Chapter

Combination Antifungal Therapy

12/2010; DOI:10.1007/978-1-4419-6640-7_10 pp.153-163

ABSTRACT Invasive fungal infections continue to cause significant morbidity and mortality among hospitalized patients. In particular,
recent studies indicate an increase in the incidence of mould infections among transplant recipients, and Candida species have risen to be the third most common pathogen isolated among intensive care unit patients [1, 2]. Advances in modern
medical treatment have led to growth in the at-risk population for fungal infections [3]. For example, Cryptococcus neoformans has re-emerged as a growing cause of invasive fungal disease due in large part to the development of novel immune therapy
for malignancies, rheumatologic disorders, and management of rejection in transplant populations [4]. Unfortunately, these
infections are associated with failures and high rates of relapse even when patients receive recommended therapy [5, 6]. Treatment
of invasive mycoses continues to be challenging and complicated by the net state of immunosuppression among infected hosts
combined with relative lack of efficacy, significant toxicity, drug–drug interactions, and drug resistance associated with
available antifungal agents.

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    Article: In vitro Interaction between Alginate Lyase and Amphotericin B against Aspergillus fumigatus Biofilm Determined by Different Methods.
    Francesca Bugli, Brunella Posteraro, Massimiliano Papi, Riccardo Torelli, Alessandro Maiorana, Francesco Paroni Sterbini, Patrizia Posteraro, Maurizio Sanguinetti, Marco De Spirito
    [show abstract] [hide abstract]
    ABSTRACT: Aspergillus fumigatus biofilms represent a problematic clinical entity, especially because of their recalcitrance to antifungal drugs, which poses a number of therapeutic implications for invasive aspergillosis, the most difficult-to-treat Aspergillus-related disease. While antibiofilm activities of deoxycholate amphotericin B (AMB) and its lipid formulations (e.g., liposomal AMB [LAMB]) are well-documented, effectiveness of these drugs in combination with nonantifungal agents is poorly understood. In the present study, in vitro interactions between polyene antifungals (AMB and LAMB) and alginate lyase (AlgL), an enzyme degrading the polysaccharides produced as extracellular polymeric substances (EPS) within the biofilm matrix, were evaluated against A. fumigatus biofilms by using the checkerboard microdilution and the time-kill assays. Furthermore, atomic force microscopy (AFM) was used to image and quantify the effects of AlgL/antifungal combinations on biofilm-growing hyphal cells. Based on FIC index values, synergy was found between both AMB formulations and AlgL, and this finding was also confirmed by the time-kill test. Finally, AFM analysis showed that when A. fumigatus biofilms were treated with AlgL or polyene alone, as well as with their combination, both reduction of hyphal thicknesses and increase of adhesive forces were observed compared to untreated controls, probably owing to different action by the enzyme or the antifungal compounds. Interestingly, physical changes were markedly noticed in A. fumigatus biofilms exposed to the AlgL/antifungal combinations compared with antifungals alone, indicating that AlgL may enhance the antibiofilm activity of both AMB and LAMB, perhaps by disrupting the hyphae-embedding EPS and thus facilitating the drugs to reach biofilm cells. Taken together, our results suggest that a combination of AlgL and polyene antifungal may prove to be a new therapeutic strategy for invasive aspergillosis, while reinforcing the EPS as a valuable antibiofilm drug target.
    Antimicrobial Agents and Chemotherapy 03/2013; 57(3):2013. · 4.84 Impact Factor
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    Article: Dynamic interaction between fluconazole and amphotericin B against Cryptococcus gattii.
    Julliana Ribeiro Alves Santos, Ludmila Ferreira Gouveia, Erika Linzi Silva Taylor, Maria Aparecida Resende-Stoianoff, Gerson Antônio Pianetti, Isabela Costa César, Daniel Assis Santos
    [show abstract] [hide abstract]
    ABSTRACT: Cryptococcus gattii is the main pathogen of cryptococcosis in healthy patients and is treated mainly with fluconazole and amphotericin B. The combination of these drugs has been questioned because the mechanisms of action could lead to a theoretical antagonistic interaction. We evaluated distinct parameters involved in the in vitro combination of fluconazole and amphotericin B against Cryptococcus gattii. Fourteen strains of C. gattii were used for the determination of MIC, fractional inhibitory concentration, time-kill curve, and postantifungal effect (PAFE). Ergosterol quantification was performed to evaluate the influence of ergosterol content on the interaction between these antifungals. Interaction between the drugs varied from synergistic to antagonistic depending on the strain and concentration tested. Increasing fluconazole levels were correlated with an antagonistic interaction. A total of 48 h was necessary for reducing the fungal viability in the presence of fluconazole, while 12 h were required for amphotericin B. When these antifungals were tested in combination, fluconazole impaired the amphotericin B activity. The ergosterol content decreased with the increase of fluconazole levels and it was correlated with the lower activity of amphotericin B. The PAFE found varied from 1 to 4 h for fluconazole and from 1 to 3 h for amphotericin B. The interaction of fluconazole and amphotericin B was concentration-dependent and special attention should be directed when these drugs are used in combination against C. gattii.
    Antimicrobial Agents and Chemotherapy 01/2012; 56(5):2553-8. · 4.84 Impact Factor
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    Article: Therapeutic use of a cationic antimicrobial peptide from the spider Acanthoscurria gomesiana in the control of experimental candidiasis.
    Diego C Rossi, Julian E Muñoz, Danielle D Carvalho, Rodrigo Belmonte, Bluma Faintuch, Primavera Borelli, Antonio Miranda, Carlos P Taborda, Sirlei Daffre
    [show abstract] [hide abstract]
    ABSTRACT: Antimicrobial peptides are present in animals, plants and microorganisms and play a fundamental role in the innate immune response. Gomesin is a cationic antimicrobial peptide purified from haemocytes of the spider Acanthoscurria gomesiana. It has a broad-spectrum of activity against bacteria, fungi, protozoa and tumour cells. Candida albicans is a commensal yeast that is part of the human microbiota. However, in immunocompromised patients, this fungus may cause skin, mucosal or systemic infections. The typical treatment for this mycosis comprises three major categories of antifungal drugs: polyenes, azoles and echinocandins; however cases of resistance to these drugs are frequently reported. With the emergence of microorganisms that are resistant to conventional antibiotics, the development of alternative treatments for candidiasis is important. In this study, we evaluate the efficacy of gomesin treatment on disseminated and vaginal candidiasis as well as its toxicity and biodistribution. Treatment with gomesin effectively reduced Candida albicans in the kidneys, spleen, liver and vagina of infected mice. The biodistribution of gomesin labelled with technetium-99 m showed that the peptide is captured in the kidneys, spleen and liver. Enhanced production of TNF-α, IFN-γ and IL-6 was detected in infected mice treated with gomesin, suggesting an immunomodulatory activity. Moreover, immunosuppressed and C. albicans-infected mice showed an increase in survival after treatment with gomesin and fluconazole. Systemic administration of gomesin was also not toxic to the mice. Gomesin proved to be effective against experimental Candida albicans infection. It can be used as an alternative therapy for candidiasis, either alone or in combination with fluconazole. Gomesin's mechanism is not fully understood, but we hypothesise that the peptide acts through the permeabilisation of the yeast membrane leading to death and/or releasing the yeast antigens that trigger the host immune response against infection. Therefore, data presented in this study reinforces the potential of gomesin as a therapeutic antifungal agent in both humans and animals.
    BMC Microbiology 03/2012; 12:28. · 3.04 Impact Factor

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Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

available antifungal agents
 
Candida species
 
cause significant morbidity
 
common pathogen
 
Cryptococcus neoformans
 
drug resistance
 
drug–drug interactions
 
fungal infections
 
growing cause
 
intensive care unit patients
 
invasive fungal disease due
 
Invasive fungal infections
 
invasive mycoses
 
net state
 
novel immune therapy
 
relative lack
 
rheumatologic disorders
 
significant toxicity
 
transplant populations
 
transplant recipients