RESUMO
Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.
Assuntos
Antifúngicos , Fusarium , Testes de Sensibilidade Microbiana , Scedosporium , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fusarium/efeitos dos fármacos , Fusarium/isolamento & purificação , Scedosporium/efeitos dos fármacos , Scedosporium/isolamento & purificação , Scedosporium/classificação , Organização Mundial da Saúde , Micoses/epidemiologia , Micoses/microbiologia , Fusariose/microbiologia , Fusariose/epidemiologia , Ascomicetos/efeitos dos fármacos , Infecções Fúngicas InvasivasRESUMO
SUMMARYAlthough Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.
Assuntos
Antifúngicos , Scedosporium , Humanos , Antifúngicos/uso terapêutico , Scedosporium/efeitos dos fármacos , Scedosporium/classificação , Farmacorresistência Fúngica , Micoses/tratamento farmacológico , Micoses/diagnóstico , Micoses/microbiologia , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/diagnóstico , Ascomicetos/classificação , Ascomicetos/efeitos dos fármacosAssuntos
Exophiala , Falência Renal Crônica , Transplante de Rim , Scedosporium , Voriconazol , Humanos , Exophiala/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Scedosporium/efeitos dos fármacos , Transplantados , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico , Masculino , Adulto , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Feoifomicose/tratamento farmacológicoRESUMO
Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture [MMV], Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 µM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 µM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.
Assuntos
Antifúngicos , Ascomicetos , Scedosporium , Humanos , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Caspofungina/farmacologia , Scedosporium/efeitos dos fármacos , Voriconazol/farmacologiaRESUMO
BACKGROUND: This study was aimed to determine the potency of Minocycline (MIN) and azoles, including itraconazole (ITR), voriconazole (VOR) and posaconazole (POS) against Scedosporium and Lomentospora species. RESULTS: This study revealed that MIN exhibited no significant antifungal activity against any of the tested strains, whereas in vitro combination of MIN with ITR, VOR or POS showed satisfactory synergistic effects against 8 (80%), 1 (10%), and 9 (90%) strains, respectively. Moreover, combined use of MIN with azoles decreased the minimum inhibitory concentration (MIC) range from 5.33-16 µg/ml to 1-16 µg/ml for ITR, from 0.42-16 µg/ml to 0.21-16 µg/ml for VOR, and from 1.33-16 µg/ml to 0.33-16 µg/ml for POS. Meanwhile, no antagonistic interactions were observed between the above combinations. The G. mellonella infection model demonstrated the in vivo synergistic antifungal effect of MIN and azoles. CONCLUSIONS: The present study demonstrated that combinations between MIN and azoles lead to synergistic antimicrobial effects on Scedosporium and Lomentospora species, while showing a potential for overcoming and preventing azole resistance.
Assuntos
Antifúngicos/farmacocinética , Ascomicetos/efeitos dos fármacos , Azóis/farmacologia , Minociclina/farmacologia , Scedosporium/efeitos dos fármacos , Animais , Azóis/classificação , Azóis/uso terapêutico , Farmacorresistência Fúngica , Sinergismo Farmacológico , Humanos , Larva/efeitos dos fármacos , Larva/microbiologia , Testes de Sensibilidade Microbiana , Minociclina/uso terapêutico , Mariposas/efeitos dos fármacos , Mariposas/microbiologiaRESUMO
BACKGROUND: Scedosporium species are a group of pathogenic fungi, which can be found worldwide around high human-impacted areas. Infections of Scedosporium have been reported in several immunocompromised and immunocompetent patients with a high mortality rate. Recently, we have isolated and identified several Scedosporium strains during an environmental survey in Thailand. RESULTS: We describe the isolate, TMMI-012, possibly a new species isolated from soils in the Chatuchak public park, Bangkok, Thailand. TMMI-012 is phylogenetically related to the Scedosporium genus and is a sibling to S. boydii but shows distinct morphological and pathological characteristics. It is fast growing and highly resistant to antifungal drugs and abiotic stresses. Pathological studies of in vitro and in vivo models confirm its high virulence and pathogenicity. CONCLUSION: TMMI-012 is considered a putative novel Scedosporium species. The high antifungal resistance of TMMI-012 compared with its sibling, Scedosporium species is likely related to its clinical impact on human health.
Assuntos
Fenômica , Filogenia , Scedosporium/classificação , Scedosporium/genética , Animais , Antifúngicos/farmacologia , Feminino , Humanos , Larva/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mariposas/microbiologia , Scedosporium/efeitos dos fármacos , Scedosporium/patogenicidade , Microbiologia do Solo , Células THP-1 , Tailândia , VirulênciaRESUMO
Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain.
Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.
Assuntos
Antifúngicos/farmacologia , Infecções Fúngicas Invasivas/microbiologia , Scedosporium/classificação , Scedosporium/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/mortalidade , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Técnicas de Tipagem Micológica , Filogenia , Estudos Retrospectivos , Scedosporium/citologia , Scedosporium/isolamento & purificação , Adulto JovemRESUMO
BACKGROUND: Scedosporium species are the second most isolated filamentous fungi from cystic fibrosis (CF) patients; however, little is known about their virulence aspects in a CF environment. In this context, the current study aimed to evaluate the (i) antifungal susceptibility profiles, (ii) ability to form biofilm and (iii) impact of biofilm formation on the susceptibility to azoles in 21 clinical isolates of Scedosporium recovered from CF patients. METHODS: Scedosporium apiospermum (n=6), S. aurantiacum (n=6), S. minutisporum (n=3) and Lomentospora prolificans (n=6) were firstly used to compare the antifungal susceptibility profile using a standard culture broth (RPMI-1640) and a mucin (M)-containing synthetic CF sputum medium (SCFM). The ability to form biofilms was investigated in polystyrene microtiter plates containing Sabouraud-dextrose (a classical medium), SCFM and SCFM+M. Mature biofilms were tested for their susceptibility to azoles by microdilution assay. RESULTS: Our results showed that the minimum inhibitory concentrations (MICs) for planktonic conidia ranged from 0.25 to >16.0 mg/L for voriconazole and 1.0 to >16.0 mg/L for posaconazole. Overall, the MICs for azoles increased from 2- to 8-folds when the susceptibility tests were performed using SCFM+M compared to RPMI-1640. All fungi formed robust biofilms on polystyrene surface at 72 h, with a significant increase in the MICs (ranging from 128- to 1024-times) against both azoles compared to the planktonic cells. CONCLUSION: These findings confirm the challenge of antifungal treatment of CF patients infected with Scedosporium/Lomentospora and also demonstrated a strong biofilm formation, with extensive increase in antifungal resistance, triggered underconditions mimicking the CF patient airway.
Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Biofilmes/efeitos dos fármacos , Fibrose Cística/complicações , Scedosporium/efeitos dos fármacos , Farmacorresistência Fúngica , Humanos , Técnicas In Vitro , Infecções Fúngicas Invasivas/tratamento farmacológico , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
In recent decades, invasive infections caused by fungal pathogens have been reported with increasing frequency. Concurrently, the rates of detected resistance mechanisms against commonly used antifungal agents in fungi are increasing. The need for novel antifungal drugs is thus imminent. In this study, the novel drug olorofim (F901318) was tested for its antifungal activity against the human fungal pathogens Lomentospora prolificans (n = 20), Scedosporium aurantiacum (n = 2), Scedosporium apiospermum (n = 6), Rasamsonia argillacea species complex (n = 23), Exophiala dermatitidis (n = 10) and azole-resistant Aspergillus fumigatus (ARAF) (n = 25) in an in vitro broth microdilution assay according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations. Whilst olorofim was ascertained to be effective against R. argillacea species complex [minimum inhibitory concentrations (MICs) of ≤0.008 mg/L], Scedosporium spp. (MICs of 0.032-0.5 mg/L), L. prolificans (MICs of 0.032-0.5 mg/L) and ARAF (MICs of ≤0.008-0.032 mg/L), the drug had an MIC of >4 mg/L against E. dermatitidis. These data demonstrate the antifungal activity of olorofim against a broad range of filamentous fungal pathogens.
Assuntos
Acetamidas/farmacologia , Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Eurotiales/efeitos dos fármacos , Exophiala/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Scedosporium/efeitos dos fármacos , Aspergillus fumigatus/isolamento & purificação , Eurotiales/isolamento & purificação , Exophiala/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Scedosporium/isolamento & purificaçãoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Infecções Fúngicas Invasivas/etiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Scedosporium/isolamento & purificação , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Farmacorresistência Fúngica Múltipla , Substituição de Medicamentos , Evolução Fatal , Neutropenia Febril/complicações , Neutropenia Febril/tratamento farmacológico , Feminino , Filgrastim/uso terapêutico , Fluconazol/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Pessoa de Meia-Idade , Combinação Piperacilina e Tazobactam/uso terapêutico , Purinas/administração & dosagem , Purinas/efeitos adversos , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Recidiva , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Scedosporium/efeitos dos fármacos , Triazóis/uso terapêutico , Valaciclovir/uso terapêutico , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.
Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Terbinafina/uso terapêutico , Voriconazol/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Infecções Fúngicas Invasivas/sangue , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Scedosporium/efeitos dos fármacos , Resultado do TratamentoRESUMO
There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 µg/ml and ranged from 0.015 to 0.03 µg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an â¼2-log10 reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds.
Assuntos
Aminopiridinas/farmacologia , Antifúngicos/farmacologia , Fusariose/tratamento farmacológico , Fusarium/efeitos dos fármacos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/tratamento farmacológico , Isoxazóis/farmacologia , Scedosporium/efeitos dos fármacos , Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Animais , Antifúngicos/sangue , Antifúngicos/farmacocinética , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Esquema de Medicação , Combinação de Medicamentos , Fusariose/imunologia , Fusariose/microbiologia , Fusariose/mortalidade , Fusarium/crescimento & desenvolvimento , Fusarium/imunologia , Meia-Vida , Humanos , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/mortalidade , Isoxazóis/sangue , Isoxazóis/farmacocinética , Rim/efeitos dos fármacos , Rim/imunologia , Rim/microbiologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Pró-Fármacos , Scedosporium/crescimento & desenvolvimento , Scedosporium/imunologia , Análise de Sobrevida , Triazóis/farmacologiaRESUMO
Scedosporium genus as a significant emerging opportunist causes a broad spectrum of disease in not only immunosuppressed but also immunocompetent patients. The lung is one of the most commonly encountered sites of Scedosporium infection. Due to its very high levels of antifungal resistance, surgery has been recommended as an important part in the treatment of pulmonary Scedosporium spp infection, even in immunocompetent cases. However, whether lung surgery could help to reduce the risk of death in immunocompetent patients is not clear.We retrospectively retrieved the records of pulmonary infections with Scedosporium species in immunocompetent patients through a comprehensive literature search. The association of surgery on all-cause mortality was explored using binary logistic regression (BLR). Receiver operating characteristic (ROC) curve analysis was carried out to evaluate the capability of the model.The comprehensive searching strategy yielded 33 case reports and 3 case series in total, with 40 individual patients being included. The overall mortality was 12.50%. The fatality rate was 9.09% (2/22) in cases with surgery and 16.67% (3/18) in cases without surgery (odds ratio, 0.50; 95% confidence interval, 0.07-3.38; Pâ=â.48). Consistently, BLR analysis identified no statistical association between surgery and reduced mortality (odds ratio, 1.19; 95% confidence interval, 0.09-15.64; Pâ=â.89), after adjusting for age, gender, and antifungal chemotherapy. The area under the ROC curve was 0.88.For immunocompetent patients with pulmonary Scedosporium spp infection, surgical therapy may not be associated with reduced mortality. Surgical excision could be considered but is not imperative in this group of patients.
Assuntos
Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/cirurgia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/cirurgia , Scedosporium/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Farmacorresistência Fúngica/fisiologia , Feminino , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/microbiologia , Micoses/mortalidade , Estudos Observacionais como Assunto , Cuidados Pós-Operatórios , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Estudos Retrospectivos , Scedosporium/isolamento & purificação , Voriconazol/administração & dosagem , Voriconazol/uso terapêuticoRESUMO
Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC50, 0.008 µg/ml; MIC90, 0.06 µg/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50, 0.25 µg/ml; MIC90, 0.5 µg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC50], 0.015 µg/ml; MEC90, 0.03 µg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 µg/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.
Assuntos
Aminopiridinas/farmacologia , Antifúngicos/farmacologia , Isoxazóis/farmacologia , Anidulafungina/farmacologia , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Farmacorresistência Fúngica , Fluconazol/farmacologia , Fusarium/efeitos dos fármacos , Micafungina/farmacologia , Testes de Sensibilidade Microbiana , Scedosporium/efeitos dos fármacosRESUMO
Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9â¯months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.
Assuntos
Antifúngicos , Fibrose Cística , Quimioterapia Combinada/métodos , Infecções Fúngicas Invasivas , Pneumopatias Fúngicas , Scedosporium , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/classificação , Fibrose Cística/complicações , Fibrose Cística/microbiologia , Fibrose Cística/terapia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Alemanha , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/microbiologia , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Testes de Função Respiratória/métodos , Scedosporium/efeitos dos fármacos , Scedosporium/isolamento & purificação , Tomografia Computadorizada por Raios X/métodosRESUMO
Isavuconazole is a new triazole with an expanded-spectrum and potent activity against moulds and yeasts. It has been authorized for use in adults for the treatment of invasive aspergillosis and for mucormycosis. The only commercially available isavuconazole susceptibility test is the minimum inhibitory concentration (MIC) strip isavuconazole test. The objective of this study was to assess the in vitro activity of isavuconazole using gradient concentration MIC strips, compared with the EUCAST broth microdilution reference method. A total of 147 clinically relevant fungal isolates comprising 120 Aspergillus sp. and 27 Scedosporium apiospermum complex were tested for susceptibility to isavuconazole using the EUCAST broth microdilution method and by the MIC strip isavuconazole test. The percent essential agreement between the two methods was calculated within a 1-fold dilution. The geometric means for the MICs using the EUCAST reference methods and the strip test were respectively: 0.60 mg/l and 0.65 mg/l for A. fumigatus, 0.70 mg/l and 0.77 mg/l for A. flavus, 1.50 mg/l and 1.25 mg/l for A. niger, 0.41 mg/l and 0.38 mg/l for A. terreus, 1.22 mg/l and 1.08 mg/l for S. apiospermum complex. The isavuconazole MIC strips showed good agreement with the EUCAST reference method. Isavuconazole MIC strips could be useful for susceptibility testing of Aspergillus sp. and S. apiospermum complex.
Assuntos
Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Nitrilas/farmacologia , Piridinas/farmacologia , Scedosporium/efeitos dos fármacos , Triazóis/farmacologia , Aspergillus/isolamento & purificação , Humanos , Micoses/microbiologia , Scedosporium/isolamento & purificaçãoRESUMO
Scedosporium spp. cause infections (scedosporiosis) in both immunocompetent and immunocompromised individuals and may persistently colonize the respiratory tract in patients with cystic fibrosis (CF). They are less susceptible against azoles than are other molds, such as Aspergillus spp., suggesting the presence of resistance mechanisms. It can be hypothesized that the decreased susceptibility of Scedosporium spp. to azoles is also CYP51 dependent. Analysis of the Scedosporium apiospermum and Scedosporiumaurantiacum genomes revealed one CYP51 gene encoding the 14-α-lanosterol demethylase. This gene from 159 clinical or environmental Scedosporium isolates and three Lomentospora prolificans isolates has been sequenced and analyzed. The Scedosporium CYP51 protein clustered with the group of known CYP51B orthologues and showed species-specific polymorphisms. A tandem repeat in the 5' upstream region of Scedosporium CYP51 like that in Aspergillus fumigatus could not be detected. Species-specific amino acid alterations in CYP51 of Scedosporium boydii, Scedosporiumellipsoideum, Scedosporium dehoogii, and Scedosporiumminutisporum isolates were located at positions that have not been described as having an impact on azole susceptibility. In contrast, two of the three Sapiospermum-specific amino acid changes (Y136F and G464S) corresponded to respective mutations in A. fumigatus CYP51A at amino acid positions 121 and 448 (Y121F and G448S, respectively) that had been linked to azole resistance.
Assuntos
Scedosporium/efeitos dos fármacos , Scedosporium/genética , Esterol 14-Desmetilase/genética , Antifúngicos/farmacologia , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , MutaçãoRESUMO
Isavuconazonium sulfate is a prodrug of isavuconazole, a broad-spectrum mould-active triazole antifungal drug. We provide a direct comparison of the in vitro activity of the prodrug versus the active metabolite against clinical isolates of Aspergillus spp., Sarocladium kiliense, and Scedosporium apiospermum using CLSI broth microdilution methods. The MIC values obtained for the prodrug were one 2-fold dilution higher than those of isavuconazole for all isolates tested. Using previously defined epidemiological cutoff values for isavuconazole and Aspergillus spp., 96.4% of isolates were wild type (WT) to isavuconazole and only 75% were WT to the prodrug. The essential agreement (±2 log2 dilutions) between prodrug and isavuconazole MIC values was 96.4% across all tested isolates. The active metabolite, isavuconazole, is recommended to use during in vitro susceptibility testing of fungal isolates.
Assuntos
Antifúngicos/uso terapêutico , Aspergillus/efeitos dos fármacos , Nitrilas/uso terapêutico , Pró-Fármacos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Aspergilose/tratamento farmacológico , Humanos , Micoses/tratamento farmacológico , Scedosporium/efeitos dos fármacosRESUMO
Species of Scedosporium and Lomentospora are considered as emerging opportunists, affecting immunosuppressed and otherwise debilitated patients, although classically they are known from causing trauma-associated infections in healthy individuals. Clinical manifestations range from local infection to pulmonary colonization and severe invasive disease, in which mortality rates may be over 80%. These unacceptably high rates are due to the clinical status of patients, diagnostic difficulties, and to intrinsic antifungal resistance of these fungi. In consequence, several consortia have been founded to increase research efforts on these orphan fungi. The current review presents recent findings and summarizes the most relevant points, including the Scedosporium/Lomentospora taxonomy, environmental distribution, epidemiology, pathology, virulence factors, immunology, diagnostic methods, and therapeutic strategies.