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 (R 2 ϭ 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.

Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model

“…Similar to the observations from the colistin PK study (18,19,26), the polymyxin B concentration in ELF was affected by the route of administration. In contrast to the high polymyxin B exposure in ELF (AUC ELF of ϳ600 mg · h/liter for 4.12 mg base/kg) ( Table 1) following pulmonary delivery, polymyxin B was undetectable in ELF following intravenous administration ( Fig.…”

“…A relatively low degree of interstrain variability (Ͻ1-fold) in AUC ELF /MIC and fAUC plasma /MIC was observed for all three strains of P. aeruginosa (Table 4). The fAUC plasma /MIC target values associated with various killing effects for aerosolized polymyxin B (Table 4) compared well with those obtained in aerosolized colistin studies using the same strains in a mouse lung infection model (26). Unlike the fAUC plasma /MIC, the AUC ELF /MIC of polymyxin B differs from that observed previously in the colistin PK/PD study (26).…”

“…The fAUC plasma /MIC target values associated with various killing effects for aerosolized polymyxin B (Table 4) compared well with those obtained in aerosolized colistin studies using the same strains in a mouse lung infection model (26). Unlike the fAUC plasma /MIC, the AUC ELF /MIC of polymyxin B differs from that observed previously in the colistin PK/PD study (26). The AUC ELF /MIC of polymyxin B to achieve bacteriostasis against P. aeruginosa was 1,326 to 1,506 (Table 4), which is much higher than the AUC ELF /MIC of colistin (684 to 1,050) (26), even after accounting for the difference in molecular weights.…”

“…The retention of polymyxin B in ELF was proposed to be due to the binding of polymyxin B to alveolar macrophages (45) and the alveolar basement membrane (46) via electrostatic interactions (47). Similar mechanisms were also suggested for the prolonged and extensive exposure observed in ELF following pulmonary administration of colistin in sheep (35), rats (36), and mice (26). The exact mechanism for the polymyxin retention in ELF is not known, and further studies are warranted.…”

“…Only recently has the importance of aerosolized polymyxins for the treatment of respiratory tract infections started attracting significant interest (17)(18)(19)(20)(21)(22)(23)(24). The majority of current preclinical and clinical PK/PD data for aerosolized polymyxins focus on CMS/colistin (12,19,21,22,(25)(26)(27), although aerosolized polymyxin B has also been used in the clinic (28). There is currently a lack of reliable PK data of aerosolized polymyxin B to guide the dosage selection of inhalational therapy.…”