In recent years, immunosuppressive drugs have become common in clinical practice, the life expectancy of cancer patients has been extended, the number of organ transplants has increased, and new intervention and life support techniques have been introduced for better care. All these changes have been associated with a substantial increase in the rate of invasive fungal infections (IFIs), mainly resulting from the rapid increase in the number of at-risk patients. Invasive pulmonary mycosis (IPM) is the most common type of invasive fungal infection.1-3 It is often severe and difficult to treat, and is accompanied by high mortality. Formerly named ‘invasive pulmonary fungal infection’, in recent guidelines on fungal infection has been renewed its definition to IPM.4-6 IPM is most common in patients with primary or secondary immunosuppression from various causes. However, it also occasionally occurs in patients with uncompromised immune function and without underlying disease.7,8
Itraconazole is a broad-spectrum, triazole antifungal agent. This drug, which is generally well-tolerated by patients, has been approved for the treatment of various kinds of mycoses, such as aspergillosis, candidiasis, cryptococcosis, and histoplasmosis.9 In 1993, intravenous itraconazole became available on the world market and has proved effective in treating invasive fungal infection. In 2004, oral itraconazole solution was approved by the State Food and Drug Administration (SFDA), China. This oral solution, which has a high bioavailability, may be used for sequential antifungal therapy. The present study aimed to evaluate the efficacy and safety of intravenous itraconazole followed by oral itraconazole solution in the treatment of IPM.
This was a post-marketing, open-label, multi-center clinical trial which recruited patients from respiratory medicine departments from 13 teaching hospitals all over China. The study was approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University.
We recruited patients who were diagnosed with IPM during hospitalization between July 2007 and January 2009. According to the diagnostic criteria for fungal infections,1-4 all patients met the criteria for ‘clinical diagnosis’ or ‘confirmed diagnosis.’ Clinical diagnosis was defined as: risk factors for fungal infection (except pulmonary cryptococcosis), radiographic features and clinical symptoms for IPM, and at least one microbiological marker (galactomannan test by ELISA, 1,3-β-D-glucan test or cryptococcus antibody test).7 Confirmed diagnosis was defined as: risk factors for fungal infection (except pulmonary cryptococcosis), radiographic features and clinical symptoms for IPM, mould detection by culture or from biopsy specimens.7
All subjects signed written informed consent.
This was an open-label study with a treatment duration of 6 weeks. After enrollment, all patients received intravenous itraconazole therapy followed by oral itraconazole solution for 6 weeks. Intravenous itraconazole was given at a dose of 200 mg bid (intravenous infusion every 12 hours) for the first two days, 200 mg qd for the subsequent 12 days. Sequential oral itraconazole solution was given at a dose of 100 mg bid for 4 weeks. Baseline characteristics were collected, including demographics, diagnosis at admission, vital signs, body height, body weight, risk factors, and medical history for other underlying diseases. Laboratory tests were conducted, including viral detection (HBV, HCV and HIV), fungal tests, radiographic examinations and other lab tests. Six visits were planned for this trial (once a week). At each visit, patients were evaluated for vital signs, fungal tests, radiographic examinations and lab tests. Body temperature was recorded for each subject every day. The efficacy evaluation was performed at the end of week 6. Concomitant medication and adverse events were documented during the whole study period. At the end of the study, information on study drug utilization and final diagnosis at discharge were recorded. For patients who withdrew from the study, the reasons for discontinuation were documented.
Evaluation of efficacy
Clinical cure was defined as complete resolution of signs and symptoms of invasive fungal infection as well as complete (or near complete) resolution of radiographic manifestations. Clinically significant improvement was defined as complete or marked resolution of signs and symptoms as well as at least 50% improvement of radiographic findings. Clinical improvement was defined as partial disappearance of baseline signs and symptoms as well as less than 50% improvement of radiographic findings. Clinical failure was defined as no change in, or worsening of, pre-treatment signs and symptoms as well as enlargement of radiographic lesions. Clinical response was defined as clinical cure or significant improvement. The clinical response rate was calculated as (number of clinical cure + number of clinically significant improvement)/number of all patients×100%.
Mycological eradication was defined as eradication of the baseline pathogen based on culture and microscopy. Mycological persistence was defined as the persistence of the baseline pathogen on microscopy and/or culture.
Cure was defined as complete resolution of all of the following four aspects: symptoms, signs, lab results and mycological evaluations. Significant improvement was defined as marked resolution of disease, but with one of the four aspects remaining abnormal. Improvement was defined as partial but not marked resolution of disease, with two of the four aspects remaining abnormal. Failure was defined as no change in, or worsening of, patient conditions.
During the study period, investigators documented lab results, vital signs and any adverse events that occurred. Adverse events were recorded as ‘very likely’, ‘probable’, ‘possible’, ‘doubtful’ and ‘not related’ to study treatment according to the definitions. In this study, the adverse event rate was calculated from all the ‘possible’, ‘probable’ and ‘very likely’ events.
Patients enrolled were then assigned to three different datasets: full analysis set (FAS), per-protocol set (PPS) and safety set (SS). According the principle of intention-to-treat analysis, patients who received at least one intravenous infusion or oral solution of the study drug and completed at least one visit were included in the FAS. The FAS was the primary dataset for efficacy evaluation. Except for those patients who discontinued treatment or violated the study protocol, all participants were included in the PPS. The PPS was the secondary dataset for efficacy evaluation. Patients who received at least one dose of study drug and had safety documents were included into the SS. The SS was the primary dataset for safety evaluation.
Statistical analysis was performed by SAS 9.1.3 software (SAS Institute, USA). Clinical efficacy evaluation and overall efficacy evaluation according to different fungi species were compared with the use of a Cochran-Mantel-Haenszel(CMH) test. A chi-square test was performed to test for response rates. Mycological results were compared using a Fisher’s Exact test, as appropriate. 95% confidence intervals (CI) were calculated by Logistic regression analysis. All tests for significance were two-tailed and a P value <0.05 was considered statistically significant.
Seventy one patients were enrolled from the departments of respiratory medicine from 13 teaching hospitals all over China. The FAS contained 60 patients which constituted 84.5% of all subjects. Of the 60 patients in the FAS, 37 were male and 23 were female. The median age was 55.5 years (range: 33.3-79.5 years). The PPS included 47 patients which constituted 66.2% of all subjects. Considering the diagnosis, 37 patients in the FAS met the criteria for ‘clinical diagnosis’ (61.7%) and 23 subjects in the FAS fulfilled the criteria for ‘confirmed diagnosis’.
Risk factors for fungal infection
Forty seven patients in the FAS were evaluated for pre-treatment risk factors. Of them, 43 patients had body temperature >38°C or <36°C. Other risk factors included long-term glucocorticoid therapy (n=16), history of invasive fungal infection (n=11), long-term antibiotic treatment (n=10), or recent use of immunosuppressive drugs (n=7).
Fifteen patients (25.0%) from the FAS lacked a documented history of underlying disease. The other 45 subjects (75.0%) had underlying diseases including (but not limited to) chronic obstructive pulmonary disease, pulmonary tuberculosis, hypertension, diabetes, hematological malignancies, solid tumors, autoimmune disease.
Of the 60 patients in the FAS, 24 patients had the same pathogen revealed by at least two sputum cultures; 14 patients had positive culture results for fungi with bronchoalveolar lavage fluid (BALF); 18 patients had fungal infection confirmed with percutaneous transthoracic lung biopsy; four patients had at least two galactomannan tests (GM tests) with a result >0.5; five patients had at least two positive 1,3-β-D-glucan tests (G tests); four patients had positive serum cryptococcus antibodies. The distribution of fungal species was as follows: in the FAS, aspergillus (n=34), candida (n=10), cryptococcus (n=6), other fungi (n=6), mixed fungal infection (n=4); in the PPS, aspergillus (n=27), candida (n=6), cryptococcus (n=5), other fungi (n=6), mixed fungal infection (n=3).
At the end of week 6, thirty seven patients in the FAS (n=60) had a clinical response and the clinical response rate was 61.7%. Of these, eight patients (13.3%) achieved clinical cure; 29 patients (48.3%) had clinically significant improvement; 18 patients (30.0%) had clinical improvement; five patients (8.3%) were classified as clinical failure. Of the 37 patients who were clinically diagnosed as IPM, seven patients (18.9%) achieved clinical cure; 16 patients (48.2%) had clinically significant improvement; 10 patients (27.0%) had clinical improvement; four patients (10.8%) were classified as clinical failures. Of the 23 patients who had a confirmed diagnosis of IPM, one (4.4%) achieved clinical cure; 13 patients (56.5%) had clinically significant improvement; eight patients (34.8%) had clinical improvement; one patient (4.4%) was classified as a clinical failure.
Clinical efficacy evaluation and clinical response rate were assessed according to different fungi species.
At the end of week 6, the clinical response rate was 58.8% (20/34) in patients with aspergillus, 70.0% (7/10) in patients with candida, 83.3% (5/6) in patients with cryptococcus, 33.3% (2/6) for patients with other fungal infections, and 75.0% (3/4) for patients who had mixed fungal infections. As a result of the Cochran-Mantel-Haenszel test, the P value was 0.3919 between different groups (P >0.05). After a chi square comparison for the clinical response rates, the P value was 0.3993 between different groups (P >0.05) (Table 1).
At the end of week 6, of the 30 patients who could be evaluated with samples from the respiratory tract (in the FAS), the mycological eradication rate was 66.7%. Of those who had a clinical diagnosis of IPM, the mycological eradication rate was 65.0%; of those who had a confirmed diagnosis of IPM, the mycological eradication rate was 70.0%. For patients who were diagnosed with aspergillosis, the mycological eradication rate was 66.7%; for patients who had candida infection, the pathogen eradication rate was 50.0%; for patients with cryptococcus, eradication rate was 0; of those who had other fungal infections, the eradication rate was 100.0%; for patients who suffered from mixed fungal infections, the mycological eradication rate was 100.0%. After a Fisher’s exact test, the P value was 0.1472 between different groups (P >0.05) (Table 2).
Overall efficacy evaluation
At the end of week 6, overall efficacy evaluation was conducted for the 60 patients in the FAS. A total of 40 patients (66.7%) had a treatment response, with ‘cure’ in 13.3% of patients (8/60), and ‘significant improvement’ in 53.3% (32/60). For those patients who had a clinical diagnosis of IPM, the overall response rate was 62.2%; for those who had confirmed diagnosis of IPM, the overall response rate was 73.9%. In patients who had aspergillosis, the overall response rate was 64.7%; for those who were diagnosed with candidosis, it was 70.0%; for patients with cryptococcus infection, the response rate was 83.3%; for those who had other fungal infections, the rate was 50.0%; for the patients with mixed fungal infections, the response rate was 75.0%. As a result of the Cochran-Mantel-Haenszel test, the P value was 0.7819 between different groups (P >0.05). After a chi square comparison for the response rates, the P value was 0.7739 between different groups (P >0.05). Thus, there was no statistically significant difference in the response rate among patients infected with different fungal species (Table 3).
The safety dataset contained 61 patients. Of these, 11 patients experienced 24 adverse events with an incidence rate of 18.0%. Of the 24 adverse events, 18 were mild, 5 were moderate and 1 was severe. The distribution of the 24 adverse events was as follows: hypokalemia (3), nausea (3), abnormal liver function tests (3), elevated bilirubin level (1), elevated ALT level (1), dermatosis (1), skin rash (1), abnormal kidney function test (1), dizziness (1), headache (1), abdominal pain (1), non-specific abnormal appetite (1), vomiting (1), diarrhea (1), night sweat (1), palpitation (1), tremor (1), swelling (1). The patient who suffered from the severe adverse events had limb and facial swelling and discontinued the study drug.
Invasive pulmonary mycosis (IPM) is very difficult to diagnose; moreover, it is often severe and develops rapidly with poor prognosis. Thus, to initiate effective anti-fungal therapy at the right time is very important in the treatment of IPM. However, great caution should be exercised to avoid the over-use of anti-fungal drugs in order to minimize drug-related adverse events. Thus, appropriate anti-fungal treatment is of great importance for patients with IPM.9
The present study suggested that sequential anti-fungal therapy with intravenous itraconazole followed by oral itraconazole solution was effective in the treatment of IPM, with a clinical response rate of 61.7%, a mycological eradication rate of 66.7% and an overall response rate of 66.7% (all evaluated at the end of week 6). Of all 60 patients in the FAS, 38 had aspergillus infection (including 4 cases of mixed fungal infection, such as aspergillus plus cryptococcus infection or aspergillus plus candida infection). This result suggested that aspergillus accounted for most of the IPM cases. Candidosis ranked a close second. Our study compared the clinical efficacy, mycological results and overall efficacy among patients with different fungal infections and all comparisons proved to be non-significant which suggested that itraconazole was equally effective for treating infections of all fungal species (including aspergillus, candida, cryptococcus).
Itraconazole is a triazole antifungal agent with broad-spectrum anti-fungal effects which has been showed to be effective in treating infections caused by aspergillus, candida and cryptococcus. Itraconazole exhibits powerful, broad-spectrum anti-fungal activity and is as effective as amphotericin B and other anti-fungal drugs. It is one of the first-line drugs for treating IPM.10,11 Based on the distribution of fungal species revealed by our study, itraconazole may also be used as empirical therapy for IPM. However, the cost of intravenous itraconazole is relatively high and restricts its long-term administration. Oral itraconazole solution is a new formulation developed recently which shows desirable bioavailability, wide tissue distribution, good capability to penetrate physiological barriers and an acceptable profile of adverse events.10-12 Vandewoude et al10 observed serum drug concentration after the sequential administration of intravenous itraconazole followed by oral solution. After 2-3 days of intravenous infusion, the average trough concentration of itraconazole and hydroxy-itraconazole reached a steady state. After oral formulation was initiated, the average trough concentration of study drug increased slightly and remained stable. Caillot et al12 treated 31 immunosuppressed IPM patients with sequential itraconazole therapy and found this treatment to be effective and safe. In our study, we demonstrated that sequential oral itraconazole solution after intravenous infusion was effective for treating IPM.
Our study showed that drug-related adverse events occurred in only 18.0% of patients; only one subject discontinued the study drug because of limb and facial swelling. Most of the patients experienced only mild adverse events which did not interfere with the study drug administration and did not have long-term effects. It should be noted that for patients with hypokalemia and impaired liver function before itraconazole administration, monitoring of liver function and electrolytes is recommended.
In conclusion, intravenous itraconazole followed by oral itraconazole solution therapy was safe and effective for treating IPM. This sequential therapy could improve patient compliance, reduce the total costs and has a preferable cost-benefit profile. Sequential therapy with intravenous itraconazole followed by oral solution is an efficacious treatment for IPM which deserves wide clinical application.
The National Collaborative Group of Sequential Itraconazole Treatment for Invasive Pulmonary Mycosis: Department of Respiratory Medicine, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University; Department of Respiratory Medicine, Zhongshan Hospital, Fudan University; Department of Respiratory Medicine, China People’s Liberation Army General Hospital; Department of Respiratory Medicine, Guangdong People’s Hospital; Department of Respiratory Medicine, Nanfang Hospital, Nanfang University; Department of Respiratory Medicine, Guangzhou Medical College First Affiliated Hospital; Department of Respiratory Medicine, Xiangya Hospital, Zhongnan Universtiy; Department of Respiratory Medicine, First Affiliated Hospital of Nanjing Medical University; Department of Respiratory Medicine, China People’s Liberation Army Nanjing General Hospital; Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University; Department of Respiratory Medicine, Huaxi Hospital, Sichuan University; Department of Respiratory Medicine, Zhejiang University First Affiliated Hospital; Department of Respiratory Medicine, Xinqiao Hospital, Third Military Medical University.
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