MRSA Update 2013 David K. Hong, MD Pediatrics/Infectious Diseases & Immunology/Allergy Santa Clara Valley Medical Center Stanford University Medical School

Objectives 1. Review the increase in community-associated MRSA infections in the last decade 2. Describe the unique infectious complications in neonates 3. Discuss strategies for effective treatment and prevention of MRSA infections

10 day old ex36wk male presents to urgent care clinic with this rash Late-preterm, previously healthy male neonate with CA S aureus localized groin pustulosis. Fortunov R M et al. Pediatrics 2007;120:937-945

What is MRSA?

Staphylococcus aureus Staphyle – “grape”; aureus – “gold” Coagulase positive

Staphylococcus aureus Staphyle – “grape”; aureus – “gold” Coagulase positive Coagulase-negative staph are usually non-pathogenic

Staphylococcus aureus Staphyle – “grape”; aureus – “gold” Coagulase positive Coagulase-negative staph are usually non-pathogenic Catalase positive Turns H2O2 into H20 and O2

Some definitions MRSA – methicillin-resistant S. aureus HA-MRSA – healthcare associated MRSA - MRSA infection occurring within 12 months of hospitalization - Nosocomial infection - Usually has multidrug resistance CA-MRSA – community associated MRSA - MRSA infection in the absence of healthcare exposure - Associated with skin and soft-tissue infections (SSTI)

More definitions SCCmec - Staphylococcal Cassette Chromosome mec or SCCmec (I-V) is a resistance island or cassette in the chromosome that encodes for methicillin resistance Mec gene - Methicillin resistance: mec gene encodes for production of penicillin binding protein 2A (PBP2A) USA300 - Dominant CA-MRSA strain in U.S. causing increase in SSTI PVL – Panton Valentine Leukocidin

Panton Valentine Leukocidin Cytotoxin that causes white cell destruction and tissue necrosis Commonly present in SCCmec type IV and V (CA-MRSA strains) Can be also present in MSSA strains Associated with skin and soft tissue infections and necrotizing pneumonia S. aureus has many other virulence factors that may modulate infection

Committee on Infectious Diseases et al. Red Book Online 653-668

Evolution of Resistance Drug Year Introduced Time to R 25%R Hospitals 25% R Comm. Penicillin 1941 1-2 yrs 6 yrs 15-20 yrs Methicillin 1961 1 yr 25-30 40-50 Vanco 1956 40 yr ? Chambers, HF EID 2001

Resistance Penicillin resistance: Gene for penicillin resistance is carried on a plasmid Encodes for a penicillinase About 80-90% of S. aureus isolates are R to penicillin

The -lactam ring R= Penicillin G (benzylpenicillin) Beta-lactamase cuts the ring here R= Penicillin G (benzylpenicillin)

R Staph -lactamase X Cephalosporin + Clavulanate Amoxicillin

MRSA Methicillin-resistance is NOT due to a super-powerful -lactamase mecA gene - PBP2a - altered penicillin-binding protein that has low affinity to -lactams

MRSA Resistance Peptidoglycan cell wall x Beta lactam abx PBP2A PBP

MLS Resistance Mechanisms in S. aureus Macrolides (e.g., erythromycin) Lincosamides (e.g., clindamycin) Streptogramin B Protein synthesis erm msrA Ribosome Efflux pump Methylase All MLS antibiotics bind basically the same target site on the ribosome in the bacterial cell. This inhibits protein synthesis. Resistance in staph in encoded by two major mechanisms: erm (erythromycin resistance/ribosome mechanism) gene: this gene encodes a methylase that affects the target binding site on the ribosome. Methylase is an enzyme that adds a methyl group to the ribosome which methylates the binding site and blocks the binding of all MLS antibiotics. msrA (methionine sulfoxide reductase) gene: this gene encodes an efflux pump which pumps macrolides (only) out the the bacterial cell before they can bind to the ribosome target site. Bacteria will still be susceptible to lincosamides (clindamycin) and streptogramin B (synercid is a comination of streptogramin A and B) Macrolides Lincosamides Streptogramin B Macrolides

A note about Clindamycin Resistance Testing

All politics is local… microbiology About 20 – 40% of S. aureus is MRSA in our area About 50 – 87% of MRSA is clindamycin sensitive

Rates of all Staphylococcus aureus infections, of methicillin-resistant S. aureus (MRSA) infections, and of methicillin-susceptible S. aureus (MSSA) infections in 33 US children's hospitals from 2002 to 2007. Rates of all Staphylococcus aureus infections, of methicillin-resistant S. aureus (MRSA) infections, and of methicillin-susceptible S. aureus (MSSA) infections in 33 US children's hospitals from 2002 to 2007. Gerber J S et al. Clin Infect Dis. 2009;49:65-71 © 2009 by the Infectious Diseases Society of America

Staphylococcus aureus and MRSA bacteremia/meningitis in NICUs Shane AL et al, Pediatrics. 2012 Apr;129(4):e914-22

Clone USA300 is remarkably similar from different patients Kennedy AD et al, PNAS 2008 Jan 29;105(4):1327-32

No difference in mortality between MSSA and MRSA Pathogenicity based on virulence factors not necessarily antibiotic resistance patterns Shane AL et al, Pediatrics. 2012 Apr;129(4):e914-22

MRSA Colonization 1/3 of people have S. aureus in their nose ~2% carry MRSA

Risk factors for Colonization and Infection Very young children or the elderly Athletes Lower SE Pet owners and veterinarians Prisoners Nail biters Health care exposure Health care workers Race

Impact of methicillin-resistant Staphylococcus aureus (MRSA) colonization on risk of subsequent infection in critically ill children. Impact of methicillin-resistant Staphylococcus aureus (MRSA) colonization on risk of subsequent infection in critically ill children. The risk of developing a subsequent MRSA infection was compared for children with and without MRSA colonization at time of admission to the pediatric intensive care unit. Patients were monitored for an infection during their hospitalization and after hospital discharge. Milstone A M et al. Clin Infect Dis. 2011;53:853-859 © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

California state law SB 1058 - passed in 2008 - requires MRSA screening (nasal swab) for following patients ICU admissions – including NICUs Inpatient hemodialysis patients patients discharged from general acute care hospital within 30 ays of admission to SHC Transfers from a skilled nursing facility (SNF)

Overlap of nares, oropharynx, and inguinal colonization among the 542 Staphylococcus aureus–colonized subjects from our total population of 1162 persons of households of persons with a recent S. aureus skin infection. Overlap of nares, oropharynx, and inguinal colonization among the 542 Staphylococcus aureus–colonized subjects from our total population of 1162 persons of households of persons with a recent S. aureus skin infection. Each circle size is proportional to the amount of S. aureus detected at that given anatomic site. Of note, nares-only surveys would have missed 48% of S. aureus–colonized persons. Miller L G et al. Clin Infect Dis. 2012;cid.cis213 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Infants with MRSA infection commonly have mothers colonized with MRSA MRSA colonization in neonates 25/35 (71%) case 4/19 (21%) control Fortunov Pediatr Infect Dis J. 2011 Jan;30(1):74-6.

Infants with MRSA infection commonly have mothers colonized with MRSA MRSA colonization in moms 12/35 (34%) case 1/19 (5%) control Fortunov Pediatr Infect Dis J. 2011 Jan;30(1):74-6.

Infants with MRSA infection commonly have mothers colonized with MRSA 8/34 (24%) identical maternal nasal and neonatal clinical isolate Fortunov Pediatr Infect Dis J. 2011 Jan;30(1):74-6.

Infants with MRSA infection commonly have mothers colonized with MRSA 21/34 (62%) identical neonatal nasal and neonatal clinical isolate Fortunov Pediatr Infect Dis J. 2011 Jan;30(1):74-6.

Infants with MRSA infection commonly have mothers colonized with MRSA 6/25 (17%) identical maternal nasal, neonatal nasal, and neonatal clinical isolate Fortunov Pediatr Infect Dis J. 2011 Jan;30(1):74-6.

Late-preterm, previously healthy male neonate with CA S aureus localized groin pustulosis. 2001-2006 at Texas Children’s Term and late-preterm <30 days 43 pustulosis – none had invasive disease 68 cellulitis/abscess – 3 had bacteremia or CSF pleocytosis 15 invasive infections Late-preterm, previously healthy male neonate with CA S aureus localized groin pustulosis. Fortunov R M et al. Pediatrics 2007;120:937-945 ©2007 by American Academy of Pediatrics

Treatment of MRSA in Neonates IV Vancomycin Clindamycin or linezolid if a non-endovascular infection For mild cases with localized disease: Topical treatment with mupirocin may be adequate in full term neonates and young infants.

What about Vancomycin? Don’t use it for MSSA infections – it does NOT work as well as beta lactam antibiotics. Change to appropriate therapy as soon as susceptibility data is available

Do not use Vancomycin for Methicillin-sensitive S. aureus (MSSA) Chang FY etl al, Medicine (Baltimore). 2003 Sep;82(5):333-9

Decolonization Nasal decolonization with mupirocin BID for 5-10 days Topical body decolonization with either chlorhexidine for 5-14 days or bleach baths (1/4 cup per ¼ tub). Bleach baths are given for 15 minutes semi-weekly for 3 months

Decolonization Systemic antibiotics are recommended for treatment of active infection only Only in select circumstances is an oral antibiotic plus rifampin recommended for decolonization (CIII) If household transmission is suspected, personal and environmental measures are recommended for contacts.

Decolonization Systemic antibiotics are recommended for treatment of active infection only Only in select circumstances is an oral antibiotic plus rifampin recommended for decolonization (CIII) If household transmission is suspected, personal and environmental measures are recommended for contacts.

Decolonization Shown to be effective in the short-term in reducing nasal carriage of MRSA Re-colonization is common Rates of SSTI are still high even when decolonized Fritz SA et al, Infect Control Hosp Epidemiol. 2011 Sep;32(9):872-80

Decolonization regimens used in NICUs – unclear benefit Milstone AM et al, Infection Control and Hospital Epidemiology , Vol. 31, No. 7 (July 2010), pp. 766-768

Prevention - Hand washing works! Pittet D et al, Lancet. 2000 Oct 14;356(9238):1307-12

Summary MRSA colonization and infection has been on the rise in the community even without exposure to healthcare facilities Both methicillin-resistant and –sensitive S. aureus can cause similar disease due to the sharing of virulence factors Patients colonized with S. aureus are more likely to have S. aureus infections Decolonization can work in the short term but the long-term effects are unknown