Geotricosis: fungemia en paciente con leucemia linfoblástica aguda / Geotrichosis: fungemia in a patient with acute lymphoblastic leukemia

La fungemia por Geotrichum spp. es poco frecuente y altamente letal. En el Instituto Nacional de Cancerología de Bogotá solo se han reportado dos casos: uno entre el 2001 y el 2007, y el otro entre el 2012 y el 2018. Este tipo de infección es más común en pacientes con algún grado de compromiso del sistema inmunitario, por lo que puede presentarse en pacientes con neoplasias hematológicas malignas. Se presenta el caso de un hombre de 27 años con recaída de leucemia linfoblástica aguda, que ingresó con poliartralgias de cinco días de duración. También cursaba con neutropenia febril, celulitis sin abscesos y bacteriemia por Staphylococcus aureus resistente a la meticilina para lo cual recibió terapia con oxacilina y cefepime. Sin embargo, persistía la neutropenia febril por lo que se sospechó una infección fúngica invasora. Se tomó un nuevo set de hemocultivos y se inició tratamiento antifúngico. En los hemocultivos se identificaron artroconidias y mediante espectrometría de masas por láser de matriz asistida de ionización-desorción se confirmó la presencia de Geotrichum spp. Se ajustó el tratamiento antifúngico con deoxicolato de anfotericina B por 14 días y voriconazol por cuatro semanas. Luego de una estancia prolongada se le dio de alta. Aunque la incidencia de la fungemia por Geotrichum spp. es baja, en pacientes con neoplasias hematológicas malignas debe considerarse en el contexto de una neutropenia febril que es persistente a pesar del tratamiento antimicrobiano de amplio espectro. La identificación de los agentes causantes de fungemias con herramientas de proteómica, como la espectrometría de masas mencionada, permite ajustar el tratamiento dirigido y reducir las complicaciones, la estancia hospitalaria y la mortalidad.

Fungemia caused by Geotrichum spp. is rare and highly lethal. The Instituto Nacional de Cancerología in Bogotá reported just two cases: one in the period 2001-2007 and the other in 2012-2018. This type of infection is more common in any kind of immunocompromised patients, so it can occur in those with hematological malignancies. Here we present the case of a 27-year-old man, diagnosed with acute lymphoblastic leukemia in relapse and admitted with polyarthralgia for five days, febrile neutropenia, non- abscessed cellulitis, and bacteremia due to methicillin-sensitive Staphylococcus aureus. The patient received therapy with oxacillin and cefepime, but the febrile neutropenia persisted. A new set of blood cultures was taken, and antifungal treatment was started because of the suspicion of invasive fungal infection. Arthroconidia were identified in blood cultures and Geotrichum spp. was confirmed using matrix-assisted laser desorption-ionization mass spectrometry. The antifungal treatment was adjusted with amphotericin B deoxycholate for 14 days and voriconazole for four weeks, and after a prolonged stay, the patient was discharged. Although the incidence of fungemia caused by Geotrichum spp. is low, it must be considered in patients with hematological malignancies and persistent febrile neutropenia despite the broadspectrum antimicrobial treatment. The confirmation of fungemia causing agents, with proteomic tools such as the mentioned mass spectrometry, allows treatment adjustment and decreases complications, hospital stay, and mortality.

Fusariosis en pacientes con cáncer: serie de 13 casos y revisión de la literatura / Fusariosis in cancer patients: 13 case series report and literature review

La fusariosis es una micosis oportunista producida por Fusarium spp. Su presentación clínica depende del estado inmunológico del huésped, especialmente, el de aquellos con enfermedades hematooncológicas, cuyas manifestaciones varían desde formas localizadas hasta infección fúngica invasora. El cultivo de piel o de sangre permite orientar el tratamiento antifúngico combinado con anfotericina B y voriconazol. Se presentan 13 casos de pacientes con cáncer en un periodo de once años que desarrollaron fusariosis diseminada; asimismo, se hizo con una revisión extensa de la literatura. En esta serie de casos, la mortalidad fue del 61,5 % (8/13), a pesar del uso del antifúngico. De los 13 pacientes, 11 tenían neoplasia hematológica y 2 neoplasia sólida. El factor de riesgo más importante fue la neutropenia profunda. El compromiso de la piel y los hemocultivos positivos facilitaron la prescripción del tratamiento combinado en la mayoría de los casos. La neutropenia febril persistente asociada a lesiones cutáneas, la onicomicosis, los nódulos o las masas pulmonares permitieron sospechar una infección fúngica invasora por Fusarium spp. El objetivo de la presentación de esta serie de casos es recordar el diagnóstico de fusariosis a la comunidad médica en contacto con pacientes oncológicos, con neutropenia febril profunda y persistentes.

The fusariosis is an opportunistic mycosis caused by Fusarium spp. Its clinical presentation depends on the immunological status of the host, especially in patients with hemato-oncological diseases, whose manifestations vary from localized to invasive fungal infections. Skin or blood culture helps to guide combined antifungal treatment with amphotericin B and voriconazole. Here, we present 13 cases in a period of eleven years of patients with cancer who developed disseminated fusariosis and their outcomes, together with a review of the related literature. In this series of cases, mortality was 61.5 % (8/13), despite the use of the antifungal. Out of the 13 cases, 11 had hematological neoplasia and 2 solid neoplasia. The most determinant risk factor was profound neutropenia. Skin involvement and positive blood cultures in most cases allowed combined treatment prescription. Persistent febrile neutropenia associated with skin lesions, onychomycosis, nodules, or lung masses lead to suspicion of Fusarium spp. fungal invasive infection. The aim of this series of cases is to remind healthcare professionals that oncological patients with deep and persistent febrile neutropenia can develop fusariosis.

Aspergilosis invasiva: definiciones, diagnóstico y tratamiento / Invasive aspergillosis: definitions, diagnosis, and treatment

Resumen La aspergilosis invasiva (AI) es una enfermedad grave y con alta mortalidad. Existen factores de riesgo y se describen brotes intrahospitalarios relacionados con construcciones. También se des cribe una entidad relacionada con la infección por COVID-19, conocida como aspergilosis pulmonar asociada a COVID-19 (APAC). Es de vital importancia implementar un tratamiento adecuado y precoz, especialmente en pacientes inmunocomprometidos y críticamente enfermos. El diagnóstico se basa en reconocer los factores predisponentes, la clínica, la obtención de imágenes, exámenes directos, cultivos, histopatología y biomarca dores como el galactomanano. La droga de elección es el voriconazol, pero se deben conocer las alternativas terapéuticas dada la creciente presencia de aislamientos resistentes.

Abstract Invasive aspergillosis (IA) is a serious disease with high mortality. There are several risk factors and in-hospital outbreaks related with construction have been described. An entity related to COVID-19 infection, known as COVID-19 associated pulmonary aspergillosis (CAPA), has recently appeared. Early and appropriate treatment is of paramount importance, especially in immunocompromised and critically ill patients. Diagnosis is based on recognition of predisposing factors, clinical signs, imaging, direct examination, culture, histopathology, and biomarkers such as galactomannan. The drug of choice is voriconazole, but alternative therapies must be taken into account given the increasing presence of resistant isolates.

Analysis of influencing factors for the metabolism of voriconazole in adult patients / 中国药房

OBJECTIVE To analyze the influencing factors for the metabolism of voriconazole in adult patients， and to provide reference for the rational use of voriconazole in clinic. METHODS The clinical data of adult patients admitted in our hospital receiving voriconazole and therapeutic drug monitoring from April 2021 to March 2022 were collected. The trough concentration of voriconazole （c0） and plasma concentration of voriconazole-N-oxide concentration （cN） were determined， and voriconazole-to-voriconazole N-oxide concentration ratio （c0/cN） was calculated. Pearson’s correlation analysis was used to analyze the influencing factors for c0 and c0/cN of voriconazole. Multiple linear regression models were used to analyze the independent influencing factors for c0 and c0/cN of voriconazole. RESULTS The underlying diseases of the patients were mainly pneumonia， kidney disease and leukemia. The detected fungi were mainly Aspergillus， Candida and yeast-like fungi. Voriconazole was mainly administered by intravenous drip， especially in patients who used proton pump inhibitor in combination. The levels of C-reactive protein （CRP）， total bilirubin （TBIL）， direct bilirubin （DBIL） and indirect bilirubin （IBIL） were positively correlated with c0 of voriconazole， while platelet count and albumin levels were negatively correlated with voriconazole c0. The levels of CRP， TBIL and DBIL were positively correlated with c0/cN， while albumin levels were negatively correlated with c0/cN. Multiple linear regression analysis showed that the independent influencing factors of voriconazole c0 included the levels of CRP and IBIL， route of administration and dose of voriconazole， and the independent influencing factors of voriconazole c0/cN were the levels of CRP and DBIL and age. CONCLUSIONS The levels of CRP and IBIL， route of administration and dose of voriconazole are independent influencing factors of voriconazole c0； the levels of CRP and DBIL and age are independent influencing factors of voriconazole c0/cN. The influence of above indexes on the metabolism of voriconazole should be considered when using voriconazole clinically； and the route of administration and dose of voriconazole should be adjusted reasonably.

Factors Influencing and Adverse Reactions of Voriconazole Clearance in Patients with Hematological Diseases / 中国实验血液学杂志

OBJECTIVE@#To monitor the changes of voriconazole minimum concentration(Cmin) in patients with hematological diseases, and evaluate the factors influencing and adverse reactions of voriconazole clearance in patients with hematological diseases, so as to provide a theoretical basis for reasonable clinical use of voriconazole.@*METHODS@#136 patients with hematological diseases who used voriconazole in Wuhan NO.1 Hospital from May 2018 to December 2019 were selected. The correlation between C-reactive protein, albumin, creatinine and voriconazole Cmin were analyzed, and the changes of voriconazole Cmin after glucocorticoid treatment was also detected. In addition, stratified analysis was used to explore the adverse events of voriconazole.@*RESULTS@#Among 136 patients, 77 were male (56.62%) and 59 were female (43.38%). There were positive correlations between voriconazole Cmin and C-reactive protein and creatinine levels (r=0.277, r=0.208), while voriconazole Cmin was negatively correlated with albumin level (r=-2.673). Voriconazole Cmin in patients treated with glucocorticoid was decreased significantly (P<0.05). In addition, sratified analysis of voriconazole Cmin showed that compared with voriconazole Cmin 1.0-5.0 mg/L group, the incidence of adverse reactions of visual impairment in voriconazole Cmin> 5.0 mg/L group was increased (χ2=4.318, P=0.038).@*CONCLUSION@#The levels of C-reactive protein, albumin and creatinine are closely related to the voriconazole Cmin, which indicate that inflammation and hyponutrition may prevent the clearance of voriconazole in patients with hematological diseases. It is necessary to monitor the voriconazole Cmin of patients with hematological diseases, and adjust the dosage in time to reduce adverse reactions.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

A real-world survey of the effect of voriconazole on tacrolimus blood concentration after lung transplantation / 中国药房

OBJECTIVE To provide a reference for the dose adjustment of tacrolimus in patients who underwent lung transplantation after combined use of voriconazole. METHODS The clinical data of lung transplantation patients who used voriconazole and tacrolimus in our hospital from January 2020 to December 2022 were collected retrospectively. The effects of voriconazole on the valley concentration， daily dose and standardized blood concentration of tacrolimus were analyzed by using SPSS 21.0 software； multiple linear regression analysis was conducted for the factors that may affect the standardized blood concentration of tacrolimus. RESULTS A total of 153 lung transplantation patients were included. After the combination of voriconazole， the average daily dose of tacrolimus decreased from 3.37 mg to 0.76 mg， and valley concentration and standardized blood concentration were increased significantly （P＜0.000 1）. The average daily dose of voriconazole was negatively correlated with the standardized blood drug concentration of tacrolimus （P＝0.000 1，r＝－0.224）. The valley concentration of voriconazole was positively correlated with valley concentration （P＜0.000 1，r＝0.316） and standardized blood concentration （P＜0.000 1，r＝ 0.249） of tacrolimus. After combination with voriconazole， the standardized blood drug concentration of patients who underwent single lung transplantation was significantly higher than those who underwent double lung transplantation， and the standardized blood concentration of tacrolimus after oral administration of voriconazole was significantly higher than after intravenous drip of voriconazole （P＜0.05）. Most liver and kidney function indicators showed no significant changes. The results of multiple factor regression analysis showed that the valley concentration of voriconazole had a significant impact on the standardized blood concentration of tacrolimus （P＜0.001）. CONCLUSIONS The valley concentration of voriconazole has greatest influence on the blood concentration and dose adjustment of tacrolimus， which is an independent influencing factor. In clinical practice， the dose of tacrolimus should be reduced in combination with voriconazole， and therapeutic drug monitoring should be conducted for both drugs.

Validation of a fast and reliable liquid chromatography tandem mass spectrometry for simultaneous quantitation of Voriconazole, Posaconazole and Linezolid in human serum / 中华检验医学杂志

Objective:To establish a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of voliconazole (VRC), posaconazole (PCZ), and linazolam (LNZ) in human serum.Methods:This study is a methodological validation by LC-MS/MS. The blood concentration results of VRC, PCZ, and LNZ in our hospital′s anti-infection patients were collected. Voriconazole, Posaconazole, and Linezolid were accurately weighed and prepared. Linezolid-[2H3] was used as the internal standard. After gradient elution on the ACE PFP column, the residuals were analyzed by LC-MS/MS in the positive electrospray ionization mode and multiple reaction monitor (MRM) mode. The method′s linearity, precision, lower limit of detection, and recovery rate were validated according to standard guidelines.Results:The linear correlation coefficient ( r) of the standard curve was above 0.99 ( r>0.99). The linear range of VRC and PCZ were 0.10 mg/L~10.00 mg/L, and the lower limit of detection were 0.01 mg/L. The linear range of LNZ was 0.50 mg/L~50.00 mg/L, and the lower limit of detection was 0.05 mg/L. The recoveries of VRC, PCZ and LNZ were 90.96%-103.18%, 91.84%-99.17%, and 97.04%-100.41%, respectively. Intra-and inter-batch precision (% CV) for VRC were less than 8.30%. Intra-and inter-batch precision (% CV) for PCZ was less than 9.78%. Intra-and inter-batch precision (% CV) for LNZ was less than 7.14%. Drug concentrations in 155 cases of VRC, 44 cases of PCZ, and 59 cases of LNZ were detected. Conclusion:We have established an LC-MS/MS method for the rapid, accurate, highly specific determination of VRC, PCZ, and LNZ concentrations in human serum. This method is suitable for analyzing large clinical sample sets.

Clinical characteristics and treatment of central nervous system aspergillosis: an analysis of 37 cases / 中华神经科杂志

Objective:To summarize the clinical characteristics and therapeutic efficacy of central nervous system (CNS) aspergillosis.Methods:The clinical manifestations, laboratory examination, neuroimaging features, treatment and prognosis of 37 cases of CNS aspergillosis diagnosed and treated in the First Medical Center of People′s Liberation Army General Hospital from January 2000 to January 2021 were retrospectively analyzed. According to the correlation between intracranial lesions and paranasal sinus lesions, they were divided into two groups: rhino-cerebral aspergillosis (RA, n=21) group and cerebral aspergillosis (CA, n=16) group. Results:Only 16.2% (6/37) of CNS aspergillosis patients had a clear background of immunosuppression, but 35.1% (13/37) were complicated with diabetes. The most common clinical manifestations were headache (73.0%, 27/37), cranial nerve involvement (59.5%, 22/37) and fever (37.8%, 14/37). Cerebrospinal fluid characteristics included increased pressure (53.8%, 14/26), increased white blood cell count (46.7%, 14/30), decreased glucose (30.0%, 9/30), increased protein (70.0%, 21/30), and high positive results of the metagenomic next-generation sequencing (mNGS) of pathogenic microorganism (7/10). Cranial magnetic resonance imaging showed that commonly involved sites were sinus, orbital apex, posterior orbit, cavernous sinus (43.2%, 16/37) and cerebral lobes (27.0%, 10/37). Treatment options included antifungal drugs alone (64.9%, 24/37), combination of drugs and surgery (27.0%, 10/37) and surgery alone (8.1%, 3/37). Compared with the CA group, RA group had fewer males [47.6% (10/21) vs 14/16, χ2=6.34, P=0.012] and older age [(54.2±19.4) years vs (38.4±18.4) years, t=2.50, P=0.017], and was more prone to headache [85.7% (18/21) vs 9/16, χ2=4.00, P=0.046) and cranial nerve involvement [81.0% (17/21) vs 5/16, χ 2=9.31, P=0.006]. The misdiagnosis rate of these patients in the early stage was 73.0% (27/37). A total of 29 patients (85.3%, 29/34) were treated with voriconazole successively, and the course of treatment was 3.0 (0.5, 10.4) months. Compared with salvage therapy, the mortality of primary therapy was lower (4/17 vs 9/12, χ2=7.54, P=0.006). All patients were followed up to December 2021, and 17 patients died, with a mortality rate of 45.9% (17/37). Conclusions:CNS aspergillosis may have no definite immunosuppressive background. Some of CNS aspergillosis patients are complicated with diabetes, and the clinical manifestations of the disease lack specificity, with high misdiagnosis rate in the early stage, no inflammatory changes in cerebrospinal fluid, and high positive rate of mNGS for pathogenic microorganism. Early and long-term application of voriconazole can significantly reduce the mortality rate.

Clinical efficacy of caspofungin combined with voriconazole in the treatment of older adult patients with pulmonary fungal infection / 中国基层医药

Objective:To investigate the clinical efficacy of caspofungin combined with voriconazole in the treatment of older adult patients with pulmonary fungal infection and its effects on pulmonary function and inflammatory factors.Methods:A total of 100 patients with pulmonary fungal infection admitted to Hangzhou Ninth People's Hospital from January 2016 to December 2020 were included in this study. They were randomly assigned to undergo treatment with either voriconazole (control group, n = 50) or caspofungin combined with voriconazole (observation group, n = 50) for 14 consecutive days. Clinical efficacy and changes in pulmonary function and inflammatory factors after treatment relative to before treatment were determined in each group. Results:Total response rate in the observation group was significantly higher than that in the control group [90.00% (45/50) vs. 74.00% (37/50), χ2 = 4.33, P < 0.05). After treatment, forced vital capacity, forced expiratory volume in 1 second, and maximum expiratory flow rate in the observation group were (2.31 ± 0.77) L, (79.30 ± 6.72)%, (86.14 ± 7.27)%, respectively, which were significantly higher than (1.78 ± 0.74) L, (73.22 ± 6.56)%, (78.16 ± 7.09)% in the control group ( t = 3.50, 4.57, 5.55, all P < 0.05). Tumor necrosis factor α, interleukin-6, and procalcitonin levels in the observation group were (8.32 ± 1.41) ng/L, (35.19 ± 3.40) μg/L, (1.94 ± 0.78) ng/L, respectively, which were significantly lower than (10.15 ± 1.58) ng/L, (46.09 ± 3.64) μg/L, (2.43 ± 0.84) ng/L in the control group ( t = 6.11, 15.43, 3.02, all P < 0.05). The incidence of adverse reactions in the observation group was 4.0% (2/50), which was significantly lower than 18.0% (9/50) in the control group ( χ2 = 5.00, P < 0.05). Conclusion:Caspofungin combined with voriconazole for the treatment of pulmonary fungal infection in older adult patients can effectively improve pulmonary function, inhibit the inflammatory response, and have no obvious adverse reactions with accurate clinical efficacy.

Spectrum of signs, symptoms, and treatment in amphotericin B杛esistant Trichosporon endophthalmitis: A series of ten cases of post朿ataract surgery cluster endophthalmitis

Purpose: The aim of this study was to present the signs, symptoms, management, and outcome of a series of cases of cluster endophthalmitis caused by a multi-drug resistant fungus, Trichosporon. Methods: This was a retrospective, non-randomized, consecutive interventional case series. Ten cases of postoperative endophthalmitis operated by a surgeon on three consecutive operation theater (OT) days presented 3�months after their surgery. All cases were microbiologically confirmed. The pathogen was found to be resistant to most antifungals, including amphotericin B. The cases had a latent period of around 45 days. Management of endophthalmitis included intravitreal injections, anterior chamber (AC) lavage, Pars Plana vitrectomy (PPV), posterior capsulotomy, IOL, and capsular bag removal. Multiple intravitreal injections were required due to recurrence of infections after initial improvement with voriconazole injections. Results: Structural integrity was maintained and infection-free status was achieved in all the eyes. The presenting vision ranged from 6/60 to PL (perception of light). Seven out of 10 had improvement in their final vision over the presenting vision. Final outcome of four patients had vision of 6/24 or better, 4 patients had vision in the range of 2/60 to 6/36 and 2 patients had PL. Conclusion: Trichosporon can cause devasting infections even in the immunocompetent, especially in association with implants and catheters. Triazoles form the mainstay of treatment of Trichosporon infection due to the high susceptibility of the organism in vitro. A regimen including voriconazole and amphotericin B may prove to be the most effective. This is the first report of an outbreak of cluster endophthalmitis caused by Trichosporon

Importancia de la monitorización de concentraciones plasmáticas de voriconazol y dificultad en ajuste de dosis en un paciente pediátrico / Voriconazole monitorization in pediatric patients, difficulties in dose adjustment

Resumen Presentamos el caso de un escolar de 10 años, con el diagnóstico de una recaída de una leucemia mieloide aguda que cursó con un episodio de una neutropenia febril de alto riesgo, posterior a un ciclo intensivo de quimioterapia, evolucionando con una infección fúngica invasora demostrada por histopatología. Se inició tratamiento con voriconazol intravenoso, evolucionando con concentraciones plasmáticas erráticas que requirieron sucesivos ajustes de dosis, lo que también ocurrió con la administración oral del medicamento. Finalmente, tuvo una respuesta favorable al tratamiento, a pesar de la dificultad de la dosificación para alcanzar niveles terapéuticos. La búsqueda activa y la terapia antifúngica anticipada, así como la monitorización seriada de concentraciones terapéuticas de voriconazol, permitieron un tratamiento antifúngico óptimo y oportuno, mejorando el pronóstico del paciente.

Abstract We present a 10-year-old male patient with a diagnosis of relapsed acute myeloid leukemia (AML), presenting with high-risk febrile neutropenia (HRFN), after a cycle of intensive chemotherapy, evolving with an invasive fungal infection demonstrated by histopathology. Treatment with intravenous voriconazole was started, with erratic plasmatic levels, which require successive dose adjustments which also occurred with oral administration. Finally, he had a favorable response to treatment, despite of the dosing difficulties to reach therapeutic levels. Active search as well as preemptive antifungal therapy, together with plasmatic level monitorization of voriconazole allowed a prompt recovery and improved the patient prognosis.

Evaluación de la dosificación de voriconazol intravenoso tres veces al día vs dos veces al día para el tratamiento de aspergilosis invasora en niños inmunocomprometidos: monitorización terapéutica y seguridad / Evaluation dosing intravenous voriconazole three times a day vs twice daily for the treatment of invasive aspergillosis in immunocompromised children: therapeutic drugs monitoring and safety

INTRODUCCIÓN: Voriconazol es el antifúngico de elección para el tratamiento de la aspergilosis invasora (AI). Concentraciones plasmáticas (CPs) > 1 μg/mL se han asociado a mejores resultados terapéuticos, las que no siempre se alcanzan durante el tratamiento en niños inmunocomprometidos. Dada la necesidad de iniciar una terapia precoz y efectiva de la infección, es relevante establecer el régimen de administración de voriconazol que se asocie con CPs óptimas en esta población. OBJETIVO: Comparar las CPs y seguridad de voriconazol intravenoso (IV), dosificado BID y TID en niños inmunocomprometidos con indicación de tratamiento antifúngico. MÉTODO: Estudio observacional retrospectivo de enero de 2015 a julio de 2018 en un hospital pediátrico de alta complejidad de Santiago de Chile, en pacientes de 0 a 17 años que recibieron tratamiento con voriconazol IV. Se excluyeron aquellos con terapia de reemplazo renal, falla hepática y/o falla renal. Se compararon las CPs valles entre un grupo con régimen de dosificación BID y otro grupo con administración TID. Se evaluaron las reacciones adversas en ambos grupos. RESULTADOS: Se obtuvieron 137 CPs valles en 76 niños, con una mediana de edad de 9 años (0-17 años) en el grupo BID y 9 años (0-16 años) en el grupo TID, con una mediana de peso de 27 kg (6-83 kg) y 28 kg (9,3-60 kg), respectivamente. Resultados: Pacientes 1 gg/mL en comparación con la administración BID (p = 0,001). Se reportaron ocho reacciones adversas, principalmente fotofobia, sin encontrarse diferencias significativas entre grupo BID y TID. CONCLUSIÓN: Dosificaciones TID están asociadas a una mayor probabilidad de obtener una adecuada exposición a voriconazol en pacientes < 12 años en comparación a dosificaciones BID, con baja frecuencia de reacciones adversas.

BACKGROUND: Voriconazole is the antifungal of choice for the treatment of invasive aspergillosis (IA). Plasma concentrations (PCs) > 1 μg / mL llave been associated with better therapeutic results which have not always been achieved during treatment in immunocompromised children. In the necessity to initiate early and effective therapy for the infection, it is relevant to establish the voriconazole administration regimen that is associated with optimal PCs in this population. AIM: To compare the PC and safety of intravenous (IV) voriconazole, dosed BID and TID in immunocompromised children with indication of antifungal treatment. METHOD: Retrospective observational study since January 2015 until July 2018 in a highly complex pediatric hospital in Santiago of Chile, in patients aged 0 to 17 years who received treatment with IV voriconazole. Those with renal replacement therapy, liver failure and / or renal failure were excluded. Trough PCs were compared between a group with BID dosing regimen versus another group with TID administration. Adverse reactions were evaluated in both groups. RESULTS: 137 trough PCs were obtained in 76 children, with a median age of 9 years (0-17 years) in the BID group and 9 years (0-16) in the TID group with a median weight of 27 kg (6-83 kg) and 28 kg (9.3-60 kg), respectively. Patients 1 gg/mL compared to BID administration (p = 0.001). Eight adverse reactions were reported, mainly photophobia, with no significant difference found between the BID and TID groups. CONCLUSION: TID dosages are associated with a greater probability of obtaining adequate exposure to voriconazole in patients < 12 years old compared to BID dosages, with a low frequency of adverse reactions.

Skin photosensitivity induced by Voriconazole in children with ABCB1 rs1045642 T/T genotype: a case report and literature review / 中华实用儿科临床杂志

The clinical data of a child with ABCB1 rs1045642 T/T genotype and skin photosensitivity induced by Voriconazole were analyzed retrospectively in Beijing Children′s Hospital, Capital Medical University in September 2020.Literature was reviewed to discuss the relationship between ABCB1 genetic polymorphism and Voriconazole pharmacokinetics.The patient was a 6.8-year-old boy, who was diagnosed with primary immunodeficiency disease.Long-term oral Voriconazole was administered for prevention and treatment of fungal infections.Skin photodistributed erythema and pigmentation occurred about 3-4 weeks after treatment.The skin lesions were significantly alleviated about 1 month after the withdrawal of Voriconazole.Gene test showed ABCB1 rs1045642 T/T in the patient.Some studies reported that ABCB1 rs1045642 T/T genotype reduced the clearance rate of Voriconazole.Monitoring such adverse reaction of Voriconazole in clinical practice is important. ABCB1 gene polymorphism is possible to correlate with the pharmacokinetics and adverse reactions of Voriconazole.However, further large-scale clinical studies are warranted to verify it.

Clinical neglect of aspergillosis in pulmonary tuberculosis co-infection: a case report of avoidable mortality in a resource-constrained setting

Background: Pulmonary aspergillosis (PA) is common among patients with tuberculosis (TB). With both infections presenting with similar clinical and radiologic features, diagnosis of PA is often made too late or missed completely due to lack of clinical suspicion and poor diagnostic laboratory capacity for mycotic infections prevalent in our settings. We present a case of preventable mortality caused by delayed diagnosis and treatment of PA in a patient with pulmonary TB (PTB). Case presentation: A 13-year-old female was diagnosed and treated for PTB, having received anti-TB regimen for 8 months in a mission hospital from where she was referred due to worsening cough, chest pain and progressive breathlessness. The patient was re-assessed and investigated, with GeneXpert detecting Mycobacterium tuberculosis, susceptible to rifampicin. Diagnosis of pulmonary tuberculosis complicated by right pneumothorax was made indicating an emergency thoracotomy and chest tube insertion and continuation of the first line anti-TB regimen. At about 2 weeks into admission, patients had features of superimposed acute bacterial sepsis with fever becoming high grade, marked neutrophilia with toxic granulation and elevated sepsis biomarker, and this necessitated empiric antibiotic treatment with parenteral meropenem and vancomycin. However, the patient only had mild clinical improvement following which there was progressively worsening respiratory symptoms and massive haemoptysis. Result of sputum fungal study was available on admission day 20 and revealed a growth of Aspergillus flavus. Treatment with intravenous voriconazole was however commenced rather late when the fungal respiratory disease could no longer be remedied. The patient died on admission day 23. Conclusion: Diagnosis of PA in patients with background TB is often made too late to guarantee timely and effective antifungal treatment with negative consequences on patients' outcomes. Improving clinical and laboratory capacities is essential to reducing mortality from PA in healthcare facilities.

Study on the relationship between blood concentration and efficacy of voriconazole in the treatment of pediatric invasive fungal infection / 药学实践杂志

Objective To explore the correlation between dose, blood concentration and efficacy of voriconazole in the treatment of invasive fungal infection in children. Methods 68 children treated with voriconazole during January 2019 to December 2019 were collected. The plasma concentration of voriconazole was assayed by high performance liquid chromatography (HPLC). The correlation between blood concentration and clinical efficacy was statistically analyzed. Results Different drug blood concentrations were obtained with different dosages: <4.0 mg/kg (6 cases) with the trough concentration ranged from 0.4 to 3.31 μg/ml (r=0.613, P=0.195). (4.0 - 7.0) mg/kg (44 cases), ranged from 0.35 to 7.02 μg/ml (r=0.325, P=0.018); >7.0 mg/kg (18 cases), ranged from 1.46 to 12.45 μg/ml (r=0.584，P＜0.023). There was a difference between the three groups (F=7.270, P=0.026). The relationship between the drug blood concentration and the therapeutic effect was obvious. In the <1.0 μg/ml group of 14 cases, 10 cases (71.4%) were effective, and 4 cases were ineffective. In the 1.0 - 5.5 μg/ml group of 48 cases, 44 cases (91.7%) were effective, and 4 cases were ineffective. In the >5.5 μg/ml group of 6 cases, 4 cases (66.7%) were effective and 2 cases ineffective. The difference among the three groups was obvious (χ2=5.360, P=0.039). Among the 68 cases, 58 cases (85.3%) were effective, and 10 cases (14.7%) were ineffective. Adverse reactions occurred in 10 cases (14.7%) with mild liver function injury, which did not affect the treatment and recovered with liver protection treatment. Conclusion This study showed that voriconazole was generally safe and effective in the treatment of invasive fungal infections in children. There was a significant dose-blood concentration and efficacy correlation. Further studies on pharmacokinetics and efficacy should be carried out to optimize the individualized treatment.

Clinical study of Voriconazole suspension formula for prevention and treatment of invasive fungal infection during allogeneic hematopoietic stem cell transplantation in children / 中华实用儿科临床杂志

Objective:To investigate the clinical efficacy, safety and compliance of Voriconazole suspension formula on the prevention and treatment of invasive fungal infection (IFI) in children with allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Clinical data of 25 children treated Voriconazole suspension formula for the prevention and treatment of IFI during the period of allo-HSCT in the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from August 1, 2020 to April 30, 2021 were retrospectively analyzed.The plasma trough concentration of Voriconazole was detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and the genotype of CYP2C19 was detected by polymerase chain reaction-restriction fragment length polymorphism (RFLP). The effect of CYP2C19 genotype on Voriconazole trough concentration was analyzed by rank-sum test, and Fisher′ s accurate test was used to analyze the influence of severity of gastrointestinal mucositis on serum trough concentration of Voriconazole in children with allo-HSCT. Results:A total of 25 children, including 18 males and 7 females were recruited.The median age at allo-HSCT was 6 (2-13) years.After initial administration of conventional dose of Voriconazole suspension formula during transplantation, plasma trough concentration of Voriconazole was intermittently monitored.Only 13 cases (52.0%) reached the target plasma trough concentration, 11 cases(44.0%) reached the target plasma trough concentration after adjusting the dose according to the plasma concentration, and 1 cases(4.0%) failed to reach it after increasing the dose twice.Genotype detection of CYP2C19 was performed in 20 children, involving 4 cases of poor metabolizers (PM), 9 cases of intermediate metabolizers (IM), 6 cases of extensive metabolizers (EM), and 1 case of ultra extensive metabolizer (UEM). A significant difference in plasma trough concentration was detected among all groups ( F=24.012, P<0.01). During the transplantation, 12 cases developed mild to moderate gastrointestinal mucositis, and 7 cases had severe gastrointestinal mucositis.The stan-dard rate of plasma trough concentration in children with severe gastrointestinal mucositis (1/7 cases, 14.3%)was significantly lower than those with mild to moderate gastrointestinal mucositis (9/12 cases, 75.0%) ( P=0.02). Five children (71.4%) with severe gastrointestinal mucositis could reach the target trough concentration after increasing the drug dose, suggesting that severe gastrointestinal mucositis had a great influence on the plasma concentration of Vorico-nazole suspension.The incidence of IFI in 25 children with allo-HSCT was 0, and the compliance of children taking Voriconazole dry suspension was 100.0%.The incidence of adverse reactions was 24.0% and all adverse reactions were relieved after symptomatic treatment. Conclusions:The plasma concentration of Voriconazole varies greatly among children and in different states of the same patient.Therefore, it is necessary to monitor the trough concentration of the drug and adjust the drug dose.The use of Voriconazole suspension formula for the prevention and treatment of fungal infection during allo-HSCT in children is clinically safe and effective, with a good compliance in children.

Pharmaceutical care of voriconazole combined with micafungin in the treatment of aspergillus endocarditis / 中国药房

OBJECTIV E To provide ideas for diagnosis and treatment of fungal endocarditis. METHODS The diagnosis and treatment of 1 case of aspergillus endocarditis participated by clinical pharmacists were analyzed. Clinical pharmacists suggested that blood macrogenomic next-generation sequencing （mNGS）detection and blood microbial culture should be performed to assist in the diagnosis of fungal endocarditis ；considering the mechanism ，target and safety of the drug ，it was suggested to use voriconazole combined with micafungin for antifungal treatment ；through combining with the patient ’s condition and weighing up the pros and cons ，the dose of micafungin was adjusted to 300 mg per day ；clinical pharmacists prevented ，evaluated and dealt with adverse drug reactions during treatment ，and also provided medication guidance and long-term follow-up for the patient after discharge. RESULTS The clinician adopted the advice of the clinical pharmacists. Aspergillus fumigatus was detected in blood mNGS，which bought time for early diagnosis and individualized treatment of the patient. After 1 month treatment of voriconazole combined with micafungin ，the patient ’s condition was well controlled. The alkaline phosphatase and γ-glutamyl transferase of the patient returned to normal after treatment with adenosylmethionine succinate. With the help of medication guidance ，education and discharge follow-up of clinical pharmacists ，the medication compliance of the patient was good and the condition was stable. CONCLUSIONS The clinical pharmacists participate in the diagnosis and treatment process of the patient ，formulate an individualized anti-infective treatment plan for the patient and achieve good results ，which reflect the professional ability and service level of the clinical pharmacist ，and provide ideas for the clinical treatment of fungal endocarditis.

Aspergilosis pulmonar asociada a COVID-19 en pacientes críticos: experiencia de un hospital público chileno / COVID-19-associated pulmonary aspergillosis in critically ill patients: experience of a Chilean public hospital

INTRODUCCIÓN: Se han descrito coinfecciones fúngicas por Aspergillus spp. en pacientes críticos cursando una infección por COVID-19. OBJETIVOS: Describir las características clínicas, diagnóstico, tratamiento y evolución de pacientes con síndrome de distrés respiratorio agudo con COVID-19, que cursan con aspergilosis pulmonar asociada a COVID-19 (CAPA por sus siglas en inglés) en un centro hospitalario público. Pacientes y MÉTODOS: Revisión de registros clínicos durante 12 meses en pacientes con diagnóstico de CAPA mediante cultivos de muestras respiratorias o determinación de galactomanano (GM). RESULTADOS: En 11 pacientes se diagnosticó CAPA probable (score APACHE II promedio de 11,7). Las muestras respiratorias se obtuvieron en 73% de los casos por lavado broncoalveolar y en 27% por aspirado endotraqueal. Se aisló A. fumigatus en 4 cultivos, A. niger, A. terreus y Aspergillus spp en una ocasión cada uno y los cultivos fueron negativos en 4 muestras. En 7 pacientes se realizó GM de muestras respiratorias, mediana: 3,6 (RIC: 1,71 - 4,4), en 10 pacientes se realizó GM sérica, mediana: 0,5 (RIC: 0,265 - 0,975) con 50% de ellas > 0,5. Dos pacientes mostraron hallazgos sugerentes de CAPA en la tomografía computada. Todos recibieron terapia anti-fúngica con voriconazol, con una duración promedio 14 días. Cuatro pacientes fallecieron. CONCLUSIONES: La presencia de CAPA debe ser un diagnóstico a considerar en pacientes críticos con COVID-19.

BACKGROUND: Aspergillus spp. fungal coinfections have been described in critically ill COVID-19 patients. AIM: To describe the clinical characteristics, diagnosis, treatment and evolution of patients with acute respiratory distress syndrome with COVID-19, who present with COVID-19 associated pulmonary aspergillosis (CAPA) in a single public hospital. METHODS: Retrospective review of clinical records during 12 months in patients diagnosed with CAPA by cultures of respiratory samples or determination of galactomannan (GM). RESULTS: Probable CAPA was diagnosed in 11 patients (average APACHE II score of 11.7). Respiratory samples were obtained in 73% of cases by bronchoalveolar lavage and in 27% by tracheal aspirate. A. fumigatus was isolated in 4 cultures, A. niger, A. terreus and Aspergillus spp on one occasion each and the cultures were negative in 4 samples. Respiratory sample GM was performed in 7 patients, median: 3.6 (IQR: 1.71 - 4.4). In 10 patients, serum GM was performed, median: 0.5 (IQR: 0.265 - 0.9 75) with 50% of them > 0.5. Two patients showed classic findings suggestive of CAPA on computed tomography. All received antifungal therapy with voriconazole, mean time 14 days. Four patients died. CONCLUSIONS: The presence of CAPA should be a diagnosis to be considered in critically ill COVID-19 patients.

Factores de Riesgo de Mortalidad en Pacientes Hematológicos con Aspergilosis Pulmonar en Clínica Médica Instituto de Previsión Social - Hospital Central. Año 2016 A 2018

ResumenIntroducción: Es una de las infecciones oportunistas de mayor impacto en el paciente con patologías hematooncológicas, su detección precoz y tratamiento oportuno impide su diseminación. Objetivo: Determinar factores de riesgo de mortalidad en pacientes hematológicos con aspergilosis pulmonar de pacientes internados en clínica médica en el Instituto de Previsión Social del Hospital Central durante 2016 a 2018. Metodología: Estudio observacional, descriptivo, transversal, se incluyó a pacientes con patologías hematooncológicas e infección por aspergillus internados por un periodo de tres años. Resultados: Se incluyó a 55 pacientes, con edad promedio de 57,2±19,5 años. El 36,3% con edades comprendidas entre 40 a 59 años. 52,8% fue sexo femenino. 56,3% presentó hipertensión arterial. 27,2% linfoma no Hodking. 34,5% se encontraba en fase de mantenimiento al momento del diagnóstico de aspergilosis pulmonar. Respecto al grado de neutropenia el 34,7% presentó neutropenia severa. El 83,6% fue diagnosticado a traves de TACAR y galactomanano. El tiempo de inicio de síntomas hasta el momento del diagnóstico en promedio de días fue de 12,4±4,7 días. 38,1% presentó esputo con aislamiento positivo. Del tratamiento antifúngicos el 78,2% recibió anfotericina B y 21,8% Voriconazol. En relación a la evolución clínica 50,9% fueron alta, el 25,45% requirieron de Unidad de cuidados intensivos, 23,6%obitaron. Conclusión: Las aspergilosis pulmonar se presentó con predominio femenino, la mayoría se encontraba con neutropenia severa en fase de mantenimiento quimioterápico, dos tercios fue tratado con anfotericina B y la mitad fue dado de alta médica.

AbstractIntroduction: It is one of the opportunistic infections with the greatest impact on the patient with hemato-oncological pathologies, its early detection and timely treatment prevents its spread. Objective: To determine risk factors for mortality in hematological patients with pulmonary aspergillosis of patients hospitalized in a medical clinic at the Social Security Institute of the Central Hospital during 2016 to 2018. Methodology: Observational, descriptive, cross-sectional study included patients with hemato-oncological pathologies and infection by aspergillus hospitalized for a period of three years. Results: 55 patients were included, with an average age of 57.2 ± 19.5 years. 36.3% with ages between 40 to 59 years. 52.8% were female. 56.3% presented hypertension. 27.2% non-Hodking lymphoma. 34.5% were in the maintenance phase at the time of pulmonary aspergillosis diagnosis. Regarding the degree of neutropenia, 34.7% presented severe neutropenia. 83.6% were diagnosed through TACAR and galactomannan. Symptom onset time until diagnosis on average days was 12.4 ± 4.7 days. 38.1% presented sputum with positive isolation. Of the antifungal treatment, 78.2% received amphotericin B and 21.8% Voriconazole. In relation to the clinical evolution, 50.9% were high, 25.45% required an intensive care unit, 23.6% obliged. Conclusion: Pulmonary aspergillosis presented with a female predominance, the majority were with severe neutropenia in the phase of chemotherapy maintenance, two thirds were treated with amphotericin B and half were discharged medically.