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

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 SusceptibilityCA-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 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

2006 AntibiogramEgleston

• Single isolate per patient per year

Clinda 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

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

Staph virulence factors

+ 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!

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 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

Questions?

2006 AntibiogramEgleston

4 pandemic MRSA clones derive from 2 distinct backgrounds

Oliveira, Lancet 2002