Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, Sein M, Sein T, Chiou CC, Chu JH, Kontoyiannis DP, Walsh TJ.
Epidemiology and outcome of zygomycosis: a review of 929 reported cases.
Clin Infect Dis. 2005 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.
Watanabe A, So M, Mitaka H, Ishisaka Y, Takagi H, Inokuchi R, Iwagami M, Kuno T.
Clinical Features and Mortality of COVID-19-Associated Mucormycosis: A Systematic Review and Meta-Analysis.
Mycopathologia. 2022 Jun;187(2-3):271-289. doi: 10.1007/s11046-022-00627-8. Epub 2022 Mar 21.
Abstract/Text
The recent increase of COVID-19-associated mucormycosis (CAM) has been commanding global attention. However, basic epidemiologic characteristics have not firmly been established. In this systematic review and meta-analysis, we sought to determine the clinical manifestations, potential risk factors, and outcomes of CAM. Observational studies reporting CAM were searched with PubMed and EMBASE databases in January 2022. We collected data on comorbidities and treatment for COVID-19, and performed a one-group meta-analysis on the frequency of orbital exenteration procedure and mortality of CAM using a random-effect model. Fifty-one observational studies, including a total of 2,312 patients with proven CAM, were identified. Among the 51 studies, 37 were conducted in India, 8 in Egypt, and 6 in other countries. The most common comorbidity was diabetes mellitus (82%). While 57% required oxygenation, 77% received systemic corticosteroids. Among CAM, 97% were rhino-orbital-cerebral (ROCM), and 2.7% were pulmonary mucormycosis. Usual presentations were headache (54%), periorbital swelling/pain (53%), facial swelling/pain (43%), ophthalmoplegia (42%), proptosis (41%), and nasal discharge/congestion (36%). Regarding the outcomes, orbital exenteration was performed in 17% (95% CI: 12-21%, I2 = 83%) of the COVID-19-associated ROCM patients. The mortality of CAM was 29% (95% CI; 22-36%, I2 = 92%). In conclusion, this systematic review and meta-analysis indicated that the most prevalent type of CAM was ROCM, and most CAM patients had diabetes mellitus and received systemic glucocorticoids. Clinicians in the endemic areas should have a high index of suspicion for this invasive fungal complication of COVID-19 when a diabetic patient who received high-dose systemic glucocorticoids developed rhino-orbital symptoms.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.
Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, Safdar A, Kantarjian H, Champlin R, Walsh TJ, Raad II.
Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases.
J Infect Dis. 2005 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.
Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR.
In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes.
Antimicrob Agents Chemother. 2002 May;46(5):1581-2. doi: 10.1128/AAC.46.5.1581-1582.2002.
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.
Wahba H, Truong MT, Lei X, Kontoyiannis DP, Marom EM.
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.
Georgiadou SP, Sipsas NV, Marom EM, Kontoyiannis DP.
The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts.
Clin Infect Dis. 2011 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.
Saltoğlu N, Taşova Y, Zorludemir S, Dündar IH.
Rhinocerebral zygomycosis treated with liposomal amphotericin B and surgery.
Mycoses. 1998 Jan-Feb;41(1-2):45-9. doi: 10.1111/j.1439-0507.1998.tb00375.x.
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.
Chamilos G, Lewis RE, Kontoyiannis DP.
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.
Kontoyiannis DP, Lewis RE.
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.
Tedder M, Spratt JA, Anstadt MP, Hegde SS, Tedder SD, Lowe JE.
Pulmonary mucormycosis: results of medical and surgical therapy.
Ann Thorac Surg. 1994 Apr;57(4):1044-50. doi: 10.1016/0003-4975(94)90243-7.
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.
Gonzalez CE, Couriel DR, Walsh TJ.
Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocyte colony-stimulating factor.
Clin Infect Dis. 1997 Feb;24(2):192-6. doi: 10.1093/clinids/24.2.192.
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.
Krishnan-Natesan S, Manavathu EK, Alangaden GJ, Chandrasekar PH.
A comparison of the fungicidal activity of amphotericin B and posaconazole against Zygomycetes in vitro.
Diagn Microbiol Infect Dis. 2009 Apr;63(4):361-4. doi: 10.1016/j.diagmicrobio.2008.12.013.
Abstract/Text
Zygomycoses is a rapidly progressive infection associated with high mortality. Although amphotericin B (AMB) has been the only treatment option for years, recent studies have demonstrated that posaconazole (PCZ) has good activity against Zygomycetes. Because rapid onset of antifungal activity is crucial in the management and never studied before, we compared the time for maximum fungicidal activity of AMB versus PCZ using time-kill curves. The MIC of AMB and PCZ against clinical isolates of Mucor spp. and Rhizopus spp. was determined by the Clinical and Laboratory Standards Institute M38-A2 method, and the fungicidal activity was examined by time-kill studies. AMB was rapidly fungicidal, with 95% killing noted as early as 6 h and 99.9% killing at 24 h; PCZ showed <70% killing at 6 h and 99.9% killing at 48 h. In vivo animal studies using AMB in the early phase, followed by a switch to high-dose PCZ later, could provide data that may have clinical implications because there are only a few drugs currently available for the management of zygomycoses.
Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Ráčil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JH, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild MJGT; VITAL and FungiScope Mucormycosis Investigators.
Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
Lancet Infect Dis. 2016 Jul;16(7):828-837. doi: 10.1016/S1473-3099(16)00071-2. Epub 2016 Mar 9.
Abstract/Text
BACKGROUND: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis.
METHODS: In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353.
FINDINGS: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595).
INTERPRETATION: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated.
FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Reed C, Bryant R, Ibrahim AS, Edwards J Jr, Filler SG, Goldberg R, Spellberg B.
Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis.
Clin Infect Dis. 2008 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.
Spellberg B, Andes D, Perez M, Anglim A, Bonilla H, Mathisen GE, Walsh TJ, Ibrahim AS.
Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis.
Antimicrob Agents Chemother. 2009 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.
Spellberg B, Ibrahim AS, Chin-Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, Fredricks D, Brass EP.
The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial.
J Antimicrob Chemother. 2012 Mar;67(3):715-22. doi: 10.1093/jac/dkr375. Epub 2011 Sep 20.
Abstract/Text
OBJECTIVES: Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted.
METHODS: Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy.
RESULTS: Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2).
CONCLUSIONS: Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.
