The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole

2013 ◽  
Vol 88 (4) ◽  
pp. 283-288 ◽  
Author(s):  
Jason N. Barreto ◽  
Cassidy L. Beach ◽  
Robert C. Wolf ◽  
Julianna A. Merten ◽  
Pritish K. Tosh ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myelodysplastic Syndromes ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Neutropenic Patients

Itraconazole for Antifungal Prophylaxis in Neutropenic Patients: An Update of a Meta-Analysis with Now 3846 Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3224-3224
Author(s):  
Axel Glasmacher ◽  
Corinna Hahn ◽  
Marie von Lilienfeld-Toal ◽  
Katjana Orlopp ◽  
Ingo Schmidt-Wolf ◽  
...  
Keyword(s):  
Relative Risk ◽  
Randomized Clinical Trials ◽  
Fungal Infections ◽  
Meta Analysis ◽  
Cochrane Review ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Significant Difference ◽  
Neutropenic Patients ◽  
Related Mortality

Abstract Invasive fungal infections, esp. from Aspergillus spp., still are a major cause of mortality and morbidity in neutropenic patients with haematological malignancies. We have published a meta-analysis on the use of itraconazole for antifungal prophylaxis (Glasmacher et al., JCO2003; 21: 4615) and now present updated results. Methods: In a continuous search of electronic databases and abstracts we identified randomized clinical trials in neutropenic patients that compared itraconazole with either nothing, oral polyenes or fluconazole. Again, analysis was restricted to proven invasive fungal infections according to EORTC/MSG criteria. Statistical analyses were performed with the Cochrane Review Manager (Version 2.4.8), relative risk ratios (RR) with their 95% confidence intervals (95%CI) and appropriate P values were reported. Subgroups were defined by itraconazole preparation and the comparator. A RR below 1 indicates better results for itraconazole. Results - New Trials: Two new trials with 54 and 195 evaluable patients (pts) were identified and the data of one unpublished trials was updated. Both studies used itraconazole solution (400 mg/d) and compared it to 400 mg/d fluconazole. One study applied intravenous solutions of both drugs if necessary. No study was powered to detect a significant difference in proven invasive fungal infections between the two drugs. One study reported a reduction of fungal-related mortality in the itraconazole arm (fluconazole 9/12, 75%, vs. itraconazole 5/11, 45%; P=0.154). Results - Meta-Analysis: The incidence of proven invasive fungal infection from all studies and arms was 4.1% and 8.3% if suspected infections were included. The reduction in the incidence of proven breakthrough invasive mycosis was significant (Table 1). As in the original analysis, the relative risk is reduced only in the group provided with itraconazole solution and with a relative risk reduction of 46%. Results - Itraconazole vs. Fluconazole: Table 2 reports a comparison of itraconazole solution vs. fluconazole for different relevant outcomes. There is a significant superiority of itraconazole for the reduction of all proven invasive fungal infections and for invasive Aspergillus infections and reductions are in the same range but not significant for the other outcomes. Conclusions: Itraconazole is still and significantly superior to its comparators, including fluconazole, in reducing the rate of breakthrough invasive fungal infections. This effect is only seen with the itraconazole oral or intravenous solution (at least 400 mg/d) which also reduce the rate of proven invasive Aspergillus infections. Table 1: Incidence of proven invasive fungal infections Subgroup No. Pts (Trials) Relative Risk 95%CI P All studies 3846 (15) 0.62 0.45–0.77 0.003 Itraconazole capsules 735 (5) 0.93 0.51–1.69 0.81 Itraconazole solution 3111 (10) 0.54 0.37–0.77 0.0008 Table 2: Comparison of itraconazole solution vs fluconazole (proven only) Outcome No. of trials Itraconazole (n/N) Fluconazole (n/N) Relative Risk 95%CI P Abbrev.: n= pts. with event; N=total pts. Invasive fungal infections 6 23/883 43/874 0.52 0.32–0.84 0.008 Invasive yeast infections 6 9/851 16//854 0.56 0.25–1.24 0.15 Invasive Aspergillus infections 5 12/850 24/853 0.50 0.26–0.98 0.04 Fungal-related Mortality 4 20/754 31/754 0.64 0.38–1.09 0.10

Itraconazole Prevents Invasive Fungal Infections in Neutropenic Patients Treated for Hematologic Malignancies: Evidence From a Meta-Analysis of 3,597 Patients

2003 ◽  
Vol 21 (24) ◽  
pp. 4615-4626 ◽  
Author(s):  
Axel Glasmacher ◽  
Archibald Prentice ◽  
Marcus Gorschlüter ◽  
Steffen Engelhart ◽  
Corinna Hahn ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Drug Discontinuation ◽  
Randomized Controlled Studies ◽  
Neutropenic Patients ◽  
First Time ◽  
New Evidence

Purpose: Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. Patients and Methods: Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. Results: Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% ± 13%; P = .002), the incidence of invasive yeast infections (mean, 53% ± 19%; P = .004) and the mortality from invasive fungal infections (mean, 35% ± 17%; P = .04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% ± 21%; P = .02) and not itraconazole capsules (mean, 75% ± 73% increase; P = .3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. Conclusion: Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and—shown for the first time for antifungal prophylaxis—reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or IV formulations (200 mg/d) of itraconazole are necessary for these effects.

scholarly journals 1,3- -D-Glucan Antigenemia for Early Diagnosis of Invasive Fungal Infections in Neutropenic Patients with Acute Leukemia

2008 ◽  
Vol 46 (6) ◽  
pp. 878-885 ◽  
Author(s):  
L. Senn ◽  
J. O. Robinson ◽  
S. Schmidt ◽  
M. Knaup ◽  
N. Asahi ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Acute Leukemia ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Neutropenic Patients

Voriconazole prophylaxis in leukemic patients: A retrospective single-center study

2019 ◽  
Vol 26 (4) ◽  
pp. 873-881
Author(s):  
Vivian Bui ◽  
Sandra AN Walker ◽  
Marion Elligsen ◽  
Anju Vyas ◽  
Alex Kiss ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Fungal Infection ◽  
Invasive Fungal Infection ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Retrospective Chart Review ◽  
Liver Function Tests ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Acute Myeloid

Background Invasive fungal infections commonly occur in acute myeloid and lymphoblastic leukemia patients receiving chemotherapy. In these patients with acute leukemia, posaconazole prophylaxis is recommended; however, voriconazole may be a less costly alternative. Objectives The objective of this study was to evaluate the efficacy and safety of voriconazole prophylaxis in acute leukemia patients. Methods A retrospective chart review of inpatients at Sunnybrook Health Sciences Centre between 2005 and 2017 was completed. Hospitalized adult acute leukemia patients who received voriconazole prophylaxis (cases) were compared to patients who received fluconazole or no prophylaxis during chemotherapy (controls). Statistical analyses comparing baseline characteristics, safety, and efficacy outcomes between the study cohorts were completed. A posaconazole literature-based weighted mean risk was compared to the voriconazole risk of invasive fungal infection identified in this study. Results Of 490 acute myeloid leukemia or acute lymphoblastic leukemia patients, 83 controls and 92 cases were eligible. Case patients received an average of 24.4 ± 10.8 days of voriconazole prophylaxis. The incidence of proven or probable invasive fungal infections with voriconazole was 3.3% (3/92) versus 7.2% (6/83) in the control cohort (p > 0.05) and was comparable to the literature reported weighted incidence of invasive fungal infection with posaconazole (2.4 ± 2.1%; 95% CI 1.3%–3.4%; p > 0.05). Voriconazole was well tolerated by patients (91%; 84/91; seven discontinued due to asymptomatic elevated liver function tests). Conclusions Voriconazole prophylaxis was found to be safe, effective, and comparable to literature-based efficacy data for risk of invasive fungal infection with posaconazole antifungal prophylaxis in patients with acute leukemia undergoing chemotherapy and could represent a significant cost advantage.

scholarly journals Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5105-5105
Author(s):  
Heather Morris ◽  
Meredith T. Moorman ◽  
Melissa C. Mackey ◽  
Harry P. Erba ◽  
Thomas W. LeBlanc ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Fungal Infection ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Second Generation ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Advisory Committees

Introduction/Background: Standard therapy for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is myelosuppressive, and patients are expected to be neutropenic for a prolonged period. Due to the high risk of infection, antimicrobial prophylaxis is warranted and should be continued throughout neutropenia. The incidence of documented invasive fungal infections ranges from 12 to 24% in patients with AML and approximately 6.5% in patients with ALL. Guidelines currently include posaconazole as a category 1 recommendation for antifungal prophylaxis, with echinocandins and other azole antifungals as category 2B. However, posaconazole can be subject to drug-drug interactions and can increase the risk of hepatotoxicity, both of which can be problematic in acute leukemia patients undergoing chemotherapy. For patients unable to receive posaconazole or another second-generation azole antifungal, micafungin is utilized. To our knowledge, there are no studies comparing second-generation azole antifungals to micafungin as prophylaxis in both AML and ALL during initial or relapsed/refractory induction therapy. The aim of this retrospective study is to compare the incidence of invasive fungal infections in patients with acute leukemia in the setting of micafungin or second-generation azole antifungal prophylaxis during initial and/or relapsed/refractory induction therapy at an academic medical center. Methods: Retrospective, single-center study from June 22, 2013 to June 22, 2018. Detailed chart reviews were performed by hand. Results: The incidence of invasive fungal infections within 100 days of chemotherapy was 11.2% in patients who received a second-generation azole and 2.7% in patients who received micafungin (P=0.7618). The incidence of invasive fungal infections within 100 days in patients who received a high intensity AML regimen was 11.2%, low intensity AML regimen 0.9%, and ALL regimen 1.8% (P=0.5378). The incidence of invasive fungal infections within 30 days of chemotherapy was 4.5% in patients who received a second-generation azole and 2.2% in patients who received micafungin (P=0.2447). The most common reason for micafungin prophylaxis was drug-drug interactions with standard ALL regimens that utilize vincristine. Of those with a documented fungal infection, 14 patients (6.3%) had a proven invasive fungal infection, and 17 patients (7.6%) had a probable/possible invasive fungal infection. The most common site of infection was in the chest (9.8%), followed by fungemia (2.2%). Other sites of infection include the brain, sinuses, liver/spleen, and skin. Beta-D-glucan was collected in 17 patients, and galactomannan antigen was collected in 26 patients. Three patients had a positive beta-D-glucan, and 1 patient had an indeterminate beta-D-glucan. Two patients had a positive galactomannan antigen. Fusarium species accounted for 4 positive cultures in patients. For those patients who did experience an invasive fungal infection, 23 out of the 31 patients (74.2%) were on posaconazole, 6 patients on micafungin (19.4%), and 2 on voriconazole (6.5%). Ten out of the 14 proven fungal infections (71.4%) occurred while on posaconazole prophylaxis, and 3 of these patients had posaconazole levels <0.7 mcg/mL. Twenty-one patients (67.7%) with documented infections had a neutrophil nadir < 0.1x109/L. The majority (93.5%) of those with breakthrough infections while on antifungal prophylaxis were switched to another antifungal. Conclusions: Micafungin is a reasonable alternative therapy for use in patients who are unable to receive second-generation azoles as antifungal prophylaxis during induction therapy for acute leukemia. Some invasive fungal infections occurred while patients had sub-therapeutic posaconazole levels, however others had breakthrough fungal infections with therapeutic levels. Our conclusions are limited by the small sample size and non-randomized, retrospective nature of this analysis. Disclosures Erba: Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. LeBlanc:Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; American Cancer Society: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Medtronic: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; Heron: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Celgene: Honoraria; Flatiron: Consultancy. Rizzieri:AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board.

scholarly journals Breakthrough Invasive Fungal Infections (bIFI) Are Uncommon in Patients with Newly Diagnosed Acute Leukemia Receiving Primary Antifungal Prophylaxis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Caitlin R. Rausch ◽  
Adam DiPippo ◽  
Prithviraj Bose ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Acute Leukemia ◽  
Induction Therapy ◽  
High Intensity ◽  
Research Funding ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Newly Diagnosed ◽  
Lower Intensity ◽  
Biphenotypic Leukemia

Introduction: Mold-active primary antifungal prophylaxis (PAP) is widely recommended in neutropenic patients (pts) with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who undergo remission-induction chemotherapy (RIC). Posaconazole (PCZ) prophylaxis resulted in fewer invasive fungal infections (IFIs) when compared to fluconazole and was associated with a survival advantage in this population (Cornely et al, 2007). Similarly, pts with acute lymphoblastic leukemia (ALL) undergoing RIC are also at risk of IFI due to prolonged neutropenia. Although PCZ is the preferred agent for PAP, the incorporation of targeted agents into acute leukemia therapy calls for more individualized choices in PAP. Other mold-active agents including voriconazole (VCZ) and isavuconazole (ISA) or the echinocandins are alternatives which may be preferred in individual settings due to variations in toxicity, patient co-morbidities, drug interactions, and cost. Little contemporary data exists to compare the incidence of breakthrough IFI (bIFIs) in pts with AML or ALL receiving PCZ, VCZ, or ISA as prophylaxis during RIC. Methods: We reviewed the medical records of all consecutive pts with newly diagnosed AML/MDS or ALL treated at our institution from 3/2016-7/2019. Included pts received high-intensity chemotherapy, or a lower-intensity venetoclax (VEN)-containing regimen, for RIC. Therapy with high-dose (&gt; 1g/m2/day) cytarabine (HiDAC), continuous cytarabine plus an anthracycline (3+7), or HyperCVAD was considered high-intensity therapy. Patients receiving PCZ, VCZ, or ISA for &gt; 5 days beginning during induction therapy were included. Baseline evidence of prior mold infection and treatment with a concomitant echinocandin were not allowed. Echinocandin use preceding mold-active PAP was allowed, however prior use of an amphotericin B product was not. bIFI were defined according to ECMM criteria (Cornely et al, 2019). Results: We identified 232 pts with AML/MDS (n=186), ALL (n=43), and biphenotypic leukemia (n=3). Among the AML/MDS pts, 31% (n=57) received a lower-intensity VEN-containing regimen, while 69% (n=129) received a high-intensity regimen with or without VEN. Nearly all pts with ALL and biphenotypic leukemia received high-intensity RIC with HyperCVAD or a HiDAC containing regimen. Of the 232 pts, PCZ (n=111), VCZ (n=84), or ISA (n=37) were used as PAP, respectively (Table 1). Most pts (n=157; 68%) received an echinocandin for a median of 6 days (range, 0-38), prior to transitioning to a mold-active triazole. Ten (4.3%) pts had a bIFI (6 proven, 1 probable, 3 possible) during induction therapy while receiving PAP (Table 2) including 9 (4.8%) pts with AML/MDS and 1 (2.3%) patient with ALL. An equal number of pts with bIFI were receiving lower-intensity, VEN-based therapy, or high-intensity therapy. Among the 84 pts receiving VCZ, 4 (4.8%) had a bIFI (4 proven); 3 pts (2.7%) receiving PCZ had a bIFI (2 proven, 1 possible); 3 pts (8.1%) receiving ISA had a bIFI (1 probable, 2 possible). C. glabrata (n=3), and C. krusei, Cryptococcus spp. and Fusarium spp. (one each) accounted for the 6 proven bIFIs. One patient had both C. glabrata and C. krusei fungemia. The probable bIFI was pneumonia with a positive Aspergillus GM from BAL. The 3 possible bIFI were pneumonia (n=2) and sinusitis (n=1). Eight pts (80%) were neutropenic (ANC &lt; 500 cells/mm3) for &gt;14 days at the time of bIFI, 1 pt was neutropenic for &gt;7 days, and 1 pt had ANC &gt; 500 cells/mm3. Seven pts with bIFI received a prior echinocandin for a median of 3 days (range, 0-15) prior to initiation of triazole PAP. Seven pts were neutropenic for &lt; 7 days (n=2), 7-14 days (n=3), or &gt; 14 days (n=2) at the time of azole initiation. bIFI occurred after a median of 20 days (range, 5-72) of azole PAP and a median of 24 days (range, 12-71) from the initiation of RIC. One patient with bIFI deceased within 42 days of starting RIC and did not achieve a response after RIC (bIFI-related mortality: 0.44%). Conclusion: The incidence (&lt;5%) and mortality (&lt; 0.5%) due to bIFI in a contemporary cohort of pts with newly diagnosed acute leukemia receiving PAP is low. bIFI occurred late in induction therapy and most often in pts with &gt; 14 days of neutropenia. Prophylaxis with VCZ, PCZ, or ISA, with or without a prior echinocandin, appear to be comparable options for PAP in pts with newly diagnosed AML or ALL undergoing RIC. Disclosures Bose: CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Kontoyiannis:Gilead Sciences: Honoraria; United Medical: Honoraria; Astellas Pharma: Consultancy; Cidara Therapeutics: Consultancy; Amplyx Pharmaceuticals: Consultancy; Mayne Pharma: Consultancy; Pharma Pharmaceutical Industries: Consultancy; Merck & Co.: Consultancy, Honoraria. OffLabel Disclosure: Voriconazole and isavuconazole are approved for the treatment of invasive fungal infections rather than the prevention, as discussed in this abstract.

scholarly journals Cost Analysis of the Use of Voriconazole, Posaconazole and Micafungin in the Primary Prophylaxis of Invasive Fungal Infections in Recipients of Allogeneic Hematopoietic Stem Cell Transplants

10.36469/9832 ◽  
2015 ◽  
Vol 3 (2) ◽  
pp. 153-161
Author(s):  
Santiago Grau ◽  
Carlos Solano ◽  
Carol García-Vidal ◽  
Isidro Jarque ◽  
Jon A. Barrueta ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cost Analysis ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Primary Prophylaxis ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Efficacy Rate ◽  
Hematopoietic Stem ◽  
The Cost

Objectives: Compare the cost of the primary prophylaxis of invasive fungal infections (IFI) with voriconazole, posaconazole, and micafungin in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in hospitals of the National Health System (NHS) in Spain. Methods: A cost analysis was made for 100 days and 180 days of prophylaxis and a decision tree model was developed. The efficacy rate of IFI prophylaxis and survival rate with liposomal amphotericin B treatment of prophylaxis failures were obtained from randomized trials and a meta-analysis of mixed treatment comparisons. The model simulation was interrupted with IFI treatment (prophylaxis failures). The costs of medication and its intravenous administration in the hospital (in the case of micafungin) were considered. Results: In the non-modeled analysis, the savings per patient of prophylaxis with voriconazole ranged from €1,709 to €9,655 compared with posaconazole oral solution, from €1,811 to €9,767 compared with posaconazole gastro-resistant tablets and from €3,376 to €7,713 compared with micafungin. In the modeled analysis, the mean cost per patient of the prophylaxis and treatment of IFIs was €6,987 to €7,619 with voriconazole, €7,749 with posaconazole, and €22,424 with micafungin. Therefore, the savings per patient of prophylaxis with voriconazole was €130 to €3,664 and €11,132 to €30,374 compared with posaconazole and micafungin, respectively. The result remained stable after modification of the number of days of antifungal prophylaxis and the cost of antifungal treatment of failures. Conclusion: Taking into account this model, antifungal prophylaxis with voriconazole in recipients of hematopoietic progenitor transplants, compared with posaconazole or micafungin, may represent savings for hospitals in Spain.

Sign in / Sign up

Export Citation Format

Share Document