The Gift That Keeps on Giving: Fluconazole Prophylaxis in Allogeneic Bone Marrow Transplantation
abstract & commentary
Synopsis: Administration of fluconazole for 75 days to allogeneic bone marrow transplant recipients is associated with a survival benefit that persists for years.
Source: Marr KA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: Long-term follow-up of a randomized, placebo-controlled trial. Blood 2000;96:2055-2061.
In 1995, slavin and colleagues reported the results of a randomized, double-blind clinical trial that demonstrated the efficacy of fluconazole in the prevention of fungal infections in bone marrow transplant recipients.1 In that study, which was completed in 1992, fluconazole was administered in a dose of 400 mg daily from the day of conditioning chemotherapy until 75 days after transplantation, or until the development of a fungal infection or severe adverse effect. Efficacy was demonstrated at the end of the period of fluconazole administration, two weeks later, and at the time of discharge.
Marr and colleagues from the Fred Hutchinson Cancer Center and the University of Washington report the long-term follow-up of the patients who participated in that study. After a mean of eight years, survival was significantly greater in the fluconazole recipients than in those assigned placebo—68 of 152 (44.7%) vs. 41 of 148 (27.7%) (P = 0.0001). Significant benefit was, however, limited to those who received allogeneic grafts; only 35 patients (11.7% of the total enrolled) received autologous grafts.
Multivariate analysis confirmed that being assigned placebo was independently associated with a significantly reduced chance of survival, as was age older than 50 years, absence of laminar airflow room isolation, a mismatched or unrelated donor, and the type and stage of disease. The incidence of death related to infection with Candida spp. (primarily C. albicans and C. tropicalis) was 8% in placebo recipients and less than 1% in those assigned fluconazole (P = 0.001).
Protection against Candida infection persisted well beyond the 75 days of fluconazole administration. Two cases of invasive candidiasis occurred after day 110 in prior fluconazole recipients, while 11 occurred in those who had received placebo, with the last occurring just after more than two years of follow-up. All these late infections occurred in recipients of allogeneic transplants and was frequently associated with extensive chronic acute graft-versus-host disease (GVHD). Nine of these cases were fatal. In contrast to the results with Candida infection, the incidence of infections with filamentous fungi was similar in the two groups.
Despite a similar overall risk of GVHD in each group, fewer fluconazole recipients died of this complication in the absence of infection (2 vs 8; P = 0.49). Severe GVHD involving the gastrointestinal tract (gut GVHD) occurred significantly more frequently in placebo recipients than in fluconazole recipients (10/125 [8%] vs 2/125 [1.6%]; P = 0.18).
Comment by Stan Deresinski, MD, FACP
In 1992, Goodman and colleagues reported that fluconazole prophylaxis during neutropenia was effective in the prevention of superficial and deep fungal infections in bone marrow recipients, most of whom had received autologous transplants.2 That trial, however, differed from the one performed by Slavin et al in which 88.3% of patients received allogeneic marrow and fluconazole was administered for a significantly longer duration. Nonetheless, those two studies led to the widespread use of fluconazole prophylaxis in marrow recipients, a use in concordance with the recently published recommendations of the Infectious Disease Society of America (see Table).
| Table-Recommendations of the Infectious Disease Society for Prevention of Invasive Candidiasis During Chemotherapy-Related Neutropenia6 |
| Fluconazole at 400 mg/d during the period of neutropenia is warranted in patients who are at significant risk of invasive candidiasis. Such patient groups include selected patients receiving standard chemotherapy for acute myelogenous leukemia, allogeneic bone-marrow transplants, or high-risk autologous bone-marrow transplants. However, in this context, it is important to understand that, among these populations, chemotherapy or bone-marrow transplant protocols do not all produce equivalent risk and that local experience with particular chemotherapy and cytokine regimens should be used to determine the relevance of prophylaxis." |
This follow-up of participants in the earlier study found an apparently unequivocal long-lasting benefit of fluconazole in the prevention of death related to invasive candidiasis. The reason for the persistence of benefit of fluconazole prophylaxis well beyond the period of its administration is unclear. It appears, however, that a 75- day period of fluconazole prophylaxis may have long lasting effects on Candida colonization and gastrointestinal tract integrity.
These effects may also explain the reduction in severe gut GVHD in fluconazole recipients. Thus, evidence strongly suggests that damage to the gastrointestinal tract plays a major role in the local and systemic manifestations of GVHD.3 Proinflammatory products of gastrointestinal Candida could conceivably play a comparable role in this scenario.
Fluconazole is not effective in the prevention of infections caused by molds, such as Aspergillus. In addition, it is not effective in the prevention of infection with Candida spp. that are resistant to this drug, such as C. krusei. Finally, some centers are reporting increasing resistance of other species, including C. albicans to fluconazole.
The results of this study indicate that allogeneic bone marrow recipients should receive prophylaxis with fluconazole for 75 days beginning with the day of conditioning chemotherapy. Whether 400 mg daily remains an adequate dose depends upon patterns of susceptibility of Candida isolates at individual institutions. A 400-mg dose of fluconazole provides peak serum concentrations of 20-30 mcg/mL and trough concentrations of 10-15 mcg/mL.4 Thus, higher doses of this triazole may prove necessary at institutions with prevalent "susceptible, dose-dependent" strains of Candida—those with MICs of 16-32 mcg/mL.
References
1. Slavin MA, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—A prospective, randomized, double-blind study. J Infect Dis 1995;171:1545-1552.
2. Goodman JL, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326: 845-851.
3. Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: Rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000; 95:2754-2759.
4. Grant SM, Clissold SP. Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39:877-916.
5. Rex JH, et al. Development of interpretive breakpoints for antifungal susceptibility testing: Conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis 1997;24:235-237.
6. Rex JH, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662-678.
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