Disclosure 49th Annual Meeting An update on the treatment of skin and soft tissue infections I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Kathryn DeSear, PharmD, BCPS, AAHIVP OWNING CHANGE: Taking Charge of Your Profession Objectives Patient Case Describe common infections of the skin and soft tissues and recognize the clinical manifestations Provide differential diagnoses of infections involving the skin and soft tissues Compare and contrast the microbial etiologies in patients with various risk factors and presentations Discuss general principles of antimicrobial therapy in the treatment of skin and soft tissue infections Patient Case Patient Case 70F with pain in right lower leg since last night Worse with standing, walking, touch Swelling also noted Some discomfort in her LLE, but much less painful Had taken systemic steroids (unknown dose) for pain/inflammation PMH: CAD, MI, HTN, RA, Bilateral Osteoporosis Admitting Note Piperacillin/tazobactam + Vancomycin x 4 days in Hospital Discharged on Day 4 with Augmentin 1
Cellulitis Pearls Normal Skin Flora Patients with cellulitis will always have a fever or leukocytosis Cellulitis is NEVER EVER EVER EVER EVER bilateral The rubor 1, dolor 2, calor 3, tumor 4 of cellulitis does not resolve with elevation Differentiates from stasis edema Cellulitis takes longer to resolve in heavier patients Extra day for each 50 lbs overweight Cellulitis progresses for a day, stabilizes for a day, and then starts to resolve Coagulase-negative staphylococci Propionibacterium acnes Diphtheroids (Corynebacteria) α-hemolytic streptococci Bacillus spp. Staphylococcus aureus* β hemolytic streptococci* 1. Rubor = redness 2. Dolor = pain 3. Calor = warmth 4. Tumor = swelling -Mark Crislip, MD * = potential pathogen Beta-hemolytic Group A Streptococcus pyogenes Group C & G Streptococcus dysgalactiae Group B Streptococcus agalactiae Bugs and Drugs Penicillin Amoxicillin Cephalosporins Dicloxacillin Clindamycin Nafcillin Vancomycin Oxacillin Ceftaroline Daptomycin Linezolid/Tedizolid Dalbavancin/Oritavancin Bactrim Doxycycline Classes of Medications Tedizolid Beta-lactams Cephalosporins Penicillins Carbapenems Monobactams Lincosamides Oxazolidinones Lipopeptides Glycopeptides Lipoglycopeptides Glycylcyclines Tedizolid Oritavancin Dalbavancin Bacteriostatic against enterococci, staphylococci, and streptococci Requires neutrophils to work effectively ESTABLISH-1 & ESTABLISH-2 in ABSSSI 6 days of tedizolid vs. 10 days linezolid Comparable to linezolid in clinical efficacy Less thrombocytopenia with shorter duration Prokocimer P. JAMA. 2013; 309:559-69.; Moran GJ. Lancet Infect Dis 2014;14(8):696-705. 2
Tedizolid Oritavancin/Dalbavancin Tedizolid 200 mg PO once Tedizolid 200 mg IV q24h daily Volume of Distribution (L) 67 80 Protein binding (%) 70 90 Bioavailability (%) 91 N/A Half-life (h) 12 AUC (mcg hr/ml) 25.6 29.2 Time to peak (h) 3.5 1.2 Cmax (mcg/ml) 2.2 3 Tedizolid Phosphate (Sivextro) Package Insert. Cubist Pharmaceuticals. Lexington, MA. 2015. Lipoglycopeptides Lipid side chain allows the medication to anchor to cell membrane of bacteria Spectrum of Activity of Glycopeptides Bacteria Dalbavancin MIC 90 Oritavancin MIC 90 Vancomycin MIC 90 MSSA 0.06 0.12 1 MRSA 0.06 0.25 2 Group A Strep (S. pyogenes) 0.03 0.25 1 Group B Strep (S. agalactiaea) 0.12 0.12 0.5 β-haemolytic Streptococcus spp. 0.06 0.5 0.5 VanA E. faecium 32 0.25 512 VanB E. faecium 0.12 0.03 64 Clostridium spp. 2 1 1 MIC 90 = minimum concentration to inhibit 90% of isolates Zhanel GG. Drugs 2010; 70 (7): 859-86. Oritavancin/Dalbavancin Rapidly bactericidal concentration-dependent killing Pharmacokinetics of Glycopeptides Dalbavancin 1g on day 1, 500mg on day 8 Oritavancin 3 mg/kg once Vancomycin 15mg/kg Q12h Half-life (h) 147-258 393 4-8 AUC (mg h/l) 27,103 146 260 Cmax (mg/l) 312 29 20-50 Vd (L/kg) 0.11 0.65-1.92 0.3 Protein binding (%) 93-98 86-90 10-55 Oritavancin/Dalbavancin Clinical efficacy DISCOVER-1 & DISCOVER-2 Dalbavancin vs. vancomycin (with option for IV to PO linezolid) for complicated SSSI Noninferior for both endpoints of early and end of treatment success SOLO-1 & SOLO-2 Single dose of oritavancin compared to IV vancomycin x 7-10 days Noninferior for both endpoints of early and post-treatment success Zhanel GG. Drugs 2010; 70 (7): 859-86. Corey GR. NEJM 2014;370:2180-90.; Corey GR. CID 2015;60(2):254-262.; Boucher HW. NEJM 2014;370:2169-79. Cost of Care Roadmap for Success Contributing factors to cost of care: Inpatient vs. outpatient reimbursement/los Complications from therapy Cost of monitoring Drug cost $ Table 8: Hospital Acquisition Costs of Comparative IV Therapies Generic Name Cost Per Vial Typical Regimen 1 Day Cost 7 Day Cost Dalbavancin 500 mg vial: $1,490 1000 mg dose day 1, and $2,980 $4,470 500 mg day 8 Oritavancin 400 mg vial: $920 1200 mg x 1 dose $2,755 $2,760 Daptomycin 500 mg vial: $365 500 mg q24h $365 $2,560 Linezolid 600 mg vial: $130 600 mg q12h $260 $1,820 Tedizolid 200 mg vial: $235 200 mg q24h $235 $1,645 Ceftaroline 400 mg vial: $54 600 mg q12h $108 $755 600 mg vial:$54 Vancomycin 1000 mg vial (plus Advantage bag): $5 1000 mg q12h $10 $65 I&D Antimicrobial Therapy Intravenous or Oral Route Admit, Observe, or Discharge Duration of Therapy 3
Classification Additional Imaging Class Patient Criteria 1 Afebrile and healthy, other than SSTI 2 Febrile and ill appearing, but no unstable comorbidities 3 Toxic appearance, one unstable comorbidity, or limb-threatening infection 4 Sepsis syndrome or life-threatening infection Poor Response Predictors Poor Outcome in LE Wounds Advanced age Chronic liver disease Chronic renal disease Asplenia Alcohol abuse Use of abx in previous 2 weeks LJ. JAC 2003;52(S1):i3-17. Reduced arterial perfusion Neuropathy Chronic venous insufficiency Diabetes Obesity Malnutrition Immunocompromise Ultrasound Rule out DVT LJ. JAC 2003;52(S1):i3-17. X-ray Foreign bodies Gas in tissues CT Scan Drainable collections MRI Investigate bone and fascia Osteomyelitis Necrotizing fasciitis The Quick Admit Tissue necrosis Sepsis Disproportionate pain AMS Immunocompromise AIDS Cancer Liver Failure Renal Failure Specific areas of infection LJ. JAC 2003;52(S1):i3-17. Classifications of Infections Skin and Soft Tissue Infection Classification Impetigo & Ecthyma Purulent infections Cutaneous abscesses Furuncles & carbuncles Erysipelas & cellulitis Necrotizing fasciitis Pyomyositis Myonecrosis & gas gangrene Impetigo & Ecthyma Topical therapy option for impetigo if only a few lesions: mupirocin or retapamulin BID x 5 days PO Tx x 7 days targeted against isolated species If no cultures: empiric therapy must cover both MSSA & BHS Stevens DL. Clin Infect Dis 2014;59(2):e10-52. Fascia 4
Impetigo & Ecthyma Purulent Infections Nonbullous Impetigo BHS, MSSA, MRSA No scarring Starts near nose or mouth Very contagious painless Bullous Impetigo MSSA, MRSA No scarring Mainly seen in children s arms, legs, trunk painless Ecthyma BHS, MSSA, MRSA Scarring painful Painful pustules involving hair follicles and epidermis Treatment of choice: I & D If systemic signs or symptoms, treat for MRSA Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition. Philadelphia, PA: Churchill Livingstone Elsevier, 2015. Stevens DL. Clin Infect Dis 2014;59(2):e10-52. Fascia Purulent Infections Furuncle Carbuncle Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition. Philadelphia, PA: Churchill Livingstone Elsevier, 2015. Cutaneous Abscess Moderate Purulent Infections Figure 1 Executive Summary Expanded Text Diagnosis Undefined (Assume purulent infection without systemic signs of infection) Purulent infection with systemic signs of infection (implying only 1 criteria be met) Purulent infection in patients who have: 1. Failed incision and drainage plus oral antibiotics 2. Immunocompromised patients 3. Systemic signs of infection (implying only 1 SIRS criteria be met) Purulent infection with SIRS response (implying 2 or more criteria must be met) Purulent infection in patients who have : 1. Failed initial antibiotic treatment 2. Markedly impaired host defenses 3. SIRS and hypotension Treatment Just I&D, no antibiotics Moderate I&D + PO MRSA active agent Not defined I&D + IV MRSA active therapy Purulent infection in patients who have: 1. Failed initial antibiotic treatment 2. Markedly impaired host defenses 3. SIRS (hypotension not mentioned) Purulent Infections Send home without antibiotics Purulent (furuncle, carbuncle, abscess) Class 3-4 -4 Class 1 Moderate SIRS + hypotension Immunocompromised Systemic sxs Fever WBC > 12 HR > 90 bpm RR > 20 bpm No systemic sxs I&D only I&D Purulence I&D/ PO Bactrim or PO Tetracycline Yes No I&D/ IV Vancomycin Recurrent abscess: PO abx x 5-10 days ± mupirocin/chg decolonization x 5 days START 5
Discharge Home PO Bactrim PO Doxycycline PO Linezolid PO Tedizolid Erysipelas Cellulitis 23 Hour Observation Status IV Dalbavancin IV Oritavancin Fascia Non-Purulent Cellulitis Non-purulent Infections Staphylococci Erysipelas Clearly demarcated Usually on face Cellulitis Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition. Philadelphia, PA: Churchill Livingstone Elsevier, 2015. Diffuse erythema with less delineated borders Commonly found on lower extremities No skin or blood cultures indicated Except in immunosuppressed, immersion injuries, animal bites Treat x 5 days unless not resolved in this time Elevate affected area Treat predisposing factors Edema Skin disorders Examine interdigital toe space in patients with lower extremity cellulitis to prevent recurrence Indications for Hospitalization Outpatient treatment is failing* Concerns over poor adherence to therapy* ly immunocompromised SIRS Hemodynamic instability Altered mental status Concern for deeper or necrotizing infection *may be candidates for quick acting IV lipoglycopeptides in 23 hour observation unit 6
Necrotizing Fasciitis Infection spreads rapidly through fascial plane to surrounding tissues Superficial Fascia Deep Fascia Necrotizing Fasciitis Often a predisposing condition in lower extremities Most infections are community-acquired & highly fatal Common pathogens: Streptococcus pyogenes, S. aureus, Vibrio, Aeromonas, Peptostreptococcus Isolated from deep tissue specimen or exudate aspiration Can be polymicrobial Perianal abscess or other areas involving genitalia Surgical procedures involving the bowel Decubitus ulcers IVDU Necrotizing Fasciitis Differentiated from cellulitis by: pain disproportionate to clinical findings Nonresponse to antimicrobial therapy Hard wooden feel of subq tissue Systemic toxicity Edema extending beyond erythema Crepitus Bullous lesions Skin necrosis or ecchymoses Necrotizing Fasciitis Treatment Repeat surgical debridement daily Aggressive fluid replenishment Empiric antibiotic choices Piperacillin/tazobactam Ceftriaxone + metronidazole Vancomycin Fluoroquinolone + metronidazole Carbapenem Streamline once etiology known and treat until: Fever resolved x 48-72 hours Clinical improvement No further need for debridement S. pyogenes should be treated with penicillin + clindamycin Pyomyositis Pyomyositis Fascia Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition. Philadelphia, PA: Churchill Livingstone Elsevier, 2015. 7
Pyomyositis Infection (pus) in the muscle Mainly in extremity but can be found in any muscle Presents with extreme pain, muscle tenderness, fever CK remains normal if no trauma (hematogenous seeding) Diagnosis confirmed by MRI Etiologies > 90% Staphylococcus aureus (CA-MRSA) Streptococcus pyogenes Streptococcus pneumoniae Gram negative enteric bacteria Vancomycin is empiric treatment of choice Myonecrosis & Gas Gangrene Clostridial infection with rapid onset C. perfringens: trauma associated C. septicum: GI malignancy associated Increasingly severe pain Skin can be pale at first but then changes to bronze, then purple-red color Gas is detected in the tissue by palpation (crepitus) or imaging SIRSShockMulti-organ failure Myonecrosis & Gas Gangrene Rapid surgical debridement can be life-saving Broad spectrum antimicrobials initiated immediately until diagnosis confirmed Vancomycin PLUS Piperacillin/tazobactam Ampicillin/sulbactam Carbapenem Definitive therapy: Penicillin + clindamycin Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8th Edition. Philadelphia, PA: Churchill Livingstone Elsevier, 2015. Figure 1 Executive Summary Expanded Text Diagnosis Cellulitis with no focus of purulence Cellulitis without systemic signs of infection Moderate Cellulitis with systemic signs of infection Undefined 1. Failed oral antibiotic treatment Penetrating trauma, evidence Undefined of MRSA infection elsewhere, 2. Systemic signs of infection nasal colonization with MRSA, 3. Immunocompromised injection drug use, or SIRS 4. Clinical signs of deeper infection (bullae, skin sloughing, hypotension, evidence of organ dysfunction) Treatment Oral: PCN VK, cephalosporin, dicloxacillin, clindamycin Agents active against streptococci Moderate Penicillin, ceftriaxone, cefazolin, clindamycin Agents active against MSSA Undefined Surgical inspection + IV (Vanco + Pip/tazo) Agent active against MRSA + streptococci ly immunocompromised: vanco + Pip/tazo or carbapenem Immunosuppressed, immersion injury, or animal bite Non-Purulent (cellulitis, erysipelas, necrotizing infection) Purulence Yes No Yes No Consult Specific Guidelines Bullae* Skin sloughing* SIRS Hypotension Organ dysfunction Penetrating trauma* MRSA infection elsewhere IVDU* IV Vancomycin *add gram negative agent with anaerobic coverage Moderate Systemic sxs Fever WBC > 12 HR > 90 bpm RR > 20 bpm IV Cefazolin IV Clindamycin This algorithm does not apply in diabetics, immunocompromised, injuries with exposure to salt or freshwater, or animal bite wounds No systemic sxs PO PCN VK PO Cephalexin PO Dicloxacillin PO Clindamycin START Discharge with: PO Penicillin VK PO Cephalexin PO Dicloxacillin PO Clindamycin Discharge with: PO Bactrim PO Doxycycline PO Linezolid PO Tedizolid Class 1 MRSA Infxn Elsewhere No Yes Elevate & Treat Predispositions -4 8
EXIT NOW SIRS Hypotension Organ Dysfunction -4 Class 4 *Patients who are class 3 solely due to unstable comorbidities may be treated with MSSA/BHS active agents, similar to class 2 options Admit and Administer*: Piperacillin/tazobactam Ceftriaxone + metronidazole Fluoroquinolone + metronidazole Carbapenem *may only need therapy against MSSA/BHS (not MRSA) EXIT NOW Bullae, Sloughing, Penetrating Trauma, Evidence of MRSA Elsewhere, IVDU, Unstable Comorbidities* Class 3 23 Hour Observation Status, Administer*: IV Dalbavancin IV Oritavancin No Yes Class 3 EXIT NOW SIRS Hypotension Organ Dysfunction -4 Class 4 Discharge with: PO Penicillin VK PO Cephalexin PO Dicloxacillin PO Clindamycin IV Penicillin IV Ceftriaxone IV Cefazolin IV Clindamycin EXIT NOW Bullae, Sloughing, Penetrating Trauma, Evidence of MRSA Elsewhere, IVDU, Unstable Comorbidities* Class 3 23 Hour Observation Status, Administer: IV Dalbavancin IV Oritavancin IV Penicillin IV Ceftriaxone IV Cefazolin IV Clindamycin *may only need therapy against MSSA/BHS (not MRSA) 9