Mucormicosis pulmonar por Cunninghamella spp. en paciente trasplantado renal / No disponible

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Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: Epidemiology and microbiological characterization of the isolates.

We studied 19 cases of proven/probable mucormycosis diagnosed from 2007 to 2015 in our hospital and assessed the microbiological characteristics of the isolates. We recorded the incidence of mucormycosis and clinical and microbiological data of infected patients. Isolates were identified to molecular level and tested for their antifungal susceptibility to azoles, amphotericin B, and liposomal amphotericin B according to the CLSI M-38 A2 procedure. The incidence of mucormycosis in cases/100,000 hospital admissions during 2007-2015 increased significantly with respect to that reported in 1988-2006 (3.3 vs. 1.2; P<0.05). Patients mainly had hematological malignancies (52.6%) and/or trauma/surgical wounds (52.6%) and had received antifungal agents before the diagnosis of mucormycosis in 68% of cases. Diagnosis was by isolation (n = 17/19) and/or direct staining (n = 17/18) of Mucorales fungi in clinical samples. Identification was by panfungal PCR in patients with negative results in culture and in direct staining. The microorganisms identified were Lichtheimia spp. (42%), Rhizopus spp. (21%), Cunninghamella bertholletiae (16%), and others (21%). Liposomal amphotericin B was always more active than the other drugs against all the microorganisms except C. bertholletiae. All patients received antifungal treatment with 1 or more antifungal agents, mainly liposomal amphotericin B (17/19). Mortality was 47.4%, although this was significantly lower in the 11 patients in whom debridement was performed (18% vs. 87.5%) (P = 0.015). The incidence of mucormycosis has risen in recent years. The proportion of cases with soft tissue involvement was high, and Lichtheimia was the most frequently involved species. The highest antifungal activity was observed with liposomal amphotericin B.

Cunninghamella echinulata causing fatally invasive fungal sinusitis.

We report a fatal case of invasive fungal sinusitis caused by Cunninghamella echinulata in a febrile, neutropenic 15-year-old male with relapsing acute leukemia. The isolate was recovered from a nasal biopsy from the right middle meatus, and microscopic examination of the tissue revealed angioinvasion and necrosis. Human infection caused by this organism has not been well documented; however, this report alerts us to its life-threatening potential.

Zigomicosis en ni˜nos: infección diseminada por Cunninghamella bertholletiae / Zygomycosis in Children: Disseminated Infection Caused by Cunninghamella bertholletiae

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Increased virulence of Cunninghamella bertholletiae in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism.

Members of the order Mucorales are emerging invasive molds that cause infections in immunocompromised patients. However, little is known about the relation between different species of Mucorales and their virulence in invasive pulmonary mucormycosis. Based upon our earlier epidemiological studies, we hypothesized that Cunninghamella bertholletiae would demonstrate increased virulence. Therefore, we studied the relative virulence of C. bertholletiae (CB), Rhizopus oryzae (RO), R. microsporus (RM), and Mucor circinelloides (MC) in experimental invasive pulmonary mucormycosis in persistently neutropenic rabbits in relation to the fungi in vitro sporangiospore germination rate and hyphal metabolic activity. Rabbits infected with CB demonstrated (1) higher lung weights in comparison to RM (P ≤ 0.05), RO and MC (P ≤ 0.001), (2) pulmonary infarcts in comparison to RO and MC (P ≤ 0.001), (3) tissue fungal burden (CFU/g) vs. MC (P ≤ 0.001), and (4) the lowest survival of 0% (0/18), in comparison to 16% (3/18, P ≤ 0.01) of RM, 81% (21/26) of RO, and 83% (15/18) of MC-infected rabbits (P ≤ 0.001). Serum PCR concentration-time-curve showed the greatest amplitude for CB. Virulence correlated directly with sporangiospore germination rate at 4 h among species, i.e., CB (67-85%) > RM (14-56%) > RO (4-30%) > MC (0%), and hyphal metabolic activity, i.e., CB (1.22-1.51) > MC (0.54-0.64) = RM (0.38-0.41) = RO (0.37-0.59). C. bertholletiae was significantly more virulent in experimental invasive pulmonary mucormycosis than R. microsporus, R. oryzae, and M. circinelloides. In vivo virulence correlated with species-dependent differences of in vitro germination rate and hyphal metabolic activity.

In vitro and in vivo antifungal susceptibilities of the Mucoralean fungus Cunninghamella.

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 µg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 µg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.

Micoparasitismo biotrofico de Fusarium oxysporum sobre Cunnighamella sp / Biotrophic mycoparasitism of Fusarium oxysporum on Cunnighamella sp

Se describe un caso de micoparasitismo biotrófico de ocurrencia natural en el suelo, entre las hifas de una cepa de Fusarium oxysporum complex y Cunninghamella sp. Las hifas de F. oxysporum se desarrollaron sobre las células vivas del hospedador, mostrando 2 tipos de efectos parasíticos: uno de enrollamiento y otro de contacto con penetración de las hifas, sin la aparente eliminación del hospedador. Esta situación poco común en la literatura, demuestra las capacidades adaptativas de esta especie al micoparasitismo en grupos filogenéticamente distantes.

This paper describes a case of mycoparasitism naturally occurring, where Fusarium oxysporum parasitizes hyphae of Cunninghamella sp, to show mycoparasitism between the two fungi. This is a case of biotrophic mycoparasitism by contact. The hyphae of F. oxysporum developed closely along the living cells of the host showing mycoparasitic effect, some for a loop, and other contact with penetration of the hyphae. This situation is rare in the literature, demonstrates the adaptive capacities of this species to mycoparasitism in phylogenetically distant groups.

A case of Cunninghamella bertholettiae rhino-cerebral infection in a leukaemic patient and review of recent published studies.

Cunninghamella bertholletiae infection occurs most frequently in neutropenic patients affected by haematological malignancies, is associated with an unfavourable outcome. We report a case of rhino-mastoidal fungal infection in a leukaemic patient. Bioptical tissue cultures yield the isolation of a mould with typical properties of Cunninghamella species. Liposomal amphotericin B (L-Amb) therapy combined with surgical intervention brought the lesion to recovery. Nevertheless, the patient died 14 days after bone marrow transplantation (BMT) from bacterial sepsis. Mastoiditis was documented at CT-scan. The conditioning regimen probably caused the reactivation of the Cunninghamella infection that led to the patient's fatal outcome; fungal hyphae were detected after autopsy of brain and lung tissue.

An unusual presentation of rhinofacial zygomycosis due to Cunninghamella sp. in an immunocompetent patient: a case report and literature review.

Zygomycosis is a rare fungal infection usually found in immunocompromised patients. It is a rapidly progressing infection with a high mortality rate. Our report describes an unusual case of rhinofacial zygomycosis due to Cunninghamella sp. in an immunocompetent patient, who presented with a slowly progressive swelling of the left cheek. An interrupted course of amphotericin B treatment caused regression of the lesion. Drug therapy was abandoned due to impairment of renal function. The patient was clinically and radiologically disease free for 2 years following cessation of therapy.

Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature.

Infections caused by Cunninghamella bertholletiae, an opportunistic fungal organism, have an extremely high mortality rate. A fatal case of C. bertholletiae fungal pneumonia occurred in a man who had received an allogeneic bone marrow transplant. Aggressive debridement and high-dose liposomal amphotericin B failed to eradicate the infection. Right lung tissue samples obtained during lobectomy were assayed for amphotericin B concentrations by high-performance liquid chromatography, and minimum inhibitory concentration (MIC) determinations of amphotericin B against C. bertholletiae were determined by the macrobroth dilution method. The MIC for the isolate of C. bertholletiae was 4 microg/ml. Amphotericin B lung concentrations averaged 9.5 microg/ml (range 3.7-13.8 microg/ml), with a corresponding serum trough concentration of 0.9 microg/ml. To our knowledge, this is the first reported case of amphotericin B concentrations measured at the site of infection in a patient with a pulmonary Cunninghamella infection, together with a corresponding MIC of the organism. The patient's death, which occurred despite aggressive debridement and high amphotericin B lung concentrations, highlights the need for novel strategies to treat infections caused by invasive molds such as C. bertholletiae.

A murine model of zygomycosis by Cunninghamella bertholletiae.

Infections by Cunninghamella bertholletiae have been on the increase in recent years. However, little is known about this fungus and its infection. To clarify the pathogenicity of C. bertholletiae, we made a murine model, and to our knowledge, the first infectious model of this fungus. ICR mice pretreated with cortisone acetate and cyclophosphamide were inoculated intratracheally with 5 x 10(5) spores of C. bertholletiae. About half of the mice died by day 4 and 90% died by day 9. C. bertholletiae was cultured from the lungs, and the pathological analysis disclosed diffuse hyphal growth in the lungs, resulting in necrosis in the later stage. Angioinvasion with alveolar hemorrhage was extremely pronounced from the early stage, and this was the most characteristic feature of this infection. Treatment with amphotericin B showed only minimal improvement of survival, comparable to the poor result of this treatment in actual human cases. In fact, our model has many similarities to the actual human infection by C. bertholletiae, and will be useful for further investigations of this infection.