Correspondence

Caspofungin versus Amphotericin B for Invasive Candidiasis

N Engl J Med 2003; 348:1287-1288March 27, 2003

Article

To the Editor:

Mora-Duarte and colleagues (Dec. 19 issue)1 fail to demonstrate that caspofungin can be considered a first-line treatment for most candida infections, because they did not use fluconazole as the comparison drug. Although Walsh, in the accompanying editorial,2 mentions this limitation, it is a shame that this carefully designed trial cannot answer this most relevant question.

There is ample evidence that amphotericin B and fluconazole are equivalent in the treatment of invasive candidiasis. Fluconazole has fewer side effects, comes in an oral formulation, and is cheaper. This matter has been reviewed by the Infectious Diseases Society of America (IDSA), and initial fluconazole treatment is recommended for most forms of invasive candida infections, with the caveat that amphotericin B be considered for patients whose condition is clinically unstable.3

Mora-Duarte and colleagues could have compared caspofungin with high-dose fluconazole (800 mg daily), switching to amphotericin B if the infecting organism was resistant to fluconazole. This strategy may have been considered too risky because delaying amphotericin B treatment for the three to four days required to identify fluconazole resistance could result in a poorer outcome. We are unaware of any evidence to this effect. The low proportion of nonsusceptible species (e.g., Candida glabrata) reported suggests that the majority of infections would have been susceptible to fluconazole at doses of 800 mg daily.4

Adam L. Brown, M.B., B.S.
James R. Greig, F.R.C.Path.
Derriford Hospital, Plymouth PL6 8DH, United Kingdom

4 References

1. 1

   Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002;347:2020-2029
   Full Text | Web of Science | Medline

2. 2

   Walsh TJ. Echinocandins -- an advance in the primary treatment of invasive candidiasis. N Engl J Med 2002;347:2070-2072
   Full Text | Web of Science | Medline

3. 3

   Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662-678
   CrossRef | Web of Science | Medline

4. 4

   Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretative breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and candida infections. Clin Infect Dis 1997;24:235-247
   CrossRef | Web of Science | Medline

Author/Editor Response

We fully acknowledge the usefulness of fluconazole for the treatment of invasive candidiasis. But our trial was prospectively designed to enroll a broad-based study population, representative of all patients with invasive candidiasis. With this intention in mind, we anticipated certain pitfalls related to the choice of an azole comparison drug. First, fluconazole, an agent with fungistatic activity against candida, has not been thoroughly evaluated in patients with neutropenia who have documented invasive candida infections. To date, the only two randomized, prospective studies have been limited to patients with candidemia who do not have neutropenia.1,2 These studies demonstrated that the efficacy of fluconazole is noninferior, but not superior, to that of amphotericin B. In fact, as Brown and Greig note, current guidelines recommend amphotericin B for clinically unstable patients with invasive candidiasis.3 Finally, there are limitations to the use of fluconazole for certain infections with candida species other than C. albicans — namely, for C. krusei and C. glabrata, which together may account for approximately 20 percent of the candida pathogens that are encountered.4 Hence, opting for an azole comparison drug would have potentially precluded the inclusion of patients with neutropenia or clinical instability and would ultimately have left unanswered questions concerning the activity of caspofungin against two common non-albicans species.

Brown and Greig speculate that high-dose fluconazole (800 mg per day) could reasonably have been chosen for evaluation. Although high-dose fluconazole is clinically appealing because of the favorable safety profile of fluconazole, high-dose therapy is neither approved for use nor recommended by the IDSA.3 Furthermore, at the time the study was initiated (in 1997), comparative data for high-dose fluconazole were unavailable.

Finally, it is worth noting that the efficacy and safety of caspofungin have been demonstrated in a comparison with fluconazole for esophageal candidiasis.5 Our study of invasive candidiasis confirms the efficacy of caspofungin against candida infections in comparison with yet another class of antifungal agents.

Nicholas A. Kartsonis, M.D.
Merck Research Laboratories, West Point, PA 19486

John Perfect, M.D.
Duke University Medical Center, Durham, NC 27710
perfe001@mc.duke.edu

5 References

1. 1

   Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994;331:1325-1330
   Full Text | Web of Science | Medline

2. 2

   Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Eur J Clin Microbiol Infect Dis 1997;16:337-345
   CrossRef | Web of Science | Medline

3. 3

   Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662-678
   CrossRef | Web of Science | Medline

4. 4

   Pfaller MA, Diekema DJ, Jones RN, Messer SA, Hollis RJ. Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000. J Clin Microbiol 2002;40:852-856
   CrossRef | Web of Science | Medline

5. 5

   Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113:294-299
   CrossRef | Web of Science | Medline

Author/Editor Response

Amphotericin B and fluconazole are each considered to be appropriate standards of care in the first-line treatment of invasive candidiasis.1 The selection of amphotericin B as the comparison drug by Mora-Duarte et al. was therefore reasonable. Amphotericin B has a broad spectrum, a low propensity for selection of resistant organisms, and a longer history in the treatment of deeply invasive candidiasis in hosts with neutropenia and in clinically unstable patients.

Although fluconazole has been shown to be comparable to and safer than amphotericin B in the treatment of candidemia, it is not superior in efficacy.2,3 If the study had been designed with fluconazole as the comparison drug at a dose of 800 mg per day, it would have been open to several criticisms: 800 mg per day is not a universally approved dose and thus might create regulatory confusion; patients in centers where C. glabrata and C. krusei were found might have a higher frequency of premature discontinuation and switching to amphotericin B; and there might be a greater reluctance to use fluconazole for treatment in hosts with neutropenia and in hemodynamically unstable patients. Thus, a study using fluconazole could be criticized for not having used amphotericin B instead.

Alternatively, a randomized, three-group study comparing the echinocandin agent, amphotericin B, and fluconazole could have been designed. The projected time to complete such a trial would be approximately half a decade. During that time, inevitable changes in the standard of care could confound such a study. Nonetheless, fluconazole has the advantages of a superior safety profile and an oral route of administration, and there may be less resistance to it due to C. glabrata than there was once believed to be.4 A subsequent trial comparing another echinocandin agent with fluconazole in the primary treatment of invasive candidiasis would provide important data and expand our understanding of this new class of lipopeptide antifungal compounds.

Thomas J. Walsh, M.D.
National Cancer Institute, Bethesda, MD 20892
walsht@mail.nih.gov

4 References

1. 1

   Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662-678
   CrossRef | Web of Science | Medline

2. 2

   Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994;331:1325-1330
   Full Text | Web of Science | Medline

3. 3

   Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Eur J Clin Microbiol Infect Dis 1997;16:337-345
   CrossRef | Web of Science | Medline

4. 4

   Diekema DJ, Messer SA, Brueggemann AB, et al. Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 2002;40:1298-1302
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   (2007) Anidulafungin and Fluconazole for Candidiasis. New England Journal of Medicine 357:13, 1347-1348
   Full Text

2. 2

   Reboli, Annette C., Rotstein, Coleman, Pappas, Peter G., Chapman, Stanley W., Kett, Daniel H., Kumar, Deepali, Betts, Robert, Wible, Michele, Goldstein, Beth P., Schranz, Jennifer, Krause, David S., Walsh, Thomas J., . (2007) Anidulafungin versus Fluconazole for Invasive Candidiasis. New England Journal of Medicine 356:24, 2472-2482
   Full Text