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 Atypical clinical and laboratory features of fish-tank granuloma: A case report

2018 ◽  
Vol 6 ◽  
pp. 2050313X1880407 ◽  
Author(s):  
Michael Sander ◽  
Judith L Isaac-Renton ◽  
Megan A Sander
Keyword(s):  
Case Report ◽  
Susceptibility Testing ◽  
Mycobacterium Marinum ◽  
In Vitro Susceptibility ◽  
Laboratory Features ◽  
In Vitro Susceptibility Testing ◽  
Fish Tank ◽  
Fish Tank Granuloma

We report a case of cutaneous Mycobacterium marinum infection with the unusual reported features of pruritus and paresthesia. In addition, we report a lack of in-vivo response to antibiotics based on 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 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 1299. In Vitro-In Vivo Discordance with β-lactams against Metallo-β-lactamase-Producing Enterobacterales: Implications for Susceptibility Testing

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S664-S664
Author(s):  
Kamilia Abdelraouf ◽  
Sergio Reyes ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Infection Model ◽  
Research Support ◽  
In Vitro Susceptibility ◽  
Fold Reduction ◽  
Testing Medium ◽  
Zinc Concentrations ◽  
In Vitro Susceptibility Testing

Abstract Background Using murine models of thigh and lung infection, we previously reported the potent in vivo activity of carbapenem human-simulated regimens against metallo-β-lactamase-producing Enterobacterales despite the observed resistance in vitro (JAC 2020 Apr 1;75(4):997-1005, AAC 2014;58(3):1671-7). In the current study, we examined the in vivo activity of cefepime human-simulated regimen against metallo-β-lactamase-producing Enterobacterales in a murine thigh infection model. Methods A population of clinical (n=21) and isogenic engineered (n=5) metallo-β-lactamase-producing Enterobacterales isolates expressing VIM, IMP or NDM but not co-expressing ESBLs or serine carbapenemases were utilized. KPC-producing strains (n=3) were included as positive controls. MICs of cefepime, piperacillin-tazobactam and meropenem were determined using broth microdilution in conventional cation-adjusted Muller Hinton and EDTA-supplemented broth at EDTA concentration of 300 mg/L (zinc-limited). The in vivo efficacy of a cefepime human-simulated regimen (2 g q8h as 2 h infusion) was determined in the neutropenic murine thigh infection model against the test isolates. Efficacy was measured as the change in log10cfu/thigh at 24 h compared with 0 h controls. Results Metallo-β-lactamase-producing Enterobacterales were found to be cefepime, piperacillin-tazobactam and meropenem non-susceptible in conventional broth. Supplementation with EDTA resulted in multi-fold reduction in the MICs and restoration of susceptibility. In accordance with the MICs generated in the zinc-limited broth, the administration of cefepime human-simulated regimen was associated with substantial bacterial reductions among mice infected with the clinical as well as the isogenic engineered metallo-β-lactamase-producing isolates. As anticipated with serine-based resistance, absence of MIC reduction in zinc-limited broth and lack of in vivo activity against KPC-producers were observed. Conclusion For metallo-β-lactamase-producing Enterobacterales, in vitro susceptibility testing to β-lactams with conventional media such as cation-adjusted Muller Hinton broth, a zinc-rich testing medium, is flawed since it does not recapitulate the host environment in which zinc concentrations are low. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

scholarly journals 1312. Metallo-β-lactamase-Producing Enterobacterales (MBL-EB): Is it Time to Rethink Our Assessment Tools?

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S668-S668
Author(s):  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Susceptibility Testing ◽  
Assessment Tools ◽  
In Vivo Studies ◽  
Infection Model ◽  
Research Support ◽  
In Vitro Susceptibility ◽  
New Agents ◽  
In Vitro Susceptibility Testing

Abstract Background We previously reported the potent in vivo activity of ceftazidime/avibactam human-simulated regimen (HSR) against MBL-EB despite the observed resistance in vitro and the lack of avibactam MBL-inhibitory activity (AAC 2014 Nov;58(11):7007-9). Similar to avibactam, relebactam (REL) is a diazabicyclooctane that inhibits serine β-lactamases belonging to Classes A - C but not MBLs. In the current study, we examined the in vivo activity of cefepime (FEP)/REL combination HSR against MBL-EB in a murine thigh infection model. Methods Six clinical MBL-EB isolates expressing VIM, IMP or NDM and co-expressing at least one β-lactamase of Classes A - C (KPC, CTX-M, TEM, SHV, ACT, CMY) were utilized. MICs of FEP and FEP/REL combination (at fixed REL concentration of 4 mg/L) were determined using broth microdilution. FEP HSR (2 g q12h as 0.5 h infusion) alone and in combination with REL HSR (250 mg q6h as 0.5 h infusion) were established in the infection model. Thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 CFU/ml. Two hours later, mice were administered the FEP HSR or the FEP/REL HSR. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Results All isolates were FEP resistant (MIC ≥ 32 mg/L). Addition of REL had no impact on the MIC of the isolates. In in vivo studies, the average bacterial burden at 0 h was 5.84 ± 0.41 log10CFU/thigh. In accordance with the in vitro susceptibility, administration of FEP HSR was associated with net bacterial growth among all isolates ranging from 0.46 ± 0.60 to 2.97 ± 0.53 log10CFU/thigh. In contrast, FEP/REL combination HSR resulted in substantial bacterial reductions among all isolates ranging from -0.73 ± 0.13 to -1.72 ± 0.14 log10CFU/thigh, indicating that REL enhanced the FEP activity in vivo. Conclusion Despite the powerful β-lactam hydrolytic capability of MBLs in vitro, FEP inactivation in the murine model was attributed predominantly to the expression of the serine β-lactamases. The in vitro/in vivo discordance in β-lactam/β-lactamase activity against MBL-EB reveals a potential flaw in the currently utilized in vitro susceptibility testing methodologies and highlights a challenge encountered during the development of new agents against these isolates. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

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