title: Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model.
abstract: Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR)Pseudomonas aeruginosaHowever, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against threeP. aeruginosastrains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (R2= 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). ThefAUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDRP. aeruginosalung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA tonyzhou@purdue.edu kim.chan@sydney.edu.au.
authors.forename: Qi Tony
authors.initials: QT
authors.lastname: Zhou
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
authors.forename: Soon-Ee
authors.initials: SE
authors.lastname: Cheah
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
authors.forename: Jinxin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia tonyzhou@purdue.edu kim.chan@sydney.edu.au.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.|Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D015992:Body Mass Index; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D003091:Colistin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003520:Cyclophosphamide; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D006801:Humans; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D020545:Respiratory Mucosa / Q000187:drug effects / Q000382:microbiology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D003520:Cyclophosphamide; D003091:Colistin
keywords: Pseudomonas aeruginosa; colistin; intratracheal administration; mouse lung infection model; multidrug-resistant bacteria; pharmacodynamics; pharmacokinetics; respiratory tract infection