Antifungal prophylaxis in adult hematopoietic stem cell transplant recipients

Invasive fungal infections (IFIs) are a frequent, costly and potentially life-threatening complication in hematopoietic stem cell transplant (HSCT) recipients. Most prevalent among the causative pathogens are Candida spp. and Aspergillus spp. Risk factors that further increase the risk of IFIs in this patient population include allogeneic transplant and acute graft versus host disease. Among strategies to improve outcomes is the administration of antifungal prophylaxis. However, optimal administration requires the identification of patients who are at the highest risk of developing a fungal infection, thus restricting concerns of drug cost, toxicity and resistance to those most likely to benefit. Currently, there are several antifungal agents recommended by the National Comprehensive Cancer Network for the prophylaxis of IFIs. These include fluconazole, itraconazole, voriconazole, posaconazole and micafungin. Fluconazole was widely considered the standard agent for prophylaxis in patients at lower risk of mold infections. New data support the efficacy of the newer triazole posaconazole and the echinocandin micafungin in this patient population..     

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.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

Therapeutic drug monitoring of voriconazole and posaconazole

Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.     

Second-generation azole antifungal agents

The development of the triazole antifungal agents in the 1980s and 1990s greatly enhanced physicians' ability to treat fungal infections due to the lower toxicity of these agents compared with previous antifungal therapies. Despite the addition of these agents, there continues to be limited therapeutic choices for a number of mycoses that cause significant disease in humans. Three new agents (voriconazole, posaconazole and ravuconazole) have been developed which appear to have expanded antifungal activity compared with prior azoles. This review discusses the pharmacology, in vitro and in vivo activity, clinical studies and toxicities of these second-generation azoles. Presently, only voriconazole is available clinically and is indicated for the treatment of esophageal candidiasis, invasive aspergillosis, and refractory infections with Scedosporium apiospermum and Fusarium spp. Posaconazole and ravuconazole are still in development for human use.     

In vitro antifungal activity of posaconazole against various pathogenic fungi

The antifungal activity of posaconazole (SCH56592), a new triazole antifungal, against stock cultures and fresh clinical isolates of a wide range of pathogenic fungi was compared with that of itraconazole, fluconazole and amphotericin B. Posaconazole inhibited growth of all the fungal species tested except Fusarium spp. at 1 mg/l or lower concentrations, showing a broad-spectrum antifungal activity. The activities of posaconazole for all the fungal species far surpassed those of fluconazole and were even superior to those of itraconazole for Aspergillus spp. as well as for many other fungal species.     

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。     

Posaconazole: a pharmacoeconomic review of its use in the prophylaxis of invasive fungal disease in immunocompromised hosts

Posaconazole (Noxafil?) is an oral, second-generation, extended-spectrum triazole whose approved indications include prophylaxis of invasive fungal disease (IFD) in immunocompromised patients. In pivotal head-to-head trials, posaconazole was significantly more effective in preventing IFD than standard azole therapy (i.e. oral fluconazole or itraconazole) in chemotherapy-induced neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) and was noninferior to treatment with fluconazole in patients with graft-versus-host disease (GVHD) who were receiving intensive immunosuppressive therapy following haematopoietic stem cell transplantation. In both indications, prophylactic posaconazole was associated with significantly lower rates of IFD-related mortality. The overall tolerability profile of posaconazole was generally similar to that of the other prophylactic treatments. The large body of modelled cost-effectiveness analyses from a healthcare payer perspective on the use of prophylactic posaconazole suggest that it is a dominant or cost-effective option relative to prophylaxis with standard azole therapy in neutropenic patients with AML/MDS, and fluconazole in patients with GVHD. Based on clinical trial data in these patient groups, antifungal prophylaxis with posaconazole was predicted to be a dominant or cost-effective option relative to prophylaxis with standard oral azoles, with regard to the incremental cost per QALY gained, life-year (LY) gained and/or other outcomes in cost-effectiveness analyses in numerous countries. In those analyses in which posaconazole did not dominate the comparator, posaconazole was considered cost effective, as the incremental cost per QALY or LY gained with posaconazole was lower than assumed willingness-to-pay thresholds. Sensitivity analyses consistently demonstrated that these results were robust to plausible changes in key model assumptions. In conclusion, prophylactic treatment with posaconazole is clinically effective in preventing IFD in neutropenic patients with AML/MDS and patients with GVHD. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of posaconazole as a dominant or cost-effective prophylactic antifungal treatment relative to prophylaxis with standard oral azoles in these patient populations at high risk of developing IFD.     

Itraconazole: pharmacology, clinical experience and future development

Itraconazole is an orally active, broad-spectrum, triazole antifungal agent which has a higher affinity for fungal cytochrome P-450 than ketoconazole but a low affinity for mammalian cytochrome P-450. Itraconazole has a broader spectrum of activity than other azole antifungals and shows interesting pharmacokinetic features in terms of its tissue distribution. These properties have resulted in reduced treatment times for a number of diseases such as vaginal candidiasis, as well as effective oral treatment of several deep mycoses, including aspergillosis and candidiasis. Currently itraconazole is registered in 42 countries for the treatment of systemic fungal infections. Further development is concentrating on antifungal prophylaxis as well as on an oral solution and an intravenous formulation.     

Fluconazole: a new antifungal agent

The chemistry, activity, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and administration of fluconazole are reviewed. Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esophageal candidiasis and cryptococcal meningitis. Like the imidazoles, fluconazole inhibits the C-14 demethylation of lanosterol, but it has little or no effect on mammalian cytochrome P-450 enzymes. Fluconazole's activity in vitro does not reflect its effectiveness in vivo. Pharmacokinetic characteristics include water solubility and excellent bioavailability, low protein binding, extensive tissue distribution, and penetration into the cerebrospinal fluid. Fluconazole is eliminated primarily by the kidneys; dosage adjustments are necessary in patients with renal insufficiency. Studies have shown fluconazole to be effective in patients with cryptococcal meningitis and candidiasis, but the superiority of fluconazole over such agents as amphotericin B, ketoconazole, clotrimazole, and itraconazole remains to be proved. Fluconazole has shown varying degrees of success in the treatment of other systemic mycoses. The adverse effects of fluconazole are relatively infrequent and are primarily gastrointestinal. Tolbutamide, warfarin, rifampin, cyclosporine, and phenytoin interact with fluconazole. The drug is available in both oral and intravenous formulations. Fluconazole is a broad-spectrum antifungal drug that appears to be similar in efficacy to other antifungals in the treatment of some systemic mycoses. More studies must be completed before fluconazole can be recommended as a first-line antifungal therapy.     

Impact of patient education on plasma concentrations and effectiveness of posaconazole oral suspension under clinical conditions

Posaconazole prophylaxis is recommended for patients with acute myeloid leukaemia during induction chemotherapy. Although a tablet formulation with better oral bioavailability is available, some patients have to rely on the oral suspension in clinical routine. Therefore, effectiveness of posaconazole oral suspension under real‐life clinical conditions and impact of patient education about the correct intake on its plasma concentrations were assessed in this study. Altogether 96 patients receiving 160 cycles of induction chemotherapy were retrospectively (40 patients) and prospectively (56 patients) analysed. Patients were assigned into two groups for each chemotherapy cycle according to the application of antifungal prophylaxis (A: posaconazole oral suspension, 200 mg three times a day ≥7 days; B: intake <7 days, fluconazole or no prophylaxis). Antifungal prophylaxis and therapy were analysed for each cycle. Additionally, plasma concentrations were determined from prospectively included subjects of group A who were intensively educated to perform a correct drug intake. Systemic antifungal therapy was statistically started less often in group A (26% vs 53%; P = 0.002). Posaconazole prophylaxis was associated with a lower risk of proven invasive fungal infection (P = 0.003). Median plasma concentration apparently increased between the first and second time of determination effected by an initial intensive on‐site patient education. The clinical effectiveness of posaconazole oral suspension was confirmed. A detailed patient education at the beginning of the treatment with posaconazole oral suspensions seems to be of primary importance for efficient plasma concentrations.     

Pharmacokinetics of antifungal agents in onychomycoses

Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.     

泊沙康唑预防侵袭性真菌感染疗效及安全性的Meta分析

目的 系统评价泊沙康唑预防侵袭性真菌感染的疗效及安全性.方法 检索PubMed、Web of Science、Embase、Cochrane Library、Clinicaltrials.gov、中国知网期刊全文数据库、维普中文科技期刊数据库、万方数据库及中国生物医学文献数据库,截止时间2019年9月20日,收集所有关...     

Posaconazole: a new broad-spectrum antifungal agent

The rising incidence of invasive fungal infections and the emergence of broader fungal resistance have led to the need for novel antifungal agents. Posaconazole is a new member of the triazole class of antifungals. It is available as an oral suspension and has a favorable toxicity profile, has demonstrated clinical efficacy in the treatment of oropharyngeal candidiasis and has shown promise as salvage therapy for invasive aspergillosis, zygomycosis, cryptococcal meningitis and a variety of other fungal infections. In addition, data from randomized controlled studies support its efficacy for use in prophylaxis of invasive fungal infections in patients who are severely immunocompromised. The wide spectrum activity of posaconazole in in vitro studies, animal models and preliminary clinical studies suggest that posaconazole represents an important addition to the antifungal armamentarium.     

Posaconazole: a new broad-spectrum antifungal agent

The rising incidence of invasive fungal infections and the emergence of broader fungal resistance have led to the need for novel antifungal agents. Posaconazole is a new member of the triazole class of antifungals. It is available as an oral suspension and has a favorable toxicity profile, has demonstrated clinical efficacy in the treatment of oropharyngeal candidiasis and has shown promise as salvage therapy for invasive aspergillosis, zygomycosis, cryptococcal meningitis and a variety of other fungal infections. In addition, data from randomized controlled studies support its efficacy for use in prophylaxis of invasive fungal infections in patients who are severely immunocompromised. The wide spectrum activity of posaconazole in in vitro studies, animal models and preliminary clinical studies suggest that posaconazole represents an important addition to the antifungal armamentarium.     

Itraconazole

Itraconazole is a broad spectrum triazole antifungal agent. It has favourable pharmacodynamic and pharmacokinetic profiles and is available as both oral and iv. formulations. Over the last two decades, clinical and animal infection studies have demonstrated the efficacy of itraconazole in a wide range of superficial fungal infections including difficult-to-treat dermatophytoses and onychomycoses. Furthermore, shortened treatment regimens have proven to be effective, ranging from 1-day treatment for vaginal candidosis to 1-week pulse therapy per month, for 2 - 4 months, in onychomycosis and follicular dermatophytosis. Clinical experience with itraconazole in the treatment of deep mycoses is less comprehensive. However, results in systemic candidosis, sporotrichosis, blastomycosis, paracoccidioiodomycosis, certain types of histoplasmosis and aspergillosis are extremely encouraging. Itraconazole is less effective in the treatment of chromomycosis and coccidioidomycosis. Nevertheless, considering the refractory nature of these diseases, itraconazole has proven to be a valuable addition to the antifungal drugs currently available for treatment. Itraconazole has been well-tolerated with doses of up to 400 mg/day being generally free of serious adverse effects. However, a potential for drug interactions exists, mediated through the cytochrome P450 enzyme 3A4 system, which should be considered when itraconazole is used as part of a multi-drug regimen.     

泊沙康唑的药动学及其药物相互作用

泊沙康唑为一新型三唑类抗真菌药,临床用于治疗和预防侵袭性真菌感染,具有高效、低毒、广谱的特点,并具有良好的耐受性,但对CYP3A4酶具有抑制作用,故可与多种药物发生药动学相互作用。本文综述了泊沙康唑的药动学特点及其药物相互作用,供临床参考,以促进临床安全合理用药。     

Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.     

Newer triazole antifungal agents: pharmacology,spectrum, clinical efficacy and limitations

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.