a Department of Hematology, University Hospital Gasthuisberg, B-3000 Leuven; b University St Jan's Hospital, Bruges; c University Hospital, Antwerp, Edegem; d University Hospital Sart Tilman, Liège; e Saint-Luc University Hospital, Brussels; f University Hospital, Gent; g University Hospital, Antwerp; h Janssen Research Foundation, Beerse, Belgium
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Abstract |
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Introduction |
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The usefulness of intravenous amphotericin B as a prophylactic agent is limited by its lack of absorption and poor compliance when used orally and by its nephrotoxicity when used intravenously.2 The antifungal azoles ketoconazole and fluconazole are orally absorbed and systemically active agents; however, they are not effective against Aspergillus spp., and some non-albicans species of Candida are resistant to fluconazole.35 An effective, broad-spectrum, non-toxic, orally active agent may therefore be required for prophylaxis in severely immunocompromised patients.
Itraconazole is an orally active broad-spectrum triazole derivative that exhibits pronounced antifungal activity against a wide range of pathogenic fungi, such as Candida and Aspergillus spp., and Cryptococcus neoformans.57 Initial studies have indicated that fungal infections occur less often in neutropenic patients with plasma itraconazole concentrations of >250 ng/mL than in those with lower concentrations.8 However, the bioavailability of itraconazole from the traditional capsule formulation can be variable in neutropenic patients. In the light of these observations, a new formulation of itraconazole with improved bioavailability has been developed, namely itraconazole oral solution containing hydroxypropyl-ß-cyclodextrin.9 This has been developed primarily for use in neutropenic patients, who should benefit not only from the improved bioavailability, but also from the easy administration of the oral solution, even if they have mucositis and swallowing problems; this may help to promote compliance.
The present study was performed to compare the efficacy and safety of itraconazole oral solution 100 mg bd with the non-absorbable combination of oral amphotericin B plus nystatin in the prevention of fungal infections in neutropenic patients. These non-absorbable drugs were, at the time of study initiation, still considered to be state-of-the-art prophylactic treatment. Amphotericin B was chosen because of its wide antifungal spectrum, and nystatin to treat mucosal colonization, an event frequently preceding invasive infection.
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Patients and methods |
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Patients
Patients were eligible for the trial if they were aged at least 16 years, had leukaemia or aplastic anaemia or had undergone bone marrow transplantation, and/or were due to receive remission induction or consolidation therapy likely to produce neutropenia (neutrophil count <0.5 x 109 cells/L) lasting at least 10 days. The same patient could be included more than once if more than 3 months had elapsed since the previous neutropenic episode and no breakthrough fungal infection was observed in the previous treatment period.
Patients were excluded if they were hospitalized for fewer than 7 days or if they were receiving other antifungal agents, rifampicin or phenytoin. Other exclusion criteria were known hypersensitivity to azole antifungal agents, evidence of fungal infection at the start of the study, and possible pregnancy or lactation.
Treatment
Eligible patients were randomized to receive either itraconazole oral solution 100 mg bd or a combination of amphotericin B capsules 500 mg tds plus nystatin oral suspension 2 MU qds. Itraconazole was given as a 10 mg/ mL oral solution immediately after a meal; the solution had to be swallowed with water after a contact time with the oral mucosa of about 10 s. Treatment was started either 34 days before or at the same time as cytostatic therapy and was continued until the neutrophil count was restored to >1.0 x 109 cells/L.
Drugs affecting gastric acid secretion, such as H2 receptor antagonists, antacids or anticholinergic agents, were not permitted within 2 h of administration of itraconazole. Standard chemotherapeutic, antibiotic and disinfectant regimens were maintained at each centre. Topical antifungal agents applied to the skin were permitted for patients with positive skin cultures.
Assessments and endpoints
Routine specimens from the mouth, nose, stools and catheter exit site were taken before starting prophylaxis, before initiating chemotherapy or radiotherapy, and twice weekly during the period of neutropenia. If a patient became febrile, further samples were taken from the same sites and from other appropriate locations (e.g. biopsy sites, drainage fluid, suspected lesions).
The primary endpoint was prophylactic failure, defined as breakthrough of proven or suspected deep fungal infection, superficial fungal infection, or fever of unknown origin despite the use of broad-spectrum antibiotics. The criteria for these endpoints are summarized in Table I.
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During the 24 h period before prophylaxis was started, blood was collected for routine haematological and biochemical investigations. These investigations were repeated at least once a week during treatment. In addition, in itraconazole-treated patients, plasma concentrations of itraconazole were measured by high performance liquid chromatography 2 h after administration on days 3, 7, 14, 21 and 28. In all patients, heart rate, blood pressure and body temperature were measured at each assessment.
Statistics
Data were analysed on an intention-to-treat basis; thus, the analysis included all patients randomized to treatment, regardless of protocol violations. Differences in trial endpoints between and within groups were analysed by the MannWhitney U-test. In patients who withdrew from the trial because of prophylactic failure, the mean time to failure was calculated by the KaplanMeier technique.
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Results |
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In both groups, the mean neutrophil count decreased from >3.0 x 109 cells/L to <0.2 x 109 cells/L after approximately 2 weeks. The mean time during which patients had a neutrophil count of <0.1 x 109 cells/L was 13.9 days in the itraconazole group and 14.7 days in the amphotericin B plus nystatin group. The mean duration of neutrophil counts of 0.10.5 x 109 cells/L was 14.3 days in the itraconazole group and 14.5 days in the amphotericin B plus nystatin group. For counts of 0.51.0 x 109 cells/L, the mean duration was 17.1 days and 15.7 days, respectively. In the itraconazole group, 121 patients (84.0%) were neutropenic for at least 10 days, compared with 115 (86.5%) in the group treated with amphotericin B plus nystatin. No significant differences in neutrophil count were seen between the two groups at any time.
The incidence of breakthrough fungal infections in the two groups is summarized in Table IV. Overall, 93 patients (64.6%) in the itraconazole group were considered to have had successful prophylaxis, compared with 71 (53.4%) in the group receiving amphotericin B plus nystatin (P = 0.066). The estimated time to prophylactic failure was 37 days in patients treated with itraconazole and 34 days in patients receiving amphotericin B plus nystatin. In most patients requiring rescue antifungal medication (itraconazole group n = 50, amphotericin B plus nystatin group n = 52), the rescue medication consisted of intravenous amphotericin B, with or without another antifungal agent.
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In the itraconazole group, 69/111 (62.2%) patients with prolonged neutropenia were considered to have had successful prophylaxis, four (3.6%) had proven deep fungal infection and four (3.6%) had suspected infection. In the amphotericin B plus nystatin group, 52/109 (47.7%) patients with prolonged neutropenia were considered to have had successful prophylaxis, six (5.5%) had proven deep fungal infection and four (3.7%) had suspected infection. The difference between the treatment groups was statistically significant (P = 0.031).
The number of patients with fungal colonization of the nose and sputum decreased from baseline to endpoint (from 5 to 3 and 7 to 4, respectively) in the itraconazole group. In the amphotericin B plus nystatin group only the number of patients with colonization of the nose decreased (from 1 to 0). The number of patients with colonization of stool increased in both groups (from 22 to 33 in the itraconazole group and from 6 to 24 in the amphotericin B plus nystatin group) and, in the amphotericin B plus nystatin group, colonization of the sputum was recorded in one patient at baseline and in 12 at endpoint. No correlation was seen between colonization at baseline or endpoint and subsequent proven or suspected fungal infection.
Plasma concentrations of itraconazole
The mean plasma concentrations of itraconazole were 383 ng/mL (range 21666 ng/mL) on day 7, 372 ng/mL (range 11605 ng/mL) on day 14 and 460 ng/mL (range 11443 ng/mL) on day 28. The low extreme values may have been caused by non-compliance.
Safety
Adverse events were reported by 63 patients (43.8%) in the itraconazole group and by 61 patients (45.9%) in the amphotericin B plus nystatin group. The most frequent events were vomiting (itraconazole group n = 14, amphotericin B plus nystatin group n = 12), diarrhoea (n = 12 and 9, respectively), nausea (n = 5 and 12, respectively) and rash (n = 2 and 13, respectively).
Most adverse events were mild or moderate; severe adverse events were reported by 23 itraconazole-treated patients and by 26 patients receiving amphotericin B plus nystatin. Seventeen patients in each group died during the trial or within 30 days after the last dose of trial medication (six died in each group with suspected or proven fungal infection); death was recorded as an adverse event in 13 patients in the itraconazole group and in nine patients in the amphotericin B plus nystatin group. Discontinuation of treatment because of adverse events (including death) was necessary in 34 itraconazole-treated patients and in 33 patients who received amphotericin B plus nystatin.
A high incidence of laboratory abnormalities was to be expected in this group of neutropenic patients, given the serious nature of their underlying disorders and concomitant medications, but no significant difference was found between the two groups. Liver function tests showed a similar number of patients reporting code-4 important abnormalities in each group. Pathological grade 1, code-4, important abnormalities were reported in 36 patients in each group. Pathological grade 2, 3 and 4, code-4, important abnormalities were reported in 20, nine and two patients, respectively, in the itraconazole group, and in 17, five and three patients in the amphotericin B plus nystatin group.
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Discussion |
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The incidence of proven or suspected deep fungal infections was similar in itraconazole-treated patients and in those treated with amphotericin B plus nystatin. The number of deaths from proven or suspected deep fungal infections was also similar in the two groups. The prominent causative organism in both groups at baseline and endpoint was Candida albicans. Superficial infections were less frequent in patients receiving itraconazole, the change in the number of patients with a colonized site (which can lead to systemic infection10) at endpoint was more favourable in the itraconazole group, and a larger proportion of itraconazole-treated patients remained free from fungal infection, indicating a trend in favour of itraconazole. A trend in favour of itraconazole was also detected in subgroups of patients with severe or prolonged neutropenia, who are at particular risk of infection, although these findings may be attributable to the higher incidence of superficial infections in patients treated with amphotericin B plus nystatin. Both treatments were well tolerated, but the considerably higher incidence of nausea and rash in patients treated with amphotericin B plus nystatin may indicate a further advantage of itraconazole.
In other recent trials of the efficacy and tolerability of itraconazole oral solution, a dosage of 5 mg/kg/day, given in two doses, was used;1113 this resulted in a lower incidence of fungal infections in neutropenic patients than with placebo, fluconazole or amphotericin B. The death rate with proven fungal infection was lower in the itraconazole arm of each trial. Moreover, a lower rate of suspected deep fungal infections requiring empirical intravenous amphotericin B rescue therapy occurred in itraconazole recipients. These superior results with itraconazole suggest that a dosage of 5 mg/kg/day is preferable to the 100 mg bd used in the present study. However, the potential for itraconazole oral solution to be more effective than other oral antifungals at preventing aspergillosis has not been conclusively demonstrated in clinical trials, possibly because they have not included enough patients who are at high risk of aspergillosis (such as allogeneic transplant recipients with chronic extensive or severe acute graft versus host disease).1114
Recent pharmacokinetic data indicate that the bioavailability of the oral solution is 60% higher when taken under fasting conditions than when taken with food.15,16 The mean plasma itraconazole concentrations in the present study might therefore have been increased further if the oral solution had been taken on an empty stomach. Nevertheless, even though itraconazole was taken after meals, the mean plasma itraconazole concentrations exceeded the 250 ng/mL needed to maintain prophylactic efficacy.17 This indicates that absorption of the oral solution is not dependent on an acid pH in the stomach. In addition, the absorption of the itraconazole oral solution is not impaired by coadministration with an antacid;18 the restriction on the use of gastric acid suppressing drugs in the protocol of this study was therefore unnecessary.
Overall conclusions from this pilot open study are limited, because no placebo group was included, and neither treatment was shown to be clearly more effective than the other. Future comparative studies should confirm the important role of the itraconazole oral solution in not only primary, but also secondary prophylaxis, and in the early empirical treatment of systemic fungal infections in neutropenic patients.
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Acknowledgments |
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Notes |
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References |
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Received 7 August 2000; returned 20 November 2000; revised 26 February 2001; accepted 7 March 2001