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.     

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.     

Pharmacologic and clinical evaluation of posaconazole

Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances.     

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.     

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...     

Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.     

Antifungal drugs: predicting clinical efficacy with pharmacodynamics

Invasive fungal infections are on the rise, particularly in hospitalized patients and immunocompromised hosts. In recent years, several new antifungals have become available at a rapid pace. Data on pharmacokinetics/pharmacodynamics of the newer/older antifungal drugs are accumulating. As with bacterial infections and antibacterial drugs, predicting the clinical efficacy of antifungal drugs based on pharmacodynamic parameters is becoming feasible. For the echinocandin class, a ratio of 10 or more for peak concentration/minimum inhibitory concentration (MIC) predicts efficacy against most Candida organisms. Increasing the currently used doses does not appear to improve efficacy. For the triazole class, a ratio of 25 or more for the pharmacodynamic parameter, AUC/MIC, predicts efficacy of the antifungal drugs against invasive Candida infections. More data are needed for invasive mold infections. The polyene class of drugs exhibit concentration-dependent activity; doses higher than those used conventionally do not show any clinical advantage. Monitoring serum levels of the newer triazoles, voriconazole and posaconazole, appears to be necessary in clinical practice to ensure efficacy and avoid toxicity. Flucytosine levels help to predict toxicity, but not efficacy. Other classes of drugs do not warrant monitoring serum concentrations. As invasive fungal infections usually occur in the setting of compromised immune defenses, clinical success does not depend upon the activity of the drugs alone; host immune factors need consideration to predict clinical outcome.     

Antifungal drugs and rational use of antifungals in treating invasive aspergillosis: the role of the hospital pharmacist

Aim:This review discusses the most common used antifungal agents in the treatment of invasive fungal infections. In addition, guidelines for the treatment of invasive aspergillosis, as used in the Ghent University Hospital, are described. Moreover, the importance of determining the effectiveness of antifungal therapy as well as the potential role of the hospital pharmacist in the management of this infection is highlighted. Methods:A review of the English-language literature was conducted using the MEDLINE database and scientific websites. Search terms including antimycotics, antifungal therapy and invasive aspergillosis were used to refine the search, and preference was given to studies published after 1992. This was completed with recent treatment guidelines. Results:An overview of the most recent advances in antifungal therapy is described. In addition, a flowchart for treatment of invasive aspergillosis (proven, probable or possible) has been developed. Conclusion:Invasive fungal infections will remain a frequent and important complication of modern medicine. Considering the clinical and financial outcome of invasive fungal infections, the role of the hospital pharmacist can be a paramount to the treatment.     

Posaconazole : a review of its use in the prophylaxis of invasive fungal infections

Posaconazole is a second-generation triazole antifungal agent with a broad spectrum of activity that includes Aspergillus spp., Candida spp. and the Zygomycetes. In the US, posaconazole oral suspension administered three times daily is indicated for prophylaxis against invasive Aspergillus and Candida infections in patients aged > or =13 years who are at high risk of developing these infections because of immunosuppression, such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy. EU-approved prophylactic indications for posaconazole are similar to those in the US.Posaconazole provided effective prophylaxis against invasive fungal infections and was generally well tolerated in two large, well designed trials in HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) that was expected to result in prolonged neutropenia. It offers coverage of clinically relevant pathogens and is potentially associated with fewer drug-drug interactions than other licensed triazole antifungal agents. Its usefulness in some patients may be limited by the lack of an intravenous formulation, although one is currently being developed. As with other antifungal agents, concerns remain regarding the potential emergence of resistance to broad-spectrum antifungal prophylaxis with posaconazole. Despite this, posaconazole is a valuable emerging option for use as prophylaxis against invasive fungal infections in immunocompromized patients who are at high risk of developing these infections.     

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.     

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.     

Current and future antifungal therapy: new targets for antifungal therapy

Invasive fungal infections will continue to cause major complications in immunocompromized patients. At the moment, the expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive fungal infections. The overview of the development of antifungal therapy which is provided here demonstrates the increased interest in this very special area of infectious diseases. Although we now have some newer and less toxic antifungal agents that are currently available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not very good. Intense efforts in antifungal drug discovery are urgently needed to develop more promising and effective antifungal agents for use in the clinical arena.     

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.     

Posaconazole

Posaconazole is a triazole antifungal agent, administered as an oral suspension, with an extended spectrum of in vitro activity. Posaconazole 800 mg/day demonstrated clinically relevant activity against a range of fungi in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal therapy in an open-label, multicentre, phase III study (330 patients received posaconazole and 279 patients served as external controls). In aspergillosis, the global response success rate at the end-of-therapy visit (primary endpoint) was significantly higher in posaconazole recipients than in external controls (42% vs 26%). Posaconazole was also associated with overall success rates of 54% in zygomycosis, 46% in fusariosis, 43% in Pseudallescheria infection, 80% in phaeohyphomycosis and 100% in histoplasmosis. Success rates were 48% in refractory candidiasis, 69% in refractory coccidioidomycosis, 48% in refractory cryptococcal infection and 82% in refractory chromoblastomycosis or mycetoma. Posaconazole also demonstrated potential in febrile neutropenia in an open-label phase II study (success rate of 81% 7 days after the end of treatment). In a noncomparative, multicentre, phase III study in patients with advanced HIV infection who had azole-refractory oropharyngeal and/or oesophageal candidiasis, posaconazole 400 or 800 mg/day resulted in a clinical response in 132 of 176 patients (75%). Oral posaconazole suspension was generally well tolerated in patients with invasive fungal infections, including patients who received treatment for >or=1 year.     

抗真菌药物联合治疗侵袭性真菌感染的研究进展

近些年,侵袭性真菌感染的发病率逐年增加。由于临床上单药治疗侵袭性真菌感染的效果欠佳,特别是耐药真菌的感染,可选择的药物极少,导致相关疾病的发病率和死亡率仍很高,故抗真菌药物的联合治疗得到了广大学者的青睐。总结了抗真菌药物联合治疗侵袭性真菌感染的机制,综述了针对中枢神经系统、肺部、血液系统、其他部位侵袭性真菌感染的联合用药情况,为临床合理使用抗菌药物提供参考依据。     

Caspofungin: first approved agent in a new class of antifungals

Caspofungin (Cancidas, Merck & Co. Inc.) is the first echinocandin antifungal agent to gain FDA-approval for use in the US. It has excellent clinical activity against Candida spp. and Aspergillus spp. but lacks significant activity against Cryptococcus neoformans. Caspofungin may have some activity against dimorphic fungi such as Histoplasma capsulatum and Coccidioides immitis, but no clinical data is available for treatment of these infections. Caspofungin has demonstrated poor activity against most filamentous fungi in vitro. Several clinical trials have demonstrated its efficacy in the treatment of oropharyngeal, oesophageal and invasive candidiasis, as well as invasive aspergillosis. As a result of caspofungin's unique mechanism of action, and the high morbidity and mortality of invasive fungal infections, there is considerable interest in using this new antifungal agent as part of a combination antifungal therapy. In vitro studies and small case series indicate that caspofungin does not appear to be antagonistic when combined with other antifungals, such as itraconazole, voriconazole or amphotericin B against Aspergillus spp. Caspofungin exerts concentration-dependent killing effects in many different in vitro and animal models of disseminated fungal infection. The usual daily dose is 50 mg/day i.v. following a 70 mg i.v. loading dose. However, higher caspofungin doses have been safely administered and up to 70 mg/day can be administered for patients who fail to respond to lower doses. Caspofungin has an excellent safety profile with reduced toxicities, compared to other licensed antifungal agents. Fever, thrombophlebitis, headache and liver enzyme elevations were the most common drug-related side effects reported in clinical trials so far. Additional data are needed to document its safety in long-term use, and with higher doses in patients with invasive fungal infections. Caspofungin is a promising agent as first-line therapy for invasive candidiasis, and as salvage therapy for invasive aspergillosis. However, more clinical data are needed to define its role as primary therapy for invasive aspergillosis, and its role in combination antifungal therapy.     

Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination

The incidence of invasive fungal infections has been increasing since the 1980s due to a growing population of immunocompromised and critically ill patients with associated risk factors including immunosuppressive chemotherapy, prolonged periods on intensive care units and infection with HIV. Persons who are severely immunocompromised are particularly vulnerable to infection from molds and yeasts that are often found naturally in the environment. In recent years, several new systemic antifungal agents have been released, significantly increasing options for the treatment of the most serious fungal infections. Newly available drugs as those in the echinocandin class include caspofungin, micafungin and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. In this review, the in vitro and in vivo activity of anidulafungin and voriconazole, both new antimycotic substances with a different mode of action, are analyzed.     

Posaconazole

Invasive fungal infections are occurring with increasing frequency secondary to medical advances in the areas of transplantation, cancer management and autoimmune diseases. Unfortunately, the currently available antifungal armamentarium does not meet the increasing needs of managing infection in these complex patient populations. Posaconazole, a new triazole antifungal agent, is being investigated for its role in treating serious infections due to yeasts and molds. This new drug offers an expanded spectrum of activity over other members of its class. In addition to potent activity against fluconazole-resistant Candida and refractory cases of aspergillosis, posaconazole demonstrates activity against Zygomycetes. Posaconazole is a well-tolerated agent that offers a diminished toxicity profile compared with other currently marketed systemic antifungal agents. Clinical success rates thus far have been promising, although the exact role of this agent in treating and preventing invasive fungal infections is yet to be determined.     

Newer systemic antifungal agents : pharmacokinetics, safety and efficacy

The past few years have seen the advent of several new antifungal agents, including those of a new class and a new generation of an existing class. Caspofungin, the first available echinocandin, has greatly expanded the antifungal armamentarium by providing a cell wall-active agent with candidacidal activity as well as demonstrated clinical efficacy in the therapy of aspergillosis refractory to available therapy. In addition, in clinical trials, caspofungin had comparable efficacy to amphotericin B for candidaemia and invasive Candida infections. Caspofungin and two more recently introduced echinocandins, micafungin and anidulafungin, are available as intravenous formulations only and characterised by potent anti-candidal activity, as well as few adverse events and drug interactions. Voriconazole, the first available second-generation triazole, available in both intravenous and oral formulations, has added a new and improved therapeutic option for primary therapy of invasive aspergillosis and salvage therapy for yeasts and other moulds. In a randomised trial, voriconazole demonstrated superior efficacy and a survival benefit compared with amphotericin B followed by other licensed antifungal therapy. This and data from a noncomparative study led to voriconazole becoming a new standard of therapy for invasive aspergillosis. Voriconazole has several important safety issues, including visual adverse events, hepatic enzyme elevation and skin reactions, as well as a number of drug interactions. Posaconazole, only available orally and requiring dose administration four times daily, shows encouraging efficacy in difficult to treat infections due to zygomycetes. Ravuconazole, available in both intravenous and oral formulations, has broad-spectrum in vitro potency and in vivo efficacy against a wide range of fungal pathogens. Clinical studies are underway. Despite the advances offered with each of these drugs, the morbidity and mortality associated with invasive fungal infections remains unacceptable, especially for the most at-risk patients. For individuals with severe immunosuppression as a result of chemotherapy, graft-versus-host disease and its therapy, or transplantation, new drugs and strategies are greatly needed.     

Clinical microbiology and infectious diseases. Management of fungal infections

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Despite remarkable progress in mycology, many uncertainties and difficulties remain. Invasive fungal infections are difficult to diagnose. Noninvasive, rapid diagnostic tools, such as the detection of Aspergillus galactomannan antigen in serum or of fungal nucleic acids by molecular methods are promising, but are still under investigation. The other difficulty in diagnosis is the lack of standard, consistent criteria. Very recently, diagnostic criteria based on host factors, as well as clinical features and microbiological results, have been proposed. Treatment of invasive fungal infections is also problematic. The development of novel antifungal compounds constitutes a major advance in antifungal therapy. These include novel azoles such as voriconazole (Pfizer), posaconazole (Schering- Plough), and ravuconazole (Eisai/Bristol-Myers Squibb), and novel echinocandins such as caspofungin (Merck), anidulafungin (Eli Lilly), and micafungin (Fujisawa Pharmaceutical). These agents appear more efficacious and less toxic than currently available antifungal drugs. However, immune status of the host remains one of the major determinants of clinical outcome. This property limits the efficiency of in vitro antifungal susceptibility tests in predicting in vivo outcome. Using immune system modifiers such as cytokines in combination with antifungal agents is beneficial in the improvement of immune status, and thus clinical outcome.