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Empirical Fluconazole versus Placebo for Intensive Care Unit Patients: A Randomized Trial

Mindy G. Schuster, MD; John E. Edwards Jr., MD; Jack D. Sobel, MD; Rabih O. Darouiche, MD; Adolf W. Karchmer, MD; Susan Hadley, MD; Gus Slotman, MD; Helene Panzer, PhD; Pinaki Biswas, PhD; and John H. Rex, MD
[+] Article and Author Information

From the University of Pennsylvania School of Medicine, Philadelphia Pennsylvania; Harbor-UCLA Medical Center, Torrance, California; Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan; Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, and University of Texas Medical School, Houston, Texas; Beth Israel Deaconess Medical Center and Tufts-New England Medical Center, Boston, Massachusetts; University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and Pfizer, New York, New York.


Acknowledgment: The authors thank Helen Bhattacharyya and Robert Swanson for help with the data tables.

Grant Support: By Pfizer, New York, New York.

Potential Financial Conflicts of Interest:Employment: H. Panzer (Pfizer), P. Biswas (Pfizer). Consultancies: J.E. Edwards (Merck & Co., Pfizer, Cerexa, Eisai, Enzon), J.D. Sobel (Merck & Co., Pfizer, Ther-Rx/KV Pharmaceutical), S. Hadley (Pfizer, Schering-Plough). Honoraria: J.D. Sobel (Merck & Co., Pfizer, Astellas). Stock ownership or options (other than mutual funds): H. Panzer (Pfizer). Grants received: M.G. Schuster (Pfizer), J.E. Edwards (Merck & Co., Pfizer, Astellas), J.D. Sobel (Merck, Pfizer), S. Hadley (Pfizer, Astellas). Grants pending: J.E. Edwards (Pfizer). Other: R.O. Darouiche (Pfizer Speakers' Bureau).

Reproducible Research Statement:Study protocol: Available from Dr. Schuster (e-mail, schustem@mail.med.upenn.edu). Statistical code and data set: Not available.

Requests for Single Reprints: Mindy G. Schuster, MD, University of Pennsylvania, Infectious Diseases, 3 Silverstein, Suite E, 3400 Spruce Street, Philadelphia, PA 19104; e-mail, schustem@mail.med.upenn.edu.

Current Author Addresses: Dr. Schuster: University of Pennsylvania, Infectious Diseases, 3 Silverstein, Suite E, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Edwards: UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509.

Dr. Sobel: Wayne State University, 3990 John R, Detroit, MI 48201.

Dr. Darouiche: Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030.

Dr. Karchmer: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.

Dr. Hadley: Tufts-New England Medical Center, 750 Washington Street, Box 41, Boston, MA 02111.

Dr. Slotman: 1765 Springdale Road, Cherry Hill, NJ 08003.

Drs. Panzer and Biswas: Pfizer, 235 East 42nd Street, New York, NY 10017.

Dr. Rex: AstraZeneca Pharmaceuticals, Alderley House, Alderley Park, Macclesfield SK10 4TF, United Kingdom.

Author Contributions: Conception and design: M.G. Schuster, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, G. Slotman, H. Panzer, J.H. Rex.

Analysis and interpretation of the data: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, G. Slotman, J.H. Rex.

Drafting of the article: M.G. Schuster, J.E. Edwards, J.D. Sobel, J.H. Rex.

Critical revision of the article for important intellectual content: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, G. Slotman, J.H. Rex.

Final approval of the article: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, S. Hadley, H. Panzer, J.H. Rex.

Provision of study materials or patients: M.G. Schuster, J.D. Sobel, A.W. Karchmer, S. Hadley.

Statistical expertise: P. Biswas.

Obtaining of funding: J.E. Edwards.

Administrative, technical, or logistic support: H. Panzer.

Collection and assembly of data: M.G. Schuster, J.D. Sobel.


Ann Intern Med. 2008;149(2):83-90. doi:10.7326/0003-4819-149-2-200807150-00004
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This randomized, multicenter, blinded, clinical trial compared fluconazole with placebo for empirical antifungal therapy in ICU patients with several risk factors for invasive candidiasis. Success, as defined by the composite end point, occurred in 44 (36%) fluconazole recipients and 48 (38%) placebo recipients (RR, 0.95 [CI, 0.69 to 1.32]; P = 0.78). To our knowledge, this is the largest multicenter study to date aimed at empirical antifungal therapy in this high-risk population. A MEDLINE search for studies published in English to February 2008 revealed several relevant clinical trials. Most had small sample sizes, had broad definitions of invasive candida infections, or were conducted in single institutions or among select patient samples. Eggimann and coworkers (12) randomly assigned patients with evidence of gastrointestinal perforation to receive fluconazole, 400 mg daily, or placebo. The rate of candidal peritonitis was 7% among the 20 placebo recipients and 1% among the 23 fluconazole recipients. Although these results are compelling despite the small sample size, they are relevant to a selected patient sample and not generalizable to most ICU patients.

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Figure.
Study flow diagram.

APACHE = Acute Physiology and Chronic Health Evaluation. * Safety sample. † Analysis sample. ‡ Outcomes were recorded for all of these patients and were included in the primary analysis. § Patients could have >1 reason for not meeting inclusion criteria.

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Why the delay in reporting clinical data?
Posted on August 14, 2008
Samuel A Shelburne
MD Anderson Cancer Center
Conflict of Interest: None Declared
TO THE EDITOR: I would like to thank Schuster and colleagues for the excellent article on the empiric use of fluconazole in critically ill patients at high-risk for disseminated candidiasis (1). Their investigation provides valuable data to a broad-array of clinicians and addresses an important, but understudied, area of biomedical research. However, I was troubled to see that, whereas the study was published in 2008, the last patient was enrolled in 1999 and that follow-up was completed in 2000 (1). This leaves me to ask, what led to an eight year delay in publication of such critical data? Given that the study was financed, monitored, and the database analyzed by Pfizer (New York, New York), I was immediately concerned that the funding source may have hindered publication of data that was likely to decrease utilization of a high-impact pharmaceutical. The fact that fluconazole remained under patent from 2000 until 2004, when it became available in generic form, further raises concern over the timing of publication (2). I sincerely hope that there is another, more innocuous, explanation for the long delay between closure of the study and publication of the data. Whatever the case may be, I would be interested in any advice the authors might have for how to minimize delay in the dissemination of clinically relevant data in the future. Finally, I ask why neither the editors of the Annals of Internal Medicine nor the accompanying editorial (3) addressed the issue of publication delay. Have such practices become so commonplace that they are not worth mentioning or addressing? 1. Schuster MG, Edwards JE, Jr., Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med. 2008;149(2):83-90. 2. FDA. US Food and Drug Administration Generic Approvals. 2004. 3. Fekete T. The answer is in: fluconazole prophylaxis is not beneficial for intensive care unit patients without neutropenia. Ann Intern Med. 2008;149(2):140-1. Conflict of Interest:

None declared

Timeliness of Clinical Trial Results Reporting
Posted on August 25, 2008
Alan S. Go
Kaiser Permanente of Northern California
Conflict of Interest: None Declared

To the Editor:

We read with interest the results of the placebo-controlled randomized trial of empirical intravenous fluconazole among critically ill patients.(1) This trial demonstrated a lack of efficacy of what was at the time a proprietary pharmaceutical agent. Given recent concerns raised about the timely reporting of clinical trial results, especially those with negative findings,(2, 3) we were curious why the results of this industry-sponsored clinical trial that was completed between 1995-2000 was not reported until 2008.

1. Schuster MG, Edwards JE, Jr., Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med. 2008;149(2):83-90. 2. Mitka M. Cholesterol drug controversy continues. JAMA. 2008;299(19):2266. 3. Mitka M. Controversies surround heart drug study: questions about Vytorin and trial sponsors' conduct. JAMA. 2008;299(8):885-7.

Conflict of Interest:

None declared

Empirical Fluconazole versus Placebo for Intensive Care Unit Patients: A Randomized Trial
Posted on August 29, 2008
Dong Heun Lee
Division of Infectious Diseases & HIV Medicine
Conflict of Interest: None Declared

We were delighted to read the article by Schuster et al. on the empirical use of fluconazole in critically ill patients in the intensive care unit (ICU) (1). Although there was an 8 year delay between the completion and publication of the study, it is an excellent example of how a "negative" study still provides us valuable data on the decision-making of empirical antifungal treatment in critically ill patients in the ICU. However, one needs to consider this 8 year gap and place it in the context of practicing medicine in 2008. First, I have a different opinion of authors' statement that "yield of Candida species in blood culture is suboptimal even with current culture techniques". Presently, the ability of automated blood culture system to recover Candida species has improved. In the simulated candidemia study by Horvath et al. (2), Candida species were isolated in 98 %( 211/216) of aerobic blood culture bottles when organisms were incubated with blood. It was detected only in 27% (58/216) of anaerobic bottles, which was not unexpected as Candida species are aerobic organisms. Most Candida species were detected within 24-48 hours in the automated blood culture system except for Candida glabrata which took longer and was detected earlier in anaerobic bottles. Although the yield was not 100%, the study demonstrated the improved ability to detect candidemia in aerobic cultures by current technology. Second, the shift from Candida albicans to non-albicans species such as Candida glabrata as causes of candidemia is well known (3). Now, the echinocandin class of antifungal drugs is available which is capable of covering fluconazole-resistant species. This may be an option of empirical treatment instead of high dose fluconazole in 2008 for patients with high risk of candidemia. On a separate point, the interim analysis needs clarification. At the beginning of the study, the target sample size was 134 participants in each group, with a total of 268 participants. However the authors' stated "after the interim analysis, further enrollment was closed because of lack of a difference in two groups." Interestingly, a total of 270 ICU participants were enrolled, which approximates the size of the initial enrollment goal of study. The wait was long for this study to be published and it does have some limitations, but it demonstrates the importance of publishing results "“ whether positive or negative -- in a timely manner.

Dong Heun Lee, MD Division of Infectious Diseases & HIV Medicine Drexel University College of Medicine Philadelphia, PA 19102

1. Schuster MG, Edwards JE Jr, Sobel JD, Darouiche RO, Karchmer AW, Hadley S, Slotman G, Panzer H, Biswas P, Rex JH. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med. 2008; 149(2):83-90.

2. Horvath LL, George BJ, Hospenthal DR. Detection of fifteen species of Candida in an automated blood culture system.J Clin Microbiol. 2007 Sep;45(9):3062-4.

3. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP; National Nosocomial Infections Surveillance System Hospitals. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002 Sep 1;35(5):627-30

Conflict of Interest:

None declared

Slow time to publication of clincial trials
Posted on September 24, 2008
Mindy G Schuster
University of Pennsylvania
Conflict of Interest: None Declared

IN RESPONSE:

We appreciate the readers' interest in our study. The authors bring up the very important issue of publication delay. Some of the delays that occurred in the reporting of this trial, and in other, similarly complex, multi-centered clinical trials conducted in critically ill patient populations, are invariably due to the difficulties in completing the dataset after the final patient is enrolled. Performance of quality assurance, data cleaning, site answers to data queries, and review of each individual case by a busy data review committee can be a cumbersome and time-intensive process, which clearly took too long in the present study.

A study such as ours is a joint venture between the investigators and the sponsor. While there was an element of initial disappointment with a trial yielding negative results, and during the long process the focus of many involved may have been diverted at times, there was no intentional delay in the publication of these results. Efforts to improve the speed of publication and promote the publication of important clinical trials that have negative findings are critical to the dissemination of data that may affect clinical practice. Policies that may speed the publication of clinical trials results include: the assignment of dedicated clinical monitors to each study site, and the formation of a publication committee and timeline at the onset of the project. Importantly, in September, 2004, the International Committee of Medical Journal Editors published an editorial stating that, beginning in September, 2005, clinical trials could only be considered for publication if they had been publicly registered prior to patient enrollment (1). This policy will help promote the reporting of all clinical trials.

With regard to the current yield of routine blood cultures for the growth of candida species, although with current blood culture systems the rate of false negative results for the detection of candidemia is lessened, the high attributable mortality rate due to candidemia still makes empiric or prophylactic therapy attractive. Dr. Lee notes correctly that there has been a shift from Candida albicans to non-albicans species, including C. glabrata, and that echinocanndins may have activity against fluconazole resistant isolates. Given the substantially higher cost of echinocandins, and the fact that most Candida species remain susceptible to fluconazole (2), it remains to be seen whether empiric therapy with an echinocandin will be beneficial and cost-effective. Dr. Lee questions, as well, the large number of patients enrolled in the trial despite the fact that the trial was terminated at the interim analysis for lack of efficacy. The interim analysis involved looking at completed patients, and enrollment was not paused, but was rapid and ongoing at the time of the analysis. Patients already on trial at the time of the decision were allowed to complete the study, and, thus, 270 patients were ultimately enrolled.

References

1. De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: A statement from the international committee of medical journal editors. NEJM , 2004: 351:1250-1251.

2. Pfaller MA, Messer SA, BoykenL, et al. Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location. Journ Clin Microbiol, 2003:41; 2176-2179.

Conflict of Interest:

Helene Panzer-employment (Pfizer) Mindy Schuster-grants received Jack Edwards-consultancies (Merck, Pfizer, Cerexa, Eisai, Enzon)

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