今日の臨床サポート

ムーコル副鼻腔炎、肺感染症

著者: 木村宗芳 虎の門病院 臨床感染症部臨床感染症科

監修: 細川直登 亀田総合病院

著者校正済:2022/04/27
現在監修レビュー中
参考ガイドライン:
  1. ヨーロッパ真菌学会(European Confederation of Medical Mycology):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.2019
患者向け説明資料

概要・推奨   

  1. ムーコル症の確定診断は、感染組織の生検で行う。生検組織は、病理検査(グロコット染色など)、培養検査に提出する。また可能であればPCR検査も追加することが望ましい(推奨度2)
  1. 肺ムーコル症の早期診断には、胸部CT検査の所見が有用なことがある。ただし、感度・特異度ともに高い所見は存在しない。そのため、疑わしい所見を見つけたときにも診断的手技(気管支鏡検査、CTガイド下肺生検、外科手術での生検)での証明を怠ってはならない(推奨度1)
  1. ムーコル症に対する抗真菌薬の第1選択はリポソーマルアムホテリシンBである。本症を疑った際には、可能な限り早期から十分量の本剤を使用することが望ましい(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
木村宗芳 : 未申告[2022年]
監修:細川直登 : 未申告[2022年]

改訂のポイント:
  1.  定期レビューに加えて、治療薬の項目にポサコナゾールを追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 本症は、糸状真菌であるムーコル目(Mucorales)に属するいくつかの菌種による感染症である。ヒトに生じるムーコル症を生じる菌種としては、Rhizopus(クモノスカビ)、Mucor(ケカビ)、Rhizomucor(リゾムコール)、Cunninghamella(クスダマカビ)、Absidia(コミケカビ)などが知られている。
  1. ムーコル感染症の診断は難しいとされる。リスク因子と病歴から本症を疑った際には可能な限り感染が疑われる組織の生検を実施し、病理組織での診断および組織培養、組織のPCR検査などによる診断を試みることが望ましい。
  1. ムーコル感染症のリスク因子として、造血幹細胞移植、固形臓器移植、血液悪性疾患、コントロール不良な糖尿病(特にケトアシドーシスを来している状態)、鉄過剰状態が挙げられる。
  1. ムーコル感染症のリスク因子として、造血幹細胞移植、固形臓器移植、血液悪性疾患、コントロール不良な糖尿病(特にケトアシドーシスを来している状態)、鉄過剰状態が挙げられる。
  1. ボリコナゾール予防投与中に出現した真菌性肺炎または真菌性副鼻腔炎はムーコル症のリスク因子とされる。
  1. 予後の悪い疾患であり、早期診断・早期治療が不可欠である。可能な限り早期に診断をつける必要があるが、本症を疑った際には、診断が確定する前から適切な治療を開始していなければならない。
  1. 治療の原則は十分量のリポソーマルアムホテリシンB点滴による治療、感染組織のデブリードマン、リスク因子の解除である。
問診・診察のポイント  
  1. リスク因子の有無を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

D P Kontoyiannis, V C Wessel, G P Bodey, K V Rolston
Zygomycosis in the 1990s in a tertiary-care cancer center.
Clin Infect Dis. 2000 Jun;30(6):851-6. doi: 10.1086/313803. Epub 2000 Jun 13.
Abstract/Text Twenty-four patients with cancer met predetermined criteria for a diagnosis of zygomycosis over a 10-year period at our institution. All had hematologic malignancy, and most had either neutropenia or steroid use as a risk factor. Pulmonary involvement mimicking invasive aspergillosis was the most common presentation, and dissemination was seen in 58% of patients on whom autopsies were performed. Three-fourths of the patients with pulmonary zygomycosis had pathogenic microorganisms other than zygomycetes isolated from respiratory specimens. The sensitivity of cultures in detecting zygomycetes from respiratory specimens was low. A culture positive for zygomycetes was typically a preterminal finding in the fatal, acute cases. Two-thirds of the patients died. Favorable outcome seemed to correlate with lack of pulmonary involvement, surgical debridement, neutrophil recovery, and a cumulative total amphotericin B dose of 2000 mg. Therapy with high-dose amphotericin B, combined with aggressive surgery and immune reconstitution, offers the best chance for survival of cancer patients with zygomycosis.

PMID 10852735
S M Trifilio, C L Bennett, P R Yarnold, J M McKoy, J Parada, J Mehta, G Chamilos, F Palella, L Kennedy, K Mullane, M S Tallman, A Evens, M H Scheetz, W Blum, D P Kontoyiannis
Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy.
Bone Marrow Transplant. 2007 Apr;39(7):425-9. doi: 10.1038/sj.bmt.1705614. Epub 2007 Feb 19.
Abstract/Text Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to voriconazole. Criteria for inclusion were 5 days or more of voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.

PMID 17310132
Nina Singh, Jose M Aguado, Hugo Bonatti, Graeme Forrest, Krishan L Gupta, Nasia Safdar, George T John, Kenneth J Pursell, Patricia Muñoz, Robin Patel, Jesus Fortun, Pilar Martin-Davila, Bruno Philippe, François Philit, Alexis Tabah, Nicolas Terzi, Valérie Chatelet, Shimon Kusne, Nina Clark, Emily Blumberg, Marino Blanes Julia, Abhi Humar, Sally Houston, Cornelia Lass-Flörl, Leonard Johnson, Erik R Dubberke, Michelle A Barron, Olivier Lortholary
Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome.
J Infect Dis. 2009 Sep 15;200(6):1002-11. doi: 10.1086/605445.
Abstract/Text BACKGROUND: Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined.
METHODS: In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days.
RESULTS: Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables.
CONCLUSIONS: The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

PMID 19659439
J Maertens, H Demuynck, E K Verbeken, P Zachée, G E Verhoef, P Vandenberghe, M A Boogaerts
Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis.
Bone Marrow Transplant. 1999 Aug;24(3):307-12. doi: 10.1038/sj.bmt.1701885.
Abstract/Text In a 10-year consecutive series of 263 allogeneic bone marrow transplant recipients, we identified five cases (1.9%) of invasive mucormycosis. Only one infection occurred within the first 100 days after transplantation, while the remainder complicated the late post-transplant course (median day of diagnosis: 343). Sites of infection were considered 'non-classical' and included pulmonary, cutaneous and gastric involvement. No case of fungal dissemination was observed. Mucormycosis was the primary cause of death in three of the five patients. Corticosteroid-treated graft-versus-host disease, either acute or chronic, or severe neutropenia were present in all cases. However, compared with a matched control population, the most striking finding was the demonstration of severe iron overload in each of the mucormycosis patients. The mean level of serum ferritin, transferrin saturation and number of transfused units of red cells (2029 microg/l, 92% and 52 units, respectively) in the study group is significantly higher compared with the control group (P < 0.05). The difference with other risk groups for mucormycosis, including deferoxamine-treated dialysis patients and acidotic diabetics, was analyzed in view of the possible pathogenic role of iron. Although these infections are often fatal, limited disease may have a better prognosis if diagnosed early and treated aggressively.

PMID 10455371
Brad Spellberg, Thomas J Walsh, Dimitrios P Kontoyiannis, John Edwards, Ashraf S Ibrahim
Recent advances in the management of mucormycosis: from bench to bedside.
Clin Infect Dis. 2009 Jun 15;48(12):1743-51. doi: 10.1086/599105.
Abstract/Text Recent therapeutic advances have the potential to improve outcomes of mucormycosis. Lipid formulations of amphotericin B (LFAB) have evolved as the cornerstone of primary therapy for mucormycosis. Posaconazole may be useful as salvage therapy, but it cannot be recommended as primary therapy for mucormycosis on the basis of available data. Preclinical and limited retrospective clinical data suggest that combination LFAB-echinocandin therapy may improve survival during mucormycosis. A definitive trial is needed to confirm these results. Combination therapy with LFAB and the iron chelator, deferasirox, also improved outcomes in animal models of mucormycosis. In contrast, combination polyene-posaconazole therapy was of no benefit in preclinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered for selected patients. Early initiation of therapy is critical to maximizing outcomes; recent developments in polymerase chain reaction technology are advancing early diagnostic strategies. Prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.

PMID 19435437
Maureen M Roden, Theoklis E Zaoutis, Wendy L Buchanan, Tena A Knudsen, Tatyana A Sarkisova, Robert L Schaufele, Michael Sein, Tin Sein, Christine C Chiou, Jaclyn H Chu, Dimitrios P Kontoyiannis, Thomas J Walsh
Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
Clin Infect Dis. 2005 Sep 1;41(5):634-53. doi: 10.1086/432579. Epub 2005 Jul 29.
Abstract/Text BACKGROUND: Zygomycosis is an increasingly emerging life-threatening infection. There is no single comprehensive literature review that describes the epidemiology and outcome of this disease.
METHODS: We reviewed reports of zygomycosis in the English-language literature since 1885 and analyzed 929 eligible cases. We included in the database only those cases for which the underlying condition, the pattern of infection, the surgical and antifungal treatments, and survival were described.
RESULTS: The mean age of patients was 38.8 years; 65% were male. The prevalence and overall mortality were 36% and 44%, respectively, for diabetes; 19% and 35%, respectively, for no underlying condition; and 17% and 66%, respectively, for malignancy. The most common types of infection were sinus (39%), pulmonary (24%), and cutaneous (19%). Dissemination developed in 23% of cases. Mortality varied with the site of infection: 96% of patients with disseminated disease died, 85% with gastrointestinal infection died, and 76% with pulmonary infection died. The majority of patients with malignancy (92 [60%] of 154) had pulmonary disease, whereas the majority of patients with diabetes (222 [66%] of 337) had sinus disease. Rhinocerebral disease was seen more frequently in patients with diabetes (145 [33%] of 337), compared with patients with malignancy (6 [4%] of 154). Hematogenous dissemination to skin was rare; however, 78 (44%) of 176 cutaneous infections were complicated by deep extension or dissemination. Survival was 3% (8 of 241 patients) for cases that were not treated, 61% (324 of 532) for cases treated with amphotericin B deoxycholate, 57% (51 of 90) for cases treated with surgery alone, and 70% (328 of 470) for cases treated with antifungal therapy and surgery. By multivariate analysis, infection due to Cunninghamella species and disseminated disease were independently associated with increased rates of death (odds ratios, 2.78 and 11.2, respectively).
CONCLUSIONS: Outcome from zygomycosis varies as a function of the underlying condition, site of infection, and use of antifungal therapy.

PMID 16080086
Sarah P Hammond, Ralf Bialek, Danny A Milner, Eva M Petschnigg, Lindsey R Baden, Francisco M Marty
Molecular methods to improve diagnosis and identification of mucormycosis.
J Clin Microbiol. 2011 Jun;49(6):2151-3. doi: 10.1128/JCM.00256-11. Epub 2011 Apr 20.
Abstract/Text Mucormycosis is difficult to diagnose. Samples from suspected cases often fail to grow Mucorales in microbiologic cultures. We identified all hematologic malignancy and stem cell transplant patients diagnosed with proven mucormycosis between 2001 and 2009 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Seminested PCR targeting Mucorales 18S ribosomal DNA and sequencing were performed on formalin-fixed paraffin-embedded tissue samples. Of 29 cases of mucormycosis, 27 had tissue samples available for PCR and sequencing. Mucorales PCR was positive in 22. Among 12 culture-positive cases, 10 were PCR positive and sequencing was concordant with culture results to the genus level in 9. Among 15 culture-negative cases, PCR was positive and sequencing allowed genus identification in 12. Mucorales PCR is useful for confirmation of the diagnosis of mucormycosis and for further characterization of the infection in cases where cultures are negative.

PMID 21508149
L Millon, R Herbrecht, F Grenouillet, F Morio, A Alanio, V Letscher-Bru, S Cassaing, T Chouaki, C Kauffmann-Lacroix, P Poirier, D Toubas, O Augereau, S Rocchi, D Garcia-Hermoso, S Bretagne, French Mycosis Study Group
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. 2015 Dec 17;. doi: 10.1016/j.cmi.2015.12.006. Epub 2015 Dec 17.
Abstract/Text The main objective of this study was to assess the diagnostic performance of a set of three Mucorales quantitative PCR assays in a retrospective multicentre study. Mucormycosis cases were recorded thanks to the French prospective surveillance programme (RESSIF network). The day of sampling of the first histological or mycological positive specimen was defined as day 0 (D0). Detection of circulating DNA was performed on frozen serum samples collected from D-30 to D30, using quantitative PCR assays targeting Rhizomucor, Lichtheimia, Mucor/Rhizopus. Forty-four patients diagnosed with probable (n = 19) or proven (n = 25) mucormycosis were included. Thirty-six of the 44 patients (81%) had at least one PCR-positive serum. The first PCR-positive sample was observed 9 days (range 0-28 days) before diagnosis was made using mycological criteria and at least 2 days (range 0-24 days) before imaging. The identifications provided with the quantitative PCR assays were all concordant with culture and/or PCR-based identification of the causal species. Survival rate at D84 was significantly higher for patients with an initially positive PCR that became negative after treatment initiation than for patients whose PCR remained positive (48% and 4%, respectively; p <10(-6)). The median time for complete negativity of PCR was 7 days (range 3-19 days) after initiation of l-AmB treatment. Despite some limitations due to the retrospective design of the study, we showed that Mucorales quantitative PCR could not only confirm the mucormycosis diagnosis when other mycological arguments were present but could also anticipate this diagnosis. Quantification of DNA loads may also be a useful adjunct to treatment monitoring.

Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 26706615
Ben De Pauw, Thomas J Walsh, J Peter Donnelly, David A Stevens, John E Edwards, Thierry Calandra, Peter G Pappas, Johan Maertens, Olivier Lortholary, Carol A Kauffman, David W Denning, Thomas F Patterson, Georg Maschmeyer, Jacques Bille, William E Dismukes, Raoul Herbrecht, William W Hope, Christopher C Kibbler, Bart Jan Kullberg, Kieren A Marr, Patricia Muñoz, Frank C Odds, John R Perfect, Angela Restrepo, Markus Ruhnke, Brahm H Segal, Jack D Sobel, Tania C Sorrell, Claudio Viscoli, John R Wingard, Theoklis Zaoutis, John E Bennett, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group
Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.
Clin Infect Dis. 2008 Jun 15;46(12):1813-21. doi: 10.1086/588660.
Abstract/Text BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies.
METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved.
RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only.
CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.

PMID 18462102
Muneyoshi Kimura, Hideki Araoka, Naoyuki Uchida, Hideaki Ohno, Yoshitsugu Miyazaki, Takeshi Fujii, Aya Nishida, Koji Izutsu, Atsushi Wake, Shuichi Taniguchi, Akiko Yoneyama
Cunninghamella bertholletiae pneumonia showing a reversed halo sign on chest computed tomography scan following cord blood transplantation.
Med Mycol. 2012 May;50(4):412-6. doi: 10.3109/13693786.2011.631153. Epub 2011 Nov 22.
Abstract/Text This is the first reported case of a patient who developed fungal pneumonia caused by Cunninghamella bertholletiae (= C. elegans) following cord blood transplantation and who showed a reversed halo sign on a chest computed tomography scan (CT). In addition, the pathological findings related to the reversed halo sign are described in detail for the first time. The patient died due to respiratory failure and at autopsy, a consolidation corresponding to the reversed halo sign noted on CT was found histologically to be composed of a central infarct with some retained air spaces surrounded by a peripheral ring-like hemorrhagic band. Pulmonary vasculatures were occluded by thrombi containing numerous Zygomycetes hyphae within the central infarct and less frequently along the surrounding hemorrhagic band. A reversed halo sign may be an early marker to initiate preemptive therapy against Zygomycetes including C. bertholletiae.

PMID 22103345
Hisham Wahba, Mylene T Truong, Xiudong Lei, Dimitrios P Kontoyiannis, Edith M Marom
Reversed halo sign in invasive pulmonary fungal infections.
Clin Infect Dis. 2008 Jun 1;46(11):1733-7. doi: 10.1086/587991.
Abstract/Text Computed tomography scans of documented pulmonary mold infections were reviewed for the presence of the reversed halo sign, a focus of ground-glass attenuation surrounded by a solid ring. The reversed halo sign was an early sign, seen in approximately 4% of patients with pulmonary mold infections, usually with zygomycosis.

PMID 18419427
Sarah P Georgiadou, Nikolaos V Sipsas, Edith M Marom, Dimitrios P Kontoyiannis
The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts.
Clin Infect Dis. 2011 May;52(9):1144-55. doi: 10.1093/cid/cir122.
Abstract/Text The halo sign is a CT finding of ground-glass opacity surrounding a pulmonary nodule or mass. The reversed halo sign is a focal rounded area of ground-glass opacity surrounded by a crescent or complete ring of consolidation. In severely immunocompromised patients, these signs are highly suggestive of early infection by an angioinvasive fungus. The halo sign and reversed halo sign are most commonly associated with invasive pulmonary aspergillosis and pulmonary mucormycosis, respectively. Many other infections and noninfectious conditions, such as neoplastic and inflammatory processes, may also manifest with pulmonary nodules associated with either sign. Although nonspecific, both signs can be useful for preemptive initiation of antifungal therapy in the appropriate clinical setting. This review aims to evaluate the diagnostic value of the halo sign and reversed halo sign in immunocompromised hosts and describes the wide spectrum of diseases associated with them.

PMID 21467021
Georgios Chamilos, Edith M Marom, Russell E Lewis, Michail S Lionakis, Dimitrios P Kontoyiannis
Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer.
Clin Infect Dis. 2005 Jul 1;41(1):60-6. doi: 10.1086/430710. Epub 2005 May 24.
Abstract/Text BACKGROUND: Pulmonary zygomycosis (PZ), an emerging mycosis among patients with cancer, has a clinical manifestation similar to that of invasive pulmonary aspergillosis (IPA). Most cases of PZ in such patients develop as breakthrough infections if treatment with antifungal agents effective against Aspergillus species is administered. However, clinical criteria to differentiate PZ from IPA are lacking.
METHODS: We retrospectively reviewed the clinical characteristics and computed tomography (CT) findings for 16 patients with cancer and PZ and for 29 contemporaneous patients with cancer and IPA at the time of infection onset (2002-2004). Patients with mixed infections were excluded. Parameters predictive of PZ by univariate analysis were included in a logistic regression model.
RESULTS: Almost all patients with PZ (15 of 16) and IPA (28 of 29) had underlying hematological malignancies and typical risk factors for invasive mold infections. In logistic regression analysis of clinical characteristics, concomitant sinusitis (odds ratio [OR], 25.7; 95% confidence interval [CI], 1.47-448.15; P = .026) and voriconazole prophylaxis (OR, 7.76; 95% CI, 1.32-45.53; P = .023) were significantly associated with PZ. The presence of multiple (> or = 10) nodules (OR, 19.8; 95% CI, 1.94-202.29; P = .012) and pleural effusion (OR, 5.07; 95% CI, 1.06-24.23; P = .042) at the time that the patient underwent the initial CT were both independent predictors of PZ in the logistic regression analysis of radiological parameters. No difference occurred in the frequency of other CT findings suggestive of pulmonary mold infections (e.g., masses, cavities, halo sign, or air-crescent sign) between the 2 patient groups.
CONCLUSIONS: PZ in immunocompromised patients with cancer could potentially be distinguished from IPA on the basis of clinical and radiological parameters; prospective validation is needed.

PMID 15937764
Dimitrios P Kontoyiannis, Russell E Lewis
How I treat mucormycosis.
Blood. 2011 Aug 4;118(5):1216-24. doi: 10.1182/blood-2011-03-316430. Epub 2011 May 26.
Abstract/Text Unlike invasive aspergillosis, the prognosis and outcome of hematologic malignancy patients who develop invasive mucormycosis have not significantly improved over the past decade as a majority of patients who develop the infection still die 12 weeks after diagnosis. However, early recognition and treatment of invasive mucormycosis syndromes, as well as individualized approaches to treatment and secondary prophylaxis, could improve the odds of survival, even in the most persistently immunosuppressed patient receiving chemotherapy and/or of stem cell transplantation. Herein, we describe the subtle clinical and radiographic clues that should alert the hematologist to the possibility of mucormycosis, and aggressive and timely treatment approaches that may limit the spread of infection before it becomes fatal. Hematology patients with this opportunistic infection require integrated care across several disciplines and frequently highly individualized and complex sequence of decision-making. We also offer perspectives for the use of 2 antifungals, amphotericin B products and posaconazole, with activity against Mucorales. The availability of posaconazole in an oral formulation that can be administered safely for prolonged periods makes it an attractive agent for long-term primary and secondary prophylaxis. However, serum drug concentration monitoring may be required to minimize breakthrough infection or relapsing mucormycosis associated with inadequate blood concentrations.

PMID 21622653
Oliver A Cornely, Ana Alastruey-Izquierdo, Dorothee Arenz, Sharon C A Chen, Eric Dannaoui, Bruno Hochhegger, Martin Hoenigl, Henrik E Jensen, Katrien Lagrou, Russell E Lewis, Sibylle C Mellinghoff, Mervyn Mer, Zoi D Pana, Danila Seidel, Donald C Sheppard, Roger Wahba, Murat Akova, Alexandre Alanio, Abdullah M S Al-Hatmi, Sevtap Arikan-Akdagli, Hamid Badali, Ronen Ben-Ami, Alexandro Bonifaz, Stéphane Bretagne, Elio Castagnola, Methee Chayakulkeeree, Arnaldo L Colombo, Dora E Corzo-León, Lubos Drgona, Andreas H Groll, Jesus Guinea, Claus-Peter Heussel, Ashraf S Ibrahim, Souha S Kanj, Nikolay Klimko, Michaela Lackner, Frederic Lamoth, Fanny Lanternier, Cornelia Lass-Floerl, Dong-Gun Lee, Thomas Lehrnbecher, Badre E Lmimouni, Mihai Mares, Georg Maschmeyer, Jacques F Meis, Joseph Meletiadis, C Orla Morrissey, Marcio Nucci, Rita Oladele, Livio Pagano, Alessandro Pasqualotto, Atul Patel, Zdenek Racil, Malcolm Richardson, Emmanuel Roilides, Markus Ruhnke, Seyedmojtaba Seyedmousavi, Neeraj Sidharthan, Nina Singh, János Sinko, Anna Skiada, Monica Slavin, Rajeev Soman, Brad Spellberg, William Steinbach, Ban Hock Tan, Andrew J Ullmann, Jörg J Vehreschild, Maria J G T Vehreschild, Thomas J Walsh, P Lewis White, Nathan P Wiederhold, Theoklis Zaoutis, Arunaloke Chakrabarti, Mucormycosis ECMM MSG Global Guideline Writing Group
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 Dec;19(12):e405-e421. doi: 10.1016/S1473-3099(19)30312-3. Epub 2019 Nov 5.
Abstract/Text 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.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31699664
Georgios Chamilos, Russell E Lewis, Dimitrios P Kontoyiannis
Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis.
Clin Infect Dis. 2008 Aug 15;47(4):503-9. doi: 10.1086/590004.
Abstract/Text BACKGROUND: Zygomycosis is an emerging opportunistic mycosis among immunocompromised patients with a particularly poor prognosis.
METHODS: We analyzed the impact of delaying effective amphotericin B-based therapy on outcome among 70 consecutive patients with hematologic malignancy who had zygomycosis in our institution during the period 1989-2006. We used classification and regression tree analysis to identify the mortality breakpoint between early and delayed treatment.
RESULTS: Delayed amphotericin B-based therapy (i.e., initiating treatment >/=6 days after diagnosis) resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment (82.9% vs. 48.6%); this remained constant across the years of the study and was an independent predictor of poor outcome (odds ratio, 8.1; 95% confidence interval, 1.7-38.2; P = .008) in multivariate analysis. Active malignancy (P = .003) and monocytopenia (P =.01) at the time of diagnosis of infection were also independently associated with a poor outcome, whereas salvage posaconazole-based therapy (P=.01) and neutrophil recovery (P = .009) were predictive of a favorable outcome.
CONCLUSIONS: Because discriminating between zygomycosis and aspergillosis in a timely fashion is difficult, the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomycosis.

PMID 18611163
T J Walsh, J L Goodman, P Pappas, I Bekersky, D N Buell, M Roden, J Barrett, E J Anaissie
Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.
Antimicrob Agents Chemother. 2001 Dec;45(12):3487-96. doi: 10.1128/AAC.45.12.3487-3496.2001.
Abstract/Text We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C(max)) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >or=7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

PMID 11709329
G Petrikkos, A Skiada, H Sambatakou, A Toskas, G Vaiopoulos, M Giannopoulou, N Katsilambros
Mucormycosis: ten-year experience at a tertiary-care center in Greece.
Eur J Clin Microbiol Infect Dis. 2003 Dec;22(12):753-6. doi: 10.1007/s10096-003-1035-y. Epub 2003 Nov 6.
Abstract/Text Presented here are the results of a retrospective analysis of all mucormycoses infections recorded at a tertiary hospital in Greece during the last 10 years. A total of 24 patients were identified, 15 male and 9 female, with ages ranging from 37 to 80 years. Twelve of the patients had soft tissue infections (2 with concomitant pulmonary infections), and 12 had rhinocerebral infections. Transmission could be traced in two cases; to nitroglycerin patches in one patient and to a lemon-tree-thorn scratch in the other. Among the 17 patients who underwent surgery, 11 survived. All seven patients on whom surgery was not performed died. Rapid diagnosis and treatment of mucormycosis are essential for patient survival. The severity of the patient's underlying condition, the degree of immunosuppression, and prompt surgical treatment are the most important factors contributing to the outcome.

PMID 14605941
Matthew A Miller, Kyle C Molina, Jonathan A Gutman, Sias Scherger, Jessica M Lum, Sherif B Mossad, Mary Burgess, Matthew P Cheng, Sally T Chuang, Samantha E Jacobs, Dante P Melendez, Dimpy P Shah, Andrea Zimmer, M Rizwan Sohail, Sadia Syed, Randall C Walker, Eric M Poeschla, Maheen Z Abidi
Mucormycosis in Hematopoietic Cell Transplant Recipients and in Patients With Hematological Malignancies in the Era of New Antifungal Agents.
Open Forum Infect Dis. 2021 Feb;8(2):ofaa646. doi: 10.1093/ofid/ofaa646. Epub 2020 Dec 30.
Abstract/Text Background: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined.
Methods: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America.
Results: Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136).
Conclusions: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
PMID 33575424
Ashraf S Ibrahim, Joel C Bowman, Valentina Avanessian, Keturah Brown, Brad Spellberg, John E Edwards, Cameron M Douglas
Caspofungin inhibits Rhizopus oryzae 1,3-beta-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis.
Antimicrob Agents Chemother. 2005 Feb;49(2):721-7. doi: 10.1128/AAC.49.2.721-727.2005.
Abstract/Text Rhizopus oryzae is the most common cause of zygomycosis, a life-threatening infection that usually occurs in patients with diabetic ketoacidosis. Despite standard therapy, the overall rate of mortality from zygomycosis remains >50%, and new strategies for treatment are urgently needed. The activities of caspofungin acetate (CAS) and other echinocandins (antifungal inhibitors of the synthesis of 1,3-beta-D-glucan synthase [GS]) against the agents of zygomycosis have remained relatively unexplored, especially in animal models of infection. We found that R. oryzae has both an FKS gene, which in other fungi encodes a subunit of the GS synthesis complex, and CAS-susceptible, membrane-associated GS activity. Low-dose but not high-dose CAS improved the survival of mice with diabetic ketoacidosis infected with a small inoculum but not a large inoculum of R. oryzae. Fungal burden, assessed by a novel quantitative PCR assay, correlated with increasing inocula and progression of disease, particularly later in the infection, when CFU counts did not. CAS decreased the brain burden of R. oryzae when it was given prophylactically but not when therapy was started after infection. These results indicate that CAS has significant but limited activity against R. oryzae in vivo and demonstrates an inverse dose-response effect. The potential for CAS to play a role in combination therapy against zygomycosis merits further investigation.

PMID 15673756
Caitlin Reed, Richard Bryant, Ashraf S Ibrahim, John Edwards, Scott G Filler, Robert Goldberg, Brad Spellberg
Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis.
Clin Infect Dis. 2008 Aug 1;47(3):364-71. doi: 10.1086/589857.
Abstract/Text BACKGROUND: It has been axiomatic that echinocandins (e.g., caspofungin) are ineffective against mucormycosis. However, on the basis of preclinical data, we recently began treating rhino-orbital-cerebral mucormycosis (ROCM) with combination polyene-caspofungin therapy.
METHODS: To determine the impact of polyene-caspofungin therapy, ROCM cases identified by an International Classification of Diseases, Ninth Revision search were retrospectively reviewed to gather data on demographic characteristics, clinical history, and outcomes. The predefined primary end point was success (i.e., the patients was alive and not in hospice care) at 30 days after hospital discharge.
RESULTS: Forty-one patients with biopsy-proven ROCM were identified over 12 years; 23 (56%) of these patients were Hispanic, and 34 (83%) were diabetic. Patients treated with polyene-caspofungin therapy (6 evaluable patients) had superior success (100% vs. 45%; Pp.02) and Kaplan-Meier survival time (Pp.02), compared with patients treated with polyene monotherapy. Patients treated with amphotericin B lipid complex had inferior success (37% vs. 72%; Pp.03) and a higher clinical failure rate (45% vs. 21%; Pp.04), compared with patients who received other polyenes. However, patients treated with amphotericin B lipid complex plus caspofungin had superior success (100% vs. 20%; Pp.009) and survival time (Pp.01), compared with patients who received amphotericin B lipid complex alone. The benefit of combination therapy, compared with monotherapy, was most pronounced in patients with cerebral involvement (success rate, 100% vs. 25%; Pp.01). In multivariate analysis, only receipt of combination therapy was significantly associated with improved outcomes (odds ratio, 10.9; 95% confidence interval, 1.3- ;Pp.02).
CONCLUSIONS: Combination polyene-caspofungin therapy represents a promising potential alternative to polyene monotherapy for patients with ROCM. Randomized, prospective investigation of these findings is warranted.

PMID 18558882
Ashraf S Ibrahim, Teclegiorgis Gebremariam, Yue Fu, John E Edwards, Brad Spellberg
Combination echinocandin-polyene treatment of murine mucormycosis.
Antimicrob Agents Chemother. 2008 Apr;52(4):1556-8. doi: 10.1128/AAC.01458-07. Epub 2008 Jan 22.
Abstract/Text We previously found that caspofungin synergized with amphotericin B lipid complex in treating murine mucormycosis. We now report a similarly enhanced activity of liposomal amphotericin combined with micafungin or anidulafungin in mice with disseminated mucormycosis. The efficacy of combination echinocandin-polyene therapy for mucormycosis is a class effect.

PMID 18212099

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