Abstract
BackgroundBacteremia-induced sepsis is a leading cause of mortality in intensive care units. To control a bacterial infection, an immune response is required, but this response might contribute to organ failure. Kidneys are one of the main organs affected by bacteremia. Combination therapies with antibacterial and anti-inflammatory effects may be beneficial in treating bacteremia. This study aimed to develop nanostructured lipid carriers (NLCs) loaded with ciprofloxacin and rolipram that exert a combination of anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-inflammatory effects. Retinol was incorporated into the nanoparticles to transport retinol-binding protein 4 (RBP4) to the kidneys, which abundantly express RBP receptors. The NLCs were fabricated by high-shear homogenization and sonication, and neutrophils were used as a model to assess their anti-inflammatory effects. Mice were injected with MRSA to establish a model of bacteremia with organ injury.ResultsThe mean nanoparticle size and zeta potential of the NLCs were 171 nm and − 39 mV, respectively. Ciprofloxacin (0.05%, w/v) and rolipram (0.02%) achieved encapsulation percentages of 88% and 96%, respectively, in the nanosystems. The minimum bactericidal concentration of free ciprofloxacin against MRSA increased from 1.95 to 15.63 µg/ml when combined with rolipram, indicating a possible drug-drug interaction that reduced the antibacterial effect. Nanoparticle inclusion promoted the anti-MRSA activity of ciprofloxacin according to time-kill curves. The NLCs were found to be largely internalized into neutrophils and exhibited superior superoxide anion inhibition than free drugs. Retinol incorporation into the nanocarriers facilitated their efficient targeting to the kidneys. The NLCs significantly mitigated MRSA burden and elastase distribution in the organs of MRSA-infected animals, and the greatest inhibition was observed in the kidneys. Bacterial clearance and neutrophil infiltration suppression attenuated the bacteremia-induced cytokine overexpression, leading to an improvement in the survival rate from 22% to 67%.ConclusionsThe dual role of our NLCs endowed them with greater efficacy in treating MRSA bacteremia than that of free drugs.
Highlights
Bacteremia-induced sepsis is a leading cause of mortality in intensive care units
By ultracentrifugation showed that the encapsulation percentages of ciprofloxacin and rolipram in the nanostructured lipid carriers (NLCs) were 88.21 ± 7.0% and 95.81 ± 12.24%, respectively
Use of NLCs for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia treatment To evaluate the protective effects of free drugs and NLCs on MRSA-induced bacteremia in mice, we examined the survival rate of the mice four days after intravenous injection of the drug-loaded formulations
Summary
Bacteremia-induced sepsis is a leading cause of mortality in intensive care units. To control a bacterial infection, an immune response is required, but this response might contribute to organ failure. Kidneys are one of the main organs affected by bacteremia. Combination therapies with antibacterial and anti-inflammatory effects may be beneficial in treating bacteremia. This study aimed to develop nanostructured lipid carriers (NLCs) loaded with cipro‐ floxacin and rolipram that exert a combination of anti-methicillin-resistant Staphylococcus aureus (MRSA) and antiinflammatory effects. The most common cause of bacteremia is Staphylococcus aureus infection [1]. The mortality of patients with critical MRSA bacteremia can exceed 60% [3]. Bacteremia, followed by acute inflammation, can lead to sepsis and multiple organ failure. The activation of proinflammatory mediators by sepsis contributes to organ damage, especially damage to the heart, lungs, and kidneys. Severe septic shock is observed in 38%−40% of patients with S. aureus bacteremia [6]
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