Gentamicin synergises with azoles against drug-resistant Candida albicans

Lü, Mengjiao; Yu, Changqiu; Cui, Xueyan; Shi, Jinyi; Yuan, Lei; Sun, Shujuan

doi:10.1016/j.ijantimicag.2017.09.012

Cited by 49 publications

(38 citation statements)

References 38 publications

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“…However, it was also clear that the gentamicin treatment (both in free or NP formulation) was able to prevent both tissue damage (supplementary Figure 3) and reduction in hemocyte numbers ( Figure 4C), whilst concomitantly ablating residual bacteria viability ( Figure 4D). This is in agreement with a recent study in G. mellonella showing that antibiotic treatment of candida albicans could reduce tissue damage in the larvae [36].…”

Section: Accepted Manuscriptsupporting

confidence: 93%

Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles

Jiang

Greene

Insua

et al. 2018

Journal of Controlled Release

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Klebsiella pneumoniae is a foremost gram-negative pathogen that can induce life-threatening nosocomial pulmonary infections. Although it can be phagocytosed successfully by lung resident macrophages, this pathogen remains viable within vacuolar compartments, resulting in chronic infection and limiting therapeutic treatment with antibiotics. In this study, we aimed to generate and evaluate a cell-penetrant antibiotic poly(lactide-co-glycolide) (PLGA)-based formulation that could successfully treat intracellular K. pneumoniae infection. Screening of formulation conditions allowed the generation of high drug loaded nanoparticles through a water-in-oil-in-water approach. We demonstrated the therapeutic usefulness of these gentamicin-loaded nanoparticles (GNPs), showing their ability to improve survival and provide extended prophylactic protection towards K. pneumoniae using a Galleria mellonella infection model. We subsequently showed that the GNPs could be phagocytosed by K. pneumoniae infected macrophages, and significantly reduce the viability of the intracellular bacteria without further stimulation of pro-inflammatory or pro-apoptotic effects on the macrophages. Taken together, these results clearly show the potential to use antibiotic loaded NPs to treat intracellular K. pneumoniae infection, reducing bacterial viability without concomitant stimulation of inflammatory or pyroptotic pathways in the treated cells.

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Section: Accepted Manuscriptsupporting

confidence: 93%

Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles

Jiang

Greene

Insua

et al. 2018

Journal of Controlled Release

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“…Some of the antibiotic derivatives, such as aminoglycoside analogs obtained by structural modifications of kanamycin A and B, tobramycin, and gentamicin were reported to have antifungal activities and to synergize with azoles against Candida spp. (Lu et al 2018). However, studies emphasizing the sensitizing effect of amikacin on fluconazole against drug-resistant Candida spp.…”

Section: Discussionmentioning

confidence: 99%

“…The MIC of fluconazole in the presence of amikacin (4,000 µg/ml) against the majority of resistant C. albicans decreased from 1,024 μg/ml to 4 μg/ml, against C. glabrata from 1,024 μg/ml to 32 μg/ml, and against C. tropicalis as well as C. famata the value of the MIC against fluconazole dropped from 128 μg/ml to 4 μg/ml (Table V). In their study, Lu et al speculated that gentamicin/fluconazole synergism could be mediated by suppressing the efflux pumps of C. albicans (Lu et al 2018). To test this hypothesis and to give an insight into the mechanism of amikacin sensitization of Candida to fluconazole, the rhodamine efflux assay in the absence and presence of amikacin (4,000 µg/ml), was performed on the three Fig.…”

Section: Discussionmentioning

confidence: 99%

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Resensitization of Fluconazole-Resistant Urinary Candida spp. Isolates by Amikacin through Downregulation of Efflux Pump Genes

Edward

Mohamed

Zakaria

2020

Polish Journal of Microbiology

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A b s t r a c tThe contribution of fluconazole-resistant Candida spp. isolates to urinary tract infections in Egypt has become a nationwide problem. A recent approach to overcome such disaster is combining conventional antifungals with non-antifungals. This study investigated the interaction of amikacin with fluconazole against resistant Candida strains isolated from the urine culture of patients admitted to Alexandria Main University Hospital. Among the collected Candida spp. isolates, 42.9% were resistant to fluconazole with MICs ranging between 128 and 1,024 µg/ml. The resistance-modifying activity of amikacin (4,000 µg/ml) was studied against fluconazole-resistant isolates where amikacin sensitized 91.7 % of resistant Candida spp. isolates to fluconazole with a modulation factor ranging between 32 and 256. The rhodamine efflux assay was performed to examine the impact of amikacin on efflux pump activity. After 120 minutes of treatment, amikacin affected the efflux pump activity of the isolates tested with a percentage of reduction in the fluorescence intensity of 8.9%. Quantitative real-time PCR was applied to assess the amikacin effect on the expression of the efflux pump genes MDR1, CDR1, and CDR2. The downregulatory effect of amikacin on the expression of the studied genes caused a percentage of reduction in the expression level ranging between 42.1 and 94%. In conclusion, amikacin resensitized resistant Candida spp. isolates to fluconazole and could be used in combination in the management of candiduria with a higher efficiency or at lower administration doses. To the best of our knowledge, this is the first study evaluating the enhancement of fluconazole activity in combination with amikacin against Candida spp. K e y w o r d s: Candida spp., amikacin, fluconazole, rhodamine efflux assay, quantitative real-time PCR Edward E.A. et al.

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“…This new model system allows for fungal burden to be monitored throughout the course of infection in a single animal via CFU count. This is unlike any other experimental system, where fungal burden is either an endpoint measure in the mouse kidney, in homogenised was moth larvae 49 ,nematodes 50 , flies 51 , or requires genetically modified fluorescent yeast strains for microscopic imaging and analyses 52 . While we did detect very low CFU counts in the PBS control 3 days post infection, we consider this spurious finding due to cross contamination as preliminary experiments of plating contents of hemolymph and faeces of naïve animals did not detect any yeast growth (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Tobacco Hornworm (Manduca sexta) caterpillars as a novel host model for the study of fungal virulence and drug efficacy

Lyons

Softley

Balfour

et al. 2019

Preprint

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29Pathogenic yeast species can cause life-threatening infections in humans. The two leading 30 yeast pathogens, Candida albicans and Cryptococcus neoformans, cause systemic infections 31 in >1.4 million patients world-wide with mortality rates approaching 75%. It is thus 32 imperative to study fungal virulence mechanisms, stress response pathways, and the efficacy 33 of antifungal drugs. This is commonly done using mammalian models. To address ethical and 34 practical concerns, invertebrate models, such as wax moth larvae, nematodes, or flies, have 35 been introduced over the last two decades. To address short-comings in existing invertebrate 36 host models, we developed fifth instar caterpillars of the Tobacco Hornworm moth Manduca 37 sexta as a novel host model for the study of fungal virulence and drug efficacy. These 38 caterpillars can be raised at standardised conditions, maintained at 37˚C, can be injected with 39 defined amounts of yeast cells, and are susceptible to the most threatening yeast pathogens, 40 including C. albicans, C. neoformans, C. auris, and C. glabrata. Infected caterpillars can be 41 rescued by treatment with commonly deployed antifungal drugs and importantly, fungal 42 burden can be assessed daily throughout the course of infection in a single caterpillar's faeces 43 and hemolymph. Notably, these animals are large enough so that weight provides a reliable 44 and reproducible measure of fungal virulence. This model combines a suite of parameters that 45 recommend it for the study of fungal virulence. 46 47 50 tuberculosis 1 . The leading yeast pathogens, Candida albicans and Cryptococcus neoformans, 51 together account for >1,400,000 life-threatening infections world-wide with mortality rates 52 approaching 75% 1 . Candidemia, most commonly caused by C. albicans, is the fourth most 53 common cause of nosocomial blood stream infections, only surpassed by infections with 54Staphylococci and Enterococcus spp. Disturbingly, candidemia incidence rates are on the 55 rise. Within less than ten years, incidence rates increased by 36% 2 . Although cryptococcosis 56 incidence rates are on the decline in North America, this AIDS-defining illness is responsible 57 for 15% of all AIDS-related deaths world-wide 2,3 . This already dire situation is further 58 confounded by the emergence of drug resistant yeast species. Patients at risk of developing 59 invasive candidemia are often prophylactically treated with fluconazole, while the 60 echinocandins are considered a first line defence strategy 4 . Yet, C. glabrata, the most 61 3 common non-albicans Candida species associated with nosocomial blood stream infections 5 , 62 is intrinsically less susceptible to azole drugs and acquires resistance to echinocandins 63 rapidly 6 . The rapid global spread of multi-drug resistant C. auris has further exacerbated the 64 threat posed by fungi. C. auris was first reported in 2009 in Japan 7 . In 2015, C. auris arrived 65 in Europe causing an outbreak involving 72 patients in a cardio-thoracic hospital i...

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Gentamicin synergises with azoles against drug-resistant Candida albicans

Cited by 49 publications

References 38 publications

Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles

Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles

Resensitization of Fluconazole-Resistant Urinary Candida spp. Isolates by Amikacin through Downregulation of Efflux Pump Genes

Tobacco Hornworm (Manduca sexta) caterpillars as a novel host model for the study of fungal virulence and drug efficacy

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