Comparing Diagnostic-Driven Approaches to Empiric Therapy in the Treatment of Invasive Aspergillosis in Patients with Hematologic Malignancy

Abstract Background Early antifungal therapy of invasive aspergillosis (IA) has been shown to be associated with improved outcome. Given the difficulty to establish the diagnosis of IA based on conventional methods, early initiation of empiric antifungal therapy has been used in patients with clinically suspected IA. Diagnostic-driven approach (DDA) relies on using novel diagnostic methods (e.g., early galactomannan testing). In this current study, we compared the outcomes of hematological malignancy (HM) patients with IA who were treated with Voriconazole using the DDA (DDA-Vori) vs. empiric therapy with a non-Voriconazole containing regimen (EMP-non-Vori) or empiric therapy with Voriconazole (EMP-Vori). Methods We retrospectively reviewed the medical records of 604 HM patients with documented, proven or probable IA (according to EORTC/MSG criteria) diagnosed between July, 1993 and February, 2016 at our center. We included 346 patients with underlying host factors, a suggestive CT findings of IA, and positive biopsy, fungal culture or galactomannan indicative of IA, and who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all causing mortality and IA attributable mortality. Results The patients’ median age was 54 years and 59% were males. By multivariate analysis, factors that were predictive of a favorable response included: localized/sinus IA vs. disseminated/pulmonary IA (P < 0.0001), not receiving WBC transfusion (P < 0.01), and DDA-VORI vs. EMP-non-Vori (P < 0.0001). On the other hand, predictors of mortality within 6 weeks of initiation of IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (P < 0.01), not having stem-cell transplant within 1 year prior of IA (P = 0.01) and EMP-non-Vori vs. DDA-Vori (P < 0.001). Conclusion DDA-Vori is associated with a better outcome (response and survival) when compared with EMP-non-Vori and equivalent outcome to EMP-Vori. The superior to equivalent outcome associated with the DDA approach could also reduce unnecessary costs and adverse events associated with widespread use of empiric therapy. Disclosures I. Raad, Merck: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant. Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

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272. Invasive Pulmonary Aspergillosis: Comparative Analysis in cancer patients with Underlying Hematologic Malignancy vs. Solid Tumor

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.347 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S150-S150

Author(s):

Rita Wilson Dib ◽

Melissa Khalil ◽

Johny Fares ◽

Dima Dandachi ◽

Ray Y Hachem ◽

...

Keyword(s):

Cancer Patients ◽

Antifungal Therapy ◽

Solid Tumor ◽

Hematopoietic Cell Transplantation ◽

Hematologic Malignancy ◽

Invasive Pulmonary Aspergillosis ◽

Response To Therapy ◽

Attributable Mortality ◽

Cancer Center ◽

Pulmonary Aspergillosis

Abstract Background Over the years, the profile of patients with invasive pulmonary aspergillosis (IPA) has extended beyond the commonly associated population with hematologic malignancy (HM) and is now comprising patients with solid tumors and patients with lung diseases. We therefore aimed to compare the clinical characteristics, diagnostic approach and therapeutic outcome of IPA in cancer patients with hematologic malignancies vs. solid tumor (ST). Methods We conducted a retrospective study evaluating consecutive cases of proven and probable IPA from March 2004 to December 2016 in a tertiary cancer center. We included patients >18 years with an underlying ST, HM, or Hematopoietic Cell Transplantation (HCT) within 1 year of IPA diagnosis. Results A total of 311 patients were analyzed: 225 had HM including HCT and 86 ST. Patients with ST were more likely to have had COPD (33% vs. 8%, P > 0.01) or other underlying pulmonary diseases when compared with HM patients (76% vs. 43%, P < 0.01). Radiation therapy prior to the infection was also notably higher in the ST group than the HM group (48% vs. 14%, P < 0.01). Patients with HM were more likely to have received steroid (38% vs. 15%, P = 0.0001) and have concurrent neutropenia 37% vs. 2%, P < 0.0001). A. fumigatus was most commonly recovered in patients with ST than in patients with HM (66% vs. 38%, P < 0.01). Monotherapy and voriconazole-based primary antifungal therapy were more often prescribed in patients with ST than in patients with HM (87% vs. 56%, P < 0.0001 and 77% vs. 53%, P = 0.0002 respectively). Complete or partial successful response to therapy was recorded in 66% of patients with ST compared with 40% in the HM group (P = 0.0001). IPA attributable mortality within 12 weeks was significantly higher in the HM than in the ST group (30% vs. 18%, P = 0.04). Conclusion Monotherapy with voriconazole were more often prescribed in patients with ST than in patients with HM. Patients with ST had a better response to antifungal therapy and a lower IPA attributable mortality within 12 weeks compared with those with HM. Disclosures All authors: No reported disclosures.

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INVASIVE ASPERGILLOSIS IN INTENSIVE CARE UNIT PATIENTS IN IRAN

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2014.24 ◽

2013 ◽

Vol 56 (2) ◽

pp. 52-56 ◽

Cited By ~ 5

Author(s):

Mohammad T. Hedayati ◽

Sadegh Khodavaisy ◽

Masoud Alialy ◽

Saeed Mahdavi Omran ◽

Mohammad R. Habibi

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Bronchoalveolar Lavage ◽

Invasive Aspergillosis ◽

Microscopic Examination ◽

Diagnostic Methods ◽

Fungal Culture ◽

Icu Patients ◽

Gm Detection ◽

Predisposing Conditions

We assessed the intensive care unit (ICU) patients for Invasive aspergillosis (IA) with culture and non-culture based diagnostic methods from Iran. Thirty-six ICU patients with underlying predisposing conditions for IA were enrolled in the study. Sixty eight Bronchoalveolar lavage (BAL) samples were collected by bronchoscope twice a weekly. BAL samples were analyzed by microscopic examination, fungal culture and galactomannan (GM) detection. The Platelia Aspergillus GM EIA was used to quantify GM indices. Samples with a BAL GM index ≥1 were considered as positive for GM. Patients were classified as having probable or possible IA. Out of 36 suspected patients to IA, 36.1% of cases showed IA which were categorized as: 4 cases of possible IA and 9 of probable IA. 76.2% of BAL samples were positive for GM. From 13 patients with IA, 11 (84.6%) had at least one positive BAL GM index. Of these patients, 9 (81.8%) showed probable IA. The main underlying predisposing conditions were neutropenia (53.8%) and COPD (30.8%). Our study has indicated that COPD must be considered as one of the main predisposing condition for occurrence of aspergillosis in ICU patients. Our data have also revealed that GM detection in BAL samples play a significant role to IA diagnosis.

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657. Diagnostic Utility of Dedicated Fungal Blood Cultures for Diagnosis of Candidemia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.850 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S385-S385

Author(s):

Bryant Yang ◽

Omai Garner ◽

Richard Ou ◽

Nicholas Stanzione

Keyword(s):

Antifungal Therapy ◽

Bacterial Culture ◽

De Novo ◽

Empiric Therapy ◽

Fungal Culture ◽

Culture Techniques ◽

Time To Positivity ◽

Positive Bacterial Culture ◽

Culture Positive ◽

Culture Negative

Abstract Background Blood culture techniques have improved to the point where they are considered sensitive enough for detection of Candida. Expert guidelines clarifying the utility of use of dedicated fungal isolator cultures are lacking, and we wondered what utility, if any, they add for the diagnosis of candidemia. Methods All patients with cultures between March 2016-February 2020 positive for Candida were examined via manual chart review, noting time to positivity and time of initiation of antifungal therapy. Results We focused on cases of candidemia where a fungal culture was ordered and turned positive (59 out of the total 181 cases of candidemia). We eliminated an additional 10 cases where fungal cultures were sent while already on antifungal therapy or in patients already known to be fungemic, given our interest in de novo diagnoses. Another case was removed due to lack of clinical details, as the patient was discharged prior to culture results and managed at a different medical facility. There were 14 cases with discordant growth (fungal culture positive, bacterial culture negative). One patient passed away prior to culture results, but in the remaining 13 cases, the fungal culture changed clinical management, in most cases by prompting initiation of antifungal therapy. The remaining 36 cases involved with concordant growth between bacterial and fungal cultures. In 11 of those cases, the fungal culture isolated yeast 12 or more hours faster than its paired bacterial culture (average 40.7 +/- 26.6 hours). In 7 of these cases, the fungal culture changed management – in the remaining cases, the patient was already on empiric therapy. Among all cultures sent in patients not receiving antifungals that isolated Candida, the overall time to positivity for fungal cultures was 37.2 +/- 13 hours, while bacterial cultures took 54 +/- 26.4 hours. Fungal Culture Results Conclusion Fungal cultures changed management in 20/59 cases of candidemia (34%) either by making the diagnosis faster than a bacterial culture or making it outright. Given the morbidity and mortality associated with candidemia, rapid diagnosis is critically important. More specific guidelines optimizing how to best utilize fungal cultures to help standardize practice among clinicians will be critical going forward. Disclosures Omai Garner, PhD, D(ABMM), Beckman Coulter (Scientific Research Study Investigator)

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Broad-Spectrum Antifungal Prophylaxis in Patients With Cancer at High Risk for Invasive Mold Infections: Counterpoint

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2008.0015 ◽

2008 ◽

Vol 6 (2) ◽

pp. 183-189 ◽

Cited By ~ 21

Author(s):

Johan Maertens ◽

Kristel Buvé ◽

Elias Anaissie

Keyword(s):

High Risk ◽

Antifungal Therapy ◽

Empiric Therapy ◽

Screening Tools ◽

Therapeutic Drug ◽

Cell Transplant ◽

Drug Bioavailability ◽

Hematopoietic Stem ◽

Study Results ◽

Invasive Mold Infections

Management of invasive mold infections in patients with prolonged neutropenia and hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) has been hampered by the difficulty in diagnosing these infections. Definite diagnosis invariably centers on histologic identification of hyphae in tissue or on culture from a sterile body site. Therefore, most practitioners have relied on prophylaxis and empiric therapy. Currently, emphasis is shifting from routine prophylaxis and empiric therapy to screening of patients with neutropenia at high risk so that clinicians can administer appropriate antifungal therapy early, when it can potentially improve patient outcome. Non–culture-based microbiologic tools are at the forefront of this paradigm shift. Commercially available methods to detect fungal antigens and sophisticated techniques to detect fungal DNA may be used as screening tools during the highest risk period. Together with assessment of clinical signs, cultures, and especially CT scanning, these methods are useful for starting antifungal therapy preemptively. While awaiting further evaluation of these tools during the postengraftment period of allogeneic HSCT, mold-active prophylaxis targeting the subgroup of patients with severe acute or chronic GVHD may be justified. However, some critical issues have not yet been adequately addressed, including the generalizability of study results, impact of mucositis and gastrointestinal GVHD on drug bioavailability, need for therapeutic drug monitoring, impact of prophylaxis on the performance of diagnostic assays, and optimal treatment of breakthrough invasive fungal infections.

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Is combination antifungal therapy for invasive aspergillosis a necessity in hematopoietic stem-cell transplant recipients?

Current Opinion in Infectious Diseases ◽

10.1097/01.qco.0000235165.08797.81 ◽

2006 ◽

Vol 19 (4) ◽

pp. 371-379 ◽

Cited By ~ 6

Author(s):

Helen L Leather ◽

John R Wingard

Keyword(s):

Stem Cell ◽

Invasive Aspergillosis ◽

Hematopoietic Stem Cell ◽

Antifungal Therapy ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Transplant Recipients ◽

Hematopoietic Stem

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Empirical Versus Pre-Emptive Antifungal Therapy in High-Risk Febrile Neutropenic Patients: An Economic Analysis.

Blood ◽

10.1182/blood.v108.11.2021.2021 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2021-2021 ◽

Cited By ~ 2

Author(s):

Michael Schwarzinger ◽

Celine Beauchamp ◽

Sebastien Maury ◽

Cecile Pautas ◽

Anne Vekhoff ◽

...

Keyword(s):

Economic Analysis ◽

Antifungal Therapy ◽

Diagnostic Methods ◽

Cost Comparison ◽

Recurrent Fever ◽

Induction Phase ◽

Cell Transplant ◽

Medication Costs ◽

Therapy Costs ◽

Neutropenic Patients

Abstract Empirical (E) antifungal therapy (ATF) is a standard of care in neutropenic patients with persistent or recurrent fever. However, the safety and cost-effectiveness of the E strategy are challenged by the development of better diagnostic methods and more effective therapies for invasive fungal infection (IFI). An economic analysis was conducted alongside a multicenter open-label randomized non-inferiority trial showing that a pre-emptive (PE) strategy based on clinical symptoms and GM Ag did not reduce the overall survival of prolonged neutropenic patients when compared to a E strategy (details provided in abstract 551005). Objective: The objective of the study was to compare hospital costs between the PE strategy and E strategy. Patients: 293 adult patients with hematologic malignancies and an expected neutropenia (<500 PMN) of ≥ 10 days following chemotherapy were randomized between E or PE strategy with polyens. All were screened 2/w for GM Ag. E patients were given ATFs in case of persistent or recurrent fever, whatever the accompanying symptoms, while PE patients were given ATFs only in case of pneumonia, severe mucositis, septic shock, sinusitis, or skin lesions evocative of filamentous infection, aspergillus colonization, or positive GM Ag. Methods: The economic analysis was conducted from the hospital perspective (€2005). Total medication costs were computed from individual records during hospital stay. Results: Overall, mean medication costs did not differ significantly between the PE and E groups (see Table). In patients in induction phase (n=151), mean medication costs were higher in the PE group than the E group (+921€, [95%CI, −1602 to +3444]) as explained by the significantly higher proportion of IFI in the PE group (16.4% vs. 3.9%, p<0.01) and the significantly higher medication costs in case of IFI (+4224€, [95%CI, +1200 to +7244]). In patients in consolidation phase (n=51) or autologous stem cell transplant (ASCT) (n=91), mean medication costs were significantly lower in the PE group than the E group (−1224€, [95%CI, −233 to −2215]) as explained by the significantly lower proportion of patients receiving ATF in the PE group (31% vs. 50%, p<0.03). Conclusion: Cost comparison between E and PE strategy showed opposite results in induction or consolidation/ASCT phases. This finding is mainly explained by different risks of developing IFI according to the therapeutic phase. (Grants: PRC 2002 AOR02028). Table: Comparison of mean(std) medication costs, antifungal therapy costs, and proportion of IFI between PE and E groups (€2005) PE strategy E strategy p Overall (n=293) Medication costs 3595 (7444), n=143 3745 (4768), n=150 ns Antifungal therapy costs 2218 (6969), n=143 2337(4093), n=150 ns Proportion of IFI 9.1% (13/143) 2.7% (4/150) <0.02 Induction (n=151) Medication costs 5714 (9843), n=73 4793 (5330), n=78 ns Antifungal therapy costs 3974 (9360, n=73 3353 (4876), n=78 ns Proportion of IFI 16.4% (12/73) 3.9% (3/78) <0.01 Consolidation or ASCT (n=142) Medication costs 13871807, n=70 2610 (3795), n=72 <0.02 Antifungal therapy costs 386 (1367), n=70 1237 (2649), n=72 <0.02 Proportion of IFI 1.4% (1/70) 1.4% (1/72) ns

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Empirical Versus Pre-Emptive Antifungal Therapy in High-Risk Febrile Neutropenic Patients: A Prospective Randomized Study.

Blood ◽

10.1182/blood.v108.11.2019.2019 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2019-2019 ◽

Cited By ~ 7

Author(s):

Catherine Cordonnier ◽

Cecile Pautas ◽

Sebastien Maury ◽

Anne Vekhoff ◽

Hassan Farhat ◽

...

Keyword(s):

Overall Survival ◽

Antifungal Therapy ◽

Clinical Symptoms ◽

Diagnostic Methods ◽

Recurrent Fever ◽

Cell Transplant ◽

Survival Difference ◽

Neutropenic Patients ◽

The Mean ◽

Related Mortality

Abstract Empirical (E) antifungal therapy (ATF) is a standard of care in febrile neutropenic patients under broad-spectrum antibiotics. However, the safety and cost-effectiveness of the E strategy are challenged, due to better diagnostic methods including galactomannan antigenemia (GM Ag) and efficient therapies for invasive fungal infection (IFI). Previous open studies have evaluated the feasibility of a pre-emptive (PE) strategy where ATF is restricted to patients with clinical symptoms and/or mycological criteria of IFI. This study is the first prospective, randomized trial comparing E vs PE strategy. Objective: The primary objective of the study was to show that a PE strategy was not inferior to a E strategy for overall survival. Patients: 293 adult patients with hematologic malignancies (acute leukemia: 199; lymphoma: 65; others:29), including 91 with autologous stem cell transplant (ASCT) and an expected neutropenia (<500 PMN) of ≥ 10 days following chemotherapy were randomized between E or PE strategy with polyens. All were screened 2/w for GM Ag. E patients were given ATFs in case of persistent or recurrent fever, whatever the accompanying symptoms, while PE patients were given ATFs only in case of pneumonia, severe mucositis, septic shock, sinusitis, or skin lesions evocative of filamentous infection, aspergillus colonization, or positive GM Ag. Methods: This is a multicenter open-label randomized non-inferiority trial. Randomization was stratified according to center, induction vs. consolidation or ASCT, and antifungal prophylaxis. The primary endpoint was the proportion of patients alive either 14 days after recovery from neutropenia or 60 days after inclusion in case of persistent neutropenia or severe complication. Non-inferiority was concluded if survival difference was above the threshold of −8% in intention-to-treat (ITT) and per protocol (PP) analyses. The secondary endpoint was the proportion of patients with IFI (EORTC-MSG definitions). Results: Among the 150 patients of the E group, and the 143 of the PE group, the mean (std) age was 52 (14) y. The mean (std) duration of neutropenia was 21 (11) days (min: 5; max: 69). Survival was not inferior in the PE group (136/143) as compared to the E group (147/150) with a survival difference of −2.9% [95% CI, −6.4% to 0.6%] in ITT (n=293) and −2.9% [95% CI, −6.8% to 0.1%] in PP (n=266) above the threshold of −8%. The IFI-related mortality was not significantly different in the PE group (3/150) and the E group (0/143) (p=0.12). However, significantly more IFI were diagnosed in the PE group (13/143) when compared to the E group (4/150) (p<0.02). The PE patients received significantly less ATFs than the E group (46% v. 66% of patients, p<0.001). Conclusion: A PE strategy based on clinical symptoms and GM Ag did not reduce the overall survival of prolonged neutropenic patients when compared to a E strategy. Although we observed significantly more IFI in the PE than in the E group, this did not translate in a higher fungal-related mortality (Grants: PHRC 2002 AOR02028)

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The Outcome of Patients (pts) with Acute Promyelocytic Leukemia (APL) Who Fail Both All–Trans-retinoic Acid (ATRA) and Arsenic Trioxide (ATO).

Blood ◽

10.1182/blood.v114.22.4143.4143 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4143-4143

Author(s):

Ravin Jain Garg ◽

Hagop Kantarjian ◽

Meetu Agrawal ◽

Farhad Ravandi ◽

Gautam Borthakur ◽

...

Keyword(s):

Salvage Therapy ◽

Research Funding ◽

Treatment Options ◽

Gemtuzumab Ozogamicin ◽

Response To Therapy ◽

The Other ◽

Cancer Center ◽

Cell Transplant ◽

All Trans Retinoic Acid ◽

New Treatment

Abstract Abstract 4143 Background ATRA-based therapy is effective for most pts with APL. For those who do not respond or relapse after ATRA, ATO induces remissions in most pts. Few pts may fail therapy with both agents, and the outcome of these pts is not known. Aim To investigate the outcome of pts who fail therapy with both ATRA and ATO, whether given concomitantly [ATRA+ATO induction] or sequentially [ATRA-based induction with ATO-based salvage]. Methods Pts with APL who were treated with both ATRA and ATO at M.D. Anderson Cancer Center were reviewed. Response to both agents was scored according to standard criteria. Pts who failed both ATRA and ATO, whether given concomitantly or sequentially, were identified. Failure was defined as no response to therapy, relapse, or death from any cause (including during therapy or in complete remission –CR–). Overall survival (OS) was considered as the time from the date the pt started ATO (together with or after ATRA) to death. Results A total of 113 pts have been treated with both ATRA and ATO therapy: 83 (73%) received ATRA and ATO as initial induction therapy and 30 (27%) received an ATRA-based induction regimen followed by ATO salvage therapy. Of them, 19 (17%) failed both agents. The median age at diagnosis was 48 yrs (range, 18 to 74). Of the 83 pts who received ATRA + ATO induction, 81 achieved CR and 4 subsequently relapsed. The other 2 pts died during induction. Two other pts who were initially treated elsewhere with chemotherapy alone (one also received stem cell transplant), received ATRA + ATO as salvage therapy upon relapse; one had sustained CR and the other had no response (NR). Thus a total of 7 patients (4 relapses after remissions of 9.2 mo, 13 mo, 9.1 mo, and 12.3 mo; 2 induction deaths; 1 NR) failed therapy with both ATRA + ATO. Among the 4 pts that relapsed, 3 received ATO + ATRA salvage therapy and achieved CR; 1 died in CR and 2 are alive in CR 70.2+ and 29.3+ months later. One pt declined further therapy. In addition, 30 pts received ATRA-based induction and, upon relapse, ATO-based salvage therapy (12 of them combined with ATRA). Twelve (40%) of these pts failed salvage with ATO: 1 had NR to therapy, 6 achieved CR and then relapsed (after median of 14.4 mo, range 3.2 to 48.9), and 5 died in CR (salvage with ATO alone in 3, ATRA+ATO in 2). Of the 7 pts with NR or relapse, 5 achieved CR with subsequent therapy (ATRA-based in 2, ATRA+ATO in 2, ATO-based in 1 on 2nd salvage; ATO-based in 1, ATRA+ATO in 1, Tamibarotene in 1 on 3rd salvage; gemtuzumab ozogamicin-based in 1 and ATRA-based in 1 as 4th salvage). Of all 19 pts that failed both ATRA and ATO, 14 (74%) died: 7 during induction or in CR and 7 after failure. The median survival from failure to ATRA and ATO (excluding those who died during induction or in CR since death defines failure for these pts) is 42 mo, with 36% alive at 4 yrs. Conclusion The outcome of patients who fail both ATRA and ATO either concomitantly or sequentially is poor. Although some pts may respond to subsequent therapies, most ultimately succumb to their disease, and others die during therapy. New treatment options are needed for this group. Disclosures: Ravandi: Cephalon: Advisory board, Honoraria. Cortes:CytRx: Research Funding; Wyeth: Research Funding.

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