Chronic endogenous fungal endophthalmitis: diagnostic and treatment challenges: A case report

Rationale:Endogenous fungal endophthalmitis (EFE) is a sight-threatening complication of systemic fungemia. As the prevalence rises, treatment remains a challenge especially when there is a failure in first-line treatment or drug-resistant fungus. This case report studies a case of chronic EFE, focusing on the diagnostic procedures, treatment options, monitoring parameters and the treatment outcomePatient concerns:A 64-year-old man with underlying well controlled diabetes mellitus was treated with 2 weeks’ course of intravenous antifungal fluconazole for pyelonephritis as his blood culture grew Candida albicans. Concurrently, he complained of 3 months of bilateral painless progressive blurring of vision. At presentation, his visual acuity (VA) was light perception both eyes. Ocular examination revealed non granulomatous inflammation with dense vitritis of both eyes.Diagnosis:He was diagnosed with EFE but the condition responded poorly with the medications.Interventions:He was treated with intravitreal (IVT) amphotericin B and fluconazole was continued. Vitrectomy was performed and intraoperative findings included bilateral fungal balls in the vitreous and retina with foveal traction in the left eye. Postoperatively, vision acuity was 6/24, N8 right eye and 2/60, N unable for left eye with extensive left macular scar and hole. Vitreous cultures were negative. He received multiple IVT amphotericin B and was started on topical steroid eye drops for persistent panuveitis with systemic fluconazole. Ocular improvement was seen after switching to IVT and topical voriconazole. Despite this, his ocular condition deteriorated and he developed neovascular glaucoma requiring 3 topical antiglaucoma agents. Panretinal photocoagulation was subsequently performed.Outcomes:At 3 months’ follow-up, his vision acuity remained at 6/24 for right eye and 2/60 for the left eye. There was no recurrence of inflammation or infection in both eyes.Lessons:Voriconazole could serve as a promising broad spectrum tri-azole agent in cases of failure in first-line treatment or drug-resistant fungus.     

伏立康唑血药浓度的测定与方法学考察

目的：建立人血浆中伏立康唑HPLC测定法,为人体药动学和药效学研究提供方法学基础。方法：取血浆0.5 mL,以劳拉西泮为内标,用乙腈-水（1∶9）2 mL以及乙腈洗脱,收集1 mL洗脱液,进样为20μL;色谱柱为Semmetry C18柱（4.6 mm×250 mm,5μm）,流动相为乙腈-水（50∶50）,流速为0.8 mL/min,在激发波长为256 nm和发射波长为372 nm处进行检测。结果：伏立康唑浓度在0.208~20.8μg/mL范围内与峰面积呈良好的线性关系（Y=0.2517ρ-0.0144,r2=0.999 8）;高、中、低3种浓度质控样品的日内和日间RSD均小于5%,相对回收率均在98%~103%范围内,将其室温放置24 h以及在-20℃反复冻融3次后,检测其回收率在83%~102%。结论：该方法操作简便、快速,准确灵敏,适用于临床药动学研究。     

Risk Factors for Voriconazole Hepatotoxicity at 12 Weeks in Lung Transplant Recipients

Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole‐associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53–12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K‐nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity.     

Comparison of micafungin and voriconazole in the treatment of invasive fungal infections in kidney transplant recipients

What is known and Objective: Invasive fungal infections are a major threat to renal transplant recipients. Micafungin and voriconazole are two useful antifungal agents for treating such infections. Our objective is to evaluate the comparative efficacy and safety of micafungin and voriconazole in the initial treatment of such infections. Methods: In this prospective, multicentre, open‐labelled, randomized, controlled trial, renal transplant recipients with invasive fungal infections were assigned to receive either micafungin or voriconazole. The enrolled subjects received a kidney transplant between March 2008 and March 2010 at one of the two transplant centres in Henan Province, China. The efficacy and adverse effects of the two treatments were compared. Results and Discussion: The clinical trial enrolled 65 patients, of whom 31 were treated with micafungin, and 34 with voriconazole. The rates of microbiological evidence of infection in the micafungin and voriconazole groups were 64·5% and 70·5%, respectively, whereas the rates of Candida as the major cultured fungus were 80·0% and 75·0%, respectively. Complicated bacterial infection rates in the two treatment groups were 38·7% and 32·4%, respectively, whereas complicated CMV viral infection occurred at a rate of 19·2% and 23·5%, respectively. Fungal infection within one to 3 months after transplant was 83·6% (26/31) and 85·3% (29/34) in the micafungin and voriconazole groups, respectively. There was no significant difference between the two groups in terms of efficacy, survival beyond 10 days and discontinuation of treatment because of lack of efficacy (P > 0·05). Mortality rates in the micafungin and voriconazole groups were 9·7% (3/31) and 12·1% (4/33), respectively. Rates of adverse effects in the two groups were 41·9% and 51·6% (P > 0·05), respectively. What is new and Conclusions: This is the first comparison of micafungin and voriconazole in renal transplant patients. Our study shows that the effectiveness of micafungin was similar to that of voriconazole in such patients.     

伏立康唑在儿童急性白血病肺曲霉菌感染二级预防中的应用

目的：探讨伏立康唑在儿童急性白血病肺曲霉菌感染二级预防中的作用。方法：回顾性分析我院2009年2月-2012年7月住院的儿童急性白血病临床诊断侵袭性肺曲霉菌感染经伏立康唑治疗有效的患儿17例,在随后的化疗中应用伏立康唑片剂,每12 h口服1次,直至粒细胞恢复,共58例次（同一患儿在多次化疗骨髓抑制期使用）,观察真菌感染情况,综合评价该药物的疗效和安全性。结果：经过伏立康唑片剂二级预防,化疗后均无真菌感染发生,无明显不良反应。结论：应用伏立康唑二级预防对儿童急性白血病临床诊断侵袭性肺曲霉菌感染有效、安全。     

Successful management of postpneumonectomy Aspergillus pleural empyema by combined surgical and anti‐fungal treatment with voriconazole and caspofungin

Aspergillus pleural empyema is a rare but often fatal infection complicating thoracic surgery. Three men and one woman aged 23–47 years were diagnosed with Aspergillus pleural empyema after lung resection. Underlying diseases were lung cancer (n = 2), Hodgkin’s disease (n = 1) and thoracic trauma (n = 1). The treatment protocol consisted of systemic anti‐fungal treatment with caspofungin and voriconazole, intrapleural application of amphotericin B and surgical debridement with secondary closure of the leaking bronchial stump. Two patients with chronic Aspergillus pleural empyema had been pretreated with itraconazole and/or amphotericin B. Two patients were treated with a thoracostoma. Two patients had undergone pneumonectomy for previously diagnosed pulmonary aspergillosis. Caspofungin was given for 13–60 days, Voriconazole for up to 100 days. Surgical debridement was performed in all cases and in two cases the created thoracostoma was closed during a second surgical procedure. Aspergillus PCR using blood samples, bronchoalveolar lavage or aspiration fluid was used for monitoring. All four patients had complete clinical and microbiological remission. Our case series shows promising results and underscores the importance of a combined therapeutic approach for Aspergillus pleural empyema consisting of anti‐fungal treatment and surgery. Voriconazole and caspofungin seem to be a suitable combination for this infection.     

Tailoring thixotropic mixed-lipid nanoconstructs of voriconazole for the management of Vulvovaginal candidiasis: Formulation,statistical optimization,in vitro characterization and in vivo assessment

Vulvovaginal candidiasis is a pervasive gynecological condition among women worldwide due to infection recurrence and resistance to conventional drugs. This calls for a novel formulation of alternative medication and with enhanced efficacy. This study aimed to fabricate mixed-lipid nanoconstructs (MLNCs) of voriconazole (VCZ) with a low concentration of lipids applying high shear homogenization and ultrasonication to form a semisolid formulation. Tefose 63 and Gelot 64 were employed as emulsifiers that are specified for vaginal preparations; as per their mucoadhesive properties and their texture enhancing characters, although usually used as lipids in different lipid carriers. A 2⁴ factorial design was established and the optimized formulation was prepared using 10% total lipids, in which solid lipids (Sterotex NF: Glyceryl monostearate) ratio was 1.92:1 and the oils percentage was 30% (Maisine: Glyceryl monooleate, in the ratio of 1:1), and the emulsifiers mixture (Tefose 63: Gelot 64) ratio was 1:1, as 10% of total formulation weight. The optimized formulation with a viscosity of 964.49 ± 57.99 cp showed spherical nanoparticles (322.72 ± 15.11 nm) that entrapped 67.16 ± 3.45% of VCZ and exhibited release of 70.08 ± 2.87% in 8 h. The optimized formulation with high bioadhesive potentials significantly reduced the fungal burden in female Wistar rats infected with vaginal candidiasis, compared to the aqueous VCZ suspension (p < .05). Furthermore, in vivo histopathological findings proved the effectiveness and the safety of the optimized MLNCs formulation after vaginal application. Inclusively, MLNCs formulation could be a promising vaginal delivery system of VCZ for the treatment of vulvovaginal candidiasis.     

Contact-Lens-Associated Purpureocillium Keratitis: Risk Factors,Microbiologic Characteristics,Clinical Course,and Outcomes

Purpose: To study the risk factors, microbiologic characteristics, clinical course, and outcomes of patients with Purpureocillium keratitis at a tertiary eye care center in south Florida. Materials and Methods: All medical records during a seven-year period starting January 1, 2007, were reviewed. Twenty-eight culture-proven Purpureocillium keratitis cases with complete medical records presenting to our institution were included in this retrospective, observational case series. Data collected included predisposing factors, therapeutic interventions, treatment duration, and visual outcomes. Results: Twenty patients (71.4%) had a history of soft contact lens use, with only two for therapeutic use. Other identified risk factors were trauma and immunosuppression. Fifteen patients (53.6%) received topical corticosteroid treatment prior to the diagnosis of fungal keratitis. Thirteen patients (46.4%) were on Natamycin treatment prior to Purpureocillium identification. As a group, the average best-corrected visual acuity (BCVA) at presentation was 1.1 logMAR; upon the final evaluation, it was 1.0 logMAR. The BCVA on last evaluation for the eight patients presenting to our institution within two weeks of onset of symptoms was 0.3 log MAR, and all patients in this group responded to medical management. The final BCVA for 20 patients presenting two weeks after onset of symptoms was 1.2 logMAR. There was a significant difference in the final BCVA between Group 1 and Group 2 (p?=?0.004), but no difference in steroid use or previous treatments. Previous steroid use tended to extend time to presentation and was significantly associated with a worse final visual outcome (1.2 versus 0.6 logMAR; p?=?0.0474). Previous Natamycin use was significantly associated with a worse final visual outcome (1.4 versus 0.6 logMAR; p?=?0.014). Conclusion: Purpureocillium keratitis can have devastating consequences to visual function and even lead to enucleation. Physicians should make every effort to arrive at an earlier microbiological diagnosis, as this is associated with better outcomes and less need for surgical intervention. The first line use of voriconazole is recommended, and steroid use should be avoided, as their previous use is associated with worse visual outcomes.