Debridement and Antifungal Therapy

1. For patients transferred to any Role 3 strategic evacuation hub, risk factors for IFI should be assessed and ongoing resuscitation requirements should be addressed as needed. The patient should undergo surgical examination, wound washout, and debridement (if indicated) within 6-12 hours of arrival. Dakin’s wound irrigations and topical antifungal treatments as described above should be initiated/continued.
2. Evacuation should be deferred in patients who are clinically unstable and require debridement / wound care every 6-12 hours. Reassess patient to meet evacuation criteria every 24 hours. The surgeon on call should be contacted to evaluate the patient and their wounds immediately on arrival to the next level of care.
3. Upon arrival to the Role 4 MTF (i.e. regional treatment facility outside of the combat zone, but prior to arrival in the United States), the patient should undergo operative exploration, wound washout, and debridement (as indicated) within 6-12 hours. Obtain histopathology and microbiology specimens on all patients with at least three risk factors for IFI and any with clinical suspicion. Topical antifungal therapy should be continued.
4. Upon arrival to an MTF in the United States, the patient should undergo surgical exploration, wound washout, and debridement within 6-12 hours. Obtain histopathology and microbiology specimens on all patients with at least three risk factors for IFI and/or who have an unhealthy wound appearance (e.g., tissue necrosis). Topical antifungal dressings may be discontinued at any level of care when the treating surgeon observes healthy granulation, or when histopathology and cultures are negative for fungal infection or colonization.
5. Following the first two debridements in theater, if tissue necrosis is observed in wounds after two consecutive debridements, start broad-spectrum antifungal and antibiotic medications immediately and obtain infectious disease consultation. Liposomal amphotericin B is the primary choice due to its effectiveness against mucormycosis, and its reduced potential to induce nephrotoxicity compared to the non-liposomal formulation.30 Although voriconazole is ineffective against mucormycosis, it has shown to be an active agent against molds that are resistant to amphotericin B (e.g., Aspergillus terreus and Scedosporium prolificans).31
6. In general, patients with IFI are severely injured, and intravenous formulations of antifungal agents are prescribed due to concern for inadequate gastrointestinal antifungal absorption in the septic patient. As soon as feasible, parameters for monitoring antifungal drug toxicities should be implemented (EKG, renal function and LFTs).
7. When voriconazole is administered intravenously, it requires a solubilizing excipient (i.e. sulfobutyl ether β-cyclodextrin), which may accumulate in patients with impaired renal function. A black box warning has been issued due to adverse effects of the accumulating solute in an animal model. Nevertheless, the effects of elevated sulfobutyl ether β-cyclodextrin are unknown in humans.32 An IV route of administration of voriconazole did not predict worsening renal dysfunction in a small retrospective study with the caveat that only a few patients received voriconazole for ≥ 7 days.33 Clinical experience to date has not shown permanent renal impairment with this off-label use of voriconazole in the wounded military population.34
8. Posaconazole is another triazole agent that has been found to have a 60-70% response rate as a salvage regimen against mucormycosis when prescribed orally.35-37 Posaconazole tablets are preferred over oral suspension as there is less variability in absorption. Therapeutic drug monitoring should be used if available to achieve trough concentrations > 1.0 µg/mL.38 Recently, an intravenous formulation was approved and has shown to be useful.39

#### Posaconazole/Voriconazole

The recommended dose of posaconazoIe (tablet formulation) is 300mg by mouth every 12 hours for 2 doses, then 300mg once daily. A posaconazole trough should be obtained on day 7 of therapy. Note, that if other formulations of posaconazole are used, the dosing will be different.

The typical starting dose of voriconazoIe is 6 mg / kg IV every 12 hours for 2 doses, followed by 4 mg / kg (the patient's actual body weight should be used for dosing). A voriconazoIe trough should be obtained on day 4 of therapy. Goal trough is 1 - 1.5 mcg / mL.

9. Dual administration of liposomal amphotericin B and a broad-spectrum triazole is recommended as the first-line antifungal agents. Among triazoles, clinical experience has been primarily with voriconazole. Many of the wounds incurred by combat casualties grow more than one mold.32 Furthermore, prescribe broad-spectrum antibiotics covering both gram-positive and gram-negative organisms (e.g., vancomycin and meropenem)are prescribed as fungal-infected wounds frequently also have bacterial growth

Initial studies have shown that combat IFI wound cultures growing order Mucorales will have a second non-Mucorales fungus present 30% of the time. Aspergillus species is more difficult to grow than order Mucorales but should be suspected and empirically treated initially as it has been shown to be virulent in this patient population.40 Therefore, dual use of a broad-spectrum triazole and liposomal amphotericin B is suggested for wounds infected with either or both of these fungi. If long-term treatment is required, the antifungal medications should be targeted based on culture results.

10. Isavuconazole is a triazole agent available in IV and oral formulations with mold activity including against mucormycosis. Isavuconazole has not been studied in randomized controlled trials but in one multicenter open-label single-arm study, isavuconazole demonstrated similar efficacy to amphotericin B formulations in an external matched control group.40

11. Particular attention should be given to aggressive debridement of non-viable tissue at each debridement procedure. The extent of necrosis and appearance of the wound before and after completion of the operation should be documented in the operative note. Appendix B shows a standardized operative note for wound description to be used for patients at increased risk for IFI. Whenever a significant amount of necrotic tissue is debrided, repeat debridement should be performed in 24 hours or less.

As aggressive surgical debridement of all necrotic and infected tissue remains the mainstay of treatment for IFI, surgical exploration and debridement should continue at least every 24 hours until cessation of necrosis occurs. Wound coverage and closure should not occur until after the wound is clean, contracting, and granulating.

12. If angioinvasive fungal elements or fungal elements among tissue are reported on histopathology, or if cultures are positive in the setting of recurrent necrosis, initiate (or continue) treatment with systemic antifungal medications. Treatment will require close consultation with infectious disease; however, as a general guideline, stop systemic antifungal medications if the wound remains clean/viable for two weeks and if the patient remains clinically stable. If the patient has a fungal infection in more than one body region (e.g., extremity/pelvis, abdomen, and chest), long-term treatment may be indicated.