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Voriconazole Treatment for Less-Common, Emerging, or Refractory Fungal Infections

  1. John R. Perfect1,
  2. Kieren A. Marr2,
  3. Thomas J. Walsh3,
  4. Richard N. Greenberg4,
  5. Bertrand DuPont7,
  6. Juliàn de la Torre-Cisneros8,
  7. Gudrun Just-Nübling9,
  8. Haran T Schlamm5,
  9. Irja Lutsar10,
  10. Ana Espinel-Ingroff6, and
  11. Elizabeth Johnson11
  1. 1Department of Medicine and Microbiology, Duke University, Durham, North Carolina
  2. 2Fred Hutchinson Cancer Center, Seattle, Washington
  3. 3National Cancer Institute, Bethesda, Maryland
  4. 4University of Kentucky, Lexington
  5. 5Pfizer, New York
  6. 6Medical College of Virginia, Richmond
  7. 7Hopital Necker, Paris, France
  8. 8University Hospital Reina Sofia, Sofia, Bulgaria
  9. 9University of Frankfurt, Frankfurt, Germany
  10. 10Pfizer, Sandwich
  11. 11Bristol Public Health Laboratory, Bristol, England
  1. Reprints or correspondence: Dr. John R. Perfect, Dept. of Medicine and Microbiology, Duke University Medical Center, 0554 Hospital S, Durham, NC 27710 (perfe001{at}mc.duke.edu).
 
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Abstract

Treatments for invasive fungal infections remain unsatisfactory. We evaluated the efficacy, tolerability, and safety of voriconazole as salvage treatment for 273 patients with refractory and intolerant-to-treatment fungal infections and as primary treatment for 28 patients with infections for which there is no approved therapy. Voriconazole was associated with satisfactory global responses in 50% of the overall cohort; specifically, successful outcomes were observed in 47% of patients whose infections failed to respond to previous antifungal therapy and in 68% of patients whose infections have no approved antifungal therapy. In this population at high risk for treatment failure, the efficacy rates for voriconazole were 43.7% for aspergillosis, 57.5% for candidiasis, 38.9% for cryptococcosis, 45.5% for fusariosis, and 30% for scedosporiosis. Voriconazole was well tolerated, and treatment-related discontinuations of therapy or dose reductions occurred for <10% of patients. Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections.

Current treatments for refractory invasive fungal infections and for less-common and emerging fungal infections remain inadequate. Treatment with voriconazole, a broad-spectrum triazole, has resulted in successful outcomes in the treatment of opportunistic fungal infections, including invasive aspergillosis [1–3], fluconazole-resistant candidiasis [4], and a variety of pediatric mycoses [3]. Furthermore, comparative trials of antifungals have confirmed that voriconazole shows similar efficacy to fluconazole for esophageal candidiasis [5] and prevents breakthrough fungal infections during empirical therapy in febrile neutropenic patients [6]. Compared with amphotericin B (AmB), it has a favorable outcome for the treatment of patients with primary invasive aspergillosis [7, 8].

Case reports have documented the successful treatment of aspergillosis in a variety of patients, including those with pneumonia refractory to AmB during neutropenia [9], those with cerebral aspergillosis [10–12], and those with chronic granulomatous disease [13, 14]. Case reports have documented successful treatment against emerging pathogens, including Fusarium species [15], Scedosporium species [3, 11, 16–19], and Paecilomyces species [20]. These encouraging clinical studies are supported by in vitro observations that confirm the agent's broad and potent antifungal activities [21–23]. With the clinical deficiencies of the present azoles and polyenes for treatment of refractory and less-common invasive fungal infections, the encouraging results of clinical studies of voriconazole provided the rationale for a multicenter, open-label, clinical study to assess its efficacy and safety for the treatment of these difficult-to-treat patients.

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Patients and Methods

Study design. Patients with documented invasive fungal infections and evidence of failure of, intolerance to, or toxicity related to currently approved antifungal treatments and those having infections with no approved therapies were eligible for the study. Initial therapy and duration were determined by the principal investigator on the basis of clinical response. Clinical, mycological, serological, and radiological evaluations plus safety assessments were performed throughout the trial.

Written informed consent for participation was given by the patient, legal guardian, or closest relative or legal representative within the guidelines for human experimentation specified by the US Department of Health and Human Services and local regulations for countries other than the United States. The study was conducted in compliance with the 1996 revisions to the Declaration of Helsinki and national and local regulations, and it was approved by local ethics review committees or institutional review boards.

Inclusion and exclusion criteria. Eligible patients had a “definite” or “probable” invasive fungal infection confirmed within 4 weeks of entry. Definite infections were those that had positive results of histopathological tests with evidence of tissue invasion, positive serological test results, and/or positive results of culture of a sample from a normally sterile body site. Patients with candiduria were excluded. Probable pulmonary aspergillosis was considered to have occurred in allogeneic bone marrow transplant (BMT) recipients, neutropenic recipients of an autologous BMT, and those with hematological malignancy when infiltrates, nodules, or cavities visible on chest radiographs and/or CT scans were not attributable to another cause and when bronchoalveolar lavage fluids or transbronchial biopsy materials were found to contain Aspergillus species by either culture or cytological examination.

Patients whose cases fulfilled the criteria for definite or probable infection were required to have evidence of refractoriness, intolerance, or toxicity associated with approved antifungal therapy, as judged by the principal investigator at the site. Refractory infection was defined as a lack of clinical response after ⩾7 days of standard antifungal treatment or as a lack of response after ⩾14 days for Candida esophagitis. Nephrotoxicity was defined as an increase in the serum creatinine level of ⩾1.5 mg/dL (or ⩾2.0 mg/dL for patients with preexisting renal impairment). Intolerability to local infusion-related events was assessed by site investigators. Intolerance was considered to have occurred after ⩾1 infusion-related episode with ⩾2 of the following symptoms: fever, chills, myalgias, bronchospasms, and vascular instability. Infections were considered to have no defined antifungal therapy if there have not been comparative trials or regulatory approvals for a specific infection.

Patients were ineligible for the study if they were receiving drugs expected to interact with voriconazole, investigational drugs, systemic antifungal agents, granulocyte transfusions, or granulocyte- or granulocyte-macrophage colony-stimulating factor for treatment of infection. Eligibility was precluded if there were laboratory abnormalities, such as a liver enzyme level of >5 times the upper limit of normal or a creatinine level >2.5 mg/dL, or if the patient was undergoing dialysis. Patients who were intolerant of azoles and those whose life expectancy was <3 days were excluded from the study.

Identification of fungal isolates. Fungal cultures were identified by the participating hospital centers and confirmed by the Public Health Laboratory, Mycological Reference Laboratory (Bristol, United Kingdom), or the Medical Mycology Research Laboratory, Medical College of Virginia/Virginia Commonwealth University (Richmond, VA). Susceptibility testing was performed by the reference laboratories by means of a microtiter format of the NCCLS methods M27A, for yeasts [24], and M38P, for molds [25].

Administration of study drugs. Intravenous voriconazole therapy was initiated at a loading dosage of 6 mg/kg q12h for the first 24 h, followed by 4 mg/kg q12h for ⩾3 days, after which patients could switch to oral therapy at 200 mg b.i.d. Patients who initiated treatment with oral voriconazole received a loading dosage of 400 mg b.i.d. on the first day, followed by a maintenance dosage of 200 mg b.i.d.; oral dosages were calculated at half-strength for patients who weighed <40 kg. The dosage of oral voriconazole could be increased to 300 mg b.i.d. for patients who had not responded to a lower dosage after 3 days. Changes from intravenous to oral therapy and dose adjustments were made at the discretion of the principal investigator.

Efficacy assessments. The primary efficacy variable was the global response evaluated at end of treatment (EOT) or at week 16 for subjects continuing with long-term voriconazole therapy at the discretion of investigators. Global response was based on a composite assessment of overall clinical, mycological, radiological, and serological responses and was evaluated on the following scale: (1) “complete response” was defined as resolution of all clinical signs and symptoms, bronchoscopic abnormalities, and/or radiographic abnormalities attributable to fungal infection present at baseline, and normal serological response (when appropriate), and mycological eradication (when obtainable); (2) “partial response” was defined as major improvement of all clinical signs and symptoms, bronchoscopic abnormalities, and/or radiographic abnormalities attributable to fungal infection, and/or normal or improved serological response; (3) “stable disease” was defined as minor or no clinical improvement but without deterioration and/or unchanged serological response; and (4) “failure” was defined as clinical deterioration necessitating alternative antifungal therapy or resulting in death, and/or worsened serological response, and/or persistence of fungal infection on the basis of culture, microscopic evaluation, or histopathological testing.

Safety assessments. Safety was monitored throughout the study. Adverse events (AEs) were recorded and monitored until resolution or stabilization. Ophthalmological acuity tests (Reduced Snellen Test or Lighthouse Test), visual fields (confrontation perimetry), and funduscopy were performed at baseline; at weeks 8, 12, or 16; and at follow-up. Complete blood cell counts and blood chemistries plus urinalysis were performed at baseline; at weeks 1, 2, 4, 8, 12, and 16; and with every dose escalation or reduction.

Statistical analysis. The study was open label and noncomparative, without requirements for hypothesis testing, statistical determination of sample size, or randomization. The modified intent-to-treat (MITT) population included patients with probable or definite fungal infections who received ⩾1 dose of voriconazole.

Satisfactory global response (defined as either complete or partial global response at EOT or as cured or improved response at follow-up) and rate of satisfactory global response (the ratio of the number of patients with satisfactory global response relative to the number of patients eligible for analysis) were the primary efficacy variables. Study-adjusted pooled estimates of satisfactory response rate (95% CI) by primary diagnosis, category of immunosuppression, and primary reason for requiring voriconazole therapy were determined. All deaths were analyzed, with patient status (alive, dead, or censored) determined for each time point. Proportions of survivors at 90 days from treatment initiation were analyzed by a Kaplan-Meier estimate, and corresponding 95% CIs were calculated using Greenwood's formula [26].

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Results

Patient Demographic Characteristics

A total of 372 patients (age, 11–87 years) entered the studies and constituted the safety population; the patients represented 14 countries and 101 medical centers. Three-hundred one (81%) of 372 patients met the criteria for the MITT efficacy population; 293 (97%) of these patients had EOT assessments performed, and 90 patients (30%) had follow-up assessments performed. Most patients had an underlying disease or immunosuppression, but 4.3% of the MITT population was considered to be immunocompetent.

Treated infections included those caused by Aspergillus and Candida species, as well as those caused by less common fungi, such as Fusarium, Scedosporium, Cryptococcus species and various dimorphic, hyalohyphomycetous, and dematiaceous fungi. Most patients (94%) had received previous systemic antifungal therapy before treatment with voriconazole; almost 3 of 4 reported that previous antifungal therapy failed to cure the infection. The overall duration of exposure to previous systemic antifungals was >14 days in ⩾50% of patients.

Efficacy

Voriconazole was administered intravenously for a median of 18 days (range, 1–138 days) and orally for a median of 69 days (range, 1–326 days). A total of 31 patients continued therapy for >16 weeks for a variety of reasons. Sixty-six (21.9%) of 301 patients underwent dosage escalation, primarily because of lack of clinical improvement. Fifty percent of patients had a satisfactory global response, with rates highest for those who had infections for which there is no approved therapy or who had preexisting renal impairment (68% and 78%, respectively; table 1). The Kaplan-Meier estimate of the proportion of patients alive at 90 days across all infections was 0.664 (95% CI, 0.609–0.719; table 2). A total of 27 patients were neutropenic (i.e., absolute neutrophil count of <500 neutrophils/μL), and 8 patients who remained neutropenic had infections that failed to respond to therapy. On the other hand, 12 (63%) of 19 patients were successfully treated during neutrophil recovery. With regard to the potential impact of azole cross-resistance, for aspergillosis, voriconazole success was observed for 24 (45%) of 53 in patients who had received previous itraconazole therapy, compared with 40 (43%) of 92 patients who had received previous AmB therapy. For candidiasis, voriconazole was successful for 33 (60%) of 55 and 15 (56%) of 27 previous recipients of fluconazole and itraconazole therapy, respectively, compared with 16 (44%) of 36 previous recipients of AmB therapy. Of the patients with fluconazole-resistant yeast infections (MIC, >64 μg/mL), voriconazole treatment was successful for 7 of 10 patients infected with Candida albicans and for 7 of 9 patients infected with non-albicans species of Candida.

Table 1
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Table 1

global satisfactory response in relationship to primary reason for requesting voriconazole therapy and category of immunosuppression in patients (modified intent-to-treat population) with refractory or intolerant-to-treatment fungal infections.

Table 2
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Table 2

global satisfactory response at the end of therapy and Kaplan-Meier estimate of the proportion of subjects alive 90 days after the initiation of voriconazole treatment in patients (modified intent-to-treat population) with refractory or intolerant-to-treatment fungal infections.

Aspergillosis. Most aspergillosis infections (107 [75%] of 142) had failed to respond to previous antifungal therapies; of the affected patients, 90% had received various AmB formulations, and 49% had received itraconazole. A satisfactory global response was reported for 62 (43.7%) of all 142 patients with aspergillosis (table 2), and, if examined for success by separate species, a similar response rate to treatment for infection occurred for the 4 major Aspergillus species (table 3). A higher satisfactory response was recorded for patients who were intolerant of other antifungals (51%) than for patients with refractory infections (41%; table 1). The Kaplan-Meier estimate of the proportion of patients alive at 90 days was 0.564 (95% CI, 0.481–0.648).

Table 3
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Table 3

Satisfactory global response at the end of therapy for patients with refractory and intolerant-to-treatment Candida or Aspergillus infections, by species.

Candidiasis. Most patients with candidiasis had refractory infections (75 [86%] of 87) and an overall treatment success rate of 55% (41 of 75 patients; table 2). The satisfactory global response rate for systemic, nonesophageal disease was 55% (27 of 49 patients), and it was slightly higher for esophageal candidiasis, at 61% (23 of 38 patients; table 2). Depending on the Candida species, satisfactory global response rates for patients with nonesophageal candidiasis ranged from 100% for cases involving Candida parapsilosis to 25% for cases involving Candida glabrata (table 4). The Kaplan-Meier estimate of the proportion of patients with candidiasis who were alive at 90 days was 0.724 (95% CI, 0.624–0.823; table 2).

Table 4
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Table 4

Susceptibility of main fungal species infecting patients with refractory or intolerant-to-treatment fungal infections (intent-to-treat population).

Other fungal infections. Satisfactory global responses were reported for patients with less-common fungi, including the following: fusariosis (5 [45%] of 11 patients), scedosporiosis (3 [30%] of 10 patients), cryptococcosis (7 [39%] of 18 patients), and penicilliosis (9 [90%] of 10 patients; table 2). Despite the <50% success rate for cryptococcosis and fusariosis, the survival estimates of patients alive at 90 days were 0.944 and 0.716, respectively (table 2). Of the 11 patients with cryptococcosis recorded to not have a satisfactory outcome, 10 had stable disease at EOT. All patients with disseminated penicilliosis and the majority of patients with cryptococcosis had AIDS as an underlying disease. The majority of patients with less-common infections had satisfactory global response (15 [65%] of 23 patients), and most were alive 90 days from the start of treatment (table 2).

Microbiological Findings

A total of 573 fungal isolates were obtained from 188 patients for identification and susceptibility testing, irrespective of whether they were the infecting strain. The isolates consisted of 296 yeasts from 6 genera and 277 molds from 24 genera. The 11 Candida species isolated constituted 94% of all yeasts; the 6 Aspergillus species constituted 54% of molds, followed by Scedosporium species (17%), Penicillium marneffei (12%), and Fusarium species (5%). Most Candida species (79%) were isolated from samples of or from the gastrointestinal tract, wounds, skin, and urine, but 13% were isolated from blood samples. Molds were isolated from lung via bronchoalveolar lavage (19%) or biopsy (18%). However, other biopsy specimens (including sinus, brain, bone, and cutaneous nodules) and blood samples yielded an additional 30% of mold isolates.

The susceptibility profiles of species with ⩾10 isolates to voriconazole, itraconazole, fluconazole, and AmB are shown in table 4. For voriconazole, itraconazole, and fluconazole, the MIC90s and MIC ranges for the Candida species are higher than those reported in the literature [22] and most likely reflect previous antifungal therapy that failed to clear the infection. However, the MIC90s for voriconazole generally remain lower than those for itraconazole and fluconazole.

Both voriconazole and itraconazole were more active than AmB against certain molds listed in table 4, with several Aspergillus fumigatus and Aspergillus terreus isolates, as well as most Scedosporium isolates with a high MIC to AmB. MIC ranges for molds with voriconazole and itraconazole are consistent with those in the literature [22]. When MICs of voriconazole for yeast and molds were grouped into high and low MICs by a cutoff point of 2 μg/mL, there was no apparent correlation between the MIC and clinical response.

Safety

All 372 patients were evaluated for safety. A total of 370 patients were receiving ⩾1 concomitant medication.

AEs. Treatment-related AEs occurred in 58% of patients, as determined by investigators. The majority of serious AEs (93%) and all deaths were related to the underlying disorder or documented fungal infection and not to voriconazole use. The most common treatment-related AEs were abnormal vision, rash, nausea, vomiting, headache, fever, and diarrhea (table 5). Thirteen (3.5%) of 372 patients discontinued the study because of treatment-related AEs; 19 patients (5%) discontinued therapy temporarily or reduced their dose as a result of treatment-related AEs. Eighteen patients (5%) discontinued therapy because of laboratory test abnormalities, but only 10 of these abnormalities were considered to be related to voriconazole treatment by the investigator. In 23 (88%) of 26 patients with preexisting renal dysfunction, renal function during treatment with voriconazole either improved or stabilized.

Table 5
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Table 5

Treatment-related adverse events reported in more than 2% of 372 patients with refractory or intolerant-to-treatment fungal infections (intent-to-treat population).

Visual AEs. Approximately 25% of patients reported visual AEs. The most common visual AEs were blurred vision and enhanced or altered visual perception. Seven patients experienced a serious visual event, 6 of whom had events that were related to an established diagnosis of an ocular infection. One patient discontinued therapy because of a visual AE of moderate severity; this AE resolved the day after discontinuation. No treatment-related visual AEs were associated with clinical changes in visual function test findings over time.

Laboratory safety tests. At least 1 new abnormal laboratory test result was seen in ∼80% of patients with normal laboratory values and in ∼65% of patients with abnormal laboratory values at baseline. Voriconazole was associated with elevations in liver function test values in both patients with normal baseline levels and those with abnormal baseline levels (table 6).

Table 6
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Table 6

Frequency of liver function test abnormalities in patients with refractory or intolerant-to-treatment fungal infections.

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Discussion

This study represents the first large-scale report of the efficacy, safety, and tolerability of voriconazole with a wide range of refractory and less-common fungal infections. The 66% survival rate at 90 days after the start of treatment and satisfactory global response of 50% overall constitute encouraging evidence of voriconazole's efficacy in this seriously ill population. The infections of ∼75% of these patients had failed to respond to previous standard antifungal treatments; 82% of the patients had received >14 days of previous therapy.

It is important to emphasize that this is a select group of patients who had infections with a high risk of failure to respond to treatment, and it is also important to place these results into historical perspective. For instance, lipid products of AmB and caspofungin performed with a 40%–50% treatment success rate for patients with refractory or drug-resistant aspergillosis [27, 28]. In the largest reported evaluation of treatment for refractory fungal infections, Walsh et al. [27] reported 556 patients treated with AmB lipid complex (ABLC) and found an overall response rate for ABLC of 57% (167 of 291 patients). In refractory aspergillosis, the overall success rate for ABLC was 42% (55 of 130 patients), compared with a rate of 44% (62 of 142) for voriconazole in this study, and compared with a previous report of voriconazole salvage therapy for aspergillosis, which reported success in 21 (38%) of 56 patients [1]. Among patients with candidiasis, ABLC-treated patients had a success rate of 71% (65 of 91), compared with a voriconazole success rate of 57.5% (50 of 87) in this study. One possible explanation for ABLC's higher success rate for candidiasis may be because patients with candiduria were included in other analysis but were excluded from this study.

The underlying condition or previous treatment exposure of the patient population substantially contributes to the clinical outcome for antifungal therapy. In this study, the impact of an underlying clinical condition and previous management was apparent. For instance, the etiology of immunosuppression that reflects the underlying disease can have a major impact on the clinical response. Patients with persistent neutropenia and an underlying malignancy had the worst prognosis, with a <50% success rate. Furthermore, clinical success was reduced in patients with infections refractory to antifungal agents (47%), compared with those receiving voriconazole for toxicity-related reasons (52%–78%). However, there was no apparent impact on outcome from previous azole therapy and, thus, no widespread clinical evidence from this study for cross-resistance to azoles.

Invasive aspergillosis is associated with significant morbidity and mortality, regardless of therapy received [29, 30]. Nevertheless, the satisfactory global response rate of 44% observed for aspergillosis compares favorably with published rates of 54% (for all patients) and 41% (for severely immunocompromised patients) for AmB followed by itraconazole [31]. These success rates are also similar to those observed in refractory cases of aspergillosis treated with caspofungin (41%) [28]. In fact, the voriconazole success rate in patients with refractory disease approaches the overall success rate of voriconazole for primary therapy of aspergillosis treatment (53%) and is better than primary therapy with AmB [8]. The Kaplan-Meier 90-day estimate of proportion of surviving patients seen here of 0.56 overall (0.33 for disseminated aspergillosis and 0.28 for cerebral aspergillosis) exceeds the recently published crude case fatality rates for invasive aspergillosis: 58%–62% of patients overall and 88% for patients with cerebral or disseminated aspergillosis [30, 32].

Fungal infections caused by Candida species are major causes of mortality and morbidity associated with chemotherapy-induced myelosuppression [33], solid-organ transplantation [34], receipt of a BMT [35], and neutropenia [7]. With voriconazole, the overall proportion of patients with candidiasis who were alive at 90 days was ∼3 of 4. The rate of success for voriconazole (60%) was lower in patients with refractory esophageal candidiasis (i.e., infections that failed to respond to fluconazole and/or AmB therapy) than was reported in a recent comparative study on primary treatment of esophageal candidiasis with fluconazole and voriconazole (∼90% success) [5].

Most instances of voriconazole treatment failure occurred after several months of prolonged immunosuppression. Clinical success of voriconazole for treatment of refractory candidemia was 52%, which is lower than the success for primary treatment of candidemia when AmB (79%) or fluconazole (70%) is used [36]. Patients with invasive nonesophageal candidiasis in the present study had a satisfactory response of ∼55%; this compares with published success rates for ABLC of 67% for patients with disseminated candidiasis whose infections are refractory to treatment [27]. With regard to Candida species, the numbers are too low to make definitive statements about each species, but success rates were lower for C. glabrata candidiasis than for C. parapsilosis candidiasis. It is likely that, in cases of refractory invasive candidiasis, voriconazole therapy will have a positive impact in at least one-half of cases.

The rates of satisfactory global response for less-common mycoses include 45% for fusariosis, 30% for scedosporiosis, and 90% for penicilliosis. Treatment of emerging invasive fungal infections is a particular challenge, with no standardized treatment regimen and high mortality rates. The 90-day Kaplan-Meier estimate of proportional survival of 0.71 and the satisfactory global response (45%) for patients with fusariosis is noteworthy, given its known resistance to AmB and given the published high mortality rate for disseminated fusariosis treated with other therapies (72%) [37]. However, recovery from neutropenia is essential for a positive clinical response and will have a major impact on all therapeutic outcomes. For voriconazole, the satisfactory global response rate of 30% and 90-day estimate of proportional survival of 0.3 for patients with scedosporiosis is encouraging: published mortality rates are 80%–100%, and AmB activity against this genus is poor [38, 39]. There is probably a species difference in treatment outcome with voriconazole.

In this study, Scedosporium apiospermum infections were successfully treated in 2 of 6 patients, compared with 1 of 4 patients with Scedosporium prolificans, but in vitro activity between the 2 species with voriconazole demonstrates increased susceptibility against S. apiospermum, compared with current azoles, but reduced susceptibility against S. prolificans [21, 22]. Clinical experience with 34 cases of scedosporiosis showed a more favorable response to voriconazole treatment of S. apiospermum infection, with success in 17 (63%) of 27 patients, compared with S. prolificans infection, with success in 2 (29%) of 7 patients [17]. The failures of treatment in children with scedosporiosis occurred primarily in those with S. prolificans infection [3].

The high response rate of penicilliosis to voriconazole (90%) suggests that voriconazole might be used for other refractory or less-common dimorphic fungal infections. Three of 5 cases of histoplasmosis, blastomycosis, and coccidioidomycosis responded to treatment, but the numbers are too low to make a definitive statement about the value of voriconazole for these specific dimorphic fungi.

There were 5 cases of classic phaeohyphomycosis (i.e., phaeohyphomycosis due to Alternaria, Bipolaris, and Exophiala species), and all infections were successfully treated with voriconazole. Although these infections are uncommon and generally require surgical management as part of the therapeutic strategy, both in vitro experience with large numbers of isolates [22] and the positive results in this study suggest that voriconazole may have a significant role in the management of phaeohyphomycosis. On the other hand, in infections with Paecilomyces species, a hyalohyphomycete, only 1 of 3 patients responded successfully to therapy.

Among all sites of fungal infection, patients with cerebral aspergillosis have the poorest treatment response rate (8%) [31]—and, correspondingly, the highest case fatality rate (88%) [30]. With regard to voriconazole, 12 patients treated for cerebral aspergillosis had a 90-day estimate of survival proportion of 0.27; 3 of 12 survived, with global success responses after treatment of 119–154 days. There are additional reports of successful voriconazole treatment for cerebral aspergillosis and scedosporiosis [1, 3, 10, 12, 18, 30, 40]. Collectively, these reports represent positive clinical experiences for the use of voriconazole in cerebral fungal mold infections. This is an important observation, because AmB formulations, itraconazole, fluconazole, and ketoconazole have a very poor track record for treatment of cerebral mold infections.

This study suggests a relatively poor response for voriconazole treatment of refractory cryptococcal meningitis, with a <39% success rate. However, most patients had stable disease as judged by stable serological values; thus, treatment was not considered to be successful. In fact, >90% of patients were still alive at the 90-day follow-up. Similarly, in a study of infection that was refractory to ABLC treatment, a low rate of success was reported for treatment of refractory cryptococcal meningitis, with only a 50% response rate [27]. With excellent in vitro voriconazole activity against Cryptococcus neoformans isolates, the drug's known penetration of human CSF (Pfizer; data on file), and the clinical activity against several life-threatening cerebral mold infections, voriconazole could become a useful drug for the management of some refractory cases of cryptococcal meningitis.

The safety data for voriconazole in this study are consistent with data from previous clinical reports of voriconazole and confirm its satisfactory tolerability in these critically ill and diverse patient groups. Voriconazole can effectively be used for patients with nephrotoxicity issues. Drug interactions may occur, and almost all of these patients were receiving other medications. Treatment-related toxicities, such as visual effects and rash, caused therapy to be suspended for 3.5% of patients, but none of the toxicities were severe. Concern about voriconazole-associated hepatotoxicity has been recently raised [41]. Liver function test abnormalities were noted in >10% of patients, but only 9 (2.4%) of 372 patients had their treatment discontinued as a result of abnormal liver test values. There have been some suggestions that liver function abnormalities correlated with plasma levels of voriconazole, but threshold levels for toxicity are uncertain [1, 42]. Voriconazole levels were not analyzed for this study. From this study, we have learned that voriconazole-associated toxicity rarely develops into a serious AE if the patient is closely monitored, even in this complex population.

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Study Group Members

We thank the investigators who participated in the study, who include the following: Australia: S. Chen and L. Dalla Pozza; Austria: W. Graninger; Belgium: M. Aou, S. de Wit, F. Jabobs, J. Maertens, and H. Spapen; Denmark: J. Gerstoft and L. R. Mathiesen; France: D. Caillot, A. Datry, C. Faucher, S. Fournier, P. Germaud, R. Herbrecht, T. Lamy, S. Lariven, H. La Selve, N. Milpied, J. J. Quoit, and F. Varaigne; Germany: C. Aul, H. Bertz, H. Breithaupt, H. R. Brodt, G. Fatkenheuer, E. Holler, P. Kujath, W. Langer, D. H. Lode, H. Ruckle-Lanz, M. Ruhnke, R. Schwerdtfeger, E. Thiel, W. Wandt, and A. Zander; Hungary: M. Egyed, A. Kiss, K. Pecze, J. Sinko, and G. Varga; Italy: A. del Favero and C. Viscoli; Spain: K. Aguirrebengoa, C. S. Cepeda, J. de la Torre Cisneros, J. J. Lahuerta Palacios, and M. Rovira; Switzerland: J. Garbino and U. Fluckiger; United Kingdom: D. Denning, A. Goldstone, and R. Hay; Canada: Eric Bow, Peter Phillips, Stephen Shafran, and Christos Tsoukas; Thailand: Khuanchai Supparatpinyo; and United States: Rodney Adam, Roblee Allen, Elias Anaissie, Timothy Babinchak, Frank Beardell, Kerry Blanchard, Janice Brown, Karin Byers, Pranatharthi Chandrasekar, Lawrence Corey, Jennifer Daly, Mark Dayton, J. Stephen Dummer, Kenneth Earhart, Robert Finberg, Phyllis Flomenberg, Kamar Godder, Donald Graham, John Graybill, Susan Hadley, Patricia Hibberd, Susan Jacobson, John Jernigen, Adolf Karchmer, Princy Kumar, Arnold Louie, Dennis Maki, Richard McDonnel, Michael Miller, Donald Murphey, David Mushatt, George Pankey, John Pottage Jr., John Powers III, L. W. Preston Church, John Pullman, Issam Raad, Kristin Razzeca, John Reinhardt, Bruce Ribner, Leland Rickman, Robert Rubin, William Scheld, John Segreti, Bryan Simmons, Marcia Sokol-Anderson, Pablo Tebas, Ellis Tobin, Jo-Anne Van Burik, Wheaton Williams, and Saul Yanovich.

  • Received September 13, 2002.
  • Accepted January 10, 2003.
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  1. Clin Infect Dis. (2003) 36 (9): 1122-1131. doi: 10.1086/374557
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