Methicillin Resistant Staphylococcus aureus (MRSA)

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Methicillin Resistant Staphylococcus aureus (MRSA)

• What is it ?
• A flesh-eating virus
• An Ebola-like pathogen
• The plague
• I dont know, but I dont want them !
• Previously common bacteria that have acquired
  resistance genes.

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Evolution of Drug Resistance in S. aureus
Penicillin
Penicillin-resistant
S. aureus
1950s
S. aureus
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MRSA Among ICU Patients (1995-2004)
Source National Nosocomial Infections
Surveillance (NNIS) System
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Methicillin-Resistant Staphylococcus aureus (MRSA)
U.S. Non-Intensive Care U.S. Intensive Care The
Nebraska Medical Center
Source National Nosocomial Infections
Surveillance (NNIS) System
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Worldwide Prevalence of MRSA Among S. aureus
Isolates
Grundmann et al. Lancet 2006 368874-85.
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S. aureus A well-armed pathogen

• Adherence and colonization
• Tissue destruction and invasion
• Toxin production and disease at a distance
• Virulence under tight regulatory control

Lowy, NEJM 1998
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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

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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, 2005)

Kuehnert MJ, et al. J Infect Dis, 2006
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Beta-lactamase producing and methicillin-resistant
S. aureus
Hospital
Community
Hospital
Community
McDonald LC. J Infect Dis, 2006
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Community-Acquired MRSA
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Community MRSA Throughout the U.S. (2007)
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Chambers HF. Personal Communication. January 19,
2007
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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

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CA-MRSA Whats Going On?
SCCmec I-V, mecIV is most commonly found in
CA-MRSA 25 KB, mobile
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Whats 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)

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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/macrophage
  s
• Associated with necrotizing skin and soft tissue
  infections and pneumonia

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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

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Staphylococcal Skin Soft Tissue Infections
Cellulitis
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Staphylococcal Disease due to Metastatic Seeding
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Staphylococcal Disease due to Metastatic Seeding
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Staphylococcal Disease due to Metastatic Seeding
Endocarditis
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Staphylococcal Toxin-Mediated Diseases
Toxic Shock Syndrome
Staphylococcal Scalded Skin Syndrome
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Staphylococcal Toxin-Mediated Diseases Food
Poisoning
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Clinical Presentation of CA-MRSA
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Clinical Presentation of CA-MRSA
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Clinical Presentation of CA-MRSA
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Clinical Disease due to CA-MRSA
Pyomyositis
Purpura fulminans, Necrotizing fasciitis
Necrotizing Pneumonia
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The distinction between CA and HA is blurring!

• Seybold U, et al. Clin Infect Dis, 2006

• Characterized 132 cases of MRSA BSI in Atlanta
• 34 of MRSA were USA 300
• 28 of pts with HA BSI factors
• 20 of pts with nosocomial BSI

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Methicillin Resistant Staphylococcus aureus (MRSA)

• Who usually gets infected with MRSA?
• ID Physicians
• Family members of those who have been previously
  diagnosed.
• Hospital personnel, especially NPs
• Residents of extended care facilities
• Patients hospitalized for other medical reasons.

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Treatment of CA-MRSA

• Most disease is skin soft tissue (75 - 80)
• Data suggests that many cases can be treated with
  ID 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 ID, or change in antibiotic therapy
  (Fridkin, NEJM, 2005)

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Recurrent Furunculosis

• Very little data indicating long-term benefit of
  decolonization regimens. Toxicity/cost/resistance
  
• Combination of topical, mucosal, and systemic
  antibiotics
• 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?

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Time-kill curves for all isolates of Methicillin
Resistant Staphylococcus Aureus (12)
Kaka, et al IDSA, 2005
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Inducible Clindamycin Resistance
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Vancomycin Treatment of MRSA
Vanc vs B-lactam for MSSA

• Time-kill assays vancomycin kills S. aureus more
  slowly than beta-lactam antibiotics
• Vancomycin treatment of R-sided 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 1982Levine et al, Ann Intern Med
1991 Chambers et al Ann Intern Med 1988
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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.

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Newer Agents to Treat MRSA
Quinupristin/Dalfopristin (Synercid) Linezolid
(Zyvox) Daptomycin (Cubicin) Tigecycline
(Tygacil) Investigational Agents
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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)
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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

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Linezolid vs Vancomycin Skin and Soft Tissue
Infection (Weigelt, et al AAC, 2005)
Clinical Success at test-of-cure

Limitations Open-label, vanc levels not stated
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Adverse Events Associated with Linezolid

• Drug Warning
• Reversible myelosuppression
• associated with linezolid therapy (particularly
  gt 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)
• Neuropathy
• Peripheral and Optic (Lee, et al, CID 2003)
• Resistance
• Increasing reports of resistant staphylococci and
  enterococci

Vaculated erythroblasts in subject receiving
Linezolid x 4 mo
(Green, et al. JAMA 2001)
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Daptomycin (2003)

• Lipopeptide antibiotic
• Fermentation product of Streptomyces roseosporus
• Water soluble
• Stable

O
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Baltz RH. In Strohl WR, ed. Biotechnology of
Antibiotics. 1997415-435.
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Bacteremia/Endocarditis Study Outcomes (ITT)
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MRSA Study Outcomes at 6 weeks (ITT)
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Decreased Renal Function
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Tigecycline (Tygacil)

• FDA Approval June 2005
• Complicated skin and skin structure infections
  Complicated intra-abdominal infections
• In-vitro activity vs. MRSA VRE

Clinical Cure M-ITT, SSTI, N 1057
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Investigational Anti-Staphylococcal Antibiotics

• Glycopeptides
• Ortivancin (Intermune)
• Dalbovancin (Vicuron)
• Telavancin (Theravance)
• DHFR inhibitor
• Iclaprim (Arpida)
• Novel B-lactams
• Ceftobiprole
• BMS-247243, RWJ 54428, CB-181963, BAL 5788, S-3578

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Other Potential Anti-Staphylococcal Agents

• Capsule 5/8 Vaccine (NABI) - FDA fast tracked
  announced 10/12/04 Halt in development 11/05
• 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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Methicillin Resistant Staphylococcus aureus (MRSA)

• How can we protect our patients, ourselves ?

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MRSA precautions
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Handwashing Compliance
Author Clinical Setting Rate of Compliance,
Preston et al. Open ward ICU 16 30
Albert et al ICUs ICUs 41 28
Larson All wards 44
Donowitz PICU 30
Graham ICU 32
Dubbert et al ICU 81
Pettinger et al SICU 51
Larson et al NICU/others 29
Doebbeling et al ICUs 40
Zimakoff et al ICUs 40
Meengs et al Emergency department 32
Pittet et al All wards 48
Boyce JM. Clin Infect Dis. 200133S135.
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Infection ControlConflicting 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

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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

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Strategies to Reduce Transmission of
Antimicrobial Resistant Bacteria in the ICU
(STAR-ICU)

• Huskins, et al. SHEA 2007. Prospective,
  cluster-randomized 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

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Life Goes On!