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Caspofungin in the treatment of invasive fungal infections
Intensive and Critical Care Nursing (2006) 22, 59—62
PHARMACY REVIEW
Caspofungin in the treatment of invasive fungal infections Simon Keady a,∗, Meera Thacker b a b
Women and Children’s Services, University College London Hospitals NHS Foundation Trust, UK Critical Care Services, Royal Free Hampstead NHS Trust, UK
Received 4 May 2005; accepted 10 May 2005
KEYWORDS Caspofungin; Fungal; Infection; Treatment; Intensive care; Adults; Children
Summary Caspofungin is a member of a new class of antifungals called Echinocandins and is the first to have marketing authorisation in the United Kingdom. This article reviews the clinical efficacy, side effect profile, dosing and administration schedule of caspofungin. The article also discusses the warnings and precautions associated with the use of this drug. Caspofungin is an effective treatment option in the management of fungal infections. © 2005 Elsevier Ltd. All rights reserved.
Introduction There continues to be an increase in the incidence of invasive fungal infections, particularly those caused by Candida spp. and Aspergillus spp. This is mainly due to the increasing numbers of critically ill and immunocompromised patients. Current antifungal treatment strategies are often limited to the use of either the azoles, e.g. fluconazole and itraconazole and amphotericin B/liposomal amphotericin. Echinocandins are a new class of antifungal agents, and the first one to be licensed is caspofungin. Caspofungin inhibits the synthesis of glucan, which is a vital component of the fungal cell wall. This inhibition leads to osmotic instability, break∗
Corresponding author. E-mail address: [email protected] (S. Keady).
down of the fungal cell wall and finally the death of the fungus itself. Caspofungin’s main fungicidal activity is against Candida spp. and Aspergillus spp. Caspofungin is currently licensed for the treatment of the following: • Invasive candidiasis in adult patients. • Invasive aspergillosis in adult patients who are refractory to or intolerant of amphotericin and/or itraconazole. (Refractory can be defined as progression of infection or failure to improve after a minimum of 7 days of effective antifungal therapy at therapeutic doses.) • Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropenic adult patients. It is currently not licensed for either the treatment of oropharyngeal or oesophageal candidiasis.
0964-3397/$ — see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.iccn.2005.05.003
60
Clinical efficacy Studies have evaluated the efficacy of caspofungin in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis.
Invasive aspergillous Maertens et al. (2002) recruited 90 patients into a multicentre open label study. All patients had either a definite aspergillosis diagnosis or a probable pulmonary aspergillosis. Patients were either refractory to or intolerant to standard antifungal treatments. Those who were refractive to the original antifungal therapy received at least 7 days of this treatment in order to ensure eligibility. Patients received caspofungin 70 mg on day 1 with 50 mg/day thereafter. Response rates were either complete (resolution of all attributable signs and symptoms and radiographic or bronchoscopic abnormalities) or partial (clinically meaningful improvement in attributable signs and symptoms and radiographic or bronchoscopic abnormalities). Treatment durations ranged from 1 to 162 days. Complete or partial responses occurred in 37 of 83 patients.
Invasive candidiasis Mora-Duarte et al. (2002), in a randomised, double blind, multicentre study compared the use of caspofungin with amphotericin B in 239 patients with invasive candidiasis. To be eligible, patients had to have had at least one positive Candida culture in the previous 4 days together with either fever, hypothermia, hypotension or signs of inflammation at the infected site in the previous 2 days. Patients received either caspofungin (70 mg day 1 followed by 50 mg/day) or amphotericin B (0.7—l mg/kg/day in neutropenic patients or 0.6—0.7 mg/kg/day in patients without neutropenia intravenous therapy was continued for a minimum of 10 days. The primary endpoint was the overall response at the end of the intravenous course. The caspofungin group demonstrated a better outcome than those treated with amphotericin B (p = 0.03). There was no significant difference between caspofungin and amphotericin B recipients in terms of mortality.
Oesophageal candidiasis Whilst caspofungin is not currently licensed for the treatment of oesophageal candidiasis, a number of studies have been conducted to explore its effi-
S. Keady, M. Thacker cacy. Villanueva et al. (2002), in a randomised, double-blind, multicentre trial, compared caspofungin or fluconazole in 177 patients with candidal oesophagitis. These patients received either caspofungin 50 mg or fluconazole 200 mg once daily for 7—21 days. The primary endpoint for this trial was a combined clinical and endoscopic response with a complete resolution of the referable symptoms at between 5 and 7 days after the end of therapy. Caspofungin demonstrated a similar efficacy to fluconazole in the treatment of oesophageal candidiasis. Villanueva et al. (2001), in another double-blind randomised trial compared caspofungin 50 or 70 mg to amphotericin B 0.5 mg/kg once daily for 14 days. The primary endpoint was as above but patient assessment was undertaken 14 days post cessation of therapy. Caspofungin was shown to be at least as effective as amphotericin B in the treatment of oesophageal candidiasis.
Paediatric and neonatal patients Whilst information regarding the use of caspofungin in children and neonates is currently limited, trials are currently underway assessing its use in children. Caspofungin has been used in a small number of neonates and Odio et al. (2004) found it effective when used for invasive candidiasis. All positive blood cultures were clear within 3—7 days. Caspofungin has also been used in children as a combination therapy when treating refractory fungal pneumonia in acute leukaemics or when undergoing allogenic bone marrow transplant. Castagnola et al. (2004) used a loading dose of 40 mg/m2 with a maintenance dose of 30 mg/m2 . The treatment was well tolerated and effective in the patients.
Dosing, administration and monitoring Caspofungin is given intravenously on day 1 as a single 70 mg dose. Further dose selection is based on the patient’s weight. Those patients over 80 kg continue on 70 mg daily whilst those less than 80 kg have a dose of 50 mg administered. Doses are administered as a slow intravenous infusion usually over an hour. Caspofungin should be reconstituted with water for injection and further diluted with sodium chloride 0.9% to a final volume of between 100 and 250 ml. Caspofungin is incompatible with diluents containing dextrose. The drug is not available as an oral formulation, which restricts its use.
Caspofungin in the treatment of invasive fungal infections
61
Table 1 Area of effect
Very common
Common
Blood and lymphatic system disorders Nervous system disorders Cardiac disorders Vascular disorders Respiratory disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions Investigations
N/A N/A N/A N/A N/A N/A N/A Fever
Anaemia Headache Tachycardia Phlebitis/thrombophlebitis Dyspnoea Abdominal pain, nausea Rash, pruritus, sweating Pain, chills, infused-vein complications
N/A
Elevated liver values (AST, ALT, alkaline phosphatase, total bilirubin),increased serum creatinine, decreased haemoglobin, decreased haematocrit, decreased blood potassium, low albumin, decreased white blood cells, increased eosinophils, decreased platelet count, decreased neutrophils, increased partial thromboplastin time, decreased total serum protein, increased urinary protein
The duration of therapy of caspofungin is based on both the patient’s clinical condition and the organism isolated. Those patients undergoing empirical therapy, the therapy is usually continued for up to 72 h after the resolution of neutropenia. Patients found to have a proven fungal infection should be treated for a minimum of 14 days and treatment continued for at least 7 days after the neutropenia and clinical symptoms have resolved. Invasive candidiasis treatment is based on the individual’s clinical and microbiological response. Once the signs and symptoms of invasive candidiasis have improved and cultures have become negative, a switch to oral antifungal therapy may be considered. In general, antifungal therapy should continue for at least 14 days after the last positive culture. For those patients with invasive aspergillosis, the same applies as for invasive candidiasis but treatment normally continues for at least 7 days after the resolution of symptoms.
Side effect profile of casopfungin Table 1 lists some of the side effects reported with caspofungin. Frequencies are defined as: very common (>10%), common (1—10%).
atic insufficiency (Child Pugh score 5—6) no dose adjustment is needed. Patients with a moderate hepatic insufficiency (Child Pugh score 7—9) should have the initial 70 mg loading dose followed by a 35 mg maintenance dose. There is no clinical experience with severe hepatic insufficiency.
Interactions Caspofungin has been shown to interact with ciclosporin A causing a transient increase in alanine transaminase (ALT) and aspartate transaminase (AST). These resolve on discontinuation of treatment. Caspofungin reduces the trough concentration of tacrolimus. Close monitoring of tacrolimus levels with appropriate dosage adjustments as necessary are required. Limited data indicates that concomitant use of caspofungin with inducers of metabolic enzymes, e.g. efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine may result in a decrease of caspofungin plasma concentrations. When administering caspofungin with these drugs, an increase in the daily dose of caspofungin to 70 mg should be considered.
Conclusions Warnings and precautions No dose adjustment is necessary for renal impairment or in patients on haemodialysis. For mild hep-
Caspofungin has shown itself to be an effective treatment for invasive fungal infections. Further work is required to determine possible interactions especially with those drugs used to treat HIV
62 immunocompromised patients. Further echinocandins are awaiting marketing approval both in the United Kingdom and Europe.
References Castagnola E, Machetti M, Cappelli B, et al. Caspofungin associated with liposomal amphotericin B or voriconazole for treatment of refractory fungal pneumonia in children with acute leukaemia or undergoing allogenic bone marrow transplant. Clin Microbiol Infect 2004;10(3):255—7. Maertens J, Raad I, Petrikkos G, et al. Update of the multicenter noncomparative study of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B. In:
S. Keady, M. Thacker 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2002, September 27—30. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347(December (25)):2020—9. Odio C, Araya R, Pinto L, et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J 2004;23(12):1093—7. Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001;33(November (9)):1529—35. Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized double-blind study of caspofungin versus fluonazole for the treatment of candidal esophagitis. Am J Med 2002;113(September (4)):294—9.
PHARMACY REVIEW
Caspofungin in the treatment of invasive fungal infections Simon Keady a,∗, Meera Thacker b a b
Women and Children’s Services, University College London Hospitals NHS Foundation Trust, UK Critical Care Services, Royal Free Hampstead NHS Trust, UK
Received 4 May 2005; accepted 10 May 2005
KEYWORDS Caspofungin; Fungal; Infection; Treatment; Intensive care; Adults; Children
Summary Caspofungin is a member of a new class of antifungals called Echinocandins and is the first to have marketing authorisation in the United Kingdom. This article reviews the clinical efficacy, side effect profile, dosing and administration schedule of caspofungin. The article also discusses the warnings and precautions associated with the use of this drug. Caspofungin is an effective treatment option in the management of fungal infections. © 2005 Elsevier Ltd. All rights reserved.
Introduction There continues to be an increase in the incidence of invasive fungal infections, particularly those caused by Candida spp. and Aspergillus spp. This is mainly due to the increasing numbers of critically ill and immunocompromised patients. Current antifungal treatment strategies are often limited to the use of either the azoles, e.g. fluconazole and itraconazole and amphotericin B/liposomal amphotericin. Echinocandins are a new class of antifungal agents, and the first one to be licensed is caspofungin. Caspofungin inhibits the synthesis of glucan, which is a vital component of the fungal cell wall. This inhibition leads to osmotic instability, break∗
Corresponding author. E-mail address: [email protected] (S. Keady).
down of the fungal cell wall and finally the death of the fungus itself. Caspofungin’s main fungicidal activity is against Candida spp. and Aspergillus spp. Caspofungin is currently licensed for the treatment of the following: • Invasive candidiasis in adult patients. • Invasive aspergillosis in adult patients who are refractory to or intolerant of amphotericin and/or itraconazole. (Refractory can be defined as progression of infection or failure to improve after a minimum of 7 days of effective antifungal therapy at therapeutic doses.) • Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropenic adult patients. It is currently not licensed for either the treatment of oropharyngeal or oesophageal candidiasis.
0964-3397/$ — see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.iccn.2005.05.003
60
Clinical efficacy Studies have evaluated the efficacy of caspofungin in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis.
Invasive aspergillous Maertens et al. (2002) recruited 90 patients into a multicentre open label study. All patients had either a definite aspergillosis diagnosis or a probable pulmonary aspergillosis. Patients were either refractory to or intolerant to standard antifungal treatments. Those who were refractive to the original antifungal therapy received at least 7 days of this treatment in order to ensure eligibility. Patients received caspofungin 70 mg on day 1 with 50 mg/day thereafter. Response rates were either complete (resolution of all attributable signs and symptoms and radiographic or bronchoscopic abnormalities) or partial (clinically meaningful improvement in attributable signs and symptoms and radiographic or bronchoscopic abnormalities). Treatment durations ranged from 1 to 162 days. Complete or partial responses occurred in 37 of 83 patients.
Invasive candidiasis Mora-Duarte et al. (2002), in a randomised, double blind, multicentre study compared the use of caspofungin with amphotericin B in 239 patients with invasive candidiasis. To be eligible, patients had to have had at least one positive Candida culture in the previous 4 days together with either fever, hypothermia, hypotension or signs of inflammation at the infected site in the previous 2 days. Patients received either caspofungin (70 mg day 1 followed by 50 mg/day) or amphotericin B (0.7—l mg/kg/day in neutropenic patients or 0.6—0.7 mg/kg/day in patients without neutropenia intravenous therapy was continued for a minimum of 10 days. The primary endpoint was the overall response at the end of the intravenous course. The caspofungin group demonstrated a better outcome than those treated with amphotericin B (p = 0.03). There was no significant difference between caspofungin and amphotericin B recipients in terms of mortality.
Oesophageal candidiasis Whilst caspofungin is not currently licensed for the treatment of oesophageal candidiasis, a number of studies have been conducted to explore its effi-
S. Keady, M. Thacker cacy. Villanueva et al. (2002), in a randomised, double-blind, multicentre trial, compared caspofungin or fluconazole in 177 patients with candidal oesophagitis. These patients received either caspofungin 50 mg or fluconazole 200 mg once daily for 7—21 days. The primary endpoint for this trial was a combined clinical and endoscopic response with a complete resolution of the referable symptoms at between 5 and 7 days after the end of therapy. Caspofungin demonstrated a similar efficacy to fluconazole in the treatment of oesophageal candidiasis. Villanueva et al. (2001), in another double-blind randomised trial compared caspofungin 50 or 70 mg to amphotericin B 0.5 mg/kg once daily for 14 days. The primary endpoint was as above but patient assessment was undertaken 14 days post cessation of therapy. Caspofungin was shown to be at least as effective as amphotericin B in the treatment of oesophageal candidiasis.
Paediatric and neonatal patients Whilst information regarding the use of caspofungin in children and neonates is currently limited, trials are currently underway assessing its use in children. Caspofungin has been used in a small number of neonates and Odio et al. (2004) found it effective when used for invasive candidiasis. All positive blood cultures were clear within 3—7 days. Caspofungin has also been used in children as a combination therapy when treating refractory fungal pneumonia in acute leukaemics or when undergoing allogenic bone marrow transplant. Castagnola et al. (2004) used a loading dose of 40 mg/m2 with a maintenance dose of 30 mg/m2 . The treatment was well tolerated and effective in the patients.
Dosing, administration and monitoring Caspofungin is given intravenously on day 1 as a single 70 mg dose. Further dose selection is based on the patient’s weight. Those patients over 80 kg continue on 70 mg daily whilst those less than 80 kg have a dose of 50 mg administered. Doses are administered as a slow intravenous infusion usually over an hour. Caspofungin should be reconstituted with water for injection and further diluted with sodium chloride 0.9% to a final volume of between 100 and 250 ml. Caspofungin is incompatible with diluents containing dextrose. The drug is not available as an oral formulation, which restricts its use.
Caspofungin in the treatment of invasive fungal infections
61
Table 1 Area of effect
Very common
Common
Blood and lymphatic system disorders Nervous system disorders Cardiac disorders Vascular disorders Respiratory disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions Investigations
N/A N/A N/A N/A N/A N/A N/A Fever
Anaemia Headache Tachycardia Phlebitis/thrombophlebitis Dyspnoea Abdominal pain, nausea Rash, pruritus, sweating Pain, chills, infused-vein complications
N/A
Elevated liver values (AST, ALT, alkaline phosphatase, total bilirubin),increased serum creatinine, decreased haemoglobin, decreased haematocrit, decreased blood potassium, low albumin, decreased white blood cells, increased eosinophils, decreased platelet count, decreased neutrophils, increased partial thromboplastin time, decreased total serum protein, increased urinary protein
The duration of therapy of caspofungin is based on both the patient’s clinical condition and the organism isolated. Those patients undergoing empirical therapy, the therapy is usually continued for up to 72 h after the resolution of neutropenia. Patients found to have a proven fungal infection should be treated for a minimum of 14 days and treatment continued for at least 7 days after the neutropenia and clinical symptoms have resolved. Invasive candidiasis treatment is based on the individual’s clinical and microbiological response. Once the signs and symptoms of invasive candidiasis have improved and cultures have become negative, a switch to oral antifungal therapy may be considered. In general, antifungal therapy should continue for at least 14 days after the last positive culture. For those patients with invasive aspergillosis, the same applies as for invasive candidiasis but treatment normally continues for at least 7 days after the resolution of symptoms.
Side effect profile of casopfungin Table 1 lists some of the side effects reported with caspofungin. Frequencies are defined as: very common (>10%), common (1—10%).
atic insufficiency (Child Pugh score 5—6) no dose adjustment is needed. Patients with a moderate hepatic insufficiency (Child Pugh score 7—9) should have the initial 70 mg loading dose followed by a 35 mg maintenance dose. There is no clinical experience with severe hepatic insufficiency.
Interactions Caspofungin has been shown to interact with ciclosporin A causing a transient increase in alanine transaminase (ALT) and aspartate transaminase (AST). These resolve on discontinuation of treatment. Caspofungin reduces the trough concentration of tacrolimus. Close monitoring of tacrolimus levels with appropriate dosage adjustments as necessary are required. Limited data indicates that concomitant use of caspofungin with inducers of metabolic enzymes, e.g. efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine may result in a decrease of caspofungin plasma concentrations. When administering caspofungin with these drugs, an increase in the daily dose of caspofungin to 70 mg should be considered.
Conclusions Warnings and precautions No dose adjustment is necessary for renal impairment or in patients on haemodialysis. For mild hep-
Caspofungin has shown itself to be an effective treatment for invasive fungal infections. Further work is required to determine possible interactions especially with those drugs used to treat HIV
62 immunocompromised patients. Further echinocandins are awaiting marketing approval both in the United Kingdom and Europe.
References Castagnola E, Machetti M, Cappelli B, et al. Caspofungin associated with liposomal amphotericin B or voriconazole for treatment of refractory fungal pneumonia in children with acute leukaemia or undergoing allogenic bone marrow transplant. Clin Microbiol Infect 2004;10(3):255—7. Maertens J, Raad I, Petrikkos G, et al. Update of the multicenter noncomparative study of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B. In:
S. Keady, M. Thacker 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2002, September 27—30. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347(December (25)):2020—9. Odio C, Araya R, Pinto L, et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J 2004;23(12):1093—7. Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001;33(November (9)):1529—35. Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized double-blind study of caspofungin versus fluonazole for the treatment of candidal esophagitis. Am J Med 2002;113(September (4)):294—9.