Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.     

Antifungal prophylaxis in solid organ transplant recipients

Solid organ transplantation is life saving for thousands of patients worldwide with end-stage organ failure, but post-transplantation invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality. To improve patient outcomes, investigators have explored various strategies of prevention, including the use of antifungal prophylaxis with both systemic and topical nonabsorbable agents. Often, the strategy is to identify those patients at highest risk for IFIs who would be expected to derive the most benefit from antifungal prophylaxis. Currently, data support the use of antifungal prophylaxis in liver, lung, small bowel and pancreas transplant recipients. By understanding the epidemiology of post-transplant IFIs and antifungal adverse effects, clinicians may target antifungal prophylaxis more optimally. Herein, we review antifungal prophylaxis with systemic agents among solid organ transplant recipients.     

Antifungal prophylaxis in solid organ transplant recipients

Solid organ transplantation is life saving for thousands of patients worldwide with end-stage organ failure, but post-transplantation invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality. To improve patient outcomes, investigators have explored various strategies of prevention, including the use of antifungal prophylaxis with both systemic and topical nonabsorbable agents. Often, the strategy is to identify those patients at highest risk for IFIs who would be expected to derive the most benefit from antifungal prophylaxis. Currently, data support the use of antifungal prophylaxis in liver, lung, small bowel and pancreas transplant recipients. By understanding the epidemiology of post-transplant IFIs and antifungal adverse effects, clinicians may target antifungal prophylaxis more optimally. Herein, we review antifungal prophylaxis with systemic agents among solid organ transplant recipients.     

The PATH (Prospective Antifungal Therapy) Alliance® registry and invasive fungal infections: update 2012

The Prospective Antifungal Therapy Alliance (PATH Alliance®) performed prospective surveillance of invasive fungal infections (IFIs) among patients hospitalized at 25 medical centers in North America between 2004 and 2008, collecting information on the epidemiology, diagnosis, treatment, and mortality rates of IFIs. In total, 7526 IFIs were identified in 6845 patients. Candida spp. (73.4%) were the most common pathogens, followed by Aspergillus spp. (13.3%), and other yeasts (6.2%). Culture was the most frequently used diagnostic test in the majority of IFI categories. Most patients with invasive candidiasis were treated with fluconazole (48.3%) and the echinocandins (34.0%), while voriconazole (45.5%) was the main antifungal agent for invasive aspergillosis. The 12-week survival rate ranged from 37.5% for hematopoietic stem cell transplant recipients to ~ 75.0% for those with HIV/AIDS. In summary, the findings of the PATH Alliance® registry provide a better understanding of the epidemiology of a vast variety and large numbers of IFIs.     

Systemic Antifungal Prophylaxis After Hematopoietic Stem Cell Transplantation: A Meta-Analysis

Background

Hematopoietic stem transplant recipients are subject to increased risk for invasive fungal infections.

Objective

This meta-analysis was undertaken to explore the comparative effectiveness of systemic antifungal prophylaxis in hematopoietic stem cell transplant recipients.

Methods

We searched PubMed and The Cochrane Register of Randomized Controlled Trials up to March 2013 for randomized studies on systemic antifungal prophylaxis after hematopoietic stem cell transplantation. We performed a meta-analysis on the relative effectiveness of systemic antifungal prophylaxis on proven or probable invasive fungal infections using direct and indirect effects. Relative effectiveness was reported as odds ratio (OR) for invasive fungal infections, causative agent, empirical antifungal therapy, and withdrawals due to drug adverse events.

Results

Twenty evaluable studies provided data on 4823 patients. The risk for invasive fungal infections while on prophylaxis was 5.1% (95% CI, 3.6−6.8%). In patients receiving fluconazole, risks of proven or probable invasive fungal infections (OR = 0.24; 95% CI, 0.11−0.50; number needed to treat [NNT] = 8), systemic candidiasis (OR = 0.11; 95% CI, 0.05−0.24; NNT = 7), and overall need for empiric antifungal treatment (OR = 0.60; 95% CI, 0.44−0.82; NNT = 8) were reduced compared with patients receiving placebo. Itraconazole was more effective than fluconazole for the prevention of aspergillosis (OR = 0.40; 95% CI, 0.19−0.83; NNT = 23) at the expense of more frequent withdrawals (OR = 3.01; 95% CI, 1.77−5.13; number needed to harm = 6). Micafungin was marginally more effective than fluconazole for the prevention of all mold infections (OR = 0.35; 95% CI, 0.10−1.18; NNT = 79) and invasive aspergillosis (OR = 0.19; 95% CI, 0.03−1.11; NNT = 78) and reducing the need for empiric antifungal treatment (OR = 0.40; 95% CI, 0.13−1.21; NNT = 8). There was a relative lack of comparisons between different antifungal prophylactic strategies, including the newer azoles, voriconazole and posaconazole, in this population. Direct effects derived from single studies showed marginally significant effects for voriconazole compared with fluconazole regarding invasive aspergillosis (OR = 0.50; 95% CI, 0.20−1.20; NNT = 35) and the need for empiric treatment (OR = 0.72; 95% CI, 0.50−1.06; NNT = 15). Voriconazole compared with itraconazole (OR = 0.59; 95% CI, 0.40−0.88; NNT = 8) and posaconazole compared with amphotericin B (OR = 0.28; 95% CI, 0.06−1.24, marginal significance; NNT = 3) were better regarding empirical antifungal treatment.

Conclusions

Even when on antifungal therapy, invasive fungal infection will develop in 1 of 20 patients undergoing hematopoietic stem cell transplantation. There is evidence for the comparable effectiveness of different antifungal drugs used for prophylaxis. Fluconazole is the most widely studied agent, but micafungin might prove to be more effective. There is a relative paucity of studies for the newer azoles, although both voriconazole and posaconazole give proof of their comparative or higher effectiveness to fluconazole in single randomized studies.     

Antifungal prophylaxis and therapy in patients with hematological malignancies and hematopoietic stem cell transplant recipients

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.     

Antifungal prophylaxis and therapy in patients with hematological malignancies and hematopoietic stem cell transplant recipients

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.     

Micafungin use in children

Invasive fungal infections (IFIs) are one of the major reasons for morbidity and mortality in immunocompromised children. The majority of IFIs are caused by Candida and Aspergillus species. Early diagnosis and prompt initiation of appropriate antifungal therapy is essential for favorable outcome. Micafungin is a member of the echinocandins, a novel class of antifungal agents that target the biosynthesis of β-1,3-D-glucan, a key fungal cell wall component. It has concentration-dependent fungicidal activity against Candida species and fungistatic activity against Aspergillus species. Although optimal dosing of micafungin in children has not been established, the recommended dosage in children is 2 mg/kg/day (100 mg/day if >40 kg bodyweight) for invasive candidiasis, 1 mg/kg/day (50 mg/day if >40 kg bodyweight) for the prophylaxis of Candida infections in patients with anticipated prolonged and severe neutropenia or in allogeneic hematopoietic stem cell transplantation recipients. Micafungin has a favorable safety and drug-drug interaction profile. The most common adverse effects in children are diarrhea, epistaxis, abdominal pain, headache, nausea, vomiting, fever, chills, elevation of alanine aminotransferase/aspartate aminotransferase values, hypokalemia, thrombocytopenia, mucositis, and rash. Because of its different mechanisms of action, micafungin shows promise as part of the prophylactic and therapeutic management of IFIs, but larger prospective and comparative trials are needed for widespread use in children.     

Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation

Introduction: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden.

Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients.

Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.     

Echinocandin antifungals: review and update

The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-beta-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas) was the first approved echinocandin, followed recently by micafungin (Mycamine) and anidulafungin (Eraxis). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.     

Antifungal prophylaxis in haematology patients: the role of voriconazole

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in haematopoietic stem cell transplant (HCT) recipients and patients with haematological malignancies. Early treatment initiation is vital for improving survival, but is hampered by difficulties in timely diagnosis. Prophylaxis with a broad-spectrum antifungal, such as voriconazole, has the potential to decrease the incidence of IFI in haematology patients. Based on a growing body of data, voriconazole appears to be effective for the primary and secondary prevention of IFIs in HCT recipients, with generally good tolerability.     

Comparison of Efficacy and Safety of Caspofungin Versus Micafungin in Pediatric Allogeneic Stem Cell Transplant Recipients: A Retrospective Analysis

Introduction

The high morbidity and mortality associated with invasive fungal infections (IFIs) provide the rationale for antifungal prophylaxis in immuno-compromised pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Caspofungin and micafungin are antifungal agents of interest for prophylaxis of IFIs because of their potency against Candida and minimal toxicity or interactions with other drugs. Few studies have demonstrated the safety and efficacy of such echinocandins as prophylaxis for IFIs in patients undergoing HSCT.

Methods

This retrospective cohort study compared caspofungin and micafungin for prevention of IFIs in 93 pediatric patients undergoing HSCT for oncological or non-oncological disease. The observation began with the first dose of antifungal agent and ended 3 months after transplantation.

Results

Patients in the micafungin group had a higher overall treatment success rate of 87.2 versus 84.8% in the caspofungin group, but the difference was not significant. There were no statistically significant differences in the incidence or type of proven/probable IFIs between the 2 groups. The low incidence of death did not differ statistically between the groups. Patients in the caspofungin group presented more frequently with fever, during and after neutropenia. In both groups, we observed an expected worsening of blood chemistry parameters. There were no adverse events definitely attributable to the two antifungal agents.

Conclusion

These results demonstrate good efficacy and tolerability for caspofungin and micafungin. However, better results with respect to the incidence and resolution of fever in the micafungin group may suggest its use in preference to that of caspofungin.

     

Micafungin use in children

Invasive fungal infections (IFIs) are one of the major reasons for morbidity and mortality in immunocompromised children. The majority of IFIs are caused by Candida and Aspergillus species. Early diagnosis and prompt initiation of appropriate antifungal therapy is essential for favorable outcome. Micafungin is a member of the echinocandins, a novel class of antifungal agents that target the biosynthesis of β-1,3-D-glucan, a key fungal cell wall component. It has concentration-dependent fungicidal activity against Candida species and fungistatic activity against Aspergillus species. Although optimal dosing of micafungin in children has not been established, the recommended dosage in children is 2 mg/kg/day (100 mg/day if >40 kg bodyweight) for invasive candidiasis, 1 mg/kg/day (50 mg/day if >40 kg bodyweight) for the prophylaxis of Candida infections in patients with anticipated prolonged and severe neutropenia or in allogeneic hematopoietic stem cell transplantation recipients. Micafungin has a favorable safety and drug–drug interaction profile. The most common adverse effects in children are diarrhea, epistaxis, abdominal pain, headache, nausea, vomiting, fever, chills, elevation of alanine aminotransferase/aspartate aminotransferase values, hypokalemia, thrombocytopenia, mucositis, and rash. Because of its different mechanisms of action, micafungin shows promise as part of the prophylactic and therapeutic management of IFIs, but larger prospective and comparative trials are needed for widespread use in children.     

Echinocandin antifungals: review and update

The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-β-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas^®) was the first approved echinocandin, followed recently by micafungin (Mycamine^®) and anidulafungin (Eraxis^®). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.     

Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies

Fungal infections represent a life-threatening complication for patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Historically, antifungal monotherapy is associated with a poor outcome. We treated three children with hematological malignancies and proven fungal infections (one cerebral mold infection, one disseminated Candida infection, one naso-pharyngeal mucor infection) with combination antifungal therapy plus granulocyte-colony-stimulation-factor-mobilized granulocyte transfusions as secondary prophylaxis during subsequent neutropenic episodes. With this approach, the fungal infection was effectively treated, and the anticancer therapy was completed without major delay. All children survived the fungal infection and the underlying malignancy. These experiences illustrate the feasibility of this approach using more than one antifungal agent together with immune-therapy in high-risk patients.     

Posaconazole: an extended-spectrum triazole antifungal agent

BACKGROUND: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent. OBJECTIVE: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592. Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site. RESULTS: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). CONCLUSIONS: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.     

Nationwide survey of treatment for pediatric patients with invasive fungal infections in Japan

In Japan, only a few antifungal agents have been approved for children, but in actual clinical practice, various antifungal agents used in adults are administered to pediatric patients with invasive fungal infections (IFIs). However, the pediatric dosages of some antifungal agents are not indicated in the package inserts or mentioned in the Japanese Mycology Study Group 2007 Guidelines for Management of Deep-seated Mycoses. We conducted a nationwide survey to determine how antifungal agents are being used to treat pediatric patients with IFIs in Japan. We sent a questionnaire to 792 medical centers that train pediatricians and received 250 (31.6 %) responses. In the past 5 years, 65 (26.0 %) of 250 facilities reported treating a total of 232 cases of IFIs. The characteristics of pediatric patients with IFIs were almost the same as adult patients except that immunological diseases and neonatal diseases are common as underlying diseases. Antifungal agents used in adults were all used in children. However, the dosages of some antifungal agents deviated from the package insert or guideline recommendations. As for the reasons for selecting a particular antifungal agent, strong antifungal activity (including potency, broad spectrum, and clinical efficacy) was favored over safety. These results can be used to revise guidelines for the management of children with IFIs.     

Current challenges in the management of invasive fungal infections

The incidence of invasive fungal infections (IFIs) has increased over the past two decades, as the populations of patients at risk have continued to rise. Early and accurate diagnosis and the subsequent usage of appropriate antifungal therapy are difficult, which leads to a high mortality rate in patients with IFI. Along with the widespread use of antifungal prophylaxis, the epidemiology of invasive fungal pathogens has changed. Non-albicans Candida, Non-fumigatus Aspergillus, and molds other than Aspergillus have become more common pathogens causing invasive diseases, and most of these emerging fungi are resistant to or less susceptible than others to standard antifungal agents. Therefore, invasive infections due to these previously rare fungi are more difficult to treat. Advances in more potent and less toxic antifungal agents, such as second-generation triazoles and echinocandins, may potentially improve the outcomes of these infections. Recent advances in detecting fungal cell-wall components and genomic DNA also allow earlier diagnosis. This article reviews the changing spectrum of invasive fungal infections and the introduction of recent advances in diagnostic tools and antifungal agents.     

Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis

We performed a retrospective observational study to examine the incidence of invasive aspergillosis (IA) among allogeneic hematopoietic stem cell transplant (HSCT) recipients, according to whether patients received at least 1 week of voriconazole prophylaxis. We report no cases of IA among 92 HSCT recipients who received voriconazole prophylaxis compared with a 10% (23/223) incidence among those receiving other systemic antifungals for prophylaxis (P < .0005).     

Micafungin for the prophylaxis and treatment of Candida infections

Invasive fungal infection is a significant cause of morbidity and mortality worldwide. The incidence of these infections is steadily increasing. In addition, strains resistant to many commonly used antifungal agents are becoming more prevalent. Many new antifungals have become commercially available in recent years, which have vastly improved the ability to treat these infections effectively. Micafungin is one of three commercially available echinocandins available for use in the USA. This class of agents possess a unique mechanism of action that helps to reduce toxicity while maintaining potent antifungal activity. Micafungin is currently approved for the treatment of esophageal candidiasis in adults and is the only in its class approved for the prophylaxis of Candida infection in patients who have undergone hematopoietic stem cell transplantation. It was also recently approved in the USA for the treatment of candidemia and other forms of invasive candiaisis (acute disseminated candiaisis, Candida peritonitis and abscess). In general, micafungin is well tolerated and has favorable safety and drug-interaction profiles.