Antifungal Prophylaxis in Critical Care Patients
Antifungal Prophylaxis in Critical Care Patients
ABSTRACT & COMMENTARY
Synopsis: Fluconazole (and perhaps other antifungal agents) may provide effective prophylaxis for selected nonneutropenic, critically ill patients, but further studies are required.
Source: Rex JH, Sobel JD. Prophylactic antifungal therapy in the intensive care unit. Clin Infect Dis. 2001;32:1191-1200.
Rex and sobel have examined the rationale of administering antifungal medication to prevent fungal infections in nonneutropenic, critically ill patients. Reasoning that antifungal prophylaxis in patients undergoing bone marrow transplantation reduces the incidence of systemic fungal infections by nearly two-thirds, they critically analyze the theoretical basis for prophylaxis in intensive care unit (ICU) patients, and review the evidence that fluconazole—as the prototypical antifungal agent—may be useful in this context.
Fungal infections, particularly invasive disease due to Candida species (especially C albicans), occur with increasing frequency in critically ill patients. Diagnosis may be difficult and is often delayed, and treatment may be initiated too late to prevent serious morbidity or even death.
Rex and Sobel begin consideration of prophylaxis by methodically analyzing statistical issues pertinent to randomized, placebo-controlled trials. They stress that for any prophylaxis trial to be achievable, a major reduction in the incidence of infection must occur. Testing an agent that leads to a 2- or 3-fold reduction in infection requires far fewer patients than one in which only a fractional reduction occurs. A second statistical consideration that drives any prophylaxis trial is clinical relevance: reduction of the rate of infection from 1% to 0.5% is clearly less compelling than a study demonstrating a decrease from 20% to 10%, even though the reduction is halved in each case. These 2 elements are of major importance. Several studies on prophylaxis have faltered because they have been inadequately powered to demonstrate statistical significance.
Is there a need for prophylaxis? With surgical precision, Rex and Sobel carefully set forth the critical defining principles: 1) Candida infections, because they constitute the vast majority of fungal infections in nonneutropenic, critically ill patients, should be the "target" 2) prophylaxis, and not early treatment (eg, beginning antifungal therapy in a febrile patient with multiple sites of Candida colonization), is the key to reducing morbidity and mortality; and 3) invasive candidiasis must be clearly defined. Although Candida in a respiratory tract specimen may not be indicative of pneumonia, there would be little disagreement that repeated isolation of Candida in blood cultures represents deep-seated Candida infection. Candida in urinary tract or wound specimens likewise poses a difficult problem of definition. Any study attempting to define the frequency of invasive candidiasis and the possible role of preventive intervention must address this issue head on.
Rex and Sobel review a number of studies citing rates of invasive Candida infections in the ICU ranging from 2% to 35% and conclude that a rate at the lower end of the range is a reasonable estimate (eg, data from the National Nosocomial Infections Surveillance indicate a 2% rate in this patient group). With this low rate, one can easily understand, given the statistical caveats previously mentioned, that only studies using large numbers of patients can be expected to show even the slightest benefit of prophylaxis.
Rex and Sobel critically review published data on antifungal prophylaxis in the ICU setting. Each of 5 studies differs somewhat in inclusion criteria, definition of infection, and specific antifungal prophylaxis. Rex and Sobel find that only 2 trials are designed well enough to provide meaningful data from which the reader may extrapolate to the clinical arena. In one, Garbino and associates administered low-dose fluconazole (100 mg/d) to more than 100 mechanically ventilated patients in a medical/surgical ICU, and they found a reduction in the incidence of invasive candidiasis from 8.9% in patients receiving placebo to 3.9% in fluconazole recipients.1 However, Rex and Sobel point out that invasive fungal infection was defined loosely, and the observed differences between groups failed to achieve statistical significance. They find a recent study by Pelz and colleagues to be more compelling.2 In this study involving 260 patients in the surgical ICU at Johns Hopkins Hospital, administration of fluconazole at a dose of 400 mg/d nearly halved the incidence of invasive candidiasis (from 15.3% in placebo recipients to 8.5% in fluconazole-treated patients). Although the intent-to-treat analysis fell just short of statistical significance (P = .07), several manipulations of the data resulted in impressive risk reductions (with P = .01). However, no statistically significant difference in mortality was observed between the 2 groups.
The high rate of infection in placebo recipients (15.3%) in the Pelz study, compared with an expected rate of approximately 2% in ICU patients overall, highlights the importance of patient selection. In the study by Pelz et al, patients were ill in a surgical ICU, had high APACHE III scores and multiple underlying medical conditions, and were elderly. But Rex and Sobel explain, ". . . this study makes clear the potential for prophylaxis: if a suitable group can be identified, prophylaxis can and will be of value."
Eggimann and colleagues appear to have identified one such group.3 Their small study, limited to carefully selected high-risk patients with recurrent gastrointestinal perforations or anastamotic leakages, found that, relative to placebo, fluconazole significantly reduced the incidence of Candida perionitis.
Rex and Sobel conclude their provocative and perspicatious review by calling for additional studies of antifungal prophylaxis in the ICU environment, with special emphasis on selection of carefully chosen subsets of patients to determine where the greatest benefit can be achieved. Looking at the data that are available at present, they conclude that it is possible ". . . that the majority of the benefit was received by the minority of the patients." They state that the recently published guidelines of the Infectious Diseases Society of America discourage routine use of antifungal prophylaxis in the ICU4 (Reviewer’s note: In fact, the guidelines do not directly address the topic), but they compellingly make the case that proper selection of patients is key. But it is also the rub: Who are these patients? Which ICU patients are most likely to derive maximal benefit? Only additional well-designed studies can provide the answers. Rex and Sobel have provided the spark that may light the way to significant advances in the management of critically ill patients.
COMMENT BY JERRY D. SMILACK, MD
Rex and Sobel place considerable importance on the study by Pelz et al2 but acknowledge that this trial was reported only in abstract form. The more complete report of the study, recently published in its entirety,5 provides some missing details. Most bothersome is that a substantial number of patients in both placebo and treatment groups had presumed, but not definite, invasive Candida infection. Included in the former category were patients with Candida isolation from only urine or vascular catheter tip cultures. Pelz et al indicate, however, that exclusion of these cases from the proven infection totals failed to alter the statistical significance of the results.
References
1. Garbino J, et al. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: A randomized, double-blind, placebo-controlled trial [abstract 58.004]. In: Program and abstracts of the 9th International Congress on Infectious Diseases (Buenos Aires).
2. Pelz RK, et al. Society of Critical Care Medicine 29th Educational and Scientific Symposium. Orlando, Fla. February 11-15, 2000. Abstracts. Crit Care Med. 1999; 27(Suppl):A33.
3. Eggimann P, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med. 1999;27:1066-1072.
4. Rex JH, et al. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:662-678.
5. Pelz RK, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg. 2001;233:542-548.
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