Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis.

BACKGROUND: Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. OBJECTIVE: This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. METHODS: Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article's Online Repository available at www.jacionline.org. RESULTS: Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. CONCLUSION: These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

A Phase I/IIa Prospective, Randomized, Open-Label Study on the Safety and Efficacy of Nebulized Liposomal Amphotericin for Invasive Pulmonary Aspergillosis.

Although nebulized liposomal amphotericin B (NLAB) is being used in invasive pulmonary aspergillosis (IPA) prophylaxis, no clinical trial has shown its efficacy as a therapeutic strategy. NAIFI is the inaugural randomized, controlled clinical trial designed to examine the safety and effectiveness of NLAB (dosage: 25 mg in 6 mL, three times per week for 6 weeks) against a placebo, in the auxiliary treatment of IPA. Throughout the three-year clinical trial, thirteen patients (six NLAB, seven placebo) were included, with 61% being onco-hematological with less than 100 neutrophils/µL. There were no significant differences noted in their pre- and post-nebulization results of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and oxygen saturation between the groups. Neither bronchospasm nor serum amphotericin B levels were reported in any patients given NLAB. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET-TC) was carried out at the baseline and after 6 weeks. A notable decrease in median SUV (standardized uptake value) was observed in NLAB patients after 6 weeks (-3.6 vs. -0.95, p: 0.039, one tail). Furthermore, a reduction in serum substance galactomannan and beta-D-Glucan was identified within NLAB recipients. NLAB is well tolerated and safe for patients with IPA. Encouraging indirect efficacy data have been derived from image monitoring or biomarkers. However, further studies involving more patients are necessary.

Successful desensitisation to paclitaxel with omalizumab.

We present the case of a patient with failed desensitisation to paclitaxel that was ultimately successful with omalizumab treatment. Our patient, a female aged between 20-25 and diagnosed with a triple negative breast cancer, received first-line treatment with carboplatin and paclitaxel. During the second cycle of paclitaxel, she experienced heat, dyspnoea, facial angioedema and vomiting. Skin tests for allergic reactions returned negative results, and drug provocation tests showed a positive result (anaphylaxis). Rapid drug desensitisation (RDD) was carried out with two bags of dilutions but at the beginning of the infusion, the patient experienced symptoms again, so the infusion was stopped. Therefore, the use of omalizumab, already reported as a successful adjuvant in desensitisation to other drugs, was considered. The anti-immunoglobulin E (IgE) monoclonal antibody was administered off-label before the first programmed desensitisation with success: total dose of paclitaxel was infused without any reaction. The patient was able to receive the complete chemotherapy treatment.

Bronchopulmonary penetration of isavuconazole in lung transplant recipients.

Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung.

Potential Implication of Azole Persistence in the Treatment Failure of Two Haematological Patients Infected with Aspergillus fumigatus.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients receiving allogeneic haematopoieticcell transplantation. The deep immunosuppression and a variety of potential additional complications developed in these patients result in IA reaching mortality rates of around 50-60%. This mortality is even higher when the patients are infected with azole-resistant isolates, demonstrating that, despite the complexity of management, adequate azole treatment can have a beneficial effect. It is therefore paramount to understand the reasons why antifungal treatment of IA infections caused by azole-susceptible isolates is often unsuccessful. In this respect, there are already various factors known to be important for treatment efficacy, for instance the drug concentrations achieved in the blood, which are thus often monitored. We hypothesize that antifungal persistence may be another important factor to consider. In this study we present two case reports of haematological patients who developed proven IA and suffered treatment failure, despite having been infected with susceptible isolates, receiving correct antifungal treatment and reaching therapeutic levels of the azole. Microbiological analysis of the recovered infective isolates showed that the patients were infected with multiple strains, several of which were persisters to voriconazole and/or isavuconazole. Therefore, we propose that azole persistence may have contributed to therapeutic failure in these patients and that this phenomenon should be considered in future studies.

Observed isavuconazole exposure: 5-year experience of azole TDM from a Spanish reference laboratory.

We aimed to assess patient exposure to isavuconazole (ISZ) from samples received in our laboratory for therapeutic antifungal monitoring. We used liquid chromatography coupled with ultraviolet (UV) absorbance detection adapted from a multiplex-validated method with photodiode array (PDA) detection to monitor the analytes. The latter device allows the characterization of the azoles UV spectra. The method was validated according to international guidelines for efficient ISZ monitoring. The assay exhibited linearity between 0.25 and 16 mg/l for ISZ. Accuracy and intra- and inter-day precision were within acceptable ranges, and the method was successfully applied to quantify azoles and major metabolites from clinical samples collected from treated patients. We focus on ISZ blood concentrations and compared them to those of voriconazole, posaconazole, and itraconazole for a period of 5 years (2017-2021). Median ISZ concentration was 2.92 mg/l (interquartile range 1.82-5.33 mg/l) with 89% of measurements classified as adequate exposure (> 1 mg/l). Additionally, 71% of samples reach concentration values > 2 mg/l. Different ISZ exposure between adults to children were found. In conclusion, ISZ achieves excellent blood concentrations compared to other azole drugs, they are almost identical to those previously described, they exceed the MICs of most fungi for which its use was recommended and they differ depending on the patient's age. The method we describe for antifungal monitoring is simple, robust, and efficient. It simultaneously analyzes azoles and metabolites, and can be used for tailored interventions, achieve exposures associated with therapeutic success, decrease treatment-related toxicity, and help prevent resistance emergence due to continuous azole sub-optimal concentrations.

Optimizing azole therapy is a challenge in clinical practice, for which therapeutic drug monitoring is of great value to assess exposure, especially by using valid methodologies. Isavuconazole reaches good blood concentrations, but moderate intra-patient variability and different exposure according to the patient's age were found.

A survey to describe common practices on antifungal monitoring among Spanish clinicians.

INTRODUCTION: We developed a survey to obtain information on the monitoring practices of major systemic antifungals for treatment and prevention of serious fungal infection. METHODS: The survey included questions relating to methodology and practice and was distributed among 137 colleagues of the Study Group of Medical Mycology (GEMICOMED) from July to December 2019. RESULTS: Monitoring was routinely carried out by most respondents, mainly for voriconazole, and was more likely used to determine the efficacy of the dose administered and less for minimizing drug toxicity. Most responders did not follow the strategies of voriconazole dosage based on CYP2C19 genotyping. Monitoring of posaconazole, itraconazole, or other azole metabolites was not carried out or scarcely demanded. Most responders rarely used flucytosine in their clinical practice nor did they monitor it. According to the answers given by some responders, monitoring isavuconazole, amphotericin B, caspofungin and fluconazole exposure would be also interesting in daily clinical practice in selected patient populations. CONCLUSIONS: The survey reveals common practices and attitudes towards antifungal monitoring, sometimes not performed as per best recommendations, offering an opportunity for education and research. Appropriate use of therapeutic drug monitoring may be an objective of antifungal stewardship programmes.

A survey to describe common practices on antifungal monitoring among Spanish clinicians / Monitorización de antifúngicos sistémicos: resultados de una encuesta distribuida en España

Introduction: We developed a survey to obtain information on the monitoring practices of major systemic antifungals for treatment and prevention of serious fungal infection. Methods: The survey included questions relating to methodology and practice and was distributed among 137 colleagues of the Study Group of Medical Mycology (GEMICOMED) from July to December 2019. Results: Monitoring was routinely carried out by most respondents, mainly for voriconazole, and was more likely used to determine the efficacy of the dose administered and less for minimizing drug toxicity. Most responders did not follow the strategies of voriconazole dosage based on CYP2C19 genotyping. Monitoring of posaconazole, itraconazole, or other azole metabolites was not carried out or scarcely demanded. Most responders rarely used flucytosine in their clinical practice nor did they monitor it. According to the answers given by some responders, monitoring isavuconazole, amphotericin B, caspofungin and fluconazole exposure would be also interesting in daily clinical practice in selected patient populations. Conclusions: The survey reveals common practices and attitudes towards antifungal monitoring, sometimes not performed as per best recommendations, offering an opportunity for education and research. Appropriate use of therapeutic drug monitoring may be an objective of antifungal stewardship programmes.(AU)

Introducción: Describimos los resultados de una encuesta diseñada para obtener información sobre prácticas de monitorización de los principales antifúngicos sistémicos utilizados en el tratamiento y la prevención de la infección fúngica grave en España. Métodos: La encuesta, que incluye preguntas relacionadas tanto con metodología como con su uso práctico, se distribuyó entre 137 compañeros del Grupo de Estudio de Micología Médica (GEMICOMED), de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Resultados: La mayoría de los encuestados respondieron utilizar la monitorización de antifúngicos de forma rutinaria, principalmente para voriconazol, y en especial para evaluar la eficacia de la dosis administrada y menos para minimizar su toxicidad. La mayoría de ellos no siguieron las estrategias de dosificación de voriconazol basadas en el conocimiento previo del genotipo CYP2C19, relacionado con su metabolización. Por el contrario, la monitorización de posaconazol, itraconazol o de algunos de sus metabolitos no se realizó o apenas se solicitó. La mayoría de los encuestados rara vez usan 5-fluocitosina en su práctica clínica y por tanto tampoco monitorizan su exposición. Un alto porcentaje consideraría de utilidad poder evaluar la exposición a isavuconazol, anfotericina B, caspofungina y fluconazol en determinadas situaciones en la práctica clínica. Conclusiones: La encuesta revela prácticas y actitudes hacia la monitorización de antifúngicos que en ocasiones no se realizan según las principales recomendaciones, lo que ofrece una oportunidad para la educación y la investigación. Abordar esta formación podría convertirse en objetivo de los programas racionales del uso de antimicrobianos a nivel nacional.(AU)

Personalized diagnostic approach and indirect quantification of extravasation in human anaphylaxis.

BACKGROUND: Anaphylaxis is the most acute and life-threatening manifestation of allergic disorders. Currently, there is a need to improve its medical management and increase the understanding of its molecular mechanisms. This study aimed to quantify the extravasation underlying human anaphylactic reactions and propose new theragnostic approaches. METHODS: Molecular determinations were performed in paired serum samples obtained during the acute phase and at baseline from patients presenting with hypersensitivity reactions. These were classified according to their severity as Grades 1, 2 and 3, the two latter being considered anaphylaxis. Tryptase levels were measured by ImmunoCAP, and serum protein concentration was quantified by Bradford assay. Human serum albumin (HSA) and haemoglobin beta subunit (HBB) levels were determined by Western blot and polyacrylamide gel electrophoresis, respectively. RESULTS: A total of 150 patients were included in the study. Of them, 112 had experienced anaphylaxis (83 and 29 with Grade 2 and 3 reactions, respectively). Tryptase diagnostic efficiency substantially improved when considering patients' baseline values (33%-54%) instead of the acute value threshold (21%). Serum protein concentration and HSA significantly decreased in anaphylaxis (p < .0001). HSA levels dropped with the severity of the reaction (6% and 15% for Grade 2 and 3 reactions, respectively). Furthermore, HBB levels increased during the acute phase of all hypersensitivity reactions (p < .0001). CONCLUSIONS: For the first time, the extravasation underlying human anaphylaxis has been evaluated based on the severity of the reaction using HSA and protein concentration measurements. Additionally, our findings propose new diagnostic and potential therapeutic approaches for this pathological event.

Bronchopulmonary Penetration of Isavuconazole in Pulmonary Transplant Recipients (PBISA01): Protocol for a Phase IV Clinical Trial With a Single Treatment Arm.

BACKGROUND: Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD. OBJECTIVE: The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD. METHODS: A total of 12 patients aged ≥18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method. RESULTS: Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022. CONCLUSIONS: There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA. TRIAL REGISTRATION: European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37275.

Dynamics of gliotoxin and bis(methylthio)gliotoxin production during the course of Aspergillus fumigatus infection.

As recently described, fungal secondary metabolism activates during infection in response to a hostile host environment. Gliotoxin and bis(methylthio)gliotoxin are two recognized secondary metabolites produced by Aspergillus fumigatus with differential cytotoxicity and involved in virulence. We sought to describe the temporal dynamics of gliotoxin and bis(methylthio)gliotoxin during A. fumigatus progression to further explore their role in the infection. First, we optimized the production of the mycotoxins under different in vitro growth conditions and then specifically measured them using an UHPLC/PDA method. The analytical conditions were selected after testing different parameters such as extraction procedures, column type, and mobile phase composition. We found that gliotoxin and bis(methylthio)gliotoxin are differentially excreted to the extracellular media during the course of A. fumigatus infection regardless of the growth format tested. Dynamic profiles show an early production of gliotoxin, which, after reaching a maximum, decreases coinciding with the increase in the production of the inactive derivative bis(methylthio)gliotoxin. Presence of gliotoxin may indicate an early phase of fungal development, whereas detection of bis(methylthio)gliotoxin may correspond to a more advanced stage of infection. Our chromatographic method successfully characterizes these secondary metabolites. Thus, it may potentially be used to further understand Aspergillus infection. LAY SUMMARY: Aspergillus fumigatus secondary metabolites may contribute to fungal survival. A new chromatographic method was applied to simultaneously characterize two relevant metabolites. Presence of toxic gliotoxin may indicate an early phase of development, whereas the detection of the inactive derivate may represent an advanced infection stage.

A survey to describe common practices on antifungal monitoring among Spanish clinicians.

INTRODUCTION: We developed a survey to obtain information on the monitoring practices of major systemic antifungals for treatment and prevention of serious fungal infection. METHODS: The survey included questions relating to methodology and practice and was distributed among 137 colleagues of the Study Group of Medical Mycology (GEMICOMED) from July to December 2019. RESULTS: Monitoring was routinely carried out by most respondents, mainly for voriconazole, and was more likely used to determine the efficacy of the dose administered and less for minimizing drug toxicity. Most responders did not follow the strategies of voriconazole dosage based on CYP2C19 genotyping. Monitoring of posaconazole, itraconazole, or other azole metabolites was not carried out or scarcely demanded. Most responders rarely used flucytosine in their clinical practice nor did they monitor it. According to the answers given by some responders, monitoring isavuconazole, amphotericin B, caspofungin and fluconazole exposure would be also interesting in daily clinical practice in selected patient populations. CONCLUSIONS: The survey reveals common practices and attitudes towards antifungal monitoring, sometimes not performed as per best recommendations, offering an opportunity for education and research. Appropriate use of therapeutic drug monitoring may be an objective of antifungal stewardship programmes.

LTP Allergy Follow-Up Study: Development of Allergy to New Plant Foods 10 Years Later.

INTRODUCTION: Allergy to nonspecific lipid transfer protein (nsLTP) is the main cause of plant-food allergy in Spain. nsLTPs are widely distributed in the plant kingdom and have high cross-reactivity but extremely variable clinical expression. Little is known about the natural evolution of this allergy, which complicates management. The objective of this study was to assess the development of allergy to new plant foods in nsLTP-sensitized patients 10 years after diagnosis. METHODS: One hundred fifty-one patients showing specific IgE to nsLTP determined by ISAC (Thermofisher) were included. After clinical workup (i.e., anamnesis, skin test, and challenge when needed), these patients were divided into two groups: 113 patients allergic to one or more plant food (74.5%) and 38 patients not allergic to any plant food (25.1%). Ten years later, a telephone interview was conducted to check whether patients had developed additional allergic reactions to plant foods. RESULTS: Ten years after diagnosis, 35 of the 113 (31%) plant-food-allergic patients sensitized to nsLTP reported reactions to new, previously tolerated plant foods, mainly Rosaceae/Prunoideae fruits and nuts followed by vegetables, Rosacea/Pomoideae fruits, legumes, and cereals. Five out of 38 (13.2%) patients previously sensitized to nsLTP but without allergy to any plant food had experienced allergic reactions to some plant food: two to Rosaceae/Prunoideae fruits, two to Rosaceae/Prunoideae fruit and nuts, and one to legumes. CONCLUSION: Patients sensitized to nsLTP developed allergic reactions to other plant foods, mainly Rosaceae-Prunoideae fruits and nuts. This was more frequent among plant-food-allergic patients than among those who had never had plant-food allergy.

Eosinophils and Chronic Respiratory Diseases in Hospitalized COVID-19 Patients.

BACKGROUND: Studies on the role of eosinophils in coronavirus disease 2019 (COVID-19) are scarce, though available findings suggest a possible association with disease severity. Our study analyzes the relationship between eosinophils and COVID-19, with a focus on disease severity and patients with underlying chronic respiratory diseases. METHODS: We performed a retrospective analysis of 3018 subjects attended at two public hospitals in Madrid (Spain) with PCR-confirmed SARS-CoV-2 infection from January 31 to April 17, 2020. Patients with eosinophil counts less than 0.02×109/L were considered to have eosinopenia. Individuals with chronic respiratory diseases (n=384) were classified according to their particular underlying condition, i.e., asthma, chronic pulmonary obstructive disease, or obstructive sleep apnea. RESULTS: Of the 3018 patients enrolled, 479 were excluded because of lack of information at the time of admission. Of 2539 subjects assessed, 1396 patients presented an eosinophil count performed on admission, revealing eosinopenia in 376 cases (26.93%). Eosinopenia on admission was associated with a higher risk of intensive care unit (ICU) or respiratory intensive care unit (RICU) admission (OR:2.21; 95%CI:1.42-3.45; p<0.001) but no increased risk of mortality (p>0.05). CONCLUSIONS: Eosinopenia on admission conferred a higher risk of severe disease (requiring ICU/RICU care), but was not associated with increased mortality. In patients with chronic respiratory diseases who develop COVID-19, age seems to be the main risk factor for progression to severe disease or death.

Increased miR-21-3p and miR-487b-3p serum levels during anaphylactic reaction in food allergic children.

BACKGROUND: Anaphylaxis is the most severe manifestation of allergic disorders. The poor knowledge of its molecular mechanisms often leads to under-diagnosis. MicroRNAs (miRNA) regulate physiologic and pathologic processes, and they have been postulated as promising diagnostic markers. The main objectives of this study were to characterize the human miRNA profile during anaphylaxis and to assess their capacity as diagnostic markers and determine their participation in the molecular mechanisms of this event. METHODS: The miRNA serum profiles from the acute and baseline phase of 5 oral food-challenged anaphylactic children (<18 years old) were obtained by next-generation sequencing (NGS). From the panel of statistically significant miRNAs obtained, several candidates were selected and analyzed in 19 anaphylactic children by qPCR. We performed system biology analysis (SBA) on their target genes to identify main functions and canonical pathways. A functional in vitro assay was carried out incubating endothelial cells (ECs) in anaphylactic conditions. RESULTS: The NGS identified 389 miRNAs among which 41 were significantly different between acute and baseline samples. The high levels of miR-21-3p (fold change = 2.28, P = .006) and miR-487b-3p (fold change = 1.04, P = .039) observed by NGS in acute serum samples were confirmed in a larger group of 19 patients. The SBA revealed molecular pathways related to the inflammation and immune system regulation. miR-21-3p increased intracellularly and in acute phase serum after EC stimulation. CONCLUSIONS: These findings provide, for the first time, some insights into the anaphylactic miRNA serum profile in children and point to miR-21-3p and miR-487b-3p as candidate biomarkers. Furthermore, the SBA revealed a possible implication of these molecules in the underlying molecular mechanisms. Moreover, ECs increased miR-21-3p intracellularly and released it to the environment in response to anaphylaxis.

Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).

OBJECTIVE: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs). METHODS: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT. RESULTS: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαß+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%. CONCLUSION: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise.

Pharmacokinetics of echinocandins in suspected candida peritonitis: A potential risk for resistance.

INTRODUCTION: A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid. MATERIALS/METHODS: Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay. RESULTS: Twenty-three critically ill patients with suspected abdominal fungal infection who were receiving an echinocandin were prospectively recruited. No specific criteria were applied to prescribe one specific echinocandin. No special clinical differences were observed among the three groups of patients. All were receiving antibiotic therapy, 80% required inotropic drugs, and fungal peritonitis was confirmed in 74% of them. The AUC0_24h (mg × h/L) obtained in serum and peritoneal fluid were: 126.84 and 34.38, 98.52 and 18.83, and 66.9 and 8.78 for anidulafungin, micafungin and caspofungin, respectively. The median concentration in peritoneal fluid ranged from 0.66 to 1.82 µg/mL for anidulafungin, 0.68-0.88 µg/mL for micafungin and 0.21-0.46 µg/mL for caspofungin. CONCLUSION: The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.