hematopoietic stem cell transplantation ( hsct ) is an effective treatment modality , for a variety of hematologic malignancies . despite improvement in the prophylaxis and treatment strategies and supportive care measures , infection still is considered as a substantial cause of morbidity and mortality in patients undergoing hsct , by the advances achieved in the control of bacterial infections after hsct , invasive fungal infections ( ifis ) are chief infectious complications in these patients . additionally , infections with less common fungi like fusarium and trichosporon species have been reported in this patient population . the incidence of ifi after allogeneic hsct is estimated to be 10% to 25% in high - risk patients . there are many risk factors that have been evaluated for the development of ifi following hsct . some of them are neutropenia duration , receiving glucocorticoids , donor type , age , underlying disease , graft - versus - host disease ( gvhd ) , organ dysfunction ( renal , hepatic , or respiratory failure ) , hyperglycemia , cytomegalovirus or hiv infections , the function of immune system , breakdown of the gut mucosa due to chemotherapy and radiation therapy , use of indwelling devices and iron overload . routinely four strategies including prophylactic , empiric , preemptive , and targeted therapy are applied for the management of fungal infections . as a common practice , high risk patients receive prophylaxis against fungal infections . for prophylaxis against candida infections in patients undergoing hsct , fluconazole has been administered during the neutropenic period . whenever possible to identify the infectious fungi , targeted treatment can be implemented . according to eortc / msg consensus group , the proved diagnosis of fungal infection in a patient with findings consistent with an endemic mycosis needs at least positive culture obtained from blood or the affected site or evidences from histopathology or direct microscopic observation . however , the diagnosis of fungal infections is difficult due to several factors . moreover , according to idsa guideline for neutropenic patients with 5 days of persistent fever after the initiation of broad spectrum antibiotics , in whom no specific cause has been determined ; starting empiric antifungal treatment can be considered . despite the advances achieved in the diagnosis and treatment of fungal infections , unfortunately there are still centers in which the proved diagnosis of fungal infections can not be made and other strategies have been used for the treatment of suspected and less well documented infections . since the introduction of amphotericin b in 1958 , the availability of lipid - based formulations of amphotericin b , echinocandins and extended - spectrum triazoles were major advances towards the treatment of fungal infections and provided the clinicians with wider treatment options . nowadays these agents are prescribed increasingly for the treatment of fungal infections due to increased number of immune compromised and critically ill patients . 
  in iran , different studies have addressed the prevalence of ifis in the setting of solid organ transplantation . but to the best of our knowledge , there is no data available on the prevalence of antifungal drugs administration in hsct setting . so the aim of this study was to assess the prevalence of treatment with antifungal agents in allogeneic hsct recipients . in this study , we present the retrospective review of records of patients who received allogeneic hsct in the hematology - oncology , bone marrow transplantation center at shariati hospital in tehran , iran , between august 2009 and august 2010 . patients received different conditioning regimens according to the underlying disease and based on the hospital protocols . none of the patients in this center received total body irradiation ( tbi ) as a part of conditioning regimen . the day of the hsct procedure was considered to be day 0 and the days after and before that , were named to be + and  respectively . engraftment was considered when anc counts of  500 10/l and platelet counts of  2000010/l were achieved for three consecutive days without transfusion . phenytoin was administered to patients receiving conditioning regimens containing busulfan for seizure prophylaxis additionally ; patients received prophylaxis against nausea and vomiting . gvhd prophylaxis consisted of cyclosporine and low dose methotrexate in patients who received allogeneic hsct . all patients received low dose acyclovir on admission which continued throughout hospitalization for prophylaxis of herpes zoster . management of fever in neutropenic patients was according to the guideline of infectious diseases society of america ( idsa ) on  the use of antimicrobial agents in neutropenic patients with cancer  . for neutropenic febrile patients an appropriate blood cultures were obtained to determine the source of infection before initiation of broad spectrum antibiotics empirically . if the fever episode was persistent after 48 hours and no etiology for the infection was identified , vancomycin was added to the previous medications . whenever fever continued for more than 5 days after initiating antibiotics and cross - checking of extracted data with the original data sheets and patients charts was done rigorously . tables , absolute frequency , percentage , median , mean , standard error of the mean , maximum and minimum values were used to summarize different types of data as appropriate . to determine the relationship between distributions of demographic or clinical covariates in allogeneic hsct patients whether or not receiving treatment with antifungal agents , we used chi - square test or fisher 's exact test for categorical data , independent sample t - test for quantitative data with parametric distributions , and mann - whitney u test for quantitative data with non - parametric distribution . the day of the hsct procedure was considered to be day 0 and the days after and before that , were named to be + and  respectively . engraftment was considered when anc counts of  500 10/l and platelet counts of  2000010/l were achieved for three consecutive days without transfusion . phenytoin was administered to patients receiving conditioning regimens containing busulfan for seizure prophylaxis additionally ; patients received prophylaxis against nausea and vomiting . gvhd prophylaxis consisted of cyclosporine and low dose methotrexate in patients who received allogeneic hsct . all patients received low dose acyclovir on admission which continued throughout hospitalization for prophylaxis of herpes zoster . also patients received cotrimoxazole for the prevention of pneumocystis carinii infection . management of fever in neutropenic patients was according to the guideline of infectious diseases society of america ( idsa ) on  the use of antimicrobial agents in neutropenic patients with cancer  . for neutropenic febrile patients an appropriate blood cultures were obtained to determine the source of infection before initiation of broad spectrum antibiotics empirically . if the fever episode was persistent after 48 hours and no etiology for the infection was identified , vancomycin was added to the previous medications . whenever fever continued for more than 5 days after initiating antibiotics and cross - checking of extracted data with the original data sheets and patients charts was done rigorously . tables , absolute frequency , percentage , median , mean , standard error of the mean , maximum and minimum values were used to summarize different types of data as appropriate . to determine the relationship between distributions of demographic or clinical covariates in allogeneic hsct patients whether or not receiving treatment with antifungal agents , we used chi - square test or fisher 's exact test for categorical data , independent sample t - test for quantitative data with parametric distributions , and mann - whitney u test for quantitative data with non - parametric distribution . all the analyses were performed using spss version 17.0 ( spss inc . , chicago , il , usa ) . during the one - year study period , eighty two patients were admitted to the ward . patients consisted of 41 men ( 68.3% ) and 19 women ( 31.7% ) with mean age of 26.3 (  1.2 ) years . thirty two patients ( 53.3% ) received hsct due to hematologic malignancies ; the rest of them received hsct because of other underlying diseases such as thalassemia , aplastic anemia and a few other infrequent diseases . in fact thalassemia was the most prevalent condition ( 26.7% ) leading to hsct followed by acute myeloid leukemia ( aml ) ( 23.3% ) in this set of patients . median time to engraftment , median duration of neutropenia and median recovery period were 12 ( range : 9 - 32 ) , 8 ( range : 2 - 22 ) and 21 ( range : 12 - 48 ) days respectively . all patients ( except one ) in this study received antifungal prophylaxis with fulconazole 100 mg twice daily orally . one patient was under treatment with posaconazole and amphotericin b before hospitalization . in 28 patients ( 46.7% ) the prophylaxis of fungal infection was switched from oral fluconazole to low dose intravenous amphotericin b ( 0.3 mg / kg / day ) due to the severity of mucositis which made the oral administration of medications impossible for the patients . among all of allogeneic hsct recipient in this study , 15 patients ( 25% ) received treatment with systemic antifungal medications . the prophylactic agent was discontinued upon the initiation of the treatment . among patients under prophylaxis with amphotericin b , in 4 patients the dose of amphotericin b increased to the therapeutic dose due to the suspected infections . the median duration of antifungal treatment for patients who received the therapeutic doses of amphotericine b was 10 ( 2 - 23 ) days . neither positive cultures nor histopathologic or direct microscopic evidences were available from the specimen obtained from patients . empiric treatment with antifungal agent was initiated with amphotericin b in 14 patients however , later in 3 patients ; treatment was switched from amphotericin b to voriconazole due to the suspicious of aspergillosis infection . characteristics of hsct recipients and the frequent regimens used for pre transplantation conditioning are summarized in table 1 and table 2 respectively . characteristic of allogeneic hsct recipients who received treatment with antifungal agents and those who did not receive treatment aml : acute myelogenous leukemia , all : acute lymphoblastic leukemia , aa : aplastic anemia , cml : chronic myeloid leukemia , mm : multiple myeloma , mds : myelodysplastic syndrome , cr : complete remission other conditions consisted of one patient with the diagnosis of paroxysmal nocturnal hemoglobinuria and one patient with myelofibrosis in each group p values are based on mann - whitney u test frequent conditioning regimens used for allogeneic hsct in patients who received treatment with antifungal agents and those who did not receive treatment all patients ( except one ) in this study received antifungal prophylaxis with fulconazole 100 mg twice daily orally . one patient was under treatment with posaconazole and amphotericin b before hospitalization . in 28 patients ( 46.7% ) the prophylaxis of fungal infection was switched from oral fluconazole to low dose intravenous amphotericin b ( 0.3 mg / kg / day ) due to the severity of mucositis which made the oral administration of medications impossible for the patients . among all of allogeneic hsct recipient in this study , 15 patients ( 25% ) received treatment with systemic antifungal medications . the prophylactic agent was discontinued upon the initiation of the treatment . among patients under prophylaxis with amphotericin b , in 4 patients the dose of amphotericin b increased to the therapeutic dose due to the suspected infections . the median duration of antifungal treatment for patients who received the therapeutic doses of amphotericine b was 10 ( 2 - 23 ) days . neither positive cultures nor histopathologic or direct microscopic evidences were available from the specimen obtained from patients . empiric treatment with antifungal agent was initiated with amphotericin b in 14 patients however , later in 3 patients ; treatment was switched from amphotericin b to voriconazole due to the suspicious of aspergillosis infection . characteristics of hsct recipients and the frequent regimens used for pre transplantation conditioning are summarized in table 1 and table 2 respectively . characteristic of allogeneic hsct recipients who received treatment with antifungal agents and those who did not receive treatment aml : acute myelogenous leukemia , all : acute lymphoblastic leukemia , aa : aplastic anemia , cml : chronic myeloid leukemia , mm : multiple myeloma , mds : myelodysplastic syndrome , cr : complete remission other conditions consisted of one patient with the diagnosis of paroxysmal nocturnal hemoglobinuria and one patient with myelofibrosis in each group p values are based on mann - whitney u test frequent conditioning regimens used for allogeneic hsct in patients who received treatment with antifungal agents and those who did not receive treatment among patients received allogeneic hsct , acute gvhd appeared in 32 ( 53.3% ) patients and the most frequent involved site was skin ( 46.9% ) . table 3 shows the acute gvhd severity and the affected organs in patients who underwent treatment with antifungal agents and those who did not receive antifungal treatment . severity of acute gvhd and the involved site in hsct recipient p values are based on chi - square test hematology - oncology wards and intensive care units are among the highest consuming antifungal agents in hospitals . it is important to know the data about antifungal agents prescribed in these wards . in this retrospective study we evaluated the prevalence of antifungal medications administered to patients receiving hsct during early post transplant period in a referral hospital in tehran . during this one - year study almost all patients received fluconazole for the prophylaxis of fungal infections ; however , in 28 patients the switch to intravenous antifungal prophylaxis was inevitable and they received low dose amphotericin b for this purpose . although due to the potential toxicity , amphotericin b was more used as a treatment option rather than prophylaxis , the approach of using this drug as a prophylactic agent goes back to the studies conducted in 1990s . in a prospective randomized trial , koh et al . , compared the efficacy of prophylactic use of fluconazole and low - dose amphotericin b against fungal infections in recipients of hsct . overall , the study showed that the incidence of proven , suspected or superficial fungal infections was not significantly different between the two groups . for example martino et al . , evaluated 395 recipients of allogeneic hsct in spain and reported that 73% of patients received fluconazole , 17% itraconazole and 4% amphotericin b for prophylaxis and 6% did not receive any antifungal agent for this purpose . none of the patients in our study received itraconazole for prophylaxis . also there are reports of poor tolerability of itraconazole . for example in a cohort of 549 high risk haematology and hsct recipients barnes et al . , found that itraconazole was poorly tolerated for prophylaxis and therapeutic serum levels were achieved only in 70% of patients . fifteen patients ( 25% ) in our study received antifungal medications due to the suspected ifis . none of the patients received azoles ( neither fluconazole nor itraconazole ) for the therapeutic purposes . the empiric antifungal drug administered for patients in our study was amphotericin b. however , in a study on sales data of five university hospitals in germany , de with et al . , showed that amphotericin b consumption decreased during the period of 2001 - 2003 in the hematology - oncology wards which was primarily attributed to increase in voriconazole administration . additionally , as it is expected the pattern of empirical antifungal administration is variable in different centers . for example in a retrospective study of four - year antifungal prescription in hematologic patients , chan et al . , reported that echinocandins were accounted for 62% of all antifungal administrations . in contrast none of the patient in our study received this category of antifungal agents . this was probably due to the unavailability of micafungin , and anidulafungin and restricted availability of caspogungin in iran . additionally , the cost of the latter drug was not covered by the medication insurance systems at the time of the study . in a meta - analysis , goldberg et al . , compared empirical or preemptive antifungal treatment with placebo , no intervention , or another antifungal treatment in patients with hematologic malignancies . the results showed that azoles were associated with lower mortality compared with amphotericin b. also administration of liposomal amphotericin b decreased the mortality and ifis more than other amphotericin b formulations . voriconazole is the first line agent for the treatment of aspergillosis infection and during our study it was prescribed when there was a suspicion of aspergillosis infection and due to the considerable high cost it was not used as an option for empiric treatment . this is the same as the study of chen et al in which they found that voriconazole was infrequently used for empirical therapy and it was prescribed in 23% of all antifungal drug administrations . additionally , most often it was used for the cases of high clinical suspicion of invasive aspergillosis . none of the patients in our study were proven cases of ifi and only in one patient the positive results of serum galactomannane test was available . although it is proposed that empiric treatment did not result in considerable decrease in mortality , it led to a significant decrease in the documented or probable ifis and is considered to be the standard practice in special patient populations . one of the patients in our study had a positive serum galactomannane test . in the absence of stronger evidences for proving fungal infections , serum galactomannane test and computed tomography ( ct ) are helpful measures for the initiation of antifungal treatment and can predict response . for example ji et al . , retrospectively studied 124 patients who received empirical antifungal agents following allogeneic hsct and concluded that patients with positive serum galactomannane test and/or chest ct scan had significantly higher response rate to empirical antifungal treatment compared with all patients . we did not observe any significant differences in neutropenia duration ( p value : 0.54 ) , length of hospital stay ( p value : 0.27 ) and number of patients developed graft versus host disease ( p value : 0.07 ) between patients received antifungal agents with those who did not receive treatment . the most important restriction in our study was the lack of microbiologic confirmation of the ifis in this center which is almost the same as most other centers in iran . another limitation is the short time patients follow up which did not allow us to assess the long - term outcomes . also it should be noted that the number of patients included in this study was limited . so it is suggested that researchers conduct a prospective larger trial for better assessment of the fungal infections and their treatment . the most important restriction in our study was the lack of microbiologic confirmation of the ifis in this center which is almost the same as most other centers in iran . another limitation is the short time patients follow up which did not allow us to assess the long - term outcomes . also it should be noted that the number of patients included in this study was limited . so it is suggested that researchers conduct a prospective larger trial for better assessment of the fungal infections and their treatment . none of the patients in this study received targeted treatment with antifungal agents and the treatment was implemented empirically .