In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

Jemel, Sana; Guillot, Jacques; Kallel, K.; Jouvion, Grégory; Brisebard, Elise; Billaud, Éliane; Jullien, Vincent; Botterel, Françoise; Dannaoui, Éric

doi:10.3390/jof7121012

Cited by 7 publications

(14 citation statements)

References 27 publications

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“…Possible explanations for the efficacy of an antifungal against resistant strains could be the use of high dosages or a lower virulence (fitness-cost) of the resistant strains as shown in the study of dos Reis et al (Dos Reis et al, 2019) in which some PSZ resistant mutants derived from a wild type strain lost their virulence. Nevertheless, in our work, the LD 90 was determined for the three strains and no difference in term of virulence was seen between AfS, AfR1 and AfR2 (Jemel et al, 2021).…”

Section: Discussionmentioning

confidence: 60%

“…Identification was confirmed by sequencing part of the gene encoding beta-tubulin. The CYP51A gene and its promoter had been previously sequenced to determine the mutations involved in azole-resistance ( Jemel et al., 2021 ). We included one azole-susceptible strain (AfS) with a wild type CYP51A sequence, one strain (AfR1) with a G54W mutation and one strain (AfR2) with a L98H point mutation in CYP51A in combination with a 34-bp tandem repeat in the promoter (TR34/L98H).…”

Section: Methodsmentioning

confidence: 99%

“…The aim of this study was to evaluate the in vitro and in vivo activity of caspofungin (CAS) in combination with voriconazole (VRZ) or posaconazole (PSZ). For in vivo evaluation, we used the Galleria mellonella model that has proven its contribution to the evaluation of antifungal efficacy for the treatment of IA ( Forastiero et al., 2015 ; Maurer et al., 2015 ; Jemel et al., 2020 ; Jemel et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates

Jemel

Raveloarisaona

Bidaud

et al. 2023

Front. Cell. Infect. Microbiol.

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Azole resistance in Aspergillus fumigatus (Af) has become a widespread threat and a major concern for optimal management of patients with invasive aspergillosis (IA). Combination of echinocandins with azoles is an attractive alternative option for the treatment of IA due to azole-resistant Af strains. The aim of this study was to evaluate the in vitro and in vivo combination of caspofungin (CAS) with either voriconazole (VRZ) or posaconazole (PSZ). In vitro interactions were assessed by two methods, and an animal model of IA in Galleria mellonella was used for in vivo evaluation. Assessment of efficacy was based on larvae mortality. Groups of 10 larvae were infected by 3 clinical strains of Af (azole susceptible, AfS; PSZ resistant, AfR1; VRZ and PSZ resistant strain, AfR2). In vitro, combination of CAS and azoles was indifferent against AfS, and AfR2, and a synergy was found for AfR1. When compared to VRZ monotherapy, the combination of VRZ at 4 µg/larva with CAS at 4 µg/larva improved survival of AfR2-infected larvae (p=0.0066). Combination of PSZ at 4µg/larva with CAS at 4 µg/larva improved survival of AfR1-infected larvae compared to CAS (p=0.0002) and PSZ (0.0024) monotherapy. Antagonism was never observed. In conclusion, the combination of caspofungin with azoles is a promising alternative for the treatment of azole resistant strains of Af.

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Section: Discussionmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates

Jemel

Raveloarisaona

Bidaud

et al. 2023

Front. Cell. Infect. Microbiol.

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“…This model has been successfully used to investigate the efficiency of azole treatment against A. fumigatus [75, 76]. In addition, a recent study has characterised the pharmacokinetics of voriconazole in infected larvae, which allowed us selecting the optimal dose to reach a high concentration of the drug in the haemolymph (above the MICs of the isolates), but that is nearly completely removed in 24 hours [77].…”

Section: Resultsmentioning

confidence: 99%

Aspergillus fumigatuscan display persistence to the fungicidal drug voriconazole

Scott

Valero

Mato-López

et al. 2022

Preprint

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Aspergillus fumigatus is a filamentous fungus that can infect the lungs of patients with immunosuppression and/or underlying lung diseases. The mortality rates associated with chronic and invasive aspergillosis infections remain very high, despite availability of antifungal treatment. In the last decade, there has been a worrisome emergence and spread of resistance to the azole class of antifungals, which are the first line therapy for the treatment of A. fumigatus infections. The mortality caused by resistant isolates is even higher, and the management of these patients is complicated as the therapeutic options are severely reduced. Nevertheless, treatment failure is also common in patients infected with azole susceptible isolates, which can be due to several non-mutually exclusive reasons, such as poor drug absorption. In addition, the phenomena of tolerance or persistence, where susceptible pathogens have the ability to survive the action of an antimicrobial for extended periods of time, have been associated with treatment failure in bacterial infections, and their occurrence in fungal infections already proposed. Here, we investigated the A. fumigatus response to the azole voriconazole and demonstrate that certain isolates of this fungal pathogen can display persistence to this antifungal. A sub-population of the persister isolates can survive for extended periods and even grow at a slow rate in the presence of supra-MIC (minimum inhibitory concentration) of voriconazole. Persistence cannot be eradicated with adjuvant drugs or antifungal drug combinations and reduces the efficacy of treatment in a Galleria mellonella model of infection. Furthermore, persistence implies a distinct transcriptional profile, demonstrating that it is an active response to the drug. For all these reasons, we propose that azole persistence may be a relevant and underestimated factor that influences the outcome of infection in human aspergillosis.

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“…G. mellonella (Tianjin, China) was used to study the effect of linezolid combined with fosfomycin on strain NO.22. As previously described, 28 Enterococcus was centrifugally precipitated in overnight cultures using phosphate buffer saline (PBS) to adjust the concentration, using a 20-μL Hamilton syringe (Hamilton, Shanghai, China) to enter the last left front leg of larvae, followed by inoculation of 10 μL of different bacterial suspensions (10 6 , 10 7 , and 10 8 CFU/larva), and the concentration that caused 80% mortality in larvae at 24 h was determined; the bacterial colony count was used to confirm the consistency of the inoculum. After 2 h of infection, we applied antibiotics (linezolid 5 and 10 mg/kg, fosfomycin 100 and 200 mg/kg) alone or in combination (linezolid 5 mg/kg + fosfomycin 100 mg/kg, linezolid 10 mg/kg + fosfomycin 200 mg/kg); 10 mg/kg of linezolid and 200 mg/kg of fosfomycin were based on human doses, and larvae injected with PBS alone were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant Enterococcus

Li¹,

Peng²,

Zhang³

et al. 2022

IDR

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Purpose We aimed to evaluate the synergistic effect of linezolid and fosfomycin on fosfomycin-sensitive and -resistant Enterococcus clinical isolates in vitro and in vivo and whether the emergence of fosfomycin resistance in Enterococcus is associated with changes in strain virulence, from the perspective of fitness cost. Methods The synergistic effect of linezolid and fosfomycin was studied via in vitro checkerboard and static time-kill assays, as well as based on the in vivo survival rate and hemolymph load of a Galleria mellonella infection model. Fosfomycin resistance was induced via a stepwise increase in concentration. Changes in the virulence of the strains after drug resistance were investigated using the G. mellonella infection model and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In vitro and in vivo growth curves and competitive experiments were used to study the fitness cost of the strain. Finally, a static time-kill assay was performed to explore the effect of the combined medication. Results In vitro and in vivo data showed that linezolid combined with fosfomycin had a good synergistic effect on Enterococcus treatment. The G. mellonella infection model and RT-qPCR data showed that the virulence of the resistant strains was weakened to varying degrees. A survival curve and competition experimental data showed that this was related to the fitness cost of strains while acquiring resistance and negatively impacted linezolid treatment; however, the combination still showed a good synergistic effect in drug-resistant strains. Conclusion Linezolid combined with fosfomycin had a synergistic effect on both fosfomycin-sensitive and -resistant Enterococcus strains. Strains incur fitness costs as they develop drug resistance, which leads to a decrease in virulence. There is an interaction between fitness cost, virulence, and drug resistance, which indirectly affects drug treatment.

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In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

Cited by 7 publications

References 27 publications

In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates

In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates

Aspergillus fumigatuscan display persistence to the fungicidal drug voriconazole

Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant Enterococcus

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