Emerging azole antifungals

Systemic and superficial fungal infections have progressively emerged over the past few decades as an increasing cause of human disease, especially in the immunocompromised host. Control of fungal disease has proved difficult because few risk factors are potentially preventable; the population at highest risk for fungal disease, the immunocompromised patient, has been steadily increasing. There is a clear need for additional safe and effective therapeutic agents for the treatment of systemic fungal disease. A new generation of triazoles that includes voriconazole, posaconazole, ravuconazole and albaconazole has emerged and are presently in different phases of clinical investigation. These new triazoles have demonstrated a broad spectrum of activity, in particular against fungal pathogens previously resistant to previously available antifungals. This review highlights the emerging azole antifungals, both those available and in clinical development, and discusses their prospects for the future.     

New generation azole antifungals in clinical investigation

Considerable progress in treating systemic mycoses has been achieved in the past years through development of new drugs in association with more advanced diagnostic procedures. Here, we review the pharmacological, microbiological and clinical development progress with the so-called ‘second generation’ triazoles: voriconazole, posaconazole, ravuconazole, isavuconazole and albaconazole. All these drugs exhibit a favourable pharmacokinetic and toxicity profile and possess high activity against resistant and emerging pathogens. However, only voriconazole and posaconazole have been adequately investigated in Phase III studies and have been approved by the regulatory agencies in the treatment and prophylaxis of invasive fungal infections, respectively. On the contrary, ravuconazole, isavuconazole and albaconazole have not been investigated in adequate clinical trials and, in the absence of proper data, the real possibilities of these agents as competitors for the treatment and prevention of invasive mycoses in the clinical setting are still unknown. The drug interactions and the variability in the absorption and/or metabolism of the triazoles, in particular voriconazole and posaconazole, may determine an unpredictable exposure of the pathogens to the antifungal treatments. Literature evidences strongly support the use of therapeutic drug monitoring for these triazoles which may be crucial for the proper management of severe invasive fungal infections.     

伏立康唑临床应用个体差异影响因素的文献分析

通过文献调研,就近年来影响伏立康唑个体差异相关因素的研究报道进行分析总结。探讨伏立康唑临床应用个体差异影响因素,为临床安全合理用药提供参考。伏立康唑个体差异受多种因素综合影响,其中CYP2C19单核苷酸多态性以及药物间相互作用是重要影响因素。应积极对伏立康唑临床应用开展相关药学监护,逐步通过构建血药浓度监测结合相关代谢基因多态性检测手段,建立个体化用药模型,实现精准化药物治疗的目的。     

CYP2C19基因多态性对侵袭性真菌感染重症患者伏立康唑血药浓度的影响

目的:研究CYP2C19基因多态性与侵袭性真菌感染重症患者伏立康唑标准化血药浓度的关系,为临床合理用药提供参考。方法:运用PCR-RFLP方法对患者CYP2C19 2(681G→A)和CYP2C19 3(636 G→A)位点进行基因型分析;使用HPLC法检测49名侵袭性真菌感染患者的伏立康唑血药浓度;并对伏立康唑血药浓度检测结果、药物疗效和不良反应与基因分型结果进行统计学分析。结果:49名患者中,同时分析CYP2C19两个位点,共有5种双位点基因型组合,包括强代谢型(extensive metabolizer,EM)的681GG-636GG、中等代谢型(intermediate metabolizer,IM)的681GA-636GG和681GG-636GA以及慢代谢型(poor metabolizer,PM)的681AA-636GG和681GA-636GA,其分布频率分别为14.29%,53.06%,8.16%,14.29%和10.2%。EM组、IM组和PM组的标准化血药浓度存在显著性差异(P<0.05),且PM组显著高于IM组,IM组显著高于EM组(P<0.05)。此外,基因多态性对各组间的药物疗效(P<0.05)和不良反应(P<0.05)均具有显著性影响。结论:CYP2C19基因多态性对伏立康唑血药浓度、疗效和不良反应产生显著影响,表明药物遗传学研究对伏立康唑临床合理用药具有重要的指导意义。     

米卡芬净与伏立康唑联合治疗侵袭性真菌感染的临床研究

目的评价米卡芬净静脉注射后口服伏立康唑治疗ICU侵袭性真菌感染(IFI)疗效及安全性。方法将侵袭性真菌感染患者,根据不同抗真菌治疗方法分成两组,A组(16例)采用米卡芬净静注后伏立康唑口服联合疗法;B组(16例),米卡芬净组静脉滴注米卡芬净(100 mg/d),观察两组患者的疗效和不良反应。结果 A组的总有效率为87.5%(14/16),药物相关的不良反应发生率6.3%(1/16);B组的总有效率56.3%(9/16),药物相关的不良反应发生率为25%(4/16)。两组总有效率较高,但有显著性差异(P0.05),A组不良反应率显著低于B组。结论两种方案对侵袭性真菌感染的患者均有效,米卡芬净联合伏立康唑疗法比单独应用米卡芬净更具有疗效优势,且安全性好,不良反应少,有显著性差异(P0.05)。     

Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis

This randomised, double‐blind, placebo‐controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non‐Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks’ treatment. The primary endpoint was 6‐ and 12‐week all‐cause mortality (Korean modified intent‐to‐treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non‐Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non‐Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was ?6.4% in non‐Koreans. This reduction was more marked in Koreans (?22.4%). Week 12 difference in all‐cause mortality between combination and monotherapy was ?17.7% (Koreans) and ?20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5‐2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non‐Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non‐Koreans.     

Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first‐ or second‐line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co‐administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft‐versus‐host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug‐drug interactions in these patients.     

Successful multimodal therapy of invasive pulmonary and central nervous system aspergillosis in a neutropenic surgical patient: case report and review of the literature

Invasive aspergillosis predominantly occurs in patients with impaired host defence and is often resistant to different therapeutically strategies. However, mortality significantly increases if the central nervous system is affected. In this report, we describe a case of successful treatment of invasive aspergillosis with cerebral involvement. The treatment consists of a medication of voriconazole and lipid-associated amphotericin B as well as a stereotactic neurosurgical procedure to drain an intracranial abscess.