Advances in antifungal therapy: updates for the clinician

February 2004

Since 2001 there have been significant developments in treatment of invasive fungal infections (IFIs), including the release of the first novel antifungal drug class in more than 30 years as well as new, oral options for severe filamentous fungal infections.

Clinicians are also expanding treatment options by using established agents in novel combination treatment strategies. The optimal strategy to use these new strategies will continue to evolve as more new agents reach the U.S. market with unique properties that offer a more diverse antifungal armamentarium to clinicians.

Newly released agents

The FDA approved caspofungin (Cancidas, Merck Sharp and Dohme), the first of the novel echinocandin class, in February 2001. Initial approval was based on data as therapy for refractory invasive aspergillosis, and although there are no comparative trials, open-label treatment experience revealed favorable response in 50% of patients with pulmonary aspergillosis. Furthermore, greater than 20% of patients with more disseminated disease who had failed conventional treatment options also responded to caspofungin therapy.

While the echinocandins are an intriguing option for aspergillosis, they are limited to fungistatic activity against Aspergillus species but possess fungicidal activity against Candida species. This activity has correlated well to clinical success against invasive candidiasis. When compared with amphotericin B deoxycholate, caspofungin was effective in 70% of patients with fewer adverse events. Based on these data, the FDA extended licensing for this agent to include candidemia and invasive candidiasis in December 2002. It is likely this agent will likely be widely used for initial therapy of systemic yeast infections as caspofungin covers a broader spectrum of Candida spp than fluconazole (Diflucan, Pfizer) with less toxicity that the amphotericin B preparations.

Most recently, data were presented that suggest caspofungin may be an attractive option for empiric therapy of febrile neutropenia. In a study of more than 1,000 neutropenic patients with persistent fever, caspofungin was found to have equal overall efficacy as liposomal amphotericin B (3 mg/kg/day). Breakthrough fungal infections occurred with similar frequency in the two treatment groups (5% caspofungin compared with 4% liposomal amphotericin B) as did overall survival (93% and 89%, respectively). The major difference between treatment arms was in the occurrence of toxicity, with significantly more patients in the liposomal amphotericin arm experiencing a drug-related toxicity (69% vs. 54%, P<0.001). These included nephrotoxicity (12 vs. 3%) and infusion-related reactions (52 vs. 35%, P<0.001).

One of the major limitations of this agent included questionable hepatotoxicity when co-administered with cyclosporine in a small number of healthy volunteers. However, recent data are emerging on safe clinical experience with these two drugs used concomitantly that indicate this may be an option in patients when the potential benefits outweigh the calculated risks. This is not a characteristic shared with other members of the echinocandin class in development.

There are two additional echinocandins in phase-3 clinical trial development. Micafungin (Fujisawa) is already approved in Japan for fungemia and respiratory and gastrointestinal mycosis. These indications are based on data from the primary, open-label study of micafungin for deep-seated fungal infections in which there was a 100% response rate for candidemia, 71% for esophageal candidiasis and 60% for invasive pulmonary aspergillosis. Data also exist for salvage and combination therapy for aspergillosis, including micafungin yielding a 37% response rate, which is similar to other agents used to treat refractory disease. In March 2003, the drug was denied approval in the United States pending more comparative data for these indications which are being obtained in further comparative studies.

In addition to its efficacy in treating infections due to Candida and Aspergillus, clinical trials with micafungin have demonstrated superiority to fluconazole as prophylaxis in patients undergoing hematopoetic stem-cell transplantation. The primary difference between the groups was the drug’s efficacy in preventing aspergillosis with 0.2% of micafungin patients versus 1.5% of fluconazole patients developing these infections. Although this did not reach statistical significance, it might be a clinically important difference to practitioners caring for these high-risk patients.

Available data regarding anidulafungin (Vicuron) are limited to esophageal candidiasis and other candidal infections. In the largest open-label study conducted with anidulafungin thus far, the agent was effective in 70%-93% of patients with candidemia and invasive candidiasis. It also performed well when compared with fluconazole for esophageal candidiasis.

Newer triazoles

Voriconazole (Vfend, Pfizer) is a new triazole that was first marketed in the United States in July 2002. It offers a broader spectrum of activity than fluconazole and is better tolerated than itraconazole (Sporanox, Janssen). It demonstrates excellent in vitro activity against many fungal pathogens, including strains of Candida and Cryptococcus spp, as well as the filamentous and dimorphic fungi Aspergillus spp and B. dermititidis, C. immitis, H. capsulatum, Malassezia spp. and Scedosporium species. Voriconazole was originally available as oral tablets and an IV formulation that included cyclodextrin. As with its predecessor, IV itraconazole, the excipient in this formulation should be used cautiously in patients with a creatinine clearance less than 50 ml/min. Voriconazole is now also available as an oral solution that facilitates administration to pediatric patients.

In the United States, the drug is approved as primary therapy for aspergillosis after elevating patient survival to 52.8% in one multinational clinical trial. It also provides a viable treatment option for pathogens not covered by the available antifungal agents, in addition to those not responding to traditional therapies. Data have been available regarding efficacy of this agent for treatment of esophageal candidiasis, and in December 2003 the FDA expanded the labeling to include this indication.

The most controversial data regarding voriconazole remains the randomized study of voriconazole versus liposomal amphotericin B for the treatment of persistent febrile neutropenia. Voriconazole did not reach the pre-specified endpoint of non-inferiority for the composite of overall survival, resolution of fever, and treatment of underlying fungal infections present at baseline. One component did occur less often in the voriconazole group, however, attracting interest of clinicians. The incidence of breakthrough fungal infections in the voriconazole arm (5 vs. 1.9% for liposomal amphotericin B and voriconazole, respectively) was significantly less, particularly for Aspergillus infections. Therefore, many clinicians have opted to use this agent in this setting while we await data of ongoing studies.

Posaconazole (Noxafil, Schering-Plough) is another third-generation triazole similar to voriconazole with a slightly extended spectrum of activity currently in clinical trials. As with the available azole antifungals, this new agent inhibits the cytochrome P450 enzyme system to some degree and therefore can precipitate drug-drug interactions. These are potentially severe, especially in patients receiving common concomitant immunosuppressives, such as cyclosporin A and tacrolimus (Prograf, Fujisawa).

The primary advantage of posaconazole over voriconazole is its activity against the zygomycetes. In a recent case series, nearly 70% of patients were successfully treated with posaconazole for various zygomycoses, including Rhizopus, Cunninghamella, Mucor and Rhizomucor. Studies of posaconazole for aspergillosis and candidiasis have also been completed, but results have not yet been released. As data continue to emerge, we will better understand the optimal place of this agent in therapy.

Ravuconazole (Eisai Inc.) is an agent that offers particular advantage over the other azole antifungal agents. This drug, currently in Phase 1/2 clinical trials, does not inhibit the cytochrome P450 enzyme system and therefore eliminates drug-drug interactions so common with other members of this class. This would be particularly meaningful for the transplant and HIV patient populations that are at risk for fungal infections while receiving multiple complex medications. Other azole agents in earlier stages of development include albaconazole (UR-9825, Uriach Group) and CS-758 (Sankyo).

Combination therapy

Now that more agents with unique mechanisms of action are available to treat fungal infections, clinicians are better able to explore combination antifungal treatment regimens, similar to the work that has been done with the antibacterial agents for decades. Antifungal combination therapy is not a new concept; amphotericin B administered with flucytosine has been the cornerstone for treatment of cryptococcal meningitis for the past 20 years.

The use of amphotericin B with azole agents has traditionally been avoided as both of these antifungal classes act on ergosterol in the fungal cell membrane. There was the concern that the azole inhibition of ergosterol biosynthesis would reduce the target ergosterol for the generally more effective and fungicidal polyene.

More recently, however, data from human treatment experience has shown that this strategy may be a viable option. In addition, the recent availability of the echinocandins class with a fungal cell wall target has made this even more attractive. Data on this treatment strategy in infected patients is only beginning to emerge. The combination of fluconazole and amphotericin B for treatment of candidemia was recently studied. More rapid clearance of the bloodstream and overall successful treatment occurred more frequently in the combination therapy arm; however, differences between the two treatment groups make it difficult to draw definitive conclusions from these data. A comprehensive discussion of combination antifungal therapy is beyond the scope of this article; however, there have recently been several exhaustive reviews on the subject.

The cost of progress

With the rise in number of available antifungal agents has come an increase in the cost of treating these infections, a factor that now must be considered by practitioners and institutions alike. There have not yet been comprehensive pharmacoeconomic analyses incorporating these newer agents, however many centers are already beginning to assess the impact of these new agents on their own practices. This will become a more intriguing area for practitioners as clinicians are provided with more treatment options that allow an increasing number of combination regimens including two and even three of these agents given together.

The great increase in the number of immunocompromised patients has led to dramatic movements in the needs of the antifungal armamentarium in the last several years. While even more newer agents are set to leap onto the clinical trial stage, clinicians continue to struggle with the optimal uses of each agent. Despite the present challenges, the future for treating IFIs is rife with promising new therapeutic options.

For more information:

• Maertens J, Raad I, Petrikkos G, et al. Update of the multicenter noncomparative study of caspofungin (CAS) in adults with invasive aspergillosis (IA) refractory (R) or intolerant (I) to other antifungal agents: analysis of 90 patients. Abstract M-868.
• van Burick J, Ratanatharathorn V, Lipton J, et al. Randomized, double-blind trial of micafungin (MI) versus fluconazole (FL) for prophylaxis of invasive fungal infections in patients (pts) undergoing hematopoietic stem cell transplant (HSCT), NIAID/BAMSG Protocol 46. Abstract M-1238.
• Both presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Sept. 27-30, 2002. San Diego.
• Walsh T, Sable C, Depauw B, et al. A randomized, double-blind, multicenter trial of caspofungin (CAS) v liposomal amphotericin B (LAMB) for empirical antifungal therapy (AEFRx) of persistently febrile neutropenic (PFN) patients (Pt). Abstract M-1761.
• Dewet, NTE, Llanos-Cuentas A, Suleiman H, et al. Micafungin (FK463) dose response and comparison with fluconazole in oesophageal candidiasis. Abstract M-1754.
• Greenberg RN, Anstead G, Herbrecht R, et al. Posaconazole (POS) experience in the treatment of zygomycosis. Abstract M-1757.
• Suleiman H, Della Negra M, Llanos-Cuentas A, et al. Open label study of micafungin in the treatment of eosphageal candidiasis (EC). Abstract M-892.
• Schranz JA, Krause D, Goldstein BP, et al. Efficacy of anidulafungin (ANID) for the treatment of candidemia. Abstract M-971.
• Krause DB, Henkel T, Goldstein BP, et al. Anidulafungin (ANID) vs. fluconazole (FLU) in esophageal candidiasis (EC): a phase 3, randomized, double-blind multicenter trial. Abstract M-1760.
• All presented at the 43rd ICAAC. Sept. 14-17, 2003. Chicago.
• Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002; 347(25):2020-2029.
• Anttila VJP. Co-administration of caspofungin and cyclosporine to a kidney transplant patient with pulmonary aspergillus infection. Scand J Infect Dis. 2003;35(11-12):893-894.
• Kohno S, Maasaoka T, Yamaguchi H. A multicenter, open-label clinical study of FK463 in patients with deep mycosis in Japan. Abstract J-834. Presented at the 41st ICAAC. Dec. 16-19, 2001. Chicago.
• Ratanatharathorn V, Flynn P, van Burick JA, et al. Micafungin in combination with systemic antifungal agents in the treatment of refractory aspergillosis (RA) in bone marrow transplant (BMT) patients. Abstract 722. Proceedings of the 44th Annual American Society of Hematology meeting. Dec. 6-10, 2002. Philadelphia.
• Ullman AJ, van Burick JA, McSweeney P, et al. An open phase II study of the efficacy of micafungin (FK463) alone and in combination for the treatment of invasive aspergillosis (IA) in adults and children. Abstract 722. Proceedings of the 13th European Congress of Clinical Microbiology and Infectious Diseases. May 10-13, 2003. Glasgow, UK.
• Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002; 347(6):408-415.
• Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infec Dis. 2003; 36(9):1122-1131.
• Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infec Dis. 2001; 33(9):1447-1454.
• Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002; 346(4):225-234.
• Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med. 1979; 301(3):126-131.
• Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis. 2003; 36(10):1221-1228.
• Steinbach WJ, Stevens DA, Denning DW. Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001. Clin Infect Dis. 2003; 37:Suppl-224.
• Kontoyiannis DP, Lewis RE. Combination chemotherapy for invasive fungal infections: what the laboratory and clinical studies tell us so far. Drug Research Update. 2003; 6:257-269.

• Elizabeth S. Dodds, PharmD, BCPS, is from the Division of Infectious Diseases and International Health, Department of Medicine, Campbell University School of Pharmacy.
• William J. Steinbach, MD, is from the Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center.