MRSA: Beyond Butt Boils

1
MRSABeyond Butt Boils

• Jeffrey S. Bennett, M.D.
• Assistant Professor of Pediatrics/Infectious
  Disease
• Director, Section of Inpatient Pediatrics
• University of Kentucky

2
Educational Goals

• 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

3
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

4
Epidemic!!
5
Ripped from the Headlines

• Jan 13, 2005 ABC News
• 'Superbug' MRSA Worries Doctors, Athletes
  Drug-Resistant Germ Found in Locker Rooms Can
  Kill Within Days
• October 17, 2007 Dallas Morning News
• U.S. deaths from staph 'superbug' may surpass
  AIDS deaths
• October 19, 2007 Chicago Tribune
• Superbug alert at high school Infection struck 2
  football players
• October 23, 2007 Wall Street Journal
• Putting Superbugs on the Defensive
• October 28, 2007 China View News
• U.S. county to close all schools amid "superbug"
  fears (Pike County, Kentucky)

6
Staphylococcus aureus Basics

• Grams stain characteristics spherical, Gram
  positive cocci in pairs and groups/clusters
• Colonize anterior nares, skin of humans and
  warm-blooded 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

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CA-MRSA Basics

• CA-MRSA are genetically distinct from
  hospital-associated 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
• Major virulence factor 2 Panton-Valentine
  Leukocidin (PVL)
• Creates lytic pores in WBC membranes, leads to
  focal tissue necrosis and rapid abscess (boil)
  formation

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CA-MRSA vs. HA-MRSASame Exterior, but Very
Different Under the Hood

• 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, 2003290 2976-2984

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Historical Resistance Timeline

• 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)

10
Resistance Timeline MRSA

• 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 Childrens Hospital, Houston,
  are CA-MRSA
• 2010 Infect Control Hosp Epidemiol 73 of
  hospital-acquired MRSA at Texas Childrens are
  CA-MRSA isolates!

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Percent of methicillin-resistant Staphylococcus
aureus casesclassified as community-associated,
20002005
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
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Percent of community-associated
methicillin-resistant Staphylococcus
aureusisolates by pulsed-field type and
inducible clindamycin resistance by year,
20002005
ICR 5 inducible clindamycin resistance
Como-Sabetti K, Harriman KH, Buck JM, et al.
Public Health Reports. May-June 2009 124 427-35
13
MRSA Infections at 25 Childrens Hospitals,
1999-2008
Herigan JC, Hersh AL, Gerber JS, et al. Pediatr
2010 125e1294-e1300
14
S. aureus at University of Kentucky
Percent
(n1000) (n1219) (n1374) (n1326)
(n1558) (n1772) (n2084) (n2240) (n2253)
Data from Clinical Microbiology Lab, Chandler
Medical Center, University of Kentucky
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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

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Clindamycin D-Test
Erythromycin resistant Clindamycin inducibly
resistant (MLSB)
Erythromycin resistant Clindamycin
susceptible (eflux mechanism)
17
Antimicrobial susceptibility and inducible
clindamycin resistance trends of CA-MRSA
isolates, Minnesota Dept of Health, 20002005

• 2000 2001 2002 2003 2004 2005 Chi-square
• (n106) (n145) (n200) (n279) (n434)
  (n301) for trend
• Characteristic Percent Percent Percent
  Percent Percent Percent (p-value)
• Erythromycin 45 43 40 28 22 13 92.8
  (plt0.01)
• Ciprofloxacin 80 77 78 68 68 59 26.9
  (plt0.01)
• Clindamycinc 83 83 86 8 86 88 NS
• Gentamicin 94 97 98 99 99 99 21.9
  (plt0.01)
• Tetracycline 93 94 91 91 94 92 NS
• Rifampin 97 100 99 99 99 100 NS
• Trimethoprim-
• sulfamethoxazole 95 100 99 100 100 99
  14.6 (plt0.01)
• Vancomycin 100 100 100 100 100 100 NS
• ER-CS 30 35 44 56 64 75 118.4 (plt0.01)
• ICR 93 82 50 36 16 14 155.9 (plt0.01)
• Clindamycin total 58 56 64 64 76 77 38.0
  (plt0.01)
• CA-MRSA community-associated
  methicillin-resistant Staphylococcus aureus
• NS not significant
• ER-CS erythromycin resistant/clindamycin
  susceptible
• ICR inducible clindamycin resistance

Como-Sabetti K, Harriman KH, Buck JM, et al.
Public Health Reports. May-June 2009 124 427-35
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Antimicrobial Management of Staphylococcus aureus
infections in US Childrens Hospitals,
1999-2008Herigan JC, Hersh AL, Gerber JS, et al.
Pediatr 2010 125e1294-e1300
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Is Current Standard Dosing of Vancomycin
Adequate?

• Standard dose 40mg/kg/day q6-8h
• AUC/MIC gt400 associated with optimal outcomes in
  adults (no pediatric study)
• CA-MRSA MIC typically lt0.5-2 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
201029368-70. Frymoyer A, et al. Pediatr Infect
Dis J 200928 398-402.
20
Vanc dosing Lets go to Monte Carlo!

• A Monte Carlo simulation models known biological
  variance, replicating real-world 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
  MICs
• Nifty, huh?!

Frymoyer A, Hersh AL, Coralic Z, Benet LZ,
Guglielmo BJ. Clin Ther. 201032534-42
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Evaluating the Empiric Dose of Vancomycin in
Pediatric PatientsMcCabe 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
• lt40mg/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 (years) Empiric Vancomycin Dose (mg/kg/day)
lt2 95
2-12 88
12-18 75
Assuming normal renal function and fluid status
22
Timekill curves of orally available
antimicrobials against MRSA.
Error bars represent 1 standard deviation.
RIF rifampicin SXTtrimethoprim/sulfamethoxazol
e.
Kaka AS, Rueda AM, Shelburne III SA. J
Antimicrob Chemother 2006 58 680683
23
Staphylococcus aureus Virulence Factors

• 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 (Panton-Valentine
  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

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Panton-Valentine Leukocidin (PVL) A Major
CA-MRSA Virulence Factor

• PVL-producing CA-MRSA are highly-associated with
  certain types of infections
• Cellulitis
• Abscesses
• Complicated osteomyelitis
• Necrotizing pneumonia and empyema
• PVL is not commonly produced by HA-MRSA
• May be found in MSSA

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CA-MRSA Clinical Manifestations
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Pneumonia

• Pneumonia common in S. aureus infections
• 10-20 rate with invasive infection
• Many are due to predisposing virus (e.g.
  influenza)
• 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

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PVL-Positive CA-MRSA and Necrotizing Pneumonia

• Young, previously healthy patient population
• 45 lt 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

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Necrotizing Pneumonia
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Staphylococcal Pneumonia

• 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 lt10-15
• Vancomycin trough of 15-20mcg/ml suggested
• Linezolid shows promise as alternative agent
• Early VATS/drainage of empyema may reduce LOS and
  shorten recovery

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Pulmonary Abscess

• 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)

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Endocarditis

• 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

32
Osteomyelitis and Septic Arthritis

• 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

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Osteomyelitis Sites of Involvement
Radius 4
Ulna 3
Hands/Feet 13
Humerus 12
Pelvis 9
Tibia 22
Femur 27
Fibula 5
34
Septic Joint Sites of Infection
1050 cases of pyogenic arthritis Principles and
Practice of Pediatric Infectious Disease 2003
p. 475
35
Osteo and Septic Joint Managment

• Empiric coverage of MRSA appropriate
• Preferably after sampling/culture from site
• Clindamycin preferred if lt10-15 local resistance
• Vancomycin trough 15-20mcg/ml is recommended by
  some experts
• 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)
37
SSSS

• Mediated by exfoliative toxins (ETA, ETB)
• Fever, widely spread, tender erythema
• 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

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Staph Scalded Skin Syndrome
39
Staph Toxic Shock Syndrome (TSS)
40
TSS

• Caused by TSST-1, Staph Enterotoxins B C (SEB,
  SEC)
• Syndrome Fever, erythroderma, hypotension, and
  multisystem organ dysfunction (at least 3)
• Initial GI symptoms, malaise, and dizziness
  associated with seemingly benign infection or
  post-op

41
TSS

• TSST-1 inhibits local inflammatory mediator
  release
• 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

42
TSS Management

• 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

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Severe Sepsis Syndrome

• Clinically similar to TSS, but fails to meet
  criteria
• 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!!

Purpura Fulminans
Necrotizing Fasciitis
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Management of CA-MRSA Infections

• 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.
• 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.

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Management of Active Infection Caused by CA-MRSA

• Incise, Drain and Culture whenever possible
• Optimal management is based on the severity of
  illness of the patient you are seeing
• 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
  deep-seated 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.

46
Management of Active Infection Caused by CA-MRSA

• Empiric antibiotic therapy
• Outpatient trimethoprim-sulfamethoxazole
  (TMP-SMZ), clindamycin, tetracycline (gt8 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

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Conclusions

• 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

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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.h
  tml
• CDC Questions and Answers about MRSA in Schools
  http//www.cdc.gov/Features/MRSAinSchools/