FOILING FUNGAL INFECTIONS

Researchers pin hopes on a new generation of medications to treat this growing problem

Advances in contemporary medicine such as intensive chemotherapy, the use of broad-spectrum antibiotics, and organ transplantation have enabled clinicians to treat critically ill patients more aggressively, thereby increasing their survival. "But, paradoxically, use of these therapeutic modalities has also led to a significant rise in the incidence of invasive fungal infections," said Esther Hilburger, Pharm.D., clinical coordinator and clinical pharmacy specialist at Sentara Healthcare in Hampton, Va.

Invasive aspergillosis remains a leading infectious complication among transplant recipients and is associated with high morbidity and mortality. Over the past few years, there has been a shift from Candida albicans to non-albicans species of Candida as the predominant causative agents of invasive fungal infections. Current treatment strategies for these infections are limited by antifungal resistance, drug toxicities, and interactions, noted Robert Adamson, Pharm.D., corporate director of clinical pharmacy services at Saint Barnabas Health Care System in Livingston, N.J. In order to overcome these limitations, there has been a recent surge in the development of newer antifungals, and innovative strategies with unique combination antifungal therapies are beginning to be explored.

Voriconazole (Vfend, Pfizer) is the only second-generation triazole antifungal currently available. It has a broad spectrum of activity, including coverage against Candida and Aspergillus species. Two other compounds in this class, posaconazole (Noxafil, Schering-Plough) and ravuconazole (Bristol-Myers Squibb), are under investigation. Hilburger anticipates that these drugs will be used in transplant recipients and hematology/oncology patients, who are at increased risk for aspergillosis and candidiasis.

The most noteworthy finding of an article published in 2002 in Antimicrobial Agents and Chemotherapy was that of all the antifungals tested in the study, posaconazole demonstrated the most potent in vitro activity against filamentous fungi, such as Rhizopus species. Posaconazole has been well tolerated in clinical trials, with the most common adverse event being gastrointestinal symptoms. Pharmacokinetic studies demonstrate that the absorption of posaconazole suspension is improved if it is administered with a liquid nutritional supplement.

Phase II studies of ravuconazole have shown that the drug has a considerably long half-life (~100 hours), which "may allow for extended-interval dosing," noted Hilburger.

The triazole antifungals are potent inhibitors of the cytochrome P450 3A4 enzyme and thus are associated with significant drug interactions. "My approach for managing these interactions is to anticipate them—by knowing which drugs can potentially interact with the triazole antifungals," said Adamson. Results of a recent study presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) showed that there is a drug interaction between posaconazole and tacrolimus, an immunosuppressive agent. "Monitoring of tacrolimus concentrations would be essential in these patients," he added.

Authors of another study presented at ICAAC in 2000 found ravuconazole to be a less potent inhibitor of the cytochrome P450 3A4 enzyme than other triazole antifungals—which would mean "possibly fewer drug-drug interactions and therefore less toxicity," noted Hilburger.

First in class

The first drug in the echinocandin class of antifungals to receive Food & Drug Administration approval was caspofungin (Cancidas, Merck). In contrast to antifungal classes such as the azoles and polyenes, the echinocandins inhibit an enzyme that is required for the synthesis of fungal cell walls, rather than interfering with the functioning of fungal cell membrane. Two additional echinocandins, anidulafungin (formerly LY303366, Vicuron Pharmaceuticals) and micafungin (Mycamine, Fujisawa) are in the final stages of clinical trials.

Table 1
Mechanism of action of investigational antifungals

Anidulafungin was originally developed by Eli Lilly & Co. Though the drug had "promising activity against a variety of species of Candida ... it had solubility problems. It required a toxic carrier and because of that, the drug was abandoned," said John Rex, M.D., formerly at the University of Texas at Houston and now with AstraZeneca. Lilly was also developing an oral formulation of the antifungal agent, which ran into difficulties due to poor oral bioavailability.

"Echinocandins in general have poor oral bioavailability and probably will have to be administered intravenously," noted Rex. He also pointed to once-daily dosing due to a long half-life and a high degree of renal safety as characteristics of this antifungal class. Vicuron Pharmaceuticals eventually licensed anidulafungin from Lilly.

Table 2
Formulations of antifungals in the pipeline

A phase III esophageal candidiasis trial showed anidulafungin to be as effective as the standard of care, fluconazole. Anidulafungin yielded endoscopic success in 97.2% of patients compared with 98.8% of patients on oral fluconazole. However, anidulafungin had a statistically significant higher relapse rate—endoscopic success at two weeks was 89.5% for the fluconazole group and 64.4% for patients receiving anidulafungin.

In a dose-ranging study presented at the 2003 ICAAC meeting, anidulafungin was also found to be effective and safe for the treatment of candidemia. Preliminary studies have also shown that anidulafungin was well tolerated when administered with cyclosporine and required no dose adjustment.

Table 3
Spectrum of activity of investigational antifungals

Additionally, initial pharmacokinetic data indicate that dosage adjustments will not be necessary in patients with liver impairment. "This property will distinguish anidulafungin from the currently approved caspofungin, which does require dosage reduction [to 50% of the daily dose after a standard loading dose] in patients with severe hepatic dysfunction," said Hilburger.

In May 2004, Vicuron announced that it had received an approvable letter from the FDA for anidulafungin. However, the letter indicated that the company's NDA submission for anidulafungin does not currently support a labeling claim for the initial treatment of esophageal candidiasis. The FDA did indicate that Vicuron could potentially achieve approval for anidulafungin upon completion of its ongoing phase III trial in invasive candidiasis/candidemia and invasive aspergillosis (in combination with liposomal amphotericin B).

Fujisawa is seeking to distinguish its echinocandin antifungal compound, micafungin, from caspofungin by indications and safety profile. The micafungin NDA seeks approval for prophylactic therapy in patients undergoing hematopoietic stem cell transplantation, for use alone or in combination with other systemic antifungal treatments in patients who are refractory to current antifungal therapy; and for use in patients where existing toxicity precludes the use of other antifungal therapy.

In a study presented at the 2002 ICAAC meeting, micafungin had a significantly higher rate of overall treatment success compared with fluconazole (80% versus 73.5%). More important, fewer patients treated with micafungin required empirical antifungal therapy (15.1% versus 21.4%) compared with those patients who received fluconazole.

"These findings provide evidence that micafungin can be an effective preventive therapy for patients undergoing bone marrow and stem cell transplants who are highly susceptible to life-threatening fungal infections," said Jo-Anne van Burik, M.D., an infectious disease specialist at the University of Minnesota and the study's lead investigator. "Moreover, micafungin is the only agent in the echinocandin class that's been tested in children as young as six months—an increasing population of immunocompromised patients," she stated.

"While an indication for prophylactic use would differentiate micafungin from caspofungin, other classes of marketed systemic antifungal drugs are used prophylactically, including fluconazole," said Hilburger.

Fujisawa will also emphasize micafungin's safety profile as an advantage over caspofungin. Safety concerns with caspofungin include anaphylactic reactions, renal insufficiency, and hepatotoxicity. Caspofungin's labeling warns against concomitant use with cyclosporine, which was associated with transient increases in liver enzymes. In contrast, the most common side effects associated with micafungin in the prophylaxis study were bilirubinemia, nausea, and diarrhea. Fujisawa believes that micafungin will offer a safety advantage over the older classes of systemic antifungals, such as azoles and amphotericin products, and over caspofungin as well.

One problematic characteristic of the newer antifungal agents, including caspofungin and voriconazole, has been their drug-interaction profiles. These drugs have documented interactions with various agents, such as immunosuppressants and protease inhibitors. "From preliminary data, it appears that micafungin does not have significant interactions with tacrolimus or cyclosporine. This could prove to be a major advantage for micafungin," stated Hilburger.

Both anidulafungin and micafungin are fungicidal against Candida species and fungistatic against Aspergillus. Adamson predicts that these new echinocandins may emerge as widely used agents for Aspergillus and fluconazole-resistant Candida species. "Many clinicians are hesitant to use amphotericin B as a first-line agent due to its notorious toxicity profile. Because these new echinocandins exhibit a more favorable side-effect profile, their use in clinical practice may become more widespread," said Adamson. A notable omission, however, in the spectrum of activity of the echinocandins is Cryptococcus neoformans.

Another novel investigational agent that may improve our therapeutic armamentarium for the treatment of invasive mycoses is nikkomycin Z (Shaman Pharmaceuticals). Nikkomycins are nucleoside-peptide compounds that inhibit synthesis of the cell-wall chitin, a polysaccharide found in most fungi. They were first described as a class of drugs in 1976 when isolated as a result of a program to discover fungicides for agricultural use.

The antifungal activity of nikkomycin Z against opportunistic fungi has been reportedly low in some experimental fungal models. However, some published in vitro data demonstrate synergistic activity against species of Candida, Cryptococcus, and Aspergillus. Based on its unique target, nikkomycin is a potential candidate for clinical development for endemic fungi, particularly in combination with other cell-wall active agents, or the triazole antifungals.

New formulation for old drug

A new formulation of an old-time antifungal drug—that's the idea behind Nyotran (nystatin, Antigenics/Abbott), liposomal nystatin. Discovered in the 1940s in a soil sample, nystatin was the first polyene antifungal. "The oldest antifungal class, polyenes bind to ergosterol, creating channels in the cell membrane. This increases permeability and causes cell death through leakage of essential nutrients," explained Hilburger.

Problems with solubility and toxicity with parenteral use limited nystatin to topical use. However, the recent liposomal reformulation of nystatin has reduced its toxicity yet preserved its antifungal activity. In vitro studies recently reviewed have yielded mixed results. In a study published in Antimicrobial Agents and Chemotherapy in 1998, liposomal nystatin was found to be more active against Aspergillus flavus isolates than all three lipid formulations of amphotericin B but less active than conventional amphotericin. Another in vitro study revealed liposomal nystatin MICs (minimum inhibitory concentrations) higher than those of all four amphotericin preparations and itraconazole for Aspergillus fumigatus.

A phase II study presented at the 2000 ICAAC meeting revealed that seven of the 16 evaluable patients with amphotericin B-refractory invasive aspergillosis were alive on day 30 after treatment with 4 mg/kg/day liposomal nystatin. The efficacy of liposomal nystatin was further demonstrated in a case report published in 2001 in Supportive Care in Cancer. Patients were successfully treated with liposomal nystatin after amphotericin B-failure (disease progression or drug-related toxicity). Liposomal nystatin cured four of the five patients, and all five had previously elevated serum creatinine levels return to normal.

For years, the treatment of invasive aspergillosis was a relatively toxic antifungal agent, conventional amphotericin B—sometimes referred to as "amphoterrible." Today clinicians are able to use the less toxic liposomal formulations of amphotericin B, but the future holds even more promise of newer antifungal agents. With innovative agents such as second-generation triazoles and echinocandins, clinicians will have a lot more treatments available against invasive fungal infections.