We protect your health through science

Investigation

Exposure and response relationship in antifungal treatment

Research Lines

Content with Investigacion Estudio de la relación exposición y respuesta en el tratamiento con antifungicos .

The prophylactic and empirical use of antifungal agents in general, and azoles and echinocandins in particular, has contributed to the emergence of strains with elevated MICs (microbiological resistance), whose clinical impact and relevance are increasingly concerning. Moreover, therapeutic failure or clinical resistance is frequently observed even in the absence of microbiological resistance.
One of the factors that may explain clinical resistance in the absence of microbiological resistance is inadequate drug exposure at the site of infection, together with the pathogen’s adaptive response to host defences or to the administered antifungal therapy.
This research line, active since 2010, aims to advance the understanding of clinical resistance in Aspergillus fumigatus infection through the study of antifungal dose–response relationships by evaluating PK/PD parameters and their role in treatment efficacy. In addition, it investigates the role of biofilms as adaptive strategies that enhance fungal resistance to antifungal agents and to host immune cells.

Exposure: Pharmacokinetics of Antifungal Agents
There is now substantial evidence that the administration of an effective antifungal agent at the appropriate dose is essential to achieve adequate drug concentrations at the site of infection. Through the development of this research line (active since 2009), our group has gained extensive expertise in the development and application of chromatographic methods (HPLC/UPLC–UV/fluorescence) for antifungal quantification, which are useful for therapeutic drug monitoring (TDM).

Techniques that allow monitoring of blood drug concentrations constitute essential tools in patient management, enabling dose optimization by determining whether drug exposure is inadequate—potentially contributing to therapeutic failure and the emergence of resistance—or, conversely, excessive, thereby increasing the risk of significant toxicity.

In addition, the application of disciplines such as pharmacogenetics to antifungal therapy is promoting personalized treatment approaches and improving the management of severe invasive fungal infections (IFIs).
The use of alternative animal models, with ethical approval and under regulatory frameworks, together with methodological advances, has facilitated the preliminary study of dose–response relationships for both established antifungal agents and newly developed compounds.

Response: Monitoring Treatment Efficacy
An aspect of major relevance in the management of severe invasive fungal infections (IFIs) is the evaluation of the efficacy of the administered therapy. This research line further explores the characterization of circulating fungal-specific biomarkers that may help distinguish infection from fungal colonization and assess the effectiveness of the established treatment.
Within this framework, our efforts have focused on the study and characterization of compounds related to fungal secondary metabolism, such as gliotoxin and its derivative bis(methylthio)gliotoxin, detected in tissue and blood samples from patients with aspergillosis and in animal models, as well as other metabolites associated with fungal virulence (e.g., fumagillin and pseurotin A).

More recently, this research line has expanded to investigate adaptive strategies such as the formation of complex biofilm structures—often multispecies in nature and involving intricate interaction mechanisms—which may explain fungal resistance to antifungal agents and host immune cells, thereby contributing to therapeutic failure (clinical resistance).

Research projects

Content with Investigacion Estudio de la relación exposición y respuesta en el tratamiento con antifungicos .

Funded Research Projects (Competitive Public Calls)

 

Projects as Principal Investigator

1.Title: Proteomic Analysis of Fungal Biofilms (Mono- and Multispecies): Importance of the Extracellular Matrix
Funding Agency: AESi 2025 (Grant No. PI25/00038)
Funding Amount: €117,500
Duration: 2026–2028
Principal Investigator: Alicia Gómez-López

2. Title: Study of Biomarkers Involved in the Development and Evolution of Fungal Biofilms
Funding Agency: AESi 2021 (Grant No. PI21CIII/00012; MPY 435/21)
Funding Amount: €40,450
Duration: 2022–2024 (extended to 2025)
Principal Investigator: Alicia Gómez-López

3. Title: Novel Strategies for Characterizing Progression and Response to Fungal Infection: Application of Advanced Chromatographic Techniques
Funding Agency: AESi FIS (Grant No. PI16CIII/00014; MPY 1347/16)
Funding Amount: €41,500
Duration: 2017–2021
Principal Investigator: Alicia Gómez-López

4. Title: Management and Maintenance of the Yeast and Filamentous Fungi Strain Collection of the National Reference Mycology Laboratory (CNM-ISCIII)
Project Reference: PEJ-2014-A-13436
Scientific Area: Technology Transfer
Duration: 2016–2018
Principal Investigator / Supervisor: Alicia Gómez-López

5. Title: Genetic Variants of Drug-Metabolizing Enzymes (CYP450) and Voriconazole Monitoring in Treated Patients: Implications for Clinical Decision-Making
Funding Agency: AES FIS 2013 (Grant No. PI13/01817; MPY 1367/13)
Funding Amount: €86,515
Duration: 2013–2016
Role: Principal Investigator

6. Title: Clinical Relevance of Azole Resistance in an Animal Model of Invasive Aspergillosis: Characterization of PK/PD Parameters
Funding Agency: ISCIII Emerging Groups Program (MPY 1354/10)
Funding Amount: €63,613 (Technical Contract – FP)
Duration: 2010–2012
Role: Principal Investigator

7. Title: Clinical Relevance of Azole Resistance in an Animal Model of Invasive Aspergillosis: Characterization of PK/PD Parameters
Funding Agency: AES FIS (Grant No. PI09/0624; MPY 1003/10)
Funding Amount: €50,820
Duration: 2010–2012
Role: Principal Investigator


Collaborating Researcher

Title: Pilot Project for the Development of a Molecular Surveillance Network for Antifungal Resistance Integrating Microbiological and Clinical Data (FunResNet)
Consortium: Biomedical Research Networking Center (CIBERINFEC), Infectious Diseases Area
Funding Agency: CIF: G85296226 (Grant No. IM23/INFEC/2)
Duration: 2024–2025
Principal Investigator: Ana Alastruey-Izquierdo
Collaborating Researcher: Alicia Gómez-López

Title: Biomarkers in Bronchoalveolar Lavage for the Diagnosis and Prognostic Assessment of Invasive Pulmonary Aspergillosis
Consortium: Biomedical Research Networking Center (CIBERINFEC), Infectious Diseases Area
Funding Agency: CIF: G85296226 (Grant No. IM23/INFEC/7)
Funding Amount: €63,000
Duration: 2024–2025
Principal Investigator: Laura Alcázar-Fuoli
Collaborating Researcher: Alicia Gómez-López

Title: Biomedical Research Networking Center (CIBER), Infectious Diseases Area
Funding Agency: CIF: G85296226 (Grant No. CB21/13/00105)
Funding Amount: €85,000 (first year)
Duration: 2022–2026
Role: Technological Development – Collaborating Researcher
Principal Investigator: Emilia Mellado-Terrado

Industry-Funded Research Projects

Title: Rezafungin: An Attempt to Optimize In Vitro Susceptibility Against a Collection of Clinical Yeasts
Funding Company/Institution: Mundipharma Research / Micología Molecular S.L.
Duration: 2025
Principal Investigator: Alicia Gómez-López

Title: Determination of Benznidazole Concentrations in Serum and Urine of Treated Rabbits
Funding Company/Institution: Micología Molecular S.L. / Fundación MundoSano
Duration: 2024
Principal Investigator: Javier Nieto
Role: Technological Development – Collaborating Researcher
Researcher: Alicia Gómez-López (Madrid, Spain)

Title: Phase IV, Single-Center, Multiple-Dose, Single-Arm Clinical Trial to Assess the Bronchopulmonary Penetration of Isavuconazole in Lung Transplant Recipients (EudraCT No. 2019-004240-30)
Duration: 2020–2021
Role: Collaborating Researcher
Principal Investigators: Piedad Ussetti-Gil; Belén Ruiz-Antorán (Hospital Puerta de Hierro, Madrid)

Title: Prospective, Randomized Pilot Study on the Feasibility of Nebulized Liposomal Amphotericin B (nL-AmB) as Adjunctive Therapy for Invasive Pulmonary Aspergillosis
Funding Company: Micología Molecular S.L.
Duration: 2019–2021
Principal Investigator: Jesús Fortún-Abete
Role: Collaborating Researcher

Title: Sequential Plasma Pharmacokinetic Study of Two Oral Posaconazole Formulations (Oral Suspension and Gastro-Resistant Tablets) in Hematology Patients at High Risk of Invasive Fungal Infections (Protocol Code POPK-1501)
Funding Company/Institution: MSD / Micología Molecular S.L.
Duration: 2017
Role: Collaborating Researcher

Title: Validation of Real-Time PCR in Blood and Peritoneal Fluid for the Diagnosis of Candida Peritonitis. Peritoneal Pharmacokinetics and Echinocandin Resistance Analysis
Duration: 2016–2018
Funding Company: Micología Molecular S.L.
Role: Collaborating Researcher

Title: In Vitro Activity of Cyanobacterial Extracts Against a Collection of Yeast and Filamentous Fungi
Duration: 2013
Funding Institution: Valoralia I+D+i
Role: Principal Investigator

Title: Arasertaconazole Nitrate: In Vitro Activity Against Candida spp. by Time–Kill Studies
Duration: 2010–2011
Funding Company: Grupo Ferrer
Role: Principal Investigator

Title: Arasertaconazole Nitrate: In Vitro Susceptibility Study Against Clinical Isolates of Candida
Duration: 2010–2011
Funding Company: Grupo Ferrer
Role: Principal Investigator

Publications

Sort
Category

Alastruey-Izquierdo A, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Anza DV, Viñuelas J, Zapico MS, Cuenca-Estrella M; the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study). Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00358-18. doi: 10.1128/AAC.00358-18. PMID: 29941643; PMCID: PMC6125503.

Alastruey-Izquierdo A, Alcazar-Fuoli L, Rivero-Menéndez O, Ayats J, Castro C, García-Rodríguez J, Goterris-Bonet L, Ibáñez-Martínez E, Linares-Sicilia MJ, Martin-Gomez MT, Martín-Mazuelos E, Pelaez T, Peman J, Rezusta A, Rojo S, Tejero R, Anza DV, Viñuelas J, Zapico MS, Cuenca-Estrella M; the FILPOP2 Project from GEMICOMED (SEIMC) and REIPI. Molecular Identification and Susceptibility Testing of Molds Isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 Study). Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00358-18. doi: 10.1128/AAC.00358-18. PMID: 29941643; PMCID: PMC6125503.

PUBMED DOI

Gonçalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martínez L, Rodrigues F, Silvestre R, Alcazar-Fuoli L, Maertens JA, Cunha C, Carvalho A. Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients. Front Microbiol. 2017 Nov 29;8:2362. doi:10.3389/fmicb.2017.02362. PMID: 29238334; PMCID: PMC5712575.

Gonçalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martínez L, Rodrigues F, Silvestre R, Alcazar-Fuoli L, Maertens JA, Cunha C, Carvalho A. Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients. Front Microbiol. 2017 Nov 29;8:2362. doi:10.3389/fmicb.2017.02362. PMID: 29238334; PMCID: PMC5712575.

PUBMED DOI

Alcazar-Fuoli L, Buitrago M, Gomez-Lopez A, Mellado E. An alternative host model of a mixed fungal infection by azole susceptible and resistant Aspergillus spp strains. Virulence. 2015;6(4):376-84. doi: 10.1080/21505594.2015.1025192. PMID: 26065322; PMCID: PMC4601236.

Alcazar-Fuoli L, Buitrago M, Gomez-Lopez A, Mellado E. An alternative host model of a mixed fungal infection by azole susceptible and resistant Aspergillus spp strains. Virulence. 2015;6(4):376-84. doi: 10.1080/21505594.2015.1025192. PMID: 26065322; PMCID: PMC4601236.

PUBMED DOI

Alcazar-Fuoli L, Cairns T, Lopez JF, Zonja B, Pérez S, Barceló D, Igarashi Y, Bowyer P, Bignell E. A modified recombineering protocol for the genetic manipulation of gene clusters in Aspergillus fumigatus. PLoS One. 2014 Nov 5;9(11):e111875. doi: 10.1371/journal.pone.0111875. PMID: 25372385; PMCID:PMC4221250.

Alcazar-Fuoli L, Cairns T, Lopez JF, Zonja B, Pérez S, Barceló D, Igarashi Y, Bowyer P, Bignell E. A modified recombineering protocol for the genetic manipulation of gene clusters in Aspergillus fumigatus. PLoS One. 2014 Nov 5;9(11):e111875. doi: 10.1371/journal.pone.0111875. PMID: 25372385; PMCID:PMC4221250.

PUBMED DOI

Bertuzzi M, Schrettl M, Alcazar-Fuoli L, Cairns TC, Muñoz A, Walker LA, Herbst S, Safari M, Cheverton AM, Chen D, Liu H, Saijo S, Fedorova ND, Armstrong-James D, Munro CA, Read ND, Filler SG, Espeso EA, Nierman WC, Haas H, Bignell EM. The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathog. 2014 Oct 16;10(10):e1004413. doi: 10.1371/journal.ppat.1004413.

Bertuzzi M, Schrettl M, Alcazar-Fuoli L, Cairns TC, Muñoz A, Walker LA, Herbst S, Safari M, Cheverton AM, Chen D, Liu H, Saijo S, Fedorova ND, Armstrong-James D, Munro CA, Read ND, Filler SG, Espeso EA, Nierman WC, Haas H, Bignell EM. The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. PLoS Pathog. 2014 Oct 16;10(10):e1004413. doi: 10.1371/journal.ppat.1004413.

DOI

Yasmin S, Alcazar-Fuoli L, Gründlinger M, Puempel T, Cairns T, Blatzer M, Lopez JF, Grimalt JO, Bignell E, Haas H. Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E497-504. doi: 10.1073/pnas.1106399108. Epub 2011 Nov 21. PMID: 22106303; PMCID: PMC3286978.

Yasmin S, Alcazar-Fuoli L, Gründlinger M, Puempel T, Cairns T, Blatzer M, Lopez JF, Grimalt JO, Bignell E, Haas H. Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E497-504. doi: 10.1073/pnas.1106399108. Epub 2011 Nov 21. PMID: 22106303; PMCID: PMC3286978.

PUBMED DOI

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity.

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity. Vigón L, Fuertes D, García-Pérez J, Torres M, Rodríguez-Mora S, Mateos E, Corona M, Saez-Marín AJ, Malo R, Navarro C, Murciano-Antón MA, Cervero M, Alcamí J, García-Gutiérrez V, Planelles V, López-Huertas MR, Coiras M (AC). Front Immunol. 2021 May 26;12:665329. doi: 10.3389/fimmu.2021.665329. eCollection 2021. PMID: 34122423.

PUBMED DOI

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission. Vigón L, Luna A, Galán M, Rodríguez-Mora S, Fuertes D, Mateos E, Piris-Villaespesa M, Bautista G, San José E, Rivera-Torres J, Steegmann JL, de Ory F, Pérez-Olmeda M, Alcamí J, Planelles V, López-Huertas MR, García-Gutiérrez V, Coiras M (AC). J Clin Med. 2020 Dec 25;10(1):42. doi: 10.3390/jcm10010042. PMID: 33375572.

PUBMED DOI

Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection

Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection. Vigón L, Rodríguez-Mora S, Luna A, Sandonís V, Mateos E, Bautista G, Steegmann JL, Climent N, Plana M, Pérez-Romero P, de Ory F, Alcamí J, García-Gutierrez V, Planelles V, López-Huertas MR, Coiras M (AC). Biochem Pharmacol. 2020 Dec;182:114203. doi: 10.1016/j.bcp.2020.114203. PMID: 32828803.

PUBMED DOI

Tyrosine Kinase Inhibition: a New Perspective in the Fight against HIV

Tyrosine Kinase Inhibition: a New Perspective in the Fight against HIV. Rodríguez-Mora S, Spivak AM, Szaniawski MA, López-Huertas MR, Alcamí J, Planelles V, Coiras M (AC). Curr HIV/AIDS Rep. 2019 Oct;16(5):414-422. doi: 10.1007/s11904-019-00462-5. PMID: 31506864. Review.

PUBMED DOI

Dasatinib protects humanized mice from acute HIV-1 infection

Dasatinib protects humanized mice from acute HIV-1 infection. Salgado M, Martinez-Picado J, Gálvez C, Rodríguez-Mora S, Rivaya B, Urrea V, Mateos E, Alcamí J, Coiras M (AC). Biochem Pharmacol. 2020 Apr;174:113625. doi: 10.1016/j.bcp.2019.113625. PMID: 31476293.

PUBMED DOI

Evaluation of resistance to HIV-1 infection ex vivo of PBMCs isolated from patients with chronic myeloid leukemia treated with different tyrosine kinase inhibitors.

Evaluation of resistance to HIV-1 infection ex vivo of PBMCs isolated from patients with chronic myeloid leukemia treated with different tyrosine kinase inhibitors. Bermejo M, Ambrosioni J, Bautista G, Climent N, Mateos E, Rovira C, Rodríguez-Mora S, López-Huertas MR, García-Gutiérrez V, Steegmann JL, Duarte R, Cervantes F, Plana M, Miró JM, Alcamí J, Coiras M (AC). Biochem Pharmacol. 2018 Oct;156:248-264. doi: 10.1016/j.bcp.2018.08.031. PMID: 30142322.

PUBMED DOI

Staphylococcus aureus Nasal Colonization in Spanish Children. The COSACO Nationwide Surveillance Study.

Staphylococcus aureus Nasal Colonization in Spanish Children. The COSACO Nationwide Surveillance Study. Del Rosal T, Méndez-Echevarría A, Garcia-Vera C, Escosa-Garcia L, Agud M, Chaves F, Román F, Gutierrez-Fernandez J, Ruiz de Gopegui E, Ruiz-Carrascoso G, Ruiz-Gallego MDC, Bernet A, Quevedo SM, Fernández-Verdugo AM, Díez-Sebastian J, Calvo C; COSACO Study Group.

PUBMED

Antimicrobial Resistance and Distribution of Staphylococcus spp. Pulsotypes Isolated from Goat and Sheep Bulk Tank Milk in Southern Spain

Antimicrobial Resistance and Distribution of Staphylococcus spp. Pulsotypes Isolated from Goat and Sheep Bulk Tank Milk in Southern Spain. Barrero-Domínguez B, Luque I, Galán-Relaño Á, Vega-Pla JL, Huerta B, Román F, Astorga RJ. Foodborne Pathog Dis. 2019 Oct;16(10):723-730. doi: 10.1089/fpd.2018.2593. Epub 2019 Jun 3.Foodborne Pathog Dis. 2019. PMID: 31157980

PUBMED

Prevalence of pSCFS7-like vectors among cfr-positive staphylococcal population in Spain

Prevalence of pSCFS7-like vectors among cfr-positive staphylococcal population in Spain. Nguyen LTT*, Román F*, Morikawa K, Trincado P, Marcos C, Rojo-Martín MD, Cafini F. Int J Antimicrob Agents. 2018 Aug;52(2):305-306.

PUBMED

Methodology for the Study of Horizontal Gene Transfer in Staphylococcus aureus.

Methodology for the Study of Horizontal Gene Transfer in Staphylococcus aureus. Cafini F, Thi Le Thuy N, Román F, Prieto J, Dubrac S, Msadek T, Morikawa K. J Vis Exp. 2017 Mar 10;(121).

PUBMED

Emergence of cfr-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis.

Emergence of cfr-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis. de Dios Caballero J, Pastor MD, Vindel A, Máiz L, Yagüe G, Salvador C, Cobo M, Morosini MI, del Campo R, Cantón R; GEIFQ Study Group. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1878-82.

PUBMED

Molecular epidemiology of community-associated methicillin-resistant Staphylococcus aureus in Spain: 2004-12.

Molecular epidemiology of community-associated methicillin-resistant Staphylococcus aureus in Spain: 2004-12. Vindel A, Trincado P, Cuevas O, Ballesteros C, Bouza E, Cercenado E. J Antimicrob Chemother. 2014 Nov;69(11):2913-9.

PUBMED

Draft Genome Sequence of Strain SA_ST125_MupR of Methicillin-Resistant Staphylococcus aureus ST125, a Major Clone in Spain.

Draft Genome Sequence of Strain SA_ST125_MupR of Methicillin-Resistant Staphylococcus aureus ST125, a Major Clone in Spain. Barrado L, Viedma E, Vindel A, Otero JR, Chaves F. Genome Announc. 2013 Aug 8;1(4).

PUBMED

Detection of linezolid-resistant Staphylococcus aureus with 23S rRNA and novel L4 riboprotein mutations in a cystic fibrosis patient in Spain.

Detection of linezolid-resistant Staphylococcus aureus with 23S rRNA and novel L4 riboprotein mutations in a cystic fibrosis patient in Spain. Román F, Roldán C, Trincado P, Ballesteros C, Carazo C, Vindel A. Antimicrob Agents Chemother. 2013 May;57(5):2428-9.

PUBMED

Content with Investigacion Estudio de la relación exposición y respuesta en el tratamiento con antifungicos .

List of staff

Additional Information

Content with Investigacion Estudio de la relación exposición y respuesta en el tratamiento con antifungicos .