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A novel, sensible, rapid, reliable and economical analytical hyphenated LC-MS/MS method has been developed as a key for the safety surveillance in chronic leukemia patients, and as a part of therapeutic drug monitoring of imatinib mesylate in human saliva. Imatinib mesylate or imatinib methane sulfonate is a tyrosine kinase inhibitor, apoptosis inducer and also known to be an anticoronaviral agent. Imatinib mesylate is a monomesylate salt of imatinib used for the treatment of gastrointestinal tumors and chronic myelogenous leukemia, and also in other complex malignancies. The lmax of imatinib mesylate was observed at 258 nm by UV spectrometry, establishing a very good linearity along with sensitivity. The detection limit (LOD) =0.2925 µg mL-1 and quantitation limit (LOQ)= 0.8977 µg mL-1 were obtained from the linear concentrations taken in the range of 2-12 µg mL-1. The correlation coefficient (r2) found was 0.999. The method validation parameters according to ICH Q2 (R1) were performed. The developed method described here, UPLC-MS/MS, was found to be novel, sensitive and rapid with improved results when successfully tested for human saliva samples without significant differences in the steady state imatinib mesylate concentrations. Current method could overcome the safety issues during therapeutic drug monitoring and pharmacokinetic behavior of the drug when tested clinically. [ABSTRACT FROM AUTHOR]

Background: The antiviral letermovir has been increasingly used as off‐label cytomegalovirus prophylaxis in solid organ transplant recipients. Observational studies have reported notable increases in tacrolimus (FK) exposure following letermovir; however, whether a significant interaction occurs in the setting of existing moderate‐to‐strong CYP3A4 inhibition is unknown. Therefore, the purpose of this study was to evaluate FK trough changes before and after letermovir among lung transplant recipients receiving azole antifungal prophylaxis. Methods: This retrospective cohort study included lung transplant recipients newly initiated on letermovir between 2019–2022 following valganciclovir intolerance. Tacrolimus doses and concentrations were collected up to 30 days before and after the letermovir start date. No pre‐emptive FK dose adjustments occurred prior to letermovir initiation. Patients admitted to the hospital or lacking an appropriately timed trough in the pre‐ or post‐period were excluded. Results: A total of 78 lung transplant recipients receiving FK (1.5 mg median total daily dose) and itraconazole (56.4%), isavuconazole (25.6%) or posaconazole (17.9%) prophylaxis were included. Letermovir was started at a median of 8.4 months post‐transplant. The pre‐/post‐letermovir median FK trough was 9.6/9.0 ng/mL (p =.151), median dose‐corrected trough was 4.2/4.7 ng/mL/mg (+11.9%, p =.032), and median weight‐based dose‐corrected trough was 362/326 [ng/mL]/[mg/kg/day] (‐9.9%, p =.036). There was no significant difference in the proportion of patients within their goal trough range before and after letermovir initiation (62% vs. 72%, p =.229). Conclusion: Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate‐to‐strong CYP3A4 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Aspergillus species cause a variety of serious clinical conditions with increasing trend in antifungal resistance. The present study aimed at evaluating hospital epidemiology and antifungal susceptibility of all isolates recorded in our clinical database since its implementation. Methods: Data on date of isolation, biological samples, patients' age and sex, clinical settings, and antifungal susceptibility tests for all Aspergillus spp. isolated from 2015 to 2022 were extracted from the clinical database. Score test for trend of odds, non-parametric Mann Kendall trend test and logistic regression analysis were used to analyze prevalence, incidence, and seasonality of Aspergillus spp. isolates. Results: A total of 1126 Aspergillus spp. isolates were evaluated. A. fumigatus was the most prevalent (44.1%) followed by A. niger (22.3%), A. flavus (17.7%) and A. terreus (10.6%). A. niger prevalence increased over time in intensive care units (p-trend = 0.0051). Overall, 16 (1.5%) were not susceptible to one azole compound, and 108 (10.9%) to amphotericin B, with A. niger showing the highest percentage (21.9%). The risk of detecting A. fumigatus was higher in June, (OR = 2.14, 95% CI [1.16; 3.98] p = 0.016) and reduced during September (OR = 0.48, 95% CI [0.27; 0.87] p = 0.015) and October as compared to January (OR = 0.39, 95% CI [0.21; 0.70] p = 0.002. A. niger showed a reduced risk of isolation from all clinical samples in the month of June as compared to January (OR = 0.34, 95% CI [0.14; 0.79] p = 0.012). Seasonal trend for A. flavus showed a higher risk of detection in September (OR = 2.7, 95% CI [1.18; 6.18] p = 0.019), October (OR = 2.32, 95% CI [1.01; 5.35] p = 0.048) and November (OR = 2.42, 95% CI [1.01; 5.79] p = 0.047) as compared to January. Conclusions: This is the first study to analyze, at once, data regarding prevalence, time trends, seasonality, species distribution and antifungal susceptibility profiles of all Aspergillus spp. isolates over a 8-year period in a tertiary care center. Surprisingly no increase in azole resistance was observed over time. [ABSTRACT FROM AUTHOR]

Background: Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein. Methods: In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose‐adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild‐type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7–161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]). Results: The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)—ratio of GMRs 1.61 (95%CI 1.23–2.11) (frequentist) and 1.63 (95%CrI 1.26–2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low. Conclusion: Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine. [ABSTRACT FROM AUTHOR]

The capacity to form biofilms is a common trait among many microorganisms present on Earth. In this study, we demonstrate for the first time that the fatal pine pitch canker agent, Fusarium circinatum, can lead a biofilm‐like lifestyle with aggregated hyphal bundles wrapped in extracellular matrix (ECM). Our research shows F. circinatum's ability to adapt to environmental changes by assuming a biofilm‐like lifestyle. This was demonstrated by varying metabolic activities exhibited by the biofilms in response to factors like temperature and pH. Further analysis revealed that while planktonic cells produced small amounts of ECM per unit of the biomass, heat‐ and azole‐exposed biofilms produced significantly more ECM than nonexposed biofilms, further demonstrating the adaptability of F. circinatum to changing environments. The increased synthesis of ECM triggered by these abiotic factors highlights the link between ECM production in biofilm and resistance to abiotic stress. This suggests that ECM‐mediated response may be one of the key survival strategies of F. circinatum biofilms in response to changing environments. Interestingly, azole exposure also led to biofilms that were resistant to DNase, which typically uncouples biofilms by penetrating the biofilm and degrading its extracellular DNA; we propose that DNases were likely hindered from reaching target cells by the ECM barricade. The interplay between antifungal treatment and DNase enzyme suggests a complex relationship between eDNA, ECM, and antifungal agents in F. circinatum biofilms. Therefore, our results show how a phytopathogen's sessile (biofilm) lifestyle could influence its response to the surrounding environment. [ABSTRACT FROM AUTHOR]

Background: In the second wave of COVID-19 pandemic, there has been an increase in number of cases with Post-COVID-19 fungal osteomyelitis of jaws. Aspergillosis was found to be one of the causes of osteomyelitis of jaw bones in these patients. Aim: To evaluate the incidence and pattern of osteomyelitis of jaw due to aspergillosis in post-COVID-19 patients and to discuss the management protocol of the same. Method: Data were obtained at our institution from the period of January 2021 to June 2021. Patients of all age groups with Post-COVID-19 osteomyelitis of jaw due to aspergillosis and those with combined aspergillosis and mucormycosis infection were included. Patients having rhino-orbito-cerebral fungal infection were excluded. Results: A total of 47 patients reported to our center. Demographically the average age of the patients was 49.11 years with 72% being males. All 47 patients (N = 100%) had received steroids. 21 of them (N = 44.7%) had diabetes mellitus and 14 (N = 29.8%) patients had other comorbidities. Out of 47 patients, 42 (N = 89.7%) patients were diagnosed with aspergillosis and the remaining 5 (N = 10.3%) cases had a mixed fungal infection of mucormycosis and aspergillosis. On fungal culture Aspergillus flavus was the most common species detected followed by Aspergillus niger and Aspergillus fumigatus. All patients were treated with oral Voriconazole and local surgical debridement. Prompt laboratory testing such as a timely KOH mount, galactomannan test, beta-D-glucan test, histopathology of tissue specimens could help to give an early and definitive diagnosis. The mortality rate we encountered in this study was nil. Conclusions: Early and definitive diagnosis and immediate initiation of antifungal drug therapy and surgical intervention will significantly reduce the rate of morbidity and mortality. [ABSTRACT FROM AUTHOR]

Copyright of Revista de la Facultad de Medicina Humana is the property of Instituto de Investigaciones en Ciencias Biomedicas de la Universidad Ricardo Palma and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Dermatophyte infections are common in tropical areas with a humid climate. In recent times, it is getting extremely challenging to treat these infections because of resistance that has occurred to the conventional antifungals, which is attributed to changes in the fungal strains. Keeping in view this issue, more advanced drugs have come into being. Voriconazole is a potential such drug with promising results. Methods: A total of 76 patients participated in the study, they were divided into two groups, with 38 participants in each group. Group A was treated with voriconazole and group B was treated with itraconazole, for 2 weeks in patients who achieved a complete response, and 4 weeks for patients who achieved a partial response. Baseline complete blood count, Liver function tests, renal function tests, blood sugar levels, and KOH microscopy was done for every patient, and was repeated after completion of treatment. Clinical response was assessed on the basis of clearance of the lesion and negativity on KOH microscopy. Results: After completion of treatment with voriconazole, 32 (84.2)% of the patients achieved a complete clearance of the lesion, while 6(15.8%) of the participants achieved partial response to the treatment. Among the patients who received oral itraconazole, 6 (15.7%) showed a complete response, 16 (42.1%) participants achieved a partial cure, while 16 (42.2%) patients did not show any improvement after the treatment. Conclusion: It is safe to conclude, that voriconazole shows better efficacy and results in treating resistant dermatophyte infections. [ABSTRACT FROM AUTHOR]

The patient was a 32-year-old woman who presented with “right eye vision loss with floating dark shadow for 10 days”. The patient had a history of anemia, a hemoglobin of 71.0g/L, and no history of other systemic diseases. The best corrected visual acuity was 0.05 and 1.0 in the right (OD) and left eye (OS), respectively. In the right eye, the conjunctival was mildly congested with significant anterior chamber reaction (Tyndall (+++)) and 1mm hypopyon. The vitreous was moderately cloudy and the fundus examination revealed a blurred view of flat retina. Optical coherence tomography (OCT) in the right eye showed a localized proliferative epiretinal membrane in the temporal macula, and the signal below is obscured. Fluorescein fundus angiography showed slight leakage of fluorescence in the late phase from retinal vessels in the right eye. The patient was initially diagnosed with right uveitis, which improved after local glucocorticoid therapy. More than 1 month later, the patient returned to the doctor due to continued and worsening vision loss in both eyes. The visual acuity decreased to FC/BE (OD) and FC/50cm (OS). The fundus was indistinct due to vitreous opacity in the right eye. Tyndall was positive with a 0.5 mm hypopyon and moderately cloudy vitreous body in the left eye. The fundus was blurred and a suspected yellowish-white lesion was observed between the optic disc and macula in this eye. To determine the cause, the patient was treated with vitrectomy combined with epiretinal membrane stripping on right eye. The vitreous obtained during the operation was smeared and cultured for bacteria and fungi. At the same time, the vitreous was sent for metagenomic next-generation sequencing, which showed Candida albicans (+). It was confirmed by further G-test, even though the smear and culture results were negative. The revised diagnosis was bilateral endogenous fungal endophthalmitis (EFE), and examination revealed that the patient had fungal vaginitis. The patient was immediately treated with bilateral intravitreal injection of voriconazole combined with systemic voriconazole. After that, vitrectomy combined with epiretinal membrane peeling was performed in the left eye due to no significant improvement. Thereafter, the patient’s binocular symptoms improved, visual acuity increased, and there has being no recurrence so far. Discussion and experience: Endogenous fungal endophthalmitis is easily misdiagnosed as uveitis in the early stage, especially in patients with no underlying disease. It is necessary to improve the awareness of this disease, carefully inquire about patients’ history, initiate antifungal treatment as soon as possible, and consider vitrectomy if necessary. [ABSTRACT FROM AUTHOR]

What is Known and Objective. Voriconazole (VRC) increases the blood concentration of Tacrolimus (TAC). However, the patterns of changes in TAC trough concentration (TAC C0) and dose-adjustment regimens after VRC discontinuation have not been reported. We aimed to explore the changing pattern of TAC C0 after VRC discontinuation and provide strategies for TAC dose adjustment and blood concentration monitoring in renal transplant recipients. Methods. The clinical data of 46 renal transplant patients pre- and during VRC medication and VRC discontinuation were retrospectively recorded, including doses and concentrations 0 of TAC and VRC; biochemical indicators such as liver and kidney function; and CYP3A5, CYP3A4, and CYP2C19 gene types. Results and Discussion. After discontinuing VRC for 2–4 days, 81% of the patients returned to their initial TAC dose, although TAC C0 and TAC dose-adjusted trough concentration (C/D) were 2.43-fold and 3.35-fold higher, respectively, than pre-VRC administration. After 5–7 days, TAC C0 and C/D gradually recovered. TAC C/D was significantly higher after VRC discontinuation when the VRC trough concentration (VRC C0) was greater than 2.43 mg/L; CYP3A5, CYP3A4, and CYP2C19 genotypes and the administration of erythromycin did not affect the change in TAC C/D. What is New and Conclusion. TAC C/D remains elevated 2–4 days after discontinuing VRC compared to pre-VRC administration, with gradual recovery observed 5–7 days after VRC discontinuation. To avoid excessive blood TAC C0 , the initial TAC dose should not be immediately reinstated upon VRC discontinuation for 2–4 days. VRC C0 are a critical factor influencing the change in TAC C/D ratio after VRC discontinuation. [ABSTRACT FROM AUTHOR]

Background: Chromoblastomycosis is the World Health Organization (WHO)-recognized fungal implantation disease that eventually leads to severe mutilation. Cladophialophora carrionii (C. carrionii) is one of the agents. However, the pathogenesis of C. carrionii is not fully investigated yet. Methods: We investigated the pathogenic potential of the fungus in a Galleria mellonella (G. mellonella) larvae infection model. Six strains of C. carrionii, and three of its environmental relative C. yegresii were tested. The G. mellonella model was also applied to determine antifungal efficacy of amphotericin B, itraconazole, voriconazole, posaconazole, and terbinafine. Results: All strains were able to infect the larvae, but virulence potentials were strain-specific and showed no correlation with clinical background of the respective isolate. Survival of larvae also varied with infection dose, and with growth speed and melanization of the fungus. Posaconazole and voriconazole exhibited best activity against Cladophialophora, followed by itraconazole and terbinafine, while limited efficacy was seen for amphotericin B. Conclusion: Infection behavior deviates significantly between strains. In vitro antifungal susceptibility of tested strains only partly explained the limited treatment efficacy in vivo. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS). Methods: In this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022. Results: The economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year. Conclusion: Compared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS. [ABSTRACT FROM AUTHOR]

Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been defined in order to detect non-wild-type (NWT) isolates harboring resistance mechanisms. We reviewed the literature in order to find studies where commercial methods were used to evaluate for in vitro susceptibility of filamentous fungi and assess their ability to detect NWT isolates according to the available ECVs. Data were found for the gradient concentration strips Etest and MIC Test Strips (MTS), broth microdilution Sensititre YeastOne (SYO), Micronaut-AM and the agar dilution VIPcheck assays. Applying itraconazole, voriconazole and posaconazole Etest ECVs for A. fumigatus, Etest was able to detect 90.3% (84/93), 61.2% (90/147) and 86% (31/36) of isolates with known cyp51A mutations, respectively. Moreover, Etest also was able to detect 3/3 fks mutants using caspofungin ECVs and 2/3 micafungin mutant isolates. Applying the voriconazole and posaconazole SYO ECVs, 57.7% (67/116) and 100% (47/47) of mutants with known cyp51A substitutions were classified as NWT, respectively. VIPcheck detected 90.3% (159/176), 80.1% (141/176) and 66% (141/176)of mutants via itraconazole, voriconazole and posaconazole, respectively, whereas Micronaut-AM detected 88% (22/25). In conclusion, Etest posaconazole and itraconazole, as well as micafungin and caspofungin ECVs, detected A. fumigatus mutants. On the other hand, while the posaconazole SYO ECV was able to detect cyp51A mutants, similar data were not observed with the SYO voriconazole ECV. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting. [ABSTRACT FROM AUTHOR]

Although rare, trans-kingdom infection features an interesting infection biology concept, in which highly versatile pathogenic attributes allow successful infections in evolutionarily highly divergent species. Corynespora cassiicola is a phytopathogenic fungus and occasionally causes human infections. Herein, we report a phaeohyphomycosis case caused by C. cassiicola. Given that sporadic reports may contribute to a lack of awareness of the transmission route, clinical manifestations, and diagnostic and clinical management, we systematically reviewed the cases reported thus far. Nine patients were identified and included in the pooled analysis, 88.9% (8/9) of whom were reported after 2010. All patients were from Asian, African, and Latin American countries, among whom 77.8% (7/9) were farmers or lived in areas with active agriculture. Exposed body parts were the major affected infection area, and clinical manifestations were mainly non-specific inflammatory reactions. Although biochemical and morphological examinations confirmed the presence of fungal infection, molecular analysis was used for the final diagnosis, with 77.8% (7/9) being identified by internal transcribed spacer sequencing. Whereas voriconazole, terbinafine, and AmB, either alone or in combination, resulted in successful infection resolution in most cases (5/9; 55.5%), those suffering from invasive facial infections and CARD9 deficiency showed poor outcomes. Our patient is the third case of invasive facial infection caused by C. cassiicola and was successfully treated with intravenous LAmB followed by oral voriconazole combined with topical antifungal irrigation. Molecular identification of fungus and prompt antifungal treatment is pivotal in the clinical success of patients suspected to have phaeohyphomycosis. Moreover, as evidenced by our data, itraconazole treatment is not recommended. [ABSTRACT FROM AUTHOR]

Purpose: While extensive research with accurate classification has been done in mycoses of the paranasal sinuses and anterior skull base, a similar understanding of lateral skull base fungal pathologies is lacking due to relative rarity and diagnostic difficulties. We introduce a series of eleven cases and two different invasive entities of Aspergillus temporal bone diseases—fungal skull base osteomyelitis (SBO)/malignant otitis externa (MOE) and chronic invasive granulomatous fungal disease (CIGFD). Methodology: A retrospective observational study was conducted at the neuro-otology unit of a tertiary care referral center between July 2017 and November 2022. Diagnosed cases of lateral skull base osteomyelitis with atypical symptoms and lack of response to culture-directed antibiotics were evaluated for fungal origin. Patient data, including history, laboratory findings, serum galactomannan assay, CT and MRI imaging findings, clinical examination findings, and co-morbidities, were analyzed. The treatment course and response were assessed. Results: A total of 11 cases were included in the study. Of these, 9 were cases of Aspergillus-induced skull base osteomyelitis (SBO) and 2 of Aspergillus-induced chronic invasive granulomatous fungal disease (CIGFD). CIGFD presented with persistent ear discharge and slowly progressive post-aural swelling, while all patients of fungal SBO had lower cranial nerve palsies. CIGFD responded to excision and antifungals, while SBO responded well to conservative anti-fungal treatment. Conclusion: In cases of lateral SBO not responding to antibiotic therapy, the possibility of fungal etiology should be considered. Aspergillus spp. seems to be the major fungal pathogen. [ABSTRACT FROM AUTHOR]

Background and Objective: Voriconazole pharmacokinetics are highly variable in pediatric patients, and the optimal dosage has yet to be determined. The purpose of this study was to describe voriconazole pharmacokinetic and pharmacodynamic targets achieved and evaluate the efficacy and safety of voriconazole for critically ill pediatrics. Methods: This is a single-center retrospective study conducted at a pediatric intensive care unit at a tertiary/quaternary hospital. Pediatrics admitted to the pediatric intensive care unit and who received voriconazole for a proven or suspected fungal infection with at least one measured trough concentration were included. The primary outcomes included the percentage of pediatric patients who achieved the pharmacokinetic and pharmacodynamic targets. Secondary outcomes included assessing the correlation between voriconazole trough concentrations and clinical/microbiological outcomes. All statistical analyses were performed using the R statistical software and Microsoft Excel. Multiple logistic regression was used to assess the predictors of both clinical and microbiologic cures. Multiple linear regression was used to determine significant factors associated with trough concentrations. Results: A total of 129 voriconazole trough concentrations were measured from 71 participants at steady state after at least three doses of voriconazole. The mean (± standard deviation) of the first and second trough concentrations were 2.9 (4.2) and 2.3 (3.3) mg/L, respectively. Among the first trough concentrations, only 33.8% were within the therapeutic range (1–5 mg/L), 46.5% were below the therapeutic range, and 19.7% were above the therapeutic range. A clinical cure occurred in 78% of patients, while a microbiologic cure occurred in 80% of patients. Conclusions: Voriconazole trough concentrations vary widely in critically ill pediatric patients and only a third of the patients achieved therapeutic concentrations with initial doses. [ABSTRACT FROM AUTHOR]

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P‐glycoprotein. However, the role of these transporter gene variants in colistin‐induced nephrotoxicity has not been studied. Utilizing targeted next‐generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24‐h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin‐induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin‐induced nephrotoxicity and facilitate dose optimization of colistimethate sodium. [ABSTRACT FROM AUTHOR]

Copyright of Biomédica: Revista del Instituto Nacional de Salud is the property of Instituto Nacional de Salud of Colombia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims: The aims of this study are to investigate the etiology, microbiological spectrum, and risk factors associated with visual outcomes of fungal endophthalmitis (FE) in a tertiary eye specialty hospital in Shanghai, China. Methods: This was a retrospective, single-center case series. The clinical characteristics, etiology, microbiological spectrum, and management, as well as the visual outcomes, were analyzed. Logistic regression was used to analyze the factors related to visual outcomes. Results: This study involved 102 eyes of 92 patients with FE, including 63 males (66.3%). The mean age was 44.4 ± 19.8 years. The most common etiology of FE was trauma (56.5%). The predominant fungal species isolated were Aspergillus spp. (31/93, 33.3%). Pars plana vitrectomy (PPV) and intravitreal antifungal agents was performed initially in 86 (84.3%) and 83 (81.4%) eyes, respectively. Only 35 (34.3%) eyes achieved final best corrected visual acuity (BCVA) of 20/400 or better. Ten (9.8%) eyes had a final BCVA of light perception or worse, and five (4.9%) had to be enucleated. The factors determining better visual outcomes included initial visual acuity better than finger-counting (FC) (odds ratio (OR) 5.811, p = 0.036), the absence of corneal infiltrate (OR 10.131, p = 0.002), and Candida species infection (OR 6.325, p = 0.011). Conclusions: Early diagnosis of FE and a timely vitrectomy, combined with an intravitreal injection of an antifungal drug, can mitigate the devastating results of intraocular fungal infection. Not being infected by Aspergillus spp., an initial BCVA that was no worse than FC, and the absence of corneal involvement were related to better visual prognosis. [ABSTRACT FROM AUTHOR]

Background Voriconazole is an antifungal drug for which therapeutic monitoring is recommended to prevent side effects. Temporary administration of the antiemetic drug fosaprepitant remarkably decreases the plasma concentration of voriconazole from the therapeutic range. The ratio of the major metabolite voriconazole N-oxide to voriconazole exceeded that at any other time for a patient who started chemotherapy during voriconazole therapy. We attributed this unpredictable result to cytochrome P450 3A4 induced by aprepitant that was converted from fosaprepitant in vivo. Methods Concentrations of voriconazole and voriconazole N-oxide were measured using liquid chromatography-mass spectrometry/mass spectrometry in primary human hepatocytes after incubation with aprepitant. Aprepitant suppressed voriconazole N-oxide formation within 24 h, followed by a continuous increase. Levels of drug-metabolizing cytochrome P450 mRNA were measured using real-time PCR in primary human hepatocytes incubated with aprepitant. Results Cytochrome P450 3A4 and 2C9 mRNA levels increased ~4- and 2-fold, respectively, over time. Cytochrome P450 3A4 induction was confirmed using reporter assays. We also assessed L-755446, a major metabolite of aprepitant that lacks a triazole ring. Both compounds dose-dependently increased reporter activity; however, induction by L-755446 was stronger than that by aprepitant. Conclusion These results indicate that aprepitant initially inhibited voriconazole metabolism via its triazole ring and increased cytochrome P450 3A4 induction following L-755446 formation. The decrease in plasma voriconazole concentration 7 days after fosaprepitant administration was mainly attributed to cytochrome P450 3A4 induction by L-755446. [ABSTRACT FROM AUTHOR]

(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of Saccharomyces cerevisiae infections has been noted. There is little knowledge about the drug susceptibility of this species. Therefore, the objective of this research was to expand it and determine the drug susceptibility profile of a local collection of clinical isolates of this species. (2) Methods: This study contained 55 clinical isolates identified as Saccharomyces cerevisiae using the MALDI-TOF method. The susceptibility of Saccharomyces cerevisiae was tested to 10 antifungals (amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin, and itraconazole) using MICRONAUT-AT tests and manogepix, a new drug, using the microdilution method according to EUCAST. (3) Results: Overall, most strains were classified as sensitive to amphotericin B and flucytosine (MIC ranges of ≤0.03–1 and ≤0.06–0.125, respectively) and also to echinocandins. However, five isolates expressed high MIC values for all of the tested azoles, indicating cross-resistance. The MIC range for manogepix was 0.001–0.125 mg/L, with an MIC50 of 0.03 mg/L and an MIC90 of 0.06 mg/L. (4) Conclusions: The occurrence of resistance to azoles may be a concerning problem and therefore should be investigated further. However, the new antifungal manogepix appears to be an interesting new therapeutic option for treating such infections. [ABSTRACT FROM AUTHOR]

Aspergillus peritonitis is a rare but highly severe complication of peritoneal dialysis with a high mortality rate. We report a case of Aspergillus fumigatus peritonitis. Despite early removal of the catheter and oral voriconazole antifungal treatment for 3 weeks, the treatment effect was unsatisfactory, resulting in prolonged hospital stay and affecting the patient's quality of life. After switching to liposomalAmphotericin B, inflammation indicators rapidly decreased and infection was controlled. Liposomalamphotericin B provides an option for treatment of Aspergillus peritonitis.

Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the in vitro activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.

Objectives:The aim of the present study was to evaluate any conjunctival metaplastic changes by impression cytology in patients who underwent topical 1% voriconazole treatment for severe fungal keratitis.Materials and Methods:The study was conducted at Ege University Faculty of Medicine, Departments of Ophthalmology and Medical Pathology. Patients who were treated with 1% topical voriconazole for fungal keratitis for at least 3 months were included. The used topical voriconazole treatment was initiated as one drop every hour and was tapered according to clinical improvement in all patients. Treatment was continued 4 times a day for at least 3 months. Impression cytology samples were collected at least 3 months after cessation of topical voriconazole from the affected eyes and from the fellow eyes as a control group. Collected specimens were transferred to the pathology department for evaluation and grading (Nelson’s grading system).Results:The mean age of the patients was 57.68±17.32 years (range, 22-87 years). The impression cytology grade of the inferior bulbar conjunctiva was 1.73±0.77 (range, 0-3) in the study group and 1.19±0.98 (range, 0-3) in the control group (p=0.03). The impression cytology grade of the temporal bulbar conjunctiva was 1.69±0.73 (range, 0-3) in the study group and 1.15±0.88 (range, 0-3) in the control group (p=0.02). The impression cytology grades of the nasal and superior bulbar conjunctiva did not differ statistically (p values 0.13 and 0.17, respectively).Conclusion:Topical voriconazole is an effective broad-spectrum antifungal drug, but it induces conjunctival squamous metaplasia. Clinicians should be aware of this possible side effect of topical voriconazole and should carefully evaluate the conjunctiva of treated patients at each visit to detect possible metaplastic changes.

Ramy Awad,1 Alaa Atef Ghaith,2 Khaled Awad,1 Marina Mamdouh Saad,1 Ahmed Ak Elmassry2 1Department of Ophthalmology, Alexandria General Ophthalmology Hospital, Alexandria, Egypt; 2Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, EgyptCorrespondence: Ahmed Ak Elmassry, Ophthalmology Department, Faculty of Medicine, Alexandria University, Champollion Street, Al Attarin, Alexandria, Egypt, Tel +2 0122 215 2435, Email ahmad.elmassry@gmail.comAbstract: Fungal keratitis is one of the major causes of microbial keratitis that may lead to corneal blindness. Many problems related to diagnosis and therapy are encountered in fungal keratitis, including difficulty in obtaining laboratory diagnoses and the availability and efficacy of antifungal medications. Intensive and prolonged use of antifungal topical preparations may not be enough. The use of antifungal medications is considered the main treatment for fungal keratitis. It is recommended to start antifungal therapy after confirmation of the clinical diagnosis with a smear or positive cultures. Topical application of antifungal medications is a mainstay for the treatment of fungal keratitis; however, systemic, intra-stromal, or intra-cameral routes may be used. Therapeutic keratoplasty is the main surgical procedure approved for the management of fungal keratitis with good success rate. Intrastromal corneal injection of antifungal medications may result in steady-state drug levels within the corneal tissue and prevent intervals of decreased antifungal drug concentration below its therapeutic level. In cases of severe fungal keratitis with deep stromal infiltration not responding to treatment, intracameral injection of antifungal agents may be effective. Collagen cross-linking has been proposed to be beneficial for cases of fungal keratitis as a stand-alone therapy or as an adjunct to antifungal medications. Although collagen cross-linking has been extensively studied in the past few years, its protocol still needs many modifications to optimize UV fluence levels, irradiation time, and concentration of riboflavin to achieve 100% microbial killing.Keywords: fungal keratitis, keratomycosis, PACK-CXL, antifungal, voriconazole, intracorneal injection, targeted therapy

Abstract Background/Objective With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. Methods A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. Result The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). Conclusion Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.

Although rare, trans-kingdom infection features an interesting infection biology concept, in which highly versatile pathogenic attributes allow successful infections in evolutionarily highly divergent species. Corynespora cassiicola is a phytopathogenic fungus and occasionally causes human infections. Herein, we report a phaeohyphomycosis case caused by C. cassiicola. Given that sporadic reports may contribute to a lack of awareness of the transmission route, clinical manifestations, and diagnostic and clinical management, we systematically reviewed the cases reported thus far. Nine patients were identified and included in the pooled analysis, 88.9% (8/9) of whom were reported after 2010. All patients were from Asian, African, and Latin American countries, among whom 77.8% (7/9) were farmers or lived in areas with active agriculture. Exposed body parts were the major affected infection area, and clinical manifestations were mainly non-specific inflammatory reactions. Although biochemical and morphological examinations confirmed the presence of fungal infection, molecular analysis was used for the final diagnosis, with 77.8% (7/9) being identified by internal transcribed spacer sequencing. Whereas voriconazole, terbinafine, and AmB, either alone or in combination, resulted in successful infection resolution in most cases (5/9; 55.5%), those suffering from invasive facial infections and CARD9 deficiency showed poor outcomes. Our patient is the third case of invasive facial infection caused by C. cassiicola and was successfully treated with intravenous LAmB followed by oral voriconazole combined with topical antifungal irrigation. Molecular identification of fungus and prompt antifungal treatment is pivotal in the clinical success of patients suspected to have phaeohyphomycosis. Moreover, as evidenced by our data, itraconazole treatment is not recommended.

Background: Dengue is the most common arboviral illness reported globally, endemic to most tropical and sub-tropical regions of the world. Dengue Shock Syndrome is a rare complication of severe Dengue infection resulting in haemorrhagic complications and refractory hypotension. We report on a case of severe dengue diagnosed in a patient with major trauma and illustrate some of the potential challenges and considerations in the clinical management of such cases. Case Presentation: A 49-year-old female presented following a road trauma incident with multiple abdominal injuries requiring urgent laparotomy. Her recovery in Intensive Care Unit was complicated by the development of Dengue Shock Syndrome characterised by a falling haemoglobin and platelet count, multiorgan dysfunction and prolonged hospital stay. Conclusions: Dengue Shock Syndrome may complicate fluid management and bleeding control in major trauma cases. Awareness of Dengue, particularly in endemic areas and returned travellers may help facilitate early diagnosis and management of complications. [ABSTRACT FROM AUTHOR]

Objectives: Fungal tissue invasion in the setting of sinonasal malignancy has been rarely described in the literature. Only a handful of studies have discussed cases of suspected chronic and acute IFS (CIFS and AIFS, respectively), having an underlying undifferentiated sinonasal carcinoma, sinonasal teratocarcinosarcoma, and NK/T-cell lymphoma. Methods: Here, we describe 3 cases of carcinoma mimicking IFS from a single institution. Results: Each of our patients presented with sinonasal complaints as an outpatient in the setting of immunosuppression. Intranasal biopsies consistently were predominated by necrotic debris, with and without fungal elements, ultimately leading to a delay of oncologic care. The final pathologies included NK/T-cell lymphoma and SNEC. All patients were followed by radiation and chemotherapy, with 1 case of mortality. Conclusions: We aim to emphasize the importance of obtaining viable tissue as pathology specimens as the presence of necrosis with fungal elements may limit the diagnosis and ultimately delay the care of an underlying sinonasal carcinoma. [ABSTRACT FROM AUTHOR]

The problem of diagnosis and treatment of fungal keratitis (FK) is very acute. Due to the slow development of clinical features and the absence of clear pathognomonic signs, this disease is characterized by a late start of the introduction of adequate etiotropic therapy. Often this leads to the development of large corneal defects requiring surgical intervention. Diagnostic methods are divided into invasive and non-invasive. Invasive methods include the study of scrapings from the surface of the cornea from the site of ulceration, biopsy of the corneal stroma or moisture of the anterior chamber using microscopic, cultural methods or polymerase chain reaction (PCR). Non-invasive techniques include confocal microscopy and optical coherence tomography of the anterior segment. They allow you to dynamically monitor the course of the pathological process and the response to ongoing therapy. Promising methods are also the detection of (1,3)-β-D-glucans in tears, the detection of the pathogen using MALDI-TOF MS. The gold standard for the treatment of FK in the world is the topical application of 5 % Natamycin (approved by the FDA, but not available in Russia). Fluconazole, Voriconazole and Amphotericin B, available in Russia, are also widely used, but their topical use is possible only in off label format. In the presence of hypopyon or an increase in the size and depth of the infiltrate, despite ongoing treatment, immediate surgical treatment is required in order to preserve the integrity of the eyeball. Such treatments include penetrating keratoplasty, anterior lamellar keratoplasty, amniotic membrane transplantation, conjunctival flaps, corneal collagen cross-linking (with unproven efficacy), and argon laser. A promising method for the treatment of FK can be the use of Ag(10 %):InP/ZnS MPA quantum dots as monotherapy or as a bioconjugate with known antifungal drugs.

Abstract Background Acute-on-chronic liver failure (ACLF) is a common clinical type of liver failure, and patients with acute-on-chronic liver failure are prone to fungal infections, especially the increasing incidence of invasive pulmonary aspergillosis (IPA). Voriconazole is recommended as the first-line antifungal agent in the treatment of invasive aspergillosis; however, no recommendation has been given for patients with severe liver cirrhosis (Child–Pugh C) and liver failure. This trial aims to examine the therapeutic effects and safety of voriconazole in the treatment of IPA in patients with liver failure. Methods This study is a non-double-blind randomized controlled trial. The 96 eligible acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis will be randomly assigned to receive either the optimized voriconazole regimen or the recommended voriconazole regimen for patients with mild to moderate liver cirrhosis (Child–Pugh A and B), at a 1:1 ratio, with an 8-week follow-up period. The antifungal efficacy of voriconazole will be the primary outcome measure. Plasma voriconazole trough concentration, the laboratory examination (CRP, PCT, ESR, etc.), chest CT, adverse events, and mortality at week 4 and 8 will be the secondary outcome measures. Discussion This trial aims to demonstrate the efficacy and safety of voriconazole in the treatment of IPA in patients with liver failure, which is expected to provide a reference for scientific optimization of voriconazole regimens and a realistic basis for the standardized treatment of acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis. Trial registration The trial was registered with the Chinese Clinical Trial Registry, ChiCTR2100048259. Registered on 5 July 2021.

(1) Background: The present study aimed to assess the antifungal effectiveness of a topical innovative formulation containing the association of an antifungal agent, voriconazole (VCZ), and the essential oil of Pinus sylvestris L. (PSEO). (2) Methods: Pseudo-ternary phase diagram and D-optimal mixture design approaches were applied for the development and the optimization of the o/w nanoemulsion. The optimized formulation (NE) was subjected to physicochemical characterization and to physical stability studies. In vitro permeation studies were carried out using the Franz cell diffusion system. The antimycotic efficacy against Microsporum canis was carried out in vitro. (3) Results: Optimal nanoemulsion showed great physical stability and was characterized by a small droplet size (19.015 nm ± 0.110 nm), a PDI of 0.146 ± 0.011, a zeta potential of −16.067 mV ± 1.833 mV, a percentage of transmittance of 95.352% ± 0.175%, and a pH of 5.64 ± 0.03. Furthermore, it exhibited a significant enhancement in apparent permeability coefficient (p < 0.05) compared to the VCZ free drug. Finally, NE presented the greatest antifungal activity against Microsporum canis in comparison with VCZ and PSEO tested alone. (4) Conclusions: These promising results suggest that this topical innovative formulation could be a good candidate to treat onychomycosis. Further ex vivo and clinical investigations are needed to support these findings.

Introduction'Real-world' data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs.MethodsData were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose.ResultsOverall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole).ConclusionsIn this 'real-world' study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.

Background: Drug-drug interactions (DDIs) are a major but preventable cause of adverse drug reactions. There is insufficient information regarding DDIs in lung transplant recipients. Objective: This study aimed to determine the prevalence of potential DDIs (pDDIs) in intensive care unit (ICU) lung transplant recipients, identify the real DDIs and the most frequently implicated medications in this vulnerable population, and determine the risk factors associated with pDDIs. Methods: This retrospective cross-sectional study included lung transplant recipients from January 2018 to December 2021. Pertinent information was retrieved from medical records. All prescribed medications were screened for pDDIs using the Lexicomp® drug interaction software. According to this interaction software, pDDIs were classified as C, D, or X (C = monitor therapy, D = consider therapy modification, X = avoid combination). The Drug Interaction Probability Scale was used to determine the causation of DDIs. All statistical analysis was performed in SPSS version 26.0. Results: 114 patients were qualified for pDDI analysis, and total pDDIs were 4051. The most common type of pDDIs was category C (3323; 82.0%), followed by D (653; 16.1%) and X (75; 1.9%). Voriconazole and posaconazole were the antifungal medicine with the most genuine DDIs. Mean tacrolimus concentration/dose (Tac C/D) before or after co-therapy was considerably lower than the Tac C/D during voriconazole or posaconazole co-therapy (p < 0.001, p = 0.027). Real DDIs caused adverse drug events (ADEs) in 20 patients. Multivariable logistic regression analyses found the number of drugs per patient (OR, 1.095; 95% CI, 1.048-1.145; p < 0.001) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR, 1.097; 95% CI, 1.021-1.179; p = 0.012) as independent risk factors predicting category X pDDIs. Conclusion: This study revealed a high incidence of both potential and real DDIs in ICU lung transplant recipients. Immunosuppressive drugs administered with azole had a high risk of causing clinically significant interactions. The number of co-administered drugs and APACHE II score were associated with an increased risk of category × drug interactions. Close monitoring of clinical and laboratory parameters is essential for ensuring successful lung transplantation and preventing adverse drug events associated with DDIs. [ABSTRACT FROM AUTHOR]

Solid organ transplant (SOT) recipients face an increased susceptibility to invasive fungal infection (IFI) due to filamentous fungi. Post-transplant invasive aspergillosis (IA) and mucormycosis are related to exceedingly high mortality rates and graft loss risk, and its management involve a unique range of clinical challenges. First, the current treatment recommendations for IA and mucormycosis among SOT recipients are critically reviewed, including the supporting evidence. Next, we discussed particular concerns in this patient population, such as drug-drug interactions (DDIs) between triazoles and post-transplant immunosuppression or treatment-related toxicity. The role for immunomodulatory and host-targeted therapies is also considered, as well as the theoretical impact of the intrinsic antifungal activity of calcineurin inhibitors. Finally, a personal opinion is made on future directions in the pharmacological approach to post-transplant IFI. Despite relevant advances in the treatment of mold IFIs in the SOT setting, such as the incorporation of isavuconazole (with lower incidence of DDIs and better tolerability than voriconazole), there remains a large room for improvement in areas such as the position of combination therapy or the optimal strategy for the reduction of baseline immunosuppression. Importantly, future studies should define the specific contribution of newer antifungal agents and classes. [ABSTRACT FROM AUTHOR]

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01–27.1 and 2.61–47.9 μM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1–3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied. [ABSTRACT FROM AUTHOR]

SB‐2 cationic resin has been employed as an unexpected and reusable heterogeneous organocatalyst in multicomponents reaction for the synthesis of the α‐aminophosphonates derivatives that act as antifungal agents, this reaction proceeds under eco‐friendly and simple procedure by condensation in one pot of substituted aromatic aldehydes, anilines and diethylphosphite. Excellent isolated product yields are obtained (up to 70 %) for (4 a–o) within shorter reaction times in solvent‐free condition. The synthesized compounds were determined by spectroscopic analyses such as: NMR (1H, 13C and 31P), IR and HRMS.Molecular geometries, electronic properties, stability and reactivity such as: HOMO/LUMO, ΔEGAP ${{{\rm \Delta }{\rm E}}_{{\rm G}{\rm A}{\rm P}}}$ , dipole moment (6.1308

Aims: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics‐related gene polymorphisms, especially CYP2C19 polymorphisms, and non‐genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. Methods: Clinical studies were performed by collecting more than one VRC trough concentration and C‐reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. Results: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cminss/D in patients with no to mild inflammation (R2 = 0.12, P <.001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T‐Bil) levels (R2 = 0.19, P <.001). In non‐clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0–t)) of VRC in the inflammatory group was significantly longer than that in the control group (P <.001), which may be due to down‐regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)‐6/signal transducer and activator of transcription (STAT) 3 pathway. Conclusions: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T‐Bil on VRC metabolism should not be disregarded. [ABSTRACT FROM AUTHOR]

Voriconazole is commonly recommended as a first‐line therapy for invasive aspergillosis infections. Elderly patients are susceptible to infectious diseases owing to their decreased physical function and immune system. Our study aims to establish a population pharmacokinetics model for elderly patients receiving intravenous voriconazole, and to optimize dosing protocols through a simulated approach. An accurate fit to the concentration–time profile of voriconazole was achieved by employing a 1‐compartment model featuring first‐order elimination. The typical clearance rate of voriconazole was found to be 3.22 L/h, with a typical volume of distribution of 194 L. The covariate analysis revealed that albumin (ALB), gamma‐glutamyl transpeptidase, and direct bilirubin had significant impacts on voriconazole clearance. Additionally, body weight was found to be associated with the volume of distribution. Individualized dosing regimens were recommended for different ALB levels based on population pharmacokinetics model prediction. The proposed dosing regimens could provide a rationale for dosage individualization, improve the clinical outcomes, and minimize drug‐related toxicities. [ABSTRACT FROM AUTHOR]

Background Fungal meningitis can be associated with epidural anesthesia procedures. Fusariosis is a rare infection typically affecting immunocompromised patients and rarely causes meningitis. During 2022–2023, public health officials responded to a large outbreak of Fusarium solani meningitis associated with epidural anesthesia in Durango, Mexico. Methods The public health response and epidemiological and clinical features of patients affected by this outbreak were described. Coordinated actions were addressed to identify the etiological agent, determine its drug susceptibility, develop diagnostic tests, and implement clinical and epidemiological protocols. Retrospective analyses of clinical variables and outcomes were performed to determine association with better patient survival. Results A total of 1801 persons exposed to epidural anesthesia were identified, of whom 80 developed meningitis. Fusarium solani was found in 3 brain biopsies and showed susceptibility to voriconazole and amphotericin B. After F solani polymerase chain reaction (PCR) implementation, 57 patients with meningitis were PCR-screened, and 31 (38.8%) had a positive result. Most patients were female (95%), and cesarean section was the most common surgical procedure (76.3%). The case fatality rate was 51.3% (41 patients) and the median hospitalization duration was 39.5 days (interquartile range, 18–86 days). Seventy-one patients (88.8%) received voriconazole/amphotericin B and 64 subjects (80%) additionally received steroids. Cox regression analysis showed an increased lethality risk in patients who received antifungal treatment after 5 days (hazard ratio, 2.1 [95% confidence interval, 1.01–4.48], P <.05). Conclusions The F solani meningitis outbreak in Durango was an unprecedented medical challenge. Timely treatment and effective healthcare management were associated with better survival outcomes. [ABSTRACT FROM AUTHOR]

Background: It is thought that paliperidone, an active metabolite of risperidone, has limited potential for pharmacokinetic drug–drug interactions (DDIs) due to minimal metabolism by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). However, DDIs have been reported and include a theoretical interaction between paliperidone and voriconazole based on interactions between risperidone and strong CYP3A4 inhibitor azoles. Aim: To describe the first recorded DDI between paliperidone and voriconazole leading to extrapyramidal side effects (EPSEs). Clinical details: A 34‐year‐old male presented with febrile neutropenia presumed due to clozapine. Clozapine was ceased and paliperidone commenced with voriconazole added to the patient's empiric piperacillin/tazobactam therapy due to a suspected fungal infection. Two days after starting voriconazole, the patient developed hypertonia and hyperreflexia in all limbs, thought most likely to be antipsychotic induced EPSEs. Paliperidone was withheld and EPSEs resolved. Outcomes: The patient had previously tolerated long‐term paliperidone at higher doses, prior to transitioning to clozapine. The development of EPSEs occurred two days post azole initiation, indicating a probable paliperidone adverse drug reaction (ADR) due to strong CYP3A4 inhibition by voriconazole. This case appears to be the first documented report of this previous theoretical DDI in practice. Further studies, including therapeutic drug monitoring, are required to confirm findings. Conclusion: Paliperidone may be affected by pharmacokinetic drug–drug interactions and patients should be monitored for ADRs when CYP3A4 inhibitors are concomitantly administered. [ABSTRACT FROM AUTHOR]

Fungal sinusitis is relatively rare, but it has become more common in recent years. When fungal sinusitis invades the orbit, it can cause proptosis, chemosis, ophthalmoplegia, retroorbital pain, and vision impairment. We present a case of an extensive orbital floor defect due to invasive fungal sinusitis. A 62-year-old man with hypertension and a history of lung adenocarcinoma, presented with right-side facial pain and swelling. On admission, the serum glucose level was 347 mg/dL, and hemoglobin A1c was 11.4%. A computed tomography scan and a Waters’ view X-ray showed right maxillary sinusitis with an orbital floor defect. On hospital day 3, functional endoscopic sinus surgery was performed by the otorhinolaryngology team, and an aspergilloma in necrotic inflammatory exudate obtained during exploration. On hospital day 7, orbital floor reconstruction with a Medpor Titan surgical implant was done. In principle, the management of invasive sino-orbital fungal infection often begins with surgical debridement and local irrigation with an antifungal agent. Exceptionally, in this case, debridement and immediate orbital floor reconstruction were performed to prevent enophthalmos caused by the extensive orbital floor defect. The patient underwent orbital floor reconstruction and received intravenous and oral voriconazole. Despite orbital invasion, there were no ophthalmic symptoms or sequelae. [ABSTRACT FROM AUTHOR]

Background and Objectives: Fusarium spp. is an emerging pathogen that presents with varied clinical presentations but there are very few studies from India that elaborate on the spectrum of infection caused by the fungus. Hence, the present study was conducted in our institute to understand the clinical spectrum of fusariosis. Materials and Methods: The present study was a retrospective study conducted at a tertiary care institute, in Hyderabad, Telangana, India for four years from January 2018 to December 2022. All the patients with clinically significant isolation of Fusarium spp. from various samples were included in the study. Results: There were 25 cases of fusariosis diagnosed during the study period. Fusarium was isolated predominantly from debrided tissue following road traffic accidents in 12/25 (84%) of the cases, nails in 3/25 (12%) and superficial leg ulcer in 1/25 (4%) of the cases. Speciation was done for four patients. Three were Fusarium incarnatum and one was Fusarium solani. The patients were treated surgically and with/without antifungal therapy and were discharged in a stable condition. Conclusion: Traumatic injuries were the major cause of infections in the present study. As Fusarium is a virulent and highly resistant pathogen, an early suspicion and an appropriate diagnosis would lead to a better outcome in these patients. [ABSTRACT FROM AUTHOR]