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 aeruginosa However, 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 three P. aeruginosa strains (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). The fAUC/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 MDR P. aeruginosa lung 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.

Keywords: Pseudomonas aeruginosa; colistin; intratracheal administration; mouse lung infection model; multidrug-resistant bacteria; pharmacodynamics; pharmacokinetics; respiratory tract infection.

FIG 1

(A) Total and unbound plasma concentration versus time of colistin after administration of single intratracheal (I.T.) doses of 2.64 and 5.28 mg base/kg and intravenous (I.V.) administration of 2.64 mg base/kg in neutropenic lung-infected mice. (B) ELF colistin concentration versus time after intratracheal administration of 2.64 and 5.28 mg base/kg colistin in neutropenic lung-infected mice.

FIG 2

Sigmoid inhibitory fit for PAO1 between the log₁₀ CFU/lung at 24 h and the PK/PD indices for ELF, namely, AUC_ELF/MIC (A), C_{max, ELF}/MIC (B), and T_{>MIC, ELF} (C), and for plasma, namely, fAUC_Plasma/MIC (D), fC_{max, Plasma}/MIC (E), and fT_{>MIC, Plasma} (F). R² is the coefficient of determination. The broken line represents the mean bacterial burden in lungs at the start of treatment.

FIG 3

Representative images of lung sections from histopathological examination of P. aeruginosa-infected mice. (A) Mouse lung from the growth control group showing interstitial necrosis and intra-alveolar flocculus material (severe damage and inflammation; SQS of >+5) (×20 magnification). (B) Mouse lung harvested at 24 h after colistin (2.64 mg/kg thrice daily) with perivascular inflammation (mild damage; SQS of >+1) (×20 magnification). The degree of inflammation and changes may not be consistent across the entire lung tissue, and these images only show significant changes observed.