scholarly journals Dynamic Interaction between Fluconazole and Amphotericin B against Cryptococcus gattii

2012 ◽  
Vol 56 (5) ◽  
pp. 2553-2558 ◽  
Author(s):  
Julliana Ribeiro Alves Santos ◽  
Ludmila Ferreira Gouveia ◽  
Erika Linzi Silva Taylor ◽  
Maria Aparecida Resende-Stoianoff ◽  
Gerson Antônio Pianetti ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Antagonistic Interaction ◽  
Ergosterol Content ◽  
Kill Curve ◽  
Time Kill ◽  
Postantifungal Effect

ABSTRACTCryptococcus gattiiis 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 thein vitrocombination of fluconazole and amphotericin B againstCryptococcus gattii. Fourteen strains ofC. gattiiwere 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 againstC. gattii.

scholarly journals In VitroInteraction between Alginate Lyase and Amphotericin B against Aspergillus fumigatus Biofilm Determined by Different Methods

2012 ◽  
Vol 57 (3) ◽  
pp. 1275-1282 ◽  
Author(s):  
Francesca Bugli ◽  
Brunella Posteraro ◽  
Massimiliano Papi ◽  
Riccardo Torelli ◽  
Alessandro Maiorana ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Extracellular Polymeric Substances ◽  
Alginate Lyase ◽  
Antifungal Drugs ◽  
Antibiofilm Activity ◽  
Content Type ◽  
Time Kill

ABSTRACTAspergillus fumigatusbiofilms 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-treatAspergillus-related disease. While the antibiofilm activities of amphotericin B (AMB) deoxycholate and its lipid formulations (e.g., liposomal AMB [LAMB]) are well documented, the effectiveness of these drugs in combination with nonantifungal agents is poorly understood. In the present study,in vitrointeractions between polyene antifungals (AMB and LAMB) and alginate lyase (AlgL), an enzyme degrading the polysaccharides produced as extracellular polymeric substances (EPSs) within the biofilm matrix, againstA. fumigatusbiofilms were evaluated 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. On the basis of fractional inhibitory concentration 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 whenA. fumigatusbiofilms were treated with AlgL or polyene alone, as well as with their combination, both a reduction of hyphal thicknesses and an increase of adhesive forces were observed compared to the findings for untreated controls, probably owing to the different action by the enzyme or the antifungal compounds. Interestingly, marked physical changes were noticed inA. fumigatusbiofilms exposed to the AlgL-antifungal combinations compared with the physical characteristics detected after exposure to the antifungals alone, indicating that AlgL may enhance the antibiofilm activity of both AMB and LAMB, perhaps by disrupting the hypha-embedding EPSs and thus facilitating the drugs to reach biofilm cells. Taken together, our results suggest that a combination of AlgL and a polyene antifungal may prove to be a new therapeutic strategy for invasive aspergillosis, while reinforcing the EPS as a valuable antibiofilm drug target.

scholarly journals New Insight into Amphotericin B Resistance in Aspergillus terreus

2013 ◽  
Vol 57 (4) ◽  
pp. 1583-1588 ◽  
Author(s):  
Gerhard Blum ◽  
Caroline Hörtnagl ◽  
Emina Jukic ◽  
Thomas Erbeznik ◽  
Thomas Pümpel ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Molecular Basis ◽  
Aspergillus Terreus ◽  
Minor Role ◽  
Content Type ◽  
Ergosterol Content ◽  
Disseminated Aspergillosis ◽  
A Minor

ABSTRACTAmphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared thein vivovirulence of an AMB-resistantAspergillus terreus(ATR) isolate with that of an AMB-susceptibleA. terreusisolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistancein vitroby comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. Thein vitrodata demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.

scholarly journals Occidiofungin's Chemical Stability andIn VitroPotency against Candida Species

2011 ◽  
Vol 56 (2) ◽  
pp. 765-769 ◽  
Author(s):  
Dayna Ellis ◽  
Jiten Gosai ◽  
Charles Emrick ◽  
Rachel Heintz ◽  
Lanette Romans ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Chemical Stability ◽  
Extreme Temperatures ◽  
Content Type ◽  
Burkholderia Contaminans ◽  
Time Kill ◽  
Postantifungal Effect ◽  
Minimal Lethal Concentration ◽  
Stable Molecule

ABSTRACTOccidiofungin is a cyclic glyco-lipopeptide produced byBurkholderia contaminans. MICs againstCandidaspecies were between 0.5 and 2.0 μg/ml. Occidiofungin retains itsin vitropotency in the presence of 5% and 50% human serum with a minimal lethal concentration (MLC) of 2 and 4 μg/ml, respectively. Time-kill and postantifungal effect (PAFE) experiments of occidiofungin againstCandida albicanswere performed. The results demonstrate that occidiofungin is fungicidal. Occidiofungin was also found to be a very stable molecule. It is resistant to extreme temperatures and pH and maintains its activity following exposure to gastric proteases.

scholarly journals In VitroInteractions between Aspirin and Amphotericin B against Planktonic Cells and Biofilm Cells of Candida albicans and C. parapsilosis

2012 ◽  
Vol 56 (6) ◽  
pp. 3250-3260 ◽  
Author(s):  
Yabin Zhou ◽  
Ganggang Wang ◽  
Yutang Li ◽  
Yang Liu ◽  
Yu Song ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Antimicrobial Agents ◽  
Positive Interactions ◽  
Antibiofilm Activity ◽  
Data Generation ◽  
Planktonic Cells ◽  
Content Type ◽  
Time Kill

ABSTRACTThe increase in drug resistance and invasion caused by biofilm formation brings enormous challenges to the management ofCandidainfection. Aspirin's antibiofilm activityin vitrowas discovered recently. The spectrophotometric method and the XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} reduction assay used for data generation make it possible to evaluate fungal biofilm growth accurately. The combined use of the most commonly used methods, the fractional inhibitory concentration index (FICI) and a newly developed method, the ΔEmodel, which uses the concentration-effect relationship over the whole concentration range instead of using the MIC index alone, makes the interpretation of results more reliable. As an attractive tool for studying the pharmacodynamics of antimicrobial agents, time-kill curves can provide detailed information about antimicrobial efficacy as a function of both time and concentration. In the present study,in vitrointeractions between aspirin (acetylsalicylic acid [ASA]) and amphotericin B (AMB) against planktonic cells and biofilm cells ofCandida albicansandC. parapsilosiswere evaluated by the checkerboard microdilution method and the time-kill test. Synergistic and indifferent effects were found for the combination of ASA and AMB against planktonic cells, while strong synergy was found against biofilm cells analyzed by FICI. The ΔEmodel gave more consistent results with FICI. The positive interactions in concentration were also confirmed by the time-kill test. Moreover, this approach also revealed the pharmacodynamics changes of ASA and synergistic action on time. Our findings suggest a potential clinical use for combination therapy with ASA and AMB to augment activity against biofilm-associated infections.

scholarly journals In Vitro Interaction and Killing-Kinetics of Amphotericin B Combined with Anidulafungin or Caspofungin against Candida auris

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1333
Author(s):  
Unai Caballero ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Nerea Jauregizar
Keyword(s):  
Amphotericin B ◽  
Antifungal Drugs ◽  
Candida Auris ◽  
Dose Requirement ◽  
Fungistatic Activity ◽  
Invasive Infections ◽  
Kill Curve ◽  
Time Kill ◽  
In Vitro Interaction

Treatment of invasive infections caused by Candida auris is challenging due to the limited therapeutic options. The combination of antifungal drugs may be an interesting and feasible approach to be investigated. The aim of this study was to examine the in vitro activity of amphotericin B in combination with anidulafungin or caspofungin against C. auris. In vitro static time–kill curve experiments were conducted for 48 h with different combinations of amphotericin B with anidulafungin or caspofungin against six blood isolates of C. auris. The antifungal activity of 0.5 mg/L of amphotericin B was limited against the six isolates of C. auris. Similarly, echinocandins alone had a negligible effect, even at the highest tested concentrations. By contrast, 1 mg/L of amphotericin B showed fungistatic activity. Synergy was rapidly achieved (8 h) with 0.5 mg/L of amphotericin B plus 2 mg/L of anidulafungin or caspofungin. These combinations lead to a sustained fungistatic effect, and the fungicidal endpoint was reached against some C. auris isolates. Additionally, ≥0.5 mg/L of either of the two echinocandins with 1 mg/L of amphotericin B resulted in fungicidal effect against all C. auris isolates. In conclusion, combinations of amphotericin B with anidulafungin or caspofungin provided greater killing with a lower dose requirement for amphotericin B compared to monotherapy, with synergistic and/or fungicidal outcomes.

Comparison of the bactericidal effects of quinolones against low-susceptible Haemophilus influenzae

2021 ◽  
Vol 70 (6) ◽  
Author(s):  
Kosei Mizoi ◽  
Takeaki Wajima ◽  
Emi Tanaka ◽  
Hidemasa Nakaminami ◽  
Norihisa Noguchi
Keyword(s):  
Haemophilus Influenzae ◽  
Type Species ◽  
Antimicrobial Agents ◽  
Content Type ◽  
Log Reduction ◽  
Link Type ◽  
Bactericidal Effects ◽  
Kill Curve ◽  
Time Kill

The increasing incidence of Haemophilus influenzae with decreased susceptibility to quinolones (quinolone low-susceptible H. influenzae ) in Japan has raised concerns about therapeutic failure. Thus, assessment of effective antimicrobial agents is necessary to establish an effective therapeutic strategy against resulting infections. In this study, in vitro bactericidal effects of quinolones on low-susceptible H. influenzae strains were evaluated using time-kill curve analysis. For tosufloxacin, log reduction values for low-susceptible strains were significantly lower than those for susceptible strains at both Cmax and 1/2 Cmax. Conversely, although the log reduction values were lower for susceptible strains, the Cmax of levofloxacin and β-lactams (amoxicillin and cefditoren) indicated bactericidal effects. In addition, higher concentrations of tosufloxacin at 2×Cmax and 4×Cmax had bactericidal effects on not only susceptible but also low-susceptible strains. These data strongly suggest that we should consider the presence of low-susceptible strains and reconsider the appropriate dosage of tosufloxacin for treatment, especially for paediatric patients.

scholarly journals Environmental Triazole Induces Cross-Resistance to Clinical Drugs and Affects Morphophysiology and Virulence of Cryptococcus gattii and C. neoformans

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Rafael Wesley Bastos ◽  
Hellem Cristina Silva Carneiro ◽  
Lorena Vívien Neves Oliveira ◽  
Karen Maia Rocha ◽  
Gustavo José Cota Freitas ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Efflux Pump ◽  
Study Data ◽  
Cryptococcus Gattii ◽  
Cross Resistance ◽  
Human Pathogens ◽  
Content Type ◽  
Clinical Drugs

ABSTRACTCryptococcus gattiiandCryptococcus neoformansare environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate that pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence ofC. gattiiandC. neoformansstrains. The results showed that tebuconazole exposure causedin vitrocross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, and ravuconazole) but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including formation of pseudohyphae inC. neoformansH99, and the surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than the nonexposed cells. Thisin vivoCR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due to increased expression of theERG11gene in both species and of efflux pump genes (AFR1andMDR1) inC. neoformans. Our study data support the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs.

scholarly journals In Vitro Pharmacodynamic Characteristics of Amphotericin B, Caspofungin, Fluconazole, and Voriconazole against Bloodstream Isolates of Infrequent Candida Species from Patients with Hematologic Malignancies

2004 ◽  
Vol 48 (11) ◽  
pp. 4453-4456 ◽  
Author(s):  
Giovanni Di Bonaventura ◽  
Ilaria Spedicato ◽  
Carla Picciani ◽  
Domenico D'Antonio ◽  
Raffaele Piccolomini
Keyword(s):  
Amphotericin B ◽  
Hematologic Malignancies ◽  
Candida Guilliermondii ◽  
Fungistatic Activity ◽  
Candida Kefyr ◽  
Candida Lusitaniae ◽  
Time Kill ◽  
Postantifungal Effect ◽  
Dose Dependent

ABSTRACT Time-kill and postantifungal effect (PAFE) of amphotericin B, caspofungin, fluconazole, and voriconazole were determined against clinical isolates of Candida guilliermondii, Candida kefyr, and Candida lusitaniae. Azoles displayed fungistatic activity and no measurable PAFE, regardless of the concentration tested. Amphotericin B and caspofungin demonstrated concentration-dependent fungicidal activity, although amphotericin B only produced a significant dose-dependent PAFE against all isolates tested.

scholarly journals Method for Measuring Postantifungal Effect in Aspergillus Species

2002 ◽  
Vol 46 (6) ◽  
pp. 1960-1965 ◽  
Author(s):  
Roxana G. Vitale ◽  
Johan W. Mouton ◽  
Javier Afeltra ◽  
Jacques F. G. M. Meis ◽  
Paul E. Verweij
Keyword(s):  
Amphotericin B ◽  
Growth Curve ◽  
Clinical Laboratory ◽  
Growth Curves ◽  
National Committee ◽  
Control Growth ◽  
And Control ◽  
Postantifungal Effect

ABSTRACT An in vitro method for determination of postantifungal effect (PAFE) in molds was developed by using three isolates each of Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, and A. ustus. MICs of amphotericin B and itraconazole were determined by using National Committee for Clinical Laboratory Standards guidelines (M38-P). The inoculum was prepared in RPMI 1640 broth buffered with MOPS (morpholinepropanesulfonic acid) at pH 7.0, and conidia were exposed to amphotericin B and itraconazole at concentrations of 4, 1, and 0.25 times the MIC, each for 4, 2, and 1 h at 37°C. The same procedure was followed for controls with drug-free medium. Following exposure, the conidia were washed three times in saline and the numbers of CFU per milliliter were determined. Exposed and control conidia were then inoculated into microtitration plates and incubated at 37°C for 48 h in a spectrophotometer reader. The optical density (OD) was measured automatically at 10-min intervals, resulting in growth curves. PAFE was quantified by comparing three arbitrary points in the control growth curve, the first increase of OD and the points when 20 and 50% of the maximal growth were reached, with the growth curve of drug-exposed conidia. Amphotericin B induced PAFE in A. fumigatus at four times the MIC after 2 and 4 h of exposure ranging from 1.83 to 6.00 h and 9.33 to 10.80 h, respectively. Significantly shorter PAFEs or lack of PAFE was observed for A. terreus, A. ustus, and A. nidulans. Itraconazole did not induce measurable PAFE in the Aspergillus isolates at any concentration or exposure time tested. Further studies are warranted to investigate the implications of PAFE in relation to clinical efficacy and dosing frequency.

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