Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP. A potential reason for this discordance is the presence of biofilm-embedded bacteria in lower respiratory tract infections. Drug selection and dosing are often based on data from bacteria grown planktonically. In the present study, an in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model was optimized to evaluate the activity of simulated epithelial lining fluid exposures of inhaled and intravenous doses of polymyxin B and tobramycin against two P. aeruginosa strains. Antibiotic activity was also determined against the P. aeruginosa strains grown planktonically. Our study revealed that inhaled antibiotic exposures were more active than their intravenous counterparts across biofilm and planktonic populations. Inhaled exposures of polymyxin B and tobramycin exhibited comparable activity against planktonic P. aeruginosa. Although inhaled polymyxin B exposures were initially more active against P. aeruginosa biofilms (through 6 h), tobramycin was more active by the end of the experiment (48 h). Together, these data slightly favor the use of inhaled tobramycin for VABP caused by biofilm-forming P. aeruginosa that are not resistant to either antibiotic. The optimized in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model may be beneficial for the development of novel anti-biofilm agents or to optimize antibiotic dosing for infections such as VABP.

铜绿假单胞菌是下呼吸道感染的重要原因，例如呼吸机相关细菌性肺炎（VABP）。使用吸入抗生素治疗 VABP 可以在感染部位实现高药物浓度，同时最大限度地减少全身毒性。尽管理论上有优势，但临床试验未能显示吸入抗生素治疗 VABP 的益处。造成这种不一致的一个潜在原因是下呼吸道感染中存在生物膜嵌入的细菌。药物选择和剂量通常基于浮游生长的细菌的数据。在本研究中，优化了体外气液界面药代动力学/药效动力学生物膜模型，以评估吸入和静脉注射剂量的多粘菌素 B 和妥布霉素模拟上皮内衬液暴露对两种铜绿假单胞菌菌株的活性。还测定了针对浮游生长的铜绿假单胞菌菌株的抗生素活性。我们的研究表明，在生物膜和浮游种群中，吸入抗生素暴露比静脉注射抗生素更活跃。吸入多粘菌素 B 和妥布霉素对浮游铜绿假单胞菌表现出相当的活性。尽管吸入多粘菌素 B 最初对铜绿假单胞菌生物膜（6 小时）更有效，但到实验结束时（48 小时），妥布霉素的活性更强。总之，这些数据稍微支持使用吸入妥布霉素来治疗由对任一抗生素均不耐药的生物膜形成铜绿假单胞菌引起的 VABP。 优化的体外气液界面药代动力学/药效生物膜模型可能有利于新型抗生物膜药物的开发或优化针对 VABP 等感染的抗生素剂量。