VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)

1
COMMUNITY ACQUIRED METHICILLIN RESISTANT
STAPHYLOCOCCUS AUREUS
Structure of Penicillin binding protein 2a from
MRSA strain 27r at 1.80 A resolution
Adapted from a presentation by Jon Rosenberg,
Infection Control and Healthcare Epidemiology,
Division of Communicable Disease Control,
California Department of Health Services
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orBacteria Run Wild, Defying Antibiotics
A new chapter in the continuing story of
antibiotic resistance is being written in
doctors' offices across the country, as a group
of common bacteria rapidly becomes resistant to
the antibiotics that have been used to treat them
for decades.
March 2, 2004
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4
U.S. Athletes Getting Superbug Skin Infections
Reuters Health Aug 21, 2003
Skin and soft tissue infections due to
antibiotic-resistant staph appear to be a growing
problem among competitive athletes in the U.S.,
according to a report released on Thursday by the
U.S. Centers for Disease Control and Prevention.
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CAMRSA Summary

• Distinct from HAMRSA
• Clinical
• Skin and soft tissue infections
• Epidemiology
• Children and young adults, summertime
• Prisons, IVDU, sports teams, aboriginal
  populations
• Phenotype
• Mono-resistant/non-MDR, rapid growth
• Genotype
• Type IV SCCmec gene, PVL and other virulence
  factors, PFGE patterns

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CAMRSA Summary

• Epidemiology
• No national surveillance
• Emerged in 1980s, increasing, epidemic levels??
• Pathogenicity
• More pathogenic, transmissible than HAMRSA
• Different from CAMSSA?
• Risk factors
• Limited studies suggest few identifiable risk
  factors
• Antibiotic use usually not a risk factor

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S. Aureus Illness and Syndromes
Prominent Cellulitis Hospital-acquired
bacteremia Hematogenous osteomyelitis Septic
arthritis Brain abscess Hospital-acquired
pneumonia Empyema Septic shock Food-borne
gastroenteritis Renal carbuncle
Sole/Most Common Furuncle or carbuncle Impetigo
bullosa Surgical wound infection Pyomyositis Botry
omycosis Acute or right-sided endocarditis Epidura
l abscess Toxic shock syndrome Scalded skin
syndrome
From Archer. Clin Infect Dis 199826117981
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S. aureus Skin Infections
Furuncles (boils)
Cellulitis
Mild
Severe
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S. aureus Why Worry?

• Pathogenicity
• Community infections
• Furuncles (boils), carbuncles, endocarditis,
  toxic shock
• Transmissibility
• Colonized (in addition to infected) persons
  sources of transmission
• Resistance
• Decreasing treatment options

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Pathogenesis of S. aureus Infections

1. Colonization
2. Local infection
3. Systemic dissemination and/or sepsis
4. Metastatic infection
5. Toxinosis

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Staphylococcus aureus Colonization

• Humans natural reservoir
• Anterior nares
• 30-50 healthy adults colonized at any one time
• 60 colonized intermittently
• 20 persistently colonized
• 20 never colonized
• Axillae, vagina, pharynx, damaged skin, rectum
• Hands, intact skin colonized transiently
• Clearance of nasal colonization eliminates hand,
  skin carriage

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Rates of S. aureus nasal carriage in various
populations
From Kluytmans et al. Clin Microbiol Rev, July
1997
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Transmission/Pathogenesis Nosocomial S. aureus


Patients
Negative
Colonized
Infected
Invasive devices
Immune suppression
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Transmission/Pathogenesis Nosocomial MRSA


Patients
Negative
Colonized
Infected
Invasive devices
Antibiotic
Immune suppression
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Transmission/Pathogenesis Community S.
aureus/MRSA
Direct inoculation?
Persons
Negative
Colonized
Infected
Break in skin
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Emergence of Resistance in S. aureus
Drug Year drug introduced Years to report resistance Years until 25 rate in hospitals Years until 25 rate in community
Penicillin 1941
1-2
6
5-20
Methicillin 1961

40-50

(projected 2001-2010)
25-30
lt1
Vancomycin 1956
? ?
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Chambers, EID 7178-182, 2001
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Methicillin-resistant Staphylococcus aureus
(MRSA) in the community who's watching?

• Commentary in Lancet. 1995 Jul 15346(8968)132-3.
  
• Asked to comment on Layton MC, Hierholzer WJ,
  Patterson JE. The evolving epidemiology of
  methicillin-resistant Staphylococcus aureus at a
  university hospital. Infect Control Hosp
  Epidemiol 19951612-17
• Among 87 patients with MRSA 36 (41) were
  community-acquired, and of these 8 (22) had no
  discernible risk factors

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Is MRSA Present and Increasing in the Community?

• Little data
• Most community infection not cultured
• Staphylococcal infections are not reportable
• Methicillin resistance is not reportable with few
  exceptions
• Community acquisition cannot be distinguished
  from nosocomial without patient interviews

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CAMRSA in Hospital Pediatrics

• Number children hospitalized at U Chicago with
  CAMRSA from 8 in 1988-1990 to 35 in 1993-1995
• Prevalence of CAMRSA without identified risk
  factors
• 10 per 100000 admissions in 1988-1990
• 259 per 100000 admissions in 1993-1995
• Herold et al,. JAMA 1998 Feb 25279(8)593-8
• Updated 1998-1999
• 23 hospitalized children with MRSA
• 10 community-acquired, 208/100,000
• Hussain et al, Pediatr Infect Dis J December 2000

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CAMRSA in Hospital Pediatrics

• Driscoll Childrens HospitalCorpus Christi, TX
• 1990-2000 196 MRSA isolations
• 7 in 1990-1996, 53 in 1997-2000, 35 in 2000
• 128 medical record reviews
• 60 (47) community acquired
• 53 (88) no identifiable risk factors
• Fergie and Purcell, Pediatr Infect Dis J. 2001
  Sep 20860-3

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CAMRSA in Dermatology Outpatients

• Prevalence of MRSA in dermatology outpatient
  clinics, Baylor College of Medicine
• 1986-1987 lt0.9
• 1988-1996 gradual increase from 1.5 to 11.9
• Increasing resistance to ciprofloxacin and
  tetracycline
• Price et al,. South Med J April 1998

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CAMRSA in Rural American Indian Community

• Indian Health Service in New Mexico
• Medical records 1997
• 112 S. aureus isolates
• 62 (55) MRSA
• 46 (74) community acquired
• No difference risk factors vs. CAMSSA
• PFGE distinguished community acquired from
  nosocomial
• Groom et al. JAMA 2001 Sep 12286(10)1201-5

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CAMRSA Colonization in Community Pediatrics

• 500 children lt 16yo U. Chicago outpatient clinic
  to receive well child care
• 24.4 colonized with S. aureus
• Three (2.5) MRSA colonized
• Hussain et al. Pediatr Infect Dis J August 2001
• 500 children Nashville well child care visits
• Four (8) MRSA colonized
• Nakamura et al. Pediatr Infect Dis J October 2001

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CAMRSA Colonization in Community

• Bellevue Hospital Pediatric Clinic
• 275 children and 225 guardians
• S. aureus colonization 35 children, 28
  guardians
• One child with nosocomial MRSA
• Shopsin et al. J Infect Dis J 2000182359-62

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MRSA Colonization in Community

• Community-acquired methicillin-resistant
  Staphylococcus aureus a meta-analysis of
  prevalence and risk factors
• Pooled CA-MRSA prevalence among 5932 patients
  from 27 retrospective studies was 30.2
• Pooled MRSA colonization rate among community
  members was 1.3
• Among studies that excluded persons with health
  care contacts, the MRSA prevalence was 0.2
• Salgado, Farr, Calfee. Clin Infect Dis
  January 2003

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CAMRSA Risk Factors

• Prospective observation children 2/2000-11/2000,
  Baylor
• 63 CAMRSA vs 81 CAMSSA
• No difference in risk factors (antibiotic
  exposure, day-care, underlying illness, previous
  hospitalizations, health care worker in home or
  contact, health care visits)
• Sattler et al. Pediatr Infect Dis J October 2002

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CAMRSA Nosocomial Transmission

• Hospital Transmission of CAMRSA among Postpartum
  Women
• Departments of Pediatrics, Columbia University,
  New York
• 8 women skin and soft-tissue MRSA infections mean
  time of 23 days (range, 4-73 days) after delivery
• 4 cases of mastitis (3 progressed to breast
  abscess), a postoperative wound infection,
  cellulitis, pustulosis
• Identical by PFGE to CA-MRSA strain MW2
• Route of transmission not discovered cultures
  from employees of the hospital, the hospital
  environment, and newborns negative
• Saiman et al. Clin Infect Dis. 2003 Nov
  1537(10)1313-9

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CAMRSA Familial Transmission

• Familial carriage of methicillin-resistant
  Staphylococcus aureus and subsequent infection in
  a premature neonate
• Index patient MRSA infection
• Infant sibling admitted 7 months previously MRSA
  infection
• Nasal Cultures from parents and two other
  siblings yielded identical MRSA from mother and
  sibling
• Hollis et al. Clin Infect Dis. 1995
  Aug21(2)328-32

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Surveillance Definition of CAMRSA

• Positive culture for MRSA obtained within 48
  hours of admission (if hospitalized)
• No history of hospitalization in past year
• No history of surgery in past year
• No history of long-term care in past year
• No history of dialysis in past year
• No permanent indwelling catheters or percutaneous
  medical devices
• No prior history of MRSA infection or colonization

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CAMRSA Surveillance Minnesota 1996-98

• Cases from 10 hospitals
• 354 patients (median age, 16 years)
• 299 (84) skin infections
• 103 (29) hospitalized
• More than 90 of isolates susceptible to all
  agents tested, with exception of ?-lactams and
  erythromycin
• 334 treated, 282 (84) initially treated with
  agents to which their isolates were
  nonsusceptible
• 174 tested, 150 (86) 1 PFGE clonal group
• Naimi et al. Clin Infect Dis October 2001

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CAMRSA Surveillance Minnesota 2000

• 4,612 patients with S. aureus identified at 10
  sentinel sites (total number S. aureus
  unavailable at two sites)
• 1164 (25) were MRSA (range 10-50)
• 994 (85) were HA-MRSA
• 133 (11) were CO-MRSA (range 4-50) after
  patient interview
• 37 (3) not enough information to classify
• 13 of presumptive CO-MRSA cases were
  reclassified as HA-MRSA after interview
• Courtesy Kathy Ledell, Minnesota Department of
  Health

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Age Distribution, Hospital Acquired MRSA,
Minnesota, 2000
Courtesy Kathy Ledell, Minnesota Department of
Health
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Age Distribution, Community Onset MRSA,
Minnesota, 2000
Courtesy Kathy Ledell, Minnesota Department of
Health
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Month of Culture, Hospital Acquired MRSA,
Minnesota, 2000
Courtesy Kathy Ledell, Minnesota Department of
Health
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Month of Culture, Community Onset MRSA,
Minnesota, 2000
Courtesy Kathy Ledell, Minnesota Department of
Health
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Susceptibility of MRSA Isolates by
Antimicrobial Agent, Minnesota 2000
Antimicrobial
Courtesy Kathy Ledell, Minnesota Department of
Health
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Susceptibility Trends, Community Onset MRSA,
1996-2001

• Susceptibility trends from 1996-2001 were
  analyzed
• Susceptibilities decreased over time
• Erythromycin 71 to 46, x2 trend16.5, plt0.001
• Ciprofloxacin 92 to 80, x2 trend15.2, plt0.001
• Clindamycin 90 to 84, x2 trend 2.7, p0.099
• No significant change in susceptibilities to
  gentamicin, rifampin, tetracycline,
  trimethoprim-sulfamethoxazole, or vancomycin
• Preliminary data 2002 erythromycin 42,
  ciprofloxacin 77, clindamycin 84

Courtesy Kathy Ledell, Minnesota Department of
Health
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Treatment of CAMRSA Are Antibiotics Needed for
Abscesses?

• 69 children CA-MRSA skin and soft tissue abscess
• Treatment drainage in 96 and wound packing in
  65
• All treated with antibiotics, only 5 (7)
  appropriate before culture
• Significant predictor of hospitalization was
  having a lesion initially gt5 cm
• 58 patients initially given ineffective
  antibiotic, antibiotic active against CA-MRSA
  given to 21 after cultures
• No significant differences in response in those
  who never received an effective antibiotic than
  in those who did
• Incision and drainage without antibiotic therapy
  effective management of CA-MRSA skin and soft
  tissue abscesses lt5 cm in immunocompetent children

Lee et al, Pediatr Infect Dis J February 2004
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Treatment of CAMRSA

• Trimethoprim-sulfamethoxazole
• Bacteriostatic, variable resistance, limited
  clinical experience vs. serious infections
• Clindamycin need to test for inducible
  resistance
• Rifampin
• Active, cannot use alone (development of
  resistance)
• Vancomycin (parenteral)
• Linezolid (expensive, bacteriostatic)

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CAMRSA - Severity

• Four Pediatric Deaths from Community-Acquired
  Methicillin-Resistant Staphylococcus aureus --
  Minnesota and North Dakota, 1997-1999
• MMWR August 20, 1999 / 48(32)707-710
• All patients in this report were initially
  treated with a cephalosporin antibiotic
• MRSA isolates from these four cases were
  susceptible to all antimicrobial agents tested
  except beta-lactams

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Staphylococcal PVL Potent Dermonecrotic Toxin

• The Panton-Valentine leukocidin of Staphylococcus
  aureus was shown to exhibit a potent
  dermonecrotic effect when injected intradermally
  into rabbits
• PVL belongs to group of exotoxins that damage the
  membrane of host defense cells
• Ward and Turner. Infect Immun May 1980

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PVL in Primary Skin Infections and Pneumonia

• 172 S. aureus strains screened for PVL genes
• 93 of furunculosis and 85 of severe necrotic
  hemorrhagic pneumonia
• 55 of cellulitis, 50 of cutaneous abscess, 23
  of osteomyelitis, 13 of finger-pulp infection
• Not detected
• infective endocarditis, mediastinitis,
  hospital-acquired pneumonia, urinary tract
  infection, enterocolitis, toxic-shock syndrome
• Lina et al. Clin Infect Dis November
  1999

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CAMRSA and PVL

• 14 CAMRSA cases in previously healthy patients
• 11 skin or soft-tissue infections
• 2 died of necrotizing pneumonia
• Panton-Valentine leukocidin genes in all
• Dufour et al. Clin Infect Dis 2002 35000000

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CAMRSA Carrying PVL Genes Worldwide Emergence

• 117 CA-MRSA isolates
• 33 United States
• 67 Europe (61 France and 6 Switzerland)
• 17 Oceania (Australia, New Zealand, Western
  Samoa)
• Most isolates primary skin and soft tissue
  infections
• All strains carried Panton-Valentine leukocidin
  locus
• Distribution of other toxin genes specific to
  each continent

Vandenesch et al. Emerging Infectious Diseases
Vol. 9, No. 8 August 2003
45
Growth Rate of CAMRSA

• CAMRSA strains grow faster than HAMRSA strains
• Mean doubling time 28 minutes vs. 38 minutes
• Enhance competitive survival in absence of
  antibiotics
• Did not compare to CAMSSA
• Okuma et al. J Clin Microbiol November 2002

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Whole genome sequencing of MRSA

• Whole genome sequences of N315 (MRSA strain
  1982), Mu50 (VISA strain 1997)
• Complex mixture of genes
• Many acquired by lateral gene transfer
• Antibiotic resistance genes carried either by
  plasmids or by mobile genetic elements
• Kuroda M et al. Lancet April 2001

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S aureus chromosome
From Kuroda et al. Lancet 2001 Apr 21
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Antibiotic Resistance Genes in MRSA
Kuroda et al. Lancet April 2001
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Staphylococcus Cassette Chromosome

• Methicillin resistance gene of MRSA carried by
  novel genetic element, SCCmec
• Integration into and excision mediated by unique
  set of recombinase genes, ccrA and ccrB

Katayama, Ito, Hiramatsu. Antimicrobial Agents
Chemotherapy June 2000
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Structures of SCCmec
Ito et al. Drug Resistance Updates 2003
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CAMRSA Carrying PVL Genes Worldwide Emergence

• All 117 CA-MRSA strains shared a type IV SCCmec
  cassette
• PFGE and MLST analysis indicated distinct genetic
  backgrounds associated with each geographic
  origin
• Within each continent, genetic background of
  CA-MRSA strains did not correspond to
  hospital-acquired MRSA

Vandenesch et al. Emerging Infectious Diseases
Vol. 9, No. 8 August 2003
52
CAMRSA - Outbreaks

• Community outbreaks have occurred among
• Injection-drug users
• Aboriginals in Canada, New Zealand, and Australia
• Native Americans/Alaska Natives in United States
• Players of close-contact sports (scrum pox)
• MSM?
• Institutional outbreaks
• Prisons, jails, developmentally disabled
• More than S. aureus in past?

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Methicillin-Resistant Staphylococcus aureus
Infections Among Competitive Sports Participants
--- Colorado, Indiana, Pennsylvania, and Los
Angeles County, 20002003 MMWR August 22, 2003 /
52(33)793-795

• Colorado 4 fencers, 1 household contact
• Pennsylvania 10 college football, 7 hospitalized
• Los Angeles 2 college football players
  hospitalized

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CAMRSA in Los Angeles

• Resistance
• Resistant to ciprofloxacin, erythromycin
• Sensitive to trimethprim/sulfa, rifampin,
  clindamycin, vancomycin
• Also linezolid, Synercid
• Los Angeles Jail
• 165,000 prisoner/year, 1,000 infections in past
  year
• Poor hygienic conditions
• Football team
• Gay men
• Extent of problem undefined
• Mode of transmission to be determined

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Pediatric CAMRSA in Los Angeles

• MRSA reportable May 5 - November 7, 2003
• Hospitalized children (lt18 years) excluding
  nosocomial
• First 13 weeks surveillance
• 62 cases, diverse races, ethnicities, mean age
  6.9 years
• Cellulitis 50 of cases
• Average length of hospitalization 7 days (range
  of 1-33 days)
• 25 initially thought to be spider, insect bites
• 24 exposed to another individual in home with
  lesions month before the childs infection
• 12 of contacts in the home subsequently
  developed skin lesion
• 11/13 initially treated with beta-lactam
  antibiotics

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Prevention and Control of CAMRSA

• Hygiene
• Hand hygiene
• Showering with soap
• Cleaning and disinfection
• Laundering personal items such as towels after
  each use
• Cleaning or laundering shared materials
• Wound care
• Covering cuts and abrasions until healed
• Consulting a health-care provider for wounds that
  do not heal or appear infected, diagnosis and
  treatment
• Role for decolonization if recurrence?

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Questions

1. At what prevalence of resistance should empiric
   treatment change?
2. What is role of antibiotics vs. ID?
3. What is optimal antibiotic therapy?
4. What is best prevention strategy
5. What is role for decolonization?
6. Can we answer these questions without
   surveillance of local population

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What can we learn from surveillance?

• Identify potential risk factors
• Explore potential prevention strategies
• Explore clinical management issues
• Follow trends regarding numbers of cases,
  susceptibilities, and at risk populations
• Explore potential virulence and host factors