ORSA Soft Tissue Infections Michelle Floris-Moore, MD, MS M. Andrew Greganti, MD

Disclosure of Financial Relationships Please note that I have had no financial relationships with commercial interests related to this educational activity within the past 12 months .

Community-Acquired ORSA Definition Diagnosis of ORSA made in outpatient setting or culture positive within 48 hours of hospitalization. AND No history within past 1 year of any of the following: Hospitalization or residence in long-term care facility; Surgery or dialysis; Indwelling catheter or percutaneous medical device.

Comparing CA-ORSA to HA-ORSA Epidemiology Clusters and outbreaks in closed populations Healthcare-associated outbreaks Underlying condition Often otherwise healthy Risk factors for HA infections. Usually underlying comorbidity. Age group Younger Older Resistance pattern Susceptible to multiple antibiotics Resistant to multiple antibiotics Genotype SCCmec IV SCCmec I, II, or III Virulence PVL present PVL absent Diederen BMW, et al. JID 2006;52:157-168

Mechanism of Resistance Acquisition of genes that code for altered penicillin- binding proteins - PBP 2A. PBP2A has low affinity for β-lactams; is resistant to oxacillin and all other β-lactams. PBP2A encoded for by mecA gene. mec A carried by a mobile genomic element, SCCmec. SCC = staphylococcal cassette chromosome

Mechanisms of Resistance CA-ORSA and HA-ORSA have different SCCmec SCCmec I, II, and III are found in HA-ORSA clones SCCmec IV found in CA-ORSA Does not carry multiple antibiotic resistance genes Associated with other elements including PVL and other exotoxin genes 2 major CA-ORSA clones in the US: USA 300 (outbreaks in correctional facilities, athletes) USA 400 (severe disease in kids, Native Americans)

Panton-Valentine Leukocidin Virulence factor reported in 1932 by Panton and Valentine. Damages cell membranes, lyses WBCs. Encoded by a mobile genetic element . Highly prevalent in CA-ORSA but rarely found in HA-ORSA. Associated with: Furunculosis Severe, rapidly progressing SSTIs. Necrotizing PNA

Factors predisposing to S. aureus infection Defects in chemotaxis - Job syndrome; Chediak-Higashi syndrome; Down syndrome; - Decompensated DM; Rheumatoid arthritis. Staphylocidal defects of PMNs Chronic Granulomatous Disease; AML; CML; Lymphoblastic leukemia.

Risk Factors for CA-ORSA SKIN CONTACT Crowded facilities: Shelters Prisons Sex partners SHARING PERSONAL ITEMS COMPROMISED SKIN INTEGRITY Sports teams Atopic dermatitis Psoriasis IDU; Tattoos Military recruits Household contacts

Other High Risk Groups People with HIV infection 1,2 Men who have sex with men 2,3 Native Americans living in rural areas 4 Pacific-Islanders 5 1. Crum-Cianflone N et al, AIDS Patient Care STDS 2009;23:499-502. 2. Lee NE et al , Clin Infect Dis 2005; 40:1529-34. 3. Centers for Disease Control & Prevention, MMWR 2003; 52:88. 4. Centers for Disease Control & Prevention, MMWR 2004; 53:767-770.

CA-ORSA Prevalence Exact prevalence of CA-ORSA in North Carolina is unknown: Individual cases not reportable. Estimates suggest 60% - 80% of community acquired - S. aureus infections in U.S. caused by ORSA. 1,2 Studies in children in NC show that 75% - 85% of community acquired-S. aureus isolates were ORSA. 3,4 Lab data at UNC suggest that about 50% of ORSA isolates from the inpatient units are CA-ORSA. 1.Daum RS. N Engl J Med 2007;357:380-390. 2. King MD et al, Ann Intern Med 2006;144:309-317. 3.Magilner D et al, NC Med J 2008;69:351-54. 4. Shapiro A, et al. NC Med J 2009;70:102-7.

Clinical Presentation of ORSA Skin and soft tissue infections Impetigo, cellulitis Folliculitis, furuncles, abscesses Invasive soft tissue infections – necrotizing fasciitis, pyomositis “Spider bite” → Always suspect S. aureus Osteomyelitis, Septic arthritis, Septic bursitis Necrotizing pneumonia (isolated or post-influenza) Bactermia Endocarditis

Necrotizing Fasciitis Bullae often present, crepitus may be absent Pain out of proportion to exam May progress very rapidly, however may also have evolved over course of a few days Requires emergent surgical debridement and drainage Initial antibiotics should provide broad spectrum coverage Include optimal agents against ORSA (Vanco) and Strep (a PCN) as well as Gram negatives and anaerobes.

Incision & Drainage Obtain specimen for culture whenever possible. I & D is part of primary therapy for furuncles/abscesses. If not amenable to I&D can perform aspiration Small furuncles – can apply moist heat Limited data 1,2 suggest that I & D may be adequate therapy for otherwise healthy patients with mild, limited (< 5cm diameter) SSTI in a site amenable to complete drainage if: no evidence of rapid progression no signs of systemic infection no other co-morbidities Lee MC, Pediatr Infect Dis J. 2004;23:123-7. Young DM, Arch Surg 2004;139:947-51.

Outpatient vs. Inpatient Treatment Unstable co-morbidity (e.g. decompensated DM) Unstable clinical status Toxic-appearing Rapidly progressive infection Limb-threatening infection (e.g. necrotizing fasciitis) Sepsis syndrome

Skin & Soft Tissue Infections Spectrum of ORSA Skin & Soft Tissue Infections

Options for Oral Antibiotic Therapy Trimethoprim-Sulfamethoxazole (TMP-SMX) Clindamycin Doxycycline (+ Rifampin, if not contraindicated) Minocycline (+ Rifampin, if not contraindicated) Linezolid should not be used routinely possibility of inducible resistance risk of bone marrow suppression high cost

TMP-SMX and Rx of CA-ORSA No randomized trials of TMP-SMX for CA-ORSA. Trial of IV TMP-SMX vs. Vanco for S. aureus infection (ORSA and OSSA) → Vanco superior overall but no treatment failures among ORSA infections in TMP-SMX group.1 Most clinicians consider TMP-SMX as first-line oral therapy for CA-ORSA. Dosage (normal renal function): 2 DS tabs BID Use of lower dose associated with higher treatment failure rate. Markowitz –Randomized but non-blinded trial. 47% of infxns were ORSA, 65% had bacteremia. 1. Markowitz et al, Ann Intern Med 1992;117:390-398

Clindamycin and Rx of CA-ORSA Widely used in treatment of SSTI. Can treat both S. aureus and Streptococci. No randomized trials for treatment of CA-ORSA. Possibility of inducible resistance to clindamycin if lab results show organism sensitive to clindamycin but resistant to erythromycin: If resistance due to inducible expression of erm gene then single step mutation → methylation of binding site for macrolides, clinda, and streptogramin → resistance to all (MLSB resistance). If erythromycin resistance due to efflux pump, organism remains sensitive to clindamycin. UNC Micro lab routinely does D-test for clindamycin susceptibility on Staph aureus isolates . If using other labs need to specifically request. 80% of USA300 clone isolates are resistant to erythro Erm gene = erythromycin methylase MSLB = macrolides, lincosamides and group B streptogramins D-test: Double disk diffusion test. Clinda and Erythro disks placed side by side on agar plate with S. aureus isolate. Creates a “D” shape when inducible clindamycin resistance present.

D-zone Test for Inducible Clindamycin Resistance Arrow - Blunting of the clindamycin zone of inhibition suggests the presence of an erm gene in the test isolate that is inducible by erythromycin Daum et al, NEJM 2007;357(40):380

Options for IV Therapy Vancomycin Linezolid Daptomycin – should not use to treat pneumonia. Inactivated by surfactant. Tigecycline

Monitoring While on Therapy Vancomycin: Renal function and vanco serum levels at least 1x per week (more frequent if unstable renal function) Aim to maintain adequate trough level (>10mg/ml, may be higher for complicated infections) while avoiding toxicity. * Daptomycin: CPK 1x per week; stop if CPK >5x ULN (symptomatic) or >10x ULN (asymptomatic). Linezolid: CBC & platelets 1x / week; stop if platelets <50,000/mm3 or ↓ in WBC or RBC. Goal is to achieve vanco serum levels that assure AUC/MIC ratio >400 (best predictive pharmacodynamic factor for efficacy) * Rybak MJ et al. Vancomycin Therapeutic Guidelines. CID 2009;49:325-327.

CAUTION Quinolones NOT RECOMMENDED for treatment of ORSA. Macrolides NOT RECOMMENDED for treatment of ORSA. Daptomycin NOT RECOMMENDED for pneumonia treatment. Rifampin should NOT be used as monotherapy (resistance develops rapidly). need to evaluate carefully for drug-drug interactions and other contra-indications to use of rifampin.

Consequences of Inadequate Treatment of Staph Aureus Infections Persistent infection at initial site. Contiguous spread. Bacteremia Endocarditis Metastatic infection e.g. Osteomyelitis (vertebral, pubic symphisis)

What about Strep? Difficult to distinguish strep from staph cellulitis based solely on clinical exam. Folliculitis most often caused by Staph. Abrupt onset of large abscess often seen with CA- ORSA (PVL+). Regional lymphadenopathy favors Strep. Both may cause necrotizing fasciitis.

What about Strep? TMP-SMX and Tetracyclines NOT RECOMMENDED for treatment of Strep. Clindamycin and β-lactams offer superior coverage for Strep. May need to use combination therapy if concerned about possibility of both ORSA and Strep infection.

Algorithm available online - http://www. unc. edu/depts/spice/CA-ORSA

Decolonization – Does it help? 15-35% of normal hosts carry S. aureus in the nares or pharynx. Nasal carriage is a risk factor for infection.1 Intranasal muciporin eliminates colonization but recolonization occurs frequently.2 No data to support efficacy of decolonization agents for patients with ORSA . Reasonable to try decolonization When individual has multiple recurrent ORSA infections. There is ongoing ORSA transmission within well-defined group. 1. Tacconelli E, et al. Clin Inf Dis 2003; 37:1629-1638. 2. Huang J, et al. Pediatrics 2009;123:e808-814.

Agents Used for Decolonization Mupirocin ointment applied intranasally BID for 10 days. Mupirocin ointment under fingernails BID Chlorhexidine 4% solution used to wash the body once daily for 10 days. Chlorhexidine-based oral spray 3-4X day.

“THE HANDS GIVE IT AWAY” A: Culture of a health care worker’s ungloved hand taken after performing an abdominal exam on a patient who had ORSA on surveillance cultures. B: Culture taken after hand cleaned with alcohol foam. Donskey CJ, Eckstein BS. NEJM 2009;360:e3

Isolation Precautions for ORSA Contact isolation Private room Gown Gloves Hand hygiene before and after patient contact Before leaving patient’s room: Remove gown → Remove gloves → Wash hands. Dedicated equipment (e.g. stethoscope)

Reporting Requirements for CA-ORSA In NC required to report outbreaks but not individual cases. Outbreak = Two or more cases linked in time or space. If at UNC Hospitals, report to Infection Control 966-1636. On-call pager 216-6652 available 24/7. If outside UNC, report to County Dept. of Health.

Today’s Case Has Diabetes Mellitus Close contact with recent ORSA cellulitis. Is a nurse with frequent patient contact Has h/o cervical fusion – increases risk for complications if infection not eradicated Treated initially with TMP-SMX DS 1 tab PO BID Clinical worsening on initial therapy I & D done at 2nd presentation. Clindamycin added but poorly tolerated.