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					             CA-MRSA
    Part of a Perfect Microbial Storm


                  Alana Arnold, PharmD
                  Associate Director-Clinical Coordinator
                  Infectious Disease Specialist




1
                       CA-MRSA
           Part of a Perfect Microbial Storm
                        Objectives

       Definitions
       Transmission
       Prevalence
       Risk Factors
       Diagnosis
       Treatment
       Prevention

2
    Staphylococcus aureus
    The family tree


       Methicillin sensitive s.aureus (MSSA)
       Methicillin resistant s.aureus (MRSA)
        – Healthcare-associated MRSA (HC-MRSA)
                          MRSA
             Hospital-onset
             Community-onset MRSA
               –   (h/o surgery, dialysis, LTC within 12 months)

        –   Community-acquired MRSA (CA-MRSA)

3
    Staphylococcus aureus
    Where do we usually see it?


       Impetigo
       Folliculitis
       Cellulitis
       Erysipelas
       Furuncles (boils)
       Staph Scalded Skin Syndrome
       Toxic Shock Syndrome

4   Swartz MN. In Mandell GL et al. Principles of Infection Dis. 2000;1037-1057.
    Other concerning infection sites

        Bacteremia and sepsis
          –   Osteo, meningitis, endocarditis, etc
        Surgical site infections
        Pneumonia
          –   Nosocomial
          –   Community-acquired
        Catheter associated infections
        Infections of prosthetic devices

5       Waldvogel FA. In Mandell GL et al> Principals and practice of Infect. Dis. 2000; 2069-2092.
    Antimicrobial Resistance

       The adaptive potential of the microbial world
        is such that for each new antibiotic that is
        introduced, several escape mechanisms are
        soon devised.
       The action of antibiotics and resistance are
        linked like light and shadow: one does not
        exist without the other.


6                                       Waldevogel, NEJM, 1999
    Methicillin-resistant Staphylococcus aureus
    (MRSA)

     First described: 1961
     Definition: MRSA is a bacterium responsible for difficult-to-treat
      infections in humans. MRSA is a strain of Staphylococcus
      aureus that is resistant to a large group of antibiotics called the
      beta-lactams, which include the penicillins and the
      cephalosporins.
     Resistance: The mecA gene (the gene responsible for methicillin
      resistance) is part of a mobile genetic element found in all
      MRSA strains. Katayama et al. demonstrated that mecA is part
      of a genomic island designated staphylococcal cassette
      chromosome mec (SCCmec).



7
    HA-MRSA
    Characteristics


       Hospital–associated strains of S. aureus                     Courtesy of the CDC
        still cause about 85% of all MRSA cases.       Large numbers of
                                                       Staphylococcus aureus bacteria,
       Hospital patients with S. aureus               which were found on the inside
                                                       surface of a catheter. The sticky-
        infections are five times more likely to die   looking substance woven
                                                       between the round cocci bacteria
        than are patients without the infection.       is known as a “biofilm”.
                                                       Biofilms help to protect the
       Multi-drug resistant (MDR) – resistant to      bacteria.

        beta-lactams UNLIKE MSSA !
       Vancomycin - one treatment option for
        HA-MRSA, but is often no longer
        effective due to rising MICs.

8
        Evolution
        From HA and CA-MRSA



        Until recently, most MRSA infections started in
         hospitals, especially among surgical and
         immunocompromised patients. (HA-MRSA)
        In the early 1980s, new strains of MRSA began to
         strike healthy people in community settings – first
         identified in Detroit. (CA-MRSA)
        Community MRSA that was NOT MDR !


9
     CA-MRSA
     Transmission


        Direct person to person contact
        Sharing of towels or personal hygiene items
        Athletic equipment
        Clothes
        Drug use equipment
        Contact sports
        Food-borne

10
     MRSA
     Prevalence


        Prevalence is increasing!!
         HA-MRSA in ICU patients
                 1989 = 27%
                 2005 = 60%
         CA-MRSA
                 Some areas report > 10% incidence in ER skin infection visits
        Review
         –   antibiogram to assess prevalence in community.
         –   risk factors for MRSA


11
     Prevalence - August 2004


        Add chart – ER incidence
        Morgan gj et al NEJM 2006; 355:666-74




12        Moran, et al. NEJM 2006;355:666-674
     CA–MRSA
     Characteristics

        Staphyloccal bacteria that have become               Courtesy of the CDC
         resistant to beta-lactam antibiotics but
         NOT multi-drug resistant (MDR).
        Several antibiotics remain effective
         against CA–MRSA, but it is an
         aggressive and rapidly evolving form of
         S. aureus.                                 Cutaneous abscess
                                                    caused by methicillin–
        Usually appears as a skin infection, but   resistant
         it can spread quickly to a bloodstream     Staphylococcus aureus
         infection or a very serious form of        bacteria.
         pneumonia.

13
     HA-MRSA and CA-MRSA
     Differences

                       HA-MRSA                         CA-MRSA
     Mean Age          Old                             Young

     SSTI %            35%                             75%

     Resistance gene   SCCmec type I,II,III            SCCmec type IV,V

     Strain Type       USA 100 and USA 200             USA 300 and USA 400

     PVL Toxin Gene    Rare 5%                         Almost 100%

     Susceptibility    Vancomycin, Linezolid           Usually susceptible to Bactrim,
                       Synercid, Daptomycin            doxycycline, clindamycin, rifampin

     Risk Factors      Recent hospitalization or       -Close contact-childcare centers,
                       surgery, recurrent abscesses,   nursing homes, prisons.
                       Long term care, IV drug user,   -Certain populations (Pacific
                       indwelling catheters, medical   Islanders, Native Americans), Contact
                       conditions such as diabetes,    sports (football, wrestling)
14                     HIV, renal failure              -Sharing of towels, equipment
     Strain Type – USA300

      Community-associated methicillin-resistant
      Staphylococcus aureus (CA-MRSA) infections are
      caused primarily by a single strain — USA300 — of
      an evolving bacterium that has spread with
      "extraordinary transmissibility" throughout the United
      States during the past five years, according to a new
      study led by National Institutes of Health (NIH)
      scientists. CA-MRSA, an emerging public health
      concern, typically causes readily treatable soft-tissue
      infections such as boils, but also can lead to life-
      threatening conditions that are difficult to treat.
       Monday, January 21, 2008 -5:00 p.m. EST NIH News
15
     Panton–Valentine Leukocidin (PVL)

        Described in 1932
        Gene common among CA-MRSA strains resulting in
         increased virulence (enhances inflammation and
         bacterial attachment)
        Toxins cause:
         –   Lysis of WBCs
         –   Dermal Necrosis
        Associated with necrotizing pneumonia (destruction of
         healthy lung tissue), fasciitis

16
     CA-MRSA
     Diagnosis


        Commonly complain of infected pimples, spider
         bites, or sores.
        Usually minor carbuncles, furuncles, abscesses.
        Can be more extensive cellulitis, deep-seated
         abscesses, septic arthritis, pneumonia and sepsis.
        Should be considered in the DDX of all SSTIs.
        Aerobic cultures should be obtained on all open
         lesions/ draining abscesses.


17
     CA-MRSA
     Treatment

        Some S. aureus infections can be treated
         without antibiotics by surgically draining the
         wound. Local incision and drainage and hot          Cultured Staphylococcus
         packs are first-line therapy for skin infections.   aureus on agar plate.

        Before prescribing an antibiotic, a doctor must
         determine if MRSA bacteria are present.
        Using the wrong drug delays treatment and
         encourages the development of more resistant
         bacteria.




18
     Treatment options

          Bactrim (PO + IV)
          Clindamycin (PO + IV)
          Tetracyclines (PO)
          Linezolid (PO + IV)
          Fluoroquinolones (PO + IV)
          Vancomycin (IV)
          Daptomycin (IV)
          Tigecycline (IV)

19
     Fluoroquinolones

        CA-MRSA can demonstrate in vitro sensitivity
          –   76% Susceptibility
          –   Strong consideration for treatment
        MSSA isolates rarely develop methicillin resistance and
         typically remain susceptible
        Overuse of fluoroquinolones may cause:
          –   MSSA colonization replaced by MRSA post-exposure
          –   Increased expression of adherence factors promote host
              colonization via over-expression of fibronectin-binding protein

     Weber SG Emerg Infect Dis 2003 Nov; 9: 1415-22. LeBlanc L Emerg Infect Dis 2006 Sep; 12: 1398-
20   405. Bisognano C Antimicrob Agents Chemother. 1997 May; 41: 906-13.
          LaPlante KL, Rybak MJ, Amjad M, Kaatz GW. Pharmacotherapy. 2007 Jan;27(1):3-10
     Bactrim®:
     Sulfamethoxazole/Trimethoprim


        95% CA-MRSA isolates are susceptible
        Excellent bioavailability and distribution
        Bactericidal pharmacodynamics
        Poor activity against Streptococcus species
         (GAS and Beta hemolytic)



21
     Bactrim
     Dosage & Dosage Forms

        Not recommended for use in patients <2 mos.
        Dosage: TRIMETHOPRIM component
         –   PO: 6 to12 mg/kg/day divided BID-TID
         –   Usual max dosing of 160-320 mg PO BID-TID
        Dosage Forms:
         –   Suspension: Trimethoprim 40 mg sulfamethoxazole 200 mg
             and per 5 mL
         –   Single strength: Trimethoprim 80 mg and sulfamethoxazole
             400 mg
         –   Double strength: Trimethoprim 160 mg and
             sulfamethoxazole 800 mg

22
     Clindamycin

        Coverage for Staphylococcal and Streptococcal
         infections
        Excellent bioavailability and distribution
        Suppresses PVL production of CA-MRSA
        Potential for emergence of resistance with high
         inoculum infections caused by strains inducibly
         resistant to erythromycin
         –   D-zone test should be performed to identify inducible
             clindamycin resistance in S. aureus determined clindamycin
             susceptible via MIC method


             LaPlante K. Antimicrobial Agents Chemotherapy. 2008;52:14
23
     Linezolid

        Activity against Staphylococcal and
         Streptococcal infections

        100% Bioavailability

        Like clindamycin, linezolid also suppresses
         PVL production in CA-MRSA


24
     Linezolid
     Drug-Drug & Drug-Food Interactions


         Serotonin syndrome possible with concomitant
          use of:
          –   Tyramine rich foods
          –   Serotonergic medications (SSRIs, MAOIs)


         Foods high in tyramine:
          –   Aged, fermented, pickled, smoked
                  Cheese, pepperoni, soy sauce, red wines, beer,
                   sauerkraut


25
     Tetracyclines
     Minocycline and Doxycycline


        Susceptibility >90% for CA-MRSA
        Potential, but unreliable coverage for Group
         A Streptococcus

        Not indicated for children <8 yrs of age
         –   Tooth enamel hypoplasia
         –   Tooth discoloration

                     Moran G NEJM. 2006;7:666-74.
26
     Headlines
        Four Pediatric Deaths from Community-Acquired
         Methicillin-Resistant Staphylococcus aureus -- Minnesota
         and North Dakota, 1997-1999 (MMWR Vol.48/No.32)
          –   Cases of community-acquired MRSA infection in patients without established
              risk factors.
        Community Acquired Methicillin-Resistant Staphylococcus
         aureus in a Rural American Indian Community
        Methicillin-Resistant Staphylococcus aureus Infections in
         correctional facilities – Georgia, California and Texas,
         2001-2003




27
     The Perfect Microbial Storm
     December 6, 2003

        Ricky Lannetti presented to ER due to rapidly
         worsening pneumonia and died within
         12hrs. He also had influenza infection during same time period.
        PMH: healthy star wide receiver for Lycoming College
        Autopsy: Death result of MRSA infection
        CDC Analysis: Staph-USA300
        During same flu season: 4 similar deaths in Baltimore
        ID specialist John Francis (John Hopkins) led team of investigators
         who made the link between USA300 and influenza.
        ―When this strain of staph ends up in the same body as the influenza
         virus,‖ says Francis, ―the result is the perfect storm, a one-two
28       punch to the immune system.‖
     In Summary:
        Necrotizing pneumonia associated with PVL toxin is a recent
         described clinical entity. It mainly occurs in children and young
         adults (median age 15 years), is fatal in 75% of cases, and is
         associated with a median survival time of 4 days.
        Necrotizing pneumonia is mainly associated with PVL-positive
         methicillin-susceptible and methicillin-resistant Staphylococcus
         aureus strains.
        Necrotizing pneumonia is often preceded by a viral-like illness.
         Viruses such as the influenza A virus have been isolated
         concomitantly with the PVL-positive S. aureus.



     Garnier F, Tristan A, François B, Etienne J, Delage-Corre M, Martin C, et al. Pneumonia and new
29   methicillin-resistant Staphylococcus aureus clone. Emerg Infect Dis. 2006 Mar.
     Predicting the future…..

        CA-MRSA rapidly increasing in prevalence
        Increase in antibiotic resistance as CA-MRSA moves
         into healthcare setting
        Increase in CA-MRSA bacteremia due to
         colonization in hospitals
        CA and HA-MRSA distinction blurring
        Increase in necrotizing pneumonia associated with
         the looming influenza pandemic infection


30
     Prevention

        Isolation and Contact Precautions within health
         care facilities
        Wash hands frequently and thoroughly.
        Use hand sanitizer if soap/water are not available.
        Keep skin cuts clean and covered.
        Don’t touch another person’s wound or bandage.
        Avoid sharing personal items (towels, razors,etc)
        Routine cleaning of athletic equipment
        Routine disinfection of countertops, exam tables or
         other treatable surfaces.
        All open wounds should be covered.
        Get immunized !!
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