Diagnosis and Management of Wound Infections

1. Diagnosis and Management of Wound Infections Neel Shah, M.D. Clinical Assistant Professor of Medicine Division of Infectious Disease

2. Lecture Outline • Diabetic wound infections • Infected decubitus ulcers • Surgical wound infections • Biofilm • Atypical organisms

3. Diabetic Foot Infection (DFU): Any wound that develops as a result of underlying diabetes mellitus, and becomes subsequently infected • Infection: Wound with local (erythema, drainage, swelling, pain, warmth), +/-systemic sign of infection ( fevers, chills, sweats, etc.) • Cost of Management: 9-13 billion $ in the U.S alone • High Morbidity and Mortality: • Lifetime Risk: 12-25% risk for diabetics to develop DFU ₂ • 5 year Mortality: 43-55%, up to 74% if amputation required₁ Diabetic Foot Infections

4. Pathogenesis of DFU/DFI Neuropathy, PVD and Microangiopathy:3 driving forces Tissue and vessel damage contributes to callus formation and ischemia, leading to ulceration (trauma and poor wound healing can also contribute) Open ulcer=impaired barrier defense (skin) Impaired ability for immune system recruitment (PVD/DM, microangiopathy)Infection Infection usually progressive in nature: Soft tissuebonesystemic(blood, end organs) Adapted from www.idb.hr

5. Microbiology of DFU/I Often polymicrobial, given ulcer is open to environment Organism types increase as a function of depth: Superficial: Staph aureus (MSSA, MRSA), CoNS and Streptococci (GAS, GBS) Deep: Add Enterococci, Enterobacteriacae, Pseudomonas Necrosis/Gangrene: Add anaerobes (Bacteroides, Clostridia) Immunosuppressed: Fungi, mycobacteria

6. Classification of Diabetic Foot Infections₃ IDSA Severity Index₄: • Mild Infection: • Presence of ≥2 signs of inflammation • Erythema ≤ 2 cm around ulcer • Limited to skin/soft tissue • No systemic illness • Moderate Infection: • At least 1 of the following: • Erythema >2 cm around ulcer • Involvement of sub-fascial space(tendon, muscle, joint, bone) • Abscess in deep tissue • + Gangrene • Severe Infection: As above, with signs of sepsis/septic shock • If NONE of the above is present (ulcer alone, no signs of inflammation, no systemic illness)—there is NO INFECTION PRESENT

7. Diagnostic Principles • Determine Severity • Use Severity Index (can also use PEDIS, UT, SAD, DFI classification systems) • Determine Depth • Bone: • Probe to bone test: If ulcer noted, do this first (>90% Sn/Sp) • Biopsy: + results 87% of the time (open>needle bx, HOLD all Abx 72 hours before bx to maximize results!) • Imaging: • MRI with contrast- Sn 90%, Sp 79%₆ • Tagged WBC bone scan- 80-85% Sn/Sp₅ • Determine Causative Organisms • Standard culture/Gram stain, KOH prep/fungal cx vs AFB stains/cx if risks present • No swabs if possible (tissue cx are best!) • 16s/18s rRNA PCR testing to detect fastidious organisms vs low burden infection

8. Treatment • Empiric therapy is based on severity-focus on polymicrobial coverage, especially GP’s (Staph/Strep)₄ • Mild (treat 1-2 weeks): • Keflex, Dicloxacillin, Augmentin • AND +/- Bactrim or Doxycycline • OR Clindamycin PO • Moderate/Severe (treat 3-6 weeks): • Levofloxacin/Moxifloxacin, IV ceftriaxone +/- PO Flagyl, IV Unasyn, IV ertapenem, IV Zosyn or IV meropenem (if MDR GN risk factors) • AND (if needed) IV vancomycin, PO linezolid, or IV daptomycin for MRSA coverage • Always obtain cultures before starting Abx, ideally from tissue and bone (if involved) • Notable Drugs: • Delafloxacin (Baxdela)- Quinolone with MRSA coverage (in vitro activity against PSA as well)-FDA approved for SSTI • Ceftaroline (Teflaro)- 5th gen cephalosporin, covers MRSA, FDA approved for SSTI • Dalba/Oritavancin-Given once weekly, covers MRSA, but may be $$

9. Decubitus Ulcer Infections • Decubitus Ulcer Infection (DUI): Signs/symptoms of infection overlying a pre-existing decubitus(pressure) ulcer • 2.5 million cases treated yearly in the U.S. • Risk factors: Elderly, neurological (spinal cord) injury, SNF residency (4-8% develop within 6 month of stay, possibly higher) • Pathogenesis: Sustained pressure >30 mm/Hg impairs blood flowischemia, lymphatic occlusionedema and necrosis of skin and tissue

10. Classification of Decubitus Ulcers Based on National Pressure Ulcer Advisory Panel (NPUAP) • Stage 1: Skin intact but with non-blanchable redness >1 hr after relief of pressure • Stage 2: Blister or dermal skin break, with or without infection • Stage 3: Full thickness dermal loss, + subcutaneous fat exposure, down to muscle (with or without infection) • Stage 4: Same as above, but with involvement of tendon, joint or bone (with or without infection) • Unstageable: Covered by eschar/slough in the wound bed

11. Microbiology • Often are polymicrobial, for same reason as diabetic ulcer infections are • GI/GU organisms can be involved given proximity of ulcers to rectum and GU tract • Wall, et al. (2003): MRSA/MSSA , CoNS, Streptococci and Proteus were predominant organisms • Heym et al. (2004): 168 tissue cx samples analyzed retrospectively from 101 patients, 29% Enterobacter, 28% Staph, 16% Enterococci

12. Diagnostic Principles • Similar to diagnosis of diabetic foot ulcer infections • Assess severity (stage), determine depth (probe to bone, stage +/- imaging), isolate pathogens (cultures, PCR) • Swabs often reflect colonization of wound surface, AVOID • Get deep tissue/bone cultures

13. Treatment If Wound Healing Poorly: Ideally, deep tissue/bone culture results should guide Abx therapy given polymicrobial nature and confusion between colonization vs infection Reassessments should be done at 2-4 week mark after intervention If appropriate treatment appears to have been given and wound still fails to heal, then imaging should be considered and possible bone bx if imaging suggests OM, or if clinical suspicion for OM is high Abx options would be similar to management of DFU/I

15. The Challenge of Biofilm: Infection vs Colonization • Both DFUs and SDU’s are exposed to skin commensal bacteria which makes extracellular biofilm • Biofilm makes wound healing difficult to resolve (in absence of infection) and infections difficult to treat • Creates diagnostic confusion-are organisms pathogenic or not?

16. Pathogenesis of biofilm

17. Possible Solutions • Tests: • Procalcitonin: • Park et al. PCT +CRP positively correlated with infection severity of DFI (cutoff to positive >0.59 ng/mL) • Uzun et al. PCT of >0.08 ng/mL (Sn 77%, Sp 100%) • Korkmaz, et al. PCT not effective in distinguishing infection from colonization, however IL6 and fibrinogen levels were more promising • ESR/CRP: ~70% Sn/Sp for ESR, CRP has low Sn (~39%) very high Sp (near 100%) • Antibiotics: • Mandell et al. Doxycycline, rifampin, daptomycin kill Staph aureus biofilm in vitro • Quinolones have antibiofilm properties against GN’s (Wang et al, Di Bonventura et al.), but resistance can form over time (Shi, et al., Feng et al.) Possible future drug target sites

18. Special Organisms • Water exposure: Pseudomonas, Aeromonas, Vibrio, M.marinum(aquarium, fishtank) • Cats: Pasturella>Capnocytophagia, Bartonella (Bacillary angiomatosis in HIV) • Dogs: Capnocytophagia>Pasturella • Rose Gardener: Sporothrix, Nocardia (appear similar clinically) • Midwest: Histoplasma (birds), Blastomyces(? water) • Immunosuppressed: Mycobacterium haemophilum, Bartonella, Cryptococcus, Fusarium, Mucor/Rhizopus • Travel or South America, Africa, Asia: Leishmania, Rickettsial infections • Sheep: Orf virus

19. References Robbins, JM et al. Mortality Rates and Diabetic Foot Ulcers: Is it Time to Communicate Mortality Risk to Patients with Diabetic Foot Ulceration? J Am Podiatr Med Assoc, 2008 Jneid J. et al. The Diabetic Foot Microbiota: A Review. Hum Microbiome Journal, 2017 Lipsky BA, et al. Diagnosis and Treatment of Diabetic Foot Infections. Clin Infect Dis, 2004 Lipsky BA et al. 2012 IDSA Clinical Practice Guidelines for the Diagnosis and Treatment of Diabetic Foot Infections, Clin Infect Dis, 2012. Palestro CJ, et al. Nuclear Medicine and Diabetic Foot Infections. SeminNucl Med, 2009 Dinh MT, et al. Diagnostic Accuracy of the physical examination and imaging tests of osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis, 2008.