Outpatient care in the era of
MRSA
Julie Gutman, MD
Pediatric Infectious Disease Fellow
August 29, 2007
MRSA
• Basic Micro
• History of MRSA
emergence
• Genetic markers
• Resistance testing
• Treatment
• Eradication
Staphylococci
• Gram-positive
• Facultative anaerobes
• Grow in clusters
– Strep usually grow in chains
S. aureus S. epi
• Catalase test (+)
– distinguishes from strep spp.
which are (-)
Site
Nose
Skin
Coagulase
positive
negative
Yellow
White
Large
Small
• S. aureus &
S. epidermidis are most Colony
Color
important clinically
Colony
Size
Hemolysis? yes
no
Emergence of MRSA
• First described in 1960
– One year after introduction of methicillin!
• Initially most cases were “hospital
acquired”
• Risk factors for Hospital Acquired:
– Hospitalization, Surgery, Dialysis
– Permanent indwelling device
• Trach, G-tube, foley, CVL
Evidence of MRSA in the
Community
• 3% colonized with MRSA at center X
• 24% colonized with MRSA at center Y
JID, Volume 178 (2), August 1998
Increasing incidence of CA- MRSA in
Hospitalized Children
• Retrospective review: Compared AugustJuly of 1988-1990 and 1993-1995
• CA-MRSA disease increased:
– 8 in 1988-90 to 35 in 1993-95.
– 10/100,000 to 259/100,000 (P<.001)
• Noted a difference in susceptibility of
isolates from children with risk factors for
MRSA vs. those with no risk factors
Herold et al. JAMA. 1998;279:593-598
MMWR
Four Pediatric Deaths from CA-MRSAMinnesota and North Dakota, 1997-1999
• First report of fatal outcomes
associated with MRSA
– Type MW2 (USA400)
Methicillin-resistant Staphylococcus aureus (MRSA) is an
emerging community-acquired pathogen among patients
without established risk factors for MRSA infection
This report describes four fatal cases among children with
community-acquired MRSA; the MRSA strains isolated from
these patients appear to be different from typical nosocomial
MRSA strains in antimicrobial susceptibility patterns and
pulsed-field gel electrophoresis (PFGE) characteristics.
MMWR, August 20, 1999 / 48(32);707-710
Incidence of CA-MRSA Disease
Fridkin, et al. NEJM 2005. 352: 1436-44.
Sequencing of CA-MRSA (MW2)
• Identified SCCmec IV with mecA gene
• Lacked the multiple resistance genes found in
HA-MRSA (SCCmec II, also I and III)
• Homology with HA-MRSA genome ~ 95%
– homology is 99.7% between HA-MRSA strains
• 18 new virulence factors
• Rapid growth rate- survival advantage
– doubling time 13-23.5m VS. 34.8 and 46.8m for
HA-MRSA
Baba, et al. 2002. Lancet. 359:1819
MRSA Genetics- SCCmecIV
• Staphylococcal cassette chromosome
(SCCmec) – mobile genetic element
• Methicillin resistance mecA gene
– Produces altered penicillin binding protein
PBP2a
• CA-MRSA generally SCCmec IV
– smaller & more mobile than other SCCmec
– HA-MRSA carries type II
– predominant circulating clones
• USA300 and USA400
Staphylococcal Cassette Chromosomes (SCC-mec). Okuma, JCM 2002
MRSA Strain Typing
• Pulsed-field gel electrophoresis (PFGE)
– Uses Sma1 restriction endonuclease
– Clones USA100- USA1000 have been designated
– Clones USA300 and USA400 predominate
• PCR-based methods
– spa typing
• DNA-sequencing of repeat regions of the Staphylococcus
protein A gene (spa): repeats are assigned a numerical code
and the spa-type is deduced from the order of specific
repeats
– multilocus sequence typing (MLST)
• Uses the sequences of 7 house-keeping genes and assigns
an allelic type to each sequence.
Antimicrobial Susceptibility
CA-MRSA vs HA-MRSA
Naima, et al. JAMA 2003
Egleston - ALL ISOLATES, MYSIS Incidence report,'06)
EPI GP
ORG
N
NOTES
VREs
E.faecium
30(pt)
53% VRE
MRSA
MRSA
646
MSSA
627
51% MRSA
OP-SSI: 65% MRSA
ESBLs
SPICE&M
MRO
E.coli
503
Kl.oxytoca
43
Kl.pneumoniae
160
Pr.mirabilis
46
Providencia sp.
3
Indole + Proteus
1
Citrobacter sp.
33
Enterobacter sp.
175
Morganella sp.
11
Ps.aeruginosa
722
Acinetobacter sp.
42
Steno.maltophilia
117
Courtesy of Dr. Jerris
2006 Wounds
• ECH
–
–
–
–
–
MRSA [65% incidence {all sources,locations}]
S.aureus
Anaerobes
E.coli
Streptococcus pyogenes (gpA strep)
• Pen 100% S, Erythro 93.1% S, Clinda 99.5% (CID.05. 41:599)
– Enterococcus faecalis
• Ceph’s are ineffective
– “SPICE” and “M”
• Serratia, Providencia, Indole + Proteus, Citrobacter,
Enterobacter and Morganella
Source: Misys Incidence query
Courtesy of Dr. Jerris
2006 Antibiogram
Egleston
Clinda
• Single isolate per patient per year
TMP/SMX
Cipro
Inducible Clinda Resistance
• Mediated through erm gene – MLSB
• Alteration in the 23S ribosomal RNA
– Part of 50S ribosomal subunit
– Occurs through methylation of adenine
• Confers resistance to:
– erythromycin and most other macrolides (M)
– lincosamides (L, lincomycin, and clindamycin)
– streptogramin type B (SB).
Consider in all Erythro Resistant isolates!!!
D- test for inducible clindamycin
resistance
• NO induction
• msrA-mediated
erythromycin
resistance
• Erythro – R
• Clinda – S
Negative reaction
Courtesy of Dr. Jerris
D- test for inducible clindamycin
resistance
• Inducible
• clindamycin
resistance
• (erm-mediated)
• Erythro – R
• Clinda – R
15 - 26 mm
Positive reaction
Photos courtesy of J. Jorgensen and K. Fiebelkorn.
Courtesy of Dr. Jerris
Egleston
Inducible
Clinda Resistance
06
Inducible
Clinda
Resistance
‘06
30
25
%
20
MSSA
15
MRSA
10
5
0
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC
*Note that the rates vary dramatically depending on the site and patient population
Courtesy of Dr. Jerris
Skin and Soft Tissue Infections
CHOA - 2006
WOUNDS:
288 isolates with MRSA (1 isolate per patient per year)
Erythro Resistant and Clinda Susceptible
► 6/288 were D-zone test positive (2.1%)
- Outpt. 2/186 (1%)
- Inpat. 4/102 (4%)
@30% of population carry this organism-CDC
Courtesy of Dr. Jerris
•
Syringes
FOR QUALITY RESULTS, SEND TISSUE,
FLUIDS ,OR ASPIRATES
(SAME SPECIMEN FOR PATHOLOGY
BUT NOT IN FORMALIN)
Courtesy of Dr. Jerris
Vancomycin Intermediate
(resistant) S. aureus (VISA)
• Japan, 1996: first documented case of VISA
– MIC=8 ug/mL
• US, July 1997, VISA-associated peritonitis
– isolate was susceptible to rifampin, chloramphenicol, bactrim,
and tetracycline.
• National Committee for Clinical Laboratory Standards
breakpoints for susceptibility:
– susceptible ≤4 ug/mL
– Intermediate = 8-16 ug/mL
– resistant ≥32 ug/mL
MMWR, August 22, 1997; 46(33);765-766
Spectrum of Disease
• more virulent than HA-MRSA.
• Infection of skin or soft tissue
– Osteomyelitis
– Pyomyositis
• Necrotizing pneumonia
• Severe sepsis
– purpura fulminans, DIC, and bilateral adrenal
hemorrhage
• Necrotizing fasciitis
• Thromboemboli
Panton Valentine Leukocidin (PVL)
• Bicomponent, pore-forming leukotoxin
– LukS-PV and LukF-PV
– Produces lysis of PMNs
• Carried on an integrated bacteriophage (phiSLT)
• Causes dermonecrosis if injected into skin of
animals
• Associated with severe disease in CA-MSSA
and CA-MRSA
• More frequently associated with sepsis, high
fever, leukopenia, hemoptysis, pleural effusion
and death than PVL (-)
Panton Valentine Leukocidin (PVL)
BUT
• PVL-negative (lukS/F-PV knockout) strains
of USA300 and USA400 were as lethal as
wild-type strains in a mouse sepsis model,
and they caused comparable skin disease
Staph
virulence
factors
Outpatient
Management of
CA-MRSA
+ Assumes
>90% “D” test
negative,
erythro
resistant CAMRSA
Baker, AAP News
September 2004
For life threatening disease
• Nafcillin + Vancomycin + Clinda (effect on
toxin) + Gent or Rifampin
• +/- Ceftriaxone for gram negatives
• NO good data to support this combo!
A Note about Wounds…
• For abscesses, DRAINAGE is key!
• Abscesses<5 cm – I&D alone sufficient!
Antibiotic Choices for Staph
• Nafcillin- preferred treatment for MSSA!
– More rapid clearance of blood cultures than
Vanc
• Bactrim- some proven efficacy for SSI
– Does NOT cover strep!
• Clindamycin- covers strep and staph!
– 10-20% resistance, should NOT use as
monotx for severe infections!
• Vancomyin- DOC for MRSA
Antibiotic Choices for Staph
• Gentamicin- used a an adjuntive therapysynergistic activity with Vanc
• Rifampin- proven efficacy in setting of
prosthetic valve endocarditis, otherwise,
little data
– Should never be used as monotherapy for
treatment!
New Antibiotic Choices for Staph
• Linezolid
– Skin and soft tissue infections, pneumonia
– Have been reports of failure when used for
endocarditis
– Can be given PO
– SE: thrombocytopenia, optic neuritis, peripheral
neuropathy
• Daptomycin
– Skin and soft tissue infections, bacteremia,
endocarditis with MRSA
– NOT for pneumonia!
– SE- musculoskeletal. Monitor CPK.
Others you may hear about…
• Tigecycline- approved for MRSA skin ond
soft tissue infections
– Extremely broad spectrum!! Covers VRE,
complicated intra-abdominal infections
– SE: GI- Nausea, Vomiting
• Quinupristin-Dalfopristin- approved for
VRE, MSSA, not MRSA
– Requires central line
– Severe myalgias, arthralgias
• Dalbavancin- once weekly dosing
– Not yet FDA approved!
Prevention Strategies, MMWR Feb 7,2003 / 52 (05);88
Community setting:
• Thoroughly clean towels, bed linens, personal
clothing
•Thoroughly wash cuts and abrasions with soap and
water
•Disinfect athletic equipment, benches, personal
equipment with commercial
disinfectant or
diluted bleach ( 1 tablespoon bleach in 1 quart water)
•Common sense personal hygiene
Individual patients:
• Local treatment I & D (antimicrobics)
Courtesy of Dr. Jerris
Decolonization- Cochrane Review
6 trials (384 participants)
Trial
Intervention
Outcome- Eradication
Harbarth
1999
IN mupirocin compared to
placebo
25% mupirocin vs. 18% placebo; RR 1.39;
Not statistically significant!
Parras
1995
IN mupirocin vs. IN fusidic
acid + PO Bactrim
Eradication: 78% mupirocin vs. 71% bactrim+
fusidic acid @ 90d
Chang
2000
Oral fusidic acid vs. no
treatment
RR 0.67 (0.18-2.42)
Not statistically significant!
Walsh
1993
Novobiocin + rifampin
(N+R) vs. Bactrim+
rifampin (B+R)
67% N+R vs. 53% B+R (P = 0.18) NS!
Resistance to rifampin- more in the bactrim
vs. novobiocin group (14% vs. 2%, P = 0.04).
Peterson
1990
Cipro + rifampin vs.
Bactrim + rifampin
6-month eradication in 3/11 cipro + rifampin
and 4/10 Bactrim + rifampin recipients.
**terminated due to cipro resistance !!!!
Muder
1994
PO rifampin, minocycline,
or rifampin +minocycline
vs. no treatment
Not statistically significant!
Rifampicin better than minocycline at day 30
but not at day 90
Single agent vs. placebo RR=8 (0.53-122)
Combined Tx vs. placebo RR=9.45 (0.62-145)
Decolonization- Cochrane Review
• SE in up to 20% of systemic agent use.
• All trials reported development of
resistance
• Authors' conclusions
–Insufficient evidence to support use
of topical or systemic antimicrobial
therapy for eradicating MRSA.
–Need for large RCT!
Decolonization
2% chlorhexidine gluconate wash +
2% mupirocin intranasally +
Oral Rifampin + Doxy for 7 days
• 74% of treated vs. 32% untreated had
negative cultures at 3 months
Simor et al., CID 2007. 178:44.
Our Protocol
• Clinda or Bactrim + Rifampin PO
• Mupirocin daily x 7 d to nares of
ENTIRE FAMILY
• Chlorhexidine gluconate washes daily for
a week, then 1-2 times weekly
• (can substitute bleach baths)
• Cross your fingers and pray.
Blood Culture VOLUME
• Volume of blood drawn for culture is the MOST IMPORTANT variable
in detecting bacteremia or fungemia
• MAX volume per BC System
For adult patients, the yield of pathogens increases in direct
proportion to the volume of blood that is cultured from 2 to 30 mL. The
yield still increases when 40 mL (or even higher) volumes of blood are
cultured, although the increase may no longer be in direct proportion
to the volume of blood cultured. For pediatric patients, the limited data
that has been published also indicate that the yield of pathogens
increases in direct proportion to the volume of blood that is cultured
[Li J, Plorde J, and Carlson L. 1994. Effects of volume and periodicity on blood
cultures. J Clin Microbiol. 32:2829-2831]
Courtesy of Dr. Jerris
Questions?
2006 Antibiogram
Egleston
4 pandemic MRSA clones derive
from 2 distinct backgrounds
Oliveira, Lancet 2002