community associated- MRSA(ca-mrsa) Dr.T.V.Rao.MD Dr.T.V.Rao MD
Staphylococci: Gram positive cocci ( from Greek staphyle, means bunch of grapes ) that occur singly and in pairs, short chains and irregular grape-like clusters. Dr.T.V.Rao MD
Discovered in 1981 Found on skin and in the nose of 1 in 3 healthy people - symptomless carriers Widespread in hospitals and community Resistant to most antibiotics When fatal - often due to septicaemia MRSA Dr.T.V.Rao MD
Methicillin resistant staphylococcus • Methicillin-resistant Staphylococcus aureus (MRSA) are identified as nosocomial pathogens throughout the world . Established risk factors for MRSA infection include recent hospitalization or surgery, residence in a long-term–care facility, dialysis, and indwelling percutaneous medical devices and catheters. Recently, however, cases of MRSA have been documented in healthy community-dwelling persons without established risk factors for MRSA acquisition. Dr.T.V.Rao MD
Healthcare system is evolving to an increased use of outpatient procedures and long-term care Many long-term-care facilities now experience infection rates comparable to those in acute hospital settings Outbreaks are common High rates of colonization with resistant strains Hospital or Acute care setting Home care Outpatient facility Long-term-care facility The Landscape of Healthcare-Associated (HCA) Infections Dr.T.V.Rao MD Nicolle LE. Clin Infect Dis. 2000;31:752-756.
Methicillin Methicillin-resistant S. aureus (MRSA) [1970s] Vancomycin  [1990s] [ 2002 ] Vancomycin Vancomycin-resistant Vancomycin -resistant S. aureus intermediate- enterococci (VRE) resistant S. aureus (VISA) Evolution of Drug Resistance in S. aureus Penicillin Penicillin-resistant S. aureus [1950s] S. aureus Dr.T.V.Rao MD
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 Dr.T.V.Rao MD
Infections historically identified as community acquired or hospital acquired, based on location and time of symptom onset Community-acquired (CA): hospitalization ≤ 48 hours Hospital-acquired (HA): hospitalization > 48 hours Associated with inherent assumptions: Community-acquired infections Hospital-acquired infections • Patients with compromised defenses • Environment with resistant microorganisms • Often associated with invasive devices or medical procedures • Otherwise healthy patients • Environment with little selective pressure, fewer resistant microorganisms • Develop spontaneously Infection Classification Dr.T.V.Rao MD Siegman-Igra Y, et al. Clin Infect Dis. 2002;34:1431-1439.
Community acquired MRsa They are apparently acquired in the community, these infections are referred to as community-acquired (CA)-MRSA (. CA-MRSA infections have been reported in North America, Europe, Australia, and New Zealand . The recent genomic sequence of a CA-MRSA isolate indicated the presence not only of a novel smaller variant of the methicillin-resistance locus (SCCmec IVa, according to Baba et al. designation , but also that of the locus for the Panton-Valentine leukocidin (PVL). Dr.T.V.Rao MD
Terminology of Ca-MRSA • Terminology has been inconsistent • Community-Onset (CO) MRSA: infection • diagnosed or index culture collected in community • • Established risk factors (RFs): recent hospitalization, surgery, dialysis, long-tern care; indwelling catheter or percutaneous medical device; history of MRSA • • Community-Acquired MRSA: Used for CO infections or CO infections in patients without established RFs, but difficult to establish with certainty where acquisition occurred • • Community-Associated MRSA: CO infections in persons without established RFs Dr.T.V.Rao MD
Epidemiologic and clinical risk factors cannot reliably distinguish between MRSA and MSSA in patients with community-acquired S aureus infections CA-MRSA strains are emerging with resistance to some non-β-lactam classes of antibiotics Strains resistant to fluoroquinolones and aminoglycosides have been isolated The distinction between CA- and HA-MRSA strains is blurring CA-MRSA: A Complex Issue Dr.T.V.Rao MD 1. Miller LG, et al. Clin Infect Dis. 2007;44:471-482. 2. Del Giudice P, et al. Br J Dermatol. 2006;154:118-124. 3. Gonzalez BE, et al. Infect Control Hosp Epidemiol. 2006;27:1051-1056. 4. Klevens RM, et al. Emerg Infect Dis. 2006;12:1991-1993. 5. Maree CL, et al. Emerg Infect Dis. 2007;13:236-242.
Methicillin-resistant S aureus strains are endemic in many communities Strains from the community may be referred to as either community-associated or community-acquired (CA) MRSA CA-MRSA is genetically different from the strains normally associated with hospital-acquired infections CA-MRSA first emerged in the 1990s Outbreaks of CA-MRSA have been reported2 CA-MRSA infections most often involve skin and soft tissue1-3 Community-Associated MRSA Dr.T.V.Rao MD 1. Zetola N, et al. Lancet Infect Dis. 2005;5:275-286. 2. McDonald LC. Clin Infect Dis. 2006;42:S65-S71. 3. Naimi TS, et al. JAMA. 2003;290:2976-2984.
Patients with HCA infections have an increased risk of infection with MRSA compared to patients with CA infections Identifying and treating patients in a timely manner is critical The prevalence of MRSA is increasing in the community and hospital settings Infection with MRSA is associated with negative outcomes MRSA is frequently associated with inappropriate treatment Growing incidences of Ca-MRSA Dr.T.V.Rao MD
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) What’s different about CA-MRSA?
Panton-Valentine Leukocidin(PVL) Toxin • Necrotizing cytotoxin • • Associated with abscesses and severepneumonia • • Also found in some methicillin susceptible • S. aureus (MSSA) isolates Dr.T.V.Rao MD
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? Recurrent Furunculosis Dr.T.V.Rao MD
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/macrophages Associated with necrotizing skin and soft tissue infections and pneumonia What is PVL (Panton-Valentine Leukocidin)?
Location of Panton-Valentine leukocidin (PVL). • The PVL locus is carried on a bacteriophage and is present in only a small percentage of S. aureus isolates from France, where this locus is associated with skin infections, and occasionally, severe necrotizing pneumonia Dr.T.V.Rao MD
Prevalence of MRSA increasing in hospitals and in the community1 Infections Due to Community- and Healthcare-Associated MRSA Dr.T.V.Rao MD 1. McDonald LC. Clin Infect Dis. 2006;42:S65-S71. 2. Naimi TS, et al. JAMA. 2003;290:2976-2984.
HA-MRSA = strains first isolated in the hospital (nosocomial pathogen); CA-MRSA = strains first isolated in the community setting. Deciphering MRSA Strains: HA-MRSA vs. CA-MRSA Dr.T.V.Rao MD 1. Carleton HA, et al. J Infect Dis. 2004;190:1730-1738. 2. Drew RH. Pharmacotherapy. 2007;27:2027-249. 3. Zetola N, et al. Lancet Infect Dis. 2005;5:275-286. 4. Klevens RM, et al. Emerg Infect Dis. 2006;12:1991-1993.
Panton-Valentine leukocidin • Panton-Valentine leukocidin (PVL) is a cytotoxin—one of the β-pore-forming toxins. The presence of PVL is associated with increased virulence of certain strains (isolates) of Staphylococcus aureus. It is present in the majority of community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates studied]and is the cause of necrotic lesions involving the skin or mucosa, including necrotic hemorrhagic pneumonia. PVL creates pores in the membranes of infected cells. PVL is produced from the genetic material of a bacteriophage that infects Staphylococcus aureus, making it more virulent. Dr.T.V.Rao MD
Panton-Valentine leukocidin (PVL) • Panton-Valentine leukocidin (PVL) is one of many toxins associated with S. aureus infection. Because it can be found in virtually all CA-MRSA strains that cause soft-tissue infections, it was long described as a key virulence factor, allowing the bacteria to target and kill specific white blood cells known as neutrophils. This view was challenged, however, when it was shown that removal of PVL from the two major epidemic CA-MRSA strains resulted in no loss of infectivity or destruction of neutrophils in a mouse model.[ Dr.T.V.Rao MD
CA-MRSA: What’s Going On? SCCmec I-V, mecIV is most commonly found in CA-MRSA; 25 KB, mobile Dr.T.V.Rao MD
Distinction Between CA-MRSAand HA-MRSA Is Blurring CA-MRSA strains are emerging in the healthcare setting, while HA-MRSA strains are moving out into the community Dr.T.V.Rao MD Klevens RM, et al. Emerg Infect Dis. 2006;12:1991-1993.
The distinction between CA and HA is blurring! • 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 Seybold U, et al. Clin Infect Dis, 2006 Dr.T.V.Rao MD
DIAGNOSIS • 1. In all pus forming lesions • Gram stain and culture of pus • 2. In all systemic infections • Blood culture • 3. In infections of other tissues • Culture of relevant tissue or exudate Dr.T.V.Rao MD
CA-MRSA diagnosis • On isolating any MRSA strains with clinical and epidemiological suspicion of CA-MRSA, further laboratory characterization needs to be undertaken to support the diagnosis. SCCmec typing is performed by determining the combination of two attributes: the class of the mec gene complex, and with the type of the ccr(chromosomal cassette recombinase) gene complex Dr.T.V.Rao MD
CA-MRSA diagnosis • The mec gene complex, comprises classes A to C, and the latter comprises types 1 to 3. The technique employed is polymerase chain reaction (PCR), either using individual reactions or in a multiplex format.9-11 In addition, the presence of the PVL gene is also detected by PCR. Dr.T.V.Rao MD
Sensitivity and resistance patterns of Staphylococcus aureusMRSA Dr.T.V.Rao MD
CA-MRSA diagnosis • Community-associated methicillin-resistant Staphylococcus aureus strain (note golden colour) showing resistance to -lactams and susceptibility to multiple antimicrobials. Key: Resistant to penicillin (P) and cefoxitin (FOX); Susceptible to erythromycin (E), clindamycin (DA), gentamicin (CN), tetracycline (TE), chloramphenicol (C),ciprofloxacin (CIP), rifampicin (RD) and cotrimoxazole (SXT). Dr.T.V.Rao MD
Plate 1b: A mecA gene negative Staphylococcus aureus with high b-lactamase activity showing borderline resistance to oxacillin (BORSA) whilst there is an inhibitory zone of 7.5 mm around the cefoxitin (FOX 10) disc. Dr.T.V.Rao MD
Non-multiple resistant MRSA susceptible to cotrimoxazole Dr.T.V.Rao MD
: A mecA gene positive Staphylococcus aureus(MRSA) but lacking b-lactamase activity. Note the large zones around penicillin (P 0.5) and oxacillin (OX 1) discs but the reduced inhibitory zone around cefoxitin (FOX 10). Dr.T.V.Rao MD
: MRSA with inducible clindamycin resistance (ICR): No inhibitory zone around erythromycin (E 5) and a flattened inhibitory zone around clindamycin (DA 2) near the erythromycin disc. Dr.T.V.Rao MD
: Staphylococcus aureus NCTC 6571. Note the approximate inhibitory zone sizes around penicillin (P 0.5), cefoxitin (FOX 10) and vancomycin (VA 5) discs are 12 mm, 10 mm and 3 mm respectively Dr.T.V.Rao MD
Plate 4: MRSA with reduced susceptibility to vancomycin (VISA/GISA). Note the reduced zone around vancomycin (VA 5) and teicoplanin (TEC 15) discs. Dr.T.V.Rao MD
Epidemiological typing • Further typing of CA-MRSA strains is possible using various methods, including pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and S. aureus protein A (spa) typing.5,12 These methods are employed when it is necessary to delineate epidemiological relationships among CA-MRSA strains isolated from different sources, such as in outbreak settings Dr.T.V.Rao MD
Initial therapy is often empiric and should cover all pathogens that may be present Knowledge of underlying risk factors for antimicrobial resistance and local Antibiogram contribute to correct treatment choice Appropriate antimicrobial therapy includes an agent or regimen that is effective against the causative pathogen(s) Broad-spectrum therapy is often recommended Adequate empiric therapy should not be delayed Optimizing Initial Antimicrobial Therapy Dr.T.V.Rao MD 1. Kollef MH. Drugs 2003;63(20):2157-2168. 2. The American Thoracic Society and the Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416.
Agents with anti-MRSA activity include: Limitations of some agents include: Emerging resistance, changing susceptibilities Bacteriostatic rather than bactericidal activity Decreased penetration or inactivity in some tissues (eg, lung) Side effects/toxicity Treating MRSA Infections TMP-SMX = trimethoprim-sulfamethoxazole. Dr.T.V.Rao MD Drew RH. Pharmacotherapy. 2007;27:227-249.
Most disease is skin & soft tissue (75% - 80%) Data suggests that many cases can be treated with I&D 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 I&D, or change in antibiotic therapy (Fridkin, NEJM, 2005) Treatment of CA-MRSA Dr.T.V.Rao MD
Treatment Algorithm: Distinguishing Between HCA and CA Infections Is a Critical Step 1. American Thoracic Society. Am J Respir Crit Care Med. 2005;171:388-416. 2. Mandell LA, et al. Clin Infect Dis. 2007;44:S27-S72.
Time-kill curves for all isolates of Methicillin Resistant Staphylococcus Aureus (12) Kaka, et al IDSA, 2005 Dr.T.V.Rao MD
New drugs on trails for use in staphylococcal infections Dr.T.V.Rao MD
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 Investigational Anti-Staphylococcal Antibiotics
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 Other Potential Anti-Staphylococcal Agents
Prevention and Control• • Cover all wounds • • Train athletes in first aid for wounds and signs of infection • • Encourage good hygiene • • Discourage sharing of items • • Establish routine cleaning schedules for shared equipment • • Encourage players to report skin lesions Dr.T.V.Rao MD
CA-MRSA Outbreak ControlMeasures Multi-component strategies used (difficult to assess individual contribution of each) • Strategies focusing on increased awareness, early detection and appropriate management, enhanced hygiene, and maintenance of a clean environment appear to have been successful at interrupting transmission Dr.T.V.Rao MD
Devised in US in the 1980’s in response to growing threat from HIV and hepatitis B Not confined to HIV and hepatitis B Treat ALL patients as a potential bio-hazard Adopt universal routine safe infection control practices to protect patients, self and colleagues from infection Universal infection control precautions Dr.T.V.Rao MD
Hand washing Personal protective equipment [PPE] Preventing/managing sharps injuries Aseptic technique Isolation Staff health Linen handling and disposal Waste disposal Spillages of body fluids Environmental cleaning Risk management/assessment Universal precautions Dr.T.V.Rao MD