TREATMENT Mucormycosis GENERAL PRINCIPLES
The successful treatment of mucormycosis requires four steps: (1) early diagnosis; (2) reversal of underlying predisposing risk factors, if possible; (3) surgical debridement; and (4) prompt antifungal therapy. Early diagnosis of mucormycosis is critical, since early initiation of therapy is associated with improved survival rates. It is also crucial to reverse (or prevent) underlying defects in host defense during treatment (e.g., by stopping or reducing the dosage of immunosuppressive medications or by rapidly restoring euglycemia and normal acid-base status). Finally, iron administration to patients with active mucormycosis should be avoided, as iron exacerbates infection in animal models. Blood transfusion typically results in some liberation of free iron due to hemolysis, so a conservative approach to red blood cell transfusions is advisable.
Blood vessel thrombosis and resulting tissue necrosis during mucormycosis can result in poor penetration of antifungal agents to the site of infection. Therefore, debridement of all necrotic tissues is critical for eradication of disease. Surgery has been found (by logistic regression and in multiple case series) to be an independent variable for favorable outcome in patients with mucormycosis. Limited data from a retrospective study support the use of intraoperative frozen sections to delineate the margins of infected tissues, with sparing of tissues lacking evidence of infection. A multidisciplinary team, including an internist, an infectious disease specialist, and surgical specialists whose expertise is relevant to the sites of infection, is typically required for the management of mucormycosis. ANTIFUNGAL THERAPY
Primary therapy for mucormycosis should be based on a polyene antifungal agent (Table 117-2), except perhaps for mild localized infection (e.g., isolated suprafascial cutaneous infection) that has been eradicated surgically in an immunocompetent patient. Amphotericin B (AmB) deoxycholate remains the only licensed antifungal agent for the treatment of mucormycosis. However, lipid formulations of AmB are significantly less nephrotoxic, can be administered at higher doses, and are probably more effective than AmB deoxycholate for this purpose. Liposomal amphotericin B (LAmB) is preferred to amphotericin B lipid complex (ABLC) for management of CNS infection on the basis of retrospective survival data and superior brain penetration; there is no clear advantage of either agent for non-CNS infections.
The optimal dosages for antifungal treatment of mucormycosis are not known. Starting dosages of 1 mg/kg per day for AmB deoxycholate and 5 mg/kg per day for LAmB and ABLC are commonly given to adults and children. Dose escalation of LAmB to 7.5 or 10 mg/kg per day for CNS mucormycosis may be considered in light of the limited penetration of polyenes into the brain. Because of auto-induction of metabolism, which results in paradoxically lower drug levels, there is no advantage to escalating the LAmB dose above 10 mg/kg per day, and doses of 5 mg/kg per day are probably adequate for non-CNS infections. ABLC dose escalation above 5 mg/kg per day is not advisable given the lack of relevant data and the drug’s potential toxicity.
Echinocandin–lipid polyene combinations improved survival rates among mice with disseminated mucormycosis (including CNS disease) and were associated with significantly better outcomes than polyene monotherapy in a small retrospective clinical study involving patients with rhino-orbital-cerebral mucormycosis. Although combination therapy may be considered on the basis of these limited data sets, definitive clinical trials are needed to establish whether it offers any real advantage over monotherapy for mucormycosis. Echinocandins should be administered at standard, FDA-approved doses, since dose escalation has resulted in paradoxical loss of efficacy in preclinical models.
In contrast to deferoxamine, the iron chelator deferasirox is fungicidal against clinical isolates of the Mucorales. In mice with DKA and disseminated mucormycosis, combination deferasirox-LAmB therapy resulted in synergistic improvement of survival rates and reduced the fungal burden in brain. Unfortunately, a randomized, double-blind, phase 2 safety clinical trial of adjunctive therapy with deferasirox (plus LAmB) documented excess mortality in the patients treated with deferasirox. It is noteworthy that the study population included primarily patients with active malignancy, and few patients in the study had diabetes mellitus as their only risk factor. Deferasirox is therefore contraindicated as therapy in patients with active malignancy, but its role in patients who have diabetes mellitus without malignancy (the setting in which its preclinical efficacy was optimal) remains uncertain.
Posaconazole is the only FDA-approved azole with in vitro activity against the Mucorales. However, pharmacokinetic/pharmacodynamic data raise concerns about the reliability with which adequate in vivo levels of orally administered posaconazole are attained. Furthermore, posaconazole is inferior in efficacy to AmB for the treatment of murine mucormycosis and is not superior to placebo for treatment of murine infection with R. oryzae. Moreover, posaconazole-polyene combination therapy is not superior to polyene monotherapy for mucormycosis in mice, and no comparative data are available for combination therapy in humans.
The roles of recombinant cytokines and neutrophil transfusions in the primary treatment of mucormycosis are not clear, although it is intuitive that earlier recovery of neutrophil counts should improve survival rates. Limited data indicate that hyperbaric oxygen may be useful in centers with the appropriate technical expertise and facilities.
In general, antifungal therapy for mucormycosis should be continued until resolution of clinical signs and symptoms of infection and resolution of underlying immunosuppression. For patients with mucormycosis who are receiving immunosuppressive medications, secondary antifungal prophylaxis is typically continued for as long as the immunosuppressive regimen is administered.
The role of radiographic follow-up in determining prognosis and therapeutic duration is being studied. Analysis of data from the phase 2 DEFEAT Mucor study indicated that early radiographic progression (within the first 2 weeks) did not predict long-term mortality risk, nor did early radiographic stability/regression predict long-term survival. Therefore, caution should be used in reacting to short-term, serial radiographic results, and greater emphasis should be placed on clinical response, particularly within the first 2–4 weeks after initiation of therapy.