scholarly journals Drug Combinations against Mucor irregularisIn Vitro

2013 ◽  
Vol 57 (7) ◽  
pp. 3395-3397 ◽  
Author(s):  
Shuzhen Zhang ◽  
Ruoyu Li ◽  
Jin Yu
Keyword(s):  
Amphotericin B ◽  
Drug Combinations ◽  
Content Type ◽  
Mucor Irregularis

ABSTRACTCombinations of terbinafine or caspofungin with amphotericin B, posaconazole, or itraconazole were studied as potential treatments against 18 isolates ofMucor irregularisin vitro. Synergism of the combinations of terbinafine with amphotericin B, posaconazole, and itraconazole against 38.9, 33.3, and 44.4% of the strains studied was observed. In contrast, synergism of the combinations of caspofungin with amphotericin B, posaconazole, and itraconazole against 99.4, 66.7, and 99.4% of the strains studied was observed. Furthermore, no antagonism was observed.

scholarly journals Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

2015 ◽  
Vol 59 (5) ◽  
pp. 2479-2487 ◽  
Author(s):  
Keerti Jain ◽  
Ashwni Kumar Verma ◽  
Prabhat Ranjan Mishra ◽  
Narendra Kumar Jain
Keyword(s):  
Drug Release ◽  
Amphotericin B ◽  
Human Erythrocytes ◽  
Antileishmanial Activity ◽  
Cell Uptake ◽  
Antiparasitic Activity ◽  
Content Type ◽  
Drug Localization

ABSTRACTThe present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency,in vitrodrug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellularLeishmania donovaniamastigotes,in vivopharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagicL. donovaniamastigotes. In thein vitrocell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs.In vivostudies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

scholarly journals In VitroActivities of Nine Antifungal Drugs against 81 Phialophora and Cyphellophora Isolates

2012 ◽  
Vol 56 (11) ◽  
pp. 6044-6047 ◽  
Author(s):  
Peiying Feng ◽  
M. Javad Najafzadeh ◽  
Jiufeng Sun ◽  
Sarah Ahmed ◽  
Liyan Xi ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Drugs ◽  
Content Type

ABSTRACTCyphellophora guyanensis(n= 15), otherCyphellophoraspecies (n= 11),Phialophora europaea(n= 43), and otherPhialophoraspecies (n= 12) were testedin vitroagainst nine antifungal drugs. The MIC90s across all of the strains (n= 81) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.5 μg/ml; voriconazole, 1 μg/ml; micafungin, 1 μg/ml; terbinafine, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 4 μg/ml; fluconazole, 8 μg/ml; amphotericin B, 16 μg/ml.

scholarly journals Leishmanicidal Activity of Isoselenocyanate Derivatives

2018 ◽  
Vol 63 (2) ◽  
pp. e00904-18 ◽  
Author(s):  
Celia Fernández-Rubio ◽  
Esther Larrea ◽  
José Peña Guerrero ◽  
Eduardo Sesma Herrero ◽  
Iñigo Gamboa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amphotericin B ◽  
Cell Cycle Progression ◽  
Leishmania Major ◽  
Antitumor Agents ◽  
Peritoneal Macrophages ◽  
Reference Drug ◽  
Content Type ◽  
Leishmanicidal Activity

ABSTRACTConventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects againstLeishmania. In this study, thein vitroleishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested againstLeishmania majorandLeishmania amazonensisparasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated inL. amazonensisandL. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 thanL. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels ofLeishmaniagenes involved in the cell cycle, such astopoisomerase-2(TOP-2),PCNA, andMCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

scholarly journals In Vitro Antifungal Combination of Flucytosine with Amphotericin B, Voriconazole, or Micafungin against Candida auris Shows No Antagonism

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
A. L. Bidaud ◽  
F. Botterel ◽  
A. Chowdhary ◽  
E. Dannaoui
Keyword(s):  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Resistant Mutants ◽  
Hospital Acquired

ABSTRACT Candida auris is an emerging, multidrug-resistant pathogen responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida species drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is, therefore, noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC ranges (geometric mean [Gmean]) of flucytosine, amphotericin B, micafungin, and voriconazole were 0.125 to 1 μg/ml (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml), and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01, and 0.5 to 1.06 for the combinations of flucytosine with amphotericin B, micafungin, and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. The combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.

scholarly journals In Vitro Activity of Chlorhexidine Compared with Seven Antifungal Agents against 98 Fusarium Isolates Recovered from Fungal Keratitis Patients

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Claudy Oliveira dos Santos ◽  
Eva Kolwijck ◽  
Henrich A. van der Lee ◽  
Marlou C. Tehupeiory-Kooreman ◽  
Abdullah M. S. Al-Hatmi ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Culture Collection ◽  
Fungal Keratitis ◽  
Molecular Techniques ◽  
Temperate Climate ◽  
Eye Drops ◽  
Fungal Culture ◽  
Content Type

ABSTRACT Fungal keratitis is a common but severe eye infection in tropical and subtropical areas of the world. In regions with a temperate climate, the frequency of infection is rising in patients with contact lenses and following trauma. Early and adequate therapy is important to prevent disease progression and loss of vision. The management of Fusarium keratitis is complex, and the optimal treatment is not well defined. We investigated the in vitro activity of chlorhexidine and seven antifungal agents against a well-characterized collection of Fusarium isolates recovered from patients with Fusarium keratitis. The fungus culture collection of the Center of Expertise in Mycology Radboudumc/CWZ was searched for Fusarium isolates that were cultured from cornea scrapings, ocular biopsy specimens, eye swabs, and contact lens fluid containers from patients with suspected keratitis. The Fusarium isolates that were cultured from patients with confirmed keratitis were all identified using conventional and molecular techniques. Antifungal susceptibility testing was performed according to the EUCAST broth microdilution reference method. The antifungal agents tested included amphotericin B, voriconazole, posaconazole, miconazole, natamycin, 5-fluorocytosine, and caspofungin. In addition, the activity of chlorhexidine was determined. The fungal culture collection contained 98 Fusarium isolates of confirmed fungal keratitis cases from 83 Dutch patients and 15 Tanzanian patients. The isolates were collected between 2007 and 2017. Fusarium oxysporum (n = 24, 24.5%) was the most frequently isolated species followed by Fusarium solani sensu stricto (n = 18, 18.4%) and Fusarium petroliphilum (n = 11, 11.2%). Amphotericin B showed the most favorable in vitro inhibition of Fusarium species followed by natamycin, voriconazole, and chlorhexidine, while 5-fluorocytosine, posaconazole, miconazole, and caspofungin showed no relevant inhibiting effect. However, chlorhexidine showed fungicidal activity against 90% of F. oxysporum strains and 100% of the F. solani strains. Our study supports the clinical efficacy of chlorhexidine and therefore warrants its further clinical evaluation for primary therapy of fungal keratitis, particularly in low and middle income countries where fungal keratitis is much more frequent and, currently, antifungal eye drops are often unavailable.

scholarly journals Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Shuyi Ma ◽  
Suraj Jaipalli ◽  
Jonah Larkins-Ford ◽  
Jenny Lohmiller ◽  
Bree B. Aldridge ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Computational Model ◽  
Drug Combinations ◽  
Broth Culture ◽  
Multiple Drug ◽  
Content Type ◽  
Drug Synergy ◽  
Drug Regimens

ABSTRACT The rapid spread of multidrug-resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen Mycobacterium tuberculosis (MTB), coupled with the large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico more than 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c upregulation reduces the antagonism of the bedaquiline-streptomycin combination. A retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (P value = 1 × 10−4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens. IMPORTANCE Multidrug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.

scholarly journals New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Ren-Yi Lu ◽  
Ting-Jun-Hong Ni ◽  
Jing Wu ◽  
Lan Yan ◽  
Quan-Zhen Lv ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Pathogenic Fungi ◽  
Control Group ◽  
Survival Times ◽  
Content Type ◽  
Fungal Burden ◽  
Wide Range

ABSTRACT In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

scholarly journals A Revised Species Concept for OpportunisticMucorSpecies Reveals Species-Specific Antifungal Susceptibility Profiles

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Lysett Wagner ◽  
Sybren de Hoog ◽  
Ana Alastruey-Izquierdo ◽  
Kerstin Voigt ◽  
Oliver Kurzai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Susceptibility Testing ◽  
Species Concept ◽  
Antifungal Susceptibility ◽  
Content Type ◽  
Mucor Indicus ◽  
Species Specific ◽  
Susceptibility Profiles ◽  
High Mics

ABSTRACTRecently, the species concept of opportunisticMucor circinelloidesand its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevantMucorspecies and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns.In vitrosusceptibility profiles of 101 mucoralean strains belonging to the genusMucor(72), the closely related speciesCokeromyces recurvatus(3),Rhizopus(12),Lichtheimia(10), andRhizomucor(4) to six antifungals (amphotericin B, natamycin, terbinafine, isavuconazole, itraconazole, and posaconazole) were determined. The most active drug for all Mucorales was amphotericin B. Antifungal susceptibility profiles of pathogenicMucorspecies were specific for isavuconazole, itraconazole, and posaconazole. The species formerly united inM. circinelloidesshowed clear differences in their antifungal susceptibilities.Cokeromyces recurvatus,Mucor ardhlaengiktus,Mucor lusitanicus(M. circinelloidesf.lusitanicus), andMucor ramosissimusexhibited high MICs to all azoles tested.Mucor indicuspresented high MICs for isavuconazole and posaconazole, andMucor amphibiorumandMucor irregularisshowed high MICs for isavuconazole. MIC values ofMucorspp. for posaconazole, isavuconazole, and itraconazole were high compared to those forRhizopusand the Lichtheimiaceae (LichtheimiaandRhizomucor). Molecular identification combined within vitrosusceptibility testing is recommended forMucorspecies, especially if azoles are applied in treatment.

scholarly journals In Vitro Evaluation of Radiolabeled Amphotericin B for Molecular Imaging of Mold Infections

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Lukas Page ◽  
Andrew J. Ullmann ◽  
Fabian Schadt ◽  
Sebastian Wurster ◽  
Samuel Samnick
Keyword(s):  
Molecular Imaging ◽  
Amphotericin B ◽  
Invasive Pulmonary Aspergillosis ◽  
Nuclear Imaging ◽  
Molecular Probes ◽  
Content Type ◽  
Diagnostic Potential ◽  
Gallium 68

ABSTRACT Invasive pulmonary aspergillosis and mucormycosis are life-threatening complications in immunocompromised patients. A rapid diagnosis followed by early antifungal treatment is essential for patient survival. Given the limited spectrum of biomarkers for invasive mold infections, recent studies have proposed the use of radiolabeled siderophores or antibodies as molecular probes to increase the specificity of radiological findings by nuclear imaging modalities. While holding enormous diagnostic potential, most of the currently available molecular probes are tailored to the detection of Aspergillus species, and their cost-intensive and sophisticated implementation restricts their accessibility at less specialized centers. In order to develop cost-efficient and broadly applicable tracers for pulmonary mold infections, this study established streamlined and high-yielding protocols to radiolabel amphotericin B (AMB) with the gamma emitter technetium-99m (99mTc-AMB) and the positron emitter gallium-68 (68Ga-AMB). The radiochemical purity of the resulting tracers consistently exceeded 99%, and both probes displayed excellent stability in human serum (>98% after 60 to 240 min at 37°C). The uptake kinetics by representative mold pathogens were assessed in an in vitro Transwell assay using infected endothelial cell layers. Both tracers accumulated intensively and specifically in Transwell inserts infected with Aspergillus fumigatus, Rhizopus arrhizus, and other clinically relevant mold pathogens compared with their accumulation in uninfected inserts and inserts infected with bacterial controls. Inoculum-dependent enrichment was confirmed by gamma counting and autoradiographic imaging. Taken together, this pilot in vitro study proposes 99mTc-AMB and 68Ga-AMB to be facile, stable, and specific probes, meriting further preclinical in vivo evaluation of radiolabeled amphotericin B for molecular imaging in invasive mycoses.

scholarly journals Fenbendazole Controls In Vitro Growth, Virulence Potential, and Animal Infection in the Cryptococcus Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Haroldo C. de Oliveira ◽  
Luna S. Joffe ◽  
Karina S. Simon ◽  
Rafael F. Castelli ◽  
Flavia C. G. Reis ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Mammalian Cells ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Macrophage Infection ◽  
Content Type ◽  
Virulence Potential ◽  
Cryptococcal Disease

ABSTRACT The human diseases caused by the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii are associated with high indices of mortality and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anticryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anticryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anticryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anticryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mouse model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

Sign in / Sign up

Export Citation Format

Share Document