scholarly journals Galactomannan and Computed Tomography-Based Preemptive Antifungal Therapy in Neutropenic Patients at High Risk for Invasive Fungal Infection: A Prospective Feasibility Study

2005 ◽  
Vol 41 (9) ◽  
pp. 1242-1250 ◽  
Author(s):  
J. Maertens ◽  
K. Theunissen ◽  
G. Verhoef ◽  
J. Verschakelen ◽  
K. Lagrou ◽  
...  
Keyword(s):  
Computed Tomography ◽  
High Risk ◽  
Fungal Infection ◽  
Feasibility Study ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Neutropenic Patients

scholarly journals Classical Empiric Antifungal Therapy Vs. D-Index Guided Early Therapy Using Micafungin for Persistent Febrile Neutropenia (CEDMIC trial): A Randomized Controlled Trial from Japan FN Study Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 816-816
Author(s):  
Shun-Ichi Kimura ◽  
Yoshinobu Kanda ◽  
Masaki Iino ◽  
Takahiro Fukuda ◽  
Emiko Sakaida ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Controlled Trial ◽  
Pharmaceutical Research ◽  
Randomized Controlled ◽  
Neutropenic Patients

Abstract Introduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61]. Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (>=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection. Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P<0.001). Similar results were obtained in per-protocol set analyses. Conclusions: DET successfully reduced the use of antifungal agents without increasing invasive fungal infection or mortality compared to EAT. This randomized controlled study revealed the feasibility of DET in high-risk neutropenic patients. Disclosures Kimura: Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kanda:Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe-Mitsubishi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Fujiwara:Shire: Consultancy; Pfizer: Consultancy; Chugai: Consultancy; Kirin: Consultancy; Kyowa-Hakko: Consultancy; Astellas: Consultancy. Suzumiya:Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; SymBio: Research Funding; Toyama Chemical: Research Funding; Takeda: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Research Funding; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Tamura:Astellas Phrma: Research Funding; Eisai: Speakers Bureau; Kyowa Hakko Kirin: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau.

scholarly journals Successful treatment of gastrointestinal mucormycosis in an adult with acute leukemia: case report and literature review

2017 ◽  
Vol 24 (1) ◽  
pp. 61 ◽  
Author(s):  
A. Alghamdi ◽  
A. Lutynski ◽  
M. Minden ◽  
C. Rotstein
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Acute Leukemia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Successful Treatment ◽  
Invasive Fungal Infection ◽  
Hematologic Malignancies ◽  
Considerable Morbidity ◽  
Delays In Diagnosis

Mucormycosis has emerged as an important cause of invasive fungal infection in patients with hematologic malignancies. Gastrointestinal mucormycosis is an unusual presentation of this invasive fungal infection, and it causes considerable morbidity and mortality. Such outcomes are due in part to a nonspecific presentation that results in delays in diagnosis and treatment. Successful treatment of gastrointestinal mucormycosis involves surgical debridement and appropriate antifungal therapy.

scholarly journals Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection

2010 ◽  
Vol 54 (6) ◽  
pp. 2409-2419 ◽  
Author(s):  
Jiun-Ling Wang ◽  
Chia-Hsuin Chang ◽  
Yinong Young-Xu ◽  
K. Arnold Chan
Keyword(s):  
Systematic Review ◽  
Liver Injury ◽  
Fungal Infection ◽  
Liver Enzyme ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Adverse Reactions ◽  
Meta Analysis ◽  
Elevated Serum ◽  
Treatment Discontinuation

ABSTRACT To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.

Antifungal Therapy in Neutropenic Oncohemopatic Patients. A Single Centre Retrospective Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5334-5334
Author(s):  
Alessandro Bonini ◽  
Alessia Tieghi ◽  
Simona Bulgarelli ◽  
Luigi Gugliotta
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Renal Insufficiency ◽  
Acute Leukemia ◽  
Fungal Infection ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Secondary Prophylaxis ◽  
Antifungal Treatment ◽  
Empiric Treatment

Abstract Infections are the most frequent complication during chemotherapy-induced neutropenia and fungal infections are a cause of morbility and mortality. We have retrospectively analysed our patients who received an antifungal treatment for a possible, probable or proven fungal infection. Between April 1998 and July 2005 we analysed 750 consecutive phases of treatment for 309 patients admitted at our Institution. The treatment phases were for: acute leukemia 253, lymphoma 168, multiple myeloma 215, chronic leukemia 19, severe aplastic anemia 12, solid tumors (breast, renal, testis cancer) 44, multiple sclerosis 5, others 34. Among them 474 (63.2%) were at high risk for infections (the risk was considered high for lenght of neutropenia, diagnosis of acute leukemia, allogeneic BMT). There were 31 allo-BMT and 145 autologous BMT. The antifungal therapy was for a first short period (until mid-1999) an empirical treatment (when fever persisted more than 4 days despite antibiotic therapy during neutropenia); after, only when another sign (clinical or radiological or microbiological) of fungal infection was present, the patients received an antifungal treatment. We treated also a small cohort of patients with a secondary prophylactic regimen (they were patients who developed a fungal infection during a previous treatment). Seventy-four patients received an antifungal treatment (10% of all phases and 15.6% of high-risk phases). The infection was possible (empiric treatment) in 4 cases, probable (presumptive therapy) in 37 cases, proven in 16 cases; 17 cases of secondary prophylaxis. The first administered drug was Amphotericin B deoxycholate (AMB) in 31/74 cases (41.9%), Abelcet (ABCT) in 6/74 (8%), Liposomal Amphotericin B (LAMB) in 18/74 cases (24.4%), Voriconazole (VCZ) in 3/74 cases (4%) and Caspofungin (Caspo) in 16/74 cases (21.7%). The schedule of treatment was: AMB 0.7–1 mg/Kg in 6 hours, ABCT 5 mg/Kg in 3 hours, LAMB 3 mg/Kg in 1 hour, VCZ 6 mg/Kg bid iv in 2 hours for 3 days then 4 mg/Kg bid orally, Caspo 70 mg iv on the first day and then 50 mg in 1 hour. For the empiric treatment the first drug was AMB 3 and Caspo 1; for presumptive therapy AMB 18, ABCT 4, LAMB 4, VCZ 1 and Caspo 10. For proven infections AMB 8, ABCT 1, LAMB 5, VCZ 1, Caspo 1; for secondary prophylaxis AMB 2, ABCT 1, LAMB 9, VCZ 1 and Caspo 4. The isolated fungi were Candida albicans 4, Aspergillus spp 4, Scedosporium 2, Fusarium solani 1, others (only histological isolation) 5. The days of treatment were 7.64 for AMB, 6.88 for ABCT, 14.22 for l-AMB, 14.1 for Caspo and 30 for VCZ. Adverse events with AMB and ABCT were similar: mild to moderate renal insufficiency (50%), fever (50%), ipokalemia (75%), chills (30%); with VCZ visual disturbances (80%) and mild hepatic insufficiency (20%); with LAMB mild renal insufficiency (10%) and low back pain (5%); no adverse events with Caspo were noted. AMB was discontinued 9/31 times (29%), ABCT 1/6 (17%) for adverse events. Our conclusions are that AMB and ABCT are problematic drugs for their poor tolerability, they need an important premedication, a hyperhydration regimen and a long-time administration; moreover for a great cohort of patients we have had to discontinue the drug. The other drugs seems to be better tolerated; no organ failures were seen and the treatment duration was longer for Caspo and LAMB. Even if the cost of these two drugs is major than others the lack of adverse events and the new mechanism of action of Caspo make these drugs probably better than ABCT, AMB and VCZ.

Oral Voriconazole for Empiric Antifungal Treatment in Uncomplicated Febrile Neutropenic Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5494-5494
Author(s):  
Kara Keasler ◽  
Joyce Broyles ◽  
Brian McClune ◽  
Francis Buadi ◽  
Donna Przepiorka
Keyword(s):  
Fungal Infection ◽  
Median Duration ◽  
Invasive Fungal Infection ◽  
Broad Spectrum ◽  
Treatment Success ◽  
Autologous Transplantation ◽  
Total Duration ◽  
Allogeneic Transplantation ◽  
Persistent Fever ◽  
Neutropenic Patients

Abstract The addition of an antifungal agent with activity against molds is considered standard of care for neutropenic patients with persistent fever treated with broad spectrum antibacterial antibiotics. The currently available intravenous agents suffer from high cost or high rates of toxicity. Voriconazole, a triazole with excellent activity against yeast and molds, has an oral bioavailability of 96% and comparable AUCs following IV and PO dosing. In 2003, we changed our standard policy to allow use of oral voriconazole in whole or in part for empiric antifungal coverage for neutropenic patients with uncomplicated persistent fever. Voriconazole was to be loaded at 6 mg/kg IV or PO q 12 hrs for 2 doses and followed by 200 mg PO BID. Over a 32-month period, 27 patients were treated for 31 episodes of persistent neutropenic fever. The cohort included 14 males and 13 females of median age 55 yrs (range, 19–78 yrs). Median weight at the time of first treatment was 84 kg (range, 62–122 kg). Nineteen patients had leukemia, 5 had lymphoma, and 3 had myeloma. Of the 31 episodes, 24 were for induction chemotherapy, 6 for autologous transplantation, and 1 for allogeneic transplantation. Standard prophylactic antibiotics included levofloxacin, fluconazole, valacyclovir and weekly nebulized amphotericin. The patients had been treated with vancomycin and cefepime, or a similar broad spectrum regimen, at the time of fever onset. The median time from fever to start of voriconazole was 4 days. All patients had an ANC<1500. The median WBC prior to voriconazole was 200 (range, 100–1700), and the median duration of ANC<500 prior to voriconazole was 9 days (range, 0–35 days). The median total duration of ANC<500 was 19 days (range, 5–86 days). The chest X-ray was abnormal in 8/30 episodes, CT scan was abnormal in 13/20 episodes, and the galactomannan assay was positive in 1/22 episodes. In 8 (26%) episodes, the patients fulfilled the criteria for possible invasive fungal infection, but none had a probable or definite invasive fungal infection at the start of voriconazole. The loading dose was given PO in 18 episodes and IV in 13 episodes. Median duration of therapy was 11 days (range, 2–54 days). Visual disturbances were reported in 0 (0%) episodes, rash in 2 (6%), creatinine ≥2.0 in 3 (10%), bilirubin ≥2.0 in 5 (16%), AST ≥100 in 2 (6%), and ALT ≥100 in 1 (3%). No patient discontinued drug because of toxicity. Success was described as resolution of fever without the need for a change in antibiotics. The success rate was 55% (95% CI, 36–73%). Fever resolved at a median of 4 days whether or not antibiotics were changed. Changes in the antibiotic regimen after voriconazole varied with the clinical circumstances; these included new antifungal agents in 7/14 and new antibacterial agents in 7/14. Gram positive cocci was the most common organism in this group of patients (10/14 (71%)), and a fungal infection (fusarium) was documented in only one patient. Day-90 survival was 81% (95% CI, 63–93%) for all patients. Neither treatment success nor Day-90 survival differed when compared by whether loading was IV vs PO, or whether the patient had a possible invasive fungal infection at the start of voriconazole. We conclude that oral voriconazole is safe for neutropenic patients with uncomplicated persistent fever, and its efficacy should be evaluated in a randomized trial.

Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1917-1917
Author(s):  
Marie Sebert ◽  
Claire Aguilar ◽  
Sylvie Chevret ◽  
Lionel Ades ◽  
Olivier Lortholary ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Fungal Infection ◽  
Predictive Factors ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Pulmonary Infection ◽  
Influenza B ◽  
Fatal Infection

Abstract Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated. Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed. Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus). Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection. Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. Disclosures Ades: celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

Systemic antifungal therapy in critically ill patients without invasive fungal infection*

2012 ◽  
Vol 40 (3) ◽  
pp. 813-822 ◽  
Author(s):  
Elie Azoulay ◽  
Hervé Dupont ◽  
Alexis Tabah ◽  
Olivier Lortholary ◽  
Jean-Paul Stahl ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Critically Ill ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Critically Ill Patients ◽  
Systemic Antifungal Therapy
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