Use Of Voriconazole Research Articles

Therapeutic drug monitoring and safety of voriconazole in patients with liver dysfunction.

This study aims to describe the distribution characteristics of voriconazole (VRC) plasma trough concentrations (Ctrough) in patients with liver dysfunction, identify factors influencing VRC Ctrough, and provide recommendations for the use of VRC in this population. We retrospectively collected medical records of hospitalized patients with liver dysfunction who used VRC and underwent therapeutic drug monitoring (TDM) at the First Hospital of Changsha. The severity of liver dysfunction was assessed by the Child-Pugh (CP) score. Multiple linear regression was employed to explore factors affecting VRC Ctrough in these patients. A total of 147 Ctrough from 102 patients with liver dysfunction were analyzed. Patients were categorized into a control group (n = 40), CP-A (n = 39), CP-B (n = 11), and CP-C group (n = 12). The initial probability of target attainment of Ctrough was 70.6%, with 6.9% of patients obtaining subtherapeutic Ctrough and 22.5% obtaining supertherapeutic Ctrough. The initial Ctrough in CP-A and B were 5.05 (0.64-9.57) mg/L and 5.37 (0.26-10.01) mg/L, respectively, significantly higher than the control group (P = 0.021 and P = 0.010). The proportion of VRC Ctrough of >5.5 mg/L in CP-A and B was 33.3% and 45.5%, respectively. Multiple linear regression analysis revealed that factors such as age ≥70 years, CP class, C-reactive protein (CRP), and direct bilirubin were significantly related to the initial VRC Ctrough. Among all measurements, patients with severe inflammation (CRP >100 mg/L), aged ≥70 years, and albumin levels of <30 or <25 g/L had significantly higher VRC Ctrough. The treatment success rate of VRC was 69.6% (71 of 102), and the rate of VRC-related adverse drug reactions was 29.4% (30 of 102). The recommended half-maintenance dose may lead to elevated VRC Ctrough in patients with CP-A and CP-B. TDM is essential for patients with advanced age, severe infections, or hypoalbuminemia to prevent excessive VRC trough levels.

9336 Bone Pain Caused By Computer Cleaners Huffing

Abstract Disclosure: M. Sokrab: None. V.S. Rao: None. P. Shah: None. J.L. Shaker: None. A 47 year-old woman was evaluated 2/2024 for bone pain especially in the forearms and lower legs. The symptoms were worse since about 4/2023. Initial evaluation 11/2023 revealed elevated alkaline phosphatase levels and markers of bone remodeling (P1NP 396 ug/dl, normal; 20-101 and C-telopeptide 4389, normal; 177-1015. The plasma fluoride level was 17.1 mcmol/L (normal; &amp;lt; 4.1). There was no history of excess exposure to fluoride from dental products. She did not drink powdered iced tea or use green tea capsules. There was no industrial fluoride exposure and she consumed city water. She used inhaled fluticasone twice weekly but was not taking other fluoride containing medications, particularly voriconazole. She reported huffing computer cleaner containing difluoroethane between mid 2023 and early 2024. On examination, she had diffuse skeletal tenderness especially over her forearms and lower legs. Lab data revealed calcium 9.2 mg/dl (normal, 8.6-10.2), albumin 4 g/dl, phosphorus 3.6 mg/dl (normal, 2.5-4.5), creatinine 1.08 mg/dl (normal, 0.5-1.1), ionized calcium 1.33 mmol/l (normal, 1.18-1.33), pH normalized ionized calcium 1.25 mmol/l (normal, 1.18-1.33), PTH 126 pg/ml (normal, 15-72), 25(OH)vitamin D 29.5 ng/ml (normal, 20-50), and alkaline phosphatase 287 u/l (normal, 40-120) with a predominant elevation of the bone isoenzyme. The bone specific alkaline phosphatase was 93.4 mcg/l (normal, 7.0-22.4). The SPEP revealed a biclonal IgG Kappa monoclonal protein too small to quantify. The repeat fluoride level was 1.2 mg/l (normal, &amp;lt;0.05). Imaging included diffuse uptake on bone scan as well as periostitis/periosteal thickening involving legs, arms, and hands. There was axial osteosclerosis. Our patient appears to have skeletal fluorosis. Although the time-line of reported huffing and symptoms is not completely consistent, we could find no other exposure to fluoride and speculate she may have been huffing before she recalls. Skeletal fluorosis (SF) is endemic in some countries generally related to drinking water or tea that is high in fluoride, In the US, SF is caused by abnormal use of fluoride-containing dental products, excessive consumption of powdered iced tea containing fluoride, chronic use of the antifungal agent voriconazole and now more often huffing abuse of computer cleaners containing difluoroethane. The number of reported cases of huffing-related SF appears to be increasing and greater awareness of this problem is needed. Presentation: 6/1/2024

Limbal Subconjunctival Abscess: A Rare Complication of Acanthamoeba Keratitis.

Acanthamoeba keratitis (AK) is a rare infection affecting the cornea. Immune-mediated sclerokeratitis is a well-documented late complication often requiring systemic immunosuppression. We present an alternative clinical presentation of subconjunctival abscesses caused by direct invasion of the Acanthamoeba and a proposed management strategy. This study was a single case report performed at a tertiary care center in the United Kingdom. A 42-year-old contact lens wearer with a history of swimming in contact lenses presented with 2 days of pain, redness, and photophobia. There was clinical suspicion for AK that was later confirmed on confocal microscopy and cultures. Four months into treatment with polyhexamethylene biguanide 0.06% monotherapy, they experienced a relapse of symptoms and developed multiple subconjunctival limbal abscesses with associated scleritis. These were drained in the office, and topical treatment changed to chlorhexidine 0.2%. The aspirate was culture-positive Acanthamoeba. Despite initially improving, the abscess reoccurred within a month. Repeat drainage was performed, and topical and oral voriconazole was added to the treatment regime. The abscess resolved leaving an area of scleromalacia. Despite immune-mediated sclerokeratitis being a more common complication of AK, infectious scleritis can also occur. Correct identification of the cause of scleritis is required to prevent mistreatment of infectious scleritis with systemic immunosuppression. The abscess resolved with repeated drainage and the use of topical and systemic voriconazole.

Favorable outcome of Lasiodiplodia theobromae keratomycosis : a clinical case and systematic review

BackroudKeratitis caused by Lasiodiplodia theobromae is rare and typically associated with a poor prognosis. Current literature lacks sufficient evidence on effective management of patients with this condition.Case presentationA 74-year-old former agricultural worker presented with a red right eye, discomfort, and decreased visual acuity, progressing over three days without treatment. Examination revealed type 2 diabetes and a non-perforating, spiculated corneal abscess with a hypopyon in the right eye. Initial treatment included a triple antibiotic therapy and supportive care. Direct mycological examination identified numerous septate mycelial filaments. Antifungal treatment with natamycin and voriconazole, both topically and orally, was initiated. Cultures confirmed Lasiodiplodia theobromae. The patient showed significant improvement. Treatment continued for eight weeks, with a final visual acuity of 20/50 due to a stromal scar.ConclusionAn extensive literature review conducted in November 2023, using databases such as PubMed and Google Scholar with the keywords “lasiodiplodia” and “keratitis” yielded no previous cases of this specific condition being managed solely with the combined use of natamycin and voriconazole. This antifungal combination is commonly included in most management protocols for fungal keratitis. Factors such as the use of corticosteroids and delayed diagnosis were noted to adversely affect the prognosis. This case and this systematic review underscores the potential for non-surgical management options in severe fungal keratitis.

Retrospective evaluation of voriconazole treatment in psittacines: 14 cases (2012-2023).

To retrospectively evaluate the clinical use of voriconazole in psittacine patients for the treatment of suspected respiratory fungal infections. 14 client-owned psittacine birds. Medical records were searched from 2012 to 2023 for voriconazole use in psittacines. Species, age, clinical signs, physical examination findings, CT reports, bloodwork results, treatment, and outcome were obtained from the records or client follow-up. African grey parrots were the most prevalent species (8/14). Dyspnea (9/14) and abnormal respiratory auscultation (11/14) were the most common examination abnormalities. An initial CT was performed in all cases, and pneumonia (10/14) and air sac disease (9/14) were the most common findings, with 8 cases having both pulmonary and air sac disease. Voriconazole doses ranged from 10 to 21 mg/kg (median, 16 mg/kg), with most cases prescribed as every-12-hour frequency (12/14). Three of 14 (21%) cases died or were euthanized within 24 days of diagnosis. One case was euthanized at 311 days, and 6 cases were lost to follow-up. Four of 14 (29%) cases lived > 12 months from diagnosis. Two of these cases cleared clinical infection after receiving voriconazole at 17 to 18 mg/kg (q 12 h). No adverse effects attributable to voriconazole were reported. Voriconazole can be safely used for the treatment of suspected fungal respiratory infection in psittacines. However, the prognosis for resolution is guarded, and prolonged treatment and repeated diagnostic imaging are necessary in many cases.

Coadministration of Voriconazole and Rifabutin Can Increase the Risk of Adverse Drug Reactions in Patients with Multiple Infections.

Coinfection of tuberculosis or nontuberculous mycobacteria and Aspergillus presents a challenge in medication selection because of the pharmacokinetic interactions between rifampin and voriconazole. Some researchers have suggested the use of rifabutin as an alternative to rifampin because of its lower hepatic cytochrome P450 enzyme induction potency despite its contraindication to drug labels. This study presents clinical cases of voriconazole and rifabutin coadministration and their potential risks. This retrospective study was conducted using clinical data from patients who met the following criteria: (1) admitted to Seoul National University Hospital between July 2014 and August 2023 and (2) concurrently administered rifabutin and voriconazole for more than 5 days. Among the 6 patients analyzed, 4 experienced adverse drug reactions (ADRs). Three patients experienced visual and auditory hallucinations, lower extremity numbness, or delirious behavior. Two patients had prolonged the time from the start of the Q wave to the end of the T wave intervals, and 1 had elevated aspartate aminotransferase and alanine aminotransferase levels. In addition, 2 patients experienced severe nausea, poor oral intake, and weight loss. Despite receiving 1.81-fold the recommended voriconazole dosage, a therapeutic concentration (1.0-5.5 mg/L) was not achieved because of cytochrome P450 induction by rifabutin. However, during septic shock, the voriconazole concentration increased by 13.7- to 36-fold. Concurrent use of rifabutin and voriconazole was associated with ADRs, including the time from the start of the Q wave to the end of the T wave prolongation, hallucinations, and severe nausea. Moreover, initially, there was a significant decrease in voriconazole concentrations; however, these concentrations substantially increased during septic shock. Therefore, it is essential to monitor drug concentrations and ADRs during concurrent use of voriconazole and rifabutin.

The Effect of Rifapentine and Rifampicin on Serum Voriconazole Levels Persist for 5 Days and 7 Days or More After Discontinuation in Tuberculosis Patients with Chronic Pulmonary Aspergillosis.

Voriconazole, a first-line therapeutic agent for chronic pulmonary aspergillosis, is metabolized by the cytochrome 450 enzymes, specifically CYP2C19 and CYP3A4. Rifampicin and rifapentine act as inducers of the cytochrome P450 enzyme. The current study explored the potential drug interactions arising from the co-administration of voriconazole with either rifampicin or rifapentine, as well as the duration of this effect on serum voriconazole levels after discontinuation of rifampicin or rifapentine. A retrospective study was conducted in tuberculosis patients with chronic pulmonary aspergillosis. These patients underwent a combination therapy involving voriconazole and rifampicin or rifapentine, or they were treated with voriconazole after discontinuation of rifampicin or rifapentine. The serum concentrations of voriconazole at steady-state were monitored. Data on demographic characteristics and the serum voriconazole levels were used for statistical analyses. A total of 124 serum voriconazole concentrations from 109 patients were included in the study. The average serum concentration of voriconazole fell below the effective therapeutic range in patients treated with both voriconazole and rifampicin or rifapentine. Notably the co-administration of rifapentine led to a substantial (>70%) decrease in serum voriconazole levels in two patients. Moreover, this interfering effect persisted for at least 7 days following rifampicin discontinuation, while it endured for 5 days or more after discontinuation of rifapentine. Concomitant use of voriconazole and rifampicin or rifapentine should be avoided, and it is not recommended to initiate voriconazole therapy within 5 or 7 days after discontinuation of rifapentine or rifampicin. Therapeutic drug monitoring not only provides a basis for the adjustment of clinical dose, but also serves as a valuable tool for identifying drug interactions.

Successful Treatment of Disseminated Fusariosis in a 15-Month-Old Boy With Refractory Acute Lymphoblastic Leukemia Using High-Dose Voriconazole.

Infections due to rare molds, such as Fusarium spp., cause severe and difficult-to-control diseases with increasing frequency. Data on fusariosis in children and on the use of voriconazole (VCZ), considered a drug of choice, are scarce in infants and children <2 years of age. We present the first, to our knowledge, pediatric case of disseminated mycosis due to Fusarium musae in a 15-month-old boy with relapsed/refractory acute lymphoblastic leukemia, diagnostics and outcome. Herein, at this severely immunocompromised patient, after prompt diagnosis, disseminated fusariosis was successfully treated with high-dose VCZ at a final dose of 15 mg/kg of body weight twice a day. This occurred by achieving adequate drug exposures as determined by drug susceptibility testing and followed by therapeutic drug monitoring without observed toxicity. Appropriate diagnostic approach and timely administration of optimal antifungal therapy with VCZ were important for the successful treatment of disseminated fusariosis. Therapeutic drug monitoring, especially in <2-year-old children, is necessary to achieve sufficient drug exposure for optimal therapeutic response without toxicity.

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4years old after liver transplantation and to develop individualized tacrolimus dosing software. A total of 663 blood concentrations from 85 patients aged 4.57months to 3.97years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Associations of cumulative voriconazole dose, treatment duration, and alkaline phosphatase with voriconazole-induced periostitis.

To investigate the associations of cumulative voriconazole dose, treatment duration, and alkaline phosphatase with voriconazole-induced periostitis. One hundred and thirty-one patients with voriconazole use were identified using a clinical informatics tool. Health record data including age, sex, immune status, alkaline phosphatase, voriconazole levels, voriconazole dose, frequency, and treatment duration were collected. Imaging studies during the duration of treatment were reviewed by two radiology trainees and imaging features of voriconazole-induced periostitis were confirmed by a board-certified musculoskeletal radiologist. The length, location in the body, location in the bone, type, and morphology of periostitis lesions were recorded. Incident voriconazole-induced periostitis was defined as new periostitis on imaging after 28days or more of voriconazole treatment in the absence of an alternative diagnosis. Univariate Firth's logistic regression models were performed using cumulative voriconazole dose, treatment duration, and average ALP as predictors and incident VIP as the outcome. There were nine patients with voriconazole-induced periostitis and 122 patients without voriconazole-induced periostitis. The most common lesion location in the body was the ribs (37%) and morphology was solid (44%). A 31.5-g increase in cumulative voriconazole dose was associated with 8% higher odds of incident periostitis. Increased treatment duration (63days) and higher average alkaline phosphatase (50IU/L) were associated with 7% higher odds of periostitis and 34% higher odds of periostitis, respectively. Increased cumulative voriconazole dose, treatment duration, and average alkaline phosphatase were associated with higher odds of voriconazole-induced periostitis.

Posaconazole versus voriconazole as antifungal prophylaxis for invasive fungal diseases in patients with hematological malignancies.

The incidence of invasive fungal diseases (IFDs) has risen in hematologic malignancy patients due to neutropenia. While posaconazole is recommended as the first-line antifungal prophylaxis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and voriconazole is an alternative, there is currently no direct comparison data available to assess their relative effectiveness. We retrospectively reviewed eligible patient charts from January 2017 to February 2019 to identify breakthrough IFD rates, drug adverse event frequency, and drug acquisition cost in AML/MDS patients. Forty-eight patients received 130 chemo cycles, with 50 (38%) cycles prescribed posaconazole and 80 (62%) prescribed voriconazole as primary IFD prophylaxis. The incidence rates of IFD in the posaconazole group were 8% (4 out of 50), of which two were probable and two were possible infections, while 6.26% (5 out of 80) of patients in the voriconazole group developed IFD, with four possible infections and one probable infection (p = 0.73). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events, with six patients compared to two patients in the posaconazole group (p = 0.15). The drug acquisition cost of posaconazole is 5.62 times more expensive than voriconazole. The use of voriconazole instead of posaconazole for 130 chemo cycles would save $166,584.6. Posaconazole and voriconazole have comparable efficacy and safety in preventing IFD in AML and MDS patients receiving chemotherapy. However, posaconazole is more costly than voriconazole.

P-78 Life-threatening fungal infection due to long term glucocorticoid usage in amiadarone thyrotoxicosis

Abstract Introduction Amiadorone-associated thyroiditis (AIT) has 2 subtypes. In type 1, there is usually underlying thyroid disease and thyrotoxicosis occurs due to increased hormone synthesis. In type 2, thyrotoxicosis occurs as a result of T4-T3 release due to destruction(1). Steroid use is recommended in the treatment of AIT. Steroids may cause infections by affecting both innate and acquired immunity. If the patient has other comorbidities, long-term hospitalization, type 2 diabetes mellitus or lymphopenia, these factors may also predispose to infection(2). Clinical Case V.E., age 63, male. The patient was diagnosed atrial fibrillation 4 years ago and was started on amiadorone. After 3 years of amiadorone use, amiadorone was discontinued in January 2023. In April, thyrotoxicosis was detected in an external center where he went with complaint of weight loss. The patient was considered to have amiadorone-associated thyroiditis and methyl prednisolone treatment was started. He used approximately 2 grams of steroid and methimazole 2×15 mg regularly for 2 months. During the period of steroid use, TSH value was always suppressed and T4 value was always 3-4 times the reference value. With the use of methyl prednisolone, severe myopathy developed especially in the proximal muscles and steroid induced diabetes was diagnosed. The patient was admitted to our hospital on 06.07.2023.TSH value was found to be suppressed and T4&amp;gt;100 pmol/liter (reference:11-22). On admission examination, there were diffuse candida plaques in the mouth. On pulmonary examination, rales were heard in the right lung and voriconazole was started because of fungal infection in the right hilar region on tomography. Steroid was discontinued and methimazole was increased to 2×30 mg in the patient who was thought to have fungal infection and had severe myopathy. Cholestyramine was added to his treatment. Voriconazole was discontinued in the patient who had visual hallucinations after 5 days of voriconazole use. During follow-up, the patient developed hypoxia 6 days later and a newly developed cavity in the lower lobe of the right lung was observed in the tomography. The findings were evaluated in favor of fungal pneumonia in the foreground and amphotericin B was started with the recommendation of infectious diseases. Galactomannan, aspergillus and Quantiferon tests were negative. The patient was consulted to pulmonology department because of the newly developed cavity and fiberoptic bronchoscopy was planned. Bronchoscopy showed no appearance suggestive of malignancy. Tuberculosis PCR was negative. T4 values and acute phase reactants completely regressed under treatment and the patient was discharged. Conclusion Steroid treatment is used in AIT type 2 and in cases of indistinguishable AIT, but it should not be ignored that this treatment has its own side effects. Especially, not giving steroids for a long time and trying to reduce the dose as soon as possible will be important in reducing steroid-related side effects.

Nomogram for the prediction of tigecycline-induced hypofibrinogenaemia in a Chinese population

Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced hypofibrinogenaemia, it remains unknown whether valproic acid or voriconazole in combination with tigecycline is associated with the decrease in fibrinogen, as both drugs could lead to coagulation disorders. The aim of this study was to develop a nomogram for the prediction of tigecycline-induced hypofibrinogenaemia. This was a multi-centre retrospective case-control study. The primary outcome was the accurate prediction of tigecycline-induced hypofibrinogenaemia. Nomograms were developed from logistic regression models with least absolute shrinkage and selection operator regression for variable selection. Model performance was assessed via calibration plots, and models were validated internally using bootstrapping on a validation cohort. In total, 2362 patients were screened, of which 611 were eligible for inclusion in this study. These 611 patients were divided into the training cohort (n=488) and the validation cohort (n=123). Predictors included in the nomogram for the total population were total dose, age, fibrinogen, prothrombin time (PT), comorbidity, and concomitant use of voriconazole. Total dose, fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concomitant use of voriconazole were selected to predict hypofibrinogenaemia in patients with malignant haematologic diseases. Both models were calibrated adequately, and their predictions were correlated with the observed outcome. The cut-offs for treatment duration in the total population and the subgroup were 10 and 6 days, respectively. Tigecycline in combination with voriconazole could increase the risk of hypofibrinogenaemia, and tigecycline-induced hypofibrinogenaemia is more likely to occur in patients with malignant haematologic diseases.

Clinical Features and Outcomes of Invasive Fusariosis in Pediatric Patients with Acute Lymphoblastic Leukemia (ALL): A Case Series in a Single Tertiary Center in North-Eastern Mexico

Abstract Background Fusariosis is a pathology that is of great clinical concern in certain at-risk patient groups. Pediatric patients with ALL are in the greatest at-risk population as they are frequently in a post-chemotherapy state. The diagnosis for IFIs can be carried out by the criteria established in the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) and the notable intrinsic resistance of the Fusarium species to most of the antifungal agents available lead to high mortality rates in immunocompromised patients. Starting in 2002, the use of voriconazole was approved as empiric monotherapy as a first line therapy for the treatment of disseminated fusariosis. Other options are liposomal amphotericin B (LAB), Posaconazole or Isavuconazole. There are a few reports combined antifungal treatment in a pediatric population. In pediatric patients, the empirical and specific antifungal treatment is mostly inferred from clinical experience in adult patients. Methods We identified six patients with culture-proven fusariosis at a tertiary healthcare center in North-Eastern Mexico from May 2018- August 2021. We reported six cases of fusariosis categorized according to the EORTC/MSG. B cell ALL diagnosis was defined as a positive result in a B-cell leukemia panel. In terms of the descriptive statistics, continuous variables were reported as medians and [Interquartile range], while categorical variables were described via counts, frequencies, and (prevalence). Results The median age was 8 [6-12], 2 of the patients were female. All of the included patients were in the remission induction phase of their therapy and all patients had a confirmed B cell ALL and all patients presented with neutropenia. Four patients had a central venous catheter present, 3 of patients had a bacterial co-infection (E. coli, S. pneumoniae, Klebsiella blee). LAB was given as empirical therapy in 3 of patients while one patient received a combination of amphotericin B and voriconazole and the remaining patient received voriconazole monotherapy. Five patients had resistance to LAB, two patients showed voriconazole resistance. The definitive treatment was LAB plus Voriconazole in 5 (83.3%) patients. Five (83.3%) patients survived. Conclusions There are no clearly established guidelines for treatment options for fusariosis in pediatric patients. The majority of our reported patients presented with LAB-resistance and the combination of LAB with voriconazole has been used to control this pathology. There is still much more to explore and further research is needed into the indicated treatment plan and the susceptibility and therapeutic strategy for this specific population.

Hypokalemia and Hyponatremia in Adult Patients Receiving Voriconazole Therapeutic Drug Monitoring.

Hypokalemia and hyponatremia are common but easily ignored adverse events in treatment with voriconazole (VCZ) that can lead to serious consequences. We intend to investigate the incidence of VCZ-induced hypokalemia and hyponatremia and their risk factors based on real-world data. A prospective study was conducted. A total of 272 patients with 414 VCZ plasma trough concentrations (C0) and VCZ N-oxide concentrations (CN) were included. The incidence of hypokalemia was 18.0% (48/266). A total of 81.2% (39/48) of patients developed hypokalemia within 14days, whereas 56.2% (27/48) of patients developed hypokalemia within 1week. The proportion of female patients in the hypokalemia group was higher than that in the nonhypokalemia group, as was the proportion of patients receiving intravenous VCZ. In the multivariate analysis, the independent risk factors for hypokalemia were sex, combined use of antibiotics, and VCZ CN/C0. The incidence of hyponatremia was 7.9% (21/266). The proportion of patients over 47years of age in the hyponatremia group was 71.4% (15/21). The number of days of VCZ use in the hyponatremia group was greater than that in the nonhyponatremia group. A total of 47.6% (10/21) of patients in the hyponatremia group had supratherapeutic VCZ C0 (>5.0µg/mL). In conclusion, hypokalemia is more likely to occur in females, in patients receiving intravenous VCZ, and in patients with the combined use of antibiotics. Hyponatremia is more likely to occur in patients older than 47years who have been using VCZ for a long time and have higher VCZ C0 values.

Necessity for a System Implementing Therapeutic Drug Monitoring in Outpatient Settings Based on the Actual Use of Voriconazole Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan: A Descriptive Epidemiological Study.

Voriconazole (VRCZ) is an antifungal drug that necessitates therapeutic monitoring (TDM). Typically, TDM is recommended for patients undergoing long-term outpatient treatment. However, in Japan, insurance reimbursement for TDM is only permitted for inpatients. There is a concern that VRCZ use is growing among outpatients, although information regarding this issue remains unavailable. Therefore, we aimed to clarify the use of VRCZ by utilizing data from the National Database of Health Insurance Claims and Specific Health Checkups in Japan. The use of branded and generic oral VRCZ from 2013 to 2019 was calculated using the defined daily doses/1000 inhabitants/d (DID) for each receipt type. Oral VRCZ was used more frequently in the outpatient setting than that in the inpatient setting, with use increasing over time. The use of generic drugs began in 2016 and accounted for 52.5% of the use in 2019 among outpatients. Considering outpatient prescriptions, 76.4-81.0% were dispensed at insurance pharmacies, indicating the need for community pharmacist involvement. Accordingly, the appropriate use of VRCZ in ambulatory care should be promoted in collaboration with community pharmacists, and a reimbursement system should be established to implement TDM in ambulatory care.

Factors Influencing and Adverse Reactions of Voriconazole Clearance in Patients with Hematological Diseases

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. 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. 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). 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.

Comparing the Real-World Use of Isavuconazole to Other Anti-Fungal Therapy for Invasive Fungal Infections in Patients with and without Underlying Disparities: A Multi-Center Retrospective Study

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with underlying malignancies and prior transplants. FDA approved Isavuconazole as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. This study aims to compare the real-world clinical outcomes and safety of isavuconazole to voriconazole and an amphotericin B-based regimen in patients with underlying malignancies and a transplant. In addition, the response to anti-fungal therapy and the outcome were compared among patients with a disparity (elderly, obese patients, patients with renal insufficiency and diabetes mellitus) versus those with no disparity. We performed a multicenter retrospective study, including patients with cancer diagnosed with an invasive fungal infection, and treated primarily with isavuconazole, voriconazole or amphotericin B. Clinical, radiologic findings, response to therapy and therapy related adverse events were evaluated during 12 weeks of follow-up. We included 112 patients aged 14 to 77 years, and most of the IFIs were classified into definite (29) or probable (51). Most cases were invasive aspergillosis (79%), followed by fusariosis (8%). Amphotericin B were used more frequently as primary therapy (38%) than isavuconazole (30%) or voriconazole (31%). Twenty one percent of the patients presented adverse events related to primary therapy, with patients receiving isavuconazole presenting less adverse events when compared to voriconazole and amphotericin (p < 0.001; p = 0.019). Favorable response to primary therapy during 12 weeks of follow-up were similar when comparing amphotericin B, isavuconazole or voriconazole use. By univariate analysis, the overall cause of mortality at 12 weeks was higher in patients receiving amphotericin B as primary therapy. However, by multivariate analysis, Fusarium infection, invasive pulmonary infection or sinus infection were the only independent risk factors associated with mortality. In the treatment of IFI for patients with underlying malignancy or a transplant, Isavuconazole was associated with the best safety profile compared to voriconazole or amphotericin B-based regimen. Regardless of the type of anti-fungal therapy used, invasive Fusarium infections and invasive pulmonary or sinus infections were the only risk factors associated with poor outcomes. Disparity criteria did not affect the response to anti-fungal therapy and overall outcome, including mortality.

Effectiveness of Voriconazole in Treating Fungal Keratitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

&#x0D; &#x0D; &#x0D; &#x0D; Antifungal intervention fails in approximately half of fungal keratitis patients, demonstrating its limitations. Voriconazole use for fungal keratitis has raised new interest because of its broad spectrum and good ocular penetration. However, its effectiveness has not been systematically evaluated. Here we try to clarify the benefits of voriconazole in fungal keratitis cases. Randomized controlled trials (RCTs) comparing vorico­nazole to placebo or other antifungal medications for fungal keratitis were searched in several databases, in­cluding PubMed, Scopus, Cochrane Library, ClinicalTrials, and WHO-ICTRP. The primary outcome that analyzed was best spectacle-corrected vision acuity (BSCVA). The secondary outcomes were treatment success, corneal perforation or need for therapeutic penetrating keratoplasty (TPK). From 621 records, nine studies were se­lected for analysis. The results were as follows: As an initial therapy, topical natamycin outperformed vori­conazole in BSCVA (mean difference = 0.14; 95% CI 0.02 to 0.26; P =.03). Voriconazole also has a greater risk of corneal perforation or TPK than natamycin (RR=1.69; 95% CI 1.11 to 2.58; P=.02). As an adjuvant, there is no significant difference found in BSCVA, treatment success, event of corneal perforation, or need for TPK between voriconazole and the other antifungal agents (itraconazole, ketoconazole, amphotericin B, natamy­cin, and placebo). This study shows that voriconazole is less superior than natamycin in treating early infec­tions of fungal keratitis. More RCTs with larger samples are needed to evaluate voriconazole's adjuvant efficacy.&#x0D; &#x0D; &#x0D; &#x0D;

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.