COMMUNITY ACQUIRED MRSA

Pisespong Patamasucon, M.D.

Pediatric Infectious Diseases

UNSOM - Las Vegas

TIMELINE FOR RESISTANCE IN HOSPITALS AND THE COMMUNITY

DrugIntroduced

(Year)

Resistance Reported (Years)

25% Resistance in

Hospitals (Years)

25% Resistance in Community

(Years)

Penicillin 1941 1 to 2 6 15 to 20

Methicillin 1961 <1 25 to 3040 to 50

(estimated)

Vancomycin 1954 >40 ? ?

1) Emerg. Infect. Dis 2001; 7:178-1822) N.Engl.J.Med 2003;348:1342-1347

Resistant staphylococci: Definitions

ResistanceMIC > 16 μg methicillin/mLMIC > 4 μg oxacillin/mL

SpeciesMRSA: Methicillin-resistant S aureusMRCNS: Methcillin-resistant coag-neg staphylococci(S epidermidis most common)

CRITERIA OF CA-MRSA

• Isolated from patients residing in the community or within 48-72 hours of hospitalization

(Problem: can be acquired in few hours and MRSA chronic carrier)

• Risk factors for MRSA is usually absence

• Susceptibility of the organism to various antibiotics

• Genome make-up

Introduction

MRSA is becoming widespread in multiple communities

MRSA pts have no epidemiological links with each other

Indicated MRSA may be becoming ENDEMIC like S. aureus to Penicillin

No reliable way to distinguish pts with MRSA from pts with MSSA at the time of admission

INTRODUCTIONHistorical

CA-MRSA - IV Drug users, recent hospitalization or resident in a nursing home

1995 Yale - New Haven Hospital

36% MRSA isolated were community acquired

1995 - Switzerland

20% MRSA isolated were CA

36% never been hospitalized

Layton MD et al. Infect.Carted.Hosp Epdermid 1995;16:18-24

Characteristics of Strains

Hospital acquired MRSA highly resistant to multiple antibiotics except Vanco, Rifampin, Gentamicin.

Community acquired MRSA sensitive to TMP/SMZ, Rifampin, Clindamycin, Linezolid, Vancomycin, except Penicillin and Cephalosporin and also Quinolones

CA - MRSA Distinguishing Features

• Absence of Hospital - Associated risk factors

• Susceptibility to most antibiotics other than β-lactams

• Distinct genotypes from HA-MRSA

• Presence of Type 4 staphylococcal chromosomal cassette mec (the element that contains the methicillin resistance determinant)

• Presence of genes encoding for toxins (Pantone-Valentine Leukocidin and many Staph Enterotoxins)

J. CLIN. MICROBIOL 2002; 40: 4289-4294

Comparison of Staphylococcal Cassette Chromosome mec Types

SCCmec Type

ccr Gene Type

mec Complex

TypeSize (kb) RE Type

I 1 B 34.3 i

II 2 A 53.0 ii

III 3 A 66.9 iii

IV 2 B 20.9-24.3 iiccr, cassette chromosome recombinase; RE, right extremity of SCCmec element

Adapted from J Infect Dis. 2002; 186:1344-1347

MRSA bacteremia is associated with

significantly higher mortality rate than

is MSSA bacteremia.

(adds ratio 1.93; 95% C.I, 1.54 - 2.42; P<.001)

CLIN. INFECT. DIS 2003; 36:53-59

NEW PROBLEMS RAISEDBY CA-MRSA

• Treatment failure with accompanying

complications or death (if β-lactam antibiotic

is used)• MRSA strains may be more difficult to treat or

more expensive to treat• Vancomycin is inherently less efficacious

ANN INTERN MED 1991; 115:674-680CLIN INFECT DIS 2000; 30:368-373

ORIGIN OF CA-MRSA

• Majority (58%) of infections were from hospital

and long term care facilities

• Injection drug use was associated with unrelated

healthcare settings.

• In an outbreak situation MRSA strains are now originated from the community

CLIN. INFECT. DIS 2004; 39: 47-54

Reasons why CA-MRSA occurs

1. S aureus is part of normal flora in 20-30% of healthy persons

2. No different in adhesion to nasal epithelial cells between MRSA and MSSA

3. Pts discharged from Hospital with MRSA may remain colonized for a long period thus providing a reservoir to communities

4. Use of antibiotic in the communities

Clinical Reports of CA-MRSA in the US and Around the World

Chicago, Illinois, USA

A study from Chicago found a 25 fold increase in

the number of children admitted to the hospital with

an MRSA infection who lacked an identified risk

factor for prior colonization.

JAMA 1998; 279:593-598

Dallas, Texas, USA

Survey of two day-care centers in Dallas, Texas each with index

case of MRSA infection, found 3% and 24% of children in the

respective centers were colonized. The isolates were

susceptible to multiple antibiotics. Forty percent of colonized

children had no risk factor.

J. INFECT DIS 1998; 178:593-598

San Francisco, California, USA

A population based community sample of 833 homeless

and urban poor in San Francisco 22.8% were colonized

with S. aureus (12.0% of S. aureus isolated were Methicillin-

resistant).

Overall prevalence of MRSA was 2.8%

CLIN. INFECT. DIS 2002; 34: 425-433

CDC four pediatric deaths from community-

acquired methicillin resistant staphylococcus

aureus -- Minnesota and North Dakota, 1997.

[No risk factors, susceptible to several antibiotics and PFGE related]

MMWR MORB MORTAL WKLY REP 1999; 48:707-710

Midwest Cluster, USA

CA - MRSA in South Texas Children• 7 cases 1990-1996 MRSA

• 53 cases 1997-2000 (35 cases alone in 2000) MRSA

• 48/53 (91%) soft tissue infection

• More susceptible to SMZ /TMZ (98% vs 82%) and Clinda 92% vs 57%) and less susceptible to tetracycline 54% vs 95% than

nosocomial MRSA.

• Majority of CA-MRSA had no risk factors

Pediatr Infect Dis 2001:20:860-863.

CA-MRSA Skin Infection in Outpatient University Health Center

- Houston, Texas 2003

• From 41 cultures from 853 patients– 10/19 (53%) patients with S. aureus has MRSA– 5 patients with risk factors (3 treated with

antibiotics, 2 exposed to household)• Clinical presentation: abscesses (73%) or

cellulitis (64%), pustules (27%), nodules and papules (27%) and crusted plaque

• MSSA: head and neck• MRSA: lower extremities.

J Am Acad Dermatol 2004; 50:277-280.

Clusters of MRSA Among Sports Team

• September 2000 in Pennsylvania– Affected college and high school football players and

wrestlers 2-10/team, 7/10 hospitalized. Risk factors: skin trauma, shaving and sharing unwashed towels.

• September 2002 in L.A.– 2 skin infections, 1 hospitalized sharing lotions and

lubricants

• January 2003 in Indiana– 2 wrestlers, no common exposures.

MMWR 2003 53:792-795

CA - MRSA among competitive sports participants Colorado, Indiana, Pennyslvania, L.A. 2000-2003.

5/70 Fencing club members and household contacts (3 confirmed, 2 probable, 1 household contact).

1 patient - paraspinal myositis with bacteremia

4 patients - abscesses (3 patients). All same PFGE.

CA - MRSA in Outbreak of Athletics

Contributing factors:

• Skin trauma either from abrasion or from clothing

• Direct contact with infected person

• Sharing uncleaned equipment and personal items or laundered.

MMWR 52 (33); 793-795.

Outbreaks of CA-MRSA Skin Infection in Los Angeles, 2002-2003

- L.A. county jail (largest 165,000 persons/yr). 928 MRSA skin infections diagnosed in 2002 having “spider bites”.

- 39/66 hospitalized cases, 10 with invasive disease (bacteremia, endocarditis and osteomyelitis).

- Pulsed-field gel electrophoresis likes other community outbreaks in U.S.A.

MMWR 2002; S1 (No. RR16)

RECENT META - ANALYSIS FROM 10 STUDIES WITH SURVEILLANCE CULTURES

IN THE COMMUNITY (Population of 8350)

• Estimated CA-MRSA Prevalence of 1.3%

CLIN. INFECT DIS 2003; 36:131-139

EPIDEMIOLOGY OF CA-MRSA

• Actual prevalence in USA is not known but reported from Vermont to California (Nationwide problem)

• Canada• Europe• Australia• Middle East• The South Pacific

J. CLIN. MICROBIOL 1999; 32:2858-2862

CA-MRSA

SCC mec element often is isolated from

staphylococcus epidermidis residing on the skin of

healthy individuals, suggesting that the SCC mec

gene was transferred from S. epidermidis to commensal

S. aureus

Trends. Microbiol 2001; 9:486-493

MRSA presenting like spider bite

MRSA (Spider Bite Like)

Diagnostic Sensitivity

• Agar and broth dilution: 98 - 100%

• Disk diffusion : 61 - 96.4%

(molecular gene detection for mec A gene or PBP 2a - usually not available commercially)

D TEST

The circular area around Clindamycin with a flat

or blunted edge adjacent to erythromycin is proof

of inducible resistance to Clindamycin.

CLINICAL PRESENTATIONS

Currently, most infections caused by CA-MRSA are skin infections (eg., abscesses, cellulitis, impetigo, furuncles).

Other types of infection: Otitis, Pneumonia, Bursitis,Osteomyclitis, Septic arthritis and Blood streaminfections.

DETECTION and LONG TERM PERSISTENCEOF CARRIAGE OF MRSA

• Cultures of the Nares (sensitivity 93% negative

predictive value 95%)• Cutaneous sites of axilla, groin and perineum

(sensitivity <39%, negative predictive value

<69%)• Duration of carriage more than 3 years

CLIN INFECT DIS 1994; 19:1123-1128

To date, no standard of care exists for the

management of CA-MRSA and treatment

guidelines have yet to be developed.

Robert C. Mollering Jr. MD, 2003

Susceptibility of CA-MRSA isolates identifiedat selected Minnesota hospitals, 1996 - 1998

Antibiotic Susceptible % Intermediately Resistant (%) Susceptible (%)

(%)Ciprofloxacin 93 3 3Clindamycin 93 1 6Erythromycin 64 9 27Gentamicin 97 1 2Oxacillin 0 0 100Rifampin 99 1 0Tetracycline 95 0.4 5TMP-SMZ 97 0 3Vancomycin 100 0 0

CLIN. INFECT DIS 2001; 33:990-996

• TMP-SMZ and CLINDAMYCIN* SIMILAR BIOAVAILABILITY ORAL OR IV

• GOOD OPTIONS FOR OUTPATIENT OF CA-MRSA

NOTE: Clindamycin should be used only if organism issensitive to erythromycin

MED CLIN NORTH AMER 1995; 79:497-508

Fluoroquinolones are an option in adult patients with

CA-MRSA; however, single-step mutations can lead to

resistance.

The nosocomial MRSA developed resistance to these drugs

after their introduction, so consider combining them with

a drug like Rifampin to decrease emergence of resistance.

MED. CLIN. NORTH. AMER 2001; 85:1-17

RX

Treatment

2001 in Minnesota 354 patients with CA-MRSA 83% were treated

initially with Beta-Lactam antibiotics

CLIN. INFECT. DIS 2001: 33:990-996

Beta-lactam antibiotics are ineffective against

CA-MRSA. Given the potential aggressiveness

and virulence of the bacterium, an inappropriate

antibiotic choice could result in significant

morbidity and even death.

EMERG. INFECT. DIS 2001; 7:178-182

Therapeutic choices in the treatment of resistant staphylococcal infections

Vancomycin

• Proven effective as initial I.V. therapy for a variety of MRSA infections

• Potential for ototoxicity and nephrotoxicity limit usefulness as long-term therapy

Teicoplanin

• Same class of drugs as vancomycin

• Appears to have comparable efficacy and to be better tolerated, particularly by I.M. injection

• Longer half-life

Therapeutic choices in the treatment (cont’d)

TMP/SMX

• Synergistic combination of trimethoprim/sulfamethoxazole

• Demonstrated in vitro and in vivo activity against resistant staphylococcal species

• Use may be limited to mild MRSA infections

Minocycline

• Most active tetracycline against resistant staphylococci

• Can be given I.V. or p.o.

• Commonly used in Japan against MRSA and MRCNS

• US experience limited, but early clinical results demonstrate high activity plus low potential for toxicity and make it an alternative for long-term oral follow-up as well as short-term parenteral use in-hospital

Therapeutic choices in the treatment of resistant staphylococcal infections

Rifampin

• Exhibits activity against staphylococci and a wide range of other organisms

• Rapid development of resistance in vitro and in vivo may limit its use to combination therapy

New quinolones

• High in vitro activity against resistant staphylococcal species

• Can be given p.o.

• Rapid development of resistance to ciprofloxacin in vivo by MRSA has been reported

SUGGESTION IN MANAGEMENTOF CA-MRSA

• Check sensitivities of MRSA to TMP-SMZ, Rifampin, Clindamycin,

Erythromycin, Vancomycin and Linezolid

• Treat with TMP-SMZ ± Rifampin or Clindamycin ± Rifampin

depending on sensitivity

• Prescribe Mupirocin (Bactoban) cream to anterior Nares twice a day

x 5 days to eradicate nasal colonization

• Recommend bathing the patient with hibiclen from the neck down

daily for 3 consecutive days to eradicate skin colonization

RESERVE DRUG(s) FOR CA-MRSA

• VANCOMYCIN - in patient [only IV form]

• LINEZOLID, Oxazolidinones

new antibiotic class [IV and PO]

also effective against VRE and also MRSA

RX

DISEASE TRANSMISSION

• Person to person contact or contact with contaminated fomites, e.g. familial transmission, non-familial outbreak (football team and wrestling teams).

• Molecular analysis of various outbreaks in the USA (Minnesota, North Dakota, Nebraska and Alabama) found to be closely related or identical.

Antimicrob. Agents Chemother 2003; 47:196-203

CA-MRSA MEASURES TO PREVENT SPREADING

• Instruct patient in hand washing

• Sharing of personal items (e.g. athletic

equipment, towels) should be avoided

• Compliance with antibiotic treatment

course

Patient, Physician, and Managed CareAntibiotic Abuse

Patients: do not understand the difference between viral andbacterial infection and antibiotics are ineffective againstviruses.

Physicians: frequently comply to satisfy patient’s demandon antibiotics and to maintain their patient base.

Managed Healthcare: increase antibiotic use by discouragingdiagnostic testing and limiting patient assessment time.

“Antimicrobial resistance to Penicillin, Methicillin, or Vancomycin is an unavoidable consequence of the selective pressure of antibiotic exposure. The quest is not whether resistance will occur, but how prevalent resistance will become.”

Minimizing the antibiotic pressure that favors the selection of resistant strains is essential in controlling the emergence of these strains.

Henry F. Chambers, M.D.Professor of MedicineChief of Infectious Diseasesat San Francisco General Hospital

February 2004

MRSA

Additional information from CDC:

www.cdc.gov/neidod/hip/aresist/mrsa.htm

(800-893-0485)CDC expert strategies and management of CA-

MRSA. Priorities for future.

RGorwitz@cdc.gov

Thank You For Thank You For Your AttentionYour Attention