DONG Wei-hua, HUANG Tai-kang, DONG Ya-lin, ZHOU Yang

(1. Research Center for Social Pharmacy, Shenyang Pharmaceutical University, Shenyang 100016, China; 2. The First Aff i liated Hospital, Medical School of Xi’an Jiaotong University, Xi’an 710061, China; 3. China Food and Drug Administration, Beijing 100810, China)

Analysis of Infuential Factors on the Effcacy of Itraconazole Injection for Treating Fungal Infections in Hematologic Malignancies Patients

DONG Wei-hua1,2, HUANG Tai-kang1,3, DONG Ya-lin2, ZHOU Yang2

(1. Research Center for Social Pharmacy, Shenyang Pharmaceutical University, Shenyang 100016, China; 2. The First Aff i liated Hospital, Medical School of Xi’an Jiaotong University, Xi’an 710061, China; 3. China Food and Drug Administration, Beijing 100810, China)

Objective To analyze the influential factors on the efficacy of itraconazole injection in the treatment of fungal infections for hematologic malignancies patients. Methods 85 hematologic malignancy patients with fungal infections were selected to treat with itraconazole injection. Multiple logistic regression was used to analyze 27 factors that probably affect the effcacy of itraconazole injection, these factors including four aspects: basic situation of the patients, use of itraconazole injection, combined drugs use, and laboratory indicators before and after treatment. Results and Conclusion Four factors such as the patient’s gender, the combination of fuconazole, macrolides, and carbamazepine were eventually conducted into the regression equation and we found the factors that reduce the effcacy of itraconazole injection were the combination use of fuconazole and carbamazepine.

itraconazole injection; logistic regression; hematologic malignancy; infuential factor

Invasive fungal infections have become an important factor which is threatening the patients’ life. Many factors such as chemotherapy, the use of all kinds of catheters, hematopoietic stem cell transplantation, the occurrence of graft versus host disease, and the utilization of broadspectrum antibiotic, lead to the increasing risk of fungal infection. During the past few years, with intensive chemotherapy and bone marrow transplantation being carried out widely, the incidence of invasive fungal infections in patients with hematologic malignancies showed an increasing trend, and it had become a common complication and one of the main causes of death during treatment. Itraconazole, a new generation of triazole broad spectrum antifungal agent, works better than fluconazole against aspergillus, sporothrix dermatitis, blastomycosis and histoplasmosis. It is the preferred drug for non-fatal histoplasmosis and blastomycosis[1]. To fnd out the factors on the efficacy of itraconazole injection in treatment of fungal infections for hematologic malignancies patients, 85 patients with hematologic malignancies were surveyed retrospectively in this study and the results would provide a reference for hematology clinicians.

1 Material and methods

1.1 Source

Invasive fungal infection patients with hematologic malignancies in a large hospital from 2008.1 to 2012.12 were selected as research subjects. In this study, hematologic malignancies include chronic myeloid leukemia, multiple myeloma, acute leukemia, non-Hodgkin’s lymphoma, acute non-lymphocytic leukemia and acute lymphoblastic leukemia. Deaths cases and patients with less than three days treatment of itraconazole injection were excluded, 85 patients were studied. The following statistics were collected: ①name, age, gender, and diagnosis; ②dosage, administration, time, and drugs combined with itraconazole injection; ③laboratory examination: fungal smear, etiological examination, (1, 3)-β-D-glucan test(G test), galactomannan test(GM test), liver and kidney function before and after treatment.

1.2 Diagnostic criteria

According to the criteria[2]of European Organization for Research and Treatment of Cancer (EORTC), the diagnostic classification is defined as follows: (1)Diagnosed: ①With fungal infection risk factors; ②With clinical features or imaging fndings of infection (The main features of pulmonary imaging are aspergilloma, nodules, voids, halo sign and crescent sign, and the secondary features include other clinical features of inflammation);③Fungal infections being confirmed by sputum culture or nasal secretions culture or lung tissue biopsy. (2) To be diagnosed: ①With fungal infection risk factors; ②With major clinical features or imaging fndings of fungal infection. (3) Suspected: ①With fungal infection risk factors; ②With clinical features of infection and persistent fever after broad-spectrum antibiotic therapy.

1.3 Evaluation criteria

The efficacy is divided into three levels: ①Cured: clinical symptoms and signs significantly change or disappear, results of etiological examination (including fungal smear, fungal culture, etc.) and imaging are negative; ②Significant improvement: clinical symptoms are improved signifcantly, results of etiology examination are negative; ③No change or progress: clinical symptoms and signs, results of etiology examination and imaging suggest no improvement or progress. Cured and signifcant improvement are defined as being effective, no change or progress is defned as being ineffective.

1.4 Dependent variable and candidate independent variables

The dependent variable that is represented by Y is antifungal efficacy of itraconazole injection, thus Y=1 is defined as being effective and Y=2 as being ineffective. Independent variables, as two categorical variables，which have a total of 27, are factors on the effcacy of itraconazole injection for treating fungal infections including demographics of patients (X1, X2), basic disease (X3～X7), usage methods of itraconazole injection (X8～X11), drugs combined with itraconazole (X12～X24) and laboratory examination before treatment (X25～ X27). The details are shown in Table 1.

Table 1 Factors on the eff i cacy of itraconazole injection and the methods of assigning values

1.5 Statistical methods

SPSS13.0 for windows software package (α=0.2) was applied to have the univariate analysis for 27 variables, and the statistically signifcant variables were then put into multivariate logistic regression (α=0.05). The final factors on the efficacy of itraconazole injection in hematological malignancies would be detected.

2 Results

2.1 General characteristics of patients

Of 85 patients, there were 52 males and 33 females. When it comes to age, 49 cases were less than 60 years old and 36 cases were older than or equal to 60 years old. The average weight of all patients was (62.2±10.9) Kg. 15 cases were proved to suffer from fungal infections, 19 were to be diagnosed, and 51 were suspected. By using antifungal treatment with itraconazole injection, 68 cases were effective and 17 cases were ineffective.

2.2 Univariate analysis of antifungal effect of itraconazole injection

SPSS13.0 for windows software package was used to have the univariate analysis for 27 independent variables. The results showed that variables X1, X11, X21, X22 were statistical signifcance (α=0.2), that is, the following factors such as gender of patients, the combination of fuconazole, macrolide and carbamazepine have correlation with antifungal effect of itraconazole injection in patients with hematologic malignancies.

2.3 Multiple logistic regression analysis of antifungal effect of itraconazole injection

Univariate analysis can only show the relationship between individual factor and the efficacy of itraconazole injection, and it can not express the combined effect of multiple factors on the results. The interaction between various variables was beyond the control of univariate analysis and more confounding effects and bias existed[3]. Therefore, multiple logistic regression can be used to analyze the significant independent variables with“forward into” methods of binary logistic in SPSS software package on the basis of univariate analysis (α=0.05). The statistical results were that combination of fluconazole or carbamazepine did correlate with antifungal efficacy. The details are shown in Table 2.

Table 2 Multiple logistic regression analysis of antifungal effect of itraconazole injection

3 Discussions

This study selected 27 variables as factors on the efficacy of itraconazole injection for treating fungal infections, including the patient's age, sex, underlying disease, usage methods of itraconazole injection, combination of drugs, as well as biochemical indicators before treatment. Among them, underlying disease includes fve kinds of hematologic malignancies: leukemia, lymphoma, myeloma, aplastic anemia and myelodysplastic syndrome. Hematologic malignancies can cause decreased immune function, causing increased risk of fungal infections, while the different diseases that may affect the therapeutic effect of antifungal in various degrees. The use methods of itraconazole such as the use of a loading dose, drug treatments time and sequential therapy can directly affect the ultimate effcacy of itraconazole. The categories of combined drugs include other antifungal agents, antiinfective drugs, corticosteroids and drugs potentially interacting with itraconazole (such as carbamazepine, rifampin, isoniazid, cyclosporine, tacrolimus, vinblastine, docetaxel, verapamil, erythromycin, clarithromycin, etc.). These combinations are likely to affect the ultimate effcacy of itraconazole. Biochemical indicators of patients included hypoalbuminemia, abnormal liver function and renal dysfunction. Hypoalbuminemia is the risk factor for fungal infections that may affect the effcacy of itraconazole. Liver and kidney dysfunction affects the absorption, distribution and metabolism of itraconazole.

27 variables were underwent the univariate analysisand four variables had statistical signifcance, that is, gender of patients and combination of fluconazole, macrolide, and carbamazepine. These four significant variables were then put into multiple logistic regressions, and the final factors were combining with fluconazole and combining with carbamazepine. When OR value was greater than 1, the factor correlated with efficacy positively. When OR value was less than 1, the factor correlated with efficacy negatively. From Table 2, we know that the efficacy of itraconazole injection was negatively correlated with the combination with fuconazole or carbamazepine for fungal infections in patients with hematologic malignancies, that is, the combination of fluconazole or carbamazepine will reduce the efficacy of itraconazole injection. An article reported that the long time use of antibiotics or hormones will affect antifungal efficacy, and the fungal infections would be difficult to control[4], but this study found that antifungal effcacy had nothing to do with the combination of antibiotics and glucocorticoids, the results may caused by the number of samples. The article also reported that age and blood cancer had nothing to do with the antifungal efficacy[4], which was consistent with the results of this study.

Because of its inhibition to CYP3A4, itraconazole can affect the plasma concentration of lots of drugs that can be metabolized by CYP3A4, thus changing the drugs’ effcacy and adverse reaction. Such drugs are like oral anticoagulants, protease inhibitors, calcium channel blockers metabolized by CYP3A4, some immunosuppressant and other drugs such as digoxin, carbamazepine, buspirone, alfentanil, alprazolam, midazolam, rifabutin and methylprednisolone[5]. This study found that the combination of carbamazepine reduced the efficacy of itraconazole, because carbamazepine was an enzyme inhibitor. It decreased the plasma concentration of itraconazole, which would lead to the effcacy of itraconazole being reduced. But this study did not find other drugs interacting with itraconazole such as immunosuppressants, calcium channel blockers, anti-TB drugs, and macrolides that affected the efficacy of itraconazole. Clarifying the facts may need to expand the samples to study and discuss further more. Fluconazole, a triazole antifungal too, is the first-line clinical antifungal agent, but when it combined with itraconazole, the efficacy of itraconazole would be reduced. The mechanism is unclear, perhaps enhanced fungal resistance was produced. Whether the results of this study can be applied clinically depends on the expanding samples research in the future.

[1] FENG Shu-ling, ZHANG Yang-lian. Medication of Common Fungal Infections [J]. Strait Pharmaceutical Journal, 2010, 22(11): 142- 144.

[2] S. Ascioglu, J. H. Rex, B. de Pauw, et al. Defning Opportunistic Invasive Fungal Infections in Immunecompromised Patients with Cancer and Hematopoietic Stem Cell Transplants: An International Consensus [J]. Clinical Infectious Diseases, 2002, 34(1): 7- 14.

[3] SHENG Xiao-yarn, NIE Jian-jun. Logistic Regression Analysis of Medication Compliance in Patients with Diabetes [J]. China Foreign Medical Treatment, 2010(21): 41- 42.

[4] LIN Zhi-guang, CHEN Bo-bin, XU Xiao-ping, et al. Study on Clinical Characteristics and related Factors of Nosocomial Fungal Infections [J]. Chinese Journal of Clinical and Pharmacology and Therapeutic (Electronic Edition), 2012, 6(2): 439-444.

[5] MIAO Cai-yun, CHEN Yi, CHEN Jiang-fei. Progress and Research in the Effect of itraconazole on Pharmacokinetic Drug-Drug Interactions [J]. Chinese Journal of Clinical and Pharmacology and Therapeutic, 2009, 14(10): 1183-1192.

Author’s information: HUANG Tai-kang, Professor. Major research area: Social pharmacy. Tel: 029-85323243, E-mail: dwh751001@sina. com