Echinocandins

Anidulafungin

The safety and efficacy of intravenous anidulafungin 50, 75, or 100 mg/day has been investigated in 123 patients, 68 evaluable, with invasive candidiasis, including candidemia [ ]. A total of eligible patients were randomized to one of three regimens. Adverse events considered to be related to treatment were reported by under 5% of patients in each dosage group. The most common events were hypotension, vomiting, constipation, nausea, and pyrexia. Three serious adverse events were reported as either probably or possibly related to treatment (neutropenic fever, n = 1; seizures, n = 2).

Caspofungin

The use of caspofungin with other agents against certain types of invasive fungal infections is appealing, given the poor response rates to standard agents and its unique mechanism of action. Two retrospective analyses have explored the safety and potential benefits of a combination of caspofungin with liposomal amphotericin B (L-AmB).

In the first analysis the efficacy and safety of caspofungin in combination with L-AmB in 48 patients with hematological malignancies with definite or probable or possible invasive aspergillosis were evaluated [ ]. Caspofungin was given intravenously as a 70 mg loading dose on day 1, followed by a daily dose of 50 mg; L-AmB was started at an intravenous dose of 5 mg/day. The median duration of therapy with the combination was 20 (range 7–180) days. The combination of caspofungin and L-AmB was well tolerated: seven patients developed mild-to-moderate renal insufficiency that was attributed to the use of L-AmB and four required withdrawal. There was hypokalemia in three of the patients. One patient had a fever associated with caspofungin and another had hepatic dysfunction of multifactorial origin. In no patient was the combination withheld due to unanticipated adverse effects.

The second analysis included 30 patients with hematological malignancies and proven (n = 6), probable (n = 4), or possible (n = 20) invasive fungal lung infections refractory to L-AmB monotherapy 3–5 mg/kg/day [ ]. The dosage of caspofungin was 50 mg/day with a single loading dose of 70 mg on day 1. The median duration of combination therapy was 24 (range 3–74) days. In 18 patients there was a favorable antifungal response, defined as improvement in both clinical and radiographic signs of fungal pneumonia. There was mild to moderate nephrotoxicity in 15 patients, necessitating the substitution of liposomal amphotericin. There were mild rises in alkaline phosphatase activity in nine patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity.

These analyses suggest that caspofungin and L-AmB can be used safely together.

Caspofungin has been investigated in a non-comparative phase II clinical study in 90 patients with invasive aspergillosis [ ]. Two patients withdrew because of drug-related adverse events; 84 developed at least one clinical adverse event. However, only 11 had an adverse event that was possibly, probably, or definitely related to caspofungin. Of the 90 patients 53 developed at least one laboratory adverse event, but only 12 were considered to have had a drug-related adverse event. Drug-related nephrotoxicity (1.1%) and hepatotoxicity (under 5%) occurred infrequently.

The efficacy and safety of caspofungin as salvage therapy for invasive aspergillosis has been studied in patients enrolled in the Caspofungin Compassionate Use Study [ ]. There was a favorable response in 20/45 patients, including nine and 11 with complete and partial responses respectively. One serious drug-related adverse event was reported in a patient with acute biphenotypic leukemia, who had an anaphylactic reaction to caspofungin, characterized by stridor/dyspnea, facial swelling, and accentuation of a pre-existing rash about 10 minutes into the infusion; all the symptoms resolved within 15 minutes of withdrawal of caspofungin and the administration of diphenhydramine and hydrocortisone.

Caspofungin 50 mg/day for a median duration of 20 (range 8–64) days has been used as first-line therapy for proven or probable pulmonary fungal infection in 32 immunocompromised patients with hematological malignancies (median age 52 years) [ ]. The overall response rate was 56% (18/32), with 12/18 complete responses and 6/18 partial responses. Granulocyte recovery and status of disease (remission/onset versus refractory/relapsed) were significantly associated with a favorable outcome. There were no clinical adverse events and only grades I and II transient increases in serum alkaline phosphatase and/or transaminase activities in 4/32 patients.

Caspofungin has been studied in a multicenter, open, non-comparative phase II trial in 83 patients with definite or probable invasive aspergillosis refractory to or intolerant of standard therapies [ ]. Common underlying conditions included hematological malignancies (48%), allogeneic blood and marrow transplantation (25%), and solid organ transplantation (11%). Caspofungin was administered in a dose of 70 mg on day 1, followed by 50 mg/day for a mean duration of 34 (range 1–162) days. There was a favorable response to caspofungin in 37 patients, including 32 of 64 with pulmonary aspergillosis and 3 of 13 with disseminated aspergillosis. Caspofungin was generally well tolerated. One serious adverse event was reported as possibly drug-related. Infusion-related reactions, nephrotoxicity, and hepatotoxicity were uncommon. Two patients discontinued caspofungin because of adverse effects.

The safety and tolerability of caspofungin have been studied in 623 patients, including 295 who received at least 50 mg/day for at least 1 week in clinical studies. In 263 patients who received caspofungin in randomized, double-blind, active-control trials, there were no serious clinical or laboratory drug-related adverse events; caspofungin was withdrawn in 2% of these patients because of drug-related adverse effects [ ].

Micafungin

In an open, non-comparative study, neonates, children, and adults with new or refractory candidemia were given micafungin for up to 42 days [ ]. A total of 126 patients were evaluable and received at least five doses. There was a complete or partial response in 83% and serious adverse events related to micafungin were uncommon.

Amphotericin

Caspofungin (Cancidas; 50 and 70 mg/day for 14 days; n = 74) has been compared with conventional amphotericin (0.5 mg/kg/day for 14 days; n = 54) in the treatment of esophageal candidiasis in a randomized, double-blind, multicenter trial in South America [ ]. Most of the patients (over 75%) were HIV-infected and about half of them had CD4 + lymphocyte counts of under 50 × 106/l. Caspofungin was well tolerated: eight patients in the amphotericin group and one patient in the combined caspofungin group developed a raised serum creatinine of over 176 μmol/l (2 mg/dl) during treatment. Of the patients who received caspofungin, 4.1% withdrew prematurely owing to drug-associated adverse effects, compared with 22% in the amphotericin arm. There was a clinical response (symptoms plus endoscopy) in 85% of the patients in the combined caspofungin group versus 67% in the amphotericin group.

Caspofungin has been compared with amphotericin in a multicenter, double-blind, randomized trial in 128 adults with endoscopically documented symptomatic Candida esophagitis [ ]. There was endoscopically verified clinical success in 74% and 89% of the patients who received caspofungin 50 and 70 mg/day respectively, and in 63% of patients given amphotericin deoxycholate 0.5 mg/kg/day. Therapy was withdrawn because of drug-related adverse events in 24% of the patients who were given amphotericin and in 4 and 7% of those who were given caspofungin 50 and 70 mg/day respectively. The most frequent adverse events with caspofungin were fever, phlebitis, headache, and rash. Fewer patients who received caspofungin had drug-related fever, chills, or nausea than those who received amphotericin. More patients who received amphotericin (91%) than caspofungin (61% and 32%) developed drug-related laboratory abnormalities, the most common in the caspofungin groups being hypoalbuminemia and increased serum activities of alkaline phosphatase and transaminases. There were drug-related increases in blood urea nitrogen concentrations in 15% of the patients who received amphotericin but in none of those who received caspofungin. Likewise, serum creatinine concentrations increased in 16 patients who received amphotericin but in only one who received caspofungin. In summary, caspofungin was as effective as amphotericin but better tolerated in the treatment of esophageal candidiasis.

In a double-blind, randomized trial, caspofungin was compared with amphotericin deoxycholate for the primary treatment of invasive candidiasis [ ]. Patients who had clinical evidence of infection and a positive culture for Candida species from blood or another site were enrolled. They were stratified according to the severity of disease, as indicated by the presence or absence of neutropenia and the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and were randomly assigned to receive either caspofungin (50 mg/day with a loading dose of 70 mg on day 1) or amphotericin (0.6–0.7 mg/kg/day or 0.7–1.0 mg/kg/day for patients with neutropenia). Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. Baseline characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. The efficacy of caspofungin was similar to that of amphotericin, with successful outcomes in 73% of the patients treated with caspofungin and in 62% of those treated with amphotericin. There were significantly fewer drug-related adverse events associated with caspofungin: fever, chills, and infusion-related events were less frequent with caspofungin. Caspofungin caused less nephrotoxicity (as defined by an increase in serum creatinine of at least twice the baseline value or an increase of at least 88.4 μmol/l: 8.4 versus 25%). Only 2.6% of those who were given caspofungin were withdrawn because of adverse events, compared with 23% of those who were given amphotericin. Thus, caspofungin was at least as effective as amphotericin for the treatment of mostly non-neutropenic patients with invasive candidiasis but significantly better tolerated.

The safety, tolerability, and efficacy of caspofungin in patients with oropharyngeal and/or esophageal candidiasis have been investigated in a phase II dose-ranging study [ ]. The patients were randomized, double-blind to either caspofungin acetate (35, 50, or 70 mg) or amphotericin (0.5 mg/kg intravenously) once daily for 7–14 days. Of 140 patients, 63% had esophageal involvement and 98% were infected with HIV. Response rates with caspofungin groups were 74–91%, and 63% with amphotericin. Fewer patients receiving any dose of caspofungin had drug-related adverse effects (fever, chills, nausea, vomiting). Two patients who took caspofungin 35 mg and one who was given amphotericin withdrew because of adverse effects. Drug-related laboratory abnormalities were also more common in patients who received amphotericin. The most common drug-related laboratory abnormalities in patients who received caspofungin were raised alanine transaminase, aspartate transaminase, and alkaline phosphatase, which were typically less than five times the upper limit of normal and resolved despite continued treatment. None of the patients receiving caspofungin and nine of those who received amphotericin developed drug-related increases in serum creatinine concentrations. No patient withdrew because of drug-related laboratory adverse effects.

Caspofungin (n = 556) has been compared with liposomal amphotericin (n = 539) in a randomized, double-blind, multinational trial as empirical antifungal therapy [ ]. Patients were stratified according to risk and whether they had previously received antifungal prophylaxis. Premature withdrawal for any cause was less common with caspofungin than amphotericin (10% versus 15%). Fewer patients who received caspofungin sustained nephrotoxicity (2.6% versus 12%), an infusion-related event (35% versus 52%), or a systemic drug-related adverse event or discontinued therapy because of drug-related adverse events.

Antifungal azoles

Caspofungin and fluconazole have been compared in adults with Candida esophagitis in a double-blind, randomized trial [ ]. Eligible patients had symptoms compatible with esophagitis, endoscopic mucosal plaques, and microscopic Candida . They were randomized to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once a day for 7–21 days. Most of them (154/177) had HIV infection, with a median CD4 count of 30 × 106/l. Favorable response rates were achieved in 66 of the 81 patients in the caspofungin arm and in 80 of the 94 patients in the fluconazole arm; symptoms had resolved in over 50% of the patients in both groups by the fifth day of treatment. Drug-related adverse effects were reported in 41% of patients given caspofungin and 32% of those given fluconazole; the most common events in both groups were phlebitis, headache, fever, nausea, diarrhea, abdominal pain, and rashes. Drug-related laboratory abnormalities developed in 29% of patients given caspofungin and in 34% of those given fluconazole. The most frequent laboratory abnormalities included reduced white blood cell count, hemoglobin concentration, and serum albumin concentration, and increased alkaline phosphatase and transaminases. No patient given caspofungin developed a serious drug-related adverse effect; therapy was withdrawn in only one patient (who was receiving fluconazole), because of an unspecified adverse effect.

In a randomized, double-blind, double-dummy comparison of intravenous anidulafungin 50 mg/day and oral fluconazole 100 mg/day for 14–21 days in 601 patients with proven esophageal candidiasis [ ]. The safety profiles were similar. Treatment-related adverse events occurred in 9.3% and 12% of patients respectively. Laboratory parameters were similar between the treatments. Drug withdrawal was required in five patients (four versus one) because of adverse events.

The dose-response relation of micafungin (50, 100, or 150 mg) has been compared with that of standard fluconazole treatment for esophageal candidiasis in a randomized, double-blind study in 245 HIV-infected patients [ ]. The incidence of adverse events was 93% with micafungin and 89% with fluconazole. The most common treatment-related adverse events were fever, abdominal pain, nausea, diarrhea, leukopenia, injection-site inflammation, and headache. There were no clinically important changes in laboratory measures. There were changes in liver function tests in 13% of patients: micafungin 24/185 patients and fluconazole 7/60 patients. There were no apparent dose-dependent differences in safety and tolerance across the investigated dosages of micafungin, and no differences in safety and tolerance between micafungin and fluconazole.

In a randomized, double-blind, multi-institutional, comparative phase III trial in antifungal prophylaxis during neutropenia in patients undergoing hemopoietic stem cell transplantation micafungin 1 mg/kg/day up to a maximum of 50 mg/day was compared with fluconazole 8 mg/kg/day up to a maximum of 400 mg/day in 882 adults and children [ ]. All the patients had at least one adverse event, but fewer micafungin-treated patients withdrew as a result (4.2% versus 7.2%). Adverse events that were considered to be drug-related occurred in 15% of micafungin-treated patients and in 17% of fluconazole-treated patients. There were no differences in liver function tests between patients who received micafungin + ciclosporin and those who received micafungin alone.

These two studies suggest a safety profile of micafungin that is at least similar to that of fluconazole.

In a large, randomized comparative study in 523 adults with esophageal candidiasis randomized to either intravenous micafungin 150 mg/day or fluconazole 200 mg/day for a median of 14 days, the incidences of drug-related adverse events were 28% for micafungin and 21% for fluconazole [ ]. Six patients taking micafungin and two taking fluconazole withdrew, most commonly because of rashes.

Anidulafungin 100 mg/day has been compared with fluconazole 400 mg/day for invasive candidiasis in a randomized, double blind phase III study in 245 mostly non-neutropenic patients [ ]. The safety profile of anidulafungin was similar to that of fluconazole and under 5% of patients withdrew because of drug-related adverse events. Infusion-related reactions after anidulafungin included flushing (2.3%), pruritus (2.3%), rashes (1.5%), and urticaria (0.8%). Other treatment-related adverse reactions included increased hepatic enzyme activities (5.3%), hypokalemia (3.1%), diarrhea (3.1%), and increased bilirubin (1.5%).

In a sequential dose escalation study, 74 adults with cancer undergoing bone marrow or peripheral blood stem cell transplantation were given fluconazole 400 mg/day and either isotonic saline (control, n = 12) or micafungin 12.5–200 mg/day (n = 62) for up to 4 weeks [ ]. The maximum tolerated dose of micafungin was not reached, based on the Southwest Oncology Group criteria for grade 3 toxicity; drug-related adverse events were rare. Common adverse events that were considered to be related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rashes (4.1%), and other rashes (4.1%). There was no clinical or kinetic evidence of an interaction of micafungin with fluconazole.