Community Assocated MRSA, CA-MRSA

DR.T.V.RAO MD 1

Dr.T.V.Rao.MD

COMMUNITY ASSOCIATED- MRSA

(CA-MRSA)

DR.T.V.RAO MD 2

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 3

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 4

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 5

• 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

THE LANDSCAPE OF HEALTHCARE-ASSOCIATED (HCA) INFECTIONS

Nicolle LE. Clin Infect Dis. 2000;31:752-756.

Hospital or Acute care setting

Home careOutpatient facility

Long-term-care facility

DR.T.V.RAO MD 6

S. aureus

Penicillin

[1950s]

Penicillin-resistant

S. aureus

EVOLUTION OF DRUG RESISTANCE IN S. AUREUS

Methicillin

[1970s]

Methicillin-resistant S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycin

intermediate-resistantS. aureus (VISA)

[ 2002 ]Vancomycin-resistant S.

aureus

DR.T.V.RAO MD 7

0

10

20

30

40

50

60

Per

cen

t R

esis

tan

ceMethicillin-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 8

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:Hospital-acquired infectionsCommunity-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

Siegman-Igra Y, et al. Clin Infect Dis. 2002;34:1431-1439.

DR.T.V.RAO MD 9

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).

COMMUNITY ACQUIRED MRSA

DR.T.V.RAO MD 10

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 11

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

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.

DR.T.V.RAO MD 12

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

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.

DR.T.V.RAO MD 13

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

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)

DR.T.V.RAO MD 15

• Necrotizing cytotoxin

• • Associated with abscesses and severe pneumonia

• • Also found in some methicillin susceptible

• S. aureus (MSSA) isolates

PANTON-VALENTINE LEUKOCIDIN(PVL) TOXIN

COMMON CLINICAL PRESENTATIONS OF CA-MRSA

DR.T.V.RAO MD 17

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?

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

DR.T.V.RAO MD 19

• 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

LOCATION OF PANTON-VALENTINE LEUKOCIDIN (PVL).

DR.T.V.RAO MD 20

Nosocomial infection

Community-acquired infection

Methicillin-resistant S aureus

0

25

50

75

100

1970 1980 2000Year

Res

ista

nt

iso

late

s (

%)

1990




0

25

50

75

100

1970 1980 2000Year

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ista

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iso

late

s (

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1990




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50

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1970 1980 2000Year

Res

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1990

Prevalence of MRSA increasing in hospitals and in the community1

INFECTIONS DUE TO COMMUNITY- AND HEALTHCARE-ASSOCIATED MRSA

1. McDonald LC. Clin Infect Dis. 2006;42:S65-S71. 2. Naimi TS, et al. JAMA. 2003;290:2976-2984.

Infections associated with CA-MRSA (n = 131)2

Infections associated with HA-MRSA (n = 937)2

Skin/Soft tissue 75%

Otitis media/externa7%

Respiratory tract 6%

Bloodstream 4%

Urinary tract 1%

Other 8%




Bloodstream 4%

Urinary tract 1%

Other 8%


Otitis media/externa 1%


Bloodstream 9%

Urinary tract 20%

Other 12%




Bloodstream 9%

Urinary tract 20%

Other 12%

Infections associated with CA-MRSA (n = 131)2

Infections associated with HA-MRSA (n = 937)2




Bloodstream 4%

Urinary tract 1%

Other 8%




Bloodstream 4%

Urinary tract 1%

Other 8%




Bloodstream 9%

Urinary tract 20%

Other 12%




Bloodstream 9%

Urinary tract 20%

Other 12%

DR.T.V.RAO MD 21

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

Common resistance

β-lactamsMacrolides

AminoglycosidesQuinolones

Lincosamides

β-lactamsMacrolides

Panton-Valentine leukocidin (PVL)

exotoxinNot common Common

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.

HA-MRSA = strains first isolated in the hospital (nosocomial pathogen);

CA-MRSA = strains first isolated in the community setting.

DR.T.V.RAO MD 22

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.

http://en.wikipedia.org/wiki/Panton-Valentine_leukocidin#cite_note-Kaneko-2

DR.T.V.RAO MD 23

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.[

http://en.wikipedia.org/wiki/Panton-Valentine_leukocidin#cite_note-13

DR.T.V.RAO MD 24

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 25

Patients with MRSA infection(n = 100 isolates)

Infection with typical CA-MRSA

strain

Healthcare-related risk factors?

Yes(n = 73)

No(n = 27)

Infection with typical HA-MRSA

strain


strain


strain

22%(16/73)

70%(19/27)

77%(56/73)

26%(7/27)

Patients with MRSA infection(n = 100 isolates)


strain

Healthcare-related risk factors?

Yes(n = 73)

No(n = 27)


strain


strain


strain

22%(16/73)

70%(19/27)

77%(56/73)

26%(7/27)

DISTINCTION BETWEEN CA-MRSAAND HA-MRSA IS BLURRING

Klevens RM, et al. Emerg Infect Dis. 2006;12:1991-1993.

CA-MRSA strains are emerging in the healthcare setting, while HA-MRSA strains are moving out into the community

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

0%

20%

40%

60%

80%

100%

Total (n=116) HA (n=107) Noso (n=49)

USA800

USA500

USA100

USA300

Seybold U, et al. Clin Infect Dis, 2006

DR.T.V.RAO MD 26

DR.T.V.RAO MD 27

• 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

DIAGNOSIS

DR.T.V.RAO MD 28

• 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

CA-MRSA DIAGNOSIS

DR.T.V.RAO MD 29

• 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.

CA-MRSA DIAGNOSIS

DR.T.V.RAO MD 30

SENSITIVITY AND RESISTANCE PATTERNS OF STAPHYLOCOCCUS AUREUS

MRSA

DR.T.V.RAO MD 31

• 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).

CA-MRSA DIAGNOSIS

DR.T.V.RAO MD 32

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 33

NON-MULTIPLE RESISTANT MRSA SUSCEPTIBLE TO COTRIMOXAZOLE

DR.T.V.RAO MD 34

: A MECA GENE POSITIVE STAPHYLOCOCCUS AUREUS(MRSA) BUT LACKING -BLACTAMASE 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 35

: 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 36

: 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 37

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 38

• 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

EPIDEMIOLOGICAL TYPING

DR.T.V.RAO MD 39

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

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.

DR.T.V.RAO MD 40

TREATING MRSA INFECTIONS• 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

Drew RH. Pharmacotherapy. 2007;27:227-249.

TMP-SMX = trimethoprim-sulfamethoxazole.

Vancomycin Linezolid Daptomycin

Tigecycline TMP-SMX Clindamycin

Vancomycin Linezolid Daptomycin

Tigecycline TMP-SMX Clindamycin

DR.T.V.RAO MD 41

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)

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.

Treat with:• Extended spectrum antipseudomonal

cephalosporin, carbapenem, or β-lactam/β-lactamase inhibitor

+• Antipseudomonal fluoroquinolone

or aminoglycoside+/-

• Anti-MRSA agent

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

Community-acquired pneumonia suspected

Treat with (non-ICU treatment):• Respiratory fluoroquinolone

or• β-lactam + macrolide

Healthcare-associated pneumonia suspected

NoYes

Note: Local prevalence and susceptibility patterns should be used when choosing an

empiric antibiotic regimen

Treat with:• Extended spectrum antipseudomonal

cephalosporin, carbapenem, or β-lactam/β-lactamase inhibitor

+• Antipseudomonal fluoroquinolone

or aminoglycoside+/-

• Anti-MRSA agent

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

Community-acquired pneumonia suspected

Treat with (non-ICU treatment):• Respiratory fluoroquinolone

or• β-lactam + macrolide

Healthcare-associated pneumonia suspected

NoYes

Note: Local prevalence and susceptibility patterns should be used when choosing an

empiric antibiotic regimen

DR.T.V.RAO MD 43

0 4 8 12 24 36 48102

103

104

105

106

107

108

109

1010

Ba

cte

ria

[C

FU

/mL

]

Time (hours)

Linezolid Rifampin SXT SXT+Rifampin Clindamycin Minocycline Control

Time-kill curves for all isolates of Methicillin Resistant Staphylococcus Aureus (12)

Kaka, et al IDSA, 2005

DR.T.V.RAO MD 44

NEW DRUGS ON TRAILS FOR USE IN STAPHYLOCOCCAL INFECTIONS

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

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

DR.T.V.RAO MD 47

• 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

PREVENTION AND CONTROL•

DR.T.V.RAO MD 48

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

CA-MRSA OUTBREAK CONTROLMEASURES

DR.T.V.RAO MD 49

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 50

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 51

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 52

YOUR HABITS KEEP THE PEOPLE AT RISK NASAL CAVITY A SOURCE OF INFECTION

DR.T.V.RAO MD 53

MAKE HAND WASHING A HABIT – SOME BODY WATCHING YOU

DR.T.V.RAO MD 54

• Programme created by Dr.T.V.Rao MD for Medical Professionals in the

Developing World• Email

• [email protected]

Health & Medicine

Community Assocated MRSA, CA-MRSA