Nineteen patients were refractory to their therapy, and five were intolerant (all related to worsening renal function). Patient ages ranged from 7 years to 74 years, with a mean age of 46.8 years. Nineteen of 24 subjects were males (79%). The most common site of infection was rhinocerebral, documented in 11 cases (46%). There were four subjects with disseminated infections (rhinocerebral and lung; rhinocerebral, brain, lung, and skeletal muscle; brain and lung; and endocarditis with septic emboli.). Others had infection of the skin, bone, lung, trachea, or abdomen (Table ).
Summary of 24 subjects treated with posaconazole (POS) for zygomycosis
Subjects had a wide range of underlying risk factors for zygomycosis infection (Table ). Eleven subjects had undergone HSCTs, which included bone marrow transplants (BMTs), and four others had diabetes mellitus without ketoacidosis. Six subjects with allogeneic HSCT had rhinocerebral infection, two had disseminated infection, and one subject each had lung, skin, or gastrointestinal infection. Three of the four subjects with diabetes mellitus as their main risk factor had rhinocerebral infections, while one patient had infection of the neck and trachea. Four others had solid-organ transplants, and their sites of infection were gastrointestinal, skin and underlying bone, rhinocerebral, and pericardial infections. One subject with red blood cell aplasia had infection of the heart. Other risk factors and sites of infection included acute myelogenous leukemia (AML) (rhinocerebral), acute lymphocytic leukemia (skin), NK-cell leukemia (lung), and non-Hodgkin lymphoma (disseminated).
Prior antifungal drug exposure.
Nine of 24 (38%) subjects received antifungal prophylaxis before the diagnosis of zygomycosis, including fluconazole (FLC), voriconazole (VRC), and itraconazole (ITC). Antifungal treatment that was administered before posaconazole was started included amphotericin B (AMB) in standard or lipid formulations (liposomal AMB [LAM] or AMB lipid complex [ABLC]), VRC, ITC, FLC, and caspofungin (CAS). At time of enrollment, patients were receiving LAM (12 patients); AMB (5 patients); ABLC (2 patients); ABLC and CAS (2 patients); LAM, CAS, and ITC (1 patient); ITC (1 patient); and VRC (1 patient).
Duration of posaconazole treatment.
Posaconazole was administered for an average of 292 days (range of 8 to 1,004 days) in this series of 24 subjects. The median duration of treatment was 182 days. Sixteen subjects (66%) continued posaconazole treatment for over 100 days, and one patient took the drug for 1,004 days. Random serum troughs from seven subjects enrolled in the protocols were assayed for their concentrations of posaconazole after more than 14 days of 800 mg/day posaconazole, and levels ranged from 0.309 μg/ml to 2.990 μg/ml. The mean ± standard error of the mean for the trough levels was 1.139 ± 0.341 μg/ml.
Table lists the results of posaconazole treatment for individual subjects. The table includes information on timing of surgery in relation to starting posaconazole. Subjects were included in these salvage protocols because they had zygomycosis refractory to therapy (n = 19) or were intolerant of standard therapy (n = 5). Overall, 19 (79%) of 24 patients had a complete (11 patients) or partial (8 patients) response. Complete or partial response was seen in 79% of those subjects enrolled due to refractory zygomycosis and in 80% of those enrolled due to intolerance to standard antifungal therapy. Subjects with underlying risk factors that included long-term immunosuppression, such as hematological malignancies with allogeneic HSCT, and subjects with solid-organ transplants also had high rates of complete or partial response (73% and 100%, respectively). Four of 5 subjects who switched from amphotericin B to posaconazole and 14 of 17 who switched from a lipid formulation of amphotericin B to posaconazole (11 of 13 from liposomal amphotericin B and 3 of 4 from amphotericin B lipid complex) experienced either a complete or partial response.
For the 19 of 24 patients (79%) who did not fail, the underlying illness did not worsen and in most instances improved or resolved. Most investigators reported that improvement was evident within 2 weeks of initiating posaconazole. Failure was associated with progression of underlying illness and no more than 31 days of posaconazole. Four of the five failures are known to have died from zygomycosis.
Nine of 24 subjects died during the study. Two died from persistent zygomycosis when treatment was withdrawn at the request of the individual or legally appointed guardian (after 8 and 14 days of posaconazole therapy), and two died of persistent zygomycosis after 29 and 31 days of posaconazole therapy. Four subjects died from their underlying illnesses after initially improving during posaconazole treatment; they had received posaconazole for 37, 198, 245, and 352 days. One subject died on day 148 from aspiration pneumonia; this individual had been diagnosed with fungal lesions in the brain as part of disseminated zygomycosis. The brain lesions did not progress while taking posaconazole. This subject was considered a partial response.
Kaplan-Meier plots of survival in the 24 subjects analyzed are provided in Fig. for each of the three time-dependent events of interest. Most of the events occurred within 90 days after beginning therapy. The 90-day survival rates were 94.7% (± 5.1%) for survival from underlying disease, 82.8% (± 7.8%) for survival from zygomycosis, and 78.4% (± 8.6%) for survival from all causes of death. After 90 days, no further deaths were due to zygomycosis, but deaths due to underlying diseases continued to occur.
FIG. 1. Kaplan-Meier survival curves for underlying disease, zygomycosis infection, and actuarial disease (all 24 subjects). Crosses indicate deaths or end of treatment with posaconazole. The solid line represents percent survival from underlying disease; it (more ...)
Of the 18 individuals who underwent surgical debridement, 15 had residual disease at the start of posaconazole therapy. Only 2 (13%) of these 15 patients had a failed outcome, compared to 3 of 6 (50%) having no surgery (P = 0.11 by Fisher's exact test). Surgery (n = 18) was marginally significantly associated with a reduced risk of experiencing a failed outcome (odds ratio, 0.12; 95% confidence interval, 0.01 to 1.10). Surgery was marginally significantly associated with a protective effect for the hazard of dying from underlying disease (P = 0.058; hazard rate, 0.17; 95% confidence interval, 0.03 to 1.07). That is, a subject was 5.7 times more likely to survive the underlying disease if he or she had surgery. Surgery was significantly associated with better overall survival (P = 0.02; hazard rate, 0.21; 95% confidence interval, 0.06 to 0.78).
Three of the 4 (75%) subjects with a disseminated infection had a failed outcome, compared to 2 of 20 (10%) subjects without a disseminated infection (P = 0.0018 by Fisher's exact test). Hence, a subject with a disseminated infection was 27 times more likely to have a failed outcome (95% confidence interval for the odds ratio, 1.8 to 399.2). Having disseminated disease was significantly associated with a reduced chance of overall survival (P = 0.0018; hazard rate, 28.56; 95% confidence interval, 3.49 to 233.88). No other risk factors were significantly associated with overall survival or outcome.
Zygomycetes were isolated in culture from 17 of 24 (71%) subjects and were Rhizopus spp. (n = 6), Mucor spp. (n = 6), Cunninghamella spp. (n = 3), and Rhizomucor spp. (n = 2). Five of six Rhizopus sp. isolates, five of six Mucor sp. isolates, one of three Cunninghamella sp. isolates, and one of two Rhizomucor sp. isolates were associated with either complete or partial responses. The MIC for one Cunninghamella sp. isolate (patient 9, failure) was 1 μg/ml, and the MIC for one Rhizopus sp. isolate (patient 12, complete response) was 4 μg/ml. Data from the other isolates are not available. Also, to date, there are no interpretive guidelines for these data.
One subject (patient 5) with a brain lesion at enrollment gradually lost visual acuity after 1 month of treatment. No definitive cause was identified, and the investigator rated the event as probably not related to the posaconazole. The individual continued to improve otherwise and remained on therapy with posaconazole for a total of 148 days. One subject, who was treated with posaconazole for 157 days, developed a non-life-threatening purpuric rash over the face and shoulders. The rash was first noticed towards the end of therapy and resolved shortly after posaconazole was discontinued (subject 17). In general, the oral suspension was well tolerated and no subject discontinued therapy due to the taste of the medication.