Antifungal Agents: In Vitro Susceptibility Testing, Pharmacodynamics, and Prospects for Combination Therapy

2004 ◽  
Vol 23 (4) ◽  
pp. 256-270 ◽  
Author(s):  
A. H. Groll ◽  
H. Kolve
Keyword(s):  
Combination Therapy ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing

scholarly journals Current and Emerging Azole Antifungal Agents

1999 ◽  
Vol 12 (1) ◽  
pp. 40-79 ◽  
Author(s):  
Daniel J. Sheehan ◽  
Christopher A. Hitchcock ◽  
Carol M. Sibley
Keyword(s):  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Current Status ◽  
In Vitro Susceptibility ◽  
Clinical Resistance ◽  
In Vitro Susceptibility Testing

SUMMARY Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

In vitro Susceptibility Testing of Candida Isolates from Clinical Specimens to Four Antifungal Agents

Chemotherapy ◽  
1990 ◽  
Vol 36 (6) ◽  
pp. 396-402 ◽  
Author(s):  
Mitsuo Ohkawa ◽  
Shuji Tokunaga ◽  
Mitsuhiro Takashima ◽  
Tadayuki Nishikawa ◽  
Haruo Hisazumi ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Susceptibility Testing ◽  
In Vitro Susceptibility ◽  
Clinical Specimens ◽  
In Vitro Susceptibility Testing

scholarly journals Antifungal Activity of Tamoxifen: In Vitro and In Vivo Activities and Mechanistic Characterization

2009 ◽  
Vol 53 (8) ◽  
pp. 3337-3346 ◽  
Author(s):  
Kristy Dolan ◽  
Sara Montgomery ◽  
Bradley Buchheit ◽  
Louis DiDone ◽  
Melanie Wellington ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Tube Formation ◽  
In Vivo Model ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing ◽  
Treat Breast Cancer

ABSTRACT Tamoxifen (TAM), an estrogen receptor antagonist used primarily to treat breast cancer, has well-recognized antifungal properties, but the activity of TAM has not been fully characterized using standardized (i.e., CLSI) in vitro susceptibility testing, nor has it been demonstrated in an in vivo model of fungal infection. In addition, its mechanism of action remains to be clearly defined at the molecular level. Here, we report that TAM displays in vitro activity (MIC, 8 to 64 μg/ml) against pathogenic yeasts (Candida albicans, other Candida spp., and Cryptococcus neoformans). In vivo, 200 mg/kg of body weight per day TAM reduced kidney fungal burden (−1.5 log10 CFU per g tissue; P = 0.008) in a murine model of disseminated candidiasis. TAM is a known inhibitor of mammalian calmodulin, and TAM-treated yeast show phenotypes consistent with decreased calmodulin function, including lysis, decreased new bud formation, disrupted actin polarization, and decreased germ tube formation. The overexpression of calmodulin suppresses TAM toxicity, hypofunctional calmodulin mutants are hypersensitive to TAM, and TAM interferes with the interaction between Myo2p and calmodulin, suggesting that TAM targets calmodulin as part of its mechanism of action. Taken together, these experiments indicate that the further study of compounds related to TAM as antifungal agents is warranted.

scholarly journals Comparative Study of Susceptibilities of Germinated and Ungerminated Conidia of Aspergillus fumigatus to Various Antifungal Agents

1999 ◽  
Vol 37 (3) ◽  
pp. 858-861 ◽  
Author(s):  
Elias K. Manavathu ◽  
Jessica Cutright ◽  
Pranatharthi H. Chandrasekar
Keyword(s):  
Comparative Study ◽  
Growth Inhibition ◽  
Aspergillus Fumigatus ◽  
Mycelial Growth ◽  
Fungicidal Activity ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing

Conidia are used as inocula for the in vitro susceptibility testing of Aspergillus fumigatus. Since the MIC is defined on the basis of visible mycelial growth, conidia should germinate and produce sporelings (germinated conidia) for monitoring of the growth inhibition and fungicidal activity of a drug. If a compound is capable of inhibiting germination of conidia while affecting or not affecting the growth of the organism, the MIC obtained will be the concentration of the drug required for the inhibition of conidial germination but not necessarily that required for inhibition of the growth of the organism. We investigated the susceptibility of germinated and ungerminated conidia to amphotericin B, itraconazole, voriconazole, and SCH56592. The MICs of various antifungal agents for germinated conidia were almost identical to those obtained for ungerminated conidia. In addition, both the germinated and ungerminated conidia were killed with almost equal efficiency by all of the compounds tested when exposed to the drugs for 24 h. These results suggest that either germinated or ungerminated conidia could be used as inocula for in vitro susceptibility studies of A. fumigatus with identical results.

scholarly journals Discovery of beta-lactamase CMY-10 inhibitors for combination therapy against multi-drug resistant Enterobacteriaceae

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244967
Author(s):  
Nousheen Parvaiz ◽  
Faisal Ahmad ◽  
Wenbo Yu ◽  
Alexander D. MacKerell ◽  
Syed Sikander Azam
Keyword(s):  
Combination Therapy ◽  
Antimicrobial Agents ◽  
Susceptibility Testing ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Activity Assay ◽  
Primary Resistance ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing

β-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving β-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the strategy of combination therapeutics and aims at identifying novel β-lactamase inhibitors that can inactivate the β-lactamase enzyme of the pathogen while allowing the β-lactam antibiotic to act against its penicillin-binding protein target. Inhibitor discovery applied the Site-Identification by Ligand Competitive Saturation (SILCS) technology to map the functional group requirements of the β-lactamase CMY-10 and generate pharmacophore models of active site. SILCS-MC, Ligand-grid Free Energy (LGFE) analysis and Machine-learning based random-forest (RF) scoring methods were then used to screen and filter a library of 700,000 compounds. From the computational screens 74 compounds were subjected to experimental validation in which β-lactamase activity assay, in vitro susceptibility testing, and Scanning Electron Microscope (SEM) analysis were conducted to explore their antibacterial potential. Eleven compounds were identified as enhancers while 7 compounds were recognized as inhibitors of CMY-10. Of these, compound 11 showed promising activity in β-lactamase activity assay, in vitro susceptibility testing against ATCC strains (E. coli, E. cloacae, E. agglomerans, E. alvei) and MDR clinical isolates (E. cloacae, E. alvei and E. agglomerans), with synergistic assay indicating its potential as a β-lactam enhancer and β-lactamase inhibitor. Structural similarity search against the active compound 11 yielded 28 more compounds. The majority of these compounds also exhibited β-lactamase inhibition potential and antibacterial activity. The non-β-lactam-based β-lactamase inhibitors identified in the current study have the potential to be used in combination therapy with lactam-based antibiotics against MDR clinical isolates that have been found resistant against last-line antibiotics.

Sign in / Sign up

Export Citation Format

Share Document