Clinical Roundtable Monograph

Opportunistic fungal and parasitic infections are an important cause of morbidity and mortality. Although these infections can affect both immunocompromised and immunocompetent individuals, HIV-infected patients and stem cell transplant recipients are at special risk. Although several therapeutic options exist to treat these infections, drug resistance is becoming an increasing issue which should be considered when selecting a treatment. Among the treatment options available, amphotericin B is characterized by broad-spectrum activity. While dose-related adverse events often occur with administration of the conventional formulation of amphotericin B, newer lipidbased formulations of amphotericin B, eg, amphotericin B colloidal dispersion, are associated with less toxicity. Further, these lipid-based formulations have better solubility, an important characteristic when treating infections that have invaded the central nervous system. This monograph discusses the application of the lipid-based amphotericin B formulations amidst the changing and emerging epidemiology of opportunistic fungal and parasitic infections, focusing on those caused by zygomycetes, cryptococcus, and leishmania. S u p p o r t e d t h r o u g h f u n d i n g f r o m T h r e e R i v e r s P h a r m a c e u t i c a l s a n d To r r e x C h i e s i P h a r m a C L I n I C A L R O u n d tA B L e M O n O g R A p h 2 Clinical Advances in hematology & Oncology Volume 8, Issue 8, Supplement 18 August 2010 Disclaimer Funding for this Clinical Roundtable Monograph has been provided by Three Rivers Pharmaceuticals and Torrex Chiesi Pharma. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2010 Millennium Medical Publishing, Inc. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. Emerging Pathogens and Resistance Patterns Presently, there is a shift in the epidemiology of invasive fungal diseases throughout Europe and the Americas.1,2 This change has become apparent through the use of surveillance programs such as SENTRY and ARTEMIS DISK. The SENTRY Antimicrobial Surveillance Program evaluated the activity of contemporary antifungal agents against Candida species, Cryptococcus species, and Aspergillus species.3 The ARTEMIS DISK Global Antifungal Surveillance Study (1997–2007) performed a 10.5-year analysis of the susceptibility of Candida species and nonCandida species to the antifungal agents fluconazole and voriconazole.4,5 The first wave of this changing epidemiology appeared during the late 1980s, for multifactorial reasons. A primary cause is the increased reliance on fluconazole as a prophylactic and therapeutic agent. For example, the increased usage of fluconazole likely explains the shift in appearance from Candida albicans to nonCandida albicans, namely Candida glabrata.6 Currently, the predominant species are non-Candida albicans Candida strains, as well as several species of molds, mainly those that cause Pithomyces and Fusarium infections.4,5,7 Various populations are at risk for the development of invasive fungal diseases, particularly patients who are undergoing allogeneic stem cell transplantation and patients receiving other treatments for hematologic malignancies. Similarly, an increase in azole-resistant molds, such as Aspergillus fumigatus, has also become apparent.8 A particular increase in the incidence of Aspergillus fumigatus has been reported in the United Kingdom, as well as the Netherlands, where it has increased remarkably from 2% to 8%.9 This increased incidence is attributable to many factors, the foremost of which is likely the heightened and extensive usage of azoles and/or azole-containing fungicides.10 The Changing Epidemiology of Opportunistic Fungal and Parasite Infections Cornelia Lass-Flörl, MD Rates of Zygomycosis, Cryptococcal, and Leishmaniasis Infections Zygomycosis, an uncommon and frequently fatal mycoses that is caused by the Zygomycetes fungi, now accounts for an ever-increasing number of hospital infections.11,12 Zygomycosis currently represents 2% of solid organ transplant patients and up to 8% of hematopoietic stem cell transplant patients.13 Epidemiologic reports have documented an increased incidence of zygomycosis in hospitals and other clinical centers.14,15 For example, more than 30% of fungal infections at the Innsbruck Medical Center in Austria are due to zygomycosis. Many of these infections occur in patients already being treated with systemic antifungal therapies, such as azoles including voriconazole. The primary risk groups for cryptococcal diseases are immunocompromised patients, such as those with HIV infection or solid organ transplant recipients; however, many individuals who do not fall into these categories are also susceptible.16 Several epidemiologic studies estimate that the global burden of HIV-associated cryptococcosis is approximately 1 million cases annually. Additionally, solid organ transplant patients are another significant risk group for cryptococcal disease. Interestingly, cryptococcosis seems to affect children to a lesser degree.17 Among HIV-infected children in the United States, the incidence of cryptococcosis is limited to 0.5–1%,18,19 although the incidence of cryptococcosis among HIV-infected children in other countries, including Thailand and South Africa, is somewhat higher.20,21 Two cryptococcal species are especially important in the clinical setting. Cryptococcus neoformans has a worldwide distribution and is responsible for the vast majority of cryptococcal infections in immunosuppressed hosts, such as HIV-infected patients. Conversely, Cryptococcus gattii causes C L I n I C A L R O u n d tA B L e M O n O g R A p h Clinical Advances in hematology & Oncology Volume 8, Issue 8, Supplement 18 August 2010 3 range of coverage of fungal and protozoa strains, including the emerging pathogens discussed. Lipid formulations of amphotericin B are now often suggested as first-line therapy due to their broad-spectrum activity against these and other emerging pathogens.23,24 References 1. Lai CC, Tan CK, Huang YT, Shao PL, Hsueh PR. Current challenges in the management of invasive fungal infections. J Infect Chemother. 2008;14:77-85. 2. Lass-Flörl C. The changing face of epidemiology of invasive fungal disease in Europe. Mycoses. 2009;52:197-205. 3. Messer SA, Moet GJ, Kirby JT, Jones RN. Activity of contemporary antifungal agents, including the novel echinocandin anidulafungin, tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2006 to 2007). J Clin Microbiol. 2009;47:1942-1946. 4. Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida Species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J Clin Microbiol. 2010;48:1366-1377. 5. Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol. 2009;47:117-123. 6. Neu N, Malik M, Lunding A, et al. Epidemiology of candidemia at a Children’s hospital, 2002 to 2006. Pediatr Infect Dis J. 2009;28:806-809. 7. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis. 2009;48:1695-1703. 8. Brakhage AA. Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants. Curr Drug Targets. 2005;6: 875-886. 9. Snelders E, van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:e219. 10. Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis. 2009;9:789-795. 11. Antoniadou A. Outbreaks of zygomycosis in hospitals. Clin Microbiol Infect. 2009;15(suppl 5):55-59. 12. Meis JF, Chakrabarti A. Changing epidemiology of an emerging infection: zygomycosis. Clin Microbiol Infect. 2009;15(suppl 5):10-14. 13. Abstract 12 presented at: 2nd International Forum on Zygomycosis; May 28-30, 2010; Porto Heli, Greece. 14. Ambrosioni J, Bouchuiguir-Wafa K, Garbino J. Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors. Int J Infect Dis. 2010 Mar 22. [Epub ahead of print] 15. Bitar D, Van Cauteren D, Lanternier F, et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006. Emerg Infect Dis. 2009;15:1395-1401. 16. Li SS, Mody CH. Cryptococcus. Proc Am Thorac Soc. 2010;7:186-196. 17. Severo CB, Xavier MO, Gazzoni AF, Severo LC. Cryptococcosis in children. Paediatr Respir Rev. 2009;10:166-171. 18. Abadi J, Nachman S, Kressel AB, Pirofski L. Cryptococcosis in children with AIDS. Clin Infect Dis. 1999;28:309-313. 19. Gonzalez CE, Shetty D, Lewis LL, Mueller BU, Pizzo PA, Walsh TJ. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996;15:796-800. 20. McCarthy KM, Morgan J, Wannemuehler KA, et al. Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS. 2006;20:2199-2206. 21. Likasitwattanakul S, Poneprasert B, Sirisanthana V. Cryptococcosis in HIVinfected children. Southeast Asian J Trop Med Public Health. 2004;35:935-939. 22. Desjeux P. Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis. 2004;27:305-318. 23. Chu P, Sadullah S. The current role of amphotericin B lipid complex in managing systemic fungal infections. Curr Med Res Opin. 2009;25:3011-3020. 24. Gullo A. Invasive fungal infections: the challenge continues. Drugs. 2009;69(suppl 1):65-73. 70% of infections among immunocompetent hosts. Unlike Cryptococcus neoformans, Cryptococcus gattii occurs only rarely in HIV-infected patients. Leishmaniasis disease is caused by the Leishmania species of protozoa. The overall global prevalence of leishmaniasis is estimated to be approximately 12 million cases; nearly 2 million of these patients will develop a clinical syndrome related to leishmaniasis.22 Leishmaniasis is extremely common in many American regions, as well as in endemic zones such as Latin America, Africa, the Indian subcontinent, the Middle East, and Mediterranean regions (Figure 1). In Europe, reemergence of leishmaniasis is a common issue, due to 3 primary scenarios. The first of these is the introduction of exotic Leishmania species or strains into Europe due to an increase in worldwide travel. Secondly, a natural spread of visceral and cutaneous leishmaniasis is caused by Leishmania infantum and Leishmania tropica from the Mediterranean region of Europe, where these species are endemic. Third, a reemergence of diseases in the Mediterranean region is caused by an increase in the number of immunosuppressed patients. Lipid Formulations of Amphotericin B—Broadspectrum Coverage and Rare Mycologic Resistance Invasive infections, especially those caused by the emerging pathogens discussed here, are an important cause of morbidity and mortality worldwide. The conventional amphotericin B formulation has long been a gold standard for the treatment of many infections. However, poor solubility and dose-related toxicities have prompted the development of lipid formulations of amphotericin B. These lipid formulations of amphotericin B offer a broad Figure 1. Geographical distribution of leishmaniasis. Light blue=leishmaniasis; dark blue=co-infection.