Introduction

The zygomycoses are non-Aspergillus mold infections and are important causes of morbidity and mortality among immunocompromised persons. These infections, also known as Mucormycosis, are caused by ubiquitous saprophytes that have little intrinsic pathogenicity in normal hosts. However, among immunocompromised individuals they are important causes of fungal infections. Although only 929 reports of zygmoycosis have been described in the past seven decades and the incidence is currently unknown, an alarming increase in the number of case reports of zygomycosis has been noted in patients with cancer, with or without hematopoietic stem cell transplantation (HSCT) over the past decades.¹ One proposed predisposing factor is widespread use of voriconazole, a new anti-fungal agent, when used for treatment or prophylaxis against Aspergillosis infection among immunocompromised patients with hematologic malignancies, or following HSCT procedures.^{2, 3, 4, 5, 6} Conversely, some have explained that the association is not causative, but rather a reflection of changes in host immune constitution, or days at risk on immunosuppressive drugs. Voriconazole is a triazole anti-fungal effective against Aspergillus species, but without appreciable activity against the Zygomycetes.⁷ Herein, investigators affiliated with the Research on Adverse Drug events And Reports (RADAR) project reviewed clinical information on 58 cancer patients who developed zygomycosis following voriconazole use.⁸

Methods

RADAR personnel contacted physicians and pharmacists from the departments of infectious disease or hematology/oncology at comprehensive medical centers throughout the US, requesting clinical information on cases of zygomycosis after exposure to voriconazole, using a standard case report form. In addition, several case reports from the medical literature that had sufficient information to complete the case report form were included. Case reports from 13 major cancer centers were used in this collaborative project. Patient data were obtained from medical records, and identification of voriconazole users (de-identified) was collected from pharmacy database. Investigators from comprehensive medical centers provided information for all patients treated at their institutions from 2002 to 2005 who were diagnosed with zygomycosis and who had prior exposure to voriconazole. The case definition included use of voriconazole for a minimum of 5 days, clinical diagnosis of zygomycosis with confirmation by either tissue or cytology, according to EORTC/MSG criteria.⁹ Cases were identified from review of microbiology laboratory records, autopsy reports or histopathology specimens. Medical records were reviewed for information on patient demographics, cancer diagnosis and disease status at the time of zygomycosis diagnosis, use of bone marrow or peripheral blood stem cells for transplantation, neutropenia, graft-versus-host disease (GVHD), diabetes mellitus, previous anti-fungal use and indication (prophylaxis or empirical, preemptive or targeted anti-fungal therapy), fungal infection site, source of culture material used for diagnostic confirmation, treatments and outcome (survival versus death); for patients who died, medical investigators also reported whether zygomycosis was the attributable cause of death. Mortality was assessed at the time of failure or success from anti-fungal therapy for zygomycosis. Statistical analysis was conducted using Fisher's exact test for discrete data, and optimal discriminant analysis for ordered data.¹⁰ This study was approved by the Institutional Review Board.

Results

Results of 58 patients who received care at 13 cancer centers for zygomycosis after exposure to voriconazole are present in Table 1. Seventy percent of these patients had diagnostic tissue confirmation of zygomycosis. The mean patient age was 44 years (range=3–72 years) and 67% were male. Hematologic malignancies, primarily acute leukemia, were the underlying cancer diagnosis for 56 of the patients. Two thirds of the patients had been recipients of HSCT, half having received stem cells from related donors. Among patients with hematologic malignancies who did not receive HSCTs, treatments included immunosuppressive agents such as denileukin diftitox (Ontak) (n=1), alemtuzumab (n=1), anti-thymocyte globulin (n=2) and fludarabine (n=1). Voriconazole had been administered for at least 7 days as primary or secondary fungal prophylaxis for 92% of the patients and as empiric treatment for suspected Aspergillus infection for the remaining 8%. Voriconazole had been administered for a mean of 80 days before zygomycosis diagnosis (median=50: range=6–700 days). Primary infection sites included the lungs (62%) or sinuses (20%). Among zygomycosis patients who had received HSCTs, the fungal infection diagnosis occurred at a mean of 150 days (median=98: range=11–925 days) after the transplantation procedure, with similar numbers of patients having experienced acute (n=11) versus chronic (n=10) GVHD. Almost all GVHD patients received corticosteroids, with several of these individuals subsequently developing diabetes mellitus. Clinical grading of GVH was not consistently reported in the case studies. More than half of the patients had concomitant infections.

Table 1 - Clinical findings for 58 patients with voriconazole-associated zygomycoses.

Full table

Over 80% of the patients received a lipid formulation of amphotericin B (see Table 2) as monotherapy (56%) or as part of combination therapy (29%). In addition, 31% received voriconazole (4% as monotherapy and 27% in combination therapy), 18% received caspofungin (all in combination therapy), and 11% received posaconazole (9% as monotherapy and 2% in combination therapy). Surgical debridement was performed most commonly among persons with sinus infections, but did not have higher overall survival rates than patients who did not have surgery (P<0.09).

Table 2 - Treatment outcomes for the 45 patients with voriconazole-associated zygomycosis.

Full table

The overall mortality rate was 73%. Of note, the treating physician attributed all deaths to zygomycosis. There was a non-significant trend (P<0.077), indicating a greater percentage of fatalities among patients treated with amphotericin B alone (20/25, or 80%), versus those patients treated with amphotericin B and caspofungin +/- voriconazole (3/7, or 43%). The heterogeneity and number of different types of conditioning regimens used for recipients of HSCT and intensive chemotherapy used for hematology patients in this case report series precluded any meaningful analysis of the relationship between chemotherapy regimen and the risk for developing zygomycosis. Patients who had received fewer than 21 days of voriconazole had the lowest mortality rate (33%). Patients who survived zygomycosis received a median of 28 days of voriconazole whereas non-survivors received a median of 90 days of voriconazole (P<0.26).

Discussion

Zygomycosis associated with extended use of voriconazole, a third generation triazole anti-fungal drug, is a recently recognized clinical entity. Although the illness was originally described in case reports from cancer centers that treat large numbers of patients with acute leukemia or that perform large numbers of allogeneic SCT procedures, this report provides information on 58 cases of zygomycosis with prior exposure to voriconazole, representing the largest cohort with this diagnosis described to date. Overall, >70% of these individuals died from the infection. In interpreting our findings, two factors should be considered. First, the high mortality rate of zygomycosis with prior exposure to voriconazole is similar to that reported for zygomycosis among patients who have not received voriconazole.¹¹ Delayed diagnosis among immunocompromised cancer patients with non-specific clinical findings, such as dyspnea, fever and pulmonary infiltrates and difficulty in surgically excising pulmonary lesions contribute to the generally poor outcomes for individuals with this infection. Even though there are no randomized prospective trials that have proven the efficacy of combination therapy over monotherapy for the treatment of invasive fungal infections, based on single institution case series many transplant centers use combination anti-fungal therapies when treating fungal infections, with the goal of achieving therapeutic synergies. In this study, although several different anti-fungal drug combinations were administered, with a lipid formulation of amphotericin B being the most commonly used single agent, the outcome was poor with each of the regimens. We observed that patients who used caspofungin in conjunction with amphotericin B did better overall compared to patients who did not receive this combination, and although the small number of patients treated with combination therapy is small, our study supports other in vivo data recently reported.¹² It should be noted that the first report of cancer patients with zygomycosis infection who were treated with the investigational triazole, posaconazole, described a 70% survival rate among 24 cancer patients with this diagnosis.¹³ Several of these individuals had developed zygomycosis after receiving voriconazole for prophylaxis against aspergillosis infection. Recently, a retrospective study of 91 patients treated with posaconazole for zygomycosis, reported encouraging data (complete and partial response rate=60%; stable disease=20% at 12 weeks) as an alternative to current therapy.¹⁴ Likewise, the results of in vitro activity for itraconazole against zygomycetes suggest that this drug may be a good candidate for future clinical trials.¹⁵

Second, breakthrough fungal infections have been described previously among immunocompromised patients who have received other anti-fungal agents, including the azole drugs fluconazole or itraconazole. Selective pressure for resistant organisms may result from inoculation from an environmental source, sub-optimal anti-fungal dosing, or from prolonged use of anti-fungal agents.^{16, 17, 18} Persons with hematologic malignancies who receive an allogeneic HSCT often receive immunosuppressants for GVHD for two to three months or longer, with concomitant anti-fungal prophylaxis during this time-period. In this study, the mean duration of voriconazole exposure, most commonly prescribed for prophylaxis, was 80 days. Interestingly, and probably for multi-factorial reasons not clearly understood, including time to diagnosis and immunosuppression, we observed that the group of patients with the lowest mortality from zygomycosis were those that had received voriconazole for <21days, suggesting that prolonged treatment (without proven benefit) may be associated with higher mortality. Our findings highlight the potential adverse effects associated with use of new anti-fungal agents for prophylaxis against fungal infections. Previously, when immunocompromised individuals developed invasive fungal infections, the causative pathogens were Aspergillus or other voriconazole susceptible organisms. Not surprisingly, cases of voriconazole-resistant invasive fungal infections are beginning to be reported from these centers. Although 2 single institution studies have reported excellent results in the prevention of Aspergillus infections in recipients of HSCT with voriconazole prophylaxis, clinicians should be aware of the possibility of breakthrough fungal infections that are not sensitive to voriconazole or other azole anti-fungals.^{19, 20} Vigilance is needed when voriconazole is used for prophylaxis pending the final results of a multi-center phase III randomized trial evaluating the use of voriconazole as prophylaxis. Our study has several limitations. The small sample size limits our ability to identify factors associated with better chances of surviving the infection. Another limitation is that clinical information was collected retrospectively, thus limiting our ability to assess attributable versus crude mortality. Diagnostic uncertainty is an important consideration. More than 90% of the cases occurred when voriconazole was administered as primary or secondary fungal prophylaxis, thus limiting the likelihood of diagnostic confounding from breakthrough infections that occur with prior exposure. Finally, a significant number of patients in this series received caspofungin, a drug without activity against zygomycetes and also reported to be associated with breakthrough fungal infections.²¹

In conclusion, zygomycosis after exposure to voriconazole is an emerging clinical entity with a mortality rate of 73% in this case series of patients with hematologic malignancies. Until the results of a randomized trial are available, the routine administration of anti-fungal agents for non-approved indications must not be done indiscriminately. When voriconazole-treated immunocompromised patients present with signs and symptoms of invasive fungal infections, clinicians should obtain a tissue diagnosis to confirm the etiologic organism and evaluate in vitro sensitivities to anti-fungal agents, consider empirical use of a zygomycosis active agent, such as posaconazole of amphotericin B, and evaluate if surgical debridement is possible. Finally, new anti-fungals with activity against zygomycosis and improved non-culture-based diagnosis are urgently needed in order to identify and combat the wide range of serious opportunistic mycosis infections that occur among immunocompromised patients.

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