J Infect Chemother DOI 10.1007/s10156-011-0251-0
ORIGINAL ARTICLE
Efficacy and safety of antifungal prophylaxis with oral itraconazole solution among patients receiving corticosteroids: who should be given prophylaxis? Noriyoshi Iriyama • Yoshihiro Matsukawa • Katsuhiro Miura Hirotake Inomata • Yukio Hirabayashi • Yoshihiro Hatta • Akira Horikoshi • Jin Takeuchi
•
Received: 16 December 2010 / Accepted: 31 March 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract The incidence of systemic fungal infections has risen, as shown by increases in the numbers of immunosuppressed or immunocompromised patients. The consequences of these fungal infections are occasionally serious. However, the efficacy of antifungal prophylaxis in patients receiving corticosteroid treatment has not been well investigated, even though they are susceptible to severe fungal infections. Therefore, we retrospectively evaluated the prophylactic efficacy of an antifungal agent—oral itraconazole solution (ITCZ-OS)—for immunosuppressed patients receiving corticosteroids in a single institution. Of 39 patients, 18 received prophylaxis with ITCZ-OS at a dose of 200 mg/day, and 21 did not. As a result, no fungal infections developed in the prophylactic group, but 7 of the 21 patients (33%) in the non-prophylactic group suffered from fungal infections consisting of 3 non-invasive candidiases, 2 invasive candidiases, and 2 invasive pulmonary aspergilloses. Among the non-prophylactic group, aging and hypoalbuminemia were statistically significantly associated with incidence of invasive fungal infections. Of the four patients with invasive fungal infections, three had concomitant chronic illness such as diabetes. Toxicity among the prophylactic group was not statistically
N. Iriyama Y. Matsukawa H. Inomata Y. Hirabayashi A. Horikoshi Department of Internal Medicine, Nihon University School of Medicine, Nerima-Hikarigaoka Hospital, 2-11-1 Hikarigaoka, Nerima-ku, Tokyo 179-0072, Japan K. Miura (&) Y. Hatta J. Takeuchi Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, 30-1 Oyaguchi Kamicho, Itabashi-ku, Tokyo 173-8610, Japan e-mail:
[email protected]
significantly different from that of the non-prophylactic group. In addition, none needed discontinuation of the drug. These results indicate the potential antifungal prophylactic effect of ITCZ-OS for a subset of patients treated with moderate or high doses of corticosteroids. Keywords Corticosteroid Fungal infection Itraconazole Prophylaxis
Introduction Corticosteroids are essential immunosuppressive agents for treatment of autoimmune diseases or lymphoproliferative disorders. However, the complication of infectious disease remains a serious issue. In particular, the genera Aspergillus and Candida are known to be major contributory pathogens that occasionally cause life-threatening invasive fungal infection among patients receiving corticosteroids [1]. Nowadays several antifungal agents, for example fluconazole (FLCZ), itraconazole (ITCZ), voriconazole (VCZ), micafungin (MCFG), or amphotericin-B (AMPHB), are widely used for treatment of fungal infections, taking into account their various formulations, pharmacokinetics, or antifungal range. Of these antifungal agents, ITCZ, which has a wide range of use against both Aspergillus and Candida, is a reasonable choice for treatment of these infections, and oral ITCZ solution (ITCZ-OS) has better bioavailability than the capsule formulation [2, 3]. Thus, the efficacy of antifungal prophylactic use of ITCZ has been well investigated mostly in neutropenic patients under chemotherapy or hematopoietic transplantation [4–8]. On the other hand, results from antifungal prophylaxis for patients receiving corticosteroids are still insufficient,
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even though these patients are at high risk of severe fungal infection. We therefore gave ITCZ-OS to selected patients being treated with moderate or high-dose corticosteroids to prevent fungal infection such as invasive aspergillosis or candidiasis. We then retrospectively evaluated the prophylactic efficacy and toxicity of ITCZ-OS in immunocompromised patients receiving corticosteroids.
Patients and methods
presence of candidiasis in the alimentary canal, serum fungal antigens, serum beta-D-glucan, microbiologic verification of pathogens, pathologic evidence, or findings of computed tomography (CT) scanning of affected organs. For diagnosis of invasive fungal infections including invasive pulmonary aspergillosis, patients were categorized into ‘‘Proven’’ or ‘‘Probable’’ according to The European Organization of Research and Treatment of Cancer/ Mycosis Study Group (EORTC/MSG) guidelines for diagnosis of fungal infection [9].
Patients
Toxicity assessment
All medical records of hospitalized patients who had initiated or escalated corticosteroid treatment (prednisolone-equivalent dose C0.5 mg/kg) for their rheumatic or hematological disease between January 2007 and August 2009 at Nihon University Nerima-Hikarigaoka Hospital were reviewed for this analysis. Patients with leukemia or malignant lymphoma who received intensive chemotherapy concomitantly with corticosteroids were not included in the analysis, because they usually experienced severe neutropenia (absolute neutrophil count\1.0 9 109/l). In contrast, patients who were administered combination chemotherapy, for example VAD (vincristine, doxorubicin, and dexamethasone) or DMVM (dexamethasone, ranimustine, vincristine, and melphalan) for multiple myeloma were included for analysis, because this chemotherapy is not associated with severe neutropenia. Patients concomitantly receiving steroid pulse or other immunosuppressive agents were also analyzed. Patients who received antifungal prophylactic agents other than ITCZ-OS (FLCZ, n = 2) were excluded in order to compare differences between a group receiving ITCZ-OS and a non-prophylactic group. Consequently, a total of 39 eligible patients were analyzed retrospectively. Development of fungal infection was evaluated and analyzed according to the presence or absence of prophylactic use of ITCZ-OS. These patients were followed to the point of de-escalation equivalent to \0.5 mg/kg prednisolone, development of fungal infection, discharge from the hospital, or any cause of death. This retrospective study was approved by the institutional review board of Nihon University Nerima-Hikarigaoka Hospital.
To evaluate adverse events, laboratory examination— including complete blood count, renal function, and hepatic function—were performed at least once a week, and development of any symptoms was carefully monitored through the treatment periods.
Diagnostic criteria for fungal infection During the observation period, patients in both prophylactic and non-prophylactic groups were given standard surveillance for fungal infection. That is, monitoring body temperature, C-reactive protein, beta-D-glucan, and serum antifungal antigens. Patients who were suspected of having fungal infection underwent sufficient diagnostic investigation. Fungal infections were diagnosed on the basis of the
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Statistical analysis Fisher’s exact test for categorical variables and Student’s t tests for continuous variables were used to assess differences in patient characteristics according to prophylactic or non-prophylactic group. Cumulative incidence of fungal infection was estimated by the Kaplan–Meier method for each group, and these were evaluated by log-rank test. Logistic regression analysis was performed to assess the relationship between age, serum albumin level, complete lymphocyte count, and incidence of invasive fungal infection. We set P value \0.05 as the level of statistical significance. All data were analyzed using JMP version 8.0.1 software (SAS Institute, Cray, NC, USA).
Results Clinical characteristics of all patients with or without antifungal prophylaxis using ITCZ-OS are shown in Table 1. A total of 18 patients received antifungal prophylaxis with ITCZ-OS (decided by the attending physician): 16 patients received ITCZ-OS 200 mg/day at the time of initiation or escalation of corticosteroids and 2 patients received ITCZ-OS within 5 days of initiation or escalation because of oral mucosa pain caused by the underlying disease. The other 21 patients did not receive any prophylaxis against fungal infections. There were no special differences in sex, age, history of corticosteroid pretreatment, performance status, observation term, initial steroid doses, serum albumin level, absolute lymphocyte count, use of other immunosuppressive agents, or other medical comorbidities between the prophylactic and nonprophylactic groups.
J Infect Chemother Table 1 Clinical characteristics for all patients Prophylaxis with ITCZ-OS Yes (n = 18)
P value No (n = 21)
Sex (M:F)
9:9
7:14
0.291
Age (years, mean ± SD)
58.9 ± 16.4
56.6 ± 17.4
0.661
Pretreatment with corticosteroids
4
9
0.173
ECOG PS C2
8
7
1.000
Observation period (days, mean ± SD)
36.8 ± 19.3
50.3 ± 32.9
0.068
Steroid dose (mg/kg/day, mean ± SD)a
1.03 ± 0.36
0.86 ± 0.34
0.936
Serum albumin (g/dl, mean ± SD) Lymphocyte (/ll, mean ± SD)
3.69 ± 0.24 1162 ± 196
3.53 ± 0.20 1515 ± 181
0.688 0.098 0.037
Primary diseases Idiopathic thrombocytopenic purpura
8
3
Systemic lupus erythematosus
0
6
0.004
Multiple myeloma
3
3
–
Polymyositis/dermatomyositis
1
3
–
Polyarteritis nodosa
2
1
–
Mixed connective tissue disease
0
1
–
Anti-phospholipid syndrome
0
1
–
Wegener granulomatosis
0
1
–
Interstitial pneumonia
0
1
–
Relapsing polychondritis
1
1
–
Hemophagocytic syndrome
1
0
–
Behc¸et disease Henoch–Scho¨nlein purpura Additional treatmentsb
1
0
–
1
0
–
8
12
0.428
Comorbiditiesc
3
5
0.582
ITCZ-OS oral itraconazole solution, ECOG PS Eastern Cooperative Oncology Group performance status a
Prednisolone-equivalent dose at study entry
b
Number of patients who received additional treatments other than corticosteroids (steroid pulse (n = 11), cyclosporine A (n = 5), mizoribine (n = 2), mycophenolate mofetil (n = 2), cyclophosphamide (n = 2), azathioprine (n = 1), and/or combination chemotherapy (n = 3))
c
Number of patients who had chronic illness other than their primary diseases (diabetes (n = 4), renal failure (n = 3), and/or prostate cancer (n = 2))
Within the observation period, no fungal infection developed in the prophylactic group, whereas fungal infections developed in 7 of 21 (33%) patients in the nonprophylactic group: 3 non-invasive candidiases (oral/ esophageal), 2 invasive candidiases, and 2 invasive pulmonary aspergilloses. Cumulative incidence of fungal infection in the prophylactic group was significantly lower than in the non-prophylactic group (Fig. 1). All of three non-invasive candidiases improved soon after treatment with ITCZ-OS. Two cases of invasive candidiases were diagnosed with the presence of both beta-D-glucan and Candida-specific antigen in the sera (probable). One case of invasive pulmonary aspergillosis was diagnosed with microbiologic verification (sputum culture), beta-D-glucan, serum Aspergillus-specific antigen, and findings of chest radiography and CT (proven), and the other was diagnosed without microbiologic verification (probable). These
invasive fungal infections were detected from 19 to 115 days after administration of corticosteroid. Although all the patients with invasive fungal infection were immediately treated with MCFG or lipid form AMPH-B intravenously, three died subsequently. In the non-prophylactic group, aging and hypoalbuminemia were statistically significantly correlated with incidence of invasive fungal infection, whereas absolute lymphocyte count was not (Fig. 2). Table 2 shows characteristics of patients who had medical comorbidities other than their primary disease and/ or invasive fungal infection during the observation period. Among the eight patients with chronic illness, none of three patients in the prophylactic group experienced any fungal infections, whereas three of five patients in the nonprophylactic group were complicated with invasive fungal infections. Reactivation of cytomegalovirus (CMV-R) was
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Discussion
Fig. 1 Cumulative incidence of fungal infection according to antifungal prophylaxis with oral itraconazole solution, prophylactic group (n = 18) versus non-prophylactic group (n = 21). Throughout the observation period, incidence of fungal infection in the prophylactic group was statistically significantly lower than that in non-prophylactic group (P = 0.0464)
also simultaneously verified in the two patients with invasive aspergilloses. Adverse events which occurred during the administration of ITCZ-OS are shown in Table 3. Overall, the proportion of each adverse event was not statistically significantly different between the prophylactic and nonprophylactic groups. However, a total of 8 patients (44%) in the prophylactic group showed moderate or severe hepatic toxicity. Of these patients, at least 4 cases were suspected to have association with ITCZ-OS. This ITCZOS associated hepatic toxicity developed on days 2–14 with moderate serum aminotransferase escalation within 5 9 ULN (upper limit of normal). Thereafter, all recovered spontaneously without cessation of ITCZ-OS. Gastrointestinal symptoms, for example diarrhea, were observed in only one patient in the prophylactic group, whereas four patients experienced diarrhea in the non-prophylactic group.
In this study, we chose ITCZ-OS for antifungal prophylaxis for patients receiving corticosteroids for a variety of reasons. First, ITCZ-OS has superior bioavailability to the capsule formulation, and this enables maintenance of adequate or sufficient plasma concentration, which is associated with antifungal effects both in therapeutic and prophylactic settings [2–4]. Second, ITCZ-OS has bivalent activity against both Candida and Aspergillus. Once invasive aspergillosis develops in immunocompromised patients, it can be life-threatening, as shown by the two patients who died of this complication. VCZ also has antifungal activity against both Candida and Aspergillus, and is thus a candidate for first-line drug, although cost and adverse effects such as visual disturbance are yet to be resolved [10]. Another antifungal agent, FLCZ, does not have any antifungal activity against Aspergillus. ITCZ-OS was tolerated quite well by patients during prophylactic administration. Hydroxypropyl-beta-cyclodextrin, a constituent of ITCZ, is known to induce abdominal discomfort, but this was rare in this study. Because abdominal discomfort in ITCZ-treated patients developed dose-dependently, a dose of 200 mg/day seemed tolerable [11]. Although ITCZ-associated hepatic toxicity was observed at least four times in the prophylactic group, these were generally transient. Overall, there was no severe adverse effect which required discontinuation of ITCZ-OS in the prophylactic group. Although no differences in patients’ background except their primary diseases were observed between non-prophylactic or prophylactic groups, morbidity of fungal infections was retrospectively evaluated, and this analysis inevitably involves selection bias. We could not conclude definitely that ITCZ-OS can effectively prevent invasive fungal infections in this study, but some speculation is possible. In our investigation, aging and hypoalbuminemia,
Fig. 2 Logistic regression analysis for age (a), serum albumin level (b), and incidence of invasive fungal infection in patients without antifungal prophylaxis. Advanced age and hypoalbuminemia were statistically significantly associated with incidence of invasive fungal infection
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J Infect Chemother Table 2 Characteristics of patients who had medical comorbidities and/or who were complicated with invasive fungal infections No
Sex
Age (years)
Primary disease
ITCZ-OS
Comorbidities
Steroid dosea
Additional treatment
Fungal infection
Other infection(s)
1
M
59
Polychondritis
?
Diabetes
1.0
–
–
–
2
F
75
PN
?
RF
0.6
Pulse
–
–
3
M
79
ITP
?
Prostate cancer
1.0
–
–
–
4
M
59
PM
-
Diabetes
0.5
CsA
Systemic candidiasis
5
M
73
IP
-
Diabetes, RF
1.0
Pulse
Systemic candidiasis
Bacteremia
6
F
76
ITP
-
Diabetes
1.0
CY
Pulmonary aspergillosis
CMV-R, PCP
7 8
M M
76 79
DM MM
-
– RF
1.0 1.7
– –
Pulmonary aspergillosis –
CMV-R –
9
M
85
PN
-
Prostate cancer
0.6
–
–
Nocardiasis
M male, F female, PM polymyositis, IP interstitial pneumonia, ITP idiopathic thrombocytopenic purpura, DM dermatomyositis, MM multiple myeloma, PN periarteritis nodosa, RF renal failure, CsA cyclosporine A, CY cyclophosphamide, CMV-R cytomegalovirus reactivation, PCP pneumocystis pneumonia a Prednisolone-equivalent dose (mg/kg/day) at study entry Table 3 Adverse events during the observation period for patients with or without antifungal prophylaxis using ITCZ-OS
Adverse events
Hyponatremia
T-Bil total bilirubin, AST aspartate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase
Number of patients (grade C3) Prophylactic group (n = 18)
Non-prophylactic group (n = 21)
4 (0)
5 (4)
P value
1.0000
Hypokalemia
2 (1)
0
1.0000
Creatinin elevation
1 (0)
1 (0)
0.2065
T-Bil elevation
1 (0)
2 (1)
1.0000
AST elevation
7 (2)
2 (0)
0.0548
ALT elevation
8 (2)
6 (0)
0.5196
ALP elevation Diarrhea
4 (0) 1 (0)
4 (0) 4 (0)
1.0000 0.3489
Nausea
0
0
–
which might well reflect the immunity or nutrition status of patients, were statistically significantly associated with the incidence of invasive fungal infection among patients receiving corticosteroids without antifungal prophylaxis. In addition, three of four patients complicated with invasive fungal infections had concomitant medical conditions, for example diabetes or chronic kidney disease. These results suggest that antifungal prophylaxis with ITCZ-OS may be beneficial for patients of advanced age (e.g. C60 years), hypoalbuminemia (e.g. \3.5 g/dl), and/or chronic illness (e.g. diabetes), to prevent severe invasive fungal infections during treatment with moderate or high doses of corticosteroids (e.g. prednisolone-equivalent dose C0.5 mg/kg). Also, patients receiving corticosteroids who were complicated with CMV-R seemed to be susceptible to severe fungal infection, as described for patients undergoing solid organ or hematopoietic stem cell transplantation [12], and thus might be candidates for antifungal prophylaxis. This study suggests the prophylactic efficacy of ITCZOS for a subset of patients; recommended guidance for
antifungal prophylaxis for patients receiving corticosteroids has not yet been established, however. Optimum dose, patient eligibility, and prevention of drug-resistance still remain to be settled. Also, circumstances such as humidity and air flow can affect the incidence of fungal infections. The need for fungal prophylaxis should be thoroughly discussed, taking hospital environments into consideration. To clarify these obscurities, well-designed larger prospective studies are needed. Acknowledgments This study was not supported by any funds. The authors would like to thank Satoshi Yamaguchi, Yuki Nishiumi, and Jun Yamamoto (Janssen Pharmaceutical K. K.) for offering sufficient information about fungal infections.
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