial Management of Staphylococcus aureus
infections in US Children’s Hospitals, 1999-2008
Herigan JC, Hersh AL, Gerber JS, et al. Pediatr 2010; 125:e1294-e1300
Is Current Standard Dosing of Vancomycin
Adequate?
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Standard dose: 40mg/kg/day ÷ q6-8h
AUC/MIC >400 associated with optimal outcomes in
adults (no pediatric study)
CA-MRSA MIC typically <0.5-2 mg/L
Current dosing may be inadequate to achieve
therapeutic levels in children for MRSA with MIC ≥ 1
Jimenez-Truque N, et al. Pediatr Infect Dis J 2010;29:368-70.
Frymoyer A, et al. Pediatr Infect Dis J 2009;28: 398-402.
Vanc dosing: Lets go to Monte
Carlo!
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A Monte Carlo simulation models known biological variance, replicating realworld conditions over thousands of simulated encounters
 i.e. Probability of achieving optimal serum concentrations can be modeled
across a range of vancomycin doses against MRSA with different MIC’s
 Nifty, huh?!
Frymoyer A, Hersh AL, Coralic Z, Benet LZ, Guglielmo BJ. Clin Ther.
2010;32:534-42
Evaluating the Empiric Dose of Vancomycin in Pediatric Patients
McCabe T, Davis GA, Iocono J, Nelson C, Kuhn RJ. (University of Kentucky College of
Pharmacy; Pending Submission)
Retrospective
chart review Jan 08
to Mar 09
Age 1m – 18y
Dx: Abscess, Osteomyelitis, and
Neutropenic Fever
Goal Trough: 15-20 mg/L
239
charts reviewed; 63 patients
included in analysis
No supratherapeutic levels or renal
impairment were noted
Calculated: k(hr-1), Vd (L/kg), t½ (hrs)
•Standard
empiric doses of
•<40mg/kg/day
divided q8h
•40-60mg/kg/day divided q8h or q6h
•60-84mg/kg/day divided q6h
Table 4
Proposed Recommendations for Empiric Vancomycin Dosing in Pediatrics*
Age
Empiric Vancomycin Dose
(years)
(mg/kg/day)
<2
95
2-12
88
12-18
75
* Assuming normal renal function and fluid status
Time–kill curves of orally available antimicrobials
against MRSA.
Error bars represent – 1 standard deviation.
RIF= rifampicin;
SXT=trimethoprim/sulfamethoxazole.
Kaka AS, Rueda AM, Shelburne III SA.
J Antimicrob Chemother 2006; 58: 680–683
Staphylococcus aureus Virulence
Factors
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Surface Proteins that promote colonization of host tissues and
attachment to host cells: fibronectin
Surface Factors that inhibit engulfment by phagocytes: polysaccharide
capsule, protein A (binds IgG, disrupting phagocytosis)
Invasins that promote bacterial spread within tissues: leukocidin (PantonValentine Leukocidin/PVL), kinases, hyaluronidase
Biochemical Properties enhancing survival in phagocytes: carotenoids,
catalase production
Immunological Disguises: Protein A, coagulase, clotting factor
Membrane-Damaging Toxins that lyse eukaryotic cell membranes:
hemolysins, leukotoxin, leukocidin (PVL)
Exotoxins that damage host tissues and provoke disease: Alpha Toxin,
Enterotoxins A-G, Toxic Shock Syndrome Toxin (TSST-1), Exfoliative
Toxin
Inherent and Acquired Antibiotic Resistance
Panton-Valentine Leukocidin (PVL)
A Major CA-MRSA Virulence Factor
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PVL-producing CA-MRSA are highly-associated
with certain types of infections
Cellulitis
 Abscesses
 Complicated osteomyelitis
 Necrotizing pneumonia and empyema
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PVL is not commonly produced by HA-MRSA
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May be found in MSSA
CA-MRSA: Clinical Manifestations
Pneumonia
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Pneumonia common in S. aureus infections
10-20% rate with invasive infection
 Many are due to predisposing virus (e.g. influenza)
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2/3 of S. aureus pneumonias demonstrate
empyema; necrotizing pneumonia w/o
empyema also happens
Pneumonia may be due to septic emboli from
other source (osteomyelitis, endocarditis) –
nodular pneumonia
PVL-Positive CA-MRSA and
Necrotizing Pneumonia
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Young, previously healthy patient population
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45% < 1yr
Flu-like prodromal illness; seems benign!
Rapid progression to severe pneumonia and a sepsis syndrome
(mortality ~40% within 48 hrs.)
Radiographic appearance: necrotizing pneumonia with cavitary
lesions or pneumatoceles, often with pleural effusion,
empyema, and/or pneumothorax (pyopneumothorax)
Therapeutic implication: consideration of Clindamycin/Linezolid
to inhibit protein (toxin) synthesis, shut off inflammatory
cascade
Necrotizing Pneumonia
Staphylococcal Pneumonia
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Early index of suspicion
Dx by culture of surgical specimen or tracheal
aspirate
Vancomycin initial drug of choice
Clinda for uncomplicated cases if local clinda
resistance is <10-15%
 Vancomycin trough of 15-20mcg/ml suggested
 Linezolid shows promise as alternative agent
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Early VATS/drainage of empyema may reduce
LOS and shorten recovery
Pulmonary Abscess
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Isolated pulmonary abscess
may occur w/o clinical sepsis
Primary or secondary
Fever, cough, CP, malaise, wt
loss
May be managed with
antibiotics alone if no
empyema (Clindamycin)
Endocarditis
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Fever, malaise, new murmur, splenomegaly, positive
blood cultures (usually multiple)
Echo aids in diagnosis (Modified Duke Criteria)
Embolic phenomena less common in young children
(petechiae, Janeway lesions)
Septic shock may be evident early or may not develop
at all; can by quite indolent (index of suspicion)
Typically, vancomycin +/- gentamicin is empiric
treatment; vancomycin trough
Osteomyelitis and Septic Arthritis
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S. aureus is leading cause in all age groups
Presents with nonspecific inflammatory
symptoms, irritability, and pain
Septic hip: surgical emergency
Empiric antibiotics often can be safely delayed
until aspiration/culture if done within 12 hours
MRI is best imaging modality for acute infection
Osteomyelitis: Sites of
Involvement
Ulna 3%
Humerus
12%
Pelvis 9%
Radius 4%
Hands/Feet
13%
Tibia 22%
Femur 27%
Fibula 5%
Septic Joint: Sites of Infection
5%
10%
25%
41%
13%
1050 cases of pyogenic arthritis; Principles and Practice of
Pediatric Infectious Disease; 2003; p. 475
Osteo and Septic Joint:
Managment
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Empiric coverage of MRSA appropriate
Preferably after sampling/culture from site
 Clindamycin preferred if <10-15% local resistance
 Vancomycin trough 15-20mcg/ml is recommended
by some experts
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Non-operative management of osteomyelitis
No abscess on MRI
 Improving clinically with treatment over first week
 Repeat imaging, consider surgery if worsening or no
improvement
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Staph Scalded Skin Syndrome
(SSSS)
SSSS
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Mediated by exfoliative
toxins (ETA, ETB)
Fever, widely spread, tender
erythema
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Quickly form bullae
Nikolsky sign
On path, skin separates at
granular layer in the
epidermis
Treatment: Supportive care
and antibiotic (oral or i.v.) to
reduce staph burden
Staph Scalded Skin Syndrome
Staph Toxic Shock Syndrome
(TSS)
TSS
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Caused by TSST-1, Staph
Enterotoxins B & C (SEB, SEC)
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Syndrome: Fever, erythroderma,
hypotension, and multisystem
organ dysfunction (at least 3)
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Initial GI symptoms, malaise, and
dizziness associated with
seemingly benign infection or
post-op
TSS
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TSST-1 inhibits local inflammatory mediator
release
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Local infection appears surprisingly normal
Identifying source site may be delayed
Eye and mouth: hyperemia, strawberry
tongue
Blood culture rarely positive
Organ failure, ARDS in first few days; 3%
mortality
DDx: RMSF, Leptospirosis, other bacterial
sepsis
TSS: Management
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High index of suspicion (phone triage)
Identify and drain/remove source ASAP
2 peripheral i.v.’s or CVL, intravascular
resuscitation
Empiric antibiotics: Vancomycin plus
Clindamycin
Intensive care; consider IVIG if not responding to abx
Desquamation 1-2 weeks later is a hallmark of TSS
Severe Sepsis Syndrome
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Clinically similar to TSS, but fails to meet criteria
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S. aureus isolated from clinical site
Hypotension
ARDS/respiratory failure
at least one other organ system involved
Historically disease of frail, immunocompromised
Increasing in healthy children today; MSSA and MRSA
Mortality rate 60%!!
Necrotizing Fasciitis
Purpura Fulminans
Management of CA-MRSA Infections
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General Rule: choice of empiric therapy should be
tempered by the severity of the infection and clinical
status of the patient. Infectious Disease specialty
consultation may be valuable in guiding diagnosis and
treatment.
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If a patient with a suspected Staphylococcal infection is
being treated a ß-lactam antibiotic (e.g. nafcillin,
cefazolin) and is not responding within 24-48 hours of
initiation of therapy, the clinician must consider the
possibility of MRSA as the etiology.
Management of Active Infection
Caused by CA-MRSA
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Incise, Drain and Culture whenever possible
Optimal management is based on the severity of illness
of the patient you are seeing:
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Hospitalization and parenteral antibiotic therapy for: systemic
toxicity, bone and joint infections, cellulitis that involves a
large area and/or is rapidly spreading, extensive and/or deepseated cutaneous abscesses not amenable to office drainage,
septic shock, necrotizing pneumonia, bacteremia, etc.
Outpatient management and oral antibiotics for: simple,
limited-area cellulitis or impetiginous lesions, superficial
cutaneous abscesses, etc.
Management of Active Infection
Caused by CA-MRSA
Empiric antibiotic therapy*:
 Outpatient: trimethoprim-sulfamethoxazole
(TMP-SMZ), clindamycin, tetracycline (>8 yrs),
linezolid (Zyvox)
 Inpatient: vancomycin, clindamycin, linezolid,
TMP-SMZ, combination therapy (e.g.
vancomycin-clindamycin)
 The future?: tygecycline (Tygacil), daptomycin
(Cubicin), anti-MRSA cephalosporins
(Ceftobiprole medocaril, others in development)
*Locate and drain all purulent foci
Conclusions
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CA-MRSA infection in children is epidemic and
severe infections are now more frequently seen
Accurate interpretation of susceptibility data is
an important element in the management of
CA-MRSA infection, including empiric dosing
Early identification of CA-MRSA infection,
incision and drainage when appropriate, and
initiation of appropriate empiric antibiotic
therapy are the mainstays of treatment
For More Information
CDC Overview of Community-Associated MRSA:
http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca.html
CDC CA-MRSA Fact Sheets for the Public:
http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_public.html
CDC Questions and Answers about MRSA in Schools:
http://www.cdc.gov/Features/MRSAinSchools/