1. Describe the strains of methicillin-resistant Staphylococcus aureus (MRSA) associated with the community- associated form of the infection and describe the 5 common risk factors for infection.

2. Summarize the genetic mechanisms that allow S aureus to colonize human skin and resist treatment with methicillin.

3. Estimate the prevalence of MRSA infections and apply appropriate measures for treatment and limiting transmission.

4. Treat complex wound infections with topical agents against bacteria, fungi, and biofilms.

5. Evaluate the role of emerging treatments for wound infections, such as bactericidal gene delivery through conjugation technology.

The New MRSA: Biology, Epidemiology, and Clinical Syndromes
Susan M. Kellie, MD, MPH, Associate Professor, Department of Medicine, Division of Infectious Diseases, University of New Mexico School of Medicine; Hospital Epidemiologist, University of New Mexico Health Sciences Center and RG Murphy Department of Veterans Affairs Health Care System, Albuquerque

Background: susceptibility—penicillin originally effective against Staphylococcus aureus; resistance developed as organism acquired ability to produce β-lactamase; currently 5% of S aureus isolates susceptible to penicillin; methicillin-resistant S aureus (MRSA) emerged in 1960s with change in mecA gene on chromosomal cassette that carries genes encoding resistance to various antibiotics; change in mecA alters penicillin binding protein (PBP)2a and prevents binding of S aureus to β-lactam antibiotic; community-associated strains of MRSA (CAMRSA) contain mec4 (smaller, possibly more mobile genetic element); by 2005 in Albuquerque, 50% to 60% of clinical isolates of S aureus (from unique patients) identified as MRSA; spread of MRSA—promoted by inadequate hand hygiene and contact precautions and inability to identify carriers

Community-associated and nosocomial MRSA: nosocomial infections defined as those occurring after 48 hr of hospitalization; community-associated infections defined as occurring during first 48 hr of hospitalization or in outpatient setting or emergency department; incidence of CAMRSA greatly increased since 2002; new community-associated strain (USA300) isolated from two-thirds of skin and soft tissue MRSA infections nationwide; in 1997, deaths of 4 children caused by new strains of MRSA distinct from nosocomial strains; outbreaks of epidemic furunculosis now widespread; MRSA causes most skin and soft tissue infections (SSTIs), especially purulent cellulitis; invasive infections (eg, necrotizing fasciitis, necrotizing pneumonia after influenza, and endocarditis) also occur; 70% of SSTIs caused by MRSA, mostly strain USA300

USA300: DNA fingerprint shows 3 groups (USA300, USA200, and USA100); clonal expansion of USA300 observed and reported in athletes, incarcerated individuals, men who have sex with men, military personnel, young children, families of patients, injection drug users, and homeless persons

Common risk factors: close contact, crowding, compromised skin, contaminated fomites (ie, shared personal items), lack of cleanliness; some researchers include previous antibiotic use (eg, in Great Britain, use of ciprofloxacin commonly associated with CAMRSA)

Progression: rapid progression from colonization to infection; 3% of recruits at Fort Sam Houston colonized with CAMRSA and ≈33% colonized with S aureus; those with CAMRSA had 10-fold higher risk of developing invasive skin infections

Arginine catabolic mobile element (ACME): genetic element encodes L-arginine deiminase pathway; generally, S aureus does not colonize undamaged human skin because of low pH (but, up to 60 other species may live on skin [eg, coagulase-negative staphylococci and Corynebacterium]); ACME allows S aureus to tolerate low pH and live on normal skin; study—showed short time from contact to infection; in many patients, MRSA not recovered from nasal swabs but recovered from wound or infection; transmission likely possible by contact with skin and fomites (MRSA shown to persist for weeks on surfaces and fabrics)

Pathogenesis: S aureus produces superantigens (resulting in, eg, toxic shock) and inhibits phagocytic chemotaxis; researchers postulate CAMRSA strains contain enhanced elements, including phenol-soluble modulin peptides (PSMs); transmission may occur through ACME; protein A of S aureus binds to TNF-receptor of host white blood cell (WBC), increasing proinflammatory response; Panton-Valentine leukocidin (PVL) virulence factor lyses WBCs; recruitment and destruction of WBCs likely responsible for necrotic response seen in purulent skin lesions

Epidemiology: community-associated strains becoming mixed with nosocomial strains in hospitals; hospital strains resistant to broad range of antibiotics and may form biofilms more effectively; community-associated strains cause significant disease in healthy people and often cause necrotizing invasive infections; CAMRSA still susceptible to many second-line antistaphylococcal agents (eg, vancomycin), but resistance has emerged; possibly novel biology enables skin-to-skin transmission

National Health and Nutrition Examination Survey (NHANES): found prevalence of colonization by MRSA increased in community from 0.9% in 2001-2002 to 1.5% in 2003-2004 (N=40,000), and increased from 2.2% to 3.1% among participants >60 yr of age

Study based on diagnostic codes: found ≈66% increase in SSTIs over past 10 yr (mostly abscessed cellulitis)

Emerging Infections Program (study 2007): showed MRSA responsible for more deaths than HIV; among reportable infections in Tennessee, only rates of infection by Chlamydia trachomatis and Neisseria gonorrhoeae exceed that of invasive MRSA; ≈30% of invasive infections caused by USA300; health care-associated strains (primarily USA100) caused majority of invasive infections; estimated that 86% of invasive MRSA associated with health care setting, based on very liberal definition of “health care-associated”

Agency for Healthcare Research and Quality (AHRQ): reported significant increase in MRSA, based on diagnostic codes

Common presentation: many patients erroneously refer to MRSA lesions as spider bites (increase index of suspicion for MRSA if patient mentions presence of “spider bites”; elicit history)

Integrated Soft Tissue Infection Clinic: established by University of California, San Francisco, in response to high prevalence of MRSA lesions in community; surgical faculty drain and clean MRSA lesions; hospital admits patients with systemic symptoms, lymphangitis, and comorbidities (eg, renal disease, liver failure, HIV); clinic treats most other patients

Treatment: antibiotics alone not effective, necessary to drain and culture lesion; antimicrobial therapy may not be necessary; patient education important to prevent transmission and recurrence; warm soaks effective; no role for topical antimicrobials; apply dry dressings; use oral agent if warranted and organism susceptible

Antibiotic use: highly controversial; eg, combination of trimethoprim-sulfamethoxazole (TMP-SMZ; eg, Bactrim) plus cephalexin (eg, Keflex) to cover Streptococcus A and MRSA; speaker recommends avoiding antibiotics for small (<5 cm) abscesses unless surrounded by large area of cellulitis or patient has systemic disease or compromised neutrophil function (eg, diabetes, liver disease); few studies have examined efficacy of antibacterials against CAMRSA

Advice for patients: cover wound; wash hands frequently; quickly dispose of soiled dressings; do not share personal items; clean sports equipment; recurrence common; shaving and wearing sweaty or soiled clothing increases risk; transmission during sexual contact possible; pets may act as reservoirs

Oral agents: TMP-SMZ not indicated for treating patients with SSTI (does not cover group A β-hemolytic streptococci); use only in cases of purulent cellulitis

CAMRSA pneumonia after influenza: 50% mortality reported for one group of patients with necrotizing pneumonia; causes large abscesses, large empyema, and severe pleuritic pain (sometimes misdiagnosed as pulmonary embolism [PE]) with rapid progression to empyema; many need decortication

Necrotizing fasciitis: case series showed 12 of 14 patients infected with CAMRSA (strain USA300); not all patients had risk factors; disease progressed slightly more slowly than group A streptococcal infection

Danger signs of systemic infection with MRSA: general—sepsis, fever, chills, light-headedness or dizziness; respiratory—chest pain after flu-like illness, bloody sputum; musculoskeletal—swelling, warmth, or pain; skin— red streaks around wound; note—fever and pain often masked by routine use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit immune response to S aureus

Parenteral agents: vancomycin drug of choice, but S aureus with intermediate resistance to vancomycin reported in patients undergoing dialysis; resistance emerges during therapy with daptomycin; possible role for linezolid (but resistance seen) in SSTI and lung infection, but not indicated in bacteremia; quinupristin-dalfopristin (Synercid) no longer used; tigecycline has static mechanism; ceftobiprol under development

Decolonization: no clear role in outpatient setting; improved hygiene often sufficient; few data on preoperative management of patients with MRSA; guidelines from Society for Thoracic Surgeons recommend use of mupirocin before median sternotomy; National Health Service (NHS) in Britain recommends decolonization of all carriers upon admission to hospital in order to decrease risk for transmission; chlorhexidine baths used at some institutions; speaker expects future development of guidelines for orthopedic implant surgery

MRSA control bundle: implemented by, eg, United States Department of Veterans Affairs hospitals; steps— perform active surveillance testing on all patients (culture samples taken from nose and chronic wounds); implement 100% compliance with hand hygiene and full contact precautions for colonized patients according to guidelines from Centers for Disease Control and Prevention (CDC); perform extensive environmental cleaning

Evidence base for MRSA control: critical to identify asymptomatic carriers; NHS reported decrease in bacteremia due to MRSA after implementing guidelines (11% decrease, compared to previous quarter)

Management of Multidrug-resistant Wound Infections
Richard L. Gamelli, MD, Robert J. Freeark Professor and Chair, Department of Surgery, Loyola University Stritch School of Medicine; Chief, Burn Center, and Director, Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, IL

Topical antibacterials: mafenide acetate—aqueous solution (Sulfamylon) does not cause metabolic acidosis or problems seen with cream-based formulation; manages gram-positive and gram-negative organisms when not multidrug-resistant (MDR); combinations—(eg, polymyxin and bacitracin, or triple combination with neomycin) provide excellent coverage of microbes; silver-impregnated materials—some configurations and methods of loading of silver on vehicle may enhance bactericidal action; silver released when in contact with wound fluid; show extended duration of action (sometimes >72 hr); caution advised if used on perineum (eg, in children), where soiling of wound likely

Biofilms: microbial community surrounded by polymeric matrix; develops on surfaces, including wounds; impermeable to antibiotics or antibodies; only planktonic cells susceptible; Dakin’s solution—dilute sodium hypochlorite (25%-50% concentrated solution) penetrates and helps strip away biofilm without inhibiting wound healing; especially effective against Pseudomonas and MRSA

Subatmospheric-pressure wound therapy: vacuum causes macrodeformation of large wound, controls edema, and facilitates delivery of systemic agents; appears to affect mitogenic response of cells; decreases bacterial load; increases blood flow (nutrient and oxygen delivery); promotes change in inflammatory profile of wound; reorganizes wound bed and formation of granulation tissue

Wound bed preparation: principles of bed preparation involve tissue quality, infection, moisture content, and edges (TIME)

Antifungals: may be added to treatment as isolated agent or mixed with other agents

Multimodal regimen: treat alternately with Dakin’s solution for 2 hr and antibiotics (in combination with antifungals, when appropriate) for 10 hr over 24- to 72-hr period; may follow with negative pressure wound therapy; wound closure occurs after successful preparation of wound bed

“Stealth” bacteria: in nature, plasmids containing antibiotic resistance genes transferred from resistant to sensitive organisms during conjugation; laboratory-developed plasmid inserted into attenuated Escherichia coli (“stealth bacteria”); donor E coli conjugate with pathogenic bacteria and transfers “killer gene,” resulting in destruction of pathogen; effective in vitro; animal burn models demonstrate topical treatment safe and effective

Study: Acinetobacter genetically similar to Pseudomonas aeruginosa but difficult to eradicate; resistance to different antimicrobial agents develops through several mechanisms; among septic animals colonized with MDR Acinetobacter, topical therapy with stealth bacteria improved survival; quantitative wound cultures showed control of Acinetobacter

Advantages: bacteria receptive to conjugation; effectiveness not influenced by antibiotic resistance; potential to reduce use of systemic antibiotics

Antibiotics as chemotherapy: although antibiotics have low toxicity toward host, many (eg, tetracycline) suppress immune system and can produce side effects