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MINI SYMPOSIUM: SUPPORTIVE CARE
Year : 2012  |  Volume : 49  |  Issue : 1  |  Page : 107-113
 

A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India


1 Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Mumbai, India
2 Department of Hematology, Seth G.S. Medical College and KEM Hospital, Mumbai, India
3 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India

Date of Web Publication25-Jul-2012

Correspondence Address:
M P Jadhav
Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Mumbai
India
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Source of Support: Department of Biotechnology, New Delhi, Conflict of Interest: None


DOI: 10.4103/0019-509X.98933

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 » Abstract 

Background: In patients with persistent fever and netropenia, amphotericin B is administered empirically for early treatment and prevention of systemic fungal infections. Despite this treatment, there are chances of breakthrough fungal infections and drug is also toxic. Materials and Methods: A multicentric, randomized, controlled clinical trial was conducted to compare liposomal amphotericin B two doses with conventional amphotericin B as empirical antifungal therapy. Results: The average body weight of patients was 26.4±14.8 (n=22), 32.9±19.4 (n=23) and 37.9±20.0 (n=20) kg in 1 mg, 3 mg Fungisome (liposomal amphotericin B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2±13.4, 16.0±10.9 and 22.7±16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively. The average duration of treatment with 1 mg and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B was 17±9.8, 16.2±8.3, and 14.7±10.7 days, respectively. The time to resolve fever was 13.3±10.2, 10.9±7.1, 10.1±6.7 days, and for absolute neutrophil count (ANC) to be above 500 cells per microliter, it took 13.4±9.6, 10.6±7.6 and 7.3±3.4 days, respectively. Liposomal formulations were well-tolerated compared to conventional amphotericin B. Conclusions: This small randomized study showed that the indigenous liposomal formulation Fungisome TM appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome.


Keywords: Febrile neutropenia, liposomal amphotericin B, leukemia


How to cite this article:
Jadhav M P, Shinde V M, Chandrakala S, Jijina F, Menon H, Arora B, Kurkure P A, Parikh P M, Kshirsagar N A. A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India. Indian J Cancer 2012;49:107-13

How to cite this URL:
Jadhav M P, Shinde V M, Chandrakala S, Jijina F, Menon H, Arora B, Kurkure P A, Parikh P M, Kshirsagar N A. A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India. Indian J Cancer [serial online] 2012 [cited 2020 Jul 11];49:107-13. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/107/98933



 » Introduction Top


More than half of the fatal infections in neutropenia patients are due to fungi, [1],[2] with Candida and Aspergillus being the most commonly observed pathogens. The likelihood of developing a fungal infection increases with the severity and duration of neutropenia, which, in the case of cancer or chemotherapy for the treatment of hematological malignancies can range from a few days to several weeks. Also, the severe immunosuppression induced by high dose corticosteroids given to some cancer patients puts them at additional risk of fungal infections. [3],[4] This provides a rationale for the prophylactic use of antifungal agents.

Amphotericin B has been the mainstay of treatment of invasive fungal infections. However, with conventional formulations, such as amphotericin B deoxycholate (Fungizone), the dosage administration is often limited by adverse effects (such as fever, chills and nephrotoxicity). [5],[6],[7] In addition, continuing underlying predisposing factors, such as neutropenia and advanced human immunodeficiency virus infection, may contribute to treatment failure.

The Department of Clinical Pharmacology, King Edward Memorial Hospital, Parel, Mumbai in collaboration with Department of Biochemistry, Delhi University with funding from Department of Biotechnology, Government of India, has developed a liposomal amphotericin B (Fungisome TM ) which has been investigated in animals and man and shown to be safe and effective. The manufactured formulation is patented and currently available in the Indian market. [6],[7],[8],[9],[10] Our indigenously developed product i.e., Fungisome (liposomal amphotericin B) has been extensively tested for pharmacokinetics, efficacy and safety in animal models. The safety and efficacy of the product has also been studied in patients suffering from various systemic fungal infections through Phase I-Phase IV studies. During our post-marketing study, we documented the safety, tolerability, effectiveness and cost advantage of indigenously developed liposomal amphotericin B in the treatment of febrile neutropenia and systemic fungal infections in actual clinical practice. This study gave us the basis to formulate the present study to investigate the use of liposomal amphotericin B in empirical therapy for presumed fungal infection in febrile neutropenic patients in a multicentric clinical trial. [7],[8],[9],[10]


 » Materials and Methods Top


This multicentric trial was conducted (July 2006-June 2008) at different sites namely department of Medical Oncology, Tata Memorial Hospital, Mumbai and departments of Hematology and Clinical Pharmacology (the main coordinating center) at King Edward Memorial Hospital, Parel, Mumbai, India.

Male and female patients above 2 years of age and below 60 years of age were eligible to participate if they had received/undergoing chemotherapy, or bone marrow transplant and had an absolute neutropenic count (ANC) of ≤ 500 neutrophil per cubic millimeter, had a suspected fungal infection demonstrated by fever (two oral equivalent temperatures ≥38 0 C measured at least 4 hours apart or a single oral equivalent temperature ≥38.5 0 C) after at least 96 hours of broad spectrum antibacterial therapy. It was also checked if patients had sufficient venous access to permit administration of study medication and monitoring of safety variables. Female patients of child-bearing potential were included in the study if they had a negative pregnancy test within 14 days.

Pregnancy, evidence of liver disease, SGOT (serum glutamic oxaloacetic transaminase) or SGPT (serum glutamic pyruvic transaminase) more than 10 times the upper limit of normal or total bilirubin more than five times the upper normal level, known allergy to any product containing amphotericin B, patients with concomitant medical condition (e.g., HIV), whose participation in opinion of investigator may create unacceptable additional risk, patients with life expectancy judged to be less than 1 week, patients who had evidence of fungal infection prior to the enrolment (documented invasive fungal infections), and previous inclusion in this trial were excluded from the study.

The study was approved by the local ethics committee of both the participating centers and also registered through with a clinical trial registry (ISRTCN 52812742). Written informed consent was obtained from each participant before enrollment into the study.

A computer-generated central randomization master plan with block size of six was generated. As per the randomization plan, the study medication labels either 1 mg or 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B were put in envelopes and sealed. Each envelop had a unique center and identification number. The whole randomization plan and the envelopes were prepared by a third party nonbiased person who was not part of the clinical trial.

The patients, who met the inclusion criteria, were assigned patient ID number and randomized as per randomization plan by opening the sealed envelope to receive 1 mg/kg/day or 3 mg/kg/day of Liposomal amphotericin B Fungisome TM or 1 mg/kg/day of conventional amphotericin B.

The drug was infused in all the three groups until the patient recovered from neutropenia (ANC ≥500 cell per cubic millimeter) for 3 consecutive days and had resolution of fever during the neutropenic period or developed serious and nonresolving adverse event (AE) or was withdrawn either at the patient request or at the investigator's discretion. The treatment continued to a maximum of 42 days. The patients were called up after 1 week for a post-treatment follow-up.

The safety and efficacy of liposomal amphotericin B (Fungisome TM ) and conventional amphotericin B was determined both clinically and mycologically. Fever resolution during the neutropenic period i.e. defervescence during neutropenia was defined as a minimum of 3 consecutive days without fever (<38°C or 100.4°F) which continued until end of therapy, indicated by recovery of ANC to >500 cell per cubic millimeter. The time to defervescence during neutropenia was defined as the number of hours from the first dose of study medication until the first time the oral temperature (or equivalent) measured <38°C or 100.4°F after turning afebrile. Complete Response was defined when two consecutive fungal cultures done at seven days interval were negative and a complete resolution of disease was confirmed on clinical, radiological and/or microbiological criteria occurred for more than 8 weeks after stopping the treatment. Partial response was defined if only partial resolution of disease occurred or recurrence of disease was observed within 2 weeks. Treatment was called unsuccessful if no response to drug therapy was observed within 2 weeks or after increasing dose to the maximally tolerated level.

Treatment was called successful if the following criteria were met: Successful treatment of fungal infection, absence of any breakthrough fungal infection during therapy or within 7 days after completion of therapy, survival of 7 days post-therapy, no premature discontinuation of study drug due to drug-related toxicity or lack of efficacy, and resolution of fever during neutropenic period.

Safety was assessed from AEs, vital signs (temperature, pulse, blood pressure, respiratory rate, etc., were recorded daily) and by clinically significant changes in laboratory evaluations (including hematological and biochemistry). The hematological (hemoglobin, hematocrit, platelets, red blood cells, white blood cells, neutrophils, eosinophills, monocytes, etc.) and biochemical (sodium, potassium, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, blood urea nitrogen, serum creatinine, total bilirubin, etc.) parameters were monitored twice weekly by comparison of baseline laboratory values with those obtained during and after the study.

Serious AEs, if any, were documented in source notes, informed to the ethics committee and to the sponsor as per the standard reporting protocol. The AEs were graded as per the WHO scale for severity i.e., mild, moderate and severe.

The infusion-related reactions (IRR) were recorded daily if they occurred during infusion and for two hours after completion of the study medication infusion; fever, (body temperature increased >0.6 0 C above preinfusion value), chills/rigors, nausea, vomiting, dyspnea and hypoxia. The investigators determined which, if any, appropriate premedications should be used to prevent IRRs on subsequent infusions. The premedication, if required, were started from treatment day 2 of the study i.e., 24 hours after first dose of study medication.

The study drug liposomal amphotericin B (Fugisome TM ), before administration (stored at 2-8°C), was sonicated using a bath sonicator with thermostat, at ambient temperature (Enertech Electronics Pvt. Ltd., New Delhi) for 45 min in order to convert multilamelar vesicles into unilamelar vesicles. The sonicated drug as per manufacturer's instructions was used within 24 h after sonication. The drug was diluted in 50 ml normal saline before intravenous administration. On day 1 of the therapy, a test dose of 1 ml was infused over 5 min. If no AE viz. anaphylaxis, fall in blood pressure, increase in heart rate, bronchospasm, hypersensitivity, etc., occurred, the remaining dose was administered 30 min later over 2 h on day 1 and over 1 h from day 2 onwards. The conventional amphotericin B was also diluted in 5% dextrose solution and the infusion was given for 4 h daily after giving the test dose on day 1.

This study was designed to demonstrate superiority of Fungisome (1 and 3 mg/kg/day) in comparison to conventional amphotericin B (1 mg/kg/day) in the empirical treatment of Febrile neutropenia. The primary end-point was the investigator assessment of overall treatment success. The proportion of patients with overall treatment success for conventional amphotericin B in the empirical treatment of febrile neutropenia is 49%. Based on the assumed overall treatment success of 58% and 64 % in the Fungisome 1 and 3 mg/kg/day group, respectively, a sample size of 138 patients was needed in the protocol set to conclude superiority of Fungisome (1 and 3 mg/kg/day) with power of 80% at one-sided α=0.20. This would determine that a proposed Fungisome 1 and 3 mg/kg/day treatment regimen is superior to the conventional amphotericin B group. It was further assumed that 10% of enrolled subjects would be excluded from per protocol analysis and hence it was planned to randomize 150 patients (50 patients in each group).

While calculating the results for clinical response, time to resolution of neutropenia, time to resoloution of fever, duration of treatment, drug cost, were considered in all assessable patients. For calculating ADR, all randomized patients were included.


 » Results Top


In this multicentric randomized clinical trial 75 patients with acute myeloid leukemia and acute lymphoblastic leukemia were screened and of which 65 patients were enrolled into the study at both centers.

The average body weight of patients was 26.4±14.8, 32.9±19.4, and 37.9±20.0 kg in 1 mg, 3 mg Fungisome (liposomal AMP B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2±13.4, 16.0±10.9 and 22.7±16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively [Table 1]. Of these 65 randomized patients, 57(87.69%) patients were assessable i.e., those who have taken minimum of eight doses of the drug. Of these, 40 (61.53%) patients completed treatment protocol and 17 (26.15%) did not completed study protocol [Table 2].
Table 1: Demographic and clinical details for liposomal and conventional amphotericin B

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Table 2: Measures of success of empirical antifungal therapy with liposomal and conventional amphotericin B

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Twenty-two patients were randomized to the dose of 1mg/kg/day (Fungisome), and 19 were assessable (86.36%), 3(13.63%) nonassessable patients experienced serious AEs and all 3 died. [Figure 1]. Two of them died due to terminal cardio respiratory arrest and one died due to the underlying disease. Of these assessable patients, 15 (79%) showed treatment success and four (21%) showed treatment failure. All 15 patients in this group completed their post-treatment 1-week follow-up, none of them showed any clinical sign and symptoms of recurrent fungal infection. The average duration of treatment in this arm was 17±9.8 days. The time to resolve fever was 13.3±10.2 days, and for ANC to be above 500 cells per microliter, it took 13.4±9.6 days. The average drug cost for the treatment was Rs. 58,097/-
Figure 1: Flow chart of the study

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Similarly, 23 patients were randomized to 3 mg/kg/day (Fungisome) dose, of which 20(86.95%) were assessable and 3(13.4%) were nonassessable. Two patients died due to sepsis on day 1 and 2 of the treatment and one patient died due to cardiorespiratory arrest on day 6 of treatment. Of these assessable patients, 13(65%) showed treatment success and seven (35%) showed treatment failure. Eleven patients completed their follow-up and two did not turn up for follow-up visit. The total duration of treatment, time required for resolution of fever and ANC was 16.2±8.3, 10.9±7.1, and 10.6±7.6 days, respectively. The drug cost of the treatment almost doubled to Rs. 1,47,788.

Twenty patients were randomized to 1 mg/kg/day (conventional), of which 18 (90%) were assessable and 2 (10%) were nonassessable [Table 2]. The patients who were nonassessable died on day 2 and 6 due to cardiorespiratory failure and sepsis, respectively. The total duration of treatment, time required for resolution of fever and ANC was 14.7.2±10.7, 10.1±6.7, and 7.3±3.4 days, respectively. The drug cost of the treatment was calculated to be Rs. 3725.

Treatment outcomes among three groups were compared by using χ2 test. Treatment outcomes revealed no statistically significant difference (P-value 0.588). One-way ANOVA was used to compare different demographic variables, it did not show any significant difference among all treatment groups viz., body weight, age, duration of treatment, time to resolve fever and ANC. However, when Kruskal Wallis multiple comparison Z value test (Dunn's Test) applied, a significant difference in the treatment cost between 1 mg conventional AMP B and 1 and 3 mg/kg/day Fungisome were reported suggesting that the treatment would be costly with liposomal amphotericin B (Fungisome TM ) preparation. [Table 3].
Table 3: Treatment outcome with liposomal and conventional amphotericin B

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When safety analysis was done, the AEs for all the three treatment groups were recorded for fever, vomiting, nausea, chills, rigors, headache and others (which included laboratory abnormality and other adverse events) reported. Vomiting nausea, fever and headache were highest with conventional amphotericin B group among all three treatments. However, chills and rigors were noted to be more with 1 mg Fungisome group. The comparison between treatment groups was also done viz, 1 mg Fungisome vs 1 mg conventional AMP B, 1 mg conventional AMP B vs 3 mg Fungisome, and 1 mg/kg/day Fungisome vs 3 mg/kg/day Fungisome was done. Also Pearson χ2 test was applied to these groups. A comparison for all AEs reported was made and has been presented in [Table 4].
Table 4: Adverse events details for all treatment groups

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 » Discussion Top


The present clinical study was an attempt to study the safety, efficacy and tolerability of indigenously developed liposomal amphotericin B in the empirical treatment of febrile neutropenia. Fever is the principle sign of infection in neutropenic patients and frequently may be the only evidence of infection. The pattern of fever in neutropenia is nonspecific and not pathognomic of any type of infection or noninfectious process and can be suppressed by the antipyretic effects of drugs such as corticosteroids. Neutropenia resulting from cytotoxic chemotherapy is the most common risk factor for severe infections in hematological malignancies. The duration of neutropenia also contribute significantly to the risk of serious infections. This risk is significantly greater at lower neutrophil counts, such that 100% patients with ANC <100 cell/μl lasting 3 weeks or more develop documented infections. The prompt initiation of the empirical antibiotics in febrile neutropenia treatment is important in the management of immunocompromised host. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infections.

Empirical antifungal therapy with amphotericin B in persistently febrile neutropenic patients and other high risk patients has shown improvements but their uses have been associated with severe toxicities. Several studies published in recent times have shown comparable results of trials of liposomal versus conventional amphotericin B for treatment of patients with fever and neutropenia. [11] These investigations found that based on efficacy, liposomal amphotericin B at dose of 3 mg/kg/day was equivalent to conventional amphotericin B 0.6 mg/kg/day as empirical therapy, but was associated with significantly fewer side effects. [12],[13],[14]

In comparison to 1 mg/kg/day, 3mg/kg/day dose of liposomal amphotericin B (Fungisome TM) resulted in quicker resolution of fever and neutropenia; however, there was not a significant difference in the total duration of the treatment with the higher dose.

When compared with the conventional amphotericin B treatment group, the duration of treatment was more or less same compared to the liposomal amphotericin B treatment groups. Surprisingly, the total duration required for resolution of fever and neutropenia was less than the other two groups of Fungisome TM . However, the overall treatment success was highest with the 1 mg/kg/day dose of liposomal amphotericin B i.e. 79% compared to 65% with 3 mg/kg/day of liposomal amphotericin B and 67% with 1mg/kg/day conventional amphotericin B group. When the inter and intratreatment group comparison was made it was evident that the conventional amphotericin B formulation led to more AEs, suggestive of better safety with liposomal amphotericin B formulation. Vomiting nausea, fever and headache were highest with conventional amphotericin B group among all three treatments. However, chills and rigors were noted to be more with 1 mg Fungisome group.

A significant difference in the treatment cost between 1 mg/kg/day conventional AMP B and 1 and 3 mg/kg/day Fungisome was observed, suggesting that the treatment would be costly with liposomal amphotericin B (Fungisome TM ) preparation.

During the conduct of the study, we observed some limitations, like cost of the formulation was very high (but much less compared to the other available international brands). [15] Also, the sample size was small. Since, the planned 50 patients per group could not be completed due to lack of continued availability of funds from the sponsor.

In a nutshell, it could be said that the liposomal formulation resulted in less AEs compared to the conventional amphotericin B group, suggesting the better safety of the formulation in the empirical treatment of febrile neutropenia. Also, higher dose Fungisome was well-tolerated by patients without any increased AEs. There was no difference in the efficacy among the three groups. However, the study was underpowered to detect a significant difference among the groups and derive meaningful conclusions and hence a study with a lager sample size is warranted.


 » Conclusions Top


This small randomized study showed that the indigenous liposomal formulation Fungisome TM appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome.


 » Acknowledgements Top


We are thankful to the Department of Biotechnology, New Delhi for providing the financial assistance for conduct of this study. We extend our thanks to Dr. Sanath Hegde for his inputs in preparation of the protocol and Dr. Priyanka Ingle for her help in conduct of this study.

 
 » References Top

1.Vartivarian SE, Anaissie EJ, Bodey GP. Emerging fungal pathogens in immunocrompromised patients: Classification, diagnosis, and management. Clin Infect Dis 1993;17:S487-91.  Back to cited text no. 1
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2.Jehu V. Managing fungal and viral infection in the immunocomprised host. Rev Res Cancer Res 1998;108:61-70.   Back to cited text no. 2
    
3.Goodrich JM, Reed EC, Mori LD. Clinical features and analysis of risk factors for invasive candidal infection after marrow transplantation. J Infect Dis 1991;164:734-40.  Back to cited text no. 3
    
4.Guiot HF, Fibber WE, Van T, Wout JK. Risk factors for fungal infections in patients with malignant haematological disorders: Implications for empirical therapy and prophylaxis. Clin Infect Dis 1994;18:525-32.  Back to cited text no. 4
    
5.Morrison SB, Longworth DL, Goormastic M. Early infectious complications in autologous bone marrow transplantation: A review of 219 patients. Bone Marrow Transplant 1996;18:265-71.  Back to cited text no. 5
    
6.Gotzsethe PC, Johansen HK. Metaanalysis of prophylactic or empirical antifungal treatment or placebo or no treatment in patients with cancer complicated by neutropenia. Br Med J 1997;314:1238-44.  Back to cited text no. 6
    
7.Bodhe PV, Kotwani RN, Kirodian BG, Kshirsagar NA, Pandya SK. Open Label, Randomised, Comparative Phase III Safety and Efficacy Study with Conventional Amphotericin B and Liposomal Amphotericin B in patients with systemic Fungal Infection. J Assoc Physicians India 2002;50:662-70.  Back to cited text no. 7
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8.Denning DW, Stevens DA. Antifungal and surgical treatment of Invasive aspergillosis: Review of 2121 published cases. Review of Inf Dis 1990;12:1147-201.  Back to cited text no. 8
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9.Gokhale PC, Kotwani RN, Dange SY, Kshirsagar NA, Pandya SK. Preclinical and Pharmaceutical testing of liposomal amphotericin B. Ind J Med Res 1993;98:75-8.  Back to cited text no. 9
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10.Ahmad I, Sarkar AK, Bachhawat BK. Effect of cholesterol in various liposomal compositions on the in vivo toxicity, therapeutic efficacy and tissue distribution of amphotericin B. Biotechnol Appl Biochem 1990;12:550-6.  Back to cited text no. 10
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11.Walsh TJ, Finberg RW, Andt C, Hiemenz J, Schwartz C, Bodensteiner D. Liposomal amphotericin B for empirical therapy in patients with persistant fever and neutropenia. N Engl J Med 1999;340;764-71.  Back to cited text no. 11
    
12.Maertens JA, Madero LR, Anne F, Lehrnbecher T, Groll AH, Jafri HS. et al. A randomized, double-blind, multicenter study of caspofungin versus liposomal Amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J 2010;29:415-20.  Back to cited text no. 12
    
13.Wingard JR, White M, Anaissie E, Raffali J. Goodmann J, Arrieta A. A randomized, double blind comparative trial evaluating the safety of amphotericin B versus liposomal amphotericin B complex in the empirical treatment of neutropenia. Clin Infect Dis 2001;31:1156-63.  Back to cited text no. 13
    
14.Niviox Y, Velten V, Letscher B, Moghanddam S, Natarajan AC, Fohrer B, et al. Factors associated with overall and attributable mortality in invasive aspergilisis. Clin Infect Dis 2008;47:1176-84.  Back to cited text no. 14
    
15.Kshirsagar NA, Panday SK, Kirodian BG, Sanath S. Liposomal drug delivery system from laboratory to clinic. J Postgrad Med 2005;51:S5-15.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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