Evaluation of Galleria mellonella larvae for measuring the efficacy and pharmacokinetics of antibiotic therapies against Pseudomonas aeruginosa infection

Hill, L. A.; Veli, Neyme; Coote, Peter J.

doi:10.1016/j.ijantimicag.2013.11.001

Cited by 103 publications

(106 citation statements)

References 22 publications

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“…Next, the ability of the drug formulations to treat infection-induced mortality was measured with bacteria (1.4 × 10 3 cfu/mL) administered at t = 0 and drug treatment 30 min later. G. mellonella was sensitive to this low inoculum of PA01 as untreated larvae did not survive more than 24 h, similar to previous responses with other P. aeruginosa strains [22,23]. Tobramycin prevented mortality in the larvae in a dose dependent manner.…”

Section: Antimicrobial Activity Of Tobramycin Nanoparticlessupporting

confidence: 86%

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Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase)

Deacon

Abdelghany

Quinn

et al. 2015

Journal of Controlled Release

135

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Inhaled antibiotics, such as tobramycin, for the treatment of Pseudomonas aeruginosa pulmonary infections are associated with the increase in life expectancy seen in cystic fibrosis (CF) patients over recent years. However, the effectiveness of this aminoglycoside is still limited by its inability to penetrate the thick DNA-rich mucus in the lungs of these patients, leading to low antibiotic exposure to resident bacteria. In this study, we created novel polymeric nanoparticle (NP) delivery vehicles for tobramycin. Using isothermal titration calorimetry, we showed that tobramycin binds with alginate polymer and, by exploiting this interaction, optimised the production of tobramycin alginate/chitosan NPs. It was established that NP antimicrobial activity against P. aeruginosa PA01 was equivalent to unencapsulated tobramycin (minimum inhibitory concentration 0.625mg/L). Galleria mellonella was employed as an in vivo model for P. aeruginosa infection. Survival rates of 90% were observed following injection of NPs, inferring low NP toxicity. After infection with P. aeruginosa, we showed that a lethal inoculum was effectively cleared by tobramycin NPs in a dose dependent manner. Crucially, a treatment with NPs prior to infection provided a longer window of antibiotic protection, doubling survival rates from 40% with free tobramycin to 80% with NP treatment. Tobramycin NPs were then functionalised with dornase alfa (recombinant human deoxyribonuclease I, DNase), demonstrating DNA degradation and improved NP penetration of CF sputum. Following incubation with CF sputum, tobramycin NPs both with and without DNase functionalisation, exhibited anti-pseudomonal effects. Overall, this work demonstrates the production of effective antimicrobial NPs, which may have clinical utility as mucus-penetrating tobramycin delivery vehicles, combining two widely used CF therapeutics into a single NP formulation. This nano-antibiotic represents a strategy to overcome the mucus barrier, increase local drug concentrations, avoid systemic adverse effects and improve outcomes for pulmonary infections in CF.

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Section: Antimicrobial Activity Of Tobramycin Nanoparticlessupporting

confidence: 86%

“…As a model for infection, it has strong evidence as an appropriate alternative method for studying novel antimicrobials with clinical relevance [21,22]. Firstly, the potential toxicity of tobramycin NPs was examined.…”

Section: Antimicrobial Activity Of Tobramycin Nanoparticlesmentioning

confidence: 99%

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase)

Deacon

Abdelghany

Quinn

et al. 2015

Journal of Controlled Release

135

View full text Add to dashboard Cite

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“…aeruginosa infection model (25)(26)(27). As previously reported (25), the inoculation of G. mellonella larvae with P. aeruginosa strain PA14 at 37°C killed the larvae in a dosedependent manner, with an optimal injection of 10 2 CFU/ml killing all larvae within 24 h (data not shown).…”

Section: Zheng Et Al Antimicrobial Agents and Chemotherapysupporting

confidence: 73%

Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

Zheng

Tharmalingam

et al. 2017

Antimicrob Agents Chemother

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The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrugresistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue ␣-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity toward mammalian cells, and the MICs against most clinical P. aeruginosa isolates were 32 to 64 g/ml, and its MICs versus other Gramnegative bacteria were 2 to 32 g/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by 8-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P Ͻ 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane, and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. aeruginosa infections.KEYWORDS antimicrobial activity, antimicrobial peptide, cecropin A2, Pseudomonas aeruginosa, tetracycline P seudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that causes life-threatening infections with high rates of mortality (1-3). It is associated with nosocomial pneumonia, wound infections, bacteremia, and sepsis among patients with various underlying diseases, including cystic fibrosis, HIV/AIDS, and cancer (4). Antibiotic therapy is challenging in this setting because clinical strains of P. aeruginosa often show extensive intrinsic resistance to a wide range of antimicrobial agents, including tetracyclines, ␤-lactams, aminoglycosides, and fluoroquinolones (5). This intrinsic resistance has generally been attributed to the low membrane permeability of P. aeruginosa, up to 100 times lower than that of Escherichia coli (6). P. aeruginosa can also withstand antibiotics that attack the outer membrane through the efficient deployment of transmembrane efflux pumps, preventing contact between the antibiotics and their intracellular targets (7-11).The ubiquitous and relentless clinical challenge of drug resistance has created a

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“…For clarity, data for treatment with FLUO are not shown because the data obtained closely followed those shown for the control group. Similar findings were described previously for other pathogens (40,43,44).…”

Section: Figsupporting

confidence: 91%

The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence

Guo

Zhang

et al. 2016

Antimicrob Agents Chemother

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e This study evaluated the synergistic effects of the selective serotonin reuptake inhibitor, fluoxetine, in combination with azoles against Candida albicans both in vitro and in vivo and explored the underlying mechanism. MICs, sessile MICs, and time-kill curves were determined for resistant C. albicans. Galleria mellonella was used as a nonvertebrate model for determining the efficacy of the drug combinations against C. albicans in vivo. For the mechanism study, gene expression levels of the SAP gene family were determined by reverse transcription (RT)-PCR, and extracellular phospholipase activities were detected in vitro by the egg yolk agar method. The combinations resulted in synergistic activity against C. albicans strains, but the same effect was not found for the non-albicans Candida strains. For the biofilms formed over 4, 8, and 12 h, synergism was seen for the combination of fluconazole and fluoxetine. In addition, the time-kill curves confirmed the synergism dynamically. The results of the G. mellonella studies agreed with the in vitro analysis. In the mechanism study, we observed that fluconazole plus fluoxetine caused downregulation of the gene expression levels of SAP1 to SAP4 and weakened the extracellular phospholipase activities of resistant C. albicans. The combinations of azoles and fluoxetine showed synergistic effects against resistant C. albicans may diminish the virulence properties of C. albicans.

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Evaluation of Galleria mellonella larvae for measuring the efficacy and pharmacokinetics of antibiotic therapies against Pseudomonas aeruginosa infection

Cited by 103 publications

References 22 publications

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase)

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase)

Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence

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