今日の臨床サポート

接合菌肺感染症

著者: 岡 秀昭 JCHO東京高輪病院感染症内科

監修: 具芳明 東京医科歯科大学大学院医歯学総合研究科 統合臨床感染症学分野

著者校正/監修レビュー済:2016/07/21
患者向け説明資料

概要・推奨   

疾患のポイント:
  1. 接合真菌感染症とは、土壌や野菜、果実などに普通に存在している接合真菌が、特定の免疫不全者に経気道的あるいは経皮的に胞子により感染し、鼻腔や肺感染症を生じる疾患である。
  1. 鼻腔、肺、消化管、皮膚、全身(播種性)に感染を起こす。
  1. 接合真菌症はまれであるが、きわめて予後が不良であり、早期診断、早期治療が望まれる。
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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:
岡 秀昭 : 未申告[2021年]
監修:具芳明 : 特に申告事項無し[2021年]

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 本来は接合菌門のなかにムコール目が分類されているが、人に重篤な感染症を生じる接合真菌はほとんどがムコール目に分類されるものであるため接合真菌とは、ムコール症とほぼ同義に扱われている[1]
  1. Rhizopus species,Mucor species,Cunninghamella bertholletiae,Apophysomyces elegans,Absidia species,Rhizomucor pusillus などの分離頻度が高い[1]
  1. 接合真菌は土壌や野菜、果実などに普通に存在しているが、特定の免疫不全者に経気道的あるいは経皮的に胞子が感染する[1]
  1. 接合真菌症は主に造血幹細胞移植、臓器移植、重篤な糖尿病、アシドーシス、コルチコステロイド、HIV、Deferoxamine(鉄キレート剤)投与中などのリスク因子を有する患者に発症する[1]
  1. カンジダやアスペルギルス症に比較して10~50分の1との報告や、造血幹細胞移植では真菌症の7%を占めて1,000例当たり3.8例と報告されている比較的珍しい真菌症である。
  1. ボリコナゾールのようなアスペルギルスに有効であるが、接合真菌に無効な抗真菌薬投与中のブレイクスルー感染としても発症する[2]
  1. 鼻脳、肺、消化管、皮膚、全身(播種)に感染を起こす。<図表>
  1. 肺接合真菌症の頻度が最も高い(24%)[1][2]
  1. 接合真菌症はまれであるが、きわめて予後が不良であり、早期診断早期治療が望まれる[1]
問診・診察のポイント  
  1. 接合真菌症のリスク因子を有するか評価する[1]

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文献 

著者: 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
雑誌名: 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  Clin Infect Dis. 2005 Sep 1;41(5):634-53. doi: 10.1086/・・・
著者: Dimitrios P Kontoyiannis, Michail S Lionakis, Russell E Lewis, Georgios Chamilos, Mimi Healy, Cheryl Perego, Amar Safdar, Hagop Kantarjian, Richard Champlin, Thomas J Walsh, Issam I Raad
雑誌名: J Infect Dis. 2005 Apr 15;191(8):1350-60. doi: 10.1086/428780. Epub 2005 Mar 16.
Abstract/Text BACKGROUND: Anecdotal evidence suggests a rise in zygomycosis in association with voriconazole (VRC) use in immunosuppressed patients.
METHODS: We performed prospective surveillance of patients with zygomycosis (group A; n = 27) and compared them with contemporaneous patients with invasive aspergillosis (group B; n = 54) and with matched contemporaneous high-risk patients without fungal infection (group C; n = 54). We also performed molecular typing and in vitro susceptibility testing of Zygomycetes isolates.
RESULTS: Nearly all patients with zygomycosis either had leukemia (n = 14) or were allogeneic bone marrow transplant recipients (n = 13). The Zygomycetes isolates (74% of which were of the genus Rhizopus) had different molecular fingerprinting profiles, and all were VRC resistant. In multivariate analysis of groups A and C, VRC prophylaxis (odds ratio [OR], 10.37 [95% confidence interval [CI]], 2.76-38.97]; P = .001), diabetes (OR, 8.39 [95% CI, 2.04-34.35]; P = .003), and malnutrition (OR, 3.70 [95% CI, 1.03-13.27]; P = .045) were found to be independent risk factors for zygomycosis. Between patients with zygomycosis (after excluding 6 patients with mixed mold infections) and patients with aspergillosis, VRC prophylaxis (OR, 20.30 [95% CI, 3.85-108.15]; P = .0001) and sinusitis (OR, 76.72 [95% CI, 6.48-908.15]; P = .001) were the only factors that favored the diagnosis of zygomycosis.
CONCLUSIONS: Zygomycosis should be considered in immunosuppressed patients who develop sinusitis while receiving VRC prophylaxis, especially those with diabetes and malnutrition.

PMID 15776383  J Infect Dis. 2005 Apr 15;191(8):1350-60. doi: 10.1086/・・・
著者: Hisham Wahba, Mylene T Truong, Xiudong Lei, Dimitrios P Kontoyiannis, Edith M Marom
雑誌名: 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  Clin Infect Dis. 2008 Jun 1;46(11):1733-7. doi: 10.1086・・・
著者: Sarah P Georgiadou, Nikolaos V Sipsas, Edith M Marom, Dimitrios P Kontoyiannis
雑誌名: 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  Clin Infect Dis. 2011 May;52(9):1144-55. doi: 10.1093/c・・・
著者: N Saltoğlu, Y Taşova, S Zorludemir, I H Dündar
雑誌名: Mycoses. 1998 Jan-Feb;41(1-2):45-9.
Abstract/Text We report three cases with rhinocerebral zygomycosis in two diabetic persons and one otherwise healthy person. The diagnosis was established by histopathological appearance and computerized tomography (CT) and/or magnetic resonance imaging (MRI) scans. These cases were successfully treated by a combination of surgery and liposomal amphotericin B.

PMID 9610133  Mycoses. 1998 Jan-Feb;41(1-2):45-9.
著者: M Tedder, J A Spratt, M P Anstadt, S S Hegde, S D Tedder, J E Lowe
雑誌名: Ann Thorac Surg. 1994 Apr;57(4):1044-50.
Abstract/Text Mucormycosis is an opportunistic fungal infection that commonly begins by invading the respiratory tract. The purpose of the present study was to define the clinical presentation of pulmonary mucormycosis and to evaluate current treatment regimens. Thirty patients treated at our institution and 225 cases reported in the literature were reviewed. For the combined groups, the mean age at presentation was 41 +/- 21 years and associated medical conditions included leukemia or lymphoma (37%), diabetes mellitus (32%), chronic renal failure (18%), history of organ transplantation (7.6%), or a known solid tumor (5.6%). The in-hospital mortality was 65% for patients with isolated pulmonary mucormycosis, 96% for those with disseminated disease, and 80% overall. The mortality in patients treated surgically was 11%, significantly lower than the 68% mortality in those treated medically (p = 0.0004). The most common causes of death were fungal sepsis (42%), respiratory insufficiency (27%), and hemoptysis (13%). Pulmonary mucormycosis has a high mortality; however, antifungal agents appear to improve survival. In addition, surgical resection may provide additional benefit to patients with pulmonary mucormycosis confined to one lung.

PMID 8166512  Ann Thorac Surg. 1994 Apr;57(4):1044-50.
著者: C E Gonzalez, D R Couriel, T J Walsh
雑誌名: Clin Infect Dis. 1997 Feb;24(2):192-6.
Abstract/Text Disseminated zygomycosis in persistently neutropenic patients has been almost uniformly fatal despite aggressive surgical and medical management. We describe a neutropenic patient with disseminated zygomycosis that involved the lungs and kidneys and was successfully treated with amphotericin B lipid complex and granulocyte colony-stimulating factor, followed by suppressive therapy with amphotericin B for 1 year. This approach preserved the patient's renal function and restored systemic host defenses. The single pulmonary lesion was resected, but no resection of renal tissue was attempted because of the bilateral extension of the renal lesions. After a 1-year period of follow-up without antifungal therapy, the patient's condition remains stable, and there has been no relapse of the infection.

PMID 9114146  Clin Infect Dis. 1997 Feb;24(2):192-6.
著者: Georgios Chamilos, Russell E Lewis, Dimitrios P Kontoyiannis
雑誌名: 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  Clin Infect Dis. 2008 Aug 15;47(4):503-9. doi: 10.1086/・・・
著者: Caitlin Reed, Richard Bryant, Ashraf S Ibrahim, John Edwards, Scott G Filler, Robert Goldberg, Brad Spellberg
雑誌名: 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  Clin Infect Dis. 2008 Aug 1;47(3):364-71. doi: 10.1086/・・・
著者: Qiu N Sun, Annette W Fothergill, Dora I McCarthy, Michael G Rinaldi, John R Graybill
雑誌名: Antimicrob Agents Chemother. 2002 May;46(5):1581-2.
Abstract/Text In vitro antifungal susceptibility testing results of a new antifungal triazole, posaconazole (POS), were compared to results with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), and fluconazole (FLC) against clinical agents of zygomycosis. The MICs of POS at which 50% and 90% of the isolates were inhibited were 0.25 and 4 microg/ml, respectively. POS was significantly more active than VRC and FLC and slightly more active than ITC. The results suggest that POS has significant potential for clinical development against the zygomycetes.

PMID 11959605  Antimicrob Agents Chemother. 2002 May;46(5):1581-2.
著者: Dimitrios P Kontoyiannis, Russell E Lewis
雑誌名: 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  Blood. 2011 Aug 4;118(5):1216-24. doi: 10.1182/blood-20・・・
著者: Brad Spellberg, David Andes, Mario Perez, Anne Anglim, Hector Bonilla, Glenn E Mathisen, Thomas J Walsh, Ashraf S Ibrahim
雑誌名: Antimicrob Agents Chemother. 2009 Jul;53(7):3122-5. doi: 10.1128/AAC.00361-09. Epub 2009 May 11.
Abstract/Text We sought to describe the safety profile of open-label, adjunctive deferasirox iron chelation therapy in eight patients with biopsy-proven mucormycosis. Deferasirox was administered for an average of 14 days (range, 7 to 21) at 5 to 20 mg/kg of body weight/day. The only adverse effects attributable to deferasirox were rashes in two patients. Deferasirox treatment was not associated with changes in renal or liver function, complete blood count, or transplant immunosuppressive levels. Thus, deferasirox appears safe as an adjunctive therapy for mucormycosis.

PMID 19433555  Antimicrob Agents Chemother. 2009 Jul;53(7):3122-5. doi・・・

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