Penetration of Clarithromycin in Experimental Pleural Empyema Model Fluid

Abstract

Background: The degree of penetration of clarithromycin into the pleural fluid has not been studied. Objective: To determine the degree to which clarithromycin penetrates into empyemic pleural fluid using a new rabbit model of empyema. Methods: An empyema was created via the intrapleural injection of 1 ml turpentine followed 24 h later by instillation of 5 ml (10¹⁰) Escherichia coli bacteria (ATCC 35218) into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracentesis and pleural fluid analysis, clarithromycin 30 mg/kg was administered intravenously. Antibiotic levels were determined on samples of pleural fluid and blood samples collected serially over 12 h. Antibiotic levels were estimated using HPLC. Results: The antibiotic penetrated well into the empyemic pleural fluid (AUC_PF/AUC_serum ratio of 1.57). The time to equilibration between the pleural fluid and blood antibiotic levels was 8 h. The peak pleural fluid level (Cmax_PF of 2.88 µg/ml) occurred 1 h (Tmax_PF of 1 h) after infusion and decreased thereafter. The Cmax_serum was 3.53 µg/ml at 1 h after administration. Conclusion: The levels of clarithromycin in the pleural fluid after intravenous administration are inhibitory for most of the usual pathogens causing empyema. The degree of penetration of clarithromycin should be considered when macrolides are selected for the treatment of patients with empyema.

Empyema thoracis: new insights into an old disease

“…Attempts have been made using a variety of species, including mice, rats, rabbits, guinea pigs and sheep, to develop a clinically reliable model of empyema. Many models require injury to the pleura to precede pathogen instillation [15][16][17][18][19], as direct bacterial administration into the pleural space often results in their complete clearance [20] or severe sepsis [21]. Other studies have suggested that a pleural effusion is required as a substrate for bacterial growth [22,23].…”

Experimental pleural empyema model in rabbits: Why, how and what are the next steps

“…This model was used for research of pharmacological characteristics and therapeutic efficacy of gentamicin 15 . Turpentine rabbit experimental empyema model with 10 10 /mL Escherichia coli was applied for the research of clarithromycin efficacy, newer quinolones and azithromycin penetration in the empyema fluid 9,26,27 . This model was also used to study linezolid and ertapenem pharmacokinetics in parapneumonic effusions 28 .…”

“…One million bacteria caused empyema in half of all animals, but with a hundred million bacteria, all animals suffered from empyema. considering these results, we decided to take 9 times more bacteria in a single (2 mL) intrapleural inoculums (4.5 10 8 /mL) S. aureus 9 .…”

“…In addition to the thoracic drainage there are other treatment modalities, such as: drainage with intrapleural application of fibrinolytics, video-assisted thoracoscopic surgery (VATS) debridement, thoracotomy with decortication, open drainage and thoracoplasty [8][9][10] . The main goal of empyema treatment is cleaning of purulent pleural content, followed by lung reexpansion intending to avoid complications and the need for second operation 1,2,11 .…”

“…The rabbit turpentine model, the pig model with umbilical cord and the rabbit model with nutritive agar were made in the last 30 years of the last century. These models were used for the basic empyema research at the beginning of the last century 13 , for studying therapeutic and drainage procedures efficacy 3,14 and antibiotics used in the empyema treatment 9,15 .…”