Infectious Diseases

Agents of Mucormycosis (Microbiology)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Mucormycosis is a general term for infections caused by a group of filamentous fungi belonging to the class Glomeromycetes, which because of recent taxonomic reclassification has replaced the former class name Zygomycetes. In the past, the term zygomycosis encompassed both agents of mucormycosis and fungi responsible for entomophthoramycosis, an uncommon subcutaneous infection encountered predominantly in the tropics. In the revised classification, all agents of mucormycosis have been placed under the subphylum Mucormycotina, whereas agents of entomophthoramycosis are now classified under the subphylum Entomophthoramycotina. Because most fungal pathogens associated with mucormycosis are also in the order Mucorales, the disease name of mucormycosis is now considered more taxonomically and clinically accurate than the previously used (and now obsolete) term zygomycosis.

Mucorales are ubiquitous throughout the environment and commonly found in decaying organic matter, soil, compost, and animal excreta. Mucorales characteristically produce large, ribbon-like hyphae with irregular diameter and only occasional septae, hence, their frequent characterization in tissue as aseptate fungi. Identification of the fungi is confirmed during culture when characteristic, saclike fruiting structures (sporangia) are observed that produce internally yellow or brown spores (sporangiospores). These sporangiospores range from 3 to 11 micrometers in diameter and are easily aerosolized and cause infections in susceptible hosts when inhaled or introduced through the cutaneous or percutaneous route.

In a review of more than 900 reported human cases of mucormycosis, Roden and colleagues found the majority of human mucormycosis cases were caused by fungi classified under the following genera:

  • Rhizopus (47%)

  • Mucor (18%)

  • Cunninghamella (7%)

  • Apophysomyces (5%)

  • Absidia species (5%)

  • Saksenaea species (5%)

  • Rhizomucor pusillus (4%)

Other genera belonging to Mucorales represented less than 3% of culture confirmed cases.

The clinical presentation of mucormycosis is broad, depending on the underlying immunosuppression of the host. Although some overlap exists, the clinical presentation can be broadly grouped according to anatomic predilictation into six syndromes: rhinocerebral infections, pulmonary, cutaneous, gastrointestinal, disseminated infections, and uncommon presentations of mucormycosis.

What is the best treatment?

  • Like other opportunistic fungal infections, timely diagnosis and reversal or reduction in underlying immunosuppression, such as recovery from neutropenia, tapering of corticosteroids, and control of hyperglycemia (acidosis), are essential for optimal response to systemic antifungal therapy.

  • Surgical resection of infected tissues in conjunction with systemic antifungal therapy has been reported to significantly improve patient survival compared to antifungal therapy alone. However, improved outcomes have been reported primarily in less severely ill patients with unifocal disease who had devitalized, infected tissue removed early in the course of treatment. Repeated removal of necrotic tissue or radical resection (e.g., complete removal of the orbit in rhinocerebral mucormycosis or lobectomy in pulmonary mucormycosis) may be required for control of the infection.

  • Lipid amphotericin B (amphotericin B lipid complex or liposomal amphotericin B) administered intravenously at 5 mg/kg/day is the standard first-line treatment for mucormycosis. Higher doses of liposomal amphotericin B (i.e., 7.5-10 mg/kg/day) are being explored as a strategy to improve treatment outcome with amphotericin B.

  • Use of lipid amphotericin B formulations is preferred over amphotericin B deoxycholate, as higher amphotericin B deoxycholate doses recommended for the treatment of mucormycosis (1-1.5 mg/kg/day) are often associated with unacceptable rates of nephrotoxicity and treatment interruption in patients populations predisposed to developing mucormycosis (e.g., diabetics, hematopoetic cell transplant recipients receiving other nephrotoxic drugs).

  • Although echinocandins have intrinsically weak activity against many Mucorales, Mucorales still express the target of echinocandins (beta 1,3-D-glucan synthase), and experimental, as well as a few clinical reports, have demonstrated benefits of combined lipid amphotericin B plus echinocandin therapy for mucormycosis.

  • Fluconazole, voriconazole, and flucytosine lack activity against Mucorales. Itraconazole has weak activity against some Mucorales but is less active than posaconazole.

  • Posaconazole has been reported to be an effective salvage therapy for patients with mucormycosis by van Burik and colleagues; however, the variable absorption of the current oral micronized suspension makes it a less-desirable treatment option during the acute phases of treatment for an aggressive infection. Posaconazole is typically initiated in patients who can tolerate oral therapy once the infection has stabilized, with some overlap of lipid amphotericin B therapy until serum posaconazole concentrations can be verified (target trough >500 ng/mL, ideal trough 1000-1500 ng/mL). Because posaconazole is generally well tolerated and can be taken by mouth, it is the preferred agent for longer-term therapy in patients who do not have evidence of progressive infection, provided oral absorption can be documented with serum drug levels.

  • Adjunctive therapies have been explored for improving tissue viability, inhibiting fungal proliferation, and enhancing host immunity.

    • Given the central role of free iron acquisition in the pathogenesis of mucormycosis, iron chelation therapy with agents that lack xenosiderophore activity (i.e., deferiprone and deferasirox) has been reported to directly inhibit growth of Mucorales in tissue and enhance host immunity. Yet, a recently reported Phase II trial examining adjunctive deferasirox for mucormycosis found lower global response rates and increased mortality in patients who received adjunctive deferasirox therapy. However, these findings were likely skewed by the higher proportion of patients in the deferasirox arm who had intensive immunosuppression or active leukemia. Nevertheless, the authors concluded that their data did not support a role for initial, adjunctive deferasirox in treatment of mucromycosis.

    • Hyperbaric oxygen therapy has been suggested to be beneficial adjunct to surgical resection and systemic antifungal therapy in patients with rhinocerebral mucromycosis or soft-tissue infections. High oxygen concentrations may directly impair the growth rate of Mucorales, improve wound healing through release of tissue growth factors, and improve neutrophil activity and putative oxidative killing mechanisms of amphotericin B. Clinical evidence supporting the benefits of hyperbaric therapy are limited, however, and treatment is often expensive and logistically difficult in severely ill patients.

    • Immune augmentation strategies, including the administration of cytokines that enhance phagocytic activity, such as granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor, and interferon-gamma alone or in combination with granulocyte transfusions, have been proposed for mucormycosis, These immune augmentation strategies carry some risk for enhancing inflammatory responses in the lung; therefore, the theoretical benefits of these strategies must be balanced with the possible risks to the patient, especially if lesions are near vital structures (i.e., central lung lesions surrounding the pulmonary artery).

  • Antifungal Resistance in Mucorales

    • Mucorales species are intrinsically resistant to many antifungal agents, including fluconazole, voriconazole, flucytosine, and echinocandins. Itraconazole and terbinafine have variable activity, whereas many Mucorales species are inhibited by posaconazole with mean inhibitory concentrations (MICs) less than 1 mcg/mL. Amphotericin B has reliable activity against Mucorales, but Rhizopus oryzae and Cunninghamella bertholletiae are relatively tolerant to the fungicidal effects of amphotericin B, and this species is less susceptible to posaconazole and amphotericin B compared to Absidia and Mucor species.

    • Recent sequencing of the Rhizopus oryzae suggests that the fungus has a 2-10-fold enrichment in gene families involved in ergosterol biosynthesis, cell wall biogenesis, cell growth, iron uptake, and production of known virulence factors compared to the more common Aspergillus fumigatus. This genetic arsenal may explain the remarkable capacity of this pathogen for rapid growth in hostile environments (i.e., host inflammatory milieu), as well as its resistance to multiple antifungal classes.

    • Data on the susceptibility of Mucorales are limited, and MIC testing is rarely performed outside of research laboratories or regional mycology reference testing centers. Standardized methods for MIC testing have been developed for filamentous fungi, but the sometimes rapid growth of Mucorales often makes test results inconsistent or difficult to interpret. Moreover, interpretative resistance breakpoints have not been defined for Mucorales. Therefore, MIC testing does not play a routine role in detecting resistance of managing patients with mucormycosis.

    • No reliably active alternative therapies for mucormycosis are available beyond lipid amphotericin B (alone or in combination with an echinocandin) and/or posaconazole. Isavuconazole, a triazole currently in Phase III trials, displays activity against some Mucorales but is unlikely to be more effective than posaconazole. Posaconazole is being developed as an intravenous formulation, which could significantly expand this triazole’s role during the acute phase of illness in a patient with mucormycosis.

How do patients contract mucormycosis, and how do I prevent spread to other patients?

Epidemiology

  • Mucormycosis is primarily acquired in immunocompromised hosts through inhalation of fungal spores from the environment. Soft-tissue infections may also develop in immunocompetent hosts following surgery, trauma, burns, direct injection, or catheter infections. Healthcare associated outbreaks of mucormycosis have been linked to contaminated bandages, needles, and tongue depressors used as splints in intravenous cannulation sites in preterm infants. Rare cases of gastrointestinal mucormycosis have been reported following ingestion of non-nutritional substances (pica), fermented porridges or alcoholic drinks, and herbal remedies contaminated with fungal spores.

  • Although no clear pattern of seasonality has been described with mucormycosis, outbreaks of respiratory and soft tissue infections have been observed following catastrophic weather events, including tsunamis, hurricanes, tornadoes, or volcanic eruptions. Mucormycosis should be considered in the differential diagnosis of any patient with progressive skin and soft tissue infection unresponsive to antibiotics following trauma during a catastrophic weather event.

  • Patient risk factors for mucormycosis include poorly controlled diabetes mellitus Type 1 or 2, metabolic acidosis, high-dose glucocorticoid therapy, penetrating trauma or burns, persistent neutropenia (i.e., >4 weeks), and chelation therapy with deferoxamine in patients on dialysis or chronic transfusion dependence. Mucormycosis has been less commonly reported in patients with renal failure without chelation therapy, malnutrition, low-birth weight infants, or patients with acquired immunodeficiency syndrome.

  • Mucormycosis cases have significantly increased over the last decade in patient populations classically at risk for opportunistic fungal infections, such as aspergillosis, including patients with hematological malignancy, recipients of hematopoietic cell transplantation (HCT), and patients undergoing solid organ transplantation. Data from the Center for Disease Control and Prevention (CDC) Transplant Associated Infection Surveillance Network (TRANSNET), which surveyed 25 U.S. Transplantation Centers from 2001-2006, noted a 1-year cumulative incidence rate of 3.8 per 1,000 HSCT and 0.6 per 1,000 solid organ transplants. The overall incidence increased from 1.7 per 1,000 in 2001 to more than 6.2 per 1000 in 2004, with Rhizopus spp. as the most common pathogen; however, the rate decreased in the subsequent 2 years of the study. The prevalence of mucormycosis in autopsy series has ranged from 1 to 5 cases per 10,000 autopsies, approximately10- to 50- fold less common than Candida or Aspergillus infection, respectively.

  • The routine use of voriconazole prophylaxis in many transplant centers has been temporally linked to an increase in mucormycosis cases since 2002. Although other clinical risk factors probably contribute equally to this trend (i.e., prolonged survival after transplant, hyperglycemia, and iron overload with prolonged corticosteroids and frequent transfusions) mucormycosis should be strongly suspected in any heavily immunosuppressed patient on voriconazole prophylaxis who develops fulminant sinusitis or nodular lung lesions.

Infection control issues

  • Patient-to-patient transmission of mucormycosis is unlikely. However, outbreaks or pseudo-outbreaks of healthcare-associated mucormycosis have been reported with contaminated bandages, tongue depressors, and other medical solutions or devices as previously described. Construction, excavation, or cleaning of airducts may aerosolize large inocula of Mucorales that, when inhaled, have been associated with slowly progressing pulmonary mucormycosis even in immunocompetent hosts.

  • Patients with soft tissue mucormycosis often have a history of preceding trauma that resulted in subcutaneous inoculation of fungal spores. Cutaneous mucormycosis has been reported even with minor trauma, including insect bites and tattooing.

  • Gloves, gown, and masking do not affect or protect against the transmission of mucormycosis.

  • There is no vaccine for mucormycosis.

  • Given the uncommon nature of infection, primary antifungal prophylaxis for mucormycosis is not recommended. However, secondary antifungal prophylaxis or chronic suppressive therapy should be considered for persistently immunosuppressed patients with intensification of therapy during periods of more severe immunosuppression. Anecdotal cases of mucormycosis reactivation in patients with acute leukemias and/or hematopoetic stem cell transplantation have been reported following more than 2 years of continuous treatment and prior good clinical response to antifungal therapy and tapering immunosuppression.

What host factors protect against mucormycosis?

  • Innate immune responses in healthy hosts typically clear sporangiospores before infection can be established.

  • To establish infection, spores must overcome killing by mononuclear and polymorphonuclear phagocytes to germinate into hypal forms, the angioinvasive form of the infection. Most inhaled spores can avoid upper host defenses and reach distal alveolar spaces. However, larger spores (>10 micrometers) may lodge in nasal turbinates, predisposing patients to sinusitis, as illustrated in Figure 1.

  • Patients with hemochromatosis (iron overload) are predisposed to mucormycosis because of the essential role free iron plays in the growth of Mucorales in vivo.

  • Patients with diabetic ketoacidosis are susceptible to developing rhinocerebral mucormycosis, perhaps because serum transferrin has a diminished capacity to bind and sequester free iron as the pH in the bloodstream falls below 7.4.

  • Historically, patients with severe hemochromatosis or aluminum toxicity received treatment with the chelation agent deferoxamine. However, deferoxamine can be utilized by some Mucorales (Rhizopus) as a xenosiderophore (foreign iron carrier protein) to form a ferrioxamine complex, which makes iron, which was previously unavailable, available to the fungus. Hence, deferoxamine therapy is associated with increased risk for fulminant mucormycosis

  • Unlike deferoxamine, newer iron chelators, such as deferiprone and deferasirox, have not been associated with increased risk for mucormycosis, because they cannot be utilized as a xenosiderophore by Mucorales. In fact, both deferiprone and deferasirox have demonstrated protective effects in experimental mucormycosis and mixed results in human mucormycosis due to their net iron-starvation effects on the fungus.

  • Mucorales have an exceptional capacity to invade blood vessels, resulting in hemorrhage and thrombosis of surrounding tissue and tissue necrosis.

  • Histopathologic examination of infected tissue typically reveals extensive necrosis with diffuse infiltration of polymorphonuclear neutrophils. Many areas with extensive ischemic necrosis demonstrate minimal inflammation despite extensive hyphal invasion. Pyogenic or a pyogranulomatous response without angioinvasion is common in tissue infections of otherwise healthy hosts.

Figure 1.

Pathophysiology of invasive mucormycosis.

Table I provides a list of predisposing conditions and their primary sites of infection.

Table I.

Predisposing Conditions and Sites of Infection
Predisposing Condition Predominary Site of Infection
Diabetes mellitus Rhinocerebral, sino-orbital, cutaneous
Malignancy Pulmonary, sinus, cutaneous, sino-orbital
Hematopoetic stem cell transplantation Pulmonary, disseminated, rhinocerebral
Solid organ transplantation Sinus, cutaneous, pulmonary, rhinocerebral, disseminated
Intravenous drug use Cerebral, endocarditis, cutaneous, disseminated
Deferoxamine therapy Disseminated, pulmonary, rhinocerebral, cutaneous, gastrointestinal
Trauma Cutaneous, ocular

What are the clinical manifestations of infection with these organisms?

  • Rhinosinusitis, rhino-orbital, and rhinocerebral infections are common manifestations of mucormycosis. Infection is initially localized to the nasal turbinates and paranasal sinuses following inhalation of sporangiospores but rapidly progresses to the orbit (sino-orbital) or brain (rhinocerebral), especially in patients with diabetic ketoacidosis or profound neutropenia.

    • Initial symptoms of sinus invasion by mucromycosis are indistinguishable from other more common causes of sinusitis. Sinus pain, congestion, headache, mouth or facial pain, otologic symptoms, and hypoosmia and anosmia are common.

    • Sinus disease often extends into contiguous structures. Maxillary sinus infection extends to the hard palate, nasal cavity, and ethmoid sinus. Sphenoid infection invades the cavernous sinus, contiguous temporal lobe, and internal caraotid artery in the siphon. Ethmoid sinus disease may invade the face or frontal lobe of the brain but easily crosses the lamina papyracea into the orbit, causing unilateral infection.

    • Periorbial edema, proptosis, chemosis, and preseptal and orbial cellulitis are early signs of orbital extension. Pain and blurring/loss of vision often indicate the invasion of the globe or optic nerve. Patients with extensive rhino-orbital or rhinocerebral disease may present with trigeminal and facial cranial nerve palsy with invasion of the cavernous sinus. A bloody nasal discharge may be the only sign that infection has invaded through the nasal turbinates into the brain.

    • Intracranial complications include epidural and subdural abscess and cavernous and less commonly sagittal sinus thrombosis. Frank meningitis is uncommon.

    • Involved tissues become red, then violaceous, and finally black with thrombosis and tissue necrosis. Necrotic eschars of the nasal cavity and turbinates may be evident with nasal endoscopy. Facial lesions, exophytic or necrotic lesions of the hard palate are often signs of rapidly progressing infection, as illustrated in Figure 2.

    • The absence of lesions does not rule out sinus mucormycosis, as necrotic or hard palate lesions may only be present in 50% of patients

    • Non-productive cough is often the only symptom of lung involvement

    • Radiographic imaging often suggests severe sinusitis but is not specific for mucormycosis. Patients may also have superimposed bacterial sinusitis or bacterial meningitis following invasion of the dura mater. Computed tomography of the sinuses typically reveals mucosal thickening, air-fluid levels, and boney erosion, as illustrated in Figure 3. Orbital muscle thickening may be detected on CT scan but can be detected earlier by MRI.

    • Severely immunosuppressed patients often present with pansinusitis highly suggestive of an aggressive fungal infection. Therefore, systemic antifungal therapy active against Mucorales (typically a lipid amphotericin B formulation) should be started immediately in severely immunosuppressed patients until surgical exploration of the sinus or biopsy can be performed.

    • Initial CT and MRI scans are sometimes unremarkable in patients during the initial stages of rhinocerebral mucormycosis but show evidence of rapid infection progression 48-72 hours later. Therefore, serial radiographic imaging is important in patients with suspected mucormycosis.

    • Rhinoscopy or nasal endoscopy should be performed as soon as possible to look for areas of tissue ischemia or necrosis. Biopsies and/or surgical exploration of suspicious lesions should be performed to establish an early definitive diagnosis.

  • Pulmonary mucormycosis is most commonly encountered in patients with prolonged neutropenia, recipients of hematopoetic cell or solid organ transplantation, or patients who have received deferoxamine therapy.

    • Pulmonary infection may occur in conjunction with sinus infection.

    • The clinical and radiographic manifestations of pulmonary mucormycosis are indistinguishable from more common molds, such as invasive pulmonary aspergillosis. Therefore, timely diagnosis is critical for patient outcome as many frontline agents used for invasive aspergillosis (i.e., voriconazole) lack activity against Mucorales. Delays in the administration of Mucorales-active therapy for pulmonary infection by as little as 6 days has been associated with a doubling of patient mortality.

    • Clinical manifestations of pulmonary mucormycosis are subtle and non-specific even in later stages of infection. Patients typically present with refractory fever on broad-spectrum antibiotics, nonproductive cough, progressive dyspnea, and pleuritic chest pain.

    • Mucormycosis can rapidly traverse tissue planes in the lung, including the bronchi, diaphragm, chest wall, and pleura.

    • Clues that may be suggestive of pulmonary mucormycosis versus aspergillosis in severely immunocompromised patients include severe sinusitis, infection that develops on voriconazole therapy, and repeated absence of detectable Aspergillus galactomannan antigen in the serum or bronchoalveolar lavage fluid.

    • Polymicrobrial pneumonia is common in patients with pulmonary mucormycisis, which can confound microbiologic diagnosis

    • Radiographic presentation of pulmonary mucormycosis is broad, including nonspecific infiltrates, nodular lesions, cavitary lesions, or even diffuse opacities.

    • High resolution chest CT is the best method for determining the extent of pulmonary mucormyciosis.

    • Thrombosis of pulmonary vessels with fungal invasion often results in wedge-shaped infarcts, as illustrated in Figure 4. Halo and air crescent signs are less common compared to pulmonary aspergillosis; however, reverse halo sign (a focal round area of ground glass opacity surrounded by a ring of consolidation) may be a more common in patients with pulmonary mucormycosis versus aspergillosis.

    • Centrally-located cavitating lesions with the air-crescent sign are often associated with increased risk for pulmonary artery erosion and massive hemoptysis.

    • Pulmonary mucormycosis will rapidly spread to the contralateral lung and distal organs if not promptly treated. Patients typically die from disseminated infection before respiratory failure occurs.

    • In immunocompetent hosts, pulmonary mucormycosis may present with a slowly progressing pneumonia with pulmonary aneurysms and pseudoaneurysyms, bronchial obstruction, or solitary nodules.

    • Diabetic patients may present with solidary endobronchial infection that has a less fulminant course than pulmonary mucormycosis in the neutropoenic or transplant population. Occasionally, these endobronchial lesions obstruct major airways or erode into pulmonary arteries leading to fatal hemoptysis.

    • Similar to Aspergillus, Mucorales can form mycetomas in preexisting lung cavities or produce a slowly progressive necrotizing pneumonia and hypersensitivity syndrome. Rhizopus species have been implicated in allergic alveolitis in farm workers and Scandinavian sawmill workers.

  • Cutaneous mucormycosis is typically the result of direct spore inoculation or exposure to skin already compromised by burn or trauma.

    • Cutaneous mucormycosis typically begins as erythema and induration of the skin at a puncture site and progresses to necrosis with a black eschar. Cutaneous infections can progress rapidly to involve the deep fascia and muscle layers. Necrotizing fasciitis has been reported in patients with cutaneous mucromycosis and is associated with an extremely poor prognosis.

    • Although the skin is a less common site of secondary involvement for disseminated mucormycosys relative to other molds (i.e., Aspergillus, Fusarium), cutaneous lesions are occasionally observed in neutropenic patients with disseminated infection.

Figure 2.

Rhinocerebral mucormycosis involving the hard palate.

Figure 3.

Computed tomography image from a patient with mucormycosis sinusitis demonstrating air-fluid level that is indistinguishable from bacterial sinusitis.

Figure 4.

Chest computed tomography image of HSCT patient with pulmonary mucormycosis.

What common complications are associated with infection with these pathogens?

  • The site of infection and underlying host factors (immunosuppression) are key prognostic determinants of mucormycosis outcome.

  • Patients with active hematologic malignancy, allogeneic hematopoetic cell transplantation, and disseminated infection have the poorest outcome with most patients dying within 12 weeks of diagnosis.

  • Early diagnosis, correction of underlying immunosuppression combined with aggressive multi-faceted treatment (i.e., systemic antifungal therapy, surgery) offers the best opportunity for patient survival.

How should I identify the Mucorales?

  • Fungal culture and identification

    • Because of the ubiquitous nature of the fungus in the environment, positive cultures occasionally reflect culture contamination rather than true disease. However, discovery of Mucorales in a specimen from the "right host" (i.e., hematopoetic cell transplant recipient) is an important diagnostic clue that should be confirmed with tissue biopsy/histopathologic confirmation.

    • Skin and sinus infection generally can be definitively diagnosed through biopsy, even in severely thrombocytopenic patients, given the accessibility of these infection sites.

    • Tissue swabs and cultures of sputum, sinus secretions, nasal mucosa, as well as bronchoalveolar lavage fluid are typically nondiagnostic but occasionally grow the fungus.

    • Blood cultures rarely grow Mucorales, despite the angioinvasive nature of the infection.

    • Identification of Mucorales to the genus and species level requires growth of the fungus in culture to identify reproductive fruiting structures of the fungus. Most species grow rapidly on rich media, such as sabouraund dextrose agar when incubated at 25-30°C.

    • Unfortunately, culture recovery of Mucorales from tissue is inherently poor because of the friable nature of the non-septate hyphae in tissue. Therefore, tissue should be minced (not homogenized) during preparation. Recovery from tissue may also be aided by growing the cultures in a reduced oxygen environment at 37°C.

  • Histology: In tissue, Mucorales hypahe can be differentiated from other more common opportunistic molds, such as Aspergillus and Fusarium, by their broad (3-25 micrometer), empty, thin-walled, mostly aseptate hyphae, as seen in Figure 5.

    • Tissue sections may show mixed hyphal forms that include folded, twisted, or compressed hyphae that can be mistaken for septae. Mistaken histologic identification is common, especially in laboratories not attuned to diagnosis of mucormycosis, and can lead to inappropriate therapy.

    • A variety of stains, including hemtoxylin and eosin, Grocott-Gomori methenamine silver, and periodic acid-schiff stains, reveal characteristic hyphal elements in tissue.

    • Treatment with fluorescent stains, such as Calcofluour white, Blankofluor, or Uvitex, may enhance detection of hyphae during microscopic examination and improve the discrimination between septate and aseptate molds in biopsy specimens.

Figure 5.

Histopathology of mucormycosis (A) hematoxylin and eosin stain and (B) Grocott's methanamine silver stain.

How do these organisms cause disease?

  • Specific virulence factors are not well characterized for Mucorales beyond their marked capacity relative to other pathogenic fungi for rapid growth in vivo.

  • The recent sequencing of a R. oryzae strain isolated from a patient with fatal infection revealed a surprising number of repetitive gene families relative to other sequenced pathogenic fungi that may have resulted from an ancestral whole-genome duplication event followed by a massive gene loss. This evolutionary path appears to have dramatically enriched the R. oryzae genome with the capabilities for maintaining growth and metabolism under highly varied environmental conditions, production of fungal virulence factors (e.g., secreted aspartic proteases and subtilases), capabilities for accelerated fungal cell wall/membrane synthesis and remodeling, and iron assimilation from host hemoglobin. Consequently, R. oryzae is genetically equipped for rapid angioinvasive growth in humans, adaptation to hostile environments, such as the host immune response, and overcoming the effects of systemically-administered antifungal agents.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Andes, D, Pascual, A, Marchetti, O. "Antifungal therapeutic drug monitoring: established and emerging indications". Antimicrob Agents Chemother. vol. 53. 2009. pp. 24-34.

(Comprehensive review on therapeutic drug monitoring with antifungal that includes specific recommendations for posaconazole monitoring in the prophylaxis and treatment of invasive fungal infection.)

Artis, WM, Fountain, JA, Delcher, HK, Jones, HE. "A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability". Diabetes. vol. 31. 1982 Dec. pp. 1109-14.

(Classic paper that demonstrated the link between free iron availability in diabetic ketoacidotic patients and the pathogenesis of mucormycosis.)

Chamilos, G, Lewis, RE, Kontoyiannis, DP. "Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis". Clin Infect Dis 2008 Aug. vol. 47. 15. pp. 503-9.

(Study in whether hematological malignancy patients that demonstrates delays in the administration of Mucorales-active antifungal therapy in patients with pulmonary mucormycosis is associated with increased mortality.)

Chamilos, G, Marom, EM, Lewis, RE, Lionakis, MS, Kontoyiannis, DP. "Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer". Clin Infect Dis. vol. 41. 2005. pp. 60-66.

(Retrospective study that examined clinical and radiographic features that may allow clinicians to distinguish invasive pulmonary mucormycosis from aspergillosis.)

Greenberg, RN, Mullane, K, Van Burik, JA. "Posaconazole as salvage therapy for zygomycosis". Antimicrobial Agents Chemother. vol. 50. 2006. pp. 126-33.

van Burik, JA, Hare, RS, Solomon, HF, Corrado, ML, Kontoyiannis, DP. "Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases". Clin Infect Dis. vol. 42. 2006. pp. e61-5.

(Two studies that summarize clinical experience, safety, and toxicity of using posaconazole for the treatment of invasive mucormycosis.)

Ibrahim, A, Gebermariam, T, Fu, Y. "The iron chelator deferasirox protects mice from mucormycosis through iron starvation". J Clin Invest. vol. 117. 2007. pp. 2649-57.

(An analysis of the mechanisms by which new generation iron chelators, which cannot be used by Mucorales as xenosiderophores, exhibit anti-mucorales activity in vitro and in vivo.)

John, BV, Chamilos, G, Kontoyiannis, DP. "Hyperbaric oxygen as an adjunctive treatment for zygomycosis". Clin Microbiol Infect. vol. 11. 2005. pp. 515-7.

(Review of published literature concerning the use of hyperbaric oxygen therapy for mucormycosis and critical analysis.)

Kontoyiannis, DP, Chamilos, G, Hassan, SA, Lewis, RE, Albert, ND, Tarrand, JJ. "Increased culture recovery of Zygomycetes under physiologic temperature conditions". Am J Clin Pathol. vol. 127. 2007. pp. 208-12.

(Laboratory study that suggested growth of Mucorales from tissue samples can be improved if samples are minced and culture is performed in microaerophilic conditions at 37°C.)

Kontoyiannis, DP, Lewis, RE. "How I treat mucormycosis". Blood. vol. 118. 2011. pp. 1216-24.

Kontoyiannis, DP, Lionakis, MS, Lewis, RE. "Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases". J Infect Dis. vol. 191. 2005. pp. 1350-60.

(Case-control study of mucormycosis in hematological malignancy patients that identified voriconazole pre-exposure as an independent risk factor for infection.)

Lass-Florl, C, Resch, G, Nachbaur, D. "The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients". Clin Infect Dis. vol. 45. 2007. pp. e101.

(Study that utilized a unique algorithm of adjunctive diagnostics tests and microscopy (calcoflour staining for septated versus nonseptated hyphae, Aspergillus galactomannan,and PCR tests) to distinguish Aspergillus infections from Mucorales infection CT-guided lung biopsy specimens.)

Ma, LJ, Ibrahim, AS, Skory, C. "Genomic analysis of the basal lineage fungus Rhizopus oryzae reveals a whole-genome duplication". PLoS Genet. 2009. pp. 5e1000549.

(Summarizes findings from genomic sequencing of Rhizopus oryzae and possible explanations for the remarkable capacity of the organism for aggressive growth, pathogenesis in humans, and possibly resistance to multiple antifungal classes.)

Neofytos, D, Horn, D, Anaissie, E. "Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry". Clin Infect Dis. vol. 48. 2009. pp. 265-7.

(Contemporary epidemiological survey of invasive fungal infections in adult HSCT patients that demonstrated that mucormycosis was the third most common invasive fungal infection and associated with significantly higher mortality than aspergillosis or candidiasis.)

Park, BJ, Pappas, PG, Wannemuehler, KA. "Invasive non-Aspergillus mold infections in the transplant recipients, United States 2001-2006". Emerging Infect Dis. vol. 17. 2011. pp. 1855-64.

(Contemporary epidemiological survey of transplant centers that demonstrated increasing incidence and high mortality rates of mucormycosis in the United States.)

Reed, C, Bryant, R, Ibrahim, AS, Edwards, J, Filler, SG, Goldberg, R, Spellberg, B. "Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis". Clin Infect Dis. vol. 47. 2008. pp. 364-71.

(Retrospective study of 41 patients with rhinocerebral mucormycosis that suggested combination of an echinocandin plus lipid amphotericin B formulation is associated with significantly improved clinical success and survival compared to lipid amphotericin B alone.)

Roden, MM, Zaoutis, TE, Buchanan, WL. "Epidemiology and outcome of zygomycosis: a review of 929 reported cases". Clin Infect Dis. vol. 41. 2005. pp. 634-53.

(The largest epidemiological survey of mucormycosis.)

Spellberg, B, Ibrahim, AS, Chin-Hong, PV. "The Deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial". J Antimicrob Chemother. 2011 Sept 20.

(A phase II trial of deferasirox adjunctive therapy for mucormycosis, which failed to show a benefit and possibly increased mortality with iron chelation therapy. However, the results may have been skewed by imbalances in the proportion of patients with poorly controlled leukemia enrolled in the deferasirox arm.)
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