colistin and squalamine

Squalamine is a steroid extracted from sharks with proven in vitro antibacterial activity. We assessed its efficacy in reducing the lung bacterial load and histological lesions when given via inhalation in a rat model of chronic Pseudomonas aeruginosa pneumonia.. Sprague-Dawley rats were inoculated by tracheal intubation with 150 μL of a solution containing 10(8) cfu/mL of agar bead-embedded P. aeruginosa strain PAO1. MICs of squalamine and colistin for this strain were 2-8 and 0.5-1 mg/L, respectively. Starting the day after infection, the animals were treated twice daily with aerosolized squalamine (3 mg), colistin (160 mg) or 0.9% saline for 6 days. The bacterial load and lung histological lesions were evaluated on the seventh day.. Aerosols of squalamine and colistin resulted in a significant reduction in median (IQR) pulmonary bacterial count compared with saline [10(3) (6 × 10(2)-2 × 10(3)), 10(3) (9 × 10(2)-6 × 10(3)) and 10(5) (9 × 10(4)-2 × 10(5)) cfu/lung, respectively; P < 0.001 for both treated groups versus saline]. The lung weight and the lung histological severity score were significantly lower in both treated groups.. In a model of chronic P. aeruginosa pneumonia, treatment twice daily with a squalamine aerosol for 6 days leads to a significant reduction in the pulmonary bacterial count and pneumonia lesions with an efficacy comparable to that of colistin.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Bacterial Load; Cholestanols; Chronic Disease; Colistin; Disease Models, Animal; Lung; Male; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Treatment Outcome

Respiratory infections with multidrug-resistant (MDR) bacteria are life-threatening in patients with cystic fibrosis (CF). Squalamine and aminosterol derivatives (ASDs) have previously demonstrated interesting antibacterial activity against bacterial reference strains. This study investigated for the first time their activity against MDR clinical isolates recovered from the sputa of CF patients.. Antibacterial activity of squalamine and two ASDs (1 and 2) was evaluated against 135 MDR gram-negative and gram-positive bacteria using the broth microdilution method for MIC determination.. For gram-negative bacteria, MICs ranged from 2 to 128 mg/L. Resistance to colistin and mucoidity were significantly associated with higher MICs of squalamine and ASDs 1 and 2. Tested compounds were active against various gram-positive bacteria with MIC values varying from 0.5 to 8 mg/L, with the exception of two capsulated isolates of Streptococcus pneumoniae demonstrating MICs of 32 mg/L.. In this study, we present new findings concerning the antibacterial potential of ASDs against MDR bacteria. Colistin-resistant, mucoid and capsulated bacteria were found to exhibit decreased susceptibility to ASDs indicating that these compounds might share some mechanistic aspects with polymyxins towards gram-negative bacteria. However, ASDs were remarkably active against gram-positive species suggesting different mechanisms of action towards gram-positive and gram-negative bacteria. As tested ASDs exhibited elevated MICs in some cases, we believe that these compounds may be developed to be locally administrated as aerosols rather than via systemic administration routes. Further work is warranted to evaluate their in vivo efficacy in aerosol formulations using a lung-infected animal model.

Topics: Anti-Bacterial Agents; Cholestanols; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests