Abstract & Commentary
Synopsis: Caspofungin was superior to amphotericin B deoxycholate in the treatment of patients with invasive candidiasis.
Source: Mora-Duarte J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020-2029.
Mora-Duarte and colleagues randomized 239 patients at multiple centers in the Americas and Europe with invasive candidiasis to receive either caspofungin (70 mg IV, then 50 mg IV qd) or amphotericin B deoxycholate (0.6 - 0.7 mg/kg/d; those with neutropenia received 0.7 - 1.0 mg/kg/d). The study was double-blind and double-dummy.
Four-fifths of the patients had bloodstream infection and one-tenth had intraabdominal infection; approximately one-tenth of each group was neutropenic. C albicans accounted for 54% of infections in patients assigned amphotericin B but only 36% of those assigned caspofungin (P = 0.009). C parapsilosis was recovered from approximately one-fifth in each group, C tropicalis from 20% of the amphotericin and 13% of the caspofungin recipients, and C krusei from 4% and 1%, respectively.
Patients in both groups received their study drug for an approximate mean duration of 12 days. One-fourth of caspofungin and one-third of amphotericin recipients were given fluconazole after at least 10 days of study drug therapy.
In the modified intention-to-treat analysis of the 224 patients with documented infection and who received at least 1 dose of a study drug, the proportion of patients with a favorable response at the end of intravenous therapy was 73.4% in the caspofungin group and 61.7% in the amphotericin B group. The difference in the proportion of patients with a favorable response was 12.7 percentage points (95.6% CI, 0.7 to 26.0; P = 0.09). The outcomes were generally similar in the 2 groups when they were stratified according to the Candida species.
In an analysis of patients who met prespecified criteria for evaluation, including receipt of study drug for at least 5 days, 80.7% of the caspofungin-treated patients and 64.9% of the amphotericin B-treated patients had successful outcomes at the end of intravenous therapy. The difference between the treatment groups for this analysis was 15.4 percentage points (95.6% confidence interval, 1.1 to 29.7; P = 0.03).
Analysis of patients with candidemia who met these same criteria found that 80.3% of the caspofungin-treated patients and 64.6% of the amphotericin B-treated patients had a successful outcome at the end of IV therapy. In this analysis, the difference was 15.2 percentage points (95% CI, 0.6 to 31.0; P = 0.06).
Management of central venous catheters did not differ significantly between the 2 groups; three-fourths in each arm were removed by day 3. Removal or retention did not affect outcomes. The outcome of treatment was not predicted by the base-line minimal inhibitory concentration; all isolates for which the minimal inhibitory concentration of caspofungin exceeded 2 µg per milliliter responded favorably to caspofungin.
There were 39 deaths in the caspofungin group (34.2%) and 38 in the amphotericin B group (30.4%, P = 0.53). Five of the caspofungin-treated patients (4.4%) and nine of the amphotericin B-treated patients (7.2%) died from Candida infection (P = 0.57).
A larger proportion of patients in the amphotericin group had toxic effects requiring a change in therapy (P = 0.03). One patient in the caspofungin group (0.9%), as compared with 40 patients in the amphotericin B group (32%), had infusion-related adverse events of moderate or severe intensity.
Significantly more patients in the amphotericin B group had nephrotoxicity effects (24.8% vs 8.4% in the caspofungin group). The death of 1 patient (a patient in the amphotericin B group who had a cardiac arrest) was judged to be drug-related.
An eye examination was performed by an ophthalmologist in 217 of the patients (96.9%); a total of 187 patients (83.5%) underwent a base-line examination, and 155 (69.2%) underwent one or more follow-up examinations. Only 7 patients (3.7%) had Candida endophthalmitis at base line; resolution was noted in all patients with follow-up examination. One patient in the amphotericin B group who had normal findings at baseline reported ocular disturbances on day 3. A follow-up eye examination confirmed the presence of endophthalmitis.
Comment by Stan Deresinski, MD, FACP
This study has demonstrated that caspofungin is superior to conventional amphotericin B in the treatment of invasive candidiasis. The number of patients with neutrophil counts less than 500/mm3 was insufficient to make firm statements about the relative efficacy of these drugs in this group. However, to the extent that fungicidal activity is critical in the treatment of invasive candidiasis in the absence of phagocytes, caspofungin would be expected to maintain efficacy in this group since it is candidacidal at concentrations at or close to its MIC.
In contrast to prior trials in the treatment of bloodstream infection with Candida and contrary to expectations, early or late removal of central venous catheters did not affect outcome. It is perhaps interesting that caspofungin is active against Candida growing in biofilm. While this is true of some lipid formulations of amphotericin, no data regarding amphotericin B deoxycholate have been reported.
The IDSA recommendations state that all patients with candidemia should have a dilated retinal examination, preferably by an ophthalmologist.1 In this study, however, only 3.7% of such exams at baseline revealed the presence of endophthalmitis and all of these resolved with systemic therapy alone. Thus, while I would not argue against the desirability of a dilated retinal examination in patients with candidemia, the cost effectiveness of an ophthalmological consultation requires further investigation.
Caspofungin is active in vitro against all species of Candida, although C guilliermondi has relatively elevated MICs. Questions have, however, been raised concerning its activity against C parapsilosis. In this study, 5 of the 9 patients with persistently positive cultures on therapy with caspofungin had C parapsilosis candidemia. These isolates, however, did not have elevated caspofungin MICs. Furthermore, 4 of these 5 enrolled at the same institution within a 4-month period and, in addition, 12 of the 14 patients with C parapsilosis at other institutions responded favorably to caspofungin therapy, and there was no apparent difference in outcome of infections with this organism between the treatment groups.
This robust study has demonstrated that caspofungin is superior to amphotericin B in the treatment of invasive candidiasis. A study similar in size to this one that compared fluconazole (400 mg qd), a drug with a narrower spectrum of activity against Candida spp. than caspofungin, to amphotericin B in nonneutropenic patients found no significant difference in outcomes.2 These findings raise important questions regarding the optimal treatment of patients with invasive candidiasis. Given the toxicity of amphotericin B, should it be discarded for this purpose? Would lipid amphotericin products fare better in clinical trials such as this one?
While the answer to the second question will require further clinical trials, the answer to the first may already be before us.
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
1. Rex JH, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis. 2000;30:662-678.
2. Rex JH, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med. 1994;331:1325-1330.
1. Deresinski S. Caspofungin: A novel antifungal agent. Infectious Disease Alert. 2001;20(13):97-100.