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Caspofungin—a new therapeutic option for oropharyngeal candidiasis
EDITORIAL
10.1111/j.1198-743X.2004.00823.x
Caspofungin—a new therapeutic option for oropharyngeal candidiasis J. Garbino Division of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland
ABSTRACT Patients with AIDS are often severely immunocompromised. These patients commonly develop opportunistic infections such as oropharyngeal candidiasis whose treatment may prove to be difficult. Caspofungin belongs to a new class of antifungal agents that have a different mode of action to azoles and polyenes. This new agent is the first inhibitor of fungal glucan synthesis to receive approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. Caspofungin is well-tolerated and represents a substantial improvement over existing therapeutic options for patients prone to azoleresistant candida infection or who cannot tolerate amphotericin B. Keywords
Echinocandin, candidiasis, oropharyngeal, renal failure, voriconazole
Clin Microbiol Infect 2004; 10: 187–189
Patients with AIDS tend to be severely immunocompromised and to develop opportunistic infections such as oropharyngeal candidiasis. The Adult and Adolescent Spectrum of Disease Project found that although there has been a decrease in the incidence of many of the infectious diseases that afflict HIV-positive patients in the USA, oesophageal candidiasis remains the third most common opportunistic infection in this patient population [1]. Patients who do not achieve viral suppression and immune reconstitution with antiretroviral therapy thus remain at high risk of opportunistic infection. Treatment of oropharyngeal candidiasis in HIV-infected patients can be challenging. Azoles are safe and effective agents for the treatment of oesophageal candidiasis and have gradually replaced amphotericin B (AmBD). However, resistance to azoles is now becoming common [2–5]. Although many Candida strains are susceptible to AmBD, patients with Candida glabrata or Candida krusei infection may require high doses [2]. This represents a problem, particularly in severely immunocompromised patients, because AmBD is known to cause a very high incidence of
Corresponding author and reprint requests: J. Garbino, Division of Infectious Diseases, University of Geneva Hospitals, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland E-mail: [email protected]
side effects and toxicity. Newer antifungals, such as voriconazole and caspofungin, have a broader spectrum of activity that includes fluconazoleresistant Candida spp. The use of these new options should therefore be considered for the treatment of refractory oropharyngeal candidiasis. As an illustration of the use of these agents, a patient in our hospital with long-standing AIDS was diagnosed with azole-refractory oropharyngeal and oesophageal candidiasis and intolerance. The patient was a 43-year-old caucasian male with AIDS stage C3 for 15 years, who had suffered from several episodes of opportunistic infections. Although fluconazole was used prophylactically because of severe immunodeficiency, the patient developed recurrent oropharyngeal candidiasis. The patient remained severely immunocompromised, with a CD4 cell count ranging between 9 and 3 ⁄ mm3, and a viral load between 60 876 and 25 302 HIV RNA copies ⁄ mL despite the antiretroviral treatment. In 2002, a culture from an oropharyngeal swab revealed Candida albicans (AmBD and voriconazole-susceptible, and fluconazole and itraconazole-resistant) and C. glabrata (AmBD and voriconazole-susceptible, fluconazole-intermediate, and itraconazole-resistant). The patient was treated with oral voriconazole 200 mg twice-daily. After treatment for 9 months, a severe papular, pruriginous erythema
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
188 Clinical Microbiology and Infection, Volume 10 Number 3, March 2004
developed on the dorsal side of the hands and the neck. The patient also experienced an episode of photosensitivity after exposure to the sun. A skin biopsy was performed, and the histological examination showed a lichenoid dermatoepidermitis. Voriconazole treatment was discontinued, as it was believed to be the cause of the rash. Following recurrence of severe oropharyngeal and oesophageal candidiasis, the patient was treated with intravenous AmBD 50 mg by continuous infusion for 24 h. This induced acute renal impairment: the creatinine levels increased from 71 lmol ⁄ L before AmBD administration to 184 lmol ⁄ L. Therefore, treatment with AmBD was discontinued and the patient was switched to intravenous caspofungin, administered once-daily with a loading dose of 70 mg followed by 50 mg ⁄ day. The patient completed treatment for 1 week, with complete resolution of clinical signs. Four days after the switch to caspofungin, the creatinine level returned to a normal value. Previous use of azoles and CD4 counts of < 50 ⁄ mm3 are associated with azole-resistant candida infections [6]. The patient described above was severely immunocompromised, had a history of azole prophylaxis, and developed an oropharyngeal and oesophageal candidiasis that was unresponsive to therapy with classical azoles. Treatment with voriconazole was not tolerated because of allergic reactions, and the use of AmBD induced renal toxicity. Caspofungin belongs to the echinocandins, a novel class of antifungal agents that have a different mode of action from that of azoles and polyenes. Echinocandins inhibit b-1,3-glucan synthesis in the fungal cell wall, while other agents act on ergosterol in the fungal cell membrane [7,8]. Caspofungin exhibits in-vitro activity even against Candida strains resistant to azoles [7,9,10]. It has also been shown to be effective and well-tolerated in patients with fluconazole-resistant oesophageal candidiasis [11,12]. In a large study of predominantly HIV-positive patients with oesophageal candidiasis, caspofungin was found to be as effective as AmBD, but better tolerated [13,14]. This new agent is the first inhibitor of fungal glucan synthesis to receive approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis [15]. It may represent a substantial improvement over existing therapy, particularly for patients with AIDS, who tend to be prone to candida infections resistant to azoles, and in
immunocompromised patients who may not be able to tolerate AmBD. In patients with invasive candidiasis, success has been observed in 73% of caspofungin recipients and in 62% of AmBD recipients, while adverse events occurred significantly more frequently among AmBD recipients than among caspofungin recipients [16]. As there is no evidence of in-vitro antagonism when caspofungin is used in combination with other antifungal agents, it is an important agent for combination therapy, a strategy already used by some clinicians for the treatment of invasive aspergillosis [17–19]. However, the precise correlation between the in-vitro interaction data and the clinical outcome currently remains unknown, and further clinical investigations are needed to determine this. REFERENCES 1. Kaplan JE, Hanson D, Dworkin MS et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 30: S5–S14. 2. Rex JH, Walsh TJ, Sobel JD et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000; 20: 662– 678. 3. Masia CM, Guiterrez RF, Ortiz de la Tabla DV et al. Determinants for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients. Eur J Clin Microbiol Infect Dis 2000; 19: 593–601. 4. Ruhnke M, Eigler A, Tennagen I, Geiseler B, Engelmann E, Traumann M. Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. J Clin Microbiol 1994; 32: 2092–2098. 5. Newman SL, Flanigan TP, Fisher A, Rinaldi MG, Stein M, Vigilante M. Clinically significant mucosal candidiasis resistant to fluconazole treatment in patients with AIDS. Clin Infect Dis 1994; 19: 684–686. 6. Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 1998; 27: 1556–1565. 7. Martinez-Suarez JV, Rodriguez-Tudela JL. In vitro activities of semisynthetic pneumocandin L-733,560 against fluconazole-resistant and -susceptible Candida albicans isolates. Antimicrob Agents Chemother 1996; 40: 1277–1279. 8. Andriole VT. The 1998 Garrod lecture. Current and future antifungal therapy: new targets for antifungal agents. J Antimicrob Chemother 1999; 44: 151–162. 9. Vazquez JA, Lynch M, Boikov D, Sobel JD. In vitro activity of a new pneumocandin antifungal, L-743, 872, against azole-susceptible and -resistant Candida species. Antimicrob Agents Chemother 1997; 41: 1612–1614. 10. Bachman SP, Patterson TF, Lopez-Ribot JL. In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol 2002; 40: 2228–2230.
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 187–189
Garbino Caspofungin as therapy for oropharyngeal candidiasis 189
11. Kartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J AIDS 2002; 31: 183–187. 12. Garbino J, Lew D, Hirschel B, Rohner P. Caspofungin in the treatment of oropharyngeal candidiasis. Infect Dis Clin Pract 2003; 57: 143. 13. Villanueva A, Arathoon EG, Gotuzzo E, Bermann RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2002; 33: 1529–1535. 14. Arathoon EG, Gotuzzo E, Noriega LM et al. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis. Antimicrob Agents Chemother 2002; 46: 451–457. 15. Mora-Duarte J, Betts R, Rotstein C et al. Caspofungin vs. amphotericin B deoxycholate in the treatment of invasive candidiasis in neutropenic and non-neutropenic patients: a multi-centre, randomized, double-blind study. N Engl J Med 2002; 347: 2020–2029. 16. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36: 1445–1457.
17. Kontoyiannis DP, Hachem R, Lewis RE et al. Efficacy and toxicity of the caspofungin ⁄ liposomal amphotericin B (CAS ⁄ LipAMB) combination in documented or possible invasive aspergillosis (IA) in patients (Pts) with hematologic malignancies [abstract M-1820]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 416. 18. Gentina T, De Botton S, Alfandri S et al. Combination antifungals for treatment of pulmonary invasive aspergillosis (IA) refractory to amphotericin B (AmB) in leukaemia patients [abstract M-860]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 386. 19. Thie´baut ASr, Antal D, Breysse MC, Pivot C. Refractory invasive fungal infections in patients (pts) with hematologic malignancies: combination of new antifungal agents (voriconazole or caspofungin) with amphotericin B [abstract M-859]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 386.
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 187–189
10.1111/j.1198-743X.2004.00823.x
Caspofungin—a new therapeutic option for oropharyngeal candidiasis J. Garbino Division of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland
ABSTRACT Patients with AIDS are often severely immunocompromised. These patients commonly develop opportunistic infections such as oropharyngeal candidiasis whose treatment may prove to be difficult. Caspofungin belongs to a new class of antifungal agents that have a different mode of action to azoles and polyenes. This new agent is the first inhibitor of fungal glucan synthesis to receive approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. Caspofungin is well-tolerated and represents a substantial improvement over existing therapeutic options for patients prone to azoleresistant candida infection or who cannot tolerate amphotericin B. Keywords
Echinocandin, candidiasis, oropharyngeal, renal failure, voriconazole
Clin Microbiol Infect 2004; 10: 187–189
Patients with AIDS tend to be severely immunocompromised and to develop opportunistic infections such as oropharyngeal candidiasis. The Adult and Adolescent Spectrum of Disease Project found that although there has been a decrease in the incidence of many of the infectious diseases that afflict HIV-positive patients in the USA, oesophageal candidiasis remains the third most common opportunistic infection in this patient population [1]. Patients who do not achieve viral suppression and immune reconstitution with antiretroviral therapy thus remain at high risk of opportunistic infection. Treatment of oropharyngeal candidiasis in HIV-infected patients can be challenging. Azoles are safe and effective agents for the treatment of oesophageal candidiasis and have gradually replaced amphotericin B (AmBD). However, resistance to azoles is now becoming common [2–5]. Although many Candida strains are susceptible to AmBD, patients with Candida glabrata or Candida krusei infection may require high doses [2]. This represents a problem, particularly in severely immunocompromised patients, because AmBD is known to cause a very high incidence of
Corresponding author and reprint requests: J. Garbino, Division of Infectious Diseases, University of Geneva Hospitals, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland E-mail: [email protected]
side effects and toxicity. Newer antifungals, such as voriconazole and caspofungin, have a broader spectrum of activity that includes fluconazoleresistant Candida spp. The use of these new options should therefore be considered for the treatment of refractory oropharyngeal candidiasis. As an illustration of the use of these agents, a patient in our hospital with long-standing AIDS was diagnosed with azole-refractory oropharyngeal and oesophageal candidiasis and intolerance. The patient was a 43-year-old caucasian male with AIDS stage C3 for 15 years, who had suffered from several episodes of opportunistic infections. Although fluconazole was used prophylactically because of severe immunodeficiency, the patient developed recurrent oropharyngeal candidiasis. The patient remained severely immunocompromised, with a CD4 cell count ranging between 9 and 3 ⁄ mm3, and a viral load between 60 876 and 25 302 HIV RNA copies ⁄ mL despite the antiretroviral treatment. In 2002, a culture from an oropharyngeal swab revealed Candida albicans (AmBD and voriconazole-susceptible, and fluconazole and itraconazole-resistant) and C. glabrata (AmBD and voriconazole-susceptible, fluconazole-intermediate, and itraconazole-resistant). The patient was treated with oral voriconazole 200 mg twice-daily. After treatment for 9 months, a severe papular, pruriginous erythema
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
188 Clinical Microbiology and Infection, Volume 10 Number 3, March 2004
developed on the dorsal side of the hands and the neck. The patient also experienced an episode of photosensitivity after exposure to the sun. A skin biopsy was performed, and the histological examination showed a lichenoid dermatoepidermitis. Voriconazole treatment was discontinued, as it was believed to be the cause of the rash. Following recurrence of severe oropharyngeal and oesophageal candidiasis, the patient was treated with intravenous AmBD 50 mg by continuous infusion for 24 h. This induced acute renal impairment: the creatinine levels increased from 71 lmol ⁄ L before AmBD administration to 184 lmol ⁄ L. Therefore, treatment with AmBD was discontinued and the patient was switched to intravenous caspofungin, administered once-daily with a loading dose of 70 mg followed by 50 mg ⁄ day. The patient completed treatment for 1 week, with complete resolution of clinical signs. Four days after the switch to caspofungin, the creatinine level returned to a normal value. Previous use of azoles and CD4 counts of < 50 ⁄ mm3 are associated with azole-resistant candida infections [6]. The patient described above was severely immunocompromised, had a history of azole prophylaxis, and developed an oropharyngeal and oesophageal candidiasis that was unresponsive to therapy with classical azoles. Treatment with voriconazole was not tolerated because of allergic reactions, and the use of AmBD induced renal toxicity. Caspofungin belongs to the echinocandins, a novel class of antifungal agents that have a different mode of action from that of azoles and polyenes. Echinocandins inhibit b-1,3-glucan synthesis in the fungal cell wall, while other agents act on ergosterol in the fungal cell membrane [7,8]. Caspofungin exhibits in-vitro activity even against Candida strains resistant to azoles [7,9,10]. It has also been shown to be effective and well-tolerated in patients with fluconazole-resistant oesophageal candidiasis [11,12]. In a large study of predominantly HIV-positive patients with oesophageal candidiasis, caspofungin was found to be as effective as AmBD, but better tolerated [13,14]. This new agent is the first inhibitor of fungal glucan synthesis to receive approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis [15]. It may represent a substantial improvement over existing therapy, particularly for patients with AIDS, who tend to be prone to candida infections resistant to azoles, and in
immunocompromised patients who may not be able to tolerate AmBD. In patients with invasive candidiasis, success has been observed in 73% of caspofungin recipients and in 62% of AmBD recipients, while adverse events occurred significantly more frequently among AmBD recipients than among caspofungin recipients [16]. As there is no evidence of in-vitro antagonism when caspofungin is used in combination with other antifungal agents, it is an important agent for combination therapy, a strategy already used by some clinicians for the treatment of invasive aspergillosis [17–19]. However, the precise correlation between the in-vitro interaction data and the clinical outcome currently remains unknown, and further clinical investigations are needed to determine this. REFERENCES 1. Kaplan JE, Hanson D, Dworkin MS et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 30: S5–S14. 2. Rex JH, Walsh TJ, Sobel JD et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000; 20: 662– 678. 3. Masia CM, Guiterrez RF, Ortiz de la Tabla DV et al. Determinants for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients. Eur J Clin Microbiol Infect Dis 2000; 19: 593–601. 4. Ruhnke M, Eigler A, Tennagen I, Geiseler B, Engelmann E, Traumann M. Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. J Clin Microbiol 1994; 32: 2092–2098. 5. Newman SL, Flanigan TP, Fisher A, Rinaldi MG, Stein M, Vigilante M. Clinically significant mucosal candidiasis resistant to fluconazole treatment in patients with AIDS. Clin Infect Dis 1994; 19: 684–686. 6. Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 1998; 27: 1556–1565. 7. Martinez-Suarez JV, Rodriguez-Tudela JL. In vitro activities of semisynthetic pneumocandin L-733,560 against fluconazole-resistant and -susceptible Candida albicans isolates. Antimicrob Agents Chemother 1996; 40: 1277–1279. 8. Andriole VT. The 1998 Garrod lecture. Current and future antifungal therapy: new targets for antifungal agents. J Antimicrob Chemother 1999; 44: 151–162. 9. Vazquez JA, Lynch M, Boikov D, Sobel JD. In vitro activity of a new pneumocandin antifungal, L-743, 872, against azole-susceptible and -resistant Candida species. Antimicrob Agents Chemother 1997; 41: 1612–1614. 10. Bachman SP, Patterson TF, Lopez-Ribot JL. In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol 2002; 40: 2228–2230.
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 187–189
Garbino Caspofungin as therapy for oropharyngeal candidiasis 189
11. Kartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J AIDS 2002; 31: 183–187. 12. Garbino J, Lew D, Hirschel B, Rohner P. Caspofungin in the treatment of oropharyngeal candidiasis. Infect Dis Clin Pract 2003; 57: 143. 13. Villanueva A, Arathoon EG, Gotuzzo E, Bermann RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2002; 33: 1529–1535. 14. Arathoon EG, Gotuzzo E, Noriega LM et al. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis. Antimicrob Agents Chemother 2002; 46: 451–457. 15. Mora-Duarte J, Betts R, Rotstein C et al. Caspofungin vs. amphotericin B deoxycholate in the treatment of invasive candidiasis in neutropenic and non-neutropenic patients: a multi-centre, randomized, double-blind study. N Engl J Med 2002; 347: 2020–2029. 16. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36: 1445–1457.
17. Kontoyiannis DP, Hachem R, Lewis RE et al. Efficacy and toxicity of the caspofungin ⁄ liposomal amphotericin B (CAS ⁄ LipAMB) combination in documented or possible invasive aspergillosis (IA) in patients (Pts) with hematologic malignancies [abstract M-1820]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 416. 18. Gentina T, De Botton S, Alfandri S et al. Combination antifungals for treatment of pulmonary invasive aspergillosis (IA) refractory to amphotericin B (AmB) in leukaemia patients [abstract M-860]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 386. 19. Thie´baut ASr, Antal D, Breysse MC, Pivot C. Refractory invasive fungal infections in patients (pts) with hematologic malignancies: combination of new antifungal agents (voriconazole or caspofungin) with amphotericin B [abstract M-859]. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Washington, DC: American Society for Microbiology, 2002; 386.
2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10, 187–189