静脉序贯口服伏立康唑治疗血液病患者合并侵袭性真菌感染疗效和安全性分析

目的探讨静脉序贯口服伏立康唑治疗血液病患者合并侵袭性真菌感染（IFI）的临床疗效和安全性。方法选取合并患有侵袭性真菌感染的血液病患者88例,按就诊顺序分为对照组和治疗组各44例,对照组采用常规抗感染药物治疗,治疗组在使用常规抗感染药物基础上,加用伏立康唑治疗,比较两组临床疗效,并观察药物不良反应。结果治疗组总有效率（90．91％）显著高于对照组（70．45％）（x^2=5．906,P〈0．05）,感染控制时间、持续用药时间和不良反应发生率显著低于对照组（t=2．019、1．987,x^2=4．062,均P〈0．05）。结论静脉序贯口服伏立康唑治疗血液病患者合并侵袭性真菌感染安全、有效,不良反应少。     

Triazole antifungal agents in invasive fungal infections: a comparative review

Invasive fungal disease continues to be a problem associated with significant morbidity and high mortality in immunocompromised and, to a lesser extent, immunocompetent individuals. Triazole antifungals have emerged as front-line drugs for the treatment and prophylaxis of many systemic mycoses. Fluconazole plays an excellent role in prophylaxis, empirical therapy, and the treatment of both superficial and invasive yeast fungal infections. Voriconazole is strongly recommended for pulmonary invasive aspergillosis. Posaconazole shows a very wide spectrum of activity and its primary clinical indications are as salvage therapy for patients with invasive aspergillosis and prophylaxis for patients with neutropenia and haematopoietic stem-cell transplant recipients. Itraconazole also has a role in the treatment of fungal skin and nail infections as well as dematiaceous fungi and endemic mycoses. Fluconazole and voriconazole are well absorbed and exhibit high oral bioavailability, whereas the oral bioavailability of itraconazole and posaconazole is lower and more variable. Posaconazole absorption depends on administration with a high-fat meal or nutritional supplements. Itraconazole and voriconazole undergo extensive hepatic metabolism involving the cytochrome P450 system. The therapeutic window for triazoles is narrow, and inattention to their pharmacokinetic properties can lead to drug levels too low for efficacy or too high for good tolerability or safety. This makes these agents prime candidates for therapeutic drug monitoring (TDM). Target drug concentrations for voriconazole and itraconazole should be >1?μg/mL and for posaconazole >1.5?μg/mL for treatment. Blood should be drawn once the patient reaches steady state, which occurs after 5 and 7 days of triazole therapy. Routine TDM of fluconazole is not required given its highly favourable pharmacokinetic profile and wide therapeutic index. The aim of this review is to provide a brief update on the pharmacology, activity, clinical efficacy, safety and cost of triazole agents (itraconazole, fluconazole, voriconazole and posaconazole) and highlight the clinical implications of similarities and differences.     

Lipid-based formulations of amphotericin B

Amphotericin B remains the drug of choice for the treatment of invasive fungal infections and visceral leishmaniasis. However, both the dose-dependent nephrotoxicity and the low response rates (10-80%) associated with amphotericin B limit its clinical use. The first marketed formulation of amphotericin B with deoxycholate, Fungizone, remains the "gold standard" in spite of its renal toxicity. Several investigations have been made to reduce the nephrotoxicity of amphotericin B by formulation strategies. Lipid-based formulations of amphotericin B were found to reduce toxicity and to increase tolerance and therapeutic efficacy. Three lipid formulations are now available in most countries: liposomal amphotericin B (AmBisome), amphotericin B lipid complex and amphotericin B colloidal dispersion. Amphotericin B colloidal dispersion was less nephrotoxic, but immediate reactions to this formulation were as frequent and severe as those to amphotericin B. Amphotericin B lipid complex appeared to be as effective as amphotericin B, with improved general and renal tolerability. Several comparative studies have confirmed that AmBisome has similar or superior efficacy relative to amphotericin B in various fungal infections, in visceral leishmaniasis and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. A significant drawback to the newer, less toxic, commercial lipid-based formulations is their cost. There is a need to develop more affordable lipid-based formulations of amphotericin B.     

伏立康唑预防血液病患者侵袭性真菌感染的疗效与安全性

目的评价伏立康唑预防血液病患者化疗或造血干细胞移植(HSCT)后侵袭性真菌感染的有效性及安全性。方法检索Cochrane图书馆、Medline、Em-base、Pubmed、CBM、CNKI、维普、万方等文献数据库,用RevMan 5.1进行meta分析。结果纳入研究4项,共1372例患者,伏立康唑组的真菌感染发生率、曲霉感染率分别低于氟康唑组、对照组;而总死亡率、念珠菌感染率与对照组无显著性差异;伏立康唑的胃肠道不良反应发生率低于伊曲康唑,视觉障碍和肝功异常发生率高于伊曲康唑。结论伏立康唑预防血液病患者化疗或HSCT后侵袭性真菌感染的总体疗效优于氟康唑,与伊曲康唑相当,在预防侵袭性曲霉感染中优于氟康唑和伊曲康唑,但应警惕其引起视觉障碍和肝功异常。     

Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections

Background:

Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy.

Objective:

To determine the utility of therapeutic drug monitoring for voriconazole.

Methods:

A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.

Results:

Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug–drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug–drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25–2 mg/L and 4–6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association.

Conclusions:

Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility.     

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..     

symbol: see text]Caspofungin and [symbol: see text]voriconazole for fungal infections

Systemic fungal infections are difficult to treat and often fatal. Established treatment options include conventional amphotericin B or one of its lipid-based or liposomal formulations, or a triazole antifungal such as fluconazole or itraconazole. [symbol: see text]Caspofungin (Cancidas--Merck Sharp & Dohme) and [symbol: see text]voriconazole (Vfend--Pfizer) are two new antifungals for severe infections caused by Candida spp. (invasive candidiasis) and Aspergillus spp. (invasive aspergillosis). Caspofungin is the first licensed echinocandin antifungal, while voriconazole is a triazole. Promotional claims for caspofungin include that it "provides an effective, yet less toxic, alternative to amphotericin B" while voriconazole is claimed to offer "significantly improved survival in invasive aspergillosis compared with amphotericin B". Here we consider the place of caspofungin and voriconazole in managing patients with severe fungal infections.     

Echinocandins in the management of invasive fungal infections, Part 2.

PURPOSE: The chemistry, pharmacology, spectrum of activity, resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, drug interactions, dosage and administration, cost, and place in therapy of echinocandins are reviewed. SUMMARY: Three echinocandins are currently available: caspofungin, micafungin, and anidulafungin. The principal mechanism of action of the echinocandins is the noncompetitive inhibition of beta-(1,3)-D-glucan synthase, an essential component of the cell wall of many fungi that is not present in mammalian cells. Echinocandins exhibit fungicidal activity against Candida species, including triazole-resistant isolates, and fungistatic activity against Aspergillus species. While fungistatic against mold, echinocandins may hold promise for the treatment of these pathogens when given in combination with amphotericin B or broad-spectrum triazoles, such as voriconazole. To date, resistance to echinocandins has been reported in only two patients. Echinocandins exhibit concentration-dependent activity against Candida species. In clinical trials, caspofungin has demonstrated efficacy in treating candidemia, esophageal candidiasis, and febrile neutropenia. Micafungin has demonstrated efficacy as antifungal prophylaxis in hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis. Anidulafungin received approved labeling from the Food and Drug Administration in February 2006. Clinical efficacy data will be forthcoming. CONCLUSION: Echinocandins are fungicidal against yeast and fungistatic against mold. Their limited toxicity profile and minimal drug-drug interactions make them an attractive new option for the treatment of invasive fungal infections. Their cost may limit their use as initial therapy for patients with fungemia in medical centers or intensive care units with a high rate of triazoleresistant Candida infections.     

Oral voriconazole for empiric antifungal treatment in patients with uncomplicated febrile neutropenia

STUDY OBJECTIVE: To determine the success rate and toxicity profile of oral voriconazole when used as empiric antifungal therapy in patients with uncomplicated persistent neutropenic fever. DESIGN: Retrospective medical record review. SETTING: University hospital. PATIENTS: Twenty-seven patients who received oral voriconazole as empiric antifungal treatment during 31 episodes of persistent neutropenic fever between August 1, 2003, and April 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data were collected on patient demographics, diagnosis, cancer treatment plan, voriconazole regimen, dates of voriconazole treatment, other antibiotics administered during the episode of fever, and adverse events. Patient survival data from at least 3 months of follow-up were also collected. Treatment success, which was defined as survival to the resolution of fever without a need to change antibiotics and without new fungal infections, was also determined. Median duration of therapy was 11 days (range 2-54 days). No patient discontinued the drug because of toxicity. The success rate was 55% (95% confidence interval [CI] 36-73%). For all patients, 90-day survival from the start of voriconazole treatment was 81% (95% CI 63-93%). Neither treatment success nor 90-day survival rates differed significantly when they were compared by the route used for loading doses or by the presence of a possible invasive fungal infection at the start of voriconazole therapy. CONCLUSION: Oral voriconazole appears to be a safe empiric antifungal treatment with an encouraging rate of activity for patients with neutropenia and uncomplicated persistent fever. Further research, including randomized controlled trials comparing the efficacy of intravenous versus oral voriconazole, is needed.     

Human mycoses and current antifungal therapy

The Focus on Fungal Infections meeting has become a popular conference for specialists in medical mycology and antifungal chemotherapy. Highlights of the 8th meeting are reported, with a focus on infection and therapy. Although the incidence of mycoses has increased, the identification of these fungal etiologic agents remains difficult. Mucosal candidiasis caused by endogenous Candida albicans and Candida species remains the most common fungal manifestation in HIV-infected patients, while systemic infection by Aspergillus species also has increased in HIV patients. Two presenters at the meeting debated whether fungal infections in AIDS patients are becoming less common and less important. Various strategies for antifungal therapy in AIDS or HIV-positive patients were presented. Most fungal infections in solid organ transplant patients are due to Candida species or Aspergillus species; however, dematiaceous (dark-pigmented) fungi are becoming more common fungal pathogens in these patients. Antifungal therapy remains difficult in this patient group. The meeting included an overview of the current status of diagnosing fungal infections through serodiagnostic techniques. If properly validated, serology can be useful in fungal diagnosis since antigens and antibodies are easier to detect than the invading organism. Premature infants are at high risk for developing invasive fungal infections. Antifungal drugs have not been tested in controlled clinical trials in these patients, thus therapy is accomplished using adult treatment regimens and anecdotal experience. As regards the new lipid-based formulations of amphotericin B, published clinical studies are only now appearing in the literature and these reports suggest that the new formulations have reduced toxicity and comparable efficacy compared to conventional amphotericin B under various clinical conditions. Correlation of minimum inhibitory concentration (MIC) values with clinical response to therapy is beginning to emerge. Two fungal cell wall-active compounds have recently entered clinical trials: an echinocandin and the chitin-synthesis inhibitor nikkomycin Z. Pradimycin and analogues have been studied through experimental animal models with good success; however, phase I clinical trials suggested drug-related toxicities and development was stopped. New molecular targets also are being investigated in antifungal therapy.     

Echinocandins in the management of invasive fungal infections, part 1.

PURPOSE: The chemistry, pharmacology, spectrum of activity, resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effiects, drug interactions, dosage and administration, cost, and place in therapy of echinocandins are reviewed. SUMMARY: Three echinocandins are currently available: caspofungin, micafungin, and anidulafungin. The principal mechanism of action of the echinocandins is the noncompetitive inhibition of beta-(1,3)-dglucan synthase, an essential component of the cell wall of many fungi that is not present in mammalian cells. Echinocandins exhibit fungicidal activity against Candida species, including triazole-resistant isolates, and fungistatic activity against Aspergillus species. While fungistatic against mold, echinocandins may hold promise for the treatment of these pathogens when given in combination with amphotericin B or broad-spectrum triazoles, such as voriconazole. To date, resistance to echinocandins has been reported in only two patients. Echinocandins exhibit concentration- dependent activity against Candida species. In clinical trials, caspofungin has demonstrated efficacy in treating candidemia, esophageal candidiasis, and febrile neutropenia. Micafungin has demonstrated efficacy as antifungal prophylaxis in hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis. Anidulafungin received approved labeling from the Food and Drug Administration in February 2006. Clinical efficacy data will be forthcoming. CONCLUSION: Echinocandins are fungicidal against yeast and fungistatic against mold. Their limited toxicity profile and minimal drug-drug interactions make them an attractive new option for the treatment of invasive fungal infections. Their cost may limit their use as initial therapy for patients with fungemia in medical centers or intensive care units with a high rate of triazoleresistant Candida infections.     

Echinocandins: role in antifungal therapy, 2005

Novel therapies to treat invasive fungal infections have revolutionised the care of patients with candidiasis, aspergillosis and other less common fungal infections. Physicians in the twenty first century have access to safer versions of conventional drugs (i.e., lipid amphotericin B products), extended-spectrum versions of established drugs (i.e., voriconazole), as well as a new class of antifungal agents; the echinocandins. The increased number of options in the antifungal armamentarium is well timed, as the incidence of both invasive candidiasis and invasive aspergillosis, and the financial burden associated with these infections, have increased significantly in the past several decades. The increasing incidence of fungal infections has risen in parallel with the increase in critically ill and immunocompromised patients. Candida is the fourth most common bloodstream isolate, approximately 50% of which are non-albicans species. Estimates suggest there to be 9.8 episodes of invasive candidiasis per 1000 admissions to surgical intensive care units, with attributable mortality at 30% and cost per episode of US44,000 dollars. The burden of candidiasis is even higher in the paediatric population, with Candida being the second most common bloodstream infection. The increase in non-albicans candidiasis mandates the introduction of new antifungal agents capable of treating these often azole-resistant isolates. In addition, there has been a rise in the incidence of invasive aspergillosis, the most common invasive mould infection following haematopoietic stem cell transplantation, with an estimated incidence of 10 - 20%. The mortality associated with invasive aspergillosis has increased by 357% since 1980. Unfortunately, the overall survival rate among patients treated with amphotericin B, and even voriconazole, remains suboptimal, as evidenced by the failure of treatment in 47% of patients in the landmark voriconazole versus amphotericin B trial. Given the increasing incidence and suboptimal outcomes of these serious fungal infections, novel therapies represent an opportunity for significant advancement in clinical care. The current challenge is to discover the optimal place for the echinocandins in the treatment of invasive fungal infections.     

Voriconazole : a review of its use in the management of invasive fungal infections

Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis.In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.     

The lipid formulations of amphotericin B

Amphotericin B spectrum covers most of the fungal pathogens involved in human diseases. Its use is limited by infusion-related effects and nephrotoxicity. As a result of strong lipophilic properties, encapsulation in liposomes or binding to lipid complexes led to the development of lipid formulations in an attempt to increase both efficacy and safety. Three lipid formulations of amphotericin B are commercially available: a liposomal preparation, a lipid complex and a colloidal dispersion. They differ in their lipid composition, shape, pharmacokinetic behaviour and clinical effects. The nephrotoxicity of these formulations is significantly decreased compared to their parent compound. Infusion-related events are lowest with liposomal amphotericin B. Increased efficacy of the lipid formulations over conventional amphotericin B, however, still has to be demonstrated. These formulations are mainly indicated for the treatment of documented fungal infections in patients failing conventional amphotericin B or with renal impairment. Liposomal amphotericin B is also indicated for empirical therapy of suspected fungal infections in febrile neutropenic patients giving this compound an advantage over the two other formulations. Lipid formulations of amphotericin B are extremely expensive. Whether the increase in cost translates into a long-term benefit for the patient is still unknown.     

Antifungal agents

At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps.     

New antifungal agents and preparations

In neutropenic patients amphotericin B remains the drug of choice for the treatment of systemic fungal infections. On the basis of a superior efficacy in combination with a lower toxicity, the triazoles have superseded the older azoles. Regularly, amphotericin B and a triazole are used simultaneously without any evidence from clinical trials that such a strategy is safe and efficacious. Liposomal preparation, lipid complex or colloidal dispersion of amphotericin B have been produced successfully to reduce toxicity. However, there is only one small randomised study that hints at the superiority of liposomal amphotericin B over amphotericin B deoxycholate. Promising new agents like candins, sordarins, high dose oral terbinafine, the third generation azoles, and liposomal nystatin are under development. The first phase II study on voriconazole in the treatment of pulmonary aspergillosis has produced encouraging results. The major promise of the new candins lies in the activity against Candida species, including those resistant to the azoles and polyenes, and in a mechanism of action totally different from the established antifungals. Cytokines and colony stimulating factors are theoretically very promising but there are no clinical studies that warrant routine use.     

Systemic antifungal therapy: new options, new challenges

The frequency of invasive fungal infections has increased dramatically in recent decades because of an expanding population at risk. Until now, treatment options for invasive mycoses have been primarily amphotericin B and the azoles, fluconazole and itraconazole. Traditional agents are limited by an inadequate spectrum of activity, drug resistance, toxicities, and drug-drug interactions. The recent approval of caspofungin and voriconazole clearly has expanded the number of existing antifungal drugs available. However, the enthusiasm that accompanies their availability is counterbalanced by limited clinical experience, high drug acquisition costs, and distinctive toxicities. The pharmacologic characteristics, extent of clinical experience (efficacy and toxicity), and drug acquisition costs among available systemic antifungal agents are compared, with emphasis on the new agents. Also, recommendations on the role of each agent are provided according to the most common indications for systemic antifungal therapy: invasive candidiasis, invasive aspergillosis, and febrile neutropenia.     

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.     

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.     

Echinocandins: A ray of hope in antifungal drug therapy

Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall.Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis.The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.