A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia

PURPOSE: Several studies have documented the efficacy of amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia. Amphotericin, however, is a toxic drug. Fluconazole has broad-spectrum antifungal activity with an excellent safety profile. Although prophylactic use of fluconazole is widespread, its efficacy as an empiric antifungal agent has not been extensively investigated.PATIENTS AND METHODS: We randomly assigned 106 patients with absolute neutropenia (≤500 cells μL) and persistent fever of undetermined origin (>38°C) despite 1 week of broad-spectrum antibiotic therapy to receive either fluconazole 400 mg orally daily or amphotericin B 0.5 mg/kg/day. Patients with obvious invasive fungal infections were excluded, as were those with abnormal renal or hepatic function. Success was defined as defervescence with the initially assigned antifungal regimen without development of clinically evident invasive fungal infection.RESULTS: Six patients were excluded from the analysis, mostly because they did not have severe neutropenia. Forty-eight patients received amphotericin B, and 52 received fluconazole. Baseline clinical characteristics and laboratory parameters as well as duration of neutropenia (7.7 versus 6.9 days), duration of fever (7.8 versus 8.1 days), and duration of hospitalization (10.4 versus 8.3 days) were similar between those receiving amphotericin and fluconazole. Treatment success rates and mortality rates were similar in the two groups: 22 (46%) patients in the amphotericin group and 29 (56%) patients in the fluconazole group responded successfully to therapy (P = 0.3), whereas 16 (33%) patients in the amphotericin group and 14 (27%) patients in the fluconazole group died during hospitalization (P = 0.5). Adverse events such as chills and fever (4 versus 1), bronchospasm (2 versus none), severe hypokalemia (25 versus 12) and nephrotoxicity (9 versus 3) were more frequently observed in patients receiving amphotericin. Adverse prognostic factors included prolonged duration of neutropenia and pneumonia.CONCLUSIONS: These results suggest that fluconazole is an equally effective but less toxic alternative to amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia.     

Micafungin compared with caspofungin for the treatment of febrile episodes in neutropenic patients with hematological malignancies: A retrospective study

BACKGROUND:Invasive fungal infections are associated with morbidity and mortality in neutropenia secondary to hematological malignancies. Empirical antifungal agents are used to reduce their consequences. Caspofungin is the only echinocandin approved for this indication. Micafungin was compared with caspofungin for the treatment of patients with hematological malignancies and prolonged neutropenia.METHODS:A retrospective cohort study was conducted involving patients who had hematological malignancies with profound neutropenia for a minimum of 10 days, and received empirical micafungin or caspofungin for a minimum of five days, between April 2005 and November 2009. Successful outcome was based on a composite end point: survival for a minimum of seven days following antifungal cessation, successful treatment of baseline fungal infection, absence of adverse events and absence of breakthrough fungal infection. Fungal infections were defined according to revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria, with modification of the diagnostic imaging criteria.RESULTS:Micafungin had similar overall success to caspofungin (60.4% [29 of 48] versus 57.3% [47 of 82], respectively; P=0.729). Survival was higher in the micafungin group compared with the caspofungin group (100% [48 of 48] versus 89% [73 of 82]; P=0.02). No baseline invasive fungal infections were identified in the micafungin group, compared with three proven infections treated successfully with caspofungin (3.7%; P=0.18). Three proven breakthrough infections were observed in the micafungin group (three of 48 [27.3%]) compared with none in the caspofungin group (zero of 82; P=0.02).CONCLUSION:Micafungin has similar efficacy to caspofungin as empirical antifungal therapy in febrile neutropenic patients with hematological malignancies. Verification of these results in a prospective trial is warranted.     

Complications of hematopoietic stem transplantation: Fungal infections

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole.     

Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/microL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.     

Efficacy and safety of micafungin for treating febrile neutropenia in hematological malignancies

Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high-performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non-Hodgkin's lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies.     

Early implementation of antifungal therapy in the management of febrile neutropenia is associated with favourable outcome during induction chemotherapy for acute leukaemias

Background: Mortality related to induction chemotherapy during the treatment of acute leukaemias (AL) has been estimated at 5–20%, and this increases with age. Fungal infection remains one of the major causes of morbidity and mortality and is considered an obstacle to the successful management of acute leukaemias. Methods: We retrospectively analysed all patients treated for acute leukaemias at a single institution between July 2006 and January 2009, to assess the impact of early antifungal therapy on outcome during induction chemotherapy. There were 44 episodes of induction chemotherapy, with a median age of patients of 61 years (range 18–81), including 29 patients with acute myeloid leukaemia, 9 with acute lymphoblastic leukaemia and 6 with relapsed AL. The median age was 61 years (range 18–81), and 20 patients were over the age of 60 years. Results: All patients who developed febrile neutropenia received broad‐spectrum antibiotics. Early empirical antifungal treatment was commenced with voriconazole (15 patients) or caspofungin (12 patients) if the febrile neutropenia did not resolve after 72 h of antibiotic therapy, in conjunction with radiological changes consistent with possible fungal infection. None of the patients succumbed during induction chemotherapy. The 120‐day mortality rate after the induction therapy was 2.2%, without any incidence of invasive fungal disease. Conclusion: Our analysis shows that early empirical treatment for fungal infection with voriconazole or caspofungin is associated with a favourable outcome of induction therapy for acute leukaemias. Further studies to confirm this finding are warranted.     

The use of itraconazole as prophylaxis against invasive fungal infection in blood and marrow transplant recipients

Invasive fungal infections play a key role in contributing to morbidity and mortality in patients undergoing treatment for haematological malignancies and related diseases. Risk factors for development of invasive fungal infections after blood or bone marrow transplantation include the use of broad‐spectrum antibiotics, steroids, mismatched or unrelated donor transplant, right atrial catheters, and prolonged or profound neutropenia. Previous attempts at use of oral itraconazole as antifungal prophylaxis in the setting of chemotherapy‐induced neutropenia were unsuccessful because of its poor absorption in capsule form. Itraconazole‐cyclodextrin is well absorbed even in the presence of chemotherapy‐induced neutropenia. Plasma levels of 250–500 ng/ml are required for prophylaxis. Studies to date show a favourable outcome in patients receiving itraconazole as prophylaxis against invasive fungal infections, although many studies looked at small numbers of patients and the incidence of invasive fungal infection in the control groups was low, prohibiting meaningful statistical evaluation. Fungi differ in their sensitivity to antifungal agents, and itraconazole is not the agent of choice in all patients. With the widespread use of antifungal prophylaxis, the possibility of resistance to antifungal agents and an increase in the number of invasive fungal infections caused by ubiquitous fungi previously considered nonpathogenic must be considered as potential problems.     

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.     

Micafungin for empirical antifungal therapy in patients with febrile neutropenia: multicenter phase 2 study

Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96 h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150 mg/day. Of the 78 evaluable patients, 54 (69 %) achieved defervescence by the time of neutrophil recovery, and 56 (72 %) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60 %, with the lower limit of a 90 % confidence interval (50.3 %) exceeding the predefined threshold success rate (50 %). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study.     

Antifungal prophylaxis during treatment for haematological malignancies: are we there yet?

Antifungal prophylaxis during treatment for haematological malignancies has been studied for 50 years, yet it has not been wholly effective even when using antifungal drugs that exhibit potent activity in vitro against a broad range of fungal pathogens. Trials have demonstrated that it can reduce the incidence of invasive fungal diseases (IFD) and fungal deaths, but only two studies have had an impact on overall mortality. Furthermore, it has not significantly reduced the need for empirical antifungal therapy. Posaconazole was effective in preventing invasive aspergillosis in two studies of high-risk patients, and consensus guidelines grade it as a suitable choice for antifungal prophylaxis of invasive mould disease; however, its bioavailability was compromised by vomiting or diarrhoea so that an alternative parenteral antifungal drug was required. A recent trial of voriconazole prophylaxis after allogeneic stem cell transplantation failed to show superiority over fluconazole. With more accurate definitions of IFD, that utilize fungal biomarkers, such as galactomannan, together with computerized tomographic imaging, there is growing interest in a diagnostic-driven strategy, which could prove to be a more efficacious approach.     

Empiric antifungal therapy in neutropenic cancer patients

Hematopoietic stem cell transplant recipients and those patients with acute leukemia are at greatest risk for invasive fungal infections particularly due to Candida and Aspergillus species during periods of profound neutropenia. Empiric antifungal therapy in persistently febrile neutropenic patients has been adopted as a standard of care. Antifungal therapeutic options include: amphotericin B, lipid formulations of amphotericin B, fluconazole, itraconazole, voriconazole, and caspofungin. Amphotericin B preparations offer a beneficial effect for survival, defervescence, and a decrease in breakthrough fungal infections. Lipid formulations of amphotericin B may provide beneficial effects over amphotericin B with regard to survival, treatment of baseline fungal infection, breakthrough fungal infection, and fewer discontinuations due to lack of efficacy. Amphotericin B compounds produce a trend for better outcomes in defervescence, treatment of baseline fungal infections, prevention of breakthrough infections, and avoidance of discontinuation compared with the azoles. Caspofungin is also effective. The optimal empiric antifungal agent and the precise time of initiation remain to be determined.     

Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia >10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients.     

Modern antifungal therapy for neutropenic fever

Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.     

Changing face of health-care associated fungal infections

PURPOSE OF REVIEW: The purpose of this review was to evaluate recent publications on the epidemiology, diagnosis and management of invasive fungal infections. RECENT FINDINGS: Epidemiological surveys have highlighted significant differences between Europe and the United States regarding the incidence and etiology of Candida bloodstream infections. Today, invasive aspergillosis is occurring in a much broader patient population than the classical immunocompromised hosts and includes mechanically ventilated intensive care unit patients and patients receiving corticosteroids for treatment of chronic lung diseases. Diagnosis is often delayed in these patients and prognosis is dismal. Measurement of galactomannan, mannan and antimannan antibodies, and beta-(1-3)-D-glucan may help to speed up diagnosis. The epidemiology of invasive mold infections is changing. The frequency of non-fumigatus Aspergillus species is increasing, uncommon hyalo-or phaeo-hyphomycoses are emerging and breakthrough mold infections intrinsically resistant to azoles have been reported. Clinical trials have shown that new azoles and echinocandins are as efficacious as amphotericin B or fluconazole for the treatment of eosophageal or invasive candidiasis, for prophylaxis of invasive fungal infections in transplant patients, or for empirical antifungal therapy in patients with persistent fever and neutropenia. SUMMARY: Recent data suggest that the epidemiology of invasive fungal infections may be changing with the emergence of uncommon molds and the occurrence of invasive aspergillosis in 'nonclassical' immunocompromised hosts. New diagnostic tools and improved antifungal agents are available to facilitate early diagnosis and offer new treatment options.     

The rationale of combination antifungal therapy in severely immunocompromised patients: empiricism versus evidence-based medicine

PURPOSE OF REVIEW: Despite expansion of the antifungal armamentarium over the past decade, the mortality rate for invasive fungal infections remains high in severely immunocompromised patients. Furthermore, in recent years, difficult-to-treat invasive infections caused by rare molds and yeasts have emerged in high-risk patients receiving antifungal prophylaxis or empirical treatment. Antifungal combinations are increasingly used in clinical practice to improve outcomes for refractory mycoses because of the suboptimal efficacy of current antifungal agents. Herein we review recent advances in the area of antifungal combinations in high-risk patients to separate empiricism from evidence-based medicine. RECENT FINDINGS: Thus far, the benefits of combination antifungal therapy have been difficult to prove for invasive fungal infections other than cryptococcal meningitis. The recent introduction of a new class of antifungal agents (the echinocandins) and extended-spectrum triazoles has rejuvenated interest in studying those combinations for difficult-to-treat aspergillosis, as recent observational studies show promise. SUMMARY: In view of the evolving epidemiology of invasive fungal infections, combination antifungal therapy could be most valuable in preemptive management of carefully selected high-risk patients; however, this should be studied in appropriate trials.     

Efficacy and safety of micafungin as an empirical antifungal therapy for suspected fungal infection in neutropenic patients with hematological disorders

This prospective multicenter study was performed to clarify the efficacy and safety of micafungin (MCFG) as an empirical antifungal therapy for suspected fungal infection in patients with hematological disorders and neutropenia. Three hundred and eighty-eight patients were enrolled; 151 patients with possible fungal infection diagnosed by radiological imaging or serological testing and 237 patients with refractory fever were included in this study. The mean dose and duration of treatment with MCFG were 154.6?mg/day and 14.0?days, respectively. The clinical response rate for patients with possible fungal infection and refractory fever was 60.1% and 65.3%, respectively. Even in persistent neutropenic patients with a neutrophil count of <500/μL throughout the MCFG treatment, the clinical response rate was 46.9%. Ninety-one drug-related adverse events (DAEs) were observed in 56 patients (14.4%) and 9 serious DAEs were observed in 6 patients (1.5%). Neither daily dose nor duration of MCFG treatment affected the incidence of DAEs. It was confirmed that MCFG has adequate clinical efficacy and is safe for the treatment of suspected fungal infections in patients with hematological disorders and neutropenia.     

A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients

Fluconazole antifungal prophylaxis is standard care in allogeneic hematopoietic stem cell transplant (HSCT) recipients, but this drug lacks anti-Aspergillus activity, the primary cause of invasive fungal infection (IFI) in many transplantation centers. We performed a randomized trial to compare itraconazole vs fluconazole, for prevention of IFIs in patients with acute leukemia (AL) and HSCT recipients. One hundred and ninety-five patients were randomly assigned to either fluconazole or itraconazole antifungal prophylaxis, after stratification into high-risk and low-risk groups. Antifungal prophylaxis was started at the beginning of chemotherapy and continued until resolution of neutropenia, or until amphotericin B treatment was started. IFI occurred in 11 (11%) of itraconazole, and in 12 (12%) fluconazole recipients. Invasive candidiasis (IC) developed in two (2%) itraconazole and one (1%) fluconazole recipients, while invasive aspergillosis (IA) developed in nine (9%) itraconazole and 11(11%) fluconazole recipients. There was no difference in the incidence of total IFI, IC and IA between the two study arms. However, there was a nonsignificant trend towards reduced mortality among patients who developed IA while receiving itraconazole prophylaxis (3/9=33% vs 8/11=73%, P=0.095).     

Antifungal therapy in patients with hematological malignancies: how to avoid overtreatment?

Historically, treatment of invasive fungal infections (IFI) has consisted of amphotericin B. However, new therapeutic agents have recently been introduced. At the same time, the relatively low incidence of IFI and the progress in the diagnostic accuracy of IFI have made routine use of empirical antifungal therapy questionable. OBJECTIVES AND METHODS: With the aim to define the present trends in the use of antifungal agents for the treatment of IFI, we prospectively observed type, safety, and efficacy of given antifungal treatment in patients with hematological malignancies during a recent 18-month period. We also analyzed the impact of restricted use of empirical antifungal therapy on IFI-related mortality. RESULTS: A total of 279 episodes of neutropenia and fever following the chemotherapy were recorded. Treatment of IFI was given during the management of 41 (14%) episodes. Voriconazole (27 episodes) and caspofungin (14 episodes) were the only antifungal agents used as initial therapy. The rate of antifungal therapy success outcome was 78%. The overall 4-week mortality rate was 8%. Two patients died of invasive pulmonary aspergillosis. Empirical antifungal therapy was given in 13 episodes with persistent febrile neutropenia (PFN) and resulted in successful outcome in 92% of cases. In general, antifungal agents were well tolerated and only two patients had to discontinue treatment because of severe adverse event. In 127 episodes of PFN, antifungal therapy was deemed unnecessary and accordingly was not administered. In this subgroup of patients, no IFI-related mortality occurred. CONCLUSION: A better tolerability and efficacy of voriconazole and caspofungin together with the availability of an oral formulation of voriconazole most probably contributed to the observed shift in the use of antifungal agents. A restricted use of empirical antifungal therapy was, in this setting, not associated with an increased IFI-related mortality.     

Novel Antifungal Drugs Against Fungal Pathogens: Do They Provide Promising Results for Treatment?

The febrile neutropenia episodes of hematological patients and their outcomes were evaluated with respect to fungal pathogens and antifungal therapy in this retrospective study. All patients, who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy due to hematological cancer from November 2010 to November 2012, were included into the study. We retrospectively collected demographic, treatment, and survival data of 126 patients with neutropenia and their 282 febrile episodes. The mean Multinational Association for Supportive Care in Cancer score was 17.18 ± 8.27. Systemic antifungal drugs were initiated in 22 patients with 30 culture-proven invasive fungal infections (IFIs), 25 attacks of 19 patients with probable invasive pulmonary aspergillosis (IPA), 42 attacks of 38 patients with possible IPA, and 31 attacks of 30 patients with suspected IFI. Voriconazole (VOR), caspofungin and liposomal amphotericin B were used to treat 72 episodes of 65 patients, 45 episodes of 37 patients and 34 episodes of 32 patients as a first-line therapy, respectively. Unfavorable conditions of our hematology ward are thought to increase the number of cases with invasive pulmonary aspergillosis and VOR use. It should be taken into consideration that increased systemic and per oral VOR usage predisposes patients to colonization and infection with azole-resistant fungal strains. Catheters should be removed in cases where patients’ conditions are convenient to remove it. Acute myeloblastic leukemia cases that are more likely to develop invasive fungal infections should be monitored closely for early diagnosis and timely initiation of antifungal drugs which directly correlates with survival rates.     

Randomized controlled monocentric comparison of once daily ceftriaxone with tobramycin and cefotaxime three times daily with tobramycin in neutropenic fever

 A prospective, randomized, controlled monocentric trial was performed to evaluate the efficacy and safety of once daily ceftriaxone 2 g plus tobramycin 5 mg/kg in comparison to cefotaxime 2 g t.i.d. plus tobramycin 5 mg/kg qd in the treatment of neutropenic fever. In cases of fever ≥38.5  °C and a neutrophil count below 1000/μl, patients with hematological malignancies were assigned to ceftriaxone or cefotaxime, each with tobramycin. The primary endpoint was defined as defervescence <37.5  °C on day 4–6 followed by at least 7 afebrile days. Secondary endpoints were overall response, defined as defervescence on day 25 and toxicity. There were 160 episodes of 114 patients included. Fever of unknown origin accounted for 79 episodes (51%), microbiologically defined infection for 36 (23%), clinically defined infection for 27 (17%), and both clinically and microbiologically defined infection for 14 episodes (9%). On an intent-to-treat basis 156 episodes could be evaluated for the primary endpoint. Ceftriaxone plus tobramycin and cefotaxime plus tobramycin resulted in a primary response in 46.9% and 45.3%, respectively. Overall response was achieved on study day 25 in 87.7% and 80%, respectively. No significant difference in toxicity was observed. Once-daily ceftriaxone plus tobramycin was not inferior to cefotaxime t.i.d. plus tobramycin qd in the empirical treatment of neutropenic fever. Received: 29 October 1999 / Accepted: 28 August 2000