Abstract
Purpose of Review
Invasive mucormycosis (IM), caused by fungi of the order Mucorales, is one of the deadliest fungal infection among hematologic cancer patients. Its incidence is also increasingly reported in immunocompetent individuals, notably with the COVID-19 pandemic. Therefore, there is an urgent need for novel diagnostic and therapeutic approaches of IM. This review discusses the current advances in this field.
Recent Findings
Early diagnosis of IM is crucial and can be improved by Mucorales-specific PCR and development of lateral-flow immunoassays for specific antigen detection. The spore coat proteins (CotH) are essential for virulence of the Mucorales and may represent a target for novel antifungal therapies. Adjuvant therapies boosting the immune response, such as interferon-γ, anti-PDR1 or fungal-specific chimeric antigen receptor (CAR) T-cells, are also considered.
Summary
The most promising perspectives for improved management of IM consist of a multilayered approach targeting both the pathogen and the host immune system.
Similar content being viewed by others
Introduction
Invasive mucormycosis (IM) is an invasive fungal disease due to filamentous fungi (molds) of the order Mucorales (e.g. Mucor, Rhizopus, Lichtheimia, Rhizomucor or Cunninghamella). These rapidly growing fungi have the ability to cause extensive tissue damages with inflammation and necrosis. Albeit relatively rare, IM is one of the deadliest infection among patients with hematologic cancer [1, 2, 3•, 4]. It may also affect patients with other immunosuppressive conditions, such as solid-organ transplant recipients and apparently immunocompetent individuals, such as those with uncontrolled diabetes mellitus and ketoacidosis [1, 2, 5, 6]. Recently, a high incidence of IM has been reported among patients with severe Coronavirus disease 2019 (COVID-19), in particular those with diabetes [7]. The SARS-CoV-2 virus may affect the pancreatic islets via the angiotensin-converting enzyme 2 (ACE2) receptor and decompensate pre-existing diabetes [8]. Moreover, insulin resistance can result from corticosteroids that are used for the treatment of COVID-19.
Pulmonary mucormycosis is the predominant presentation of IM among severely immunocompromised patients who may also present dissemination of the disease to other organs, while rhino- orbito-cerebral (ROC) mucormycosis is more frequently observed among diabetic patients [2]. Cutaneous mucormycosis mainly occurs after trauma or burns, in particular when wounds are contaminated by dust or mud (e.g. tornadoes, hurricanes, flooding) [9, 10].
IM represents the second most frequent invasive mold disease after invasive aspergillosis in immunocompromised patients accounting for 8–9% and 2–3% of cases among hematopoietic stem cell and solid organ transplant recipients, respectively [6, 11]. The incidence of IM greatly varies from one country to another with the highest incidence reported from South Asia (14 cases per 100,000 inhabitants in India and Pakistan) and lower incidences in Europe and USA (< 0.5 per 100,000) [12], which may be related to local climatic conditions, prevalence of diabetes and access to healthcare systems. Most epidemiological studies suggest that the incidence of IM is increasing, as the consequence of the expanding population of patients with prolonged immunosuppressive conditions in developed countries and the increasing prevalence of diabetes mellitus in low-income countries [12–16]. However, other triggers might be involved, such as improved diagnostic procedures (e.g. molecular methods) and possibly the impact of global warming and the increasing incidence of natural disasters. Notably, the COVID-19 pandemic has been associated with a huge rise of reported cases of IM, especially in India where its incidence has doubled [8, 17].
The mortality rate of IM remains high (about 40–50%) and the prognosis did not significantly improve over the last decades [3•, 18–20]. A similar poor outcome has been reported among patients with COVID-19–associated mucormycosis (CAM) [7, 8, 17]. A lower mortality rate has been reported among diabetic patients with ROC compared to that in hematologic patients with other localizations of the disease (mainly pulmonary) in some studies, but not all [3•, 5, 19, 20]. Disseminated forms and cerebral mucormycosis are associated with the worst outcome with up to 80% mortality rates [3•, 20].
Considering the global increasing incidence of IM and its particularly high mortality rate, there is an urgent need to improve our diagnostic and therapeutic approaches of this fungal disease. The aim of this review is to present the limitations of the current “state of the art” in the management of mucormycosis and to discuss research developments and novel perspectives for the future, which are summarized in Table 1.
Diagnosis of Mucormycosis
Current Approach
While the clinical presentation of ROC mucormycosis is very suggestive of the diagnosis in a patient at risk, pulmonary mucormycosis cannot be distinguished from other invasive mold infections, unless a reverse halo sign is present at chest CT, which is a good predictor of IM [21, 22]. Extrapulmonary IM in immunocompromised hosts (e.g. abdominal, cerebral) is not associated with any specific clinical or radiological presentation and may be misdiagnosed.
The microbiological diagnosis of IM is particularly difficult because of the low yield of cultures from clinical samples with 25 to 40% of cases being documented by histopathology only (i.e. presence of broad non-septate hyphae suggestive of Mucorales) [3•, 20, 23••]. The diagnosis of IM usually requires invasive procedures for the acquisition of deep tissue samples, which may result in significant delays. Rapid non-invasive diagnostic tools are needed for early diagnosis and prompt initiation of targeted antifungal therapy. The current commercialized kits for the detection of fungal biomarkers, such as the galactomannan and 1,3-β-d-glucan, cannot detect IM [24•]. Mucorales-specific PCRs currently represent the most sensitive approach and the unique diagnostic test that can be performed in serum for early diagnosis of IM. However, there is a lack of commercial and standardized methods [25••]. A combination of three real-time PCR targeting Mucor/Rhizopus, Rhizomucor and Lichtheimia spp. showed a sensitivity of 80–85% for detection of probable or proven IM in serum samples, which preceded diagnosis by conventional methods [26••, 27, 28]. This multiplex PCR also showed good sensitivity and specificity (100% and 97%, respectively) for the diagnosis of IM in bronchoalveolar lavage (BAL) samples [29]. Recently, a multiplex real-time PCR kit for a large panel of pathogenic Mucorales has been marketed (MucorGenius™, Pathonostics, Maastricht, The Netherlands) and demonstrated similar sensitivity for IM detection in serum samples (75%) and in pulmonary samples (100%) [30, 31]. Because of the low sensitivity of culture in tissue samples, use of in-house pan-Mucorales PCR assays targeting the conserved ribosomal DNA (mainly 18S rDNA or 28S rDNA and internal transcribed spacer [ITS] region) are helpful for diagnosis in native or formalin-fixed paraffin-embedded (FFPE) tissue samples [32–34].
Future Directions
The lack of a Mucorales-specific fungal biomarker that can be easily detected in serum is still a gap in the diagnostic approach of IM. Indeed, a test for such biomarkers may be cheaper and more broadly available than PCR. While Mucorales do not produce galactomannan and have few 1,3-β-d-glucan, other polysaccharides of their cell wall could be used as targets. A lateral flow immunoassay (LFA) with an antibody binding to α-1,6 mannan has been developed and showed good in silico performance for the detection of Mucorales (Mucor and Rhizopus) from culture extracts [35]. A clinical evaluation is still lacking. Another LFA targeting an extracellular polysaccharide, which is specific to Rhizopus arrhizus, has been developed and was successfully tested in spiked human serum and BAL [36].
Novel PCR approaches use targets that are more sensitive or more specific for discrimination of Mucorales at species level compared to the ribosomal DNA targets. PCR targeting the mitochondrial DNA (e.g. rnl gene, encoding for large-subunit ribosomal RNA) was more sensitive compared to PCR targeting nuclear ribosomal RNA (18S rDNA) for detection of Mucorales in FFPE tissue samples and more accurate for species identification [37]. Another candidate for a more specific detection of Mucorales is the spore coat protein (CotH), which is essential for angio-invasion via binding to the glucose-regulated protein 78 (GRP78) at the surface of endothelial cell [38, 39]. A PCR assay for CotH detection in urine demonstrated good performance in a murine model of IM and in patients with proven IM (about 90% sensitivity and 100% specificity) [40].
Metagenomic next generation sequencing has also demonstrated some utility for the early diagnosis of IM in case reports when other conventional methods have failed [41–43].
A preliminary study analyzing murine and human breath samples by thermal desorption gas chromatography/tandem mass spectrometry (GC–MS/MS) found distinct volatile metabolite (sequiterpene) profiles for the most frequent pathogenic Mucorales [44]. Such non-invasive approach might deserve further investigation as a diagnostic tool for IM or a screening strategy in high-risk patients.
Novel perspectives for the diagnosis of IM should also consider the use of positron emission tomography (PET) and magnetic resonance imaging (MRI) with a fungal specific radiolabeled marker, such as monoclonal antibodies or iron siderophores. These approaches, which have been studied in animal models for the diagnosis of invasive aspergillosis [45–50], have not yet been investigated for IM diagnosis.
Treatment of Mucormycosis
Current Approach
The treatment of IM relies on three major axes of equal importance: (i) early appropriate antifungal therapy, (ii) source control by surgery, and (iii) correction of immunosuppression [25••].
Only two antifungal drug classes are approved for the treatment of IM, the polyene amphotericin B and the new generation triazoles posaconazole and isavuconazole [25••]. Liposomal amphotericin B (L-AmB) at high doses (5–10 mg/kg/day) is the preferred first-line treatment. Its use is limited by renal toxicity and the lack of an oral formulation. In retrospective analyses of large cohorts, L-AmB was associated with lower mortality rates compared to that observed with other antifungal regimens [3•, 51, 52]. Posaconazole or isavuconazole, which are available as intravenous or oral formulations, are alternative options in case of preexisting or acute renal insufficiency and are privileged for maintenance outpatient therapy [25••]. In a single arm open-label trial, isavuconazole as first-line treatment of IM demonstrated similar success rates compared to those observed in a historical cohort of patients treated with amphotericin B formulations [23••]. Although posaconazole salvage therapy has been associated with acceptable success rates, data of its efficacy as first-line treatment of IM are lacking [53, 54]. It is noteworthy that the in vitro activity of posaconazole and isavuconazole against the Mucorales exhibits inter- and intra-species/genus variability with some isolates (mainly Mucor circinelloides and Rhizopus spp.) exhibiting high minimal inhibitory concentrations (MICs) [55], but there is no evidence that these differences affect the outcome [23••, 53, 54]. Combination therapies of L-AmB with either an echinocandin (caspofungin) or posaconazole are marginally recommended. The adjunction of caspofungin or anidulafungin to L-AmB or amphotericin B lipid complex showed improved efficacy compared to the monotherapies in a murine model of IM [56, 57]. However, results of clinical studies assessing the potential benefit of this combination were controversial [18, 19, 58, 59]. The combination of posaconazole and L-AmB did not demonstrate any synergism in a murine model of IM and there is no evidence of its clinical benefit, although its use has been reported [60, 61]. In the absence of comparative prospective studies, the actual impact of antifungal drug combinations on outcome cannot be assessed because of multiple biases. Indeed, many clinicians would favor combined therapies for more severe or refractory cases.
There is strong evidence that antifungal therapy alone is not sufficient to cure mucormycosis and that surgical source control should be performed whenever possible. Surgery was associated with a higher survival rate in several cohort studies of IM [2, 3•, 5, 19, 20, 52, 62–64]. Surgery should be early and as complete as possible, which may be difficult to achieve in the setting of profound thrombopenia and neutropenia in hematologic cancer patients, and in case of multiple infectious foci or invasion of adjacent anatomical structures.
Recovery of neutropenia is also a predictor of better outcome in hematologic cancer patients [62]. Recombinant human granulocyte–macrophage or granulocyte colony-stimulating factor (GM-CSF or G-CSF) is frequently used to accelerate neutrophil recovery following myeloablative chemotherapy of hematologic cancer, and their use as adjunctive therapy for the treatment of invasive mold infections has been considered [65]. In a murine model of Rhizopus oryzae disseminated infection, the adjunction of GM-CSF to L-AmB therapy could prolong survival and reduce fungal burden compared to L-AmB treatment alone [66]. Some case-series, especially in the pediatric population, reported promising results of adjunctive GM-CSF therapy for refractory IM, but comparative studies are lacking [67, 68]. Use of granulocyte transfusion as secondary prophylaxis or adjunctive treatment of IM or other invasive fungal infections has also been reported [69, 70]. However, one retrospective study showed that patients with invasive pulmonary aspergillosis who received adjunctive granulocyte transfusion had a high rate of pulmonary reactions and an overall worse outcome compared to those who were treated by antifungal therapy alone [71]. In patients receiving corticosteroid therapy, tapering of corticosteroid dosing is recommended whenever possible [25••]. In diabetic patients with IM, control of the underlying conditions with reversion of hyperglycemia and ketoacidosis is also warranted [25••].
Hyperoxic and hyperbaric conditions have an inhibitory effect on the growth of Mucorales in vitro and may also enhance the antifungal activity of amphotericin B and favor tissue healing [72, 73]. This practice has been occasionally applied for the treatment of IM with an overall good survival rate in case reports or case-series [2, 73]. One retrospective cohort study of hematologic cancer patients with IM found that treatment with hyperbaric oxygen was associated with better outcome [19]. However, prospective randomized comparative studies are lacking to demonstrate its benefit and this approach received a moderate strength of recommendation in guidelines [25••].
Because iron homeostasis is important for the virulence of Mucorales, iron chelators have been considered as adjunctive therapy of IM. Deferasirox showed promising results with synergistic effect in combination with L-AmB for the treatment of IM in diabetic mice [74]. In neutropenic mice, deferasirox was effective only when administered with a prolonged interdose interval, although no evidence of toxicity could be demonstrated [74]. Although deferasirox was safe for the treatment of IM in a small open-label case series or as compassionate use [75, 76], it failed to demonstrate its efficacy in combination with L-AmB and was even associated with a worse outcome compared to L-AmB monotherapy in a small placebo-controlled trial [77]. These results could be explained by an imbalance between both groups with a predominance of neutropenic patients in the deferasirox arm. While iron chelators cannot be recommended for the treatment of IM on the basis of current data, their utility in diabetic patients should be further investigated [25••].
Future Directions
Novel antifungal drugs are needed for the treatment of IM because of the limited efficacy and the potential toxicity of the only two available antifungal drug classes (i.e. amphotericin B and triazoles).
Novel antifungal drugs that are currently in phase II/III clinical trials include some first-in-class molecules (fosmanogepix, olorofim, ibrexafungerp) and modified compounds from existing antifungal drug classes with improved pharmacologic properties (rezafungin, tetrazoles, encochleated amphotericin B) [78].
Among the first-in-class antifungals, only fosmanogepix displays some effect against Mucorales. Fosmanogepix is an inhibitor of the glycosylphosphatidylinositol (GPI) biosynthesis pathway, which is required for the anchorage of mannoproteins in the cell membrane and cell wall [79]. It has a potent fungistatic effect with broad spectrum activity against most pathogenic yeasts and molds [78]. However, it has limited in vitro activity against Mucorales with MIC50 (i.e. encompassing 50% of isolates) of 4 to 16 mg/L [80]. The efficacy of fosmanogepix was tested in mice infected by two strains of Rhizopus arrhizus with MICs of 0.25 and 4 mg/L, respectively [81]. Fosmanogepix demonstrated a significant effect against both strains versus the placebo, which was comparable to that of isavuconazole. In another murine experiment using a R. arrhizus strain with low fosmanogepix MIC (0.25 mg/L), fosmanogepix was equally effective than L-AmB and the combination of both drugs was synergistic [82]. Although these results are encouraging, data about the efficacy of fosmanogepix against other species of Mucorales including isolates with higher MICs are needed. A small phase II non-comparative open-label study assessing the efficacy of fosmanogepix for the treatment of invasive aspergillosis and other invasive mold infections including IM has just been completed and results are expected (AEGIS, NCT04240886). While fosmanogepix displays some interesting properties, such as its oral bioavailability and its good penetration in the central nervous system, its potential for a future application in the treatment of IM seems limited.
The tetrazoles (VT-1161, VT-1598) have similar mechanism of action than other azole compounds, but a decreased affinity for human cytochrome P450 isoenzymes, which results in less hepatotoxicity and drug-drug interactions [83]. VT-1598 and VT-1161 displayed variable activity against R. arrhizus var. arrhizus, but not var. delemar [84, 85]. VT-1161 was effective in preventing and treating mice infected with R. arrhizus var. arrhizus [84, 86]. Data about the in vitro and in vivo efficacy of tetrazoles against other Mucorales are lacking.
To overcome the lack of oral bioavailability and toxicity of amphotericin B, a novel formulation of encochleated drug has been developed. Cochleates consist of a calcium-phospholipid anhydrous crystal that prevents hydrophobic amphotericin B from degradation in the gastro-intestinal tract and enables targeted delivery of the drug in the macrophages with reduced toxicity [87••]. In a phase I study, oral encochleated amphotericin B was well tolerated with only minor adverse events and no renal toxicity [88••]. Two phase II studies have assessed its efficacy for the treatment of chronic mucocutaneous and vulvovaginal candidiasis [87••]. Pre-clinical and clinical data of the efficacy of oral encochleated amphotericin B for the treatment of IM are currently lacking.
Among the novel antifungal agents that are in pre-clinical stage of development, strategies targeting the spore coat proteins homologs (CotH), which play a specific role in the virulence of the Mucorales, may represent the most promising perspective for the treatment of IM. CotH are a family of kinase proteins playing a role in morphogenesis (e.g. spore formation, cell wall structure), stress adaptation and virulence [89•]. CotH3, a surface protein of the Mucorales, binds to the glucose-regulated protein 78 (GRP78) receptor at the surface of human nasal epithelial cells and endothelial cells, which enables tissue invasion and angio-invasion [38, 39, 90•]. Elevated concentrations of iron, hyperglycemia and ketone bodies increase the expression of the GRP78 receptor and anti-GRP78 antibodies were shown to protect diabetic ketoacidotic (DKA) mice from IM [39]. Conversely, a Rhizopus oryzae mutant with reduced CotH3 expression exhibited a loss of ability to invade endothelial cells and decreased virulence in a DKA murine model of IM [38]. A similar effect could be obtained by polyclonal antibodies against CotH3, which was shown to protect both DKA and neutropenic mice from IM [91••]. This mechanism of pathogenicity seems to be predominant in patients with uncontrolled diabetes who are more prone to develop ROC mucormycosis. In pulmonary mucormycosis, which affects mainly hematologic cancer patients, lung invasion and angio-invasion seems to be mediated by another CotH protein (CotH7) via the integrin β1 receptor expressed at the surface of alveolar epithelial cells and subsequent activation of the epidermal growth factor receptor (EGFR) [90•]. Indeed, anti-integrin β1 antibodies could protect mice from pulmonary IM [90•]. These distinct pathways of pathogenesis may explain the predisposition of diabetic patients to develop ROC mucormycosis. The GRP78 receptor was also shown to play a role in recognition of the SARS-CoV-2 spike protein and to enable the translocation to the lung epithelial cell membrane of the angiotensin–converting enzyme 2 (ACE2) receptor, the major ligand of the virus [92]. The stress resulting from severe COVID-19 may therefore result in overexpression of GRP78 and favor IM [93]. This better understanding of the pathogenesis of IM opens perspectives for individualized therapeutic approach according to the type of underlying conditions and localization of the disease.
Because restoration of the host immune is another crucial determinant for the outcome of IM, strategies to boost the immune system are also investigated. Adjunctive therapy with interferon-γ and/or the checkpoint inhibitor anti-PDR1 antibody nivolumab has been used with success to treat refractory IM in some case reports [94–96]. This approach would deserve further investigation in randomized controlled trials.
Other strategies would consist of generating a specific and targeted response against the fungal pathogen. Ex vivo genetically modified T cells expressing a fungal-specific chimeric antigen receptor (CAR), such as dectin-1, demonstrated in vitro and in vivo (murine model) effect against Aspergillus [97]. Transfusion of leucocytes loaded ex vivo by the antifungal drug posaconazole could enhance activity of the drug in a murine model of invasive aspergillosis [98]. Such approaches have not yet been tested for the treatment of IM.
Conclusion
Despite improved diagnostic approaches with the development of molecular methods (e.g. PCR) and novel therapies (e.g. isavuconazole), the prognosis of IM remains poor with no significant decrease of the mortality rates over the last decade. The recent development of international guidelines for the management of IM and the development of a tool, the European QUALity (EQUAL) score, to assess adherence to these guidelines, may be helpful to improve the standardization of the management and the prognosis of IM [25••, 99, 100].
Because of the extremely aggressive and invasive course of the disease, the management of IM should involve multiple and distinct approaches, including screening for early detection, prompt appropriate antifungal therapy, surgery, correction of the underlying predisposing conditions (i.e. immunosuppression or hyperglycemia) and strategies to boost the immune response. While novel antifungal drugs that are currently in phase II/III clinical trials, such as fosmonagepix, olorofim or ibrexafungerp, seem to have no or little place for the treatment of IM, other antifungal strategies, which are currently at a pre-clinical stage, such as CotH3 or anti-integrin β1 antibodies, look promising. Strategies focusing on the host immune response, such as interferon-γ or anti-PDR1 antibody (nivolumab) also deserve further investigation in randomized controlled trials. Because IM is a relatively rare disease, it is difficult to initiate such large clinical trials and to get support from funding agencies for laboratory and clinical research. However, the recent burden of IM in the setting of the COVID-19 pandemic has brought more attention to this severe disease.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DCM, Chen SC. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports. Clin Microbiol Infect. 2019;25:26–34. https://doi.org/10.1016/j.cmi.2018.07.011.
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, Sein M, Sein T, Chiou CC, Chu JH, Kontoyiannis DP, Walsh TJ. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. https://doi.org/10.1086/432579.
• Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, Lass-Florl C, Bouza E, Klimko N, Gaustad P, Richardson M, Hamal P, Akova M, Meis JF, Rodriguez-Tudela JL, Roilides E, Mitrousia-Ziouva A, Petrikkos G, European Confederation of Medical Mycology Working Group on Z. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859–67. https://doi.org/10.1111/j.1469-0691.2010.03456.x. Large epidemiological study of mucormycosis.
Skiada A, Pavleas I, Drogari-Apiranthitou M. 2020. Epidemiology and diagnosis of mucormycosis: an update. J Fungi (Basel) 6. https://doi.org/10.3390/jof6040265
Cag Y, Erdem H, Gunduz M, Komur S, Ankarali H, Ural S, Tasbakan M, Tattevin P, Tombak A, Ozturk-Engin D, Sagmak Tartar A, Batirel A, Tekin R, Duygu F, Caskurlu H, Kurtaran B, Durdu B, Haciseyitoglu D, Rello J. Survival in rhino-orbito-cerebral mucormycosis: an international, multicenter ID-IRI study. Eur J Intern Med. 2022. https://doi.org/10.1016/j.ejim.2022.03.008.10.1016/j.ejim.2022.03.008.
Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, Anaissie EJ, Brumble LM, Herwaldt L, Ito J, Kontoyiannis DP, Lyon GM, Marr KA, Morrison VA, Park BJ, Patterson TF, Perl TM, Oster RA, Schuster MG, Walker R, Walsh TJ, Wannemuehler KA, Chiller TM. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50:1101–11. https://doi.org/10.1086/651262.
John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis. J Fungi (Basel) (2021);7. https://doi.org/10.3390/jof7040298
Muthu V, Rudramurthy SM, Chakrabarti A, Agarwal R. Epidemiology and pathophysiology of COVID-19-associated mucormycosis: India versus the rest of the world. Mycopathologia. 2021;186:739–54. https://doi.org/10.1007/s11046-021-00584-8.
Kueht M, Villarreal JA, Reece E, Galvan NTN, Mysore K, Restrepo A, Quintanilla N, Rana A, Goss J. Cutaneous mucormycosis in solid organ transplant recipients after hurricane harvey: short- and long-term management. Plast Reconstr Surg Glob Open. 2019;7:e2041. https://doi.org/10.1097/GOX.0000000000002041.
Neblett Fanfair R, Benedict K, Bos J, Bennett SD, Lo YC, Adebanjo T, Etienne K, Deak E, Derado G, Shieh WJ, Drew C, Zaki S, Sugerman D, Gade L, Thompson EH, Sutton DA, Engelthaler DM, Schupp JM, Brandt ME, Harris JR, Lockhart SR, Turabelidze G, Park BJ. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med. 2012;367:2214–25. https://doi.org/10.1056/NEJMoa1204781.
Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, Ito J, Andes DR, Baddley JW, Brown JM, Brumble LM, Freifeld AG, Hadley S, Herwaldt LA, Kauffman CA, Knapp K, Lyon GM, Morrison VA, Papanicolaou G, Patterson TF, Perl TM, Schuster MG, Walker R, Wannemuehler KA, Wingard JR, Chiller TM, Pappas PG. 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;50:1091–100. https://doi.org/10.1086/651263.
Prakash H, Chakrabarti A. Global epidemiology of mucormycosis. J Fungi (Basel) (2019);5. https://doi.org/10.3390/jof5010026
Bitar D, Van Cauteren D, Lanternier F, Dannaoui E, Che D, Dromer F, Desenclos JC, Lortholary O. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006. Emerg Infect Dis. 2009;15:1395–401. https://doi.org/10.3201/eid1509.090334.
Guinea J, Escribano P, Vena A, Munoz P, Martinez-Jimenez MDC, Padilla B, Bouza E. Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: epidemiology and microbiological characterization of the isolates. PLoS One. 2017;12:e0179136. https://doi.org/10.1371/journal.pone.0179136.
Parra Farinas R, Alonso-Sardon M, Velasco-Tirado V, Perez IG, Carbonell C, Alvarez Artero E, Romero-Alegria A, Pardo-Lledias J, Belhassen-Garcia M. Increasing Incidence of mucormycosis in Spanish inpatients from 1997 to 2018. Mycoses. 2022;65:344–53. https://doi.org/10.1111/myc.13418.
Saegeman V, Maertens J, Meersseman W, Spriet I, Verbeken E, Lagrou K. Increasing incidence of mucormycosis in University Hospital, Belgium. Emerg Infect Dis. 2010;16:1456–8. https://doi.org/10.3201/eid1609.100276.
Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, Savio J, Sethuraman N, Madan S, Shastri P, Thangaraju D, Marak R, Tadepalli K, Savaj P, Sunavala A, Gupta N, Singhal T, Muthu V, Chakrabarti A, MucoCovi N. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis. 2021;27:2349–59. https://doi.org/10.3201/eid2709.210934.
Abidi MZ, Sohail MR, Cummins N, Wilhelm M, Wengenack N, Brumble L, Shah H, Jane Hata D, McCullough A, Wendel A, Vikram HR, Kusne S, Litzow M, Letendre L, Lahr BD, Poeschla E, Walker RC. Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies. Mycoses. 2014;57:687–98. https://doi.org/10.1111/myc.12222.
Kyvernitakis A, Torres HA, Jiang Y, Chamilos G, Lewis RE, Kontoyiannis DP. Initial use of combination treatment does not impact survival of 106 patients with haematologic malignancies and mucormycosis: a propensity score analysis. Clin Microbiol Infect. 2016;22(811):e1–8. https://doi.org/10.1016/j.cmi.2016.03.029.
Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, Bitar D, Dromer F, Lortholary O, French Mycosis Study G. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis. 2012;54(Suppl 1):S35-43. https://doi.org/10.1093/cid/cir880.
Georgiadou SP, Sipsas NV, Marom EM, Kontoyiannis DP. The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts. Clin Infect Dis. 2011;52:1144–55. https://doi.org/10.1093/cid/cir122.
Legouge C, Caillot D, Chretien ML, Lafon I, Ferrant E, Audia S, Pages PB, Roques M, Estivalet L, Martin L, Maitre T, Bastie JN, Dalle F. The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia? Clin Infect Dis. 2014;58:672–8. https://doi.org/10.1093/cid/cit929.
•• Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Racil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JH, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild M, Vital FMI. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16:828–37. https://doi.org/10.1016/S1473-3099(16)00071-2. Study showing the efficacy of isavuconazole as first-line therapy of mucormycosis.
• Lamoth F, Alexander BD. Nonmolecular methods for the diagnosis of respiratory fungal infections. Clin Lab Med. 2014;34:315–36. https://doi.org/10.1016/j.cll.2014.02.006. Important study about the performance of PCR for early detection of mucormycosis in serum samples.
•• Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, Hoenigl M, Jensen HE, Lagrou K, Lewis RE, Mellinghoff SC, Mer M, Pana ZD, Seidel D, Sheppard DC, Wahba R, Akova M, Alanio A, Al-Hatmi AMS, Arikan-Akdagli S, Badali H, Ben-Ami R, Bonifaz A, Bretagne S, Castagnola E, Chayakulkeeree M, Colombo AL, Corzo-Leon DE, Drgona L, Groll AH, Guinea J, Heussel CP, Ibrahim AS, Kanj SS, Klimko N, Lackner M, Lamoth F, Lanternier F, Lass-Floerl C, Lee DG, Lehrnbecher T, Lmimouni BE, Mares M, Maschmeyer G, Meis JF, Meletiadis J, Morrissey CO, Nucci M, Oladele R, Pagano L, Pasqualotto A, Patel A, Racil Z, Richardson M, Roilides E, Ruhnke M, Seyedmousavi S, Sidharthan N, Singh N, Sinko J, Skiada A, Slavin M, Soman R, Spellberg B, Steinbach W, Tan BH, Ullmann AJ, Vehreschild JJ, Vehreschild M, Walsh TJ, White PL, Wiederhold NP, Zaoutis T, Chakrabarti A, Mucormycosis EMSGGGWG. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19:e405–21. https://doi.org/10.1016/S1473-3099(19)30312-3. Reference guideline for the management of mucormycosis.
•• Millon L, Caillot D, Berceanu A, Bretagne S, Lanternier F, Morio F, Letscher-Bru V, Dalle F, Denis B, Alanio A, Boutoille D, Bougnoux ME, Botterel F, Chouaki T, Charbonnier A, Ader F, Dupont D, Bellanger AP, Rocchi S, Scherer E, Gbaguidi-Haore H, Herbrecht R. Evaluation of serum mucorales polymerase chain reaction (PCR) for the diagnosis of mucormycoses: the MODIMUCOR prospective Trial. Clin Infect Dis. 2022;75:777–85. https://doi.org/10.1093/cid/ciab1066. Important study about the performance of PCR for early detection of mucormycosis in serum samples.
Millon L, Herbrecht R, Grenouillet F, Morio F, Alanio A, Letscher-Bru V, Cassaing S, Chouaki T, Kauffmann-Lacroix C, Poirier P, Toubas D, Augereau O, Rocchi S, Garcia-Hermoso D, Bretagne S, French Mycosis Study G. Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF). Clin Microbiol Infect. 2016;22(810):e1–8. https://doi.org/10.1016/j.cmi.2015.12.006.
Millon L, Larosa F, Lepiller Q, Legrand F, Rocchi S, Daguindau E, Scherer E, Bellanger AP, Leroy J, Grenouillet F. Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients. Clin Infect Dis. 2013;56:e95-101. https://doi.org/10.1093/cid/cit094.
Scherer E, Iriart X, Bellanger AP, Dupont D, Guitard J, Gabriel F, Cassaing S, Charpentier E, Guenounou S, Cornet M, Botterel F, Rocchi S, Berceanu A, Millon L. Quantitative PCR (qPCR) Detection of mucorales DNA in bronchoalveolar lavage fluid to diagnose pulmonary mucormycosis. J Clin Microbiol. (2018);56. https://doi.org/10.1128/JCM.00289-18
Guegan H, Iriart X, Bougnoux ME, Berry A, Robert-Gangneux F, Gangneux JP. Evaluation of MucorGenius(R) mucorales PCR assay for the diagnosis of pulmonary mucormycosis. J Infect. 2020;81:311–7. https://doi.org/10.1016/j.jinf.2020.05.051.
Mercier T, Reynders M, Beuselinck K, Guldentops E, Maertens J, Lagrou K. Serial detection of circulating mucorales DNA in invasive mucormycosis: a retrospective multicenter evaluation. J Fungi (Basel). (2019);5. https://doi.org/10.3390/jof5040113
Gholinejad-Ghadi N, Shokohi T, Seifi Z, Aghili SR, Roilides E, Nikkhah M, Pormosa R, Karami H, Larjani LV, Ghasemi M, Haghani I. Identification of Mucorales in patients with proven invasive mucormycosis by polymerase chain reaction in tissue samples. Mycoses. 2018;61:909–15. https://doi.org/10.1111/myc.12837.
Jillwin J, Rudramurthy SM, Singh S, Bal A, Das A, Radotra B, Prakash H, Dhaliwal M, Kaur H, Ghosh AK, Chakrabarti A. Molecular identification of pathogenic fungi in formalin-fixed and paraffin-embedded tissues. J Med Microbiol. (2021);70. https://doi.org/10.1099/jmm.0.001282
Lockhart SR, Bialek R, Kibbler CC, Cuenca-Estrella M, Jensen HE, Kontoyiannis DP. Molecular techniques for genus and species determination of fungi from fresh and paraffin-embedded formalin-fixed tissue in the revised EORTC/MSGERC definitions of invasive fungal infection. Clin Infect Dis. 2021;72:S109–13. https://doi.org/10.1093/cid/ciaa1836.
Burnham-Marusich AR, Hubbard B, Kvam AJ, Gates-Hollingsworth M, Green HR, Soukup E, Limper AH, Kozel TR. Conservation of Mannan synthesis in fungi of the zygomycota and ascomycota reveals a broad diagnostic target. mSphere (2018);3. https://doi.org/10.1128/mSphere.00094-18
Davies GE, Thornton CR. Development of a monoclonal antibody and a serodiagnostic lateral-flow device specific to Rhizopus arrhizus (Syn. R. oryzae), the principal global agent of mucormycosis in humans. J Fungi (Basel) (2022);8. https://doi.org/10.3390/jof8070756
Caramalho R, Madl L, Rosam K, Rambach G, Speth C, Pallua J, Larentis T, Araujo R, Alastruey-Izquierdo A, Lass-Florl C, Lackner M. Evaluation of a novel mitochondrial pan-mucorales marker for the detection, identification, quantification, and growth stage determination of mucormycetes. J Fungi (Basel) (2019);5. https://doi.org/10.3390/jof5040098
Gebremariam T, Liu M, Luo G, Bruno V, Phan QT, Waring AJ, Edwards JE Jr, Filler SG, Yeaman MR, Ibrahim AS. CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest. 2014;124:237–50. https://doi.org/10.1172/JCI71349.
Liu M, Spellberg B, Phan QT, Fu Y, Fu Y, Lee AS, Edwards JE Jr, Filler SG, Ibrahim AS. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest. 2010;120:1914–24. https://doi.org/10.1172/JCI42164.
Baldin C, Soliman SSM, Jeon HH, Alkhazraji S, Gebremariam T, Gu Y, Bruno VM, Cornely OA, Leather HL, Sugrue MW, Wingard JR, Stevens DA, Edwards JE, Jr., Ibrahim AS. PCR-based approach targeting mucorales-specific gene family for diagnosis of mucormycosis. J Clin Microbiol (2018);56. https://doi.org/10.1128/JCM.00746-18
Liu Y, Zhang J, Han B, Du L, Shi Z, Wang C, Xu M, Luo Y. Case report: diagnostic value of metagenomics next generation sequencing in intracranial infection caused by mucor. Front Med (Lausanne). 2021;8:682758. https://doi.org/10.3389/fmed.2021.682758.
Sun Y, Li H, Chen J, Ma Z, Han P, Liu Y, Wen J, Ren F, Ma X. Case report: metagenomics next-generation sequencing can be performed for the diagnosis of disseminated mucormycosis. Front Med (Lausanne). 2021;8:675030. https://doi.org/10.3389/fmed.2021.675030.
Zhang Q, Liu X, Liu Y, Wang H, Zhao R, Lv X, Wei X, Zhou K. Nasal and cutaneous mucormycosis in two patients with lymphoma after chemotherapy and target therapy: early detection by metagenomic next-generation sequencing. Front Cell Infect Microbiol. 2022;12:960766. https://doi.org/10.3389/fcimb.2022.960766.
Koshy S, Ismail N, Astudillo CL, Haeger CM, Aloum O, Acharige MT, Farmakiotis D, Baden LR, Marty FM, Kontoyiannis DP, Fredenburgh L, Koo S. Breath-Based diagnosis of invasive mucormycosis (IM). Open Forum Infect Dis. 2017;4:S53–4. https://doi.org/10.1093/ofid/ofx162.124.
Davies G, Rolle AM, Maurer A, Spycher PR, Schillinger C, Solouk-Saran D, Hasenberg M, Weski J, Fonslet J, Dubois A, Boschetti F, Denat F, Gunzer M, Eichner M, Ryder LS, Jensen M, Schibli R, Pichler BJ, Wiehr S, Thornton CR. Towards translational immunoPET/MR imaging of invasive pulmonary aspergillosis: the humanised monoclonal antibody JF5 detects Aspergillus lung infections in vivo. Theranostics. 2017;7:3398–414. https://doi.org/10.7150/thno.20919.
Kaeopookum P, Summer D, Pfister J, Orasch T, Lechner BE, Petrik M, Novy Z, Matuszczak B, Rangger C, Haas H, Decristoforo C. Modifying the siderophore triacetylfusarinine C for molecular imaging of fungal infection. Mol Imaging Biol. 2019;21:1097–106. https://doi.org/10.1007/s11307-019-01325-6.
Petrik M, Haas H, Dobrozemsky G, Lass-Florl C, Helbok A, Blatzer M, Dietrich H, Decristoforo C. 68Ga-siderophores for PET imaging of invasive pulmonary aspergillosis: proof of principle. J Nucl Med. 2010;51:639–45. https://doi.org/10.2967/jnumed.109.072462.
Pfister J, Summer D, Petrik M, Khoylou M, Lichius A, Kaeopookum P, Kochinke L, Orasch T, Haas H, Decristoforo C. Hybrid imaging of Aspergillus fumigatus pulmonary infection with fluorescent, (68)Ga-labelled siderophores. Biomolecules (2020);10. https://doi.org/10.3390/biom10020168
Rolle AM, Hasenberg M, Thornton CR, Solouk-Saran D, Mann L, Weski J, Maurer A, Fischer E, Spycher PR, Schibli R, Boschetti F, Stegemann-Koniszewski S, Bruder D, Severin GW, Autenrieth SE, Krappmann S, Davies G, Pichler BJ, Gunzer M, Wiehr S. ImmunoPET/MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci U S A. 2016;113:E1026–33. https://doi.org/10.1073/pnas.1518836113.
Thornton CR. Molecular imaging of invasive pulmonary Aspergillosis using immunoPET/MRI: the future looks bright. Front Microbiol. 2018;9:691. https://doi.org/10.3389/fmicb.2018.00691.
Pagano L, Valentini CG, Posteraro B, Girmenia C, Ossi C, Pan A, Candoni A, Nosari A, Riva M, Cattaneo C, Rossini F, Fianchi L, Caira M, Sanguinetti M, Gesu GP, Lombardi G, Vianelli N, Stanzani M, Mirone E, Pinsi G, Facchetti F, Manca N, Savi L, Mettimano M, Selva V, Caserta I, Scarpellini P, Morace G, D'Arminio Monforte A, Grossi P, Giudici D, Tortorano AM, Bonini A, Ricci L, Picardi M, Rossano F, Fanci R, Pecile P, Fumagalli L, Ferrari L, Capecchi PL, Romano C, Busca A, Barbui A, Garzia M, Minniti RR, Farina G, Montagna MT, Bruno F, Morelli O, Chierichini A, Placanica PM, Castagnola E, Bandettini R, Giordano S, Monastero R, Tosti ME, Rossi MR, Spedini P, Piane R, Nucci M, Pallavicini F, Bassetti M, Cristini F, M LAS, Viviani M. 2009. Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology). J Chemother. 21:322-9. https://doi.org/10.1179/joc.2009.21.3.322
Singh N, Aguado JM, Bonatti H, Forrest G, Gupta KL, Safdar N, John GT, Pursell KJ, Munoz P, Patel R, Fortun J, Martin-Davila P, Philippe B, Philit F, Tabah A, Terzi N, Chatelet V, Kusne S, Clark N, Blumberg E, Julia MB, Humar A, Houston S, Lass-Florl C, Johnson L, Dubberke ER, Barron MA, Lortholary O. Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis. 2009;200:1002–11. https://doi.org/10.1086/605445.
Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, Herbrecht R, Langston A, Marr KA, Schiller G, Schuster M, Wingard JR, Gonzalez CE, Revankar SG, Corcoran G, Kryscio RJ, Hare R. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126–33. https://doi.org/10.1128/AAC.50.1.126-133.2006.
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. 2006;42:e61–5. https://doi.org/10.1086/500212.
Espinel-Ingroff A, Chakrabarti A, Chowdhary A, Cordoba S, Dannaoui E, Dufresne P, Fothergill A, Ghannoum M, Gonzalez GM, Guarro J, Kidd S, Lass-Florl C, Meis JF, Pelaez T, Tortorano AM, Turnidge J. Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales. Antimicrob Agents Chemother. 2015;59:1745–50. https://doi.org/10.1128/AAC.04435-14.
Ibrahim AS, Gebremariam T, Fu Y, Edwards JE Jr, Spellberg B. Combination echinocandin-polyene treatment of murine mucormycosis. Antimicrob Agents Chemother. 2008;52:1556–8. https://doi.org/10.1128/AAC.01458-07.
Spellberg B, Fu Y, Edwards JE Jr, Ibrahim AS. Combination therapy with amphotericin B lipid complex and caspofungin acetate of disseminated zygomycosis in diabetic ketoacidotic mice. Antimicrob Agents Chemother. 2005;49:830–2. https://doi.org/10.1128/AAC.49.2.830-832.2005.
Klimko NN, Khostelidi SN, Volkova AG, Popova MO, Bogomolova TS, Zuborovskaya LS, Kolbin AS, Medvedeva NV, Zuzgin IS, Simkin SM, Vasilyeva NV, Afanasiev BV. Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg. Russia Mycoses. 2014;57(Suppl 3):91–6. https://doi.org/10.1111/myc.12247.
Reed C, Bryant R, Ibrahim AS, Edwards J Jr, Filler SG, Goldberg R, Spellberg B. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47:364–71. https://doi.org/10.1086/589857.
Ibrahim AS, Gebremariam T, Schwartz JA, Edwards JE Jr, Spellberg B. Posaconazole mono- or combination therapy for treatment of murine zygomycosis. Antimicrob Agents Chemother. 2009;53:772–5. https://doi.org/10.1128/AAC.01124-08.
Pagano L, Cornely OA, Busca A, Caira M, Cesaro S, Gasbarrino C, Girmenia C, Heinz WJ, Herbrecht R, Lass-Florl C, Nosari A, Potenza L, Racil Z, Rickerts V, Sheppard DC, Simon A, Ullmann AJ, Valentini CG, Vehreschild JJ, Candoni A, Vehreschild MJ. Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries. Haematologica. 2013;98:e127–30. https://doi.org/10.3324/haematol.2012.083063.
Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis. 2000;30:851–6. https://doi.org/10.1086/313803.
Tedder M, Spratt JA, Anstadt MP, Hegde SS, Tedder SD, Lowe JE. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg. 1994;57:1044–50. https://doi.org/10.1016/0003-4975(94)90243-7.
Zaoutis TE, Roilides E, Chiou CC, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, Sein M, Sein T, Prasad PA, Chu JH, Walsh TJ. Zygomycosis in children: a systematic review and analysis of reported cases. Pediatr Infect Dis J. 2007;26:723–7. https://doi.org/10.1097/INF.0b013e318062115c.
Lamoth F, Kontoyiannis DP. Therapeutic challenges of non-Aspergillus invasive mold infections in immunosuppressed patients. Antimicrob Agents Chemother. (2019);63. https://doi.org/10.1128/AAC.01244-19
Rodriguez MM, Calvo E, Marine M, Pastor FJ, Fernandez-Ballart J, Guarro J. Efficacy of liposomal amphotericin B combined with gamma interferon or granulocyte-macrophage colony-stimulating factor for treatment of systemic zygomycosis in mice. Antimicrob Agents Chemother. 2009;53:3569–71. https://doi.org/10.1128/AAC.00456-09.
Abzug MJ, Walsh TJ. Interferon-gamma and colony-stimulating factors as adjuvant therapy for refractory fungal infections in children. Pediatr Infect Dis J. 2004;23:769–73. https://doi.org/10.1097/01.inf.0000134314.65398.bf.
Chen TK, Batra JS, Michalik DE, Casillas J, Patel R, Ruiz ME, Hara H, Patel B, Kadapakkam M, Ch’Ng J, Small CB, Zagaliotis P, Ragsdale CE, Leal LO, Roilides E, Walsh TJ. Recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) as adjuvant therapy for invasive fungal diseases. Open Forum Infect Dis. 2022;9:ofac535. https://doi.org/10.1093/ofid/ofac535.
Loeffen YGT, Scharloo F, Goemans BF, Heitink-Polle KMJ, Lindemans CA, van der Bruggen T, Hagen F, Wolfs TFW. Mucormycosis in children with hematologic malignancies: a case series and review of the literature. Pediatr Infect Dis J. 2022;41:e369–76. https://doi.org/10.1097/INF.0000000000003608.
Mousset S, Hermann S, Klein SA, Bialleck H, Duchscherer M, Bomke B, Wassmann B, Bohme A, Hoelzer D, Martin H. Prophylactic and interventional granulocyte transfusions in patients with haematological malignancies and life-threatening infections during neutropenia. Ann Hematol. 2005;84:734–41. https://doi.org/10.1007/s00277-005-1055-z.
Raad II, Chaftari AM, Al Shuaibi MM, Jiang Y, Shomali W, Cortes JE, Lichtiger B, Hachem RY. Granulocyte transfusions in hematologic malignancy patients with invasive pulmonary aspergillosis: outcomes and complications. Ann Oncol. 2013;24:1873–9. https://doi.org/10.1093/annonc/mdt110.
Farina C, Marchesi G, Passera M, Diliberto C, Russello G, Favalli A. In vitro activity of Amphotericin B against zygomycetes isolated from deep mycoses: a comparative study between incubation in aerobic and hyperbaric atmosphere. Med Mycol. 2012;50:427–32. https://doi.org/10.3109/13693786.2011.614964.
John BV, Chamilos G, Kontoyiannis DP. Hyperbaric oxygen as an adjunctive treatment for zygomycosis. Clin Microbiol Infect. 2005;11:515–7. https://doi.org/10.1111/j.1469-0691.2005.01170.x.
Ibrahim AS, Gebermariam T, Fu Y, Lin L, Husseiny MI, French SW, Schwartz J, Skory CD, Edwards JE Jr, Spellberg BJ. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest. 2007;117:2649–57. https://doi.org/10.1172/JCI32338.
Soman R, Gupta N, Shetty A, Rodrigues C. Deferasirox in mucormycosis: hopefully, not defeated. J Antimicrob Chemother. 2012;67:783–4. https://doi.org/10.1093/jac/dkr529.
Spellberg B, Andes D, Perez M, Anglim A, Bonilla H, Mathisen GE, Walsh TJ, Ibrahim AS. Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis. Antimicrob Agents Chemother. 2009;53:3122–5. https://doi.org/10.1128/AAC.00361-09.
Spellberg B, Ibrahim AS, Chin-Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, Fredricks D, Brass EP. The Deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother. 2012;67:715–22. https://doi.org/10.1093/jac/dkr375.
Lamoth F, Lewis RE, Kontoyiannis DP. Investigational antifungal agents for invasive mycoses: a clinical perspective. Clin Infect Dis. 2022. https://doi.org/10.1093/cid/ciab1070.10.1093/cid/ciab1070.
Shaw KJ, Ibrahim AS. Fosmanogepix: a review of the first-in-class broad spectrum agent for the treatment of invasive fungal infections. J Fungi (Basel) (2020);6. https://doi.org/10.3390/jof6040239
Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A. In vitro activity of APX001A against rare moulds using EUCAST and CLSI methodologies. J Antimicrob Chemother. 2019;74:1295–9. https://doi.org/10.1093/jac/dkz022.
Gebremariam T, Alkhazraji S, Alqarihi A, Wiederhold NP, Shaw KJ, Patterson TF, Filler SG, Ibrahim AS. Fosmanogepix (APX001) is effective in the treatment of pulmonary murine mucormycosis due to Rhizopus arrhizus. Antimicrob Agents Chemother. (2020);64. https://doi.org/10.1128/AAC.00178-20
Gebremariam T, Gu Y, Alkhazraji S, Youssef E, Shaw KJ, Ibrahim AS. The combination treatment of fosmanogepix and liposomal amphotericin B Is superior to monotherapy in treating experimental invasive mold infections. Antimicrob Agents Chemother. 2022;66:e0038022. https://doi.org/10.1128/aac.00380-22.
Gonzalez-Lara MF, Sifuentes-Osornio J, Ostrosky-Zeichner L. Drugs in clinical development for fungal infections. Drugs. 2017;77:1505–18. https://doi.org/10.1007/s40265-017-0805-2.
Gebremariam T, Wiederhold NP, Fothergill AW, Garvey EP, Hoekstra WJ, Schotzinger RJ, Patterson TF, Filler SG, Ibrahim AS. VT-1161 Protects Immunosuppressed mice from Rhizopus arrhizus var. arrhizus infection. Antimicrob Agents Chemother. 2015;59:7815–7. https://doi.org/10.1128/AAC.01437-15.
Wiederhold NP, Patterson HP, Tran BH, Yates CM, Schotzinger RJ, Garvey EP. Fungal-specific Cyp51 inhibitor VT-1598 demonstrates in vitro activity against Candida and Cryptococcus species, endemic fungi, including Coccidioides species, Aspergillus species and Rhizopus arrhizus. J Antimicrob Chemother. 2018;73:404–8. https://doi.org/10.1093/jac/dkx410.
Gebremariam T, Alkhazraji S, Lin L, Wiederhold NP, Garvey EP, Hoekstra WJ, Schotzinger RJ, Patterson TF, Filler SG, Ibrahim AS. Prophylactic treatment with VT-1161 protects immunosuppressed mice from Rhizopus arrhizus var. arrhizus infection. Antimicrob Agents Chemother (2017);61. https://doi.org/10.1128/AAC.00390-17
•• Aigner M, Lass-Florl C. Encochleated Amphotericin B: is the oral availability of amphotericin B finally reached? J Fungi (Basel). 2020;6:66. https://doi.org/10.3390/jof6020066. Important study that improves our understanding of the pathogenesis of mucormycosis and suggests novel therapeutic strategies of interest.
•• Skipper CP, Atukunda M, Stadelman A, Engen NW, Bangdiwala AS, Hullsiek KH, Abassi M, Rhein J, Nicol MR, Laker E, Williams DA, Mannino R, Matkovits T, Meya DB, Boulware DR. Phase I EnACT trial of the safety and tolerability of a novel oral formulation of amphotericin B. Antimicrob Agents Chemother. (2020);64. https://doi.org/10.1128/AAC.00838-20. Important study supporting a novel and promising antifungal strategy for the treatment of mucormycosis.
• Szebenyi C, Gu Y, Gebremariam T, Kocsube S, Kiss-Vetrab S, Jager O, Patai R, Spisak K, Sinka R, Binder U, Homa M, Vagvolgyi C, Ibrahim AS, Nagy G, Papp T. cotH genes are necessary for normal spore formation and virulence in Mucor lusitanicus. mBio. (2023). https://doi.org/10.1128/mbio.03386-22. Study that improves our understanding of the pathogenesis of mucormycosis and suggests novel therapeutic strategies of interest.
• Alqarihi A, Gebremariam T, Gu Y, Swidergall M, Alkhazraji S, Soliman SSM, Bruno VM, Edwards JE Jr, Filler SG, Uppuluri P, Ibrahim AS. GRP78 and integrins play different roles in host cell invasion during mucormycosis. mBio (2020);11. https://doi.org/10.1128/mBio.01087-20. Study that improves our understanding of the pathogenesis of mucormycosis and suggests novel therapeutic strategies of interest.
•• Gebremariam T, Alkhazraji S, Soliman SSM, Gu Y, Jeon HH, Zhang L, French SW, Stevens DA, Edwards JE Jr, Filler SG, Uppuluri P, Ibrahim AS. Anti-CotH3 antibodies protect mice from mucormycosis by prevention of invasion and augmenting opsonophagocytosis. Sci Adv. 2019;5:eaaw1327. https://doi.org/10.1126/sciadv.aaw1327. Important study supporting a novel and promising antifungal strategy for the treatment of mucormycosis.
Carlos AJ, Ha DP, Yeh DW, Van Krieken R, Tseng CC, Zhang P, Gill P, Machida K, Lee AS. The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection. J Biol Chem. 2021;296:100759. https://doi.org/10.1016/j.jbc.2021.100759.
Elgohary AM, Elfiky AA, Barakat K. GRP78: a possible relationship of COVID-19 and the mucormycosis; in silico perspective. Comput Biol Med. 2021;139:104956. https://doi.org/10.1016/j.compbiomed.2021.104956.
Grimaldi D, Pradier O, Hotchkiss RS, Vincent JL. Nivolumab plus interferon-gamma in the treatment of intractable mucormycosis. Lancet Infect Dis. 2017;17:18. https://doi.org/10.1016/S1473-3099(16)30541-2.
Serris A, Ouedrani A, Uhel F, Gazzano M, Bedarida V, Rouzaud C, Bougnoux ME, Raphalen JH, Poiree S, Lambotte O, Martin-Blondel G, Lanternier F. Case report: immune checkpoint blockade plus interferon-gamma add-on antifungal therapy in the treatment of refractory covid-associated pulmonary Aspergillosis and cerebral mucormycosis. Front Immunol. 2022;13:900522. https://doi.org/10.3389/fimmu.2022.900522.
Tawfik DM, Dereux C, Tremblay JA, Boibieux A, Braye F, Cazauran JB, Rabodonirina M, Cerrato E, Guichard A, Venet F, Monneret G, Payen D, Lukaszewicz AC, Textoris J. Interferon gamma as an immune modulating adjunct therapy for invasive mucormycosis after severe burn - a case report. Front Immunol. 2022;13:883638. https://doi.org/10.3389/fimmu.2022.883638.
Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, Roszik J, Rabinovich B, Olivares S, Krishnamurthy J, Zhang L, Najjar AM, Huls MH, Lee DA, Champlin RE, Kontoyiannis DP, Cooper LJ. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014;111:10660–5. https://doi.org/10.1073/pnas.1312789111.
Baistrocchi SR, Lee MJ, Lehoux M, Ralph B, Snarr BD, Robitaille R, Sheppard DC. Posaconazole-loaded leukocytes as a novel treatment strategy targeting invasive pulmonary aspergillosis. J Infect Dis. 2017;215:1734–41. https://doi.org/10.1093/infdis/jiw513.
Koehler P, Mellinghoff SC, Lagrou K, Alanio A, Arenz D, Hoenigl M, Koehler FC, Lass-Florl C, Meis JF, Richardson M, Cornely OA. Development and validation of the European QUALity (EQUAL) score for mucormycosis management in haematology. J Antimicrob Chemother. 2019;74:1704–12. https://doi.org/10.1093/jac/dkz051.
Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Florl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102:433–44. https://doi.org/10.3324/haematol.2016.152900.
Funding
Open access funding provided by University of Lausanne
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
FL has received research funding from Gilead, MSD, Pfizer and Novartis, has participated to advisory boards of Gilead, MSD and Pfizer, and has received honoraria for conferences from Gilead and Mundipharma. All contracts were made with and fees paid to his institution (CHUV).
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Lamoth, F. Novel Approaches in the Management of Mucormycosis. Curr Fungal Infect Rep 17, 98–107 (2023). https://doi.org/10.1007/s12281-023-00463-3
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12281-023-00463-3