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
The Lancet Infectious Diseases, December 2019, Volume 19, Issue 12, Pages e405-e421
Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
Suspected mucormycosis requires urgent intervention, because of the often rapidly progressive and destructive nature of the infection. 1 2 Delayed initiation of therapy is associated with increased mortality. 1 Maximising survival rates requires rapid diagnostic and therapeutic intervention, including immediate involvement of a multidisciplinary medical, surgical, radiological, and laboratory-based team. 3 Readily available guidance is important to ensure efficient diagnosis and treatment, and to optimise patient prognosis. Optimal management depends on recognising disease patterns and the available diagnostic and therapeutic options, which differ between the regions of the world.
Currently available guidelines are limited to specific patient groups in haematology, 4 or a specific geographical region, 5 or require an update. 6 7 8 Recently, several critical developments have fundamentally changed the management of this condition. These include the development of new and more widely used molecular techniques for the diagnosis of mucormycosis, the licensing of isavuconazole for treatment of mucormycosis, and the availability of new formulations of posaconazole. Moreover, previous guidelines did not include comprehensive clinical and radiological imaging, pathological and histological findings, nor did they provide details on surgery as a core element of mucormycosis management.
The European Confederation of Medical Mycology (ECMM), together with the Mycoses Study Group Education & Research Consortium (MSG ERC), issues this comprehensive guidance document to facilitate clinical decision-making, and simultaneously provides an overview of the areas of uncertainty in the field. 9 10 We aimed to address limitations of previous recommendations, by engaging physicians and scientists involved in various aspects of mucormycosis management, representing the fields of microbiology, pathology, radiology, infectious diseases, surgery, paediatrics, haematology, intensive care, dermatology, and pharmcology. In addition, the guideline group comprises experts from all parts of the world and provides management pathways for different regional environments ( panel ; for further information on guideline development, systematic approach, authors and contributors, literature search terms and work flow, see appendix pp 1–4 ).
In December, 2017, experts were identified based on their publication activity in the field of mucormycosis in the previous 5 years, their involvement in patient management, and their distribution over world regions defined by the United Nations. Experts were invited to develop this guideline in January, 2018.
This guideline follows the structure and definitions of previous guidelines on invasive fungal infections which are in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Appraisal of Guidelines for Research & Evaluation (AGREE) systems. The PICO (population, intervention, comparison, and outcome) approach is reflected by the tables.
Both, diagnostic assays and treatment strategies might alter patient course, and are thus regarded as interventions. First, a population is defined; then the intention or objective is stated, followed by the intervention. For such logical sequence, strength of recommendation (SOR) and quality of evidence (QOE) are provided, followed by the references on which the recommendation is based. SOR and QOE are results of two independent evaluations, thus allowing a strong recommendation even in the absence of the highest quality evidence ( table 1 ).
|Grade A||The guideline group strongly supports a recommendation for use|
|Grade B||The guideline group moderately supports a recommendation for use|
|Grade C||The guideline group marginally supports a recommendation for use|
|Grade D||The guideline group supports a recommendation against use|
|Quality of evidence||Definition|
|Level I||Evidence from at least 1 properly designed randomised, controlled trial (orientated on the primary endpoint of the trial); note: poor quality of planning, inconsistency of results, indirectness of evidence etc would lower the SOR|
|Level II||Evidence from at least one well designed clinical trial (including secondary endpoints), without randomisation; from cohort or case-controlled analytic studies (preferably from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments; note: every level II item of evidence must have at least one added index|
|Level III||Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees|
|Added Index||Defining the source of level II evidence|
|r||Meta-analysis or systematic review of randomised controlled trials|
|t||Transferred evidence—ie, results from different patient cohorts, or similar immune-status situation|
|h||Comparator group: historical control|
|a||For published abstract presented at an international symposium or meeting|
Search strings used were “mucormyc* OR zygomyc*”, “cavernous sinus syndrome OR orbital apex syndrome AND etiology”, and for the epidemiological section “mucormyc* OR zygomyc* AND (case*[Title/Abstract] OR patient*[Title/ Abstract] OR report[Title/Abstract]) AND (“2013/01/01”[PDat] : “2017/12/31”[PDat])”.
From January to February, 2018, video conferences on the methodology were held, and a video tutorial added in March, 2018. Assistance and supervision to the group were provided by the coordinators (OAC, AC). Documents were shared among the authors on a password-protected OneDrive (Microsoft Corp, Redmont WA, USA) repository, and were updated several times per day. Updates on PICO tables were written in red font; after spellcheck and formatting font colour was changed to blue for consideration by the group. Contents discussed and agreed on were changed to black font. Once all tables were finalised, a writing group (OAC, AAI, DA, SCAC, ED, BH, MH, HEJ, KL, REL, SCM, MMe, ZP, DS, DCS, RW, AC) contributed the first draft, which was circulated to all participants for approval in October, 2018. Recommendations were consensus-based. If no consensus was found, majority vote was used.
In November, 2018, a 4-week public consultation phase ensued. Comments received were evaluated, and either dismissed or used to change the manuscript, resulting in a final author review in December, 2018. 51 scientific societies from 33 countries reviewed and endorsed the guidance document.
Epidemiology of mucormycosis
As medical science advances, the patient populations most at risk for mucormycosis expand accordingly. In the mid-20th century, diabetes evolved as a major risk factor for mucormycosis, while in more recent years, underlying malignancy emerged as another important risk factor due to the increasing number of patients undergoing chemotherapy or cancer immunotherapy. 11 12 13 Furthermore, with more solid organ and haematopoietic stem-cell transplantations (HSCT) being performed, increasing numbers of cases have also been reported in these patient groups. 14 At the same time, diabetes continues to represent the predominant risk factor for mucormycosis in settings where health-care access for diabetes management is more limited. 13
For further information on patient populations, incidence and prevalence of mucormycosis and incidence rates compared to other mould infections, see appendix pp 4–6 .
Pathogens causing mucormycosis
The term mucormycosis is frequently used interchangeably with zygomycosis. The latter term referred to infections caused by fungi of the former phylum Zygomycota (comprising Mucorales, Entomophthorales, and others), which became obsolete with phylogenetic reanalysis of the kingdom Fungi. 15 16 Today, mucormycosis describes infections caused by fungi of the order Mucorales. The most frequently reported pathogens in mucormycosis are Rhizopus spp, Mucor spp, and Lichtheimia spp (formerly of the genera Absidia and Mycocladus ), followed by Rhizomucor spp, Cunninghamella spp, Apophysomyces spp, and Saksenaea spp. 11 17 18 Lichtheimia spp were identified as the major cause of mucormycosis in a single hospital in Spain, indicating geographical variation and the need to know local epidemiology. 19
Clinical manifestations of mucormycosis
For further information on clinical manifestations, see appendix p 6 .
In immunocompromised patients, the main route of infection seems to be through inhalation of sporangiospores causing pulmonary infection. Pulmonary mucormycosis typically develops in patients with profound neutropenia 11 and graft-versus-host disease, 20 whereas diabetic patients typically present with rhino-orbital disease. Prolonged fever is seen in most patients, although some patients might be asymptomatic. 21 Radiological findings often vary in configuration, size, number, and distribution of lesions; typical examples are given below. 22 23 24 25 Pulmonary mucormycosis can spread contiguously into other organs, for example through the diaphragm into the abdomen.
Cutaneous and soft-tissue mucormycosis are the most common forms of mucormycosis in immunocompetent patients, primarily after skin disruption due to traumatic injury (eg from natural disasters, motor vehicle accidents, improvised explosive devices in theatres of war, or iatrogenic sources), surgery, or burns. 26 27 28 29 30 31 Abscesses, skin swelling, necrosis, dry ulcers, and eschars are characteristic presentations ( figure 1A and G ). 32 33 34
For further information on cutaneous and soft-tissue mucormycosis, see appendix p 6 .
Rhino-orbito-cerebral mucormycosis typically develops in patients with diabetes, whereas such patients very rarely develop lung infection. 11 It has been described in haematology patients, too. 35 Rhino-orbital-cerebral infection usually originates from the paranasal sinuses, with bone destruction and subsequent invasion of the orbit, eye, and brain. 36 37 38 39 Unilateral facial oedema, proptosis, and palatal or palpebral fistula developing into necrosis may be present ( figure 1B, F ).
For further information on rhino-orbito-cerebral mucormycosis see appendix p 6 .
Primary gastrointestinal disease is a rare manifestation of mucormycosis that can present with symptoms similar to other common gastrointestinal diseases. 40 41 However, gastrointestinal mucormycosis is the most common manifestation of mucormycosis in neonates, where it carries a high mortality. 42
For further information on gastrointestinal mucormycosis, see appendix p 6 .
For further information on renal and abdominal mucormycosis, see appendix p 7 .
All-cause mortality rates for mucormycosis range from 40% to 80% with varying rates depending on underlying conditions and sites of infection. 11 19 49 50 51 The highest survival rates are reported in patients with a healthy immune status and those without comorbidities. The poorest prognosis is observed in patients with haematological malignancies and HSCT recipients 11 and in patients with extensive burns. 51 Disseminated disease, especially to the CNS is often associated with mortality rates higher than 80%. 11 Conversely, lower mortality is seen with localised sinus or skin infection, where earlier tissue-based diagnosis is often feasible and surgical debridement may result in cure. Mortality is also high in neonates and other immunocompromised patients with gastrointestinal mucormycosis, possibly related to delay in diagnosis and polymicrobial sepsis. Generally, improved survival is related to earlier diagnosis and application of early, multidisciplinary treatment approaches involving aggressive surgical debridement. 19 52 53 54 Despite improved understanding of the disease and the availability of more therapeutic options, survival rates in mucormycosis remain poor. 19 55 56
The capability of diagnosing mucormycosis depends on the availability of imaging techniques, trained personnel, and mycological and histological investigations. Patients with suspected mucormycosis should be referred immediately to a facility with the highest care level. In case of any delay, management should be initiated following this guidance document. If all diagnostic options are available, one should follow the management pathway depicted in figure 2 .
For further information on diagnosing mucormycosis, see appendix p 7 .
In patients with haematological malignancy and suspected pulmonary mucormycosis, pulmonary CT scan is recommended for the detection of the reversed halo sign, an area of ground glass opacity surrounded by a ring of consolidation on thoracic CT, or vessel occlusion on CT pulmonary angiography. In diabetic patients with facial pain, sinusitis, proptosis, ophthalmoplegia, or newly diagnosed amaurosis, or both, cranial CT or MRI is strongly recommended to determine if sinusitis is present. If sinusitis is diagnosed, endoscopy is strongly recommended to diagnose mucormycosis. If disease of the eye or brain is suspected, MRI should be conducted in lieu of a CT scan due to substantially greater sensitivity. If mucormycosis is a potential diagnosis, biopsy is strongly recommended. Once mucormycosis has been proven in a patient with underlying malignancy, cranial, thoracic and abdominal imaging studies to determine the extent of disease are recommended with moderate strength. In view of the rapid progress of mucormycosis, weekly CT scans are strongly recommended, particularly in unstable patients ( appendix p 7 ).
Histopathology in mucormycosis
Mucormycosis is usually suspected based on results of direct microscopy of clinical specimens, preferably stained with fluorescent brighteners calcofluor white (Sigma Aldrich, St Louis, MO, USA) or blankophor (Tanatax Chemicals, Ede, The Netherlands). To confirm an infection, non-pigmented hyphae showing tissue invasion must be shown in tissue sections stained with haematoxylin-eosin (HE), periodic acid-Schiff stain (PAS), or Grocott-Gomori's methenamine-silver stain (GMS), or both. 57 58 Histopathologically, Mucorales hyphae have a variable width of 6–16 μm, but may be up to 25 μm, and are non-septate or pauci-septate. In tissue, the hyphae appear ribbon-like with an irregular pattern of branching ( figure 4A–C ). 57 Hyphae can artefactually seem to have septae because tissue can fold over itself during processing, which can create artificial lines that can be confused with septations. Similarly, the historically described 90° branching angle of Mucorales in tissue, versus 45° branching angle of septate moulds, can be difficult to identify in tissue due to interstitial pressures exerted on the fungi by the tissue and alterations in tissue architecture during processing. Thus the wider and irregular (ribbon-like) nature of the hyphae are more reliable distinguishing characteristics than septations and angle of branching.
The lesions of mucormycosis are characteristic but non-specific. 59 60 61 In acute lesions, haemorrhagic infarction, coagulation necrosis, angioinvasion, infiltration by neutrophils (in non-neutropenic hosts), and perineural invasion are characteristic features; 62 whereas, in chronic lesions, a pyogranulomatous inflammation with presence of giant cells, and sometimes hyphae covered by the Splendore-Hoeppli phenomenon, 63 64 which describes deeply eosinophilic material surrounding the pathogen, are seen (figure A–C). 17 62 65 66 67
Obtaining a diagnosis of mucormycosis on histomorphological basis is challenging, and the most common cause for incorrect morphological diagnosis is the misidentification of Mucorales as Aspergillus spp (figure A–C). 58 The application of immunohistochemistry with commercially available monoclonal antibodies 68 69 70 or PCR techniques on either fresh or formalin-fixed paraffin-embedded tissue 19 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 have been shown to be highly specific, although a variation in sensitivity has been reported, in addition, these tests might not be widely available ( appendix p 9 ).
Hyphae of Mucorales can be distinguished from septate hyaline moulds due to their greater width and irregular pattern of branching. However, there are no data available to describe the accuracy of distinguishing Mucorales from other moulds based on these characteristics. Therefore, it is strongly recommended to confirm the diagnosis of mucormycosis in tissue by culture or by application of molecular or in-situ identification techniques, at centres where such assays are available ( appendix p 9 ).
For further information on antigen biomarkers, see appendix p 10 .
Culture and microscopy
Culture of specimens is strongly recommended for genus and species identification, and for antifungal susceptibility testing. Homogenisation of tissue should be avoided before culturing. Incubation at 30°C and 37°C separately is strongly recommended ( appendix p 11 ). Direct microscopy with fluorescent brighteners from clinical specimens is strongly recommended mainly focusing on septation, branching angle, and hyphal width.
For further information on culture and microscopy, see appendix p 10 .
For further information on susceptibility testing, see appendix p 11–12 .
The use of standard methods for antifungal susceptibility testing to guide antifungal treatment in Mucorales is marginally supported and may be clinically useful in cases of treatment failure. However, we strongly recommend the use of these methods primarily to establish epidemiological knowledge in the field. Currently, commercial methods such as E-test are recommended for use in mucormycosis with marginal strength only ( appendix p 11 ).
Molecular-based methods for direct detection
For further information on molecular-based methods, see appendix p 13 .
Currently, in the absence of a standardised test, the use of molecular methods on both fresh clinical material and paraffin sections for the diagnosis of mucormycosis is moderately supported. Fresh material is preferred over paraffin-embedded tissue because formalin damages DNA. Detection of DNA in serum as well as in other body fluids is very promising but because of lack of standardisation supported with moderate strength only ( appendix p 13 ).
Genus and species identification
Although some genera, such as Cunninghamella , can be associated with an increased mortality rate in patients 11 96 and have been shown to be more virulent in experimental models, 97 there is currently sparse evidence that identification of the causative Mucorales to the genus or species level, or both, could guide the choice of the antifungal treatment.
By contrast, identification to the species level is of importance for improved epidemiological knowledge of the disease. In particular, the clinical picture can be different depending on the species. 11 96 98 99 Moreover, species identification is valuable for investigation of health care-associated mucormycosis and outbreaks. 100 101 102 103
For further information on genus and species identification, see appendix p 14–15 .
Identification to the genus and species level is strongly supported for improved epidemiological understanding of mucormycosis. Guiding treatment by identification to the genus level is supported with marginal strength. Molecular identification is strongly supported and preferred over morphology. Because the best technique for molecular identification, internal transcribed spacer (ITS) sequencing is strongly supported. Matrix assisted laser desorption ionisation time of flight (MALDI-TOF) identification is moderately supported because it relies mainly on in-house databases, and many laboratories do not have that capacity ( appendix p 15 ).
Treatment approaches to mucormycosis
The ability to treat mucormycosis effectively depends on the availability of the surgical techniques and antifungal drugs discussed below. If all treatment options are available one should follow the management pathways detailed in figure 5A and appendix p 25 . If local or regional capabilities differ, less comprehensive pathways need to be followed; examples are given in figure 5B, C , and appendix p 26 .
Surgical treatment for mucormycosis
For further information on surgical treatment, see appendix p 16 .
Recommendations —The guideline group strongly supports an early complete surgical treatment for mucormycosis whenever possible, in addition to systemic antifungal treatment. Resection or debridement should be repeated as required ( appendix p 16 ).
Drug treatment for mucormycosis
For further information on prophylaxis, see appendix p 18 .
Recommendations —In neutropenic patients or those with graft versus host disease, primary prophylaxis with posaconazole delayed release tablets is recommended with moderate strength, and prophylaxis with oral suspension is recommended with marginal strength to prevent mucormycosis.
For further information on secondary prophylaxis, see appendix p 18 .
Recommendations —In immunosuppressed patients with previous diagnosis of mucormycosis, surgical resection and continuation or restart of the last drug effective in that patient is strongly recommended.
For further information on fever-driven treatment, see appendix p 19 .
Recommendations —The guideline group recommends against initiation of treatment for mucormycosis when fever of unknown origin is the sole evidence of infection.
For further information on fever-driven treatment, see appendix p 19 .
Recommendations —In any immunocompromised patient with suspected mucormycosis, immediate treatment initiation is strongly ecommended. Every attempt to attain a diagnosis should be made at the time of initiation of therapy, but should not delay therapy.
First-line antifungal monotherapy
Evidence —In several case series, the use of liposomal amphotericin B successfully treated mucormycosis with various organ involvement patterns. 17 50 67 104 105 106 107 108 109 Daily doses ranged from 1 mg/kg per day to 10 mg/kg per day. 104 110 Recipients of increased doses tended to have increased response rates. 104 Patients receiving 10 mg/kg per day had substantial serum creatinine increases that were mostly reversible. 104 106 Doses higher than 10 mg/kg per day did not result in higher blood concentrations. 111 In CNS involvement, animal models and the above observations support use of liposomal amphotericin B at 10 mg/kg per day. 112 In the absence of CNS involvement, amphotericin B lipid complex 5 mg/kg per day has been used successfully. 17 112 113 In kidney transplant recipients, amphotericin B lipid complex 10 mg/kg per day has been given. 114 Amphotericin B deoxycholate has been the drug of choice for decades. 11 17 66 109 It is effective, but its use is limited by its substantial toxicity, specifically in the doses and treatment durations needed for mucormycosis ( table 2 ). 115 116 Use of amphotericin B deoxycholate should be restricted to settings in which there is no other antifungal therapy available.
|Any||To cure and to increase survival rates||Amphotericin B, any formulation, escalation to full dose over days||D||IIu||Chamilos 1 (N=70, give full daily dose from day 1)|
|Any||To cure and to increase survival rates||Amphotericin B, liposomal, 5–10 mg/kg per day||A||IIu||Gleissner 144 (N=16, haematology); Pagano 109 (N=5); Cornely 106 (N=4); Pagano 105 (N=44); Rüping 67 (N=21); Shoham 50 (N=28); Skiada 17 (N=130); Lanternier 104 (N=34, 18 haematology, six diabetic); Kyvernitakis 108 (N=41); Stanzani 107 (N=97, increased renal toxicity with cyclosporine)|
|CNS involvement||To cure||Amphotericin B, liposomal, 10 mg/kg per day, initial 28 days||A||III||Ibrahim 112 (Animal); Lanternier 104 (N=9)|
|SOT adults||To cure||Amphotericin B, lipid formulation; dose not given||A||IIh||Singh 145 (N=25); Sun 146 (N=14); Lanternier 147 (N=3)|
|SOT adults||To cure||Amphotericin B, lipid complex; 10 mg/kg per day||A||III||Forrest 114 (N=6, 3 of 6 died)|
|Any, without CNS involvement||To cure||Amphotericin B, lipid complex; 5 mg/kg per day||B||IIu||Larkin 113 (N=10); Ibrahim 112 (animal); Skiada 17 (N=7)|
|Haematological malignancy||To cure||Amphotericin B, liposomal; 1–<5 mg/kg per day ± surgery||C||III||Nosari 110 (N=13, 8 of 13 treated, 5/8 died); Li 148 (N=7, 2 of 7 died)|
|Any||To cure||Isavuconazole PO or IV; 3 × 200 mg day 1–2, 1 × 200 mg/d from day 3||B||IIh||Marty 49 (N=21, 11 haematology, 4 diabetes, overall mortality comparable to amphotericin B formulations)|
|Any||To cure||Posaconazole DR tablet or intravenously 2 × 300 mg day 1, 1 × 300 mg from day 2||B||IItu||Duarte; 122 Maertens; 124 Cornely; 123 Cornely 125 (higher trough levels than oral suspension, intravenous bridging when oral dosing not feasible)|
|Any||To cure||Posaconazole oral suspension; 4 × 200 mg/day or 2 × 400 mg/day||C||IIu||Rüping 67 (N=8); Skiada 17 (N=17); Dannaoui 149 (animal, emphasises preference of amphotericin B, liposomal)|
|Any||To cure||Amphotericin B, deoxycholate, any dose (if alternative therapy available)||D||IIt||Walsh 116 (renal toxicity); Pagano 109 (N=9); Roden 11 (N=532); Ullmann 115 (renal toxicity); Chakrabarti 66 (N=10); Skiada1 17 (N=21)|
|Orbital mucormycosis||To cure||Retrobulbar injection of amphotericin B deoxycholate in addition to systemic therapy||D||III||Hirabayashi 50 (N=1, post-injection inflammatory response, risk for acute compartment syndrome)|
The efficacy of isavuconazole was similar to an external matched control group treated with amphotericin B formulations. This limited size study enrolled 21 patients with isavuconazole first-line treatment, and compared efficacy results to 33 matched patients from the FungiScope registry. 49 117 As a result, isavuconazole has been licenced in the USA for first-line treatment of mucormycosis. 118 By contrast with other mould-active azoles, isavuconazole is less hepatotoxic although it can result in shortening the QTc interval. 119 120 121 Posaconazole oral suspension has been used successfully in first-line treatment. 17 67 Recently, concerns about its oral bioavailability led to the development of a delayed release tablet with improved exposure 122 123 and an intravenous infusion formulation ( table 2 ). 124 125
Recommendations —First-line treatment with liposomal amphotericin B 5–10 mg/kg per day is strongly supported across all patterns of organ involvement. If substantial renal toxicity develops, the dose can be reduced as necessary, but doses below 5 mg/kg per day are recommended with marginal strength only. 104 110 Doses should not be slowly increased over several days; rather, the full daily dose should be given from the first treatment day. Amphotericin B lipid complex 5 mg/kg per day is recommended with moderate strength for patients without CNS involvement. Use of amphotericin B deoxycholate is discouraged whenever alternatives are available. Isavuconazole is recommended with moderate strength for the first-line treatment of mucormycosis. The group marginally supports use of posaconazole oral suspension, and moderately supports posaconazole delayed release tablets and infusion for first-line treatment ( table 2 ).
First-line antifungal combination therapy
Evidence —In animal models, some antifungal combinations have shown the potential to improve cure and survival rates with no antagonism noted. 126 127 Results from some patient series are promising. 128 129 130 However, a historical control study 55 and a propensity score analysis failed to show benefits of double and triple antifungal combinations in patients with haematological malignancy. 108 In trauma patients, specifically in blast injury, more than one mould species can cause mixed infection warranting empirical combination therapy with liposomal amphotericin B and either posaconazole or voriconazole. 29 131 The downsides of combination therapy are unclear aside from potential added toxicity, drug interactions, and cost.
Recommendations —There are no definitive data to guide the use of antifungal combination therapy. Limited data support combinations of polyenes and azoles or polyenes plus echinocandins. Combination therapy can be rationally given due to lack of enhanced toxicity with possible but unproven benefit; however, data are too limited to support this beyond a marginal recommendation.
For further information on first-line combination therapy, see appendix p 19 .
Antifungal salvage treatment
Evidence —In general, there are two drug-related reasons for treatment failures, refractory mucormycosis or toxicity of first-line regimens—ie, intolerance to a drug. For amphotericin B formulations, particularly renal toxicity can be a limiting factor, while for the azole class hepatic toxicity has the highest prevalence. Toxicity can be caused by previous antifungals, or expected due to pre-existing organ damage. Only two drug classes have proven efficacy in mucormycosis, thus salvage treatment mostly means switching to the other class. Isavuconazole salvage treatment was successful in both clinical scenarios, refractory disease, and intolerance or toxicity. 49 132 In Europe, isavuconazole is licenced for salvage treatment of mucormycosis only. Posaconazole treatment with oral suspension achieved cure in two non-randomised clinical trials 133 134 and in case series. 17 135 Liposomal amphotericin B was effective as salvage treatment, 109 as was amphotericin B lipid complex, 113 136 and amphotericin B colloidal dispersion. 137
Recommendations —Isavuconazole is strongly supported as salvage treatment. Posaconazole delayed release tablets or infusions are strongly supported for salvage treatment, and when available should be preferred over posaconazole oral suspension, which in turn is marginally supported for salvage treatment. In cases of primary treatment failure with isavuconazole or posaconazole, the guideline group supports recommendations for all three lipid-based amphotericin B formulations with strong to moderate strength.
For further information on salvage treatment, see appendix p 20 .
Treatment duration for mucormycosis
Evidence —The duration of therapy necessary to treat mucormycosis is unknown. In general, weeks to months of therapy are given. If immune defect is resolved—eg diabetes is controlled, neutropenia definitively resolved, immunosuppression can be tapered or stopped, therapy can be continued until resolution of signs and symptoms of infection, and substantial radiographical improvement. Median duration of isavuconazole first-line or salvage treatment was 84 days intravenous or oral route or both. 49 Across several posaconazole oral suspension studies, treatment duration ranged from 1 week to almost 3 years, mean duration was approximately 6 months. 113 133 134 138 139 The wide range reflects the pattern of organs involved, with competing risks from underlying conditions. Late relapse in long-term survivors have been documented ( appendix p 21 ). 140
Recommendations —The guideline group strongly supports treatment until permanent reversal of immunosuppression and complete response on imaging, which might be difficult to determine because of scarring and postoperative changes. Treatment duration is a personalised decision. There is moderate support for intravenous treatment until stable disease is achieved. When switching to oral treatment, use of isavuconazole or posaconazole delayed release tablets is strongly supported. Posaconazole oral suspension can be used, but is marginally supported, especially when formulations with higher exposure are available ( appendix p 21 ).
Therapeutic drug monitoring in mucormycosis ( appendix p 22 ), specific considerations on treatment of mucormycosis in children ( appendix p 23 ), adjunctive treatments for mucormycosis ( appendix p 27 ), intensive care and crtically ill patients with mucormycosis ( appendix p 29 ), health economics ( appendix p 29 ), and future directions ( appendix p 30 ) are available in the appendix where indicated.
Treatment pathways for mucormycosis
The proposed treatment algorithms for adult ( appendix p 25 ; figure 5 ) and for paediatric patients ( appendix p 25 ) are based on case series, retrospective studies, and expert opinion. Large, randomised controlled trials investigating efficacy of treatment regimens are lacking. Surgical debridement should be performed whenever feasible in parallel to antifungal treatment. 11 17 141 142 The drug of choice is liposomal amphotericin B. 67 109 In case of renal failure, posaconazole or isavuconazole were shown to be effective. If a patient is intolerant to liposomal amphotericin B, its dose can be reduced, but should stay ≥5 mg/kg bodyweight. In case of extensive disease, rapid progression, or poor general condition, the addition of isavuconazole or posaconazole can be considered. 133 134 135
Treatment should be continued until resolution of initially indicative findings on imaging and reconstitution of host immune system. Isavuconazole or posaconazole may be administered as maintenance therapy. 143
OAC and AC coordinated the work of the authors and guided the development of the guideline. OAC, AC, AAI, DA, SCAC, ED, BH, MH, HEJ, KL, REL, SCM, MMe, ZP, DS, DCS, and RW wrote the initial manuscript draft. All authors contributed to the literature review, compilation of data tables and interpretation and assessment of recommendations. All authors participated in review and revisions, approved the final manuscript, and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Declaration of interests
OAC reports research grants from Actelion, Amplyx, Arsanis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, F2G, Gilead, GSK, Leeds University, Matinas, Medicines Company, MedPace, Melinta, Merck/MSD, Miltenyi, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres; is a consultant to Allecra Therapeutics, Amplyx, Actelion, Astellas, Basilea, Cidara, Da Volterra, Entasis Therapeutics, F2G, Gilead, IQVIA, Janssen, Matinas, Menarini, Merck/MSD, Paratek, PSI, Scynexis, Seres, Summit, Tetraphase, Vical, and received lecture honoraria from Astellas, Basilea, Gilead, Merck/MSD and Pfizer ED reports grants from Gilead, MSD; personal fees from Pfizer, Astellas; non-financial support from MSD and Pfizer. AM reports grants from Sanofi and ROCHE. AAI reports grants and personal fees from GILEAD, personal fees from Pfizer, grants from F2G, grants from Scynexis, personal fees from Astellas, personal fees from MSD. SAA reports grants from Pfizer. SCAC reports grants from MSD Australia. MH reports reports personal fees from Basilea, Merck, Practitioner Network; and grants and personal fees from Gilead. KL reports grants, personal fees, and non-financial support from MSD, Gilead, and Pfizer; and personal fees from Abbott. REL reports personal fees from Gilead and grants from Merck. DCS reports grants from Merck and personal fees from Merck, Astellas, and AVIR. AA reports non-financial support from MSD, Gilead, and Pfizer; and personal fees from Gilead sciences and Pathoquest. RB reports grants and personal fees from Merck and Pfizer. SB reports grants from MSD; personal fees from Gilead and other from Pfizer. EC reports personal fees from Astellas and Basilea. MC reports personal fees from Astellas, Pfizer, LF Asia, Meiji, and MSD, and non-financial support from Astellas, Pfizer, and LF Asia. ALC reports grants from Astellas; grants, personal fees, and non-financial support from Pfizer; personal fees and non-financial support from Biotoscana; personal fees and non-financial support from MSD; and personal fees and non-financial support from Gilead. LD reports personal fees and non-financial support from MSD and Pfizer; and non-financial support from Teva. AHG reports grants and personal fees from Gilead, Merck, Sharp & Dohme, and Pfizer; and personal fees from Astellas and Basilea. JG reports grants from Scynexis, CIDARA; and personal fees from Gilead, Pfizer, Astellas, MSD, and United Medical. CPH reports personal fees from Schering-Plough; grants and personal fees from Pfizer, Boehringer Ingelheim, Siemens; personal fees from Basilea, Novartis, Roche, Astellas, Gilead, MSD, Lilly, Intermune, Fresenius, Essex, AstraZeneca, Bracco, MEDA Pharma, Chiesi, Covidien, Pierre Fabre, Grifols, Bayer; and grants from MeVis, German Center for Lung Research. ASI reports grants from Amplyx Pharmaceuticals, grants from Astellas Pharma USA and is founder and shareholder from Vitalex Biosciences. NK reports personal fees from Astellas, Gilead, Merck, and Pfizer. FLan reports personal fees from Gilead, MSD, and Basilea. CLF reports reports grants from Gilead and Astellas; and personal fees from Gilead, Merck Sharp & Dohme, Basilea. DGL reports consultant fees from Astellas, GILEAD, MSD, Pfizer, and Yuhan; has served as a board member for Gilead and Yuhan; and has received research support, travel support and payment for lectures, including service on Speaker's bureaus, from Astellas, GILEAD, MSD, Pfizer, and Yuhan. TL reports grants from Gilead; personal fees and non-financial support from Gilead, Astellas, and MSD; and personal fees from Basilea. GM reports personal fees from Gilead and Pfizer. JFM reports personal fees from Scynexis, Gilead, Merck, United Medical, and Teva; grants from F2G, Pulmocide, and Amplyx. JM reports grants from Astellas, Gilead, MSD, and Pfizer. COM reporsts grants from Gilead and Merck. MN reports grants from Pfizer; and personal fees from Gilead, Scynexis, Cidara, Teva, United Medical, MSD, and Jansen. LP reports grants from Gilead, MSD, and Pfizer. APas reports grants from Gilead; and personal fees from Gilead, United Medical. ZR reports grants from Astellas and Teva. MRi reports personal fees from Gilead, MSD, and Basilea. ER reports grants from Gilead, Pfizer, Merck, and Sanofi; personal fees and non-financial support from Pfizer, Merck, and Astellas. MRu reports personal fees from Scynexis, Daiichi Sankyo, and Kedplasma GmbH. JS reports personal fees from Pfizer and MSD. MS reports grants and personal fees from Gilead and Merck. BS reports personal fees from Cempra, Bayer, Forge, Shionogi, Alexion, Synthetic Biologics, Paratek, Ovagene, Accuryx, and Bioversys; and is shareholder for Motif, BioAIM, Synthetic Biologics, Mycomed, and ExBaq. WS reports fees from Astellas and Merck. BHT reports grants from Pfizer. AJU reports personal fees from MSD, Basilea, and Aicuris. JJV reports personal fees from Merck/MSD, Gilead, Pfizer, Astellas Pharma, Basilea, Deutsches Zentrum für Infektionsforschung, Uniklinik Freiburg/Kongress und Kommunikation, Akademie für Infektionsmedizin, Universität Manchester, Deutsche Gesellschaft für Infektiologie, Ärztekammer Nordrhein, Uniklinik Aachen, Back Bay Strategies, and Deutsche Gesellschaft für Innere Medizin; and grants from Merck/MSD, Gilead, Pfizer, Astellas Pharma, Basilea, Deutsches Zentrum für Infektionsforschung, Bundesministerium für Bildung und Forschung. MJGTV reports having been on speakers' bureau for Pfizer, MSD/Merck, Gilead Sciences, Organobalance and Astellas Pharma; received research funding from 3M, Astellas Pharma, DaVolterra and Gilead Sciences; and is a consultant to Berlin Chemie, MSD/Merck and Astellas Pharma. TJW reports grants from Amplyx, Astellas, Merck, Scynexis, Allergan, Medicines Company, Lediant, and Tetraphase; and having served on Advisory Boards of Astellas, Merck, Scynexis, Allergan, Medicines. PLW reports personal fees from Gilead, MSD; and grants from Bruker. NPW reports grants from Astellas, bioMerieux, F2G, and Viamet; and personal fees from Mayne Pharma. All other authors declare no competing interests.
The following authors are fellows of the European Confederation of Medical Mycology (ECMM): OAC, AAI, SCAC, ED, BH, MH, HEJ, KL, DCS, AC, MA, AA, AMSA, SAA, HB, SB, MC, ALC, LD, AHG, ASI, SSK, NK, ML, FL, FL, CLF, MM, GM, JFM, JM, COM, MN, RO, LP, AP, MR, ER, SS, JS, JJV, MJGTV, TJW, PLW, and NPW. The following authors are members of the Mycoses Study Group and Research Consortium (MSG ERC): OAC, SCAC, DCS, ASI, BS, WS, TJW, NPW, TZ. The following authors are members of the Excellence Center (EC) for Medical Mycology of the European Confederation of Medical Mycology (ECMM): OAC, DA, SCM, DS, JJV, MJGTV, KL, ML, CL-F, JFM, and MR. We thank Valentina Arsic Arsenijevic, Neoh Chin Fen, and Adilia Warris for review and valuable contributions to the manuscript. The authors are indebted to Kerstin Albus, Susann Blossfeld, and Jon Salmanton-Garcia for technical support with this manuscript.
- 1 G Chamilos, RE Lewis, DP Kontoyiannis. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47:503-509
- 2 C Vaughan, A Bartolo, N Vallabh, SC Leong. A meta-analysis of survival factors in rhino-orbital-cerebral mucormycosis—has anything changed in the past 20 years?. Clin Otolaryngol. 2018;43:1454-1464
- 3 HY Sun, N Singh. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis. 2011;11:301-311
- 4 F Tissot, S Agrawal, L Pagano, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102:433-444
- 5 HC Kung, PY Huang, WT Chen, et al. 2016 guidelines for the use of antifungal agents in patients with invasive fungal diseases in Taiwan. J Microbiol Immunol Infect. 2018;51:1-17
- 6 OA Cornely, S Arikan-Akdagli, E Dannaoui, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20:5-26
- 7 CC Blyth, NM Gilroy, SD Guy, et al. Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014;44:1333-1349
- 8 A Skiada, F Lanternier, AH Groll, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica. 2013;98:492-504
- 9 OA Cornely, C Lass-Florl, K Lagrou, V Arsic-Arsenijevic, M Hoenigl. Improving outcome of fungal diseases. Guiding experts and patients towards excellence. Mycoses. 2017;60:420-425
- 10 M Hoenigl, JP Gangneux, E Segal, et al. Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: new leadership is about working together. Mycoses. 2018;61:885-894
- 11 MM Roden, TE Zaoutis, WL Buchanan, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634-653
- 12 H Prakash, AK Ghosh, SM Rudramurthy, et al. A prospective multicenter study on mucormycosis in India: epidemiology, diagnosis, and treatment. Med Mycol. 2019;57:395-402
- 13 DE Corzo-Leon, LD Chora-Hernandez, AP Rodriguez-Zulueta, TJ Walsh. Diabetes mellitus as the major risk factor for mucormycosis in Mexico: epidemiology, diagnosis, and outcomes of reported cases. Med Mycol. 2018;56:29-43
- 14 M Cuenca-Estrella, L Bernal-Martinez, G Isla, A Gomez-Lopez, L Alcazar-Fuoli, MJ Buitrago. Incidence of zygomycosis in transplant recipients. Clin Microbiol Infect. 2009;15:37-40
- 15 DS Hibbett, M Binder, JF Bischoff, et al. A higher-level phylogenetic classification of the Fungi. Mycol Res. 2007;111:509-547
- 16 KJ Kwon-Chung. Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygomycosis) and nomenclature of the disease: molecular mycologic perspectives. Clin Infect Dis. 2012;54:S8-S15
- 17 A Skiada, L Pagano, A Groll, et al. 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;17:1859-1867
- 18 SR Sridhara, G Paragache, NK Panda, A Chakrabarti. Mucormycosis in immunocompetent individuals: an increasing trend. J Otolaryngol. 2005;34:402-406
- 19 J Guinea, P Escribano, A Vena, et al. Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: Epidemiology and microbiological characterization of the isolates. PLoS One. 2017;12:
- 20 A Xhaard, F Lanternier, R Porcher, et al. Mucormycosis after allogeneic haematopoietic stem cell transplantation: a French multicentre cohort study (2003–2008). Clin Microbiol Infect. 2012;18:e396-e400
- 21 L Pagano, P Ricci, A Tonso, et al. Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. Br J Haematol. 1997;99:331-336
- 22 MM Hammer, R Madan, H Hatabu. Pulmonary mucormycosis: radiologic features at presentation and over time. AJR Am J Roentgenol. 2018;210:742-747
- 23 BD Nam, TJ Kim, KS Lee, TS Kim, J Han, MJ Chung. Pulmonary mucormycosis: serial morphologic changes on computed tomography correlate with clinical and pathologic findings. Eur Radiol. 2018;28:788-795
- 24 H Wahba, MT Truong, X Lei, DP Kontoyiannis, EM Marom. Reversed halo sign in invasive pulmonary fungal infections. Clin Infect Dis. 2008;46:1733-1737
- 25 C Legouge, D Caillot, ML Chretien, et al. The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?. Clin Infect Dis. 2014;58:672-678
- 26 K Singla, T Samra, N Bhatia. Primary cutaneous mucormycosis in a trauma patient with Morel-Lavallee lesion. Indian J Crit Care Med. 2018;22:375-377
- 27 R Neblett Fanfair, K Benedict, J Bos, et al. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med. 2012;367:2214-2225
- 28 K Al-Tarrah, M Abdelaty, A Behbahani, E Mokaddas, H Soliman, A Albader. Cutaneous mucormycosis postcosmetic surgery: a case report and review of the literature. Medicine (Baltimore). 2016;95:
- 29 T Warkentien, C Rodriguez, B Lloyd, et al. Invasive mold infections following combat-related injuries. Clin Infect Dis. 2012;55:1441-1449
- 30 CJ Rodriguez, DR Tribble, DL Malone, et al. Treatment of suspected invasive fungal infection in war wounds. Mil Med. 2018;183:142-146
- 31 RJ Hay. Mucormycosis: an infectious complication of traumatic injury. Lancet. 2005;365:830-831
- 32 NS Jayasuriya, WM Tilakaratne, EA Amaratunga, MK Ekanayake. An unusual presentation of rhinofacial zygomycosis due to, sp in an immunocompetent patient: a case report and literature review. Oral Dis. 2006;12:67-69
- 33 Y Wang, M Zhu, Y Bao, et al. Cutaneous mucormycosis caused by, in an immunocompetent patient: a case report and review of literature. Medicine (Baltimore). 2018;97:
- 34 JS Jundt, MEK Wong, AM Tatara, NM Demian. Invasive cutaneous facial mucormycosis in a trauma patient. J Oral Maxillofac Surg. 2018;76:1930.e1-1930.e5
- 35 A Candoni, N Klimko, A Busca, et al. Fungal infections of the central nervous system and paranasal sinuses in onco-haematologic patients. Epidemiological study reporting the diagnostic-therapeutic approach and outcome in 89 cases. Mycoses. 2019;62:252-260
- 36 MS Bae, EJ Kim, KM Lee, WS Choi. Rapidly progressive rhino-orbito-cerebralmucormycosis complicated with unilateral internal carotid artery occlusion: a case report. Neurointervention. 2012;7:45-49
- 37 M Vallverdu Vidal, S Iglesias Moles, M Palomar Martinez. Rhino-orbital-cerebral mucormycosis in a critically ill patient. Med Intensiva. 2017;41:509-510
- 38 A Bhansali, S Bhadada, A Sharma, et al. Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgrad Med J. 2004;80:670-674
- 39 LC Goh, ED Shakri, HY Ong, et al. A seven-year retrospective analysis of the clinicopathological and mycological manifestations of fungal rhinosinusitis in a single-centre tropical climate hospital. J Laryngol Otol. 2017;131:813-816
- 40 SR Thomson, PG Bade, M Taams, V Chrystal. Gastrointestinal mucormycosis. Br J Surg. 1991;78:952-954
- 41 R Dekkers, PE Verweij, CM Weemaes, RS Severijnen, JH Van Krieken, A Warris. Gastrointestinal zygomycosis due to, var., as a manifestation of chronic granulomatous disease. Med Mycol. 2008;46:491-494
- 42 E Roilides, TE Zaoutis, A Katragkou, DK Benjamin Jr, TJ Walsh. Zygomycosis in neonates: an uncommon but life-threatening infection. Am J Perinatol. 2009;26:565-573
- 43 KS Chugh, V Sakhuja, KL Gupta, et al. Renal mucormycosis: computerized tomographic findings and their diagnostic significance. Am J Kidney Dis. 1993;22:393-397
- 44 R Sharma, G Shivanand, R Kumar, et al. Isolated renal mucormycosis: an unusual cause of acute renal infarction in a boy with aplastic anaemia. Br J Radiol. 2006;79:e19-e21
- 45 RS Marak, R Misra, MS Ansari, et al. Successful medical management of renal zygomycosis: a summary of two cases and a review of the Indian literature. Med Mycol. 2010;48:1088-1095
- 46 AJ Thomas, S Shah, MS Mathews, N Chacko. - renal mucormycosis in a healthy host: a case report from south India. Indian J Med Microbiol. 2008;26:269-271
- 47 J Yu, RY Li. Primary renal zygomycosis due to. Med Mycol. 2006;44:461-466
- 48 L Jianhong, H Xianliang, J Xuewu. Isolated renal mucormycosis in children. J Urol. 2004;171:387-388
- 49 FM Marty, L Ostrosky-Zeichner, OA Cornely, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16:828-837
- 50 S Shoham, SS Magill, WG Merz, et al. Primary treatment of zygomycosis with liposomal amphotericin B: analysis of 28 cases. Med Mycol. 2010;48:511-517
- 51 M Legrand, M Gits-Muselli, L Boutin, et al. Detection of circulating mucorales DNA in critically ill burn patients: preliminary report of a screening strategy for early diagnosis and treatment. Clin Infect Dis. 2016;63:1312-1317
- 52 HL Hong, YM Lee, T Kim, et al. Risk factors for mortality in patients with invasive mucormycosis. Infect Chemother. 2013;45:292-298
- 53 SK Palejwala, TT Zangeneh, SA Goldstein, GM Lemole. An aggressive multidisciplinary approach reduces mortality in rhinocerebral mucormycosis. J Neurol Surg B. 2016;77:P088
- 54 TJ Walsh, A Skiada, OA Cornely, et al. Development of new strategies for early diagnosis of mucormycosis from bench to bedside. Mycoses. 2014;57:2-7
- 55 MZ Abidi, MR Sohail, N Cummins, et al. 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;57:687-698
- 56 D Bitar, D Che. [Epidemiology of mucormycosis in metropolitan France, 1997–2010]. Med Sci (Paris). 2013;29:7-12 (in French).
- 57 J Guarner, ME Brandt. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24:247-280
- 58 VL Kung, RD Chernock, CD Burnham. Diagnostic accuracy of fungal identification in histopathology and cytopathology specimens. Eur J Clin Microbiol Infect Dis. 2018;37:157-165
- 59 M Chermetz, M Gobbo, K Rupel, et al. Combined orofacial aspergillosis and mucormycosis: fatal complication of a recurrent paediatric glioma-case report and review of literature. Mycopathologia. 2016;181:723-733
- 60 S Davoudi, A Kasraianfard, Z Ahmadinejad, et al. Cytomegalovirus reactivation and preemptive therapy after liver transplant. Exp Clin Transplant. 2014;12:72-75
- 61 HS Dhaliwal, A Singh, SK Sinha, et al. Diagnosed only if considered: isolated renal mucormycosis. Lancet. 2015;385:
- 62 JL Frater, GS Hall, GW Procop. Histologic features of zygomycosis: emphasis on perineural invasion and fungal morphology. Arch Pathol Lab Med. 2001;125:375-378
- 63 RJC Hoeppli. Histological observations in experimental schistosomiasis japonica. Chin Med J (Engl). 1932;46:1179-1186
- 64 A Splendore. Sobre a cultura d'una nova especie de cogumello pathogenico. Revista de Sociedade Scientifica de Sao Paulo. 1908;62:62-63
- 65 R Ben-Ami, M Luna, RE Lewis, TJ Walsh, DP Kontoyiannis. A clinicopathological study of pulmonary mucormycosis in cancer patients: extensive angioinvasion but limited inflammatory response. J Infect. 2009;59:134-138
- 66 A Chakrabarti, SS Chatterjee, A Das, et al. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J. 2009;85:573-581
- 67 MJ Ruping, WJ Heinz, AJ Kindo, et al. Forty-one recent cases of invasive zygomycosis from a global clinical registry. J Antimicrob Chemother. 2010;65:296-302
- 68 HE Jensen, J Salonen, TO Ekfors. The use of immunohistochemistry to improve sensitivity and specificity in the diagnosis of systemic mycoses in patients with haematological malignancies. J Pathol. 1997;181:100-105
- 69 J Jung, YS Park, H Sung, et al. Using immunohistochemistry to assess the accuracy of histomorphologic diagnosis of aspergillosis and mucormycosis. Clin Infect Dis. 2015;61:1664-1670
- 70 K Sunagawa, T Ishige, Y Kusumi, et al. Renal abscess involving mucormycosis by immunohistochemical detection in a patient with acute lymphocytic leukemia: a case report and literature review. Jpn J Infect Dis. 2013;66:345-347
- 71 L Bernal-Martinez, MJ Buitrago, MV Castelli, JL Rodriguez-Tudela, M Cuenca-Estrella. Development of a single tube multiplex real-time PCR to detect the most clinically relevant Mucormycetes species. Clin Microbiol Infect. 2013;19:e1-e7
- 72 M Drogari-Apiranthitou, I Panayiotides, I Galani, et al. Diagnostic value of a semi-nested PCR for the diagnosis of mucormycosis and aspergillosis from paraffin-embedded tissue: a single center experience. Pathol Res Pract. 2016;212:393-397
- 73 K Ruangritchankul, A Chindamporn, N Worasilchai, U Poumsuk, S Keelawat, A Bychkov. Invasive fungal disease in university hospital: a PCR-based study of autopsy cases. Int J Clin Exp Pathol. 2015;8:14840-14852
- 74 E Salehi, MT Hedayati, J Zoll, et al. Discrimination of aspergillosis, mucormycosis, fusariosis, and scedosporiosis in formalin-fixed paraffin-embedded tissue specimens by use of multiple real-time quantitative PCR assays. J Clin Microbiol. 2016;54:2798-2803
- 75 J Springer, D Goldenberger, F Schmidt, et al. Development and application of two independent real-time PCR assays to detect clinically relevant Mucorales species. J Med Microbiol. 2016;65:227-234
- 76 J Springer, M Lackner, C Ensinger, et al. Clinical evaluation of a Mucorales-specific real-time PCR assay in tissue and serum samples. J Med Microbiol. 2016;65:1414-1421
- 77 K Zaman, SM Rudramurthy, A Das, et al. Molecular diagnosis of rhino-orbito-cerebral mucormycosis from fresh tissue samples. J Med Microbiol. 2017;66:1124-1129
- 78 P Schwarz, S Bretagne, JC Gantier, et al. Molecular identification of Zygomycetes from culture and experimentally infected tissues. J Clin Microbiol. 2006;44:340-349
- 79 C Lass-Florl, G Resch, D Nachbaur, et al. The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis. 2007;45:e101-e104
- 80 A Lau, S Chen, T Sorrell, et al. Development and clinical application of a panfungal PCR assay to detect and identify fungal DNA in tissue specimens. J Clin Microbiol. 2007;45:380-385
- 81 V Rickerts, S Mousset, E Lambrecht, et al. Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens. Clin Infect Dis. 2007;44:1078-1083
- 82 M Kasai, SM Harrington, A Francesconi, et al. Detection of a molecular biomarker for zygomycetes by quantitative PCR assays of plasma, bronchoalveolar lavage, and lung tissue in a rabbit model of experimental pulmonary zygomycosis. J Clin Microbiol. 2008;46:3690-3702
- 83 K Hrncirova, M Lengerova, I Kocmanova, et al. Rapid detection and identification of mucormycetes from culture and tissue samples by use of high-resolution melt analysis. J Clin Microbiol. 2010;48:3392-3394
- 84 MJ Buitrago, L Bernal-Martinez, MV Castelli, JL Rodriguez-Tudela, M Cuenca-Estrella. Performance of panfungal- and specific-PCR-based procedures for etiological diagnosis of invasive fungal diseases on tissue biopsy specimens with proven infection: a 7-year retrospective analysis from a reference laboratory. J Clin Microbiol. 2014;52:1737-1740
- 85 A Alanio, D Garcia-Hermoso, S Mercier-Delarue, et al. Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry. Clin Microbiol Infect. 2015;21:594
- 86 RT Hayden, X Qian, GW Procop, GD Roberts, RV Lloyd. In situ hybridization for the identification of filamentous fungi in tissue section. Diagn Mol Pathol. 2002;11:119-126
- 87 K Nagao, T Ota, A Tanikawa, et al. Genetic identification and detection of human pathogenic, species, a major mucormycosis agent, by multiplex PCR based on internal transcribed spacer region of rRNA gene. J Dermatol Sci. 2005;39:23-31
- 88 R Bialek, F Konrad, J Kern, et al. PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue. J Clin Pathol. 2005;58:1180-1184
- 89 V Rickerts, G Just-Nubling, F Konrad, et al. Diagnosis of invasive aspergillosis and mucormycosis in immunocompromised patients by seminested PCR assay of tissue samples. Eur J Clin Microbiol Infect Dis. 2006;25:8-13
- 90 DJ Hata, SP Buckwalter, BS Pritt, GD Roberts, NL Wengenack. Real-time PCR method for detection of zygomycetes. J Clin Microbiol. 2008;46:2353-2358
- 91 E Dannaoui, P Schwarz, M Slany, et al. Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation. J Clin Microbiol. 2010;48:2043-2046
- 92 SP Hammond, R Bialek, DA Milner, EM Petschnigg, LR Baden, FM Marty. Molecular methods to improve diagnosis and identification of mucormycosis. J Clin Microbiol. 2011;49:2151-2153
- 93 MJ Buitrago, JM Aguado, A Ballen, et al. Efficacy of DNA amplification in tissue biopsy samples to improve the detection of invasive fungal disease. Clin Microbiol Infect. 2013;19:e271-e277
- 94 L Gade, S Hurst, SA Balajee, SR Lockhart, AP Litvintseva. Detection of mucormycetes and other pathogenic fungi in formalin fixed paraffin embedded and fresh tissues using the extended region of 28S rDNA. Med Mycol. 2017;55:385-395
- 95 NG Ghadi, T Shokohi, Z Seifi, et al. Identification of Mucorales in patients with proven invasive mucormycosis by polymerase chain reaction in tissue samples. Mycoses. 2018;1:909-915
- 96 MZ Gomes, RE Lewis, DP Kontoyiannis. Mucormycosis caused by unusual mucormycetes, non-, -, and -species. Clin Microbiol Rev. 2011;24:411-445
- 97 V Petraitis, R Petraitiene, C Antachopoulos, et al. Increased virulence of, in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism. Med Mycol. 2013;51:72-82
- 98 F Lanternier, E Dannaoui, G Morizot, et al. A global analysis of mucormycosis in France: the RetroZygo study (2005–2007). Clin Infect Dis. 2012;54:S35-S43
- 99 XL Lu, ZH Liu, YN Shen, et al. Primary cutaneous zygomycosis caused by, : a new endemic zygomycosis? A case report and review of 6 cases reported from China. Clin Infect Dis. 2009;49:e39-e43
- 100 KA Etienne, J Gillece, R Hilsabeck, et al. Whole genome sequence typing to investigate the apophysomyces outbreak following a tornado in Joplin, Missouri, 2011. PLoS One. 2012;7:
- 101 D Garcia-Hermoso, A Criscuolo, SC Lee, et al. Outbreak of invasive wound mucormycosis in a burn unit due to multiple strains of, f., resolved by whole-genome sequencing. MBio. 2018;9:
- 102 B Rammaert, F Lanternier, JR Zahar, et al. Healthcare-associated mucormycosis. Clin Infect Dis. 2012;54:S44-S54
- 103 VC Cheng, JF Chan, AH Ngan, et al. Outbreak of intestinal infection due to. J Clin Microbiol. 2009;47:2834-2843
- 104 F Lanternier, S Poiree, C Elie, et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother. 2015;70:3116-3123
- 105 L Pagano, CG Valentini, B Posteraro, et al. Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology). J Chemother. 2009;21:322-329
- 106 OA Cornely, J Maertens, M Bresnik, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289-1297
- 107 M Stanzani, N Vianelli, M Cavo, A Maritati, M Morotti, RE Lewis. Retrospective cohort analysis of liposomal amphotericin b nephrotoxicity in patients with hematological malignancies. Antimicrob Agents Chemother. 2017;61:
- 108 A Kyvernitakis, HA Torres, Y Jiang, G Chamilos, RE Lewis, DP Kontoyiannis. 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
- 109 L Pagano, M Offidani, L Fianchi, et al. Mucormycosis in hematologic patients. Haematologica. 2004;89:207-214
- 110 A Nosari, P Oreste, M Montillo, et al. Mucormycosis in hematologic malignancies: an emerging fungal infection. Haematologica. 2000;85:1068-1071
- 111 TJ Walsh, JL Goodman, P Pappas, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with, species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother. 2001;45:3487-3496
- 112 AS Ibrahim, T Gebremariam, MI Husseiny, et al. Comparison of lipid amphotericin B preparations in treating murine zygomycosis. Antimicrob Agents Chemother. 2008;52:1573-1576
- 113 JA Larkin, JA Montero. Efficacy and safety of amphotericin B lipid complex for zygomycosis. Infect Med. 2003;20:201-206
- 114 GN Forrest, K Mankes. Outcomes of invasive zygomycosis infections in renal transplant recipients. Transpl Infect Dis. 2007;9:161-164
- 115 AJ Ullmann, MA Sanz, A Tramarin, et al. Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clin Infect Dis. 2006;43:e29-e38
- 116 TJ Walsh, RW Finberg, C Arndt, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;34:764-771
- 117 E Roilides, C Antachopoulos. Isavuconazole: an azole active against mucormycosis. Lancet Infect Dis. 2016;16:761-762
- 118 RO Abuodeh, JN Galgiani, GM Scalarone. Molecular approaches to the study of. Int J Med Microbiol. 2002;292:373-380
- 119 SC Mellinghoff, M Bassetti, D Dorfel, et al. Isavuconazole shortens the QTc interval. Mycoses. 2017;61:256-260
- 120 JA Maertens, II Raad, KA Marr, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387:760-769
- 121 AJ DiPippo, CR Rausch, DP Kontoyiannis. Tolerability of isavuconazole after posaconazole toxicity in leukemia patients. Mycoses. 2018;62:81-86
- 122 RF Duarte, J Lopez-Jimenez, OA Cornely, et al. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014;58:5758-5765
- 123 OA Cornely, RF Duarte, S Haider, et al. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother. 2016;71:
- 124 J Maertens, OA Cornely, AJ Ullmann, et al. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014;58:3610-3617
- 125 OA Cornely, MN Robertson, S Haider, et al. Pharmacokinetics and safety results from the phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease. J Antimicrob Chemother. 2017;72:3406-3413
- 126 AS Ibrahim, T Gebremariam, Y Fu, JE Edwards Jr, B Spellberg. Combination echinocandin-polyene treatment of murine mucormycosis. Antimicrob Agents Chemother. 2008;52:1556-1558
- 127 AS Ibrahim, T Gebremariam, JA Schwartz, JE Edwards Jr, B Spellberg. Posaconazole mono- or combination therapy for treatment of murine zygomycosis. Antimicrob Agents Chemother. 2009;53:772-775
- 128 NN Klimko, SN Khostelidi, AG Volkova, et al. Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg, Russia. Mycoses. 2014;57:91-96
- 129 C Reed, R Bryant, AS Ibrahim, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47:364-371
- 130 JD Jenks, SL Reed, D Seidel, et al. Rare mold infections caused by Mucorales,, and fusarium, San Diego: the role of antifungal combination therapy. Int J Antimicrob Agents. 2018;52:706-712
- 131 CJ Rodriguez, DR Tribble, DL Malone, et al. Treatment of suspected invasive fungal infection in war wounds. Mil Med. 2018;183:142-146
- 132 FM Marty, OA Cornely, KM Mullane, et al. Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species. Mycoses. 2018;61:485-497
- 133 RN Greenberg, K Mullane, JA van Burik, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126-133
- 134 JA van Burik, RS Hare, HF Solomon, ML Corrado, DP Kontoyiannis. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42:e61-e65
- 135 JJ Vehreschild, A Birtel, MJ Vehreschild, et al. Mucormycosis treated with posaconazole: review of 96 case reports. Crit Rev Microbiol. 2013;39:310-324
- 136 TJ Walsh, JW Hiemenz, NL Seibel, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis. 1998;26:1383-1396
- 137 R Herbrecht, V Letscher-Bru, RA Bowden, et al. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis. 2001;20:460-466
- 138 JH Kim, RJ Benefield, K Ditolla. Utilization of posaconazole oral suspension or delayed-released tablet salvage treatment for invasive fungal infection. Mycoses. 2016;59:726-733
- 139 J Ma, R Jia, J Li, et al. Retrospective clinical study of eighty-one cases of intracranial mucormycosis. J Glob Infect Dis. 2015;7:143-150
- 140 S Davoudi, P Anderlini, GN Fuller, DP Kontoyiannis. A long-term survivor of disseminated aspergillus and mucorales infection: an instructive case. Mycopathologia. 2014;178:465-470
- 141 CG Valentini, A Candoni, L Fianchi, et al. Efficacy of combined surgery and antifungal therapies for the management of invasive zygomycoses in patients with haematological malignancies. Mycoses. 2010;53:89-92
- 142 M Tedder, JA Spratt, MP Anstadt, SS Hegde, SD Tedder, JE Lowe. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg. 1994;57:1044-1050
- 143 DP Kontoyiannis, RE Lewis. How I treat mucormycosis. Blood. 2011;118:1216-1224
- 144 B Gleissner, A Schilling, I Anagnostopolous, I Siehl, E Thiel. Improved outcome of zygomycosis in patients with hematological diseases?. Leuk Lymphoma. 2004;45:1351-1360
- 145 N Singh, JM Aguado, H Bonatti, 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;200:1002-1011
- 146 HY Sun, JM Aguado, H Bonatti, et al. Pulmonary zygomycosis in solid organ transplant recipients in the current era. Am J Transplant. 2009;9:2166-2171
- 147 F Lanternier, HY Sun, P Ribaud, N Singh, DP Kontoyiannis, O Lortholary. Mucormycosis in organ and stem cell transplant recipients. Clin Infect Dis. 2012;54:1629-1636
- 148 YH Li, P Sun, JC Guo. Clinical analysis of diabetic combined pulmonary mucormycosis. Mycopathologia. 2017;182:1111-1117
- 149 E Dannaoui, JF Meis, D Loebenberg, PE Verweij. Activity of posaconazole in treatment of experimental disseminated zygomycosis. Antimicrob Agents Chemother. 2003;47:3647-3650
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