teaser
Micafungin is the second echinocandin to become available for clinical use. It is approved for various indications involving Candida and its clinical role appears to resemble that of caspofungin
Mario Cruciani
MD
Preventive Medicine Centre
and HIV Outpatient Clinic
Consultant in Infectious Diseases
G Fracastoro Hospital
San Bonifacio
Verona, Italy
Until recently therapy for invasive mycoses was based on a relatively small number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other long-established and more newly discovered antifungal agents, including new azoles and members of the echinocandin class (caspofungin, micafungin and anidulafungin), have been added to the therapeutic armamentarium.[1—4] Micafungin is the second agent of the echinocandin class to become approved for clinical use in the US, Europe and several Asian countries. This review outlines the main characteristics of micafungin and its role in treating fungal infections.
Echinocandins’ mechanism of action
The echinocandins are a new class of antifungal agents that act at the level of the fungal cell wall by inhibiting synthesis of beta-(1-3) D-glucan — an essential component of the cell wall of many fungi that is not present in mammalian cells.
Echinocandins show excellent activity against Candida and Aspergillus species, but are marginally active against dimorphic fungi such as Histoplasma capsulatum and Coccidioides immitis, and have no effect on Cryptococcus neoformans and the zygomycetes. Echinocandins have fungicidal activity against Candida spp and fungistatic activity against Aspergillus spp.
All the echinocandins have good antifungal activity in vitro for most isolates of Candida spp, including those that are either amphotericin B-resistant or fluconazole-resistant (such as C glabrata); they are less active against C parapsilosis and C guillermondii. However, it is important to point out that standardised susceptibility testing methods for echinocandins have yet to be developed, and results of in-vitro susceptibility
tests do not necessarily correlate with clinical outcomes.[4]
In susceptible species acquired resistance to echinocandins is rare. However, recent reports have raised concern about the possibility of cross-resistance among the echinocandins and between echinocandins and azoles.[4,5]
Reduced C glabrata susceptibility secondary to an FKS1 mutation has been reported during treatment of candidaemia with caspofungin.[6]
Pharmacokinetics of micafungin
As with other compounds in its class, micafungin shows poor oral bioavailability, high protein binding and low urine and cerebrospinal fluid concentrations. As with other echinocandins, micafungin is available only as an intravenous formulation. The main comparative pharmacokinetic features of micafungin, caspofungin and anidulafungin are summarised in Table 1. Unlike caspofungin and anidulafungin, micafungin does not
require a loading dose.
The echinocandins are a poor substrate for cytochrome P450 enzymes, and fewer drug interactions are expected.[4,7] Drug interaction studies have demonstrated that no dosage adjustments are necessary when micafungin is coadministered with ciclosporin, mycophenolate, sirolimus or tacrolimus.[8—10]
Clinical experience
Clinical experience with micafungin encompasses treatment of invasive fungal infections and oesophageal candidiasis.
Results of a large (>500-patient), randomised, double-blind study comparing micafungin (100 mg daily) with liposomal amphotericin (3 mg/kg daily) in treating invasive candidosis and candidaemia show that the two compounds have equivalent efficacy (89% of success), but micafungin is tolerated better than the comparator.[11] The majority of patients (88%) were not neutropenic, and more than 50% of them were in the intensive care unit. In both groups non-C albicans was responsible for nearly 60% of infectious episodes.
In another multicentre, randomised, double-blind trial, micafungin (100 mg or 150 mg daily) was compared with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in 595 adults with candidaemia and other forms of invasive candidiasis.[12] Approximately 85% of patients had candidaemia and most cases were non-neutropenic and without neoplastic conditions. Treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. Moreover, there were no significant differences in mortality, relapsing and emerging infections, or adverse events among the study arms.
Prophylaxis of fungal infections with micafungin has been evaluated in another well-designed trial conducted among 882 adult and paediatric patients undergoing allogeneic or autologous haematopoietic stem-cell transplantation (HSCT).13 Patients were randomised to receive daily infusions of either 50 mg micafungin or 400 mg fluconazole. Overall treatment success was 80% in the micafungin arm and 73.5% in the fluconazole arm. The proportion of patients in the micafungin arm requiring empirical antifungal therapy was significantly lower compared with the fluconazole arm (15% vs 21%). Mortality was decreased, although not significantly, in the micafungin arm (4.2% vs 5.7% respectively). The authors conclude that micafungin may provide an option for prophylaxis in patients undergoing HSCT.
Data from other uncontrolled small trials investigating the role of micafungin in treating neutropenic patients are available, but add little to the evidence.[14,15]
Clinical experience with micafungin in treating invasive aspergillosis is limited to case reports or series of patients treated with micafungin, alone or in combination with other antifungal agents.[16—19] The single most important case of experience is a multinational, noncomparative study evaluating micafungin’s safety and efficacy alone or in combination with other systemic antifungal agents, mostly in patients refractory or intolerant to previous antifungal therapy.[19] A favourable response rate at the end of therapy was seen in 35.6% (80/225) of patients. These results suggest micafungin has clinical efficacy similar to that of caspofungin in treating invasive aspergillosis.
Micafungin has also been evaluated in a noncomparative study in 58 paediatric patients with proven or probable invasive aspergillosis. Only two patients received micafungin alone, while the others received combination therapy with other antifungals (in the large majority, liposomal amphotericin B). Overall response (complete plus partial) was obtained in 26/58 (45%)
patients. Rate of response was higher in patients with A flavus than A fumigatus (55% vs 24%). These results indicate that micafungin (especially in combination) should be considered an option for treating invasive aspergillosis in paediatric patients.[20]
Micafungin has been extensively evaluated in four randomised studies carried out in more than 1,300 patients with episodes of oesophageal candidiasis, mostly in HIV-infected patients and sustained by C albicans.[21—24] A dose-dependent response was determined with a cure rate ranging from 33.3% in patients on 12.5 mg daily dosage up to 94.7% in patients on 100—150 mg daily dosage.[21,22] Micafungin was found noninferior to the comparator, intravenous fluconazole 200 mg daily. Improvement was often perceived within three to five days of treatment.[22,23]
Finally, in a recent multicentre, double-blind, randomised non-inferiority study in 452 patients with oesophageal candidiasis, alternate-day intravenous dosing of 300 mg micafungin was as effective as daily intravenous doses of either 150 mg micafungin or 50 mg caspofungin.[24]
Micafungin has an excellent overall safety profile, with reduced toxicity compared with other licensed antifungal agents. In comparative studies micafungin’s safety profile was superior to that of liposomal amphotericin B and similar to that of fluconazole and caspofungin.
The most frequently reported micafungin-related adverse events were nausea (2.8%), vomiting (2.5%), phlebitis (2.5%), hypokalaemia (2.1%), pyrexia (2.1%), diarrhoea (2.0%), and increases in alkaline phosphatase (2.7%), aspartate aminotransferase (2.3%) and alanine aminotransferase (2.0%).[25]
Micafungin’s role in treating fungal infections
The potential clinical role of micafungin appears to be similar to that of caspofungin. Labelled indications approved by the EMEA for micafungin include oesophageal candidiasis, candidaemia and other invasive infections caused by Candida species (in both adult and paediatric patients). Micafungin is also indicated for prophylaxis of candidal infections in patients undergoing HSCT, again in both adult and paediatric patients. Caspofungin may also be used for empirical treatment of presumed fungal infections in neutropenic patients, and for treating invasive aspergillosis in patients refractory or intolerant to other antifungal agents. Micafungin is not approved for this indication, but recent data suggest it may also be effective, alone or in combination with other antifungal agents, in treating invasive aspergillosis[9, 20].
All the available echinocandins are approved for treating Candida oesophagitis, a mucous membrane infection most commonly diagnosed in HIV-infected patients. However, in the evaluation of antifungal drug efficacy this condition should not be included with invasive fungal infections such as candidaemia or aspergillosis. Treatment of oesophageal candidiasis with any of the available echinocandins is unlikely to become the standard of care, given the plethora of effective drugs available, the lack of clinical superiority to justify the high cost associated with the echinocandins, and the absence of an oral formulation. In cases where echinocandin therapy is after all preferred, the three echinocandins currently available probably have equivalent efficacy in treating oesophageal candidiasis.[26-29]
There is also considerable interest in using this new antifungal agent as part of combination antifungal therapy. [29,30] Echinocandins are fungistatic against moulds, and may be promising for treating these pathogens when given in combination with amphotericin B or broad-spectrum triazoles such as voriconazole.
[[HPE42_29]]
Conclusion
The incidence of fungal infections is increasing as the at-risk population expands. Candida and Aspergillus are the most common causes of invasive fungal infections, accounting for 70—90% and 10—20% of all invasive mycoses, respectively. Unfortunately, no adequate diagnostic tool exists to detect many of the invasive fungal infections.
Fortunately, the armamentarium for treating severe fungal infections keeps growing, with the introduction of new broad-spectrum antifungal agents, including echinocandins. As a class, echinocandins demonstrate a minor incidence of serious adverse effects, have limited potential for the selection of resistant strains, and limited potential for drug—drug interactions. Thus, they represent an attractive option for treating invasive fungal infections, namely candidiasis and aspergillosis.
Finally, the increasing incidence of systemic fungal infections and rising medical costs have highlighted the need for an economic appraisal of antifungal agents to determine the most cost-effective therapeutic option.31 Therefore, future clinical trials investigating management of fungal infections should incorporate economic outcome measures based on validated
principles and appropriate models.
References
1. Denning DW. Lancet 2003;362:1142-51.
2. Chandrasekar PH, Sobel JD. Clin Infect Dis
2006;42;8:1171-8.
3. Deresinski SC, Stevens DA. Clin Infect Dis 2003;36:1445-57.
4. Eschenauer G, et al. Ther Clin Risk Manag 2007;3:71-97.
5. Moudgal V, et al. Antimicrob Agents Chemother 2005;49:767-9.
6. Cleary JD, et al. Antimicrob Agents Chemother 2008;52:2263-5.
7. Zaas K, Alexander BD. Expert Opin Pharmacother 2005;6:1657-68.
8. Hebert MF, et al. J Clin Pharmacol 2005;45:954-60.
9. Hebert MF, et al. J Clin Pharmacol 2005;45:1018-24.
10. Hebert MF, et al. J Clin Pharmacol 2005;45:1145-52.
11. Kuse ER, et al. Lancet 2007;369:1519-27.
12. Pappas PG, et al. Clin Infect Dis 2007;45:883-93.
13. Van Burik JA, et al. Clin Infect Dis 2004;39:1407-16.
14. Toubai T, et al. Intern Med 2007;46:3-9.
15. Hashino S, et al. Int J Hematol 2008;87:91-7.
16. Yokote T, et al. Ann Hematol 2004;83:64-6.
17. Ota S, et al. Int J Hematol 2004;79:390-3.
18. Kohno S, et al. Scand J Infect Dis 2004;36:372-9.
19. Denning DW, et al. J Infect 2006;53(5):337-49.
20. Flynn PM, et al. Abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27—30, 2006. San Francisco: American Society for Microbiology; 2006:407 (abst M-891).
21. Pettengell K, et al. Aliment Pharmacol Ther 2004;20:2.475-81.
22. De Wet N, et al. Clin Infect Dis 2004;39:842-9.
23. De Wet NT, et al. Aliment Pharmacol Ther 005;21:899-907.
24. Buell D, et al. Abstracts of the 45th Interscience Conference
on Antimicrobial Agents and Chemotherapy, December 16—19,
2005. Washington, DC: American Society for Microbiology; 2005 (abst M-719—2005).
25. Mycamine (package insert). Deerfield (IL): Fujisawa Healthcare Inc; 2005.
26. Pappas PG, et al. Clin Infect Dis 2004;38:161-89.
27. Darouiche RO. Clin Infect Dis 2004;39:850-2.
28. Morris MI, Villmann M. Am J Health-Syst Pharm 2006;63:1813-20.
29. Morris MI, Villmann M. Am J Health-Syst Pharm 2006;63:1693-703.
30. Marr KA, et al. Clin Infect Dis 2004;39:797-802.
31. Johnson MD, et al. Expert Opin Pharmacother 2005;6:2617-32.
