J Infect Chemother (2003) 9:40–45 DOI 10.1007/s10156-002-0207-5
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2003
ORIGINAL ARTICLE Kürs¸at Kaptan · Ali Ug˘ ur Ural · Türker Çetin · Ferit Avcu Cengiz Beyan · Atilla Yalçin
Itraconazole is not effective for the prophylaxis of fungal infections in patients with neutropenia
Received: March 25, 2002 / Accepted: October 1, 2002
Abstract Fungal infections are a major problem among patients with hematological malignancies. To evaluate the efficacy of itraconazole (200 mg twice daily) in the prophylaxis of fungal infections in neutropenic patients, we conducted a prospective trial. A total of 61 patients with acute leukemia (113 cytotoxic chemotherapy episodes) were enrolled in the study. One patient in the itraconazole group was excluded because itraconazole was not taken due to gastrointestinal hemorrhage. Because the duration of neutropenia (neutrophil count, ⬍0.5 ⫻ 109/l) did not reach 7 days, 3 (1 patient) and 13 (4 patients) cytotoxic chemotherapy episodes in the itraconazole and control groups, respectively, were excluded. After these exclusions, the study population consisted of 31 patients (54 cytotoxic chemotherapy episodes) who had taken itraconazole and 24 patients (43 cytotoxic chemotherapy episodes) who had not taken itraconazole. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (absolute neutrophil count, ⬎1 ⫻ 109/l) unless a systemic fungal infection was documented or suspected. Thirteen episodes (24%) in the itraconazole group and 7 episodes (16%) in the control group proceeded to intravenous amphotericin B (P ⬎ 0.05). Fungal infections occurred in 9 episodes (17%) in the itraconazole group and in 5 episodes (12%) in the control group (P ⬎ 0.05). Overall mortality was five deaths in the itraconazole group and two in the control group. These deaths were not due to clinically documented fungal infection. In our study, efficacy of itraconazole in the prophylaxis of fungal infections in neutropenic patients was not detected.
Key words Acute leukemia · Itraconazole · Fungal infections · Antifungal prophylaxis
Introduction Among neutropenic patients with a hematological malignancy, infections remain a major problem, and fungal infections are an important cause of morbidity and mortality.1,2 There is a high mortality rate with these infections, because of the difficulty of successful treatment and diagnosis, and antifungal prophylaxis may be useful to reduce these fungal infections. For these reasons, several drugs have been evaluated. Intranasal administration of amphotericin B did not show a significant benefit over placebo as prophylaxis against aspergillosis.3 Moreover, prophylactic treatment with liposomal formulations is limited by their high cost. Fluconazole has been studied extensively and has only been shown to significantly reduce superficial and hematogenous candidiasis and mortality in bone-marrow transplant patients.4–6 However, fluconazole offers no protection against Aspergillus spp., and several pathogenic Candida spp. are resistant (C. krusei) or show low sensitivity (C. glabrata) to this compound.6–9 Itraconazole is a triazole compound with activity against a wide range of yeasts and filamentous fungi, including Candida and Aspergillus spp.10,11 For this reason, the current trial was set up to establish the potential role of itraconazole prophylaxis in preventing fungal infections in patients admitted with acute leukemia and treated with standard or high-dose chemotherapy.
Patients and methods K. Kaptan (*) · A.U. Ural · T. Çetin · F. Avcu · C. Beyan · A. Yalçin Department of Hematology, Gülhane Military Medical Academy, School of Medicine, 06018 Etlik, Ankara, Turkey Tel. ⫹90-312-3231072; Fax ⫹90-312-3227780 e-mail:
[email protected]
Patients eligible for the study were adult patients who were hospitalized at our center and who had acute leukemia and were to undergo remission-induction, reinduction, or postremission consolidation chemotherapy to induce neu-
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tropenia (neutrophil count, ⬍0.5 ⫻ 109/l) with a duration of at least 7 days. Patients were excluded if they were known to have hypersensitivity to triazoles, if they had been treated with antifungal agents in the previous 15 days, if there was overt infection or evidence of preexisting fungal infection, or if they had hepatic or renal dysfunction. Patients who received supportive care or low-dose palliative chemotherapy only were not eligible. Therefore, we were able to present an unselected case series. Patients were nursed in conventional single or double rooms that were not equipped with air filtration facilities. Granulocyte colony stimulating factor (G-CSF) was given according to the clinical indications. A three-lumen subclavian intravenous catheter was inserted in each patient. All patients were clinically evaluated at baseline, and were subsequently examined daily for clinical signs of fungal infection for the duration of study, and twice weekly after the prophylactic regimen was stopped. Standard biochemical tests were performed. Removed catheters were examined for the presence of yeast or molds in as the fungal trial end point. Surveillance cultures were taken from mouth, nose, and anus at baseline and weekly thereafter. Fungal colonization was defined by the presence of fungi in a surveillance culture and no clinical sign or symptom of infection at that site. The control group fulfilled the inclusion criteria but did not take itraconazole. Patients were randomized blindly to the itraconazole or the control group. After informed consent was obtained, prophylaxis was started on the first day of chemotherapy. Itraconazole (100-mg capsule; Janssen-Cilag, Johnson-Johnson, Istanbul, Turkey) was administered at a dose of 200 mg twice daily with a meal and a Cola beverage. All subjects ingested the same meals, as far as was possible. Itraconazole was not given together with compounds that reduce gastric acid secretion; such drugs were administered at least 2 h after the intake of itraconazole. None of the patients were taking any other prophylactic drug. The prophylaxis was discontinued in the following situations: bone marrow recovery, defined as an absolute neutrophil count of more than 1 ⫻ 109/l for 3 consecutive days; initiation of empirical antifungal therapy; documentation of any fungal infection, either superficial or systemic; or occurrence of adverse side effect(s) related to the study drug. When the axillary temperature was above 38.5°C, or when infection was suspected, samples for microbiological cultures, including at least two separate blood specimens, were obtained, one of which was withdrawn through the intravenous catheter. Treatment with cefepime and amikacin, given intravenously, was started. If fever persisted, vancomycin, given intravenously, was added after 72 h. Empirical treatment with amphotericin was added to the combination if fever persisted for another 72 h. At the beginning of the intravenous antibiotic treatment, and every 3 days thereafter, chest and sinus X-rays were obtained and other relevant investigations were performed for the duration of the febrile period. Blood cultures were drawn every third day and whenever the axillary temperature rose above 38.5°C.
Definition of fungal infection Superficial fungal infection A superficial fungal infection was defined as a clinically apparent infection of the oropharynx, esophagus, or skin, along with positive mycology at the site of infection. Suspected deep fungal infection Suspected deep fungal infections were defined as clinical signs and symptoms (with or without radiological lesions) with fever of unknown origin (FUO) unresponsive to broad-spectrum antibacterials, or any relapsing fever after initial response to antibiotics for which empirical intravenous amphotericin B was started, highly suggestive radiological lesions (X-ray or computed tomography [CT] scan) for deep fungal infection without mycological evidence by culture or histology (e.g., hepatosplenic candidiasis and some types of pulmonary aspergillosis), or clinical signs or symptoms (with or without radiological lesions) not highly suggestive of fungal infection, but associated with suggestive fungal isolation (e.g., from sputum or nasal cavities for aspergillosis). Proven deep fungal infection Proven deep fungal infection was defined as one in which there was both clinical evidence of blood or tissue infection and a culture or biopsy specimen from the involved site demonstrating a pathogenic fungal organism. For Candida septicemia to be diagnosed, two separate positive blood cultures were required. A fever that required empiric treatment with intravenous amphotericin B after at least 72 h of treatment with broadspectrum antibiotics without clinical signs and symptoms was defined as fever of unknown origin (FUO). To compare the efficacy and tolerance to itraconazole, the following variables were measured: proven deep fungal infection, suspected deep fungal infection, superficial fungal infection, compliance, treatment interruption caused by side effects, and mortality. Compliance Compliance was monitored by the attending nurses. It was deemed excellent if the patient took all doses of the study drug, good if a patient missed fewer than 20% of the total number of doses, and poor if the patient missed more. Side effects Side effects were monitored clinically on the daily rounds by staff asking about nausea and vomiting related to the administration of itraconazole, and by looking for rashes. Serum electrolyte analyses and tests for liver and renal function were done three times weekly.
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Statistical analysis The statistical analysis was performed with Minitab Statistical Software Rel 13.0 (Minitab, State College, PA, USA). Data values are given as medians (ranges). Comparisons were made with Fisher’s exact test, the-χ2 test, and Student’s t-test where appropriate.
Results The study was done between September 1999 and November 2000. The clinical characteristics of the patients evaluated during the study are shown in Table 1. A total of 61 patients (113 cytotoxic chemotherapy episodes) were enrolled in the study. One patient randomized to the itraconazole group was excluded, because itraconazole had not been taken due to gastrointestinal hemorrhage. Three cytotoxic chemotherapy episodes in the itraconazole group and 13 cytotoxic chemotherapy episodes in the control group were excluded because the duration of neutropenia (⬍0.5 ⫻ 109/l) did not reach 7 days. For the same reason, 1 patient in the itraconazole group and 4 patients in the control group were excluded. After these exclusions, of the 55 evaluable patients (97 cytotoxic chemotherapy episodes), 31 patients (54 cytotoxic chemotherapy episodes) received itraconazole and 24 patients (43 cytotoxic chemotherapy episodes) did not take itraconazole (controls). Both patient groups received a median of one (range, 1–4) course of cytotoxic chemotherapy during the study period (P ⫽ 0.06). In 2 (4%) of the 54 treatment cycles during this study, itraconazole was not given due to gastric irritation and cardiac arrhythmia. There were no significant differences between the two groups with regard to age, sex, underlying diseases, use of central venous catheters, median duration and severity of
neutropenia, nasal colonization by Aspergillus species, and number of patients with Candida species at baseline and after the prophylaxis (Table 1). In the itraconazole group, the ratio of those with nasal colonization by Aspergillus species was 15/54 at baseline and 11/54 after the prophylaxis (P ⬎ 0.05). In the control group, this ratio was 12/43 and 9/43 at baseline and after the prophylaxis, respectively (P ⬎ 0.05). Colonization by Candida species at baseline in the itraconazole group changed from 5/54 to 2/54 after chemotherapy (P ⬎ 0.05) and in the control group the ratio changed from 4/43 to 2/43 (P ⬎ 0.05). Fungal infections and need for amphotericin B During the trial, systemic antifungal treatments (intravenous amphotericin B) were initiated for 13 episodes (24%) in the itraconazole group and 7 episodes (16%) in the control group (P ⬎ 0.05) (Tables 2 and 3). These are also the overall failure rates in both groups (defined as the sum of treatment episodes in which empirical amphotericin B was administered and/or the patient developed a fungal infection). A fungal infection occurred in nine episodes (17%) in the itraconazole group and in five episodes (12%) in the control group (P ⬎ 0.05). Itraconazole did not reduce the incidence of deep fungal infection, which occurred in seven episodes (13%) in the itraconazole recipients compared with four episodes (9%) in controls (P ⬎ 0.05). The fungal infection was superficial in two episodes (4%) in the itraconazole group and in one episode (2%) in the control group (P ⬎ 0.05). All these infections were clinically apparent, and culture documented oropharyngeal candidiasis. Proven deep fungal infection occurred in two episodes (4%) in the itraconazole group and in two episodes (5%) in the control group (P ⬎ 0.05). Fungemia due to Candida species was documented in one episode in each group. Infections
Table 1. Patient and disease characteristics at the beginning of treatment Characteristic
Itraconazole
Control
Patients with neutropenia Episodes of cytotoxic chemotherapy Males/females Mean age (range); years Underlying disease Acute myeloid leukemia Acute lymphoblastic leukemia Disease status before treatment course First induction therapy Induction of ⱖ second remission Consolidation of first remission Consolidation of ⱖ second remission Central venous catheter Mean duration of neutropenia (range); days Treatment episodes with granulocyte count ⬍100/mm3 Treatment episodes using G-CSF Mean duration of prophylactic treatment (range); days Aspergillus species at baseline Candida species at baseline Mortality
31 54 23:8 33.39 (20–73)
24 43 18:6 38.4 (21–69)
17 14
14 10
23 14 15 2 100% 15.6 (8–31) 85% (46/54) 13% (7/54) 10.4 (9–31) 15/54 5/54 5
21 10 11 1 100% 14.2 (9–29) 81% (35/43) 12% (5/43) – 12/43 4/43 2
G-CSF, Granulocyte colony-stimulating factor
43 Table 2. Distribution of antifungal treatment and fungal infections
Systemic antifungal treatment Fungal infection Superficial fungal infection Deep fungal infection Suspected invasive Aspergillus infection Suspected deep Aspergillus infection Proven deep fungal infection Fungemia (Candida spp.) BAL (⫹) Aspergillus fumigatus FUO or empirical amphotericin B treatment
Itraconazole (n ⫽ 54)
Control (n ⫽ 43)
P value
13 (24%) 9 (17%) 2 (4%) 7 (13%) 1 (2%) 4 (7%) 2 (4%) 1 1
7 (16%) 5 (12%) 1 (2%) 4 (9%) – 2 (5%) 2 (5%) 1 1
⬎0.05 ⬎0.05 ⬎0.05 ⬎0.05 – ⬎0.05 ⬎0.05
4 (7%)
2 (5%)
⬎0.05
BAL, Bronchoalveolar lavage; FUO, fever of unknown origin
Table 3. The results of amphotericin therapy Response rate to amphotericin Itraconazole (n ⫽ 54)
Control (n ⫽ 43)
Fungal infection Superficial fungal infection Deep fungal infection Suspected invasive Aspergillus infection Suspected deep Aspergillus infection Proven deep fungal infection Fungemia (Candida spp.) BAL (⫹) Aspergillus fumigatus FUO or empirical amphotericin B treatment
6/9 2/2 4/7 1/1 1/4 2/2 1/1 1/1 1/4
4/5 1/1 3/4 – 1/2 2/2 1/1 1/1 ⫺/2
Total
7/13
4/7
due to Aspergillus fumigatus that were positive in bronchoalveolar lavage (BAL) fluid were documented in one episode in each group. Two episodes (5%) in the control group and four episodes (7%) in the itraconazole group were graded as having a suspected deep aspergillosis infection, based on a very typical halo sign on serial X-rays and CT scans, although the fungal organism was not positive (P ⬎ 0.05). In one episode in the itraconazole group, pulmonary lesions strongly suggestive of invasive aspergillosis on High Resolution (HR)-CT scans were detected and this patient was successfully treated with intravenous amphotericin B. In the itraconazole and control groups, FUO without documented infection developed in the remaining four (7%) and two (5%) episodes, respectively. In episodes, the patients received antibacterial treatment and proceeded to intravenous empirical amphotericin B. The difference in the incidence of FUO between the groups was not statistically significant (P ⬎ 0.05). Compliance and adverse effects In the itraconazole group, compliance was defined as excellent in 92% and as good in 8% of the episodes. No major toxicity was seen. The drug was stopped because of adverse events in only 2 patients. The adverse events that caused itraconazole to be stopped were gastric irritation and cardiac arrhythmia.
Although the finding could not be quantitated due to many confounding factors, there was a clinical impression that hypokalemia occurred at a greater rate in patients with itraconazole. Potassium supplements or potassium-sparing agents were sufficient to restore normokalemia.
Survival The overall mortality in the two groups was similar; five patients in the itraconazole group and two in the control group died, but no death due to fungal infections occurred in either group. The difference in mortality was not statistically significant (P ⬎ 0.05). In the itraconazole group, death from proven bacterial infections occurred in two patients, owing to ongoing septicemia caused by bacterial infection (with Escherichia coli in one and Enterococcus in another), and owing to advanced underlying malignancy in the others. In the control group, death was due to central nervous system (CNS) bleeding in the two patients.
Discussion Systemic fungal infections represent a major challenge in the care of patients who undergo chemotherapy for hema-
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tological malignancies. Their incidence has increased, their diagnosis is elusive, and the therapeutic options are limited. Therefore, antifungal prophylaxis has a potential role among the strategies designed to overcome this problem. A small randomized controlled trial of antifungal prophylaxis with 400 mg/day itraconazole in patients with acute leukemia showed a nonsignificant reduction of invasive fungal infections.12 Unfortunately, in this study, drug monitoring was not done. Bohme et al.13 also reported no significant reduction of invasive fungal infection in patients who had received 400 mg/day itraconazole compared with a historical group. However, the historical control group in their study had received oral amphotericin B. Also, Menichetti et al.14 with the Gruppo Haliano Malattie Ematologiche dell’Adulto (GIMEMA) infection program, failed to show a significant reduction in the incidence of invasive aspergillosis. On the other hand, many studies reported a reduction of invasive fungal infection with itraconazole as antifungal prophylaxis in patients with acute leukemia.3,15–17 In two large prophylactic trials with itraconazole in neutropenic patients, a clinically relevant reduction in the number of cases of deep fungal infection, including Aspergillus infection, was obtained in favor of itraconazole oral solution compared with oral amphotericin B, placebo, and fluconazole.14,18 However, our study did not show a significant difference between the patients given itraconazole and the control group (P ⬎ 0.05), similar to observations in many other studies. Although the study showed no significant difference between the two study groups, the analysis of the impact of the use of itraconazole on the incidence of invasive aspergillosis was hampered by the low observed incidence of this infection (only 1 [2%] treatment episode). Statistical conclusions in regard to very small incidences are difficult to interpret. A similar low incidence of invasive aspergillosis has been observed in other trials of antifungal prophylaxis.4,6 It may be that invasive fungal infections are still difficult to diagnose, and new strategies should include the evaluation of new diagnostic tools. The incidence of aspergillosis varies greatly between different hospitals, even in the same country. Furthermore, at our center, patients’ fungal flora may be different from that in other centers that reported a significant reduction with itraconazole as antifungal prophylaxis. Also, reported results of itraconazole prophylaxis studies showed differences between study centers. Candida species accounted for superficial fungal infections in two treatment episodes in the itraconazole group and one treatment episode in the control group. In addition, Candida species was responsible for fungemia in one treatment episode in each group. These differences were not statistically significant. The prophylactic use of itraconazole did not seem to be associated with the selection and emergence of resistant Candida organisms in line with observations in other clinical trials.9,14,19 A possible explanation for the low frequency of superficial fungal infection is that both groups received oral fluconazole solution as a mouthwash. In the itraconazole arm of the trial, the need for the administration of empirical amphotericin B (7%) was not different from that in the control arm (5%; P ⬎ 0.05). In a
prospective, randomized trial of patients with hematological malignancies, the incidence of use of intravenous amphotericin B was essentially similar in patients treated with itraconazole capsules and in those receiving placebo in addition to oral amphotericin B.12 The frequency of initiation of empirical therapy with amphotericin B in various clinical trials of antifungal prophylaxis has ranged from 18% to 61%.6,8 The reasons for these discrepancies may be related to different antibiotic regimens and guidelines for the initiation of empirical amphotericin B.6,8,20 In fact, itraconazole prophylaxis had no effect on reducing the administration of empirical amphotericin B in the present study (Tables 2 and 3). As observed in other clinical trials of antifungal prophylaxis in neutropenic patients,21 the overall mortality in our patients was not influenced by the use of itraconazole. However, no death due to fungal infection was seen in either group. It was also reported that prophylactic antifungal treatment in patients with cancer and neutropenia seemed to have no survival benefit.12 A reliable evaluation of the impact of antifungal prophylaxis on survival, however, would require stricter definitions of the causes of death than are usually possible for these patients with multiple concurrent complications of uncontrolled malignancy and its treatment. The question as to whether azole prophylaxis prolongs the duration of neutropenia has been a concern raised by some investigators, who also noted a higher incidence of bacteremias in azole-treated patients.20 However, our study does not support this opinion, because the mean duration of neutropenia was similar in both groups. In general, treatment with the itraconazole oral solution is well tolerated.22 However, in the present study, itraconazole capsules were well tolerated; only one patient developed gastric irritation. Nausea and vomiting did occur, to similar extents in both groups. Compliance was good, even in patients with mucositis. Biochemical abnormalities are inherent in the patient population studied. All observed increases and decreases in biochemical values were similar in the two groups, pointing to the background laboratory abnormalities in this population. According to our data, itraconazole is safe to use. Itraconazole, in the capsule formulation, may have erratic absorption, and, also, it is not reliably absorbed in neutropenic patients with chemotherapy-induced damage to the intestinal mucosa.17 Therefore, monitoring of drug concentrations is important and recommended in lifethreatening situations. However, in the present study, itraconazole serum levels could not be measured because of the technical insufficiency. For this reason, it may be suggested that the lack of efficacy of itraconazole is related to its low serum level. Also, the fungal flora of patients at our center may be resistant to itraconazole. In conclusion, the prophylactic administration of itraconazole capsules in patients with hematological malignancies and neutropenia at our center showed no efficacy in reducing the incidence of fungal infections, although it was well tolerated and was not associated with clinically significant adverse events. However, the use of a better-absorbed
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preparation, such as itraconazole solution, or higher doses of itraconazole capsules, may offer more effective prophylaxis.
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