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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
• Catalase test (+)– distinguishes from strep spp.
which are (-)
• S. aureus & S. epidermidis are most important clinically
S. aureus S. epi
Site Nose Skin
Coagulase positive negative
Colony Color
Yellow White
Colony Size Large Small
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 August- July 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
MMWRFour Pediatric Deaths from CA-MRSA- Minnesota 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
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
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.
Egleston - ALL ISOLATES, MYSIS Incidence report,'06)
EPI GP ORG N NOTES
VREs E.faecium 30(pt) 53% VRE
MRSA MRSA 646 51% MRSAOP-SSI: 65% MRSA MSSA 627
ESBLs E.coli 503
Kl.oxytoca 43
Kl.pneumoniae 160
Pr.mirabilis 46
SPICE&M Providencia sp. 3
Indole + Proteus 1
Citrobacter sp. 33
Enterobacter sp. 175
Morganella sp. 11
MRO Ps.aeruginosa 722
Acinetobacter sp. 42
Steno.maltophilia 117Courtesy 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
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
Courtesy of Dr. Jerris
• NO induction
• msrA-mediated erythromycin resistance
• Erythro – R
• Clinda – S
Negative reaction
D- test for inducible clindamycin resistance
15 - 26 mm15 - 26 mm
Photos courtesy of J. Jorgensen and K. FiebelkornPhotos courtesy of J. Jorgensen and K. Fiebelkorn..
Courtesy of Dr. Jerris
• Inducible
• clindamycin resistance
• (erm-mediated)
• Erythro – R
• Clinda – RPositive reaction
*Note that the rates vary dramatically depending on the site and patient population
Courtesy of Dr. Jerris
EglestonInducible Clinda Resistance ‘06
Skin and Soft Tissue InfectionsCHOA - 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
•
FOR QUALITY RESULTS, SEND TISSUE,
FLUIDS ,OR ASPIRATES
(SAME SPECIMEN FOR PATHOLOGY
BUT NOT IN FORMALIN)
Syringes
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
+ Assumes >90% “D” test negative, erythro resistant CA-MRSA
Baker, AAP News September 2004
Outpatient Management of
CA-MRSA
For life threatening disease
• Nafcillin + Vancomycin + Clinda (effect on toxin) + Gent or Rifampin
• +/- Ceftriaxone for gram negatives
• NO good data to support this combo!
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 therapy- synergistic activity with Vanc
• Rifampin- proven efficacy in setting of prosthetic valve endocarditis, otherwise, little data– Should never be used as monotherapy for
treatment!
• 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.
New Antibiotic Choices for Staph
• 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!
Others you may hear about…
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)
Prevention Strategies, MMWR Feb 7,2003 / 52 (05);88
Courtesy of Dr. Jerris
Decolonization- Cochrane Review6 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