Introduction

Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). The majority of infections are caused by Candida and Aspergillus species, usually several weeks to months post-transplant.¹ The incidence of aspergillosis in transplant patients has been increasing, and mortality rates remain high.² Current evidence-based guidelines recommend 400 mg fluconazole daily after HSCT for the prevention of invasive yeast infections.³

However, fluconazole has no activity against Aspergillus or the more recently recognized emerging non-Aspergillus mold infections. As a result, while many centers continue using fluconazole, a number of centers have broadened coverage with more potent antifungal drugs to prevent mold infections.⁴ Emergence of resistant Candida infections has been reported with prolonged exposure to azole drugs, especially at non-lethal concentrations.⁵

Voriconazole, an extended spectrum triazole agent, has excellent clinical activity in aspergillosis and has been shown to be particularly effective in the prevention of breakthrough fungal infections, especially in patients at high risk for aspergillosis.⁶ It also has excellent in vitro activity against many Candida species, although the in vitro MIC90 (Minimum Inhibitory Concentration required to inhibit the growth of 90% of organisms) for Candida glabrata are higher than for other fluconazole-sensitive Candida species (0.5–1 versus 2).⁷ Voriconazole has no activity against zygomycetes. Although voriconazole is not approved for empiric use in neutropenic fever, the reduction in breakthrough fungal infections seen in patients receiving the drug⁸ makes it an attractive candidate for prevention of aspergillosis. A recent study has reported an association between successful therapeutic outcome in Aspergillus infections and sustaining voriconazole concentrations above the MIC;⁹ suggesting the possible need for therapeutic drug monitoring.

While our standard antifungal prophylaxis for allograft recipients is itraconazole,¹⁰ we switch to voriconazole when patients receive corticosteroids or have had a mold infection in the past. We have also implemented voriconazole therapeutic drug monitoring.¹¹ The purpose of this retrospective review was to determine the efficacy of voriconazole in preventing invasive fungal infections in our patient population and to find out if there was any correlation between drug levels and efficacy.

Patients and methods

Seventy-one adult allogeneic HSCT recipients with hematologic malignancies who received voriconazole post-transplant for at least 7 days, and in whom complete clinical, microbiological and pharmacokinetic data were available were studied. Fifty-four patients switched from itraconazole to voriconazole after starting corticosteroid therapy for acute or chronic graft-versus-host disease (GVHD). These patients had started itraconazole on the day of stem cell infusion. The remaining 17 patients received voriconazole from the day of stem cell infusion because of a prior history of suspected or confirmed aspergillosis.

Voriconazole was usually administered at the dose of 200 mg twice daily orally, and was continued until a month beyond discontinuation of all immunosuppression or development of a fungal infection requiring change in therapy. Steady-state trough blood levels of voriconazole were drawn before the morning dose and measured at least 5 days after the drug was initiated and measured as previously described.^{11, 12} Although the period following stem cell transplantation includes the administration of many drugs metabolized by the cytochrome P450 system, there were no drugs given concomitantly that were known to change voriconazole disposition.

Patients underwent radiologic studies as clinically indicated. Sequential galactomannan testing was not performed. Patients were treated between January 2003 and May 2006. The retrospective review was approved by Northwestern University's institutional review board as part of a project evaluating outcome of allogeneic HSCT.

Results

Table 1 shows patient characteristics. The duration of prior itraconazole therapy in the 54 patients who switched from itraconazole to voriconazole was 1–161 days (median 14). The total duration of exposure to voriconazole was 13 805 patient-days (38 years).

Table 1 - Patient characteristics.

Full table

Most patients received corticosteroids at some point in time while on voriconazole. The dose of steroids varied according to severity of GVHD, with the majority of patients (81%) receiving intravenous methylprednisolone. The maximum daily dose of corticosteroids was 2 mg/kg (median maximum daily dose 500 mg).

Ten microbiologically confirmed fungal infections were seen, six Candida and four Zygomycetes. Not a single case of aspergillosis was seen. Patients in whom the fungus was seen on bronchoalveolar lavage or endotracheal tube aspirate had lung infiltrates compromising pulmonary status, and no other known cause for the pulmonary infiltrates (compatible with possible to probable infection by the European Organization for Research and Treatment of Cancer criteria). Table 2 provides detailed information on the 10 cases. Concomitant bacteremia was seen in all six patients with candidiasis and in two of the patients with zygomycosis.

Table 2 - Breakthrough fungal infections.

Full table

All the patients with candidiasis received caspofungin. The two candidiasis cases (Patients 1 and 4) in which the fungal infection was felt to have contributed died of polymicrobial sepsis. Clearance of Candida was demonstrated on repeat bronchoscopy in three patients (Patients 2, 3 and 6). As most patients had concomitant infections, attributable mortality could not be definitely established. Patients in whom death was felt to be at least partly due to the fungal infection were those in whom pulmonary infiltrates did not resolve (and indeed progressed), and in whom there was no other predominant cause of death.

Among the zygomycosis cases, patients 7 and 9 were treated with posaconazole, patient 8 received amphotericin B lipid complex, and patient 10 received liposomal ampotericin B. Patient 8 had received prophylactic itraconazole for over 4 months before a change was made to voriconazole prophylaxis when signs and symptoms of sinusitis developed. Zygomycosis involving the sinuses was confirmed 7 days later. It is unlikely that voriconazole contributed to the development of zygomycosis in this case. Similarly, patient 10 had received itraconazole for almost 2.5 months before a change was made to voriconazole. Zygomycosis was diagnosed less than 3 weeks later, suggesting that the contribution of voriconazole therapy to zygomycosis in this case is debatable. Figures 1 and 2 show the actuarial probability of invasive fungal infections (18% at 1 year) and zygomycosis (7% at 1 year), respectively, from the initiation of voriconazole therapy.

Figure 1.

Probability of development of invasive fungal infection after starting voriconazole.

Full figure and legend (10K)

Figure 2.

Probability of development of zygomycosis after starting voriconazole.

Full figure and legend (10K)

Table 3 shows plasma voriconazole trough levels. Excluding the four zygomycosis cases, all six candidiasis cases were seen among the 43 patients with voriconazole levels of 2 g/ml and none among the 24 with levels of >2 g/ml (P=0.061; Fisher's exact test). Including the four zygomycosis cases, the six candidiasis cases were seen among the 44 patients with voriconazole levels of 2 g/ml and none among the 27 with levels of >2 g/ml (P=0.049; Fisher's exact test).

Table 3 - Voriconazole levels.

Full table

Discussion

Our data show that voriconazole is effective in preventing Aspergillus infections in immunocompromised allogeneic HSCT recipients. While there is some breakthrough zygomycosis, the incidence appears to be low. The study also suggests that there may be a link between low plasma voriconazole levels and breakthrough infections with fungi that are otherwise susceptible to the drug, a relationship that requires exploration in a prospective study. The limitations of the data are their retrospective nature, a relatively small number of patients, and the lack of availability of MICs in the specific fungi isolated in patients.

The observed efficacy of voriconazole in preventing Aspergillus infections confirms the results reported by Siwek et al.¹³ who found no cases of aspergillosis among 92 allogeneic HSCT recipients. Prophylactic fluconazole improves survival of HSCT recipients.¹⁴ Since fluconazole has no activity against Aspergillus species, it is not unreasonable to expect that voriconazole would have similar benefit on survival because of its broader spectrum of activity. However, there are no randomized data to support or refute this hypothesis.

The overall incidence of zygomycosis in cancer patients appears to be increasing.^{15, 16} However, there is a concern that prior voriconazole use predisposes to zygomycosis.^{13, 17, 18} Our data appear to support the suggestion of breakthrough zygomycosis. However, we do not believe that it is a problem unique to voriconazole or one that is solely attributable to it. Two patients in this study (Patients 8 and 10; Table 2) had received prophylactic itraconazole for 122 and 63 days, respectively, before switching to voriconazole on account of GVHD requiring corticosteroids, and had been on voriconazole for only 7 and 17 days, respectively, before zygomycosis was diagnosed. Patient 8 had symptoms of sinusitis for a few days before the diagnosis being made, and patient 10 had pulmonary infiltrates for approximately a week before the diagnosis was made. This suggests that prior itraconazole therapy may have been responsible for the development of zygomycosis in two of the four patients. We have reported another case of breakthrough zygomycosis and aspergillosis on itraconazole prophylaxis.¹⁹

Indeed, as Figure 3 (measured from the time of starting itraconazole in those who started it before switching to voriconazole, or from the time of starting voriconazole in those who did not receive itraconazole) shows, over 2.5 months of combined itraconazole/voriconazole therapy have elapsed before the first episode of zygomycosis occurs. This suggests that therapy/prophylaxis effective against aspergillosis may need to continue for several weeks before breakthrough zygomycosis becomes a risk.

Figure 3.

Probability of development of zygomycosis from the day of stem cell infusion (that is after starting itraconazole or voriconazole).

Full figure and legend (10K)

After seeing the results of this analysis, we have streamlined our antifungal prophylaxis practice in allogeneic HSCT recipients by eliminating itraconazole entirely and administering voriconazole from the beginning in all patients. The recent approval of posaconazole raises the intriguing possibility of alternating prophylaxis between voriconazole and posaconazole every 1–2 months in patients who require prolonged broad-spectrum antifungal prophylaxis. The experience with itraconazole and voriconazole suggests that switching to posaconazole exclusively for prophylaxis may not be an optimum solution as other serious mycoses may emerge – and such an approach should ideally be undertaken only in the setting of a clinical trial.

The rate of breakthrough Candida infections in this study appears similar to that reported with fluconazole²⁰ with a shift towards more resistant species. It is interesting that plasma steady-state trough voriconazole levels around the time the infection occurred were <0.2, <0.2, 0.33, 0.55, 0.63 and 1.78 g/ml in the six candidiasis cases (Table 2). The lack of occurrence of breakthrough candidiasis in patients with drug levels of >2 g/ml appears to be statistically significant. Of course, it should be noted that the interval between obtaining drug level and diagnosis of a fungal infection exceeded 4 weeks in two Candida cases and one mucor case. Likewise, as the diagnosis of Candida infection was determined from broncho-alveolar lavage in 5/6 patients, the possibility of colonization or contamination cannot be ruled out. This is not unexpected considering the retrospective nature of the study.

Analysis of data for 249 patients from six phase III clinical trials of voriconazole has demonstrated a significant correlation between drug levels and end-of-treatment outcome assessment.²¹ Using MIC data for voriconazole in over 8000 clinical isolates, the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute has now proposed interpretive breakpoints for voriconazole and Candida species.²² These are as follows: <1 g/ml susceptible, 2 g/ml susceptible dose dependent, and >4 g/ml resistant. Although the majority of C glabrata isolates were susceptible to voriconazole, among the fluconazole-resistant isolates, 44% were susceptible to voriconazole in a dose-dependent manner (MIC 2 g/ml). Such organisms would require higher plasma concentrations to eradicate infection.

Previously published data suggest that drug levels can affect outcome of antifungal therapy in clinical practice. The maximum amount of information is available for itraconazole showing that blood levels of itraconazole exceeding a threshold are needed to reduce the risk of Aspergillus infections.^{23, 24, 25}

Data on file at the United States Food and Drug Administration show that success rate in patients with fungal infections, whose mean voriconazole plasma levels were <0.5 g/ml, was 46% compared to 56% with mean plasma levels >0.5 g/ml.²¹ A recent study⁹ reported a significant association between higher plasma voriconazole levels and therapeutic success in patients with documented Aspergillus infection. Favorable responses were observed in 10 of 10 patients with drug concentrations >2.05 g/ml and in 10 of 18 patients with concentrations <2.05 g/ml (P=0.014).

While our observation does seem to be compelling in combination with the above data, the lack of aspergillosis in patients with low voriconazole levels in this series would seem to weaken the case for a relationship between drug levels and outcome. One possible explanation is that the incidence of aspergillosis in our patient population is not high enough to have this modest-sized series show a difference in outcome between patients with low and optimum drug levels.

This study, our previous observations of large inter-patient variability in plasma voriconazole levels,¹¹ and other data⁹ are insufficient to recommend starting routine therapeutic drug monitoring in all patients on voriconazole. However, we feel that future prospective clinical trials of voriconazole should incorporate therapeutic drug monitoring. Consideration should be given to checking drug levels in patients who are being treated with the drug for confirmed aspergillosis, and in those who develop breakthrough infections with Candida or Aspergillus species while on the drug.

We conclude that voriconazole is effective at preventing aspergillosis. Breakthrough zygomycosis is a potential problem in a small number of patients treated with voriconazole (or itraconazole followed by voriconazole) for a prolonged period of time. Breakthrough infections with organisms susceptible to voriconazole in a dose-dependent manner may occur in patients with low trough levels suggesting that the role of therapeutic drug monitoring needs to be explored prospectively.

References

1. Nucci M, Marr KA. Emerging fungal infections. Clin Infect Dis 2005; 41: 521–526. | Article | PubMed | ISI |
2. Singh N, Paterson DL. Aspergillus Infections in transplant patients. Clin Microbiol Rev 2005; 18: 44–69. | Article | PubMed | ISI | ChemPort |
3. Sullivan KM, Dykewicz CA, Longworth DL, Boeckh M, Baden LR, Rubin RH et al. Preventing opportunistic infections after hematopoietic stem cell transplantation: The Centers for Disease Control, Infectious Disease Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology (Am Soc Hematol Educ Program) 2001, 392–421.
4. Trifilio SM, Verma A, Mehta J. Antimicrobial prophylaxis in hematopoietic stem cell transplant recipients: heterogeneity of current clinical practice. Bone Marrow Transplant 2004; 33: 735–739. | Article | PubMed | ISI | ChemPort |
5. Andes D, Forrest A, Lepak A, Nett J, Marchillo K, Lincoln L. Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans. Antimicrob Agents Chemother 2006; 50: 2374–2383. | Article | PubMed | ISI | ChemPort |
6. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–415. | Article | PubMed | ISI | ChemPort |
7. Ostrosky-Zeichner L, Rex JH, Pappas PG, Hamill RJ, Larsen RA, Horowitz HW et al. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrobiol Agents Chemother 2003; 47: 3149–3154. | Article | ChemPort |
8. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225–234. | Article | PubMed | ISI | ChemPort |
9. Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570–1572. | Article | PubMed | ISI | ChemPort |
10. Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527–1533. | Article | PubMed | ISI | ChemPort |
11. Trifilio S, Ortiz R, Pennick G, Verma A, Pi J, Stosor V et al. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2005; 35: 509–513. | Article | PubMed | ISI | ChemPort |
12. Pennick GJ, Clark M, Sutton DA, Rinaldi MG. Development and validation of a high-performance liquid chromatography assay for voriconazole. Antimicrob Agents Chemother 2003; 47: 2348–2350. | Article | PubMed | ISI | ChemPort |
13. Siwek GT, Pfaller MA, Polgreen PM, Cobb S, Hoth P, Magalheas-Silverman M et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 2006; 55: 209–212. | Article | PubMed | ISI | ChemPort |
14. Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME 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. | PubMed | ISI | ChemPort |
15. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–653. | Article | PubMed | ISI |
16. Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis, clinical manifestations, and management. Infect Dis Clin North Am 2006; 20: 581–607. | Article | PubMed | ISI |
17. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350: 950–952. | Article | PubMed | ISI | ChemPort |
18. Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case–control observational study of 27 recent cases. J Infect Dis 2005; 191: 1350–1360. | Article | PubMed | ISI |
19. Verma A, Williams S, Trifilio S, Zembower T, Mehta J. Successful treatment of concomitant pulmonary zygomycosis and aspergillosis with a combination of amphotericin B lipid complex, caspofungin, and voriconazole in a patient on immunosuppression for chronic graft-versus-host disease. Bone Marrow Transplant 2004; 33: 1065–1066. | Article | PubMed | ISI | ChemPort |
20. Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000; 181: 309–316. | Article | PubMed | ISI | ChemPort |
21. www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_02_FDA-voriconazole.htm (Accessed 9 November 2006; page search term 'Voriconazole Efficacy Response Assessment').
22. Pfaller MA, Diekema DJ, Rex JH, Espinel-Ingroff A, Johnson EM, Andes D et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol 2006; 44: 819–826. | Article | PubMed | ISI | ChemPort |
23. Boogaerts MA, Verhoef GE, Zachee P, Demuynck H, Verbist L, De Beule K. Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma levels. Mycoses 1989; 32 (Suppl 1): 103–108. | PubMed | ISI |
24. Berenguer J, Ali NM, Allende MC, Lee J, Garrett K, Battaglia S et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother 1994; 38: 1303–1308. | PubMed | ISI | ChemPort |
25. Glasmacher A, Hahn C, Leutner C, Molitor E, Wardelmann E, Losem C et al. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 1999; 42: 443–451. | Article | PubMed | ISI | ChemPort |

Acknowledgements

No financial support was received for this work.