Management of Suspected Staphylococcal Infections in

Children in the Era of Community MRSA

Thursday, May 15, 200812:00 – 1:00 p.m. EDT

© American Academy of Pediatrics 2008

Moderator: Marlene R. Miller, MD, MSc, FAAPVice President, Quality - NACHRIDirector of Quality and Safety & Associate ProfessorJohns Hopkins Children’s CentersBaltimore, Maryland

This activity was funded through an educational grant from the

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Speaker: George K. Siberry, MD, MPH, FAAPAssistant Professor of PediatricsMedical Director, Harriet Lane ClinicJohns Hopkins Medical InstitutionsBaltimore, Maryland

MRSA

George K Siberry, MD, MPHPediatric Infectious Diseases

General Pediatrics & Adolescent MedicineJohns Hopkins Medical Institutions

May 15, 2008Disclosure: Nothing to Disclose

Learning Objectives

• Understand the emergence and origin of methicillin-resistant S. aureus (MRSA) strains causing infections in healthy children

• Recognize the clinical presentations of community staphylococcal infections

• Learn how to work with your local laboratory to understand local antibiotic susceptibility patterns

• Develop an approach to the management of suspected staphylococcal infections in children in the face of high rates of community MRSA

Vignette

• 2 year old with painful red swelling on thigh, T 102, otherwise well. August, 2002.

• Started as a “spider bite” (Baltimore!)• Exam reveals fluctuant lesion, that yields

copious pus with lancing, leaving a “crater”• Mother and 6 year old brother have had similar

skin infections in past 2 months• Treated with cephalexin• Culture grows MRSA• 2 day follow-up: no fever; no drainage; lesion

healing

Learning Objectives

• Understand the emergence and origin of methicillin-resistant S. aureus (MRSA) strains causing infections in healthy children

• Recognize the clinical presentations of community staphylococcal infections

• Learn how to work with your local laboratory to understand local antibiotic susceptibility patterns

• Develop an approach to the management of suspected staphylococcal infections in children in the face of high rates of community MRSA

MRSA: A Healthcare Associated Infection

• Hospitalization (1 year)• Surgery (1 year)• Long-term care • Dialysis • Permanent indwelling catheters or percutaneous

medical devices • Recent antibiotic use (6 months)• Intravenous drug use• *History of MRSA• *close contact with risk factor

MRSA first appeared in 1960s

Community-Acquired Methicillin-Resistant Staphylococcus aureus in Children With No

Identified Predisposing Risk

JAMA, February 25, 1998 – 279(8)

Betsy C. Herold, MD; Lilly C. Immergluck, MD; Melinda C. Maranan, MD; Diane S. Lauderdale, PhD; Ryan E.

Gaskin; Susan Boyle-Vavra, PhD; Cindy D. Leitch; Robert S. Daum, MD

Emergence of MRSA in the Community

Emergence of MRSA in the Community

Emergence of MRSA in the Community

A Clone of Methicillin-Resistant Staphylococcus aureus among Professional

Football Players

N Engl J Med 2005; 352:468-75

Sophia V. Kazakova, MD, MPH, PhD; Jeffrey C. Hageman, MHS, et al.

Strain Characteristics• Worldwide, the genetic backgrounds of

MRSA strains that emerged in the community vary, but these strains share some features– Distinct from strains established in healthcare– Non-multi-resistant– SCCmec IV or V– Panton Valentine Leukocidin (PVL) toxin genes– Propensity to cause infection in healthy

persons

Dice (Opt:0.50%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]

100

9080706050

PFT SCCmecMLST pvl

USA300 8 IV POS

USA700 72 IV NEG

USA100 5 I I NEG

USA800 5 IV NEG

USA400 1 IV POS

USA500 8 IV, I I NEG

USA1000 59 IV NEG/POS

USA900 15 MSSA NEG

USA600 45 I I NEG

USA200 36 I I NEG

USA1100 30 IV POS

USA1200 MSSA POS

S. aureus Pulsed-Field Types

McDougal et al J Clin Micro 2003;41:5113-20

Prevalence of MRSA Nasal Colonization by Age, 2001-02 and 2003-04

NHANES Nasal Swab Survey*

0

0.51

1.5

2

2.53

3.5

1-5 6-11 12-19 20-29 30-39 40-49 50-59 60+

Age in years

Percent MRSA

Colonized

2001-02 2003-04

Overall MRSA Prevalence:2001-02: 0.8%2003-04: 1.5%

*Preliminary ResultsCourtesy: Dr Rachel Gorwitz, CDC

Possible Virulence Factors• Panton-Valentine Leukocidin toxin (PVL)

– Associated with necrotizing pneumonia, skin disease, ↑d complications in S. aureus osteomyelitis

– Strongly linked to “community” MRSA strains– Also in some MSSA strains– Recent studies both support and refute role in virulence

• Arginine catabolic mobile element (ACME)– Likely acquired from S. epidermidis– Encodes arginine deaminase pathway– Inhibits PMN function, enhances survival at low pH– USA300-0114 and related strains, some USA100

Learning Objectives

• Understand the emergence and origin of methicillin-resistant S. aureus (MRSA) strains causing infections in healthy children

• Recognize the clinical presentations of community staphylococcal infections

• Learn how to work with your local laboratory to understand local antibiotic susceptibility patterns

• Develop an approach to the management of suspected staphylococcal infections in children in the face of high rates of community MRSA

Community Associated MRSA (CA-MRSA): Predominance of Skin and Soft Tissue

Infections

• 48/53 (91%) of CA-MRSA (Fergie, PIDJ2001)

• 2542/2659 (96%) CA-MRSA (Kaplan, PIDJ 2005)

Gorwitz RJ, et al CDC Strategies forclinical management of MRSA in the community: Summary of an experts’ meetingconvened by the CDC 2006. Available athttp://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca.html.

Brown Recluse Spider: Be Skeptical!

http://spiders.ucr.edu/images/colorloxmap.gif By permission of Dr Rick Vetter

54%

51%

60%60%

67%

74%

39%

15%

55%

68%

72%

MRSA Was the Most Commonly Identified Cause of Purulent SSTIs Among Adult ED Patients

(EMERGEncy ID Net), August 2004

Moran et al NEJM 2006Courtesy: Dr Rachel Gorwitz, CDC

97% MRSA -> USA 300

Pediatric SSTI: Dominance and Seasonal Pattern of MRSA

(Baltimore, Nov 2003-Oct 2005)

• 76-77% MRSA overall; 87% CA-MRSA• Rates especially high during both SUMMER periods

– Quarter 3 = July/August/September

0

20

40

60

80

100

120

140

1 2 3 4

Quarter

Num

ber

of Is

olat

es

MSSA

MRSA 35%

65%

25%

24%

76% 27%

73% 75%

*

Seasonality Trends of Culture-Proven MSSA and MRSA Infections Over the Study Period by Quarter

Adapted from: SZCZESIUL PIDJ 2007

Learning Objectives

• Understand the emergence and origin of methicillin-resistant S. aureus (MRSA) strains causing infections in healthy children

• Recognize the clinical presentations of community staphylococcal infections

• Learn how to work with your local laboratory to understand local antibiotic susceptibility patterns

• Develop an approach to the management of suspected staphylococcal infections in children in the face of high rates of community MRSA

Reproduced with permission. Fridkin et al. NEJM April 2005

Greater Susceptibility to Other Antibiotics but Varies by Region

Antibiotic Susceptibility (%) of Isolates from Pediatric Staphylococcal SSTIs

• Highest levels of susceptibility to TMP-SMX and to Clindamycin for CA-MRSA and for ALL S. aureus

• Variations in susceptibility by region and over time

• Ask local laboratory/experts for trends in your area

Adapted from. SZCZESIUL PIDJ 2007

MRSA (n = 217)

Antibiotic

HA (n = 28) CA (n = 189) All MRSA

Erythromycin 11 6 7

Clindamycin 93 97 96

TMP-SMX 100 100 100

Gatifloxacin 4 10 9

Tetracycline 82 83 83

Interpreting Clindamycin Susceptiblity

• Initial susceptiblity report….– Erythro-R & Clinda-R Resistant to clindamycin– Erythro-S & Clinda-S Susceptible to clindamycin– Erythro-R but Clinda-S Need D test to confirm clinda resistance

• D test– NEGATIVE = Clindamycin susceptible (efflux mechanism of

erythro resistance)– POSITIVE = Inducible clindamycin resistance (iMLSB)

• Inducible clindamycin resistance– Avoid clindamycin for serious infections if iMLS present– Clindamycin treatment: Inducible strain-> selection of mutant with

consitutive production -> treatment failure– Occurs without macrolide exposure in patient– Less certain relevance in less serious infections– Frequency varies by region and over time

On LEFT plate, blunting of zone of inhibition around clindamyin (C) disk on side adjacent to erythromycin (E) disk is a positive D-test, indicating presence of iMLS. On RIGHT plate, there is circular zone of inhibition around clindamycin disk, a negative D-test that indicates the absence of iMLS and confirms clindamycin susceptibility.

EErythrodisk

CClindadisk

POSITIVE D TEST NEGATIVE D TEST

Blunted “D”No blunting

Reproduced with permission. Siberry ASCP Tech Sample Microbiology No. MB-3, pp. 19-23

D Test for Inducible Clindamycin Resistance

Learning Objectives

• Understand the emergence and origin of methicillin-resistant S. aureus (MRSA) strains causing infections in healthy children

• Recognize the clinical presentations of community staphylococcal infections

• Learn how to work with your local laboratory to understand local antibiotic susceptibility patterns

• Develop an approach to the management of suspected staphylococcal infections in children in the face of high rates of community MRSA

Management Principles: SSTI where CA-MRSA Prevalent

• Drain purulent collections– Fitch MT, Manthey DE, McGinnis HD, Nicks BA,

Pariyadath M. Abscess Incision and Drainage. NEJM 2007; 357:e20 [Videos in Clinical Medicine]

• Send specimens for culture [change from previous practice!]

• Assessment of severity of illness– Outpatient management if non-severe illness and

reliable follow up

• Empiric antibiotics – Know local trends in antibiotic resistance

• 50 adults with cutaneous abscesses

• Random assigmnent to cephadrine vs placebo

• Incision & Drainage for all

• 7 day follow-up:– Ceph: 26/27 improved– Placebo: 22/23 improved

• No cultures; Pre C-MRSA

Drainage of Skin Abscesses is Essential

Llera et al. Ann Emerg Med 1985;14:15-19

Good Outcome Despite Use of “Ineffective” Antibiotic Pediatric CAMRSA SSTI

• Children with CA-MRSA skin abscesses• 96% I&D• 62 (93%)- “ineffective antibiotic”• 94% improved at follow-up (1-6d)

– Most NOT changed to effective antibiotic

• Risk factors for hospitalizaont at 1st f/u– Larger Size (>5cm) – NOT ineffective antibiotic

Lee MC et all PIDJ 2004; 23(2):123.

Antibiotics May Improve Outcome in a Minority of MRSA SSTI Patients – But Which Ones?

• Observational study: adults with CA-MRSA SSTI• Rates of Treatment failure….

– 16 (5%) of 312 episodes with active Abx– 29 (13%) of 219 episodes with inactive ABx (p=.001)

• Small reduction in treatment failure rate if “active antimicrobial therapy” prescribed at the time of initial I&D or wound culture

• Independent predictor of treatment failure in MV analysis– Use of inactive Abx – NOT size of the lesion

• Importance of antibiotics for most patients remains unclear Ruhe CID 2007

Specimens for Cellulitis

• Especially if associated with severe illness or non-response to empiric therapy

• Better yield from point of maximal inflammation 21 children (3mos-16 yrs old) with cellulitis– PMI positive in 57%: 29% SA, 10% GABHS– Leading edge positive 5%: only CoNS

• Method– Aspirate using 20-gauge needle (22-gauge for face)

on tuberculin syringe with 0.2ml of non-bacteriostatic saline

– Saline used to flush sample onto plate

Howe PIDJ 1987;6(7):685

Initial Management of Suspected S. aureus Skin/Soft Tissue Infections

Repro-duced with permis-sion. Baker AAP News 2008

I & DOral antibiotic Rx

TMP/SXT† Clindamycin§ Doxycycline (if >7 years)

Follow-up at 48h

HospitalizeI & D (when indicated)Empirical vancomycin or clindamycin§ until culture results known

HospitalizeI & D (when indicated)Empirical vancomycin PLUS nafcillin other agents

Initial Management of Suspected S. aureus Skin/Soft Tissue Infections

Reproduced with permission. Baker AAP News 2008

Manage as for Severe Infection

Initial Management of Suspected S. aureus Skin/Soft Tissue Infections

Reproduced with permission. Baker AAP News 2008

I & DOral antibiotic Rx

TMP/SXT† Clindamycin§ Doxycycline (if >7 years)

Follow-up at 48h

* Immunocompromise: any chronic illness except asthma or eczema† TMP/SXT = trimethoprim/sulfamethoxazole if group A Streptococcus unlikely§ Consider prevalence of clindamycin susceptible and “D” test negative CA-MRSA strains in the community

Initial Management of Suspected S. aureus Skin/Soft Tissue Infections

• Evaluation and treatment for other pathogens and processes

• Consultation with an expert in management of CA MRSA infections

HospitalizeI & D (when indicated)Empirical vancomycin or clindamycin§ until culture results known

HospitalizeI & D (when indicated)Empirical vancomycin PLUS nafcillin other agents

Repro-duced with permis-sion. Baker AAP News 2008

Athletics Associated MRSA Infections

• Recommendations for infection control– Avoid body shaving– Reduce turf burns– Exclude until MRSA infection healed– Cover open wounds– Change water and disinfect whirlpool between

uses

Begier EM et al CID 2004;39:1446-53.

Recurrent Infections• MRSA Skin/Abscess study – Dallas*

– 12% with prior cutaneous abscess– 4.3% recurrent abscess within 2-6 months

• “Ping-pong” of infections in household• Poor predictors of who will get recurrent infections• Mixed data about role of (nasal) colonization• Consider trial of decolonization

– If anterior nares culture positive – 5 days intranasal mupirocin BID +/- chlorhexidine– Efficacy not proven!

*Lee MC et all PIDJ 2004; 23(2):123.

Concern for Immunodeficiency

• Recurrent, severe infections, especially if due to different S. aureus strains

• Principal defenses against S. aureus– Skin and mucosal surfaces– Phagocytes

• If evaluating, focus on abnormal number or function of phagocytes:– Neutropenia, CGD, Job (Hyper IgE), LAD

Invasive Infections

CA-MRSA: SSTI Typical…but Invasive Disease Alarming

• Sepsis/invasive disease less common– increasing?– 2003-4: 3/21 pediatric influenza deaths assoc with MRSA– 2006-07: 15/72 pediatric influenza deaths associated

with MRSA [CDC Health advisory 268, Jan 2008 ]

– 2 children with MRSA sepsis and Waterhouse-Friedrichson syndrome [Adem NEJM 2005]

– 62% of invasive SA due to CA MRSA [Gonzalez CID 2005] • 67% had pulmonary disease• 43% with osteomyelitis + pneumonia (emboli)

– Adolescents with CA MRSA sepsis [Gonzalez Ped 2005]

• bone/joint, pulmonary, thrombosis

Approach to Management

• “Amid a sea of boils, an invasive disease case will leap out and bite you!”

• Invasive illness– Usually systemically ill at presentation– Does not usually progress from a boil– Blood cultures often positive– **MRSA common in your community->

increase suspicion of MRSA in serious illness

Incidence of Invasive CA-MRSAVaries by Age and Race*

Active Bacterial Core Surveillance (ABCS), 2005

0

5

10

15

20

25

<1 1 2-4 5-17 18-34 35-49 50-64 >64

Age in years

White BlackRate per 100,000 persons

*Preliminary Results (Courtesy of Monina Klevens and Melissa Morrison)

Overall Incidence:4.6 per 100,000

Courtesy: Dr Rachel Gorwitz, CDC

Distribution of CA-MRSA Cases by Syndrome, ABCs 2005

Disease Syndrome (%)

Bacteremia 529 (65%)Pneumonia 115 (14%)Cellulitis 189 (23%)Osteomyelitis 64 (8%)Endocarditis 106 (13%)Septic shock 40 (5%)Total 813 (100%)

Bacteremia with TRIAD: Lung lesions + Osteomyelitis + Thrombosis

Adapted from Dr Rachel Gorwitz, CDC

Treatment of Suspected Invasive S. Aureus Infections

• Hospitalize – consider ID consult• Empiric

– Vancomycin (or Linezolid)*– Add gentamicin or rifampin, if severe illness– Add oxacillin if endocarditis suspected– Alternative for less serious illness: clindamycin (if

clinda-S MRSA prevalent) or oxacillin (if MRSA not common in the community)

• Culture-proven MRSA– Endocarditis: Vanco + [gent or rifampin] + ID consult– Skin, Bone, Other tissue focus

• Susceptibility report• Vancomycin, Linezolid, Clindamycin (Dtest negative)• Other options: TMP/SMX, Doxycycline (>8 yr old)

*(Dapto, Tigecycline- adults); ceftobiprole under study

HOSPITAL SETTING

COMMUNITY SETTING

Hospital Transmission of CA-MRSA

• 8 MRSA skin/soft tissue infections in postpartum women without risk factors– Delivered August 2002 (NYC)– Mean 23 days (4-73 days)– 4 mastitis/abscess, 1 each: wound, cellulitis,

pustulosis, pustulosis/UTI– 3 readmitted

• Infants not affected or colonized• Identical MRSA with CA characteristics

– PFGE idential; PVL, scc type IV

Saiman CID 2003;37:1313

Role of CA-MRSA in Bacteremia• 116 consecutive MRSA BSI isolates from

Grady Hospital over 7.5 months in 2004– 39/116 (34%) were due to the USA300

genotype– 10/49 (20%) of the nosocomial isolates were

USA300– 30/107 (28%) of the healthcare-associated

isolates were USA300

• “CA” MRSA has become a healthcare-associated pathogen

Naimi et al. JAMA. 2003;290(22):2976-84Seybold et al. Clin Infect Dis. 2006;42:647-56

Vignette

• 2 year old with painful red swelling on thigh, T 102, otherwise well. August.

• Started as a “spider bite” (Baltimore)• Exam reveals fluctuant lesion, that yields

copious pus with lancing, leaving a “crater”• Mother and 6 year old brother have had similar

skin infections in past 2 months• Treated with cephalexin• Culture grows MRSA• 2 day follow-up: no fever; no drainage; lesion

healing

Thank You

Questions?