TM Community-Acquired MRSA: Update on Epidemiology, Treatment, and Prevention John S. Bradley, MD, FAAP Infectious Diseases Division University of California,

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Community-Acquired MRSA:Update on Epidemiology,

Treatment, and Prevention

John S. Bradley, MD, FAAPInfectious Diseases DivisionUniversity of California, San DiegoRady Children’s Hospital San Diego

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Prepared for your next patient.

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Disclaimers Statements and opinions expressed are those of the authors and not

necessarily those of the American Academy of Pediatrics.

Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.

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CA-MRSA

• Epidemiology• Pathogenicity• Clinical Presentation• Treatment (New Guidelines)• Prevention

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Epidemiology:Virulent CA-MRSA

• First clinical reports in the US appeared about 10 years ago

• Likely to have emerged several times in the past (many different clones described, but only a few have been successful over time)…still evolving!

• May now be losing methicillin-resistance genes, but still virulent!!

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CA-MRSA

• Differs in clinical disease compared with MSSA and past hospital-acquired MRSA strains– Uniformly resistant only to beta-lactam

antibiotics (penicillins, cephalosporins, carbapenems)*

– Variably resistant to macrolides and to lincosamides (clindamycin)

*Except ceftaroline, just approved by FDA for adults in October 2010.

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CA-MRSA:Primary PFGE type: USA 300 (CDC) • SCCmec types (Staphylococcal Chromosome Cassette)

Deurenberg RH, Vink C, Kalenic S, et al. The molecular evolution of methicillin-resistant Staphylococus aureus. Clin Microbiol and Infect. 2006;13(3):222-235.

Methicillin-resistance cassette associated with CA-MRSA

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Increased virulence inCA-MRSA USA 300appears to be linked tovirulence factors ORAlterations in geneRegulation• Phenol soluble modulins• Panton-Valentine leukocidin• α-hemolysins• Arginine catabolic mobile

element (ACME)• agr (accessory gene regulator)

Kobayashi SD, DeLeo FR. An update on community-associated MRSA virulence. Curr Opin Pharmacol. 2009;9(5):545-551.

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CA-MRSA: PMN Killing Following Phagocytosis

Kobayashi SD, DeLeo FR. An update on community-associated MRSA virulence. Curr Opin Pharmacol. 2009;9(5):545-551.

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CA-MRSA: Mouse Lung Infection Model

Saline control in lungs Staph without PVL Staph with PVL

Subsequently found to be a dysregulated PVL hyperproducer.

Labandeira-Rey M, Couzon F, Boisset S, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315(5815):1130-1133.

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CA-MRSA: Necrotizing Pneumonia

Labandeira-Rey M, Couzon F, Boisset S, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315(5815):1130-1133.

PVL PVL

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CA-MRSA: What it Does

• CA-MRSA appears to cause deeper, more invasive infections than MSSA

• CA-MRSA appears to cause necrotizing fasciitis at a greater rate than MSSA

• CA-MRSA does not appear to cause bacteremic disease more frequently

• CA-MRSA appears to cause recurrent infections more frequently

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CA-MRSA

• CA-MRSA appears to have a selective advantage in the community, and represents an increasing proportion of staph responsible for hospitalizations, just like penicillin-resistant strains did over 30 years ago

• In many regions of the USA, rates of MRSA have stabilized at 40-90% (we don’t know why rates vary)

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ClinicalCharacteristics

and Management

Dallas, Texas

Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;23(2):123-127.

All children with abscesses (n = 69)

The “spider bite”

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Complicated MRSA PneumoniaEnhanced Destruction of Lung with Influenza Co-infection

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Complicated MRSA PneumoniaLate Fibrosis

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Necrotizing Fasciitis with MRSA

Cellulitis (short arrow)

Panniculitis (long arrow)

Fasciitis (arrowhead)

Gram-positive cocci in clusters (arrow)Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Eng J Med. 2005;352(14):1445-1453.

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CA-MRSA in Pediatrics

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CA-MRSA in Pediatrics

2 weeks post skin grafting[But no Necrotizing Fasciitis since in SD in 3 years]

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CA-MRSA: Complication Rates

• This is not the old Staph: all of the information/publication/experience regarding the old MSSA strains may not apply to CA-MRSA

• Complication rates are higher and response to treatment is slower; inflammation and induration may not be resolved by 10-14 days

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CA-MRSA: Diagnosis

• Cultures are important for all presumed staph infections as many are still MSSA

• Rapid tests are now available– From cultured organisms: latex particles coated with

monoclonal antibody to PBP 2a– PCR from colonized anatomic sites, looking for the

mecA methicillin resistance genes

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IDSA Guidelines for CA-MRSA

Endorsed by the AAPJanuary 2011

Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

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CA-MRSA:Community-Acquired Pneumonia (CAP)• For children hospitalized with severe CAP empiric therapy for MRSA is recommended (pending sputum and/or blood culture results):

– Those requiring an intensive care unit (ICU) admission, OR– Necrotizing or cavitary infiltrates, OR– Empyema

• Vancomycin recommended for children – If the patient is stable without ongoing bacteremia

or intravascular infection, clindamycin can be usedas empirical therapy if the clindamycin resistance rate is low (eg, 10%)

– Linezolid is an alternative [watch for more data on this issue]


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CA-MRSA:Adjunctive Therapy for MRSA

• Not routinely recommended: Protein synthesis inhibitors (eg, clindamycin and linezolid) and intravenous immunoglobulin (IVIG)– Some experts may consider these agents in selected

scenarios (eg, necrotizing pneumonia or severe sepsis)


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CA-MRSA:Vancomycin Dosing for Children• Vancomycin 15 mg/kg/dose every 6 h (60 mg/kg/day) is

recommended for serious or invasive disease (data are limited to guide vancomycin dosing in children).

• Trough concentrations of 15–20 mcg/mL should be considered in those with serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (eg, necrotizing fasciitis)– The efficacy and safety of this dose requires additional study

• [AUC:MIC > 400]Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

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CA-MRSA:Treatment for Skin / Skin Structure Infections (SSTI)

• Hospitalized children with complicated SSTI:– Vancomycin – Clindamycin is an option if the patient is stable, without

ongoing bacteremia or intravascular infection, and if the clindamycin resistance rate is low (eg,10%); allows transition to oral therapy

– Linezolid is an alternative


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CA-MRSA: TherapyInvasive, Serious Disease

• Roles not well defined for pediatrics:– Linezolid (Zyvox®): IV/PO, bacteriostatic in vitro (?not in

vivo?) Superior to vancomycin for treatment of adults with MRSA

pneumonia (IDSA 2010 abstract)– Daptomycin (Cubicin®): rapidly bactericidal, but virtually

NO pediatric data and NOT EFFECTIVE for pneumonia

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• Oral antibiotics for Abscess/Cellulitis:– Clindamycin (if local strains susceptible) Staph + Strep [tastes

bad]– TMP-SMX (Septra/Bactrim) Staph + ?Strep [no prospective,

controlled studies vs clinda]– Doxycycline [bacteriostatic, for children older than 7 years]– Linezolid (Zyvox) Staph + Strep [expensive! Marrow toxicity for

courses beyond 10 days]Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

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All you need is drainage!

Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J. 2004;23(2):123-127.

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CA-MRSA:Therapy of Mild –

Moderate Infections

How solid are the data supporting the use of

TMP-SMX?…retrospective

Retrospective review of convalescent therapy of MRSA infections (Baylor College of Medicine)

Hyun DY, Mason EO, Forbes A, et al. Trimethoprim-sulfamethoxazole or clindamycin for treatment of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J. 2009;28(1):57-29.

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CA-MRSA:Therapy of Mild – Moderate Infections

A child with fever, induration or abscess, seen in the ED, has a 40% chance of failing TMP-SMX with infection presumed to be caused by MSSA, MRSA or Gp A strep

Retrospective review of non-cultured, non-drained skin infections

Elliott DJ, Zaoutis TE, Troxel AB, et al. Empiric antimicrobial therapy for pediatric skin and soft-tissue infections in the era of methicillin-resistant Staphylococcus aureus. Pediatrics. 2009;123(6):e959-e966.

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• Minor skin infections (such as impetigo) and secondarily infected skin lesions (eg, eczema, ulcers, or lacerations):– Topical 2% mupirocin ointment

• Cutaneous abscess:– Incision and drainage may be sufficient – Consider oral antibiotics for more severe cases

• Cellulitis: Consider oral antibiotics


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CA-MRSA:Bone and Joint Infections• Surgical debridement and drainage of associated soft

tissue abscesses is the mainstay of therapy – Antibiotics intravenously:

• Vancomycin

– Antibiotics intravenous and oral:• Clindamycin • TMP-SMX 4 mg/kg/dose in combination with rifampin• Linezolid

– Some experts recommend the addition of rifampin to IV or oral regimens


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CA-MRSA:Bone and Joint Infections• The optimal duration of therapy for MRSA

osteomyelitis is unknown:– A minimum of 4-6 weeks– An additional 1–3 months ( for chronic

infection or if debridement is not performed) may be required

• CRP (and/or ESR) may be helpful to guide response to therapy

• Magnetic resonance imaging (MRI) with gadolinium is the imaging modality of choice for osteomyelitis


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CA-MRSA:Bacteremia / Endocarditis• Vancomycin is recommended for the treatment of bacteremia and infective

endocarditis – Duration of therapy may range from 2 to 6 weeks depending on source, presence

of endovascular infection, and metastatic foci – Data regarding the safety and efficacy of alternative agents in children are limited;

daptomycin may be an option

• Clindamycin or linezolid may be considered in children whose bacteremia rapidly clears and is not related to an endovascular focus

• Data are insufficient to support the routine use of combination therapy with rifampin or gentamicin in children with bacteremia or infective endocarditis; the decision to use combination therapy should be individualizedLui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of

methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

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CA-MRSA:Decolonization for Recurrent SSTI• Decolonization may be considered in selected cases if

– A patient develops a recurrent SSTI despite optimizing wound care and hygiene measures

– Ongoing transmission is occurring despite optimizing wound care and hygiene measures

• Decolonization strategies should be offered in conjunction with ongoing hygiene measures:– Nasal decolonization with mupirocin twice daily for 5–10 days with or without

concurrent topical body decolonization regimens with a skin antiseptic solution (eg, chlorhexidine*) for 5–14 days or dilute bleach baths

• Oral antimicrobial therapy is not routinely recommended for decolonization*In San Diego, we use chlorhexidine every other day, or 3x/wk to decrease rates of recurrence


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CA-MRSA in Sports

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Current CA-MRSA:Pediatric Antibiotic Research

• NIH/NICHD-sponsored trials of oral therapy/I&D for uncomplicated skin infections (clinda vs cephalexin vs TMP-SMX vs I&D)

• Daptomycin is in pediatric clinical trials for complicated skin infections

• Phase I PK studies ceftaroline, dalbavancin and torezolid

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CA-MRSA:Summary• Respect CA-MRSA!• Vancomycin is still the preferred drug for invasive infection in

children– Many new options are appearing for adults, not yet tested

in children– Optimal dosing in children is not well defined

• Clindamycin/TMP-SMX are reasonable options for mild/mod disease (little prospective data exist)

• Whatever you use, do not automatically assume that the child will respond!

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Documents

TM Community-Acquired MRSA: Update on Epidemiology, Treatment, and Prevention John S. Bradley, MD, FAAP Infectious Diseases Division University of California,