Comparison of the EUCAST-AFST broth dilution method with the CLSI reference broth dilution method (M38-A) for susceptibility testing of posaconazole and voriconazole against Aspergillus spp.

The susceptibilities of 40 clinical isolates of Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus) were determined for posaconazole and voriconazole by the CLSI M38-A and EUCAST-AFST broth dilution methods. Where a discrepancy was observed between the methods, the EUCAST method tended to give higher MIC values. Overall, the level of agreement was 92.5% and the intra-class correlation coefficient was > 0.90.     

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.     

血液系统恶性肿瘤患者伏立康唑谷浓度高变异性分析

目的 探讨影响血液系统恶性肿瘤患者伏立康唑谷浓度变异的潜在因素。方法 回顾性地收集2015年11月至2017年9月期间进行伏立康唑治疗药物监测的血液系统恶性肿瘤患者的病史信息、临床资料、用药情况和实验室数据等,分析人口学、生理病理、合并用药、CYP2C19基因型等与标准化谷浓度的相关性。结果 研究最终纳入176例患者241例监测数据,结果显示血液系统恶性肿瘤患者伏立康唑标准化谷浓度存在较大变异（范围从0.38-14.72 mg·L-1）。单因素和多因素Logistic回归分析结果提示,CYP2C19 *1/*1（快代谢型）是标准化谷浓度<1.0 mg·L-1的危险因素（OR: 4.445, 95% CI: 1.514–38.449, P: 0.015）;C反应蛋白（OR: 2.377, 95% CI: 1.116, 5.063, P: 0.025）、合并使用奥美拉唑（OR: 4.537, 95% CI: 1.716, 14.637, P: 0.018）及CYP2C19 *2/*2,*2/*3和*3/*3（慢代谢型）（OR: 10.199, 95% CI: 2.516, 21.342, P: 0.001）是VCZ标准化谷浓度> 5.5 mg·L-1的危险因素。结论 血液系统恶性肿瘤患者伏立康唑谷浓度变异度高,影响因素多。CYP2C19基因型、合用奥美拉唑、以及患者炎症水平可能是治疗时需考虑的因素。     

Inhibitory effect of isavuconazole,ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague–Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5 mg/kg isavuconazole), group C (5 mg/kg ketoconazole), and group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra‐high‐performance liquid chromatography–tandem mass spectrometry method (UPLC–MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The C_max of methadone in groups C and D increased to 2.7‐fold and 5‐fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p < 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC₅₀ for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76 μM, 8.33 μM, and 4.45 μM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.     

Adverse effects of voriconazole: Over a decade of use

Voriconazole use has increased since the drug's introduction in 2002, and new and unique adverse effects are emerging as patients undergo prolonged therapy. Most concerning is the increased risk of cutaneous malignancies, primarily squamous cell carcinoma (SCC); this risk is duration dependent and the associated malignancies tend to be more aggressive and multifocal. Voriconazole is also associated with phototoxicity (which may be a precursor to malignancy), periostitis, hallucinations and encephalopathy, peripheral neuropathy, alopecia, nail changes, hyponatremia, and other adverse effects. Some toxicities (neuropsychiatric and gastrointestinal including hepatic) are seen in clear association with supratherapeutic serum voriconazole levels; thus, careful monitoring of voriconazole levels is a critical component of safe drug use. Guidelines for screening for adverse effects after long‐term voriconazole use may be beneficial and need to be established.     

三氮唑类抗真菌药的治疗药物监测研究进展

近年来,真菌感染,尤其是深部真菌感染严重地威胁到患者的健康和生命,因此抗真菌药物的研究开发及临床应用日益受到重视。三氮唑类抗真菌药是临床使用最广泛的抗真菌药物;其临床疗效得到了广泛的肯定。代表药物有氟康唑（Fluconazole）、伊曲康唑（Itraconazole）、伏立康唑（Voriconazole）、泊沙康唑（Posaconazole）等。由于在吸收、代谢和排泄等方面的差异和药物相互作用的影响,导致许多抗真菌药物血药浓度的个体差异较大。临床实践表明抗真菌药物的血药浓度与其疗效和毒副作用有相关性,对其进行治疗药物监测可优化治疗效果同时降低毒副作用。本文就近年来国内外三氮唑类抗真菌药物治疗药物监测、的研究进展进行综述。     

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。     

Disseminated Fusarium oxysporum neurospinal infection

We report a case of disseminated meningospondylodiscitis in an elderly diabetic patient caused by Fusarium oxysporum. As the clinical presentation was nonspecific, the diagnosis of the condition could only be arrived at after laboratory and imaging studies. The diagnosis of the condition requires a high index of suspicion. Patient underwent thorough surgical debridement along with a short course of variconazole and remained asymptomatic after 36 months of diagnosis. Fusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. It is known to cause local infections (nail, cornea) in healthy humans and disseminated infection only in the immunocompromised.     

Haemorrhagic cystitis following the administration of voriconazole in the treatment of central nervous system aspergillosis: a case report

Central nervous system aspergillosis (CNS-A) is a rare and fatal fungal infection. Voriconazole is the recommended treatment for CNS-A. The therapeutic effect of voriconazole is good, but its use is limited due to adverse reactions. This case report describes a 37-year-old male patient that had previously been diagnosed with acute lymphoblastic leukaemia. He had received immunosuppressive agents for 1 year following a haematopoietic bone marrow transplant. He presented with a 1-month history of left limb weakness as well as recurrent fever. Brain magnetic resonance imaging showed that he had multiple cerebral infarctions. Subsequently, he was diagnosed with CNS-A by metagenomic next-generation sequencing. Voriconazole was added to his treatment regimen, but it resulted in severe haemorrhagic cystitis and possibly bladder rupture. The dose of voriconazole was adjusted and reparative bladder surgery was undertaken immediately. Eventually, the patient was successfully treated with voriconazole and there was no recurrence of symptoms after 1 year of follow-up. Haemorrhagic cystitis is a rare adverse drug reaction associated with voriconazole use. Based on the experience with this current case, physicians should be aware of urinary tract complications with voriconazole including haemorrhagic cystitis.