Inhaled amikacin for pneumonia treatment and dissemination prevention: an experimental model of severe monolateral Pseudomonas aeruginosa pneumonia

Abstract

Background Pseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia. Methods We ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers. Results The median (25–75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75–5.69), 0.72 (0.12–3.35), and 0.90 (0–4.55) log10 CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas. Conclusions In a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

Detection of pharmaceutical contamination in amphipods of Lake Baikal by the HPLC-MS method

“…For instance, acetaminophen has been previously detected in water (Meyer et al, 2022), suggesting that this active ingredient is regularly released into the ecosystem of Lake Baikal. The presence of other pharmaceutical contaminants such as dimetridazole, metronidazole, and amikacin may be attributed to successful use of antibiotics in livestock to treat and prevent infectious diseases (Stephens, 1987; Granja, 2013; Motos et al, 2023).…”

Virtual Screening of Potential RoxS Inhibitors and Evaluation of Their Antimicrobial Activity in Combination with Antibiotics against Clinically Resistant Bacteria

“…Combination therapy is a sustainable option for reducing bacterial resistance [ 33 ]. Unfortunately, routinely used antibiotics are often ineffective against MDR and XDR strains, even with combination therapies [ 34 ]. Since TCS is currently found in bacteria but not in humans or other mammals, it can be used as a novel target for antibacterial drug action [ 35 ].…”

Aerosol therapy in adult critically ill patients: a consensus statement regarding aerosol administration strategies during various modes of respiratory support

“…Nebulization of bronchodilators targeted at the tracheobronchial tree can be assessed by its immediate response, such as the changes in airway resistance, intrinsic positive end-expiratory pressure, or lung compliance. However, other drugs with longer onset time, such as antibiotics and steroids, are challenging, as they require optimal techniques to reach desired levels of drug deposition in the lung parenchyma, and it may be difficult to assess the drug deposition and patient response [ 7 , 8 ]. Factors that impact aerosol delivery include patient characteristics, breathing parameters, the severity of airway disease, the characteristics of aerosol devices, their integration into respiratory support devices and the interface of these devices to patients, ease of use, and patient comfort [ 1 – 4 , 9 , 10 ].…”