Liposomal Amphotericin B (L-AMB) Is Superior to Amphotericin B Deoxycholate (AmB-d) in Preventing Breakthrough Fungal Infections in Patients with Prolonged Neutropenia and Fever: Results of a Sub-Group Analysis of an Empirical Antifungal Therapy Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1336-1336
Author(s):  
Catherine Cordonnier ◽  
Thomas J. Walsh ◽  
Mark Bresnik
Keyword(s):  
Treatment Group ◽  
Antifungal Therapy ◽  
Median Duration ◽  
Fungal Infections ◽  
Clinical Success ◽  
Group Analysis ◽  
Candida Spp ◽  
All Cause Mortality ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

Abstract In a trial of empirical antifungal therapy in persistently febrile neutropenic patients, L-AMB was shown to be comparable in overall efficacy with significantly less nephrotoxicity and infusion-related reactions when compared to AmB-d. In addition, significantly fewer proven breakthrough invasive fungal infections (IFI) occurred in the L-AMB treatment group. (Walsh TJ, et al, NEJM1999; 340: 764–71). In order to better evaluate the maximum efficacy benefit of L-AMB in a higher risk patient subset, a sub-group analysis was performed on those patients with duration of neutropenia greater than or equal to the median duration for the entire study population. The results of this sub-group analysis are presented. Methods: From the original data set, the median duration of neutropenia from the time of treatment initiation was determined. Clinical success (defined by a composite endpoint), frequency of proven breakthrough IFI and all cause mortality were reported by treatment group for patients with duration of neutropenia greater than or equal to the median. Investigator-reported proven breakthrough IFI were reviewed and verified by an independent, blinded expert. Results: A total of 687 patients were enrolled in the trial. Median duration of neutropenia following initiation of antifungal therapy was 7 days (range 1–50). 392 patients had neutropenia >/= 7 days, (L-AMB=205), (AmB-d=187). Clinical success: L-AMB: 128/205 (62.4%); AmB-d: 112/187 (59.9%), and all cause mortality: L-AMB: 19/205 (9.3%); AmB-d: 24/187 (12.8%) were not significantly different. The frequency of proven breakthrough IFI favored L-AMB: L-AMB: 7/205 (3.4%); AmB-d: 18/187 (9.6%), p=0.01. Organisms isolated: L-AMB: 2 Candida spp (blood); 4 Aspergillus spp. (3 pneumonia, 1 wound); 1 Mucor sp (pneumonia). AmB-d: 9 Candida spp (8 blood, 1 pneumonia); 7 Aspergillus spp (4 pneumonia, 1 sinus, 1 pericarditis, 1 wound); 1 Cryptococcus albidus (blood); 1 unclassified mould (pneumonia). The difference in emergent proven IFI for the patients with neutropenia <7d trended in favor of L-AMB, but was not statistically significant: L-AMB 3/138 (2.2%); AmB-d 8/157 (5.1%). Conclusions: Overall clinical success and all cause mortality remained equivalent for the 2 treatment arms in the subset of patients with prolonged neutropenia. However, L-AMB significantly reduced the frequency of proven breakthrough IFI in this high-risk patient population. These data support the efficacy of L-AMB as empirical therapy, particularly for persistently neutropenic patients at higher risk for invasive fungal infections.

Empirical Antifungal Therapy for Patients with Neutropenia and Persitent Fever - Systematic Review and Meta-Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4961-4961
Author(s):  
Elad Goldberg ◽  
Anat Gafter-Gvili ◽  
Mical Paul ◽  
Eyal Robenshtok ◽  
Liat Vidal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Meta Analysis ◽  
Persistent Fever ◽  
All Cause Mortality ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

Abstract Background: Opportunistic invasive fungal infections (IFIs) are a major concern in the management of immunocompromised patients with hematological malignancies. The practice of administering antifungal therapy to neutropenic patients with persistent fever has become a standard care. Conflicting data exists concerning the efficacy of empirical antifungal therapy. Objectives: This study aims to evaluate if empirical antifungal therapy reduces mortality and prevents invasive fungal infections (IFI). Methods: Systematic review and meta-analysis including randomized controlled trials (RCTs) comparing empirical antifungal treatment with placebo or no intervention (control), or another regimen, in neutropenic patients with persistent fever. The Cochrane Library, MEDLINE, conference proceedings and references were searched until 2007. Outcomes assessed were: All-cause mortality, documented IFI, and adverse events. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Results: Our search yielded 26 trials, 6 of which compared polyenes or azoles to control, and 20 compared between different regimens of polyenes, azoles or glucan synthesis inhibitors. Compared to control, there was no difference in all-cause mortality (RR 0.98; 95% CI 0.58–1.66, 5 trials, Fig.1). The risk for developing documented IFI was lower (RR 0.23; 95% CI 0.08–0.65, 4 trials, 4 events in the treatment group versus 18 in the control). When azoles (fluconazole, ketoconazole, itraconazole, voriconazole) were compared to polyenes (amphotericin B in 8 trials, liposomal ampho B in 1 trial) there was a trend in favor of azoles for decreased all-cause mortality (RR 0.89; 95% CI 0.73–1.09, 9 trials) and for decreased documented IFI (RR 0.70; 95% CI 0.47–1.04, 8 trials). Adverse events of any kind were less frequent in the azole group (RR 0.40; 95% CI 0.34–0.66, 5 trials), as were those which required discontinuation (RR 0.48; 95% CI 0.38–0.62, 7 trials). Conclusions: Our review demonstrates that empirical antifungal therapy does not reduce mortality. Although it reduces IFIs, data are based on a small number of trials and events. The use of amphotericin B as empirical antifungal therapy seems unwarranted since it appears to be less effective than azoles, with no mortality benefit and an increased rate of side effects. Future trials should pursue a pre-emptive approach using improved diagnostic tools (such as galactomannan testing, high resolution CT), to identify the patients for whom antifungal treatment is warranted. Figure Figure

Micafungin Versus Voriconazole for Empirical Antifungal Therapy In Febrile Neutropenic Patients with Acute Myeloid Leukemia: A Randomized, Controlled Trial.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1062-1062
Author(s):  
Tatsuo Oyake ◽  
Shugo Kowata ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antifungal Therapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Controlled Trial ◽  
End Point ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients ◽  
Acute Myeloid

Abstract Abstract 1062 Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality among neutropenic patients after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with VRCZ (6 mg/kg twice on day 1 followed by 4 mg/kg twice daily) as first-line empirical antifungal treatment for 95 hospitalized FN patients with AML during induction or consolidation chemotherapy (MCFG, 49; VRCZ, 46). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and VRCZ was 10 and 9 days, respectively. The efficacy rates of MCFG and VRCZ were not significantly different (37.8% vs. 32.4%). The rates of breakthrough fungal infections (proven, probable and possible IFIs), successful treatment of baseline fungal infections, survival 7 days after end of therapy, and resolution of fever during neutropenia were similar in the two groups. However, premature discontinuation of therapy occurred less often in the MCFG group than in the VRCZ group (32.4% vs. 55.9%, P=0.0457*). In safety evaluation, there were fewer adverse events in the MCFG group than in the VRCZ group (27.0% vs. 64.7%, P=0.0013*). *: Chi square test Conclusions: MCFG was as effective as VRCZ, and better tolerated than VRCZ as empirical antifungal therapy in FN patients with AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients

1998 ◽  
Vol 42 (9) ◽  
pp. 2391-2398 ◽  
Author(s):  
Thomas J. Walsh ◽  
Vijay Yeldandi ◽  
Maureen McEvoy ◽  
Corina Gonzalez ◽  
Stephen Chanock ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Therapy ◽  
High Performance ◽  
Fungal Infections ◽  
Empirical Therapy ◽  
Liposomal Formulation ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

ABSTRACT The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

scholarly journals Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections

2020 ◽  
Vol 7 (1) ◽  
pp. 17
Author(s):  
Frederic Lamoth ◽  
Russell E. Lewis ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Antifungal Therapy ◽  
Susceptibility Testing ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Invasive Fungal Infections ◽  
Antifungal Susceptibility Testing ◽  
Candida Auris ◽  
Candida Spp ◽  
Neutropenic Patients

Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among Candida and Aspergillus spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for Candida spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non-albicans Candida spp. (notably emerging Candida auris). For Aspergillus spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among A. fumigatus. For non-Aspergillus molds (e.g., Mucorales, Fusarium or Scedosporium spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice.

P963 Empirical antifungal therapy in febrile neutropenic patients-systematic review

2007 ◽  
Vol 29 ◽  
pp. S253-S254
Author(s):  
E. Goldberg ◽  
A. Gafter-Gvili ◽  
M. Paul ◽  
E. Robenshtok ◽  
L. Vidal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Antifungal Therapy ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

scholarly journals Forum Report: Issues in Clinical Trials of Empirical Antifungal Therapy in Treating Febrile Neutropenic Patients

2003 ◽  
Vol 36 (Supplement_3) ◽  
pp. S117-S122 ◽  
Author(s):  
John E. Bennett ◽  
John Powers ◽  
Thomas Walsh ◽  
Claudio Viscoli ◽  
Ben de Pauw ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antifungal Therapy ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients

Invasive Fungal Infection in Febrile Patients with Hematologic Malignancies Undergoing Chemotherapy in Iran

2019 ◽  
Vol 19 (3) ◽  
pp. 302-307 ◽  
Author(s):  
Saba Sheikhbahaei ◽  
Alireza Mohammadi ◽  
Roya Sherkat ◽  
Alireza Emami Naeini ◽  
Majid Yaran ◽  
...  
Keyword(s):  
Blood Culture ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Fungal Species ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Severe Neutropenia ◽  
Candida Spp

Background: Patients with hematological malignancies undergoing cytotoxic chemotherapy are susceptible to develop invasive fungal infections particularly Aspergillus and Candida spp. Early detection of these infections is required to start immediate antifungal therapy and increase the survival of these patients. Method: Our study included consecutive patients of any age with hematologic malignancies who were hospitalized to receive chemotherapy and suffer from persistent fever (rectal temperature >38.5°C) for more than 5 days despite receiving broad-spectrum antibiotics. A whole blood sample was taken and sent for blood culture. PCR was also conducted for Aspergillus and Candida species. Results: One hundred and two patients were investigated according to the inclusion criteria. The most common hematologic malignancy was AML affecting 38 patients (37.2%). Six patients were diagnosed with invasive fungal infections (A. fumigatus n=3, C. albicans n=2, A. flavus n=1) by PCR (5.8%) while blood culture showed fungus only in 1 patient. Three more cases were known as probable IFI since they responded to antifungal therapy but the PCR result was negative for them. AML was the most prevalent malignancy in IFI patients (83.3%) and odds ratio for severing neutropenia was 21.5. Odds for each of the baseline characteristics of patients including gender, age>60, diabetes mellitus, previous IFI, history of using more than 3 antibiotics, antifungal prophylaxis, episodes of chemotherapy> 8 and chemotherapy regimen of daunarubicin+cytarabine were calculated. Conclusion: We found that multiplex real-time PCR assay is more accurate than blood culture in detecting fungal species and the results are prepared sooner. Among all factors, the only type of cancer (AML) and severe neutropenia, were found to be risk factors for the development of fungal infections in all hematologic cancer patients and previous IFI was a risk factor only AML patients.

PCR-Based Liposomal Amphotericin B Treatment Following Allogeneic Stem Cell Transplantation Is a Safe Treatment Strategy: Preliminary Results of a Prospective Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 192-192 ◽  
Author(s):  
Holger Hebart ◽  
L. Klingspor ◽  
Thomas Klingebiehl ◽  
Juergen Loeffler ◽  
J. Tollemar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Post Transplantation ◽  
Pcr Screening ◽  
Group A ◽  
Empirical Antifungal Therapy ◽  
Group B

Abstract A prospective randomized multi-center trial was initiated comparing PCR-based preemptive and empirical antifungal therapy with AmBisome in patients after allogeneic stem cell transplantation. A total of 408 patients were randomized at the time of transplant to the antifungal treatment strategy. PCR screening was planned twice weekly during stay in hospital and once weekly after discharge until day 100 post-transplantation. Antifungal prophylaxis consisted of up to 200 mg fluconazole/day. Antifungal therapy was initiated in the PCR group in PCR+ patients with signs of infection and patients with 2 consecutive positive PCR results, and in the empirical treatment group (group B) after 120 hours of febrile neutropenia not responding to broad-spectrum antibacterial therapy. Antifungal treatment consisted of AmBisome at 3 mg/kg for 3 days (loading dose) followed by AmBisome at 1 mg/kg in clinically stable patients, AmBisome at 3 mg/kg was continued in clinically unstable patients. Treatment was stopped according to pre-defined study rules. The two arms were well balanced with regard to age, gender, donor type, underlying disease and stage, and conditioning regimens applied. Out of 403 evaluable patients 196 were randomized to group A and 207 to group B. AmBisome therapy was initiated in 109 patients in group A and in 76 patients in group B (P<0.05). Eleven patients in group A and 16 patients in group B developed proven invasive fungal infections (IFI), overall mortality at 100 and 180 days was not different. Survival curves demonstrated a lower mortality until day 30 post-transplantation for patients receiving PCR-based antifungal therapy with AmBisome (deaths in group A, n=4; group B, n=13; P=0.03). During this early time period when regular PCR-screening was performed, only 1 patient in group A (candidiasis) and 5 patients in group B (invasive aspergillosis, n=1; candidiasis, n=4) succumbed to IFI (P=0.1). This study prospectively compared PCR-based versus empirical antifungal therapy with AmBisome after allogeneic SCT. A reduction in early mortality and a trend for a lower rate of proven invasive fungal infections was documented until day 30 post-transplantation indicating that close fungal PCR monitoring allows to stratify patients at high risk for the subsequent development of invasive fungal infections. Survival at day 100 and 180 post-transplantation was not different.

Results of a Randomized, Double-Blind Trial of Fluconazole (FLU) vs. Voriconazole (VORI) for the Prevention of Invasive Fungal Infections (IFI) in 600 Allogeneic Blood and Marrow Transplant (BMT) Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 163-163 ◽  
Author(s):  
John R. Wingard ◽  
Shelly L. Carter ◽  
Thomas J. Walsh ◽  
Joanne Kurtzberg ◽  
Trudy N. Small ◽  
...  
Keyword(s):  
Overall Survival ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Survival Rates ◽  
Double Blind Trial ◽  
Double Blind ◽  
Free Survival ◽  
Blind Trial ◽  
Empirical Antifungal Therapy ◽  
Standard Risk

Abstract A multi-center, randomized, double blind trial was performed to determine the impact of FLU (400 mg daily in adults) vs. VORI (200 mg twice daily in adults) on the prevention of IFIs in standard risk allogeneic BMT patients receiving full-intensity conditioning regimens. 600 patients with AML (n=230), ALL (n=122), CML (n=103), MDS (n=98), lymphoma (n=43) and other diseases (n=4) were randomized; 295 to FLU, 305 to VORI between 2003 and 2006 (1 not transplanted). Study drugs were given for 100 days; in those receiving prednisone at a dose of ≥1 mg/kg/day at day 100 or for recipients of T cell depleted grafts with CD4+ counts &lt;200 at day 100, drugs were administered for 180 days. All patients had serum galactomannan (GM) assayed twice weekly for 60 days, then once to twice weekly until day 100, depending on severity of graft versus host disease (GVHD). Positive GM, radiology or the presence of suspicious symptoms or signs triggered intensive evaluation for IFI. Empirical antifungal therapy was permitted for suspected IFI during diagnostic assessment but was limited to ≤14 days. The primary endpoint was freedom from IFI or death at 6 months (fungal-free survival) in the intent to treat cohort. Median recipient age was 43 years (range, 3-66) with 92% &gt;18 years; 55% male; 95% with HLA A, B, and DRB1 matched donor; stem cell graft was related donor marrow or PBSC in 56%. There were no significant differences between the two arms in patient, disease type or risk, or transplant characteristics. Rates of engraftment, acute or chronic GVHD, non-fungal infections, expected or unexpected severe adverse events, and rates of premature study drug withdrawal were similar in both arms (p=NS). At a median follow-up of 12 months, overall survival was 80% at 6 months and 67% at 12 months. A blinded data review committee reviewed source documents of all reported fungal infections, deaths, patients with a positive GM and those given empirical antifungal therapy. There were 25 proven, 30 probable, 15 presumptive, and 74 possible IFIs. The cumulative rates of proven, probable and presumptive IFI were similar in the two arms: 10.6% for FLU and 6.6% for VORI at 6 months (p=0.11) and 13.1% and 11.6% at 12 months (p=0.50), respectively. Microbiologically documented IFIs at 6 months in each arm (FLU and VORI) were caused by Aspergillus (16 and 7, p=0.05), Candida (3 and 3), Zygomycetes (3 and 2), and other (1 and 1). Fungal-free survival rates were similar: 76% for FLU and 78% for VORI at 6 months (p=NS) and 65% and 63% at 12 months (p=NS), respectively. Event-free and overall survival rates also were similar in both arms at 6 and 12 months (p=NS). There were no differences in fungal-free survival rates in patients who received prophylactic fluconazole or voriconazole when intensive monitoring and early empirical therapy were employed in standard risk allogeneic BMT recipients.

Sign in / Sign up

Export Citation Format

Share Document