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The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida-resistant isolates. The aim of this study was to analyze the pharmacokinetics (PK)/pharmacodynamics (PD) of caspofungin in plasma and PF samples from liver transplant recipients. Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and PF samples on days 1, 3, and 8. Data were analyzed using nonlinear mixed-effect modeling and Monte Carlo simulations. Area under the curve (AUC) values for plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTAs) were calculated using area under the unbound plasma concentration-time curve from 0 to 24 h at steady state (fAUC0-24)/MIC ratios, with MICs ranging from 0.008 to 8 mg/L. All of the patients included were monitored weekly for Candida colonization and for Candida infections. Twenty patients were included. The median daily dose of caspofungin was 0.81 mg/kg. Plasma (n = 395) and PF (n = 50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination produced an effective PK/PD relationship in plasma, achieving a PTA of ≥90% with MICs ranging from 0.008 to 0.12 mg/L for Candida albicans and Candida glabrata. In PF, PTAs at D8 were optimal only for a MIC of 0.008 mg/L in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF. PF concentrations of caspofungin were low. Simulations showed that the PTAs for Candida spp. in PF were not optimal, which might suggest a potential risk of resistance.
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Líquido Ascítico , Trasplante de Hígado , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Caspofungina , Equinocandinas/farmacocinética , Equinocandinas/uso terapéutico , Humanos , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Data on the risk factors and outcome of intra-abdominal fungal infections (IAFI) following simultaneous pancreas-kidney transplantation (PKT) are scarce. MATERIALS/METHODS: A retrospective monocentric study was conducted on all patients who underwent simultaneous PKT from January 2007 to December 2016. Deep sites positive cultures for fungi during the first post-transplantation year were collected. Clinical, radiological, and microbiological data of proven and probable invasive fungal infections were analysed. RESULTS: Among sixteen PKT patients, 15 were included. Seven patients (47%) developed an invasive fungal infection, exclusively IAFI (six proven, one probable). The proven IAFI included four peritonitis, one pancreatic necrosis with infected hematoma, and one patient with positive preservation fluid only (PF). Candida albicans (n = 4) was the most prevalent species (associated with Galactomyces candidus in one case), C glabrata, C dubliniensis, and C krusei were found in one case each. Three patients had either a positive direct examination and/or culture for renal or pancreatic PF and the culture of PF was positive for the same species that caused IAFI. IAFIs were significantly associated with pancreatic graft arterial thrombosis (5/7 vs 0/8, P = .007) and fungal contamination of PF (3/7 vs 0/8, P = .008). Among patients with IAFI, all required an early surgical revision post-transplantation [1-18 days] and six had early or delayed pancreatic graft removal. One patient died in the first post-transplant year. CONCLUSION: IAFI is a common complication in PKT, associated with pancreatic graft thrombosis or fungal contamination of the graft PF, and can sometimes lead to pancreatic detransplantation.
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Trasplante de Riñón , Micosis , Geotrichum , Humanos , Páncreas , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Liver transplant recipients are at high risk of developing invasive aspergillosis and in particular by Aspergillus fumigatus which is the most commonly encountered species in this population. Other non-fumigatus Aspergillus species with reduced susceptibility to antifungal drugs can also be involved. Accurate identification associated to antifungal susceptibility testing is essential for therapy adjustment. We report a case of invasive pulmonary aspergillosis due to Aspergillus pseudodeflectus in a liver transplant recipient. To our knowledge, this is the first reported case of invasive aspergillosis due to this species with a reduced susceptibility to azoles. CASE PRESENTATION: A 64 year-old woman with drug-induced fulminant hepatitis underwent liver transplantation. Prophylactic treatment with caspofungin was introduced due to aspergillosis risk factors consisting in hemodialysis and fulminant hepatitis. Six weeks after transplantation, CT scan showed a right pulmonary opacity associated with an increase of galactomannan (index 5.4). Culture of BAL grew with several colonies of Aspergillus sp. The diagnosis of invasive aspergillosis was probable according to the EORTC criteria. The antifungal susceptibility tests (Etest®) revealed low MICs to echinocandins and amphotericin B) but high MICs to azoles. After these results, voriconazole was switched to liposomal amphotericin B. The patient died one month after diagnosis from a refractory septic shock with multiple organ failure. A molecular identification of isolate, based on partial ß-tubulin and calmodulin genes, was performed and identified A. pseudodeflectus. CONCLUSIONS: Our case raises the question of pathogenicity of this species, which belongs to Aspergillus section Usti and is genetically and morphologically very close to Aspergillus calidoustus that was previously reported in human transplant recipients.
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Aspergilosis/diagnóstico , Aspergillus/aislamiento & purificación , Trasplante de Hígado/efectos adversos , Hígado/microbiología , Receptores de Trasplantes , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/etiología , Aspergilosis/microbiología , Aspergillus/genética , Aspergillus/patogenicidad , Equinocandinas/uso terapéutico , Femenino , Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/etiología , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Voriconazol/uso terapéuticoRESUMEN
Liver transplant recipients are at risk of invasive fungal infections, especially candidiasis. Echinocandin is recommended as prophylactic treatment but is increasingly associated with resistance. Our aim was to assess echinocandin drug resistance in Candida spp. isolated from liver transplant recipients treated with this antifungal class. For this, all liver-transplanted patients in a University Hospital (Créteil, France) between January and June of 2013 and 2015 were included. Susceptibilities of Candida isolates to echinocandins were tested by Etest and the EUCAST reference method. Isolates were analyzed by FKS sequencing and genotyped based on microsatellites or multilocus sequence typing (MLST) profiles. Ninety-four patients were included, and 39 patients were colonized or infected and treated with echinocandin. Echinocandin resistance appeared in 3 (8%) of the treated patients within 1 month of treatment. One patient was colonized by resistant Candida glabrata, one by resistant Candida dubliniensis, and one by resistant Candida albicans Molecular analysis found three mutations in FKS2 HS1 (F659S, S663A, and D666E) for C. glabrata and one mutation in FKS1 HS1 (S645P) for C. dubliniensis and C. albicans Susceptible and resistant isolates belonged to the same genotype. To our knowledge, this is the first study on echinocandin resistance in Candida spp. in a liver transplant population. Most resistant isolates were found around/in digestive sites, perhaps due to lower diffusion of echinocandin in these sites. This work documents the risk of emergence of resistance to echinocandin, even after short-term treatment.
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Candida/efectos de los fármacos , Candida/genética , Farmacorresistencia Fúngica/efectos de los fármacos , Equinocandinas/farmacología , Trasplante de Hígado , Adulto , Anciano , Candida/aislamiento & purificación , Equinocandinas/uso terapéutico , Femenino , Francia , Proteínas Fúngicas/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , MutaciónRESUMEN
We report here a case of cavitary pneumonia due to Rhizopus homothallicus in a diabetic patient. This is the first proven case of R. homothallicus infection in Western countries and the third case described worldwide. The organism was isolated from lung biopsy and identified after amplification and sequencing of the internal transcribed spacer region.
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Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/patología , Mucormicosis/diagnóstico , Mucormicosis/patología , Rhizopus/aislamiento & purificación , Adulto , Biopsia , Análisis por Conglomerados , ADN de Hongos/química , ADN de Hongos/genética , ADN Espaciador Ribosómico/química , ADN Espaciador Ribosómico/genética , Complicaciones de la Diabetes/diagnóstico , Complicaciones de la Diabetes/patología , Femenino , Histocitoquímica , Humanos , Pulmón/patología , Enfermedades Pulmonares/microbiología , Microscopía , Mucormicosis/microbiología , Filogenia , Rhizopus/clasificación , Rhizopus/genética , Análisis de Secuencia de ADNRESUMEN
Invasive fungal infections (IFI) are complications after liver transplantation involving high morbidity and mortality. (1,3)-ß-d-glucan (BG) is a biomarker for IFI, but its utility remains uncertain. This study was designed to evaluate the impact of BG following their diagnosis. Between January 2013 and May 2016, 271 liver transplants were performed in our institution. Serum samples were tested for BG (Fungitell®, Associates Cape Code Inc., Falmouth, MA, USA) at least weekly between liver transplantation and the discharge of patients. Nineteen patients (7%) were diagnosed with IFI, including 13 cases of invasive candidiasis (IC), eight cases of invasive pulmonary aspergillosis, and one case of septic arthritis due to Scedosporium apiospernum. Using a single BG sample for the primary analysis of IFI, 95% (21/22) of the subjects had positive BG (>80 pg/mL) at the time of IFI diagnosis. The area under the ROC curves to predict IFI was 0.78 (95% CI: 0.73-0.83). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BG for IFI were 75% (95% CI: 65-83), 65% (62-68), 17% (13-21), and 96% (94-97), respectively. Based on their high NPV, the BG test appears to constitute a good biomarker to rule out a diagnosis of IFI.
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Infecciones Fúngicas Invasoras/sangre , Infecciones Fúngicas Invasoras/etiología , Trasplante de Hígado/efectos adversos , beta-Glucanos/sangre , Adulto , Anciano , Antifúngicos/uso terapéutico , Biomarcadores , Quimioprevención , Femenino , Humanos , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/prevención & control , Masculino , Persona de Mediana Edad , Mortalidad , Proteoglicanos , Curva ROC , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
In recent years, we have moved from the sporadic description of terbinafine-resistant (TerR) Trichophyton spp. isolates to the Indian outbreak due to T. indotineae. Population flows have spread TerR worldwide, altering local epidemiology. We conducted a prospective multicentric study to determine the relative frequency of TerR isolates in France (Paris area) and of the newly introduced T. indotineae species. TerR isolates were screened by the terbinafine-containing-agar-medium (TCAM) method and confirmed by EUCAST. Sequencing methods were used to identify isolates to the species/genotype level and to analyze substitutions in the squalene epoxidase gene (SQLE). In total, 3 isolates out of 580 (T. rubrumn = 1; T. interdigitalen = 1; T. indotineaen = 1) grew on TCAM, showed terbinafine resistance by EUCAST and harbored the Phe397Leu (n = 2) or Leu393Ser (n = 1) substitution in the SQLE. ITS-sequencing of isolates of the T. mentagrophytes/interdigitale complex (n = 125) revealed a relative frequency of 4.8% for T. indotineae and the presence of T. mentagrophytes genotype VII. Despite the detection of terbinafine resistance, isolates from this complex remained susceptible to itraconazole, voriconazole and amorolfine. Terbinafine resistance is present in France and the dermatophyte epidemiology is changing. Efficient systems must be implemented to survey the evolution of newly introduced species and to identify TerR isolates.
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Paecilomyces spp. are emerging fungal pathogens, where Paecilomyceslilacinus and Paecilomyces variotii are the most reported species. Taxonomic and phylogenetic revisions in this genus have shown that P. variotii represents a species complex, whereas P. lilacinus is related to another genus called Purpureocillium. The aims of this study were to identify clinical isolates of Paecilomyces spp. at the species level, and to determine their antifungal susceptibility profiles. 70 clinical Paecilomyces spp. isolates were identified by MALDI-TOF Mass Spectrometry (MS) and by multilocus rDNA genes sequencing including ITS and the D1/D2 genes. Among the 70 Paecilomyces spp. isolates, 28 were identified as P. lilacinum, 26 as P. variotii stricto sensu, and 16 as P. maximus. For antifungal susceptibility testing, Minimal Inhibitory Concentrations (MICs) or Minimal Effective Concentrations (MECs) were determined for 8 antifungals. All P. lilacinum isolates had high MICs and MECs of amphotericin B and echinocandins, respectively, unlike P. variotii and P. maximus. For azole drugs, MICs were molecule- and species- dependent. The differences in in vitro susceptibility to antifungals underline the importance of accurate species identification. The MALDI-TOF MS can be a good alternative in routine laboratory to ensure fast identification of Paecilomyces spp. and P. lilacinum.
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BACKGROUND: Cirrhosis is not recognised as one of the main risk factors of invasive pulmonary aspergillosis (IPA), although its prevalence is increasing. The aim of our study was to identify factors for IPA in such patients with a positive Aspergillus sp. culture in respiratory samples and to evaluate its impact on outcome. METHODS: We conducted a monocentric retrospective study between January 2005 and December 2015. All cirrhotic patients hospitalised in our liver ICU with a positive Aspergillus sp. respiratory sample were included. These patients were case-matched with cirrhotic patients without positive Aspergillus respiratory sample. Finally, the patients were classified as having putative aspergillosis or colonisation according to the criteria described previously. RESULTS: In total, 986 cirrhotic patients were admitted to ICU during the study period. Among these, sixty patients had a positive Aspergillus sp. respiratory sample. Chronic obstructive pulmonary disease (COPD) comorbidity and organ supports were significantly associated with Aspergillus colonisation. Seventeen patients (28%) were diagnosed as proven or putative IPA and 43 were considered as colonised by Aspergillus sp. The median delay between ICU admission and an IPA diagnosis was 2 [2-24] days. Only COPD was predictive of the presence of IPA (OR 6.44; 95% CI 1.43-28.92; p = 0.0151) in patients with a positive Aspergillus sp. culture. The probability of in-hospital mortality was 71% in the IPA group versus 19% in the colonisation group (p = 0.0001). CONCLUSION: Patients with cirrhosis can be at risk of IPA, especially with COPD. Antifungal agents should be given as soon as possible mainly in cirrhotic patients with COPD.
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Opportunistic subcutaneous fungal infections are increasing nowadays due to the growing number of medical conditions causing immunosuppression, especially organ transplant. The incidence rate of subcutaneous phaeohyphomycosis is very low. Most studies found are case reports. They showed a wide variation of clinical presentations. Pyrenochaeta romeroi, a fungus from the Dematiaceae group is a saprophyte found in soil and plants and a possible causative agent of phaeohyphomycosis. We present a rare case of subcutaneous phaeohyphomycosis caused by P. romeroi mimicking a synovial cyst in a diabetic patient.
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Entamoeba histolytica is the protozoan parasite agent of amoebiasis, an infectious disease of the human intestine and liver. Specific active pathogenic factors are secreted toward the external milieu upon interaction of the parasite with human tissue. Trafficking dynamics and secretion of these factors is not known and characterization of the dynamics interplay of subcellular compartments such as the ER or Golgi apparatus is still pending. In this work, we took advantage of cell fractionation and a wide proteomic analysis to search for principal components of the endomembrane system in E. histolytica. Over 1500 proteins were identified and the two top categories contained components of trafficking machinery and GTPases. Trafficking related proteins account for over 100 markers from the ER, Golgi, MVB, and retromers. The lack of important components supporting Golgi polarization was also highlighted. The data further describe principal components of the endosomal traffic highlighting Alix in isolated vesicles and during parasite division. BIOLOGICAL SIGNIFICANCE: This work represents the first in-depth proteomics analysis of subcellular compartments in E. histolytica and allows a detailed map of vesicle traffic components in an ancient single-cell organism that lacks a stereotypical ER and Golgi apparatus to be established.
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Retículo Endoplásmico/metabolismo , Entamoeba histolytica/metabolismo , Aparato de Golgi/metabolismo , Membranas Intracelulares/metabolismo , Proteoma/metabolismo , Proteómica , Proteínas Protozoarias/metabolismo , Humanos , Transporte de ProteínasRESUMEN
OBJECTIVES: Current methods for cryptococcal antigen detection have some limitations. This study aimed at evaluating a lateral flow assay (LFA) for the diagnosis of cryptococcosis in a French University medical center. METHODS: A retrospective study was performed on samples collected from patients with a definitive diagnosis of cryptococcosis (group I 66 samples; 28 patients) or with non-Cryptococcus invasive fungal infection (group II 18 samples; 17 patients). In addition, 274 samples from 205 consecutive patients, either suspected of cryptococcal infection or routinely screened during their follow-up, were prospectively tested (group III). Cryptococcal antigen was assayed using LFA and an EIA. A latex-based test was used for confirmation. RESULTS: Sensitivity calculated on group I and specificity on group II, were respectively at 100% and 90.0%. Two false positives were related to Trichosporon fungemia. Per-sample analysis on group III revealed sensitivity, specificity, positive and negative predictive values all at 100% for CSF, and at 100%, 98.9%, 75% and 100%, respectively for serum samples. LFA enabled the diagnosis of two cases of asymptomatic cryptococcosis. CONCLUSION: The excellent diagnostic value and practicality (visual reading results in 15 min) of LFA make it fully appropriate for the diagnosis of cryptococcosis in this particular setting.
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Antígenos Fúngicos/análisis , Cromatografía de Afinidad , Criptococosis/diagnóstico , Cryptococcus gattii/aislamiento & purificación , Cryptococcus neoformans/aislamiento & purificación , Centros Médicos Académicos , Anciano , Antígenos Fúngicos/sangre , Antígenos Fúngicos/líquido cefalorraquídeo , Enfermedades Asintomáticas , Líquido del Lavado Bronquioalveolar/microbiología , Criptococosis/microbiología , Cryptococcus neoformans/inmunología , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Entamoeba histolytica is the protozoan parasite agent of amebiasis, an infectious disease of the human intestine and liver. This parasite contact and kills human cells by an active process involving pathogenic factors. Cellular traffic and secretion activities are poorly characterized in E. histolytica. In this work, we took advantage of a wide proteomic analysis to search for principal components of the endomembrane system in E. histolytica. A total of 5683 peptides matching with 1531 proteins (FDR of 1%) were identified which corresponds to roughly 20% of the total amebic proteome. Bioinformatics investigations searching for domain homologies (Smart and InterProScan programs) and functional descriptions (KEGG and GO terms) allowed this data to be organized into distinct categories. This data represents the first in-depth proteomics analysis of subcellular compartments in E. histolytica and allows a detailed map of vesicle traffic components in an ancient single-cell organism that lacks a stereotypical ER and Golgi apparatus to be established. The data are related to [1].