Review
Mucormycosis: its contemporary face and management strategies

https://doi.org/10.1016/S1473-3099(10)70316-9Get rights and content

Summary

Several countries have seen rising frequencies of mucormycosis among patients with haematological disorders, malignancies, or diabetes mellitus, and among transplant recipients. Growing numbers of immunocompromised hosts, widespread use of antifungal agents inactive against mucormycosis, or other unidentified factors, could be contributing to this situation. The predominant clinical manifestations of mucormycosis vary from host to host. Additionally, risk factors specific to different subgroups have been identified, such as leukaemia, allogeneic haemopoietic stem-cell transplant, voriconazole prophylaxis, diabetes, and malnutrition. We summarise the current state of knowledge of characteristics and risk factors and discuss topical developments in therapeutic methods and strategies in the management of mucormycosis.

Introduction

With the advent of effective antifungal agents against Candida and Aspergillus spp, a growing population of immunocompromised hosts, improved diagnostic tools, and possible selection pressure from widespread use of broad-spectrum antifungal agents, mucormycosis has emerged as an important infection. Mucormycosis and entomophthoramycosis were previously encompassed by the term zygomycosis.1 Changes in high-level taxonomy in reference to molecular phylogenetic analyses have, however, led to the class name Zygomycota being replaced by Glomeromycota.2 In this new classification, all the agents of mucormycosis have been placed under the subphylum Mucormycotina and the agents of entomophthoramycosis are now in the subphylum Entomophthoramycotina. Since the phylum Zygomycota no longer exists, the disease name zygomycosis has become obsolete.3

Mucormycotina are characterised by large, ribbon-like hyphae with only occasional septae (aseptate fungi). These fungi cause mucormycosis, which comprises severe and potentially life-threatening infections, particularly in immunocompromised hosts. Improvements in culture-based morphological and molecular identification of fungi in the past two decades have led to expansion of the number of species known to cause mucormycosis. Infections are, however, primarily caused by those in the order Mucorales and the family Mucoraceae.4

Mucormycosis was reported in the Transplant Associated Infectious Surveillance Network study to occur in 9% of haemopoietic stem-cell transplant (HSCT) recipients and 2·1% of solid-organ transplant recipients.5, 6 Increases in incidence of mucormycosis have been reported in several countries in the past few years.7, 8, 9, 10, 11, 12, 13, 14 In developed countries, such as the USA, France, and Austria, mucormycosis mainly occurs in transplant recipients and neutropenic patients, although in France the frequency is rising among patients with diabetes mellitus.10, 11, 12, 13 In India the frequency has risen from 13 cases per year in 1990–99 to 36 cases per year in 2000–04, and 50 cases per year in 2006–07,7, 8, 9 and the highest-risk group is patients with uncontrolled diabetes.15

In immunocompetent patients, Apophysomyces elegans has emerged as an important pathogen for mucormycosis, leading to primarily cutaneous and rhino-orbital-cerebral disease with infections and generally occurring after traumatic inoculation.16, 17, 18 Additionally, several studies from India have reported isolated renal mucormycosis due to A elegans, mostly in immunocompetent young adults.7, 8, 9 Although rare, mucormycosis outbreaks—defined as more than two cases in 2–6 months—have been reported to occur in hospitals.19

In this Review we summarise the current state of knowledge about features of and risk factors for mucormycosis, and provide updates on potential therapeutic options and strategies for the management of this infection.

Section snippets

Clinical manifestations

Invasive mucormycosis is characterised by the rapid development of tissue necrosis as a result of vascular invasion and subsequent thrombosis. Disease may manifest as rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, or disseminated forms.1 In a review of 929 patients with mucormycosis assessed in 1940–2003, diabetes was the most frequent underlying condition (36%).20 The predominant clinical manifestations differ from host to host. Patients with diabetes most frequently present

Treatment

Successful treatment of mucormycosis requires early diagnosis, reversal of underlying risk factors, reduction, if possible, of immunosuppression, prompt administration of antifungal therapy, and surgical debridement when applicable.43 Delayed initiation of an amphotericin-B-based regimen (>6 days after diagnosis) has been reported to be associated with doubled mortality at 12 weeks.44 In patients with diabetes, with or without ketoacidosis, efforts should be made to restore euglycaemia and

Preventive strategies

In patients with GVHD who are receiving immunosuppressive therapy, and in patients with neutropenia due to chemotherapy for acute myelogenous leukaemia and myelodysplastic syndrome, prophylaxis with posaconazole substantially decreases the incidence of invasive fungal infections, particularly invasive aspergillosis.78, 79 In two studies mortality associated with invasive fungal infections was lowered,78, 79 although overall mortality was only lowered in one.78 These findings, along with the

Conclusions

Mucormycosis is an important opportunistic fungal infection, particularly in patients with haematological disorders, malignancy, and diabetes mellitus, and in those undergoing transplantation. Whether the rising rates in certain populations are related to evolving characteristics of patients or to antimicrobial selection pressure from prescription practices for current antifungal agents deserves further investigation. Liposomal amphotericin B is the preferred therapeutic agent for mucormycosis.

Search strategy and selection criteria

Data were identified by searches of PubMed for articles published from 1950 to 2010, with the terms “zygomycetes”, “mucormycosis”, “Mucorales” and “breakthrough”, “voriconazole”, “posaconazole”, “echinocandins”, “caspofungin”, “micafungin”, “anidulafungin”, “hematological malignancy”, “transplant”, “polyene”, “amphotericin B deoxycholate”, “liposomal amphotericin B”, “amphotericin B lipid complex”, “calcineurin inhibitors”, “tacrolimus”, “cyclosporine”, “mammalian target of rapamycin”,

References (136)

  • LJ Lekakis et al.

    Fatal rhizopus pneumonia in allogeneic stem cell transplant patients despite posaconazole prophylaxis: two cases and review of the literature

    Biol Blood Marrow Transplant

    (2009)
  • DW Denning

    Echinocandin antifungal drugs

    Lancet

    (2003)
  • HY Sun et al.

    Characterisation of breakthrough invasive mycoses in echinocandin recipients: an evidence-based review

    Int J Antimicrob Agents

    (2010)
  • M Terblanche et al.

    Statins and sepsis: multiple modifications at multiple levels

    Lancet Infect Dis

    (2007)
  • LV Roze et al.

    Lovastatin triggers an apoptosis-like cell death process in the fungus Mucor racemosus

    Fungal Genet Biol

    (1998)
  • DP Kontoyiannis et al.

    Agents of mucormycosis and entomophthoramycosis

  • JE Bennett

    Introduction to mycoses

  • JA Ribes et al.

    Zygomycetes in human disease

    Clin Microbiol Rev

    (2000)
  • DP Kontoyiannis et al.

    Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database

    Clin Infect Dis

    (2010)
  • PG Pappas et al.

    Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

    Clin Infect Dis

    (2010)
  • A Chakrabarti et al.

    The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus

    Med Mycol

    (2006)
  • A Chakrabarti et al.

    Invasive zygomycosis in India: experience in a tertiary care hospital

    Postgrad Med J

    (2009)
  • DP Kontoyiannis et al.

    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

    (2005)
  • D Bitar et al.

    Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006

    Emerg Infect Dis

    (2009)
  • S Husain et al.

    Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-aspergillus mycelial fungi

    Clin Infect Dis

    (2003)
  • I Stelzmueller et al.

    Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients

    Transpl Int

    (2008)
  • G Chamilos et al.

    Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage

    Antimicrob Agents Chemother

    (2008)
  • A Diwakar et al.

    Zygomycosis—a case report and overview of the disease in India

    Mycoses

    (2007)
  • L Garcia-Covarrubias et al.

    Rhino-orbitocerebral mucormycosis attributable to Apophysomyces elegans in an immunocompetent individual: case report and review of the literature

    J Trauma

    (2001)
  • KP Liang et al.

    Rhino-orbitocerebral mucormycosis caused by Apophysomyces elegans

    J Clin Microbiol

    (2006)
  • MM Roden et al.

    Epidemiology and outcome of zygomycosis: a review of 929 reported cases

    Clin Infect Dis

    (2005)
  • G Chamilos et al.

    Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer

    Clin Infect Dis

    (2005)
  • H Wahba et al.

    Reversed halo sign in invasive pulmonary fungal infections

    Clin Infect Dis

    (2008)
  • OS Lo et al.

    Ileocolonic mucormycosis in adult immunocompromised patients: a surgeon's perspective

    World J Gastroenterol

    (2010)
  • R Kalpatti et al.

    Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease

    Pediatr Blood Cancer

    (2010)
  • N Singh et al.

    Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome

    J Infect Dis

    (2009)
  • SM Trifilio et al.

    Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy

    Bone Marrow Transplant

    (2007)
  • FM Marty et al.

    Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants

    N Engl J Med

    (2004)
  • GT Siwek et al.

    Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis

    Clin Infect Dis

    (2004)
  • A Imhof et al.

    Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole

    Clin Infect Dis

    (2004)
  • MJ Ruping et al.

    Forty-one recent cases of invasive zygomycosis from a global clinical registry

    J Antimicrob Chemother

    (2010)
  • T Martin et al.

    Voriconazole is safe and effective as prophylaxis for early and late fungal infections following allogeneic hematopoietic stem cell transplantation

    Transpl Infect Dis

    (2009)
  • A Torres et al.

    Voriconazole as primary antifungal prophylaxis in patients with neutropenia after hematopoietic stem cell transplantation or chemotherapy for acute myeloid leukemia

    Eur J Haematol

    (2010)
  • U Gergis et al.

    Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD

    Bone Marrow Transplant

    (2009)
  • S Trifilio et al.

    Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole

    Bone Marrow Transplant

    (2007)
  • TJ Walsh et al.

    Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever

    N Engl J Med

    (2002)
  • S Vigouroux et al.

    Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required

    Clin Infect Dis

    (2005)
  • L Pagano et al.

    Breakthrough zygomycosis and voriconazole

    J Infect Dis

    (2005)
  • GA Lamaris et al.

    Increased virulence of Zygomycetes organisms following exposure to voriconazole: a study involving fly and murine models of zygomycosis

    J Infect Dis

    (2009)
  • B Spellberg et al.

    Recent advances in the management of mucormycosis: from bench to bedside

    Clin Infect Dis

    (2009)
  • Cited by (138)

    View all citing articles on Scopus
    View full text