COMMUNITY ACQUIRED MRSA Pisespong Patamasucon, M.D. Pediatric Infectious Diseases UNSOM - Las Vegas

TIMELINE FOR RESISTANCE IN HOSPITALS AND THE COMMUNITY Drug Introduced (Year) Resistance Reported (Years) 25% Resistance in Hospitals (Years) 25% Resistance in Community (Years) Penicillin19411 to 2615 to 20 Methicillin1961<125 to to 50 (estimated) Vancomycin1954>40?? 1) Emerg. Infect. Dis 2001; 7: ) N.Engl.J.Med 2003;348:

Resistant staphylococci: Definitions Resistance MIC > 16 μg methicillin/mL MIC > 4 μgoxacillin/mL Species MRSA: Methicillin-resistant S aureus MRCNS: Methcillin-resistant coag-neg staphylococci (S epidermidis most common)

CRITERIA OF CA-MRSA Isolated from patients residing in the community or within 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

INTRODUCTION Historical CA-MRSA - IV Drug users, recent hospitalization or resident in a nursing home 1995 Yale - New Haven Hospital 36% MRSA isolated were community acquired 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:

Comparison of Staphylococcal Cassette Chromosome mec Types SCCmec Type ccr Gene Type mec Complex Type Size (kb)RE Type I1B34.3i II2A53.0ii III3A66.9iii IV2B ii ccr, cassette chromosome recombinase; RE, right extremity of SCCmec element Adapted from J Infect Dis. 2002; 186:

MRSA bacteremia is associated with significantly higher mortality rate than is MSSA bacteremia. (adds ratio 1.93; 95% C.I, ; P<.001) CLIN. INFECT. DIS 2003; 36:53-59

NEW PROBLEMS RAISED BY 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: CLIN INFECT DIS 2000; 30:

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:

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:

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:

CDC four pediatric deaths from community- acquired methicillin resistant staphylococcus aureus -- Minnesota and North Dakota, [No risk factors, susceptible to several antibiotics and PFGE related] MMWR MORB MORTAL WKLY REP 1999; 48: Midwest Cluster, USA

CA - MRSA in South Texas Children 7 cases MRSA 53 cases (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:

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:

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 :

CA - MRSA among competitive sports participants Colorado, Indiana, Pennyslvania, L.A /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);

Outbreaks of CA-MRSA Skin Infection in Los Angeles, 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:

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:

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:

MRSA presenting like spider bite

MRSA (Spider Bite Like)

Diagnostic Sensitivity Agar and broth dilution: % Disk diffusion : % (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 stream infections.

DETECTION and LONG TERM PERSISTENCE OF 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:

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 identified at selected Minnesota hospitals, Antibiotic Susceptible% Intermediately Resistant (%) Susceptible (%) (%) Ciprofloxacin Clindamycin Erythromycin Gentamicin Oxacillin Rifampin Tetracycline TMP-SMZ Vancomycin CLIN. INFECT DIS 2001; 33:

TMP-SMZ and CLINDAMYCIN* SIMILAR BIOAVAILABILITY ORAL OR IV GOOD OPTIONS FOR OUTPATIENT OF CA-MRSA NOTE: Clindamycin should be used only if organism is sensitive to erythromycin MED CLIN NORTH AMER 1995; 79:

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:

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:

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 MANAGEMENT OF 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:

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 Care Antibiotic Abuse Patients: do not understand the difference between viral and bacterial infection and antibiotics are ineffective against viruses. Physicians:frequently comply to satisfy patient’s demand on antibiotics and to maintain their patient base. Managed Healthcare: increase antibiotic use by discouraging diagnostic 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 Medicine Chief of Infectious Diseases at San Francisco General Hospital February 2004

MRSA Additional information from CDC: ( ) CDC expert strategies and management of CA- MRSA. Priorities for future.

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