COMMUNITY ASSOCIATED- MRSA (CA-MRSA) Dr.T.V.Rao.MDDR.T.V.RAO MD 1
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 2
MRSA• 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 DR.T.V.RAO MD 3
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 4
THE LANDSCAPE OF HEALTHCARE-ASSOCIATED (HCA) INFECTIONS• Healthcare system is evolving to an increased use of outpatient procedures and long-term care Hospital or Acute care setting Home care Outpatient facility Long-term-care facility• 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 DR.T.V.RAO MD 5Nicolle LE. Clin Infect Dis. 2000;31:752-756.
EVOLUTION OF DRUG RESISTANCE IN S. AUREUS Penicillin Methicillin Penicillin-resistant Methicillin-S. aureus resistant [1950s] S. aureus [1970s] S. aureus (MRSA) Vancomycin  [1990s] Vancomycin Vancomycin Vancomycin-resistant -resistant S. [ 2002 ] intermediate- enterococci (VRE) aureus resistant S. aureus (VISA)DR.T.V.RAO MD 6
Methicillin-Resistant Staphylococcus aureus (MRSA) 60Percent Resistance 50 40 30 20 10 0 89 91 93 95 97 99 01 03 05 19 19 19 19 19 19 20 20 20Source: National Nosocomial Infections U.S. Non-Intensive CareSurveillance (NNIS) System U.S. Intensive CareDR.T.V.RAO MD 7 The Nebraska Medical Center
INFECTION CLASSIFICATION• 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 • Otherwise healthy patients • Patients with compromised defenses • Environment with little selective pressure, • Environment with resistant microorganisms fewer resistant microorganisms • Often associated with invasive devices or • Develop spontaneously medical procedures DR.T.V.RAO MD 8Siegman-Igra Y, et al. Clin Infect Dis. 2002;34:1431-1439.
COMMUNITY ACQUIRED MRSAThey are apparently acquired in thecommunity, these infections arereferred to as community-acquired(CA)-MRSA (. CA-MRSA infectionshave been reported in NorthAmerica, Europe, Australia, and NewZealand . The recent genomicsequence of a CA-MRSA isolateindicated the presence not only of anovel smaller variant of themethicillin-resistance locus(SCCmec IVa, according to Baba etal. designation , but also that of thelocus for the Panton-Valentineleukocidin (PVL).DR.T.V.RAO MD 9
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 RFsDR.T.V.RAO MD 10
CA-MRSA: A COMPLEX ISSUE• 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 DR.T.V.RAO MD1. 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. 112006;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.
COMMUNITY-ASSOCIATED MRSA• 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 DR.T.V.RAO MD 121. 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.
GROWING INCIDENCES OF CA-MRSA• 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 DR.T.V.RAO MD 13
WHAT’S 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)
PANTON-VALENTINE LEUKOCIDIN (PVL) TOXIN• Necrotizing cytotoxin• • Associated with abscesses and severe pneumonia• • Also found in some methicillin susceptible• S. aureus (MSSA) isolatesDR.T.V.RAO MD 15
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? DR.T.V.RAO MD 17
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/macrophages• Associated with necrotizing skin and soft tissue infections and pneumonia
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 pneumoniaDR.T.V.RAO MD 19
INFECTIONS DUE TO COMMUNITY- AND HEALTHCARE-ASSOCIATED MRSA Prevalence of MRSA Infections associated increasing in hospitals with CA-MRSA (n = 131)2 and in the community 1 Other 8% Urinary tract 1% Bloodstream 4% Methicillin-resistant S aureus Respiratory tract 6% 100 Otitis media/externa7% Nosocomial infection Resistant isolates (%) Community-acquired infection 75 Skin/Soft tissue 75% 50 Infections associated with HA-MRSA (n = 937)2 Other 12% 25 Urinary tract 20% Skin/Soft tissue 37% 0 1970 1980 1990 2000 Year Bloodstream 9% Otitis media/externa 1% Respiratory tract 22% DR.T.V.RAO MD 201. McDonald LC. Clin Infect Dis. 2006;42:S65-S71. 2. Naimi TS, et al. JAMA. 2003;290:2976-2984.
DECIPHERING MRSA STRAINS: HA-MRSA VS. CA-MRSA HA-MRSA CA-MRSA Genetic characteristics SCC mec type I, II, or III SCC mec type IV β-lactams Macrolides β-lactams Common Aminoglycosides resistance Quinolones Macrolides Lincosamides Panton-Valentine leukocidin (PVL) Not common Common exotoxin HA-MRSA = strains first isolated in the hospital (nosocomial pathogen); CA-MRSA = strains first isolated in the community setting.1. Carleton HA, et al.MD 21 DR.T.V.RAO 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 22
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 23
CA-MRSA: What’s Going On?SCCmec I-V, mecIV is most commonly found in CA-MRSA; 25 KB, mobileDR.T.V.RAO MD 24
DISTINCTION BETWEEN CA-MRSA AND HA-MRSA IS BLURRING Patients with MRSA infection (n = 100 isolates) Healthcare-related risk factors? Yes No (n = 73) (n = 27) Infection Infection Infection Infection with typical with typical with typical with typical CA-MRSA HA-MRSA CA-MRSA HA-MRSA strain strain strain strain 22% 77% 70% 26% (16/73) (56/73) (19/27) (7/27) CA-MRSA strains are emerging in the healthcare setting, while HA-MRSA strains are moving out into the community DR.T.V.RAO MD 25Klevens RM, et al. Emerg Infect Dis. 2006;12:1991-1993.
THE DISTINCTION BETWEEN CA AND HA IS BLURRING! 100% 80%Seybold U, et al. Clin 60% USA800Infect Dis, 2006 USA500 USA100 40% USA300 20% 0% Total (n=116) HA (n=107) Noso (n=49) • 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 DR.T.V.RAO MD 26
DIAGNOSIS• . In all pus forming 1 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 exudateDR.T.V.RAO MD 27
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 complexDR.T.V.RAO MD 28
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 29
SENSITIVITY AND RESISTANCE PATTERNS OF STAPHYLOCOCCUS AUREUS MRSADR.T.V.RAO MD 30
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) andDR.T.V.RAO MD cotrimoxazole (SXT). 31
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 32
NON-MULTIPLE RESISTANT MRSA SUSCEPTIBLE TO COTRIMOXAZOLEDR.T.V.RAO MD 33
: 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 34
: 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 35
: 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 RESPECTIVELYDR.T.V.RAO MD 36
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 37
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 settingsDR.T.V.RAO MD 38
OPTIMIZING INITIAL ANTIMICROBIAL THERAPY • 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 DR.T.V.RAO MD 391. 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.
TREATING MRSA INFECTIONS• Agents with anti-MRSA activity include: Vancomycin Linezolid Daptomycin Tigecycline TMP-SMX Clindamycin• 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/toxicityTMP-SMX = trimethoprim-sulfamethoxazole. DR.T.V.RAO MD 40Drew RH. Pharmacotherapy. 2007;27:227-249.
TREATMENT OF CA-MRSA • 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)DR.T.V.RAO MD 41
TREATMENT ALGORITHM: DISTINGUISHING BETWEEN HCA AND CA INFECTIONS IS A CRITICAL STEP Patient presents to hospital with suspected pneumonia Underlying risk factors for healthcare- associated infection? • Recent hospitalization • Residence in nursing home • Home infusion therapy • Chronic dialysis • Home wound care • Family member with resistant pathogen Yes No Healthcare-associated Community-acquired pneumonia suspected pneumonia suspected Treat with: Treat with (non-ICU treatment):• Extended spectrum antipseudomonal • Respiratory fluoroquinolone cephalosporin, carbapenem, or or β-lactam/β-lactamase inhibitor • β-lactam + macrolide + • Antipseudomonal fluoroquinolone or aminoglycoside Note: Local prevalence and susceptibility +/- patterns should be used when choosing an • Anti-MRSA agent empiric antibiotic regimen 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) 10 10 Linezolid Rifampin 9 SXT 10 SXT+Rifampin Clindamycin 8 Minocycline 10Bacteria [CFU/mL] Control 7 10 6 Kaka, et al 10 IDSA, 2005 5 10 4 10 3 10 2 10 0 4 8 12 24 36 48 DR.T.V.RAO MD 43 Time (hours)
NEW DRUGS ON TRAILS FOR USE IN STAPHYLOCOCCAL INFECTIONSDR.T.V.RAO MD 44
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
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 lesionsDR.T.V.RAO MD 47
CA-MRSA OUTBREAK CONTROL MEASURESMulti-component strategiesused (difficult to assessindividual contribution ofeach)• Strategies focusing onincreased awareness, earlydetection and appropriatemanagement, enhancedhygiene, and maintenance ofa clean environment appearto have been successful atinterrupting transmissionDR.T.V.RAO MD 48
UNIVERSAL INFECTION CONTROL PRECAUTIONS• 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 DR.T.V.RAO MD 49
UNIVERSAL PRECAUTIONS• 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 DR.T.V.RAO MD 50
HAND WASHING• Single most effective action to prevent HAI - resident/transient bacteria• Correct method - ensuring all surfaces are cleaned - more important than agent used or length of time taken• No recommended frequency - should be determined by intended/completed actions• Research indicates: • poor techniques - not all surfaces cleaned • frequency diminishes with workload/distance • poor compliance with guidelines/training DR.T.V.RAO MD 51
YOUR HABITS KEEP THE PEOPLE AT RISK NASAL CAVITY A SOURCE OF INFECTIONDR.T.V.RAO MD 52
MAKE HAND WASHING A HABIT – SOME BODY WATCHING YOUDR.T.V.RAO MD 53
• Programme created by Dr.T.V.Rao MD for Medical Professionals in the Developing World • Email • email@example.comDR.T.V.RAO MD 54