Mora-Duarte J, Betts, R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis.
Overall Study Question
This was a prospective, randomized, double blind non-inferiority study conducted in 56 institutions in 20 countries between November 1997 and June 2001. The study was designed to determine whether caspofungin was as effective as amphotericin B for the treatment of invasive candidiasis.
Adult patients were included if they had one or more positive candida cultures from blood or another sterile site within the previous four days. Patients had to have at least one of the following clinical signs of infection during the previous two days: fever (a temperature that exceeded 38.3, or two readings that exceeded 37.8), clinically significant hypothermia (a temperature of less than 36.0), hypotension (systolic blood pressure < 90 mmHg, or a decrease > 30 mmHg), or signs of inflammation at a candida-infected site.
Patients were excluded if positive cultures were from urine, sputum, bronchoalveolar-lavage, oropharyngeal or esophageal specimens. Patients with suspected endocarditis, osteomyelitis, or meningitis were excluded, as were patients who were receiving rifampin, ritonavir, or cyclosporine or had received antifungal therapy for more than two days.
Patients were stratified according to the presence or absence of neutropenia and the score on the Acute Physiology and Chronic Health Evaluation (APACHE II) (≤ 20 or > 20). Patients were then randomized to receive a caspofungin 70 mg IV loading dose, followed by 50 mg IV per day; or amphotericin B 0.6-0.7 IV mg/kg/day (non-neutropenic patients) or 0.7-1.0 IV mg/kg/day (neutropenic patients). A minimum of 10 days of intravenous therapy was required. After 10 days, therapy could be switched to oral fluconazole 400 mg/day for non-neutropenic patients whose clinical condition had improved, had follow-up cultures that had been negative for 48 hours, and whose candida isolates were susceptible to fluconazole. Patients with C. krusei or C. glabrata infection were continued on intravenous therapy. All patients received antifungal therapy for a minimum of 14 days following the most recent positive candida culture. Evaluations were performed on day 10 of IV therapy, at the end of IV therapy, at the end of all antifungal therapy (IV and oral fluconazole), and at both follow-up visits.
The primary study end point was an overall response to treatment at the end of intravenous therapy. During the six-to-eight week period after treatment, a patient was considered to have a relapse if an invasive candida infection had recurred or if antifungal therapy for a proven or suspected candida infection was again administered. A favorable overall response was defined as the resolution of all symptoms and signs of candida infection and culture-confirmed eradication (or presumptive eradication for certain non-blood infections). The outcome was considered unfavorable if the infection was clinically or microbiologically unresponsive, if the study drug was withdrawn before there was documented improvement, or if toxic effects required a change in antifungal therapy.
What was the declared relationship between authors and sponsors for this study?
This trial was supported by grants from Merck. Drs. Rotstein, Colombo, and Perfect have reported serving as consultants for Merck and receiving research grants and lecture fees from Merck. Dr. Thompson-Moya has reported receiving lecture fees from Merck.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
Yes. Patients were randomized according to a computer-generated schedule maintained by pharmacists at each participating institution.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. A total of 239 patients were enrolled in the study over the 44-month study period. Of these, 224 patients were included in the modified intention-to-treat analysis (MITT) and 185 were included in the population of patients who met pre-specified criteria for evaluation (PSCFE). The MITT analysis was the primary analysis and included patients who had a documented diagnosis of invasive candidiasis and who received the study treatment for at least one day. The PSCFE was inclusion in the MITT, no concomitant antifungal therapy, no protocol violations that might interfere with the assessment of efficacy, an appropriate evaluation at the end of treatment, and receipt of the study treatment for at least five days. Reasons for why patients were not included in the MITT or analysis of patients who met PSCFE are described by the authors.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Patients and investigators were blinded to the initial treatment allocation and a double-dummy technique was used to maintain this blinding. However, the administration of IV amphotericin B causes infusion-related toxicities (e.g. fever, chills, rigors, nausea and vomiting) in 70-90% of patient and these events may have been a source of unblinding during the conduct of the study. It was not stated whether pre-medications were permitted or used.
4. Were the groups similar at the start of the trial?
Yes. Overall, patients in the caspofungin and amphotericin B groups appeared to have similar measured baseline characteristics. In particular, the groups were similar with respect to the presence of neutropenia and mean APACHE II scores. There was, however, a higher prevalence of patients with C. albicans infections in the amphotericin B group as compared to the caspofungin group (54% vs. 36%, p = 0.009). There was no statistically significant difference in infections caused by other candida species between the two groups.
5. Aside from the experimental intervention, were the groups treated equally?
Yes. There appeared to be no difference in further treatment of patients assigned to caspofungin or amphotericin B.
What were the Results?
1. How large was the treatment effect?
This trial was powered as a non-inferiority trial and caspofungin would be deemed non-inferior if the two-sided 95.6% CI for the difference in efficacy between the two treatment groups, adjusted for neutropenic status and APACHE II score, included zero and the lower boundary was not lower than .0%.
In the primary MITT analysis, 73.4% of the caspofungin group and 61.7% of the amphotericin B group had a favorable response at the end of intravenous therapy. After adjustment for the two stratification variables (neutropenia and APACHE II score), the difference in the patients with a favorable response was 12.7% (95.6% CI 7 to 26.0, p = 0.09). In the analysis of patients who met PSCFE, a favorable response was found in 80.7% of the caspofungin-treated patients and 64.9% of the amphotericin-treated patients, with a difference of 15.4% (95% CI 1.1 to 29.7, p = 0.03).
Drug-related adverse events were more common in the amphotericin B group. Fever, chills, and moderate-severe infusion-related adverse events were identified in 48.8% of the amphotericin B group vs. 20.2% of the caspofungin group (p = 0.002). Significantly more patients in the amphotericin B group had elevated blood urea nitrogen (15.8% vs. 1.9% in the caspofungin group, p = 0.02), elevated serum creatinine (22.6% vs. 3.7%, p = 0.05), and decreased serum potassium (23.4% vs. 9.9%, p = 0.04). There were also more toxic effects requiring change in antifungal therapy in the amphotericin B group (16.5% vs. 2.8% in the caspofungin group, p = 0.03).
Based on these results, IV caspofungin appears to be non-inferior to IV amphotericin B. More drug-related adverse events occurred with amphotericin B than with caspofungin.
2. How precise was the estimate of the treatment effect?
In the primary MITT analysis, the 95.6% CI included zero and the lower boundary was not lower than .0%, indicating that caspofungin is not inferior to amphotericin (p = 0.09). In the analysis of patients who met PSCFE, the 95.6% CI was entirely above zero (p = 0.03). The authors state in their methods that caspofungin would demonstrate superiority to amphotericin if the CI was entirely above zero, however this trial was powered as a non-inferiority, not a superiority trial.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
Yes. Serious candidemia infections occur frequently in the acute care setting. Current treatment options are limited due to the toxic effects of amphotericin B deoxycholate or the cost of lipid formulations of amphotericin B. Fluconazole is a recognized alternative, however it would be inappropriate given this patient population. Current guidelines recommend amphotericin B for clinically unstable patients with invasive candidiasis. In addition, fluconazole has not been thoroughly evaluated in patients with neutropenia who have documented invasive candida infections. Finally, fluconazole has limited activity against certain non-albicans candida species specifically C. krusei and C. glabrata which were base-line candida isolates in 10.1% of patients treated with amphotericin B and 16.8% of patients treated with caspofungin.Although caspofungin is more costly than amphotericin B deoxycholate, it is less expensive than the currently available lipid amphotericin B products.
Typical daily acquisition costs for commonly used antifungals for invasive candida infections are as follows: amphotericin B deoxycholate (1mg/70kg/day) $50-55 CAN, amphotericin B lipid complex (5mg/70kg/day) $795 CAN, amphotericin B liposomal (5mg/70kg/day) $1470 CAN and caspofungin (70mg/day) $567 CAN. In addition, caspofungin appears to be less toxic and is not inferior to amphotericin B for the treatment of invasive candidiasis.Transplant recipients (solid organ or stem cell) are at high risk for developing candidiasis. Patients receiving cyclosporine, a commonly used immuno-suppressant in transplant recipients, were excluded from this study. Only 6 patients in the caspofungin group and 1 patient in the amphotericin B group had received a transplant, thus, these results should be used with caution in the transplant patient population. In addition, these results cannot be extrapolated to patients with suspected candida endocarditis, osteomyelitis, or meningitis. Furthermore, the activity of caspofungin was similar in patients with or without neutropenia, although the actual number of neutropenic patients enrolled was small (14/109 caspofungin vs. 10/115 amphotericin B). This study would be applicable to institutions whose microbiological characteristics of candida infections are similar to those of this study (i.e. 55% non-albicans candida infections).
2. Were all clinically important outcomes considered?
3. Are the likely treatment benefits worth the potential harms and costs?
Caspofungin appears to be a safe and efficacious alternative to amphotericin B deoxycholate in patients with invasive candida infections. Based on this study, there are fewer drug-related adverse events with the administration of caspofungin. In addition, the cost would be less compared to the lipid preparations of amphotericin B used in patients who could not tolerate amphotericin B deoxycholate due to nephrotoxicity.
Candidemia is now the fourth leading cause of nosocomial bloodstream infections in the United States and has an associated mortality of approximately 38%. Amphotericin B and fluconazole is recommended for the primary treatment of candidemia. However, amphotericin B administration may be complicated by dose-limiting nephrotoxicity and infusion-related adverse events. Fluconazole has a fewer adverse events, but has limited activity in non-albicans Candida spp. such as C. krusei. The echinocandins, caspofungin, anidulafungin and micafungin, represent a novel class of antifungal agents. Their unique mechanism of action, non-competitive inhibition of glucan synthesis, a critical component of the fungal cell wall, is expected to result in no cross-resistance with currently available agents. Mammalian cells do not produce β-(1,3)-D-glucan, thus the echinocandins specifically target the fungal cell wall. In addition, the echinocandin molecules are large and only administered parenterally.
Caspofungin is the only commercially available echinocandin. Caspofungin has a broad spectrum of antifungal activity in vitro. It exhibits activity against Aspergillus spp. including A. fumigatus, A. flavus, and A. terreus. In vitro studies revealed activity against azole-sensitive and esistant Candida species and amphotericin-resistant Candida species. Caspofungin has demonstrated limited activity in vitro against Cryptococcus neoformans. It is also active against Pneumocystis carinii because the cell wall of the cyst form of the fungus contains the β-(1,3)-D-glucan synthase enzyme. It lacks sufficient activity against Fusarium, Paecilomyces, Rhizopus, Histoplasma, and Blastomyces spp. However, the in vitro activity should be interpreted cautiously because standardized methods to test the susceptibility of fungal pathogens to echinocandins have yet to be developed. Caspofungin is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. This indication was based on findings from a study evaluating the use of caspofungin in 54 patients with acute invasive aspergillosis who underwent alvage therapy after they failed primary therapy for more than one week or had significant nephrotoxicity. This was compared to a historical control group of 210 patients and was presented in abstract form. It demonstrated caspofungin recipients had a better outcome than the historical controls, except in patients with severe persisting neutropenia, which traditionally do poorly. Randomized clinical trials need to be completed to determine the place of caspofungin in the treatment of invasive aspergillosis. Prior to this paper, the only published randomized clinical trials compared either amphotericin B or fluconazole to caspofungin for the treatment of oropharyngeal and esophageal candidiasis.
This is a critical study as it is represents the first prospective, randomized clinical trial comparing this new class of antifungal agents, the echinocandins, to the gold standard, amphotericin B for the treatment of invasive candida infections. These results should be used with caution in solid organ and stem cell transplant recipients as well as neutropenic patients as these groups were not well studied. In the intention-to-treat analysis, the response rate at each time point was higher in the caspofungin group than in the amphotericin B group. There was no difference in rate of clearance of candida from the bloodstream or rate of relapse, rather, a higher rate of toxicity with amphotericin B requiring a change in antifungal agent and thus treatment failure accounted for most of the differences in outcome. Mora-Duarte and colleagues have demonstrated that caspofungin is an effective and safe agent in the primary treatment of invasive candidiasis in this study population.
Many questions about the echinocandins remain to be answered.
What is the correlation between the MIC and clinical outcome?
What is the optimal dose/duration of therapy?
How does this agent compare to azoles for the treatment of sensitive fungal pathogens?
What is the effectiveness and toxicity in children?
Since echinocandins have a unique mechanism of action, what is the therapeutic potential of combination or sequential therapy with other antifungal agents?
How do the echinocandins compare with the less toxic lipid-based amphotericin B preparations?
Hopefully these questions will be answered by future investigative trials.