Approach Considerations
Correction of the underlying abnormality, prompt initiation of liposomal amphotericin B therapy, and surgical resection are critical. [1, 72, 76]
Other important considerations in medical management include the following:
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Diabetic ketoacidosis requires insulin and volume repletion with intravenous fluids.
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Neutropenia is associated with hematologic malignancy and it should be reversed, if possible, with the use of colony-stimulating factors and the withdrawal of cytotoxic chemotherapy.
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Wean off glucocorticosteroids and other immunosuppressive drugs.
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Interrupt deferoxamine therapy; hydroxypyridine chelating agents may be substituted for deferoxamine
The use of contaminated bandages and other dressings has caused cutaneous mucormycosis. Failure to examine areas under dressings or to recognize the significance of deterioration in preexisting wounds may produce severe cutaneous and, ultimately, disseminated disease. Placing patients with severe prolonged neutropenia in rooms equipped with high-efficiency particulate air (HEPA) filters, when feasible, may be beneficial.
Antifungal Therapy
No prospective comparative studies of the primary treatment of mucormycosis have been performed, largely because of the rarity of this disease. In current practice, amphotericin B and isavuconazole are the 2 antifungal agents licensed by the US Food and Drug Administration (FDA) for the primary therapy of mucormycosis. First-line treatment is with an amphotericin derivative, preferably the liposomal form of amphotericin B to minimize nephrotoxicity. Other options include amphotericin B deoxycholate, isavuconazole, and posaconazole. In patients with extensive disease or rapid progression, the addition of posaconazole or isavuconazole to amphotericin B may be considered [77, 78, 39] ; definitive data are not available.
Although some reports have described a combination of different classes of antifungal agents, trials are needed to determine the efficacy of this approach. [79] Potential advantages would include more rapid fungicidal activity and lower risk of resistance. Potential disadvantages would include the risk for antagonism, additive or synergistic toxicity, more drug-drug interactions, and higher cost. [80]
Liposomal and lipid complex amphotericin B
Amphotericin B has proven efficacy in the treatment of mucormycosis. The liposomal formulation (AmBisome) is the drug of choice based on efficacy and safety data. [81, 82, 83, 39] ECMM recommends a dosage of 5-10 mg/kg of liposomal amphotericin B; the dose need not be slowly increased; instead, a full dose should be given on day 1 of treatment. [39] High doses of liposomal amphotericin B ≥ 7.5 mg/kg were tested in a pilot study (Ambizygo); the response rate was 43% among patients who received the higher dose during the first week compared with 0% in patients who did not. [84] A high dose combined with surgery led to an overall response rate of 36% and 45% at week 4 and 12 respectively. [84] A higher dose of 10mg/kg is recommended in patients with CNS involvement. [39]
The use of higher doses, however, has been associated with rates of nephrotoxicity up to 40% without a concomitant mortality benefit. [72, 79, 85, 84]
Amphotericin B
Amphotericin B deoxycholate can also be used to treat mucormycosis, particularly when other formulations prove too costly. The typical dose is 1-1.5 mg/kg/d. The total dose given over the course of therapy is usually 2.5-3 g. High doses of this drug are required, and nephrotoxicity may result. This is of particular concern because many patients who develop mucormycosis have preexisting renal disease (eg, diabetics, transplant recipients). Monitoring the renal function of patients taking amphotericin B is critical; doubling of serum creatinine over the baseline levels is an indication for changing to liposomal amphotericin B.
In addition, careful monitoring and repletion of serum electrolytes (eg, potassium, phosphorus, magnesium) should be performed when administering any formulation of amphotericin B.
Isavuconazole
Isavuconazole (Cresemba) is a novel triazole antifungal agent that was approved for the treatment of mucormycosis in March 2015. The prodrug isavuconazonium sulfate is rapidly metabolized by serum butylcholinesterase to the active form, isavuconazole (ISZ). [75]
The efficacy of isavuconazole in the treatment of invasive mucormycosis has not been evaluated in randomized controlled trials because of the rarity of this disease. The approval of this medication was based on a noncomparative, single-arm, open-label, matched, case-control trial (VITAL). Of 149 patients enrolled, 37 had proven (86%) or probable (14%) mucormycosis. Twenty-one patients received primary treatment with ISZ, whereas 11 patients received isavuconazole salvage therapy; 5 were intolerant to other antifungals. Controls treated with amphotericin (67% liposomal, 12% lipid complex, 21% deoxycholate) were matched from the Fungiscope Registry. Isavuconazole- and amphotericin-treated patients had similar day-42 weighted all-cause mortality at 33% and 41%, respectively. Patients received isavuconazole for a median of 84 days versus 18 for amphotericin, suggesting more favorable tolerability. [86] ECMM recommends isavuconazole with moderate strength as first-line treatment. [39] Isavuconazole brain penetration is low in necrotic center, however it is adequate in inflammatory brain tissue, comparable to plasma concentration. [87] Isavuconazole was efficacious in Mucorales CNS infection in a retrospective study. [88]
Isavuconazole offers several advantages over other triazoles (ie, posaconazole, voriconazole), apart from its wider spectrum of antifungal activity. The drug has excellent oral bioavailability not reliant on food intake or gastric pH and is also available in an intravenous formulation, which does not contain the nephrotoxic solubilizing agent cyclodextrin. Switching between oral and IV forms does not require dose adjustment. ISZ displays linear and predictable pharmacokinetics with minimal CYP3A4 interactions, reducing or eliminating the need for therapeutic drug monitoring. Unlike voriconazole, ISZ does not cause phototoxicity, increased risk of squamous cell carcinoma, or visual disturbance. The clinical significance of ISZ-related QTc shortening is unknown, but it is reasonable to avoid this medication in patients with familial short QT syndrome and to avoid co-administrating with sodium channel–blocking antiepileptics. [89]
Given the highly variable, species-dependent susceptibility pattern of the Mucorales to isavuconazole, clinical susceptibility testing may be indicated in some situations. [90]
Posaconazole
Posaconazole, another triazole antifungal, has been shown to be superior to fluconazole or itraconazole as prophylaxis against invasive mold infection (both aspergillosis and mucormycosis) in patients with hematologic malignancy who have neutropenia or GVHD. The number needed to treat (NNT) to prevent one fungal infection was 27 and to prevent one death was 35. [91]
Posaconazole can be used for off-label salvage treatment of mucormycosis in patients intolerant to amphotericin B. Issues with the absorption of the oral suspension of posaconazole, particularly decreased absorption in the setting of proton pump inhibitor (PPI) or antimotility agent (eg, metoclopramide) use have been overcome with the introduction of a delayed-release tablet formulation. [81, 75] An intravenous formulation is also available. Therapeutic drug monitoring is strongly recommended for patients on posaconazole being treated for mucormycosis. [39]
Several case reports have discussed the use of posaconazole, [73, 92] including as salvage therapy. [93] A review of 96 patients treated with posaconazole found that complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%), with an overall mortality of 24%. [77] Rickerts et al reported that liposomal amphotericin B plus posaconazole was successful in the treatment of disseminated mucormycosis in a patient who could not undergo surgery; however, the benefit of dual antifungal therapy is unclear. [79, 94]
Posaconazole has also been used as step-down therapy after the initial administration and control of the disease with liposomal amphotericin B. [95, 96]
Other agents and combination therapy
Other azoles (ie, fluconazole, voriconazole) are ineffective against Mucorales species. With the use of voriconazole prophylaxis in high-risk patients, such as transplant recipients, mucormycosis has been reported. [97, 98, 99]
Most Mucorales species show moderate in vitro resistance to the echinocandins; these agents cannot be used in the treatment of mucormycosis. [29] Animal and limited clinical data have suggested that combination therapy with amphotericin and an echinocandin may improve survival. [81, 82, 100, 101, 102] However, a recent retrospective cohort study of combination liposomal amphotericin B (L-AmB) with posaconazole, L-AmB with echinocandins, and posaconazole with echinocandins showed no differences in mortality between monotherapy and combination treatment groups. [103] The in vitro combinations of isavuconazole with micafungin or amphotericin resulted in a range of interactions, some concentration-dependent, ranging from antagonism to synergy against various Mucorales. [104]
Further clinical trials are needed before antifungal combination therapy can be definitively recommended. Currently there is a clinical trial assessing the combination of inhaled amphotericin +IV liposomal amphotericin B vs IV amphotericin alone, and other novel therapies are being evaluated out based on medical patent review and in-vitro data. [105, 106]
Surgical Intervention
Debridement of necrotic tissue in combination with medical therapy is mandatory for patient survival. In rhinocerebral disease, surgical care includes drainage of the sinuses and may require excision of the orbital contents and involved brain). Repeated surgery may be required, especially for rhinocerebral mucormycosis.
Excise pulmonary lesions if they are localized to a single lobe, excise cutaneous lesions entirely, and resect any GI masses, for good disease control.
An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. Courtesy of A Allworth, MD, Brisbane, Australia.
Adjunctive Therapies
Hyperbaric oxygen therapy after surgical debridement has been used, especially in cases of cutaneous disease and rhinocerebral disease in diabetics, but its effectiveness has not been extensively studied. Treatment of mucormycosis is not one of the approved uses of hyperbaric oxygen. [92, 107] High oxygen concentrations may improve neutrophil function, inhibit the growth of Mucorales, and improve wound healing.
Colony-stimulating factors have been used to enhance immune responses, specifically in neutropenic patients, as have interferon-gamma and white blood cell transfusions. The usefulness of these interventions is unclear.
Finally, the use of iron chelators without xenosiderophore activity (eg, deferasirox) has been described in case reports. [107] Older iron chelators, namely deferoxamine, can be exploited as an iron source by Rhizopus, thereby increasing the risk for mucormycosis. [75] Newer agents such as deferasirox were hypothesized to decrease the risk of mucormycosis via iron starvation; however, they have not proven clinically efficacious. [108] In an immunosuppressed murine model of pulmonary mucormycosis, a combination of deferasirox with posaconazole increased the AUC/MIC of posaconazole but failed to demonstrate improved efficacy over monotherapy. [109] In the DEFEAT MUCOR study, 20 patients with mucormycosis were randomly assigned to L-AmB plus deferasirox or L-AmB plus placebo; the deferasirox arm had a higher 90-day mortality rate. [110, 111]
Consultations
Patient survival from mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy. To that effect, consultations with various specialists are critical.
Infectious disease consultation is warranted for management of antifungal therapy and coordination of medical care.
Surgical specialty consultations depend on the location of disease, as follows:
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Otolaryngology (ENT) consultation and neurosurgery consultation for rhinocerebral mucormycosis
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Thoracic surgery consultation for pulmonary involvement
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Gastroenterology (GI) surgery consultation for gastrointestinal involvement
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Plastic surgery consultation for cutaneous involvement
In addition, endocrinology consultation may be necessary for the management of unstable diabetes, hematology/oncology consultation may be needed for the management of issues related to underlying malignancy, and surgical intensive care unit (SICU) consultation is important for perioperative care.
Duration of Therapy and Long-Term Monitoring
There is no definitive guidance on duration of therapy, and weeks to months of therapy usually are given; ECMM strongly suggests treatment until immunosuppression is resolved, diabetes is effectively controlled, and complete response is seen on imaging. [39]
Successful courses of amphotericin B typically last 4-6 weeks. Primary or salvage isavuconazole therapy may be continued for several months given its higher tolerability compared with amphotericin. Repeated surgical debridement of necrotic tissue identified by follow-up head computed tomography (CT) scan or magnetic resonance imaging (MRI) is often indicated.
Ongoing clinical surveillance and diagnostic imaging are required to ensure complete resolution of mucormycosis and to detect relapse.
Educate patients about the signs of disease, such as facial swelling and black nasal discharge, and instruct patients to present promptly for evaluation if these signs occur.
Prevention
Primary Prophylaxis
There is no evidence for primary prophylaxis towards mucormycosis. The ECMM has a moderately strong recommendation regarding primary prophylaxis with oral (B-II) or IV posconazole (B111), and marginally recommends (C-II) posaconazole oral suspension among patients who are neutropenic or have graft versus host disease (GvHD). [39] Isavuconazole is marginally recommended (C-II) for primary prophylaxis among neutropenic patients; in a study consisting of 147 patients, isavuconazole prophylaxis was less effective than voriconazole or posconazole for invasive fungal disease as two patients had breakthrough mucormycosis despite being on isavuconzole. [39, 112] For patients with solid organ transplant (SOT), posaconazole or isavuconazole is marginally (C-II, C111) recommended. [39]
Secondary Prophylaxis
The ECMM strongly recommends secondary prophylaxis for patients with a previous history of mucormycosis who are undergoing immunosuppression. [39]
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Postmortem photograph of a woman with diabetes and left rhinocerebral mucormycosis complicating ketoacidosis. Rhizopus oryzae was the causative organism. Note the orbital and facial cellulitis and the black nasal discharge. Courtesy of A Allworth, MD, Brisbane, Australia.
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The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Note the proptosis. Courtesy of A Allworth, MD, Brisbane, Australia.
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The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Chemosis is shown in this photograph. Internal and external ophthalmoplegia, no light perception, and afferent pupil defect were present, which is consistent with orbital apex syndrome. Courtesy of A Allworth, MD, Brisbane, Australia.
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An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. Courtesy of A Allworth, MD, Brisbane, Australia.
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An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Picture of the patient after successful treatment with repeated surgical debridement and high-dose liposomal amphotericin B. Courtesy of A Allworth, MD, Brisbane, Australia.
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Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. Courtesy of A Allworth, MD, Brisbane, Australia.
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Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions.
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Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. This CT scan of the patient shows resolution of pulmonary mucormycosis after 5 months of antifungal treatment.
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Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent multiple surgeries to control rhinocerebral Mucor infection, including partial right frontal lobectomy and right orbital exenteration. He was treated with amphotericin B and his diabetes mellitus was controlled. The disease did not progress, and long-term isavuconazole therapy was initiated for salvage/maintenance therapy.
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Rhino-orbital-cerebral mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.
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Pulmonary mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.
