teaser
Georgios Aperis
MD PhD
General (Internal) Medicine Specialist
Department of Clinical Oncology
Western General Hospital
Edinburgh
Scotland
UK
The incidence of candidiasis has risen dramatically in the last 20 years.(1) Advances in chemotherapy, in treatment of HIV-infected patients and in transplantation medicine have led to increased survival of immunosuppressed patients who are prone to developing fungal infections. Among fungal infections, candidaemia is the fourth most common cause of bloodstream infections in hospitalised patients.(2) Invasive candidiasis and candidaemia are both associated with high mortality (38%; for some species of Candida, mortality exceeds 60%).(3,4)
Amphotericin B was the only available antifungal for treating candidaemia and invasive candidiasis until the late 1980s, when liposomal formulations of amphotericin B and the triazoles fluconazole and itraconazole became available.(5) However, the toxicity of amphotericin B and the development of resistance to fluconazole especially by Candida glabrata and C krusei created the need for new antifungals. In the last 10 years the echinocandin antifungals caspofungin, micafungin and anidulafungin and the new extended-spectrum triazoles voriconazole and posaconazole have been added to the antifungal armamentarium.(6) Also, BAL8557, a new triazole antifungal, is undergoing phase III clinical trials and results for its efficacy and safety are encouraging. An anticandidal vaccine has also been undergoing experimental studies and appears protective in B-cell deficient mice by stimulating TH1-lymphocytes.
Recently, the efficacy of new compounds has been investigated via a high-throughput screen on Caenorhabditis elegans and further on Galleria mellonella and mice. Among these substances enoxacin and the caffeic acid phenethyl ester (CAPE) appear to prolong survival of C elegans and mice previously infected with C albicans.(7) Moreover, it is believed that farnesol, a substance produced by Candida, creates oxidative stress on other fungal pathogens, enabling its growth. Farnesol at high concentrations has been shown to inhibit filamentation of C albicans and appears to prolong survival of Galleria mellonella previously infected by C albicans.
This paper aims to analyse new treatment options that are available or will be in the next few years.
Echinocandins
The echinocandin antifungals, developed over the last 10 years, exhibit their action by inhibiting synthesis of 1,3-beta glucan, a major component of fungal cell wall.(8) In the USA three members of this class are available: caspofungin, micafungin and anidulafungin. In Europe, only caspofungin is available for use in treating Candida infections. All three echinocandins are effective in treating invasive candidiasis, candidaemia and oesophageal candidiasis.
Caspofungin, the oldest echinocandin, is approved by the FDA for treating candidaemia, oesophageal candidiasis and intra-abdominal abscess, as well as peritonitis and pleural effusion due to Candida spp.(9) In Europe, caspofungin is approved for use in treating invasive candidiasis.(10) As shown by multicentre studies, caspofungin at 50 mg daily intravenously (IV) appears to be marginally superior to amphotericin B in treating candidaemia and invasive candidiasis, and better tolerated.(11)
In treating oesophageal candidiasis, caspofungin at 70 mg daily IV appears to be superior to amphotericin B, and better tolerated.(12) Again, caspofungin at 50 mg appeared to be as effective as fluconazole in treating oesophageal candidiasis, treating 81% of patients, and recurrence rates were not statistically significant between the two regimens.(13)
Micafungin is approved by the FDA for treating oesophageal candidiasis and for prophylaxis of patients who have undergone haematopoietic cell transplantation.(9) Micafungin, administered at 50 mg or 100 mg daily IV in patients with candidaemia, resulted in an 83.3% response rate.(14) In treating oesophageal candidiasis, micafungin at 50–150 mg daily IV was effective in 91.5–100% of patients.(15,16) Micafungin at 100 mg intravenously daily was found to be as effective as liposomal amphotericin B in treating candidaemia and invasive candidiasis.(17) The success rate was 89.6% for micafungin and 89.5% for liposomal amphotericin B. However, treatment-related adverse events and discontinuation rate were lower in the micafungin group. Micafungin at 150 mg IV daily appears to be as effective as fluconazole in treating oesophageal candidiasis, resulting in a 94.2% clinical success rate.(18)
Anidulafungin, which is the newest echinocandin, is approved by the FDA for treating candidaemia, oesophageal candidiasis, intra-abdominal abscess and peritonitis.(9) Anidulafungin at 50–100 mg daily IV appeared to be effective in treating candidaemia, resulting in an 85–90% success rate, and the effect was dose-dependent.(19,20) In treating oesophageal candidiasis, anidulafungin at 50mg daily IV appeared to be as effective as fluconazole, resulting in a 97.2% success rate; however, anidulafungin was associated with higher relapse rate.(21) In treating candidaemia, anidulafungin at 100 mg daily IV has been shown to be superior to fluconazole (75.6% vs 60.2% respectively).(22)
Triazoles
The newer triazole antifungals voriconazole and posaconazole exhibit their action by inhibiting lanosterol 14α-demethylase – an enzyme involved in ergosterol biosynthesis.(23) Results from several clinical studies have shown the efficacy of voriconazole and posaconazole in treating candidiasis.
Voriconazole is approved by the FDA for treating candidaemia in non-neutropenic patients and oesophageal candidiasis, and for treating disseminated candidiasis involving the skin, abdomen, kidney, bladder and wounds.(9) In Europe, voriconazole is approved for treating invasive candidiasis refractory to fluconazole (especially for C krusei).(10)
Voriconazole at 6 mg/kg twice daily IV and/or 200 mg twice daily orally has been shown to be as effective as fluconazole/amphotericin B in treating candidaemia in non-neutropenic patients, and to be associated with less serious side-effects.(24) In treating oesophageal candidiasis, voriconazole at 200 mg twice daily orally appeared to be as effective as fluconazole, resulting in a 98.3% success rate. However, fluconazole was better tolerated.25 Voriconazole at 6 mg/kg IV or orally twice daily has been used in treating invasive and oesophageal candidiasis in patients refractory to or intolerant of conventional antifungals, resulting in a 55–61% response rate.(26,27)
Posaconazole is approved by the FDA for prophylaxis of invasive candidiasis in patients over 13 years of age with severe immunosuppression due to haematopoietic cell transplantation and graft-versus-host disease, and in patients with prolonged neutropenia after chemotherapy due to haematological malignancies.(9) In Europe, posaconazole is approved for treating fungal infections refractory to or intolerant of conventional therapies.(10) Posaconazole at 100 mg daily orally has been shown to have equal effectiveness compared with fluconazole in treating oropharyngeal candidiasis, with a success rate of 91.7%. However, posaconazole was associated with lower relapse rates compared with fluconazole.(28)
Posaconazole has been shown to be effective in treating invasive candidiasis refractory to conventional therapies, resulting in a 48% response rate. Posaconazole has been found to be effective in treating oropharyngeal and/or oesophageal candidiasis refractory to fluconazole or itraconazole or both. Posaconazole given at either 400 mg twice daily orally for three days, then 400 mg once daily for 25 days, or 400 mg twice daily for 28 days resulted in a 75% clinical response rate. Clinical response rate was similar for the different posaconazole regimens and did not differ between groups receiving prior treatment with fluconazole, itraconazole or both.(29)
BAL4815 (Basilea Pharmaceutica) is a new antifungal triazole undergoing phase III clinical trials. BAL8557, a water-soluble prodrug of BAL4815, at doses of 50 mg or 100 mg orally daily, has shown efficacy in treating oesophageal candidiasis and is well tolerated.(30,31)
Recently, research has focused on the pathogenesis of Candida infections. Filamentation and biofilm formation are recognised as major virulence factors of C albicans. Compounds that inhibit filamentation may have anticandidal activity. Caenorhabditis elegans and mice have been used in these studies, as the similarities between them and humans have been recognised. Enoxacin, a fluoroquinolone, and CAPE, a propolis derivative, have been shown to prolong survival in mice previously infected with C albicans. CAPE has been shown to inhibit both filamentation and biofilm formation. Both CAPE and enoxacin exhibit antifungal activity without inhibiting growth of the yeast.(7)
Farnesol, also a quorum-sensing molecule, has been shown to inhibit filamentation in C albicans. Both quorum-sensing and filamentation are considered important factors in biofilm formation.(32) Galleria mellonella is a well-recognised model for studying Candida pathogenesis. Farnesol at high concentrations has been shown to increase survival of G mellonella (unpublished data).
Finally, a recombinant anticandidal vaccine has been tested in mice. This showed a protective effect against vaginal, oropharyngeal and disseminated candidiasis.(33) However, its role in protection against candidiasis in humans has not yet been tested.
Conclusion
In the last five years new agents have been added to the antifungal armamentarium. For treating candidaemia and invasive candidiasis, the echinocandin antifungals caspofungin and anidulafungin appear to be first-line options. In treating oesophageal candidiasis, fluconazole remains the treatment of choice. However, several parameters have to be taken into account when deciding on treatment: the patient (neutropenic or not), the species and the toxicity of the antifungal agent. The role of other new triazoles – ravuconazole and albaconazole – plus other antifungal agents such as sordarins and aureobasodin A have to be clarified in the next two years.(23) Moreover, the role of antifungal compounds such as farnesol, enoxacin and CAPE have to be elucidated as further studies become available. However, the more options are available, the greater is the responsibility to use them correctly, taking into account the fact that treatment should always be individualised.
References
1. Clin Infect Dis 1997;25:43-59.
2. Int J Infect Dis 2004;8:111-20.
3. Clin Infect Dis 2003;37:1172-7.
4. Arch Intern Med 1988;148:2642-5.
5. Expert Opin Investig Drugs 2006;15:1319-36.
6. Clin Infect Dis 2006;43:1060-8.
7. PLoS Pathog 2007;3:e18.
8. Expert Rev Anti Infect Ther 2006;4:325-42.
9. BMA/RPSGB. British National Formulary 53. London: British Medical Association/Royal Pharmaceutical Society of Great Britain; 2007.
10. N Engl J Med 2002;347:2020-9.
11. Clin Infect Dis 2001;33:1529-35.
12. Am J Med 2002;113:294-9.
13. Eur J Clin Microbiol Infect Dis 2005;24:654-61.
14. Aliment Pharmacol Ther 2004;20:475-81.
15. Clin Infect Dis 2004;39:842-9.
16. Lancet 2007; 369:1519-27.
17. Aliment Pharmacol Ther 2005;21:899-907.
18. Antimicrob Agents Chemother 2004;48:2021-4.
19. Antimicrob Agents Chemother 2005;49:4795-7.
20. Clin Infect Dis 2004;39:770-5.
21. Expert Opin Investig Drugs 2006;15:579-602.
22. Lancet 2005;366:1435-42.
23. Clin Infect Dis 2001;33:1447-54.
24. Clin Infect Dis 2003;36:1122-31.
25. Eur J Clin Microbiol Infect Dis 2003;22:651-5.
26. Clin Infect Dis 2006;42:1179-86.
27. Clin Infect Dis 2007;44:607-14.
28. Antimicrob Agents Chemother 2006;50:286-93.
29. Antimicrob Agents Chemother 2006;50:279-85.
30. Appl Environ Microbiol 2002;68:5459-63.
31. J Infect Dis 2006;194:256-60.
