Approach

In all susceptible patients with suspected mucormycosis, promptly starting appropriate antifungal therapy and surgical debridement is essential for good outcomes in this otherwise rapidly fatal disease.[4]​ In appropriate circumstances, immune function should be reconstituted if possible to improve outcome. This may require recovery of neutropenia, tapering of corticosteroids, or reversal of acidosis. Available data suggest that a delay in initiating treatment of 6 days or longer after diagnosis results in a twofold increase in mortality at 12 weeks after diagnosis.[55]

Surgery

Surgery is key to remove necrotic tissue and curb the spread of infection. Necrosis occurs due to vascular thrombosis, which precludes adequate delivery of antifungal agents.[3]​ Surgery plays a vital role in all forms of mucormycosis whenever feasible; however, some patients may be too unwell to undergo surgery.[12] In patients with rhino-orbito-cerebral mucormycosis, extensive surgical debridement frequently requires removing the paranasal sinuses along with disease from the nose and the orbit, if involved.[56] In patients with isolated cutaneous disease due to burns or in trauma patients, aggressive surgical debridement to remove all necrotic tissue is essential.

Antifungal induction therapy

Antifungal therapy is recommended in addition to surgery, or as a first-line treatment in those who are not suitable for surgery.

Amphotericin-B is recommended first line.[12] Amphotericin-B belongs to the polyene class of antifungals and is the most effective therapy against agents of mucormycosis. Liposomal and lipid formulations are preferred over the deoxycholate formulation as they minimize renal dysfunction, infusion reactions, and toxicity. Amphotericin-B deoxycholate is effective but should be avoided; its use is limited by substantial toxicity in the doses and treatment durations needed for mucormycosis. It should only be used in settings where no other antifungal treatment options are available.[12] Treatment with liposomal amphotericin-B has been reported to result in better survival in cancer patients, compared with amphotericin-B deoxycholate (67% versus 39%).[57] Liposomal amphotericin-B also appears to be more effective in rhinocerebral disease.[57] Liposomal amphotericin-B is more effective than the lipid formulation in treating central nervous system disease, making it the first-line agent in central nervous system mucormycosis, with the lipid formulation a second-line agent.[57]

Posaconazole or isavuconazonium (a prodrug of isavuconazole) are azole antifungals and may be used intravenously as a second-line treatment. They are the preferred treatments in patients with pre-existing renal compromise as amphotericin-B can cause nephrotoxicity, even lipid or liposomal formulations.[12]

Isavuconazonium has been approved by the Food and Drug Administration (FDA) for the treatment of invasive mucormycosis. It has less nephrotoxic potential than other intravenous azoles.[58] No therapeutic drug monitoring is needed.​

Breakthrough infection with Rhizopus oryzae has been reported in patients on posaconazole prophylaxis.[59] Posaconazole requires about 1 week to reach steady-state serum concentrations and, hence, should not be the initial therapy for a patient with mucormycosis. Consider therapeutic monitoring of posaconazole blood levels in the following:

  • No clinical response is noted

  • In pediatric patients

  • If there is mucositis, malabsorption, or inability to tolerate high fat meals

  • With a resistant organism

  • There is infection at sanctuary sites

  • There is coprescribing with proton-pump inhibitors, anticonvulsants, H2 antagonists, or gastric motility agents.

Trough levels can be measured after 5-7 days of initiating therapy with a goal of >1 mg/L.[1]​ In a study of patients with graft-versus-host disease following hematopoietic stem cell transplant, the patients who developed invasive fungal infections (IFIs) had median and peak posaconazole levels of 0.611 micrograms/mL and 0.635 micrograms/mL, respectively, while the patients without IFIs had median and peak posaconazole levels of 0.922 micrograms/mL and 1.36 micrograms/mL, respectively.[59][60]

Amphotericin-B is associated with nephrotoxicity, hypokalemia, anemia, and infusion-related adverse reactions. Azole antifungals are hepatotoxic (monitor liver function during therapy) and undergo a number of potential drug-drug interactions. Data in pregnant women with mucormycosis are not widely available.

The regimens presented in this topic depend on the geographical location as not all recommended treatments have regulatory approval in all regions or are available for use in all clinical settings.[12]

Antifungal maintenance therapy

Further treatment depends on the initial clinical response and whether the patient experiences toxicity from the initial treatment regimens.

Once the patient is stable or has a partial response, either continue the first-line regimen or change to a suitable oral regimen.[12]​ Oral isavuconazonium or posaconazole are the preferred options for step-down treatment.[12]

Duration of therapy depends on clinical response and resolution of any immune defect; weeks to months of therapy are typically required. Consult an infectious disease specialist for further guidance on when to transition to oral therapy, or taper or stop therapy.[12]

Antifungal therapy: treatment failure

Salvage antifungal therapy is recommended in patients with treatment failure (i.e., due to refractory mucormycosis or toxicity/intolerance to first-line regimens). The choice of drug for salvage therapy depends on the drug used initially. As only two drug classes are recommended for mucormycosis, salvage therapy typically involves switching to the other drug class.[12]

Salvage therapy with isavuconazonium or posaconazole can be considered in patients who do not respond to, or experience toxicity with, initial treatment with amphotericin-B. Liposomal amphotericin-B, and amphotericin-B lipid complex, are suitable salvage options for cases of primary treatment failure with azole antifungals.[12]

Combination antifungal therapy may be used as salvage therapy (and also as initial therapy in immunocompromised patients due to their poor prognosis).[61][62]​​​ Treatment guidelines only marginally recommend combination therapy, largely due to a lack of evidence demonstrating harm rather than evidence indicating clear benefit.[12] There is the potential for an increased risk of toxicity. Consult an infectious disease specialist for further guidance on using combination therapy.​

Specific management of underlying medical problem

Patients with diabetes mellitus (rhino-orbito-cerebral disease is the most common)

  • Reversal of acidosis is essential.

  • Glycemic control is encouraged.

Transplant recipients (solid organ/stem cell) (sinopulmonary disease is the most common)

  • Discontinuing or reducing immunosuppressive agents such as corticosteroids and chemotherapy whenever feasible is encouraged.[3]​​

  • Giving granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon gamma may be beneficial by reversing therapy-induced neutropenia.[2]​ In hematology patients with mucormycosis and ongoing neutropenia, G-CSF has been used as an adjunct to antifungal therapy in several small patient cohorts.[12]​ Several case reports suggest that interferon gamma may be an effective treatment, including a case of abdominal mucormycosis unresponsive to conventional therapy that improved with nivolumab and interferon gamma.[63] Interferon gamma was also successfully used in an immunocompetent patient with invasive cutaneous mucormycosis after severe burns, leading to rapid clinical improvement and immune recovery.[64]​​ However, adequate controlled trials are lacking.[3]​​

Patients with iron overload

  • Avoiding use of deferoxamine as an iron chelator is recommended. Alternatives include suitable hydroxypyridinone iron chelators (e.g., deferiprone, deferasirox).[65]

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