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