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Recent therapeutic advances in Mucormycosis

Mucormycosis, a rare angioinvasive disease, has emerged as a serious opportunistic fungal infection. It spreads rapidly causing tissue infarction and necrosis in post-COVID patients. Rhino-orbital-cerebral (ROC) presentation is the most common form.[1] Treatment includes extensive surgical debridement, high doses of systemic Amphotericin B (AmB), control of underlying disease and other supportive measures.

We emphasize that recent therapeutic advances have the potential to improve outcomes of Mucormycosis. Management strategies are based on recent preclinical and limited clinical data. Their validation requires definitive, prospective, and controlled clinical trials. Lipid formulations of amphotericin B (LFAB) have evolved as the primary therapy for Mucormycosis. Based on available data Posaconazole may be used as a salvage therapy but not recommended as primary therapy. Animal models and retrospective limited preclinical data have shown combinations of LFAB- echinocandin and azole-echinocandin therapy improve survival during Mucormycosis.[1] Immune stimulation due to enhanced exposure of β-glucan on the fungal surface and expressions of target enzyme for echinocandins by R. Oryzae, may be one of the mechanisms by which echinocandins improve outcomes. [2,3] However,combination LFAB-echinocandin therapy if considered for mucormycosis, echinocandins should be administered at US Food and Drug Administration-approved dosages. Combination of LFAB and the iron chelator also showed favourable results in animal models. However, the ongoing phase II, DEFEAT Mucor clinical trial failed to demonstrate a benefit of the combination regimen.[4] Ultimately, randomized, prospective phase III clinical trials will be required to determine whether combination therapeutic regimen is superior to monotherapy with an LFAB. Salvage therapy can also be considered with Granulocyte colony-stimulating factor-mobilized granulocyte transfusions which may provide additional support for persistently neutropenic patients Administration of granulocyte macrophage colony-stimulating factor or interferon-γ in nonneutropenic patients with refractory infection may further augment host response and antifungal effect. [1]

Radiological advances

Imaging modalities, such as CT and MRI with or without contrast, provide excellent structural resolution for visualizing advanced diseases, but generally are of limited value in detecting early disease. Therefore, for early diagnosis and treatment, metabolic and functional imaging techniques complement the role of anatomic imaging modalities for the optimal management of these patients. Limited studies have shown FDG, a nonspecific tracer has been found to accumulate at the sites of infection and can aid in detecting and localizing the exact sites of infection.[5]

The mechanism of increased FDG uptake in the inflammatory cells is due to upregulation of cellular glucose metabolism secondary to “respiratory burst”.[6] Study conducted by Hot et al, showed benefit of FDG PET in early diagnosis and staging of invasive fungal sinusitis. [7] One study conducted by Dumarey et al showed FDG-labelled autologous leukocytes more specific as neutrophils have more affinity to acute infections.[8] Another study proved FDG PET/CT is valuable in the early diagnosis and management of Mucormycosis with serial follow up (18)F-FDG PET/CT until complete patient recovery.[9] However more studies need to be done in proving the role of PET scan on early diagnosis and disease resolution post treatment.

Orbital Reconstruction

ROCM patients post orbital exenteration present with cosmetic deformity, persistent nasoorbital fistulas, which might need orbital reconstructions. A successful rehabilitation of anophthalmic socket needs a socket reconstruction with exenteration prosthetic fitting that mimics the contralateral globe. Various free flaps have been used to reconstruct the anophthalmic eye. Temporalis fascia is the most commonly used flap. Other flaps used are Radial artery free forearm flap, dorsalis pedis flap, gracilis free flap, latismus dorsi or rectus muscle free flap. However, flaps have limitations of its pedicle length, inability to provide bulk of tissue, donor site morbidity. Prosthetic rehabilitation with custom-made ocular prosthesis yields better and more satisfactory results both esthetically and psychologically as compared to a stock eye prosthesis. Advantages of custom-made ocular prosthesis is it retains shape of the socket, prevents accumulation of fluid in the cavity, maintains palpebral opening similar to natural eye.[5]

Transcutaneous retrobulbar injection of amphotericin B in rhino-orbital-cerebral mucormycosis

Several case reports have described transcutaneous retrobulbar injection of amphotericin B (TRAMB) and conservative orbital debridement with or without irrigation with amphotericin B as a viable option in halting orbital progression and providing as an opportunity to avoid orbital exenteration. Randomized clinical studies are required to prove the success rate of TRAMB, however it can be used as an adjunctive treatment with background of adequate sinus debridement.

Facio maxillary prosthesis

Rehabilitation of patients with faciomaxillary resection involving maxillae, hard and soft palate presents a significant challenge in restoring cosmetic deformity, speech, deglutition, mastication and respiration. Prosthodontic management using distraction osteogenesis, osseointegrated implants, bone grafts, and magnet attachments can be used to rovide support and stability of a large definitive obturator.[6]

Prosthodontic rehabilitation of patients with bimaxillary resection involving the maxilla, hard and soft palates, and paranasal sinuses presents a significant challenge in restoring speech, deglutition, mastication, and respiration. This clinical report describes the prosthodontic management of a young girl treated for leukemia who required a bilateral maxillectomy secondary to mucormycosis. Distraction osteogenesis, bone grafts, osseointegrated implants, and magnet attachments were used to provide retention, support, and stability of a large definitive obturator.

Hyperbaric oxygen therapy

Hyperbaric oxygen suppresses fungal growth in vitro and has theoretical value in treating mucormycosis because it reduces the tissue hypoxia and acidosis that accompany vascular invasion by the fungus.

References

1: Goldstein, Ellie JC, et al. "Recent advances in the management of mucormycosis: from bench to bedside." Clinical Infectious Diseases 48.12 (2009): 1743-1751.

2: Ibrahim AS, Bowman JC, Avanessian V, et al. Caspofungin inhibits Rhizopus oryzae 1,3-β-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis, Antimicrob Agents Chemother, 2005, vol. 49 (pg. 721-7)

3. Lamaris GA, Lewis RE, Chamilos G, et al. Caspofungin-mediated β-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae, J Infect Dis, 2008, vol. 198 (pg. 186-92)

4. Spellberg, Brad, et al. "The Deferasirox–AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial." Journal of Antimicrobial Chemotherapy 67.3 (2012): 715-722.

5. Debnath N, Gupta R, Meenakshi A, Ramkumar K, John J. A Simplified approach to fabricate a custome-made ocular prosthesis. Int J Prosthodont Restor Dent. 2013;3(1):25–29. doi: 10.5005/jpjournals-10019-1071 .

6. Oh, Won-suck, and Eleni Roumanas. "Dental implant–assisted prosthetic rehabilitation of a patient with a bilateral maxillectomy defect secondary to mucormycosis." The Journal of prosthetic dentistry 96.2 (2006): 88-95.

7. Zhuang H, Alavi A. 18-Fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Semin Nucl Med 2002; 32:47–59 8.Bleeker-Rovers CP, Vos FJ, Corstens FH, Oyen WJ. Imaging of infectious diseases using [18F] fluorodeoxyglucose PET. Q J Nucl Med Mol Imaging 2008; 52:17–29

9.Hot A, Maunoury C, Poiree S, et al. Diagnostic contribution of positron emission tomography with [18F]fluorodeoxyglucose for invasive fungal infections. Clin Microbiol Infect 2011; 17:409–417 [Crossref] [Medline] [Google Scholar]

10. Dumarey N, Egrise D, Blocklet D, et al. Imaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006; 47:625–632

11. Liu, Yuejian, et al. "Utility of 18F-FDG PET/CT in diagnosis and management of mucormycosis." Clinical nuclear medicine 38.9 (2013): e370-1.




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