scholarly journals Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Soon-Ee Cheah ◽  
Jinxin Zhao ◽  
Ke Chen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Inflammation ◽  
Pulmonary Delivery ◽  
Lung Infection ◽  
Dose Fractionation ◽  
Antimicrobial Efficacy ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Intratracheal Delivery

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 = 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.

scholarly journals 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

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Zhou ◽  
Nikolas J. Onufrak ◽  
Veronika Wirth ◽  
Ke Chen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Drug Exposure ◽  
Polymyxin B ◽  
Dose Fractionation ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Tract Infections

ABSTRACT Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R 2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.

scholarly journals Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Mei-Ling Han ◽  
Ke Chen ◽  
Nikolas J. Onufrak ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Dose Fractionation ◽  
Mouse Lung ◽  
Infection Model ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type

ABSTRACT The pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin.

scholarly journals Efficacy of a Conjugate Vaccine Containing Polymannuronic Acid and Flagellin against Experimental Pseudomonas aeruginosa Lung Infection in Mice

2011 ◽  
Vol 79 (8) ◽  
pp. 3455-3464 ◽  
Author(s):  
Victoria L. Campodónico ◽  
Nicolas J. Llosa ◽  
Leticia V. Bentancor ◽  
Tomas Maira-Litran ◽  
Gerald B. Pier
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Conjugate Vaccine ◽  
Protective Efficacy ◽  
Lung Infection ◽  
Microbial Pathogens ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Flagellar Proteins ◽  
Toll Like Receptor 5

ABSTRACTVaccines that could effectively preventPseudomonas aeruginosapulmonary infections in the settings of cystic fibrosis (CF) and nosocomial pneumonia could be exceedingly useful, but to date no effective immunotherapy targeting this pathogen has been successfully developed for routine use in humans. Evaluations using animals and limited human trials of vaccines and their associated immune effectors against differentP. aeruginosaantigens have suggested that antibody to the conserved surface polysaccharide alginate, as well as the flagellar proteins, often give high levels of protection. However, alginate itself does not elicit protective antibody in humans, and flagellar vaccines containing the two predominant serotypes of this antigen may not provide sufficient coverage against variant flagellar types. To evaluate if combining these antigens in a conjugate vaccine would be potentially efficacious, we conjugated polymannuronic acid (PMA), containing the blocks of mannuronic acid conserved in allP. aeruginosaalginates, to type a flagellin (FLA) and evaluated immunogenicity, opsonic killing activity, and passive protective efficacy in mice. The PMA-FLA conjugate was highly immunogenic in mice and rabbits and elicited opsonic antibodies against mucoid but not nonmucoidP. aeruginosa, but nonetheless rabbit antibody to PMA-FLA showed evidence of protective efficacy against both types of this organism in a mouse lung infection model. Importantly, the PMA-FLA conjugate vaccine did not elicit antibodies that neutralized the Toll-like receptor 5 (TLR5)-activating activity of flagellin, an important part of innate immunity to flagellated microbial pathogens. Conjugation of PMA to FLA appears to be a promising path for developing a broadly protective vaccine againstP. aeruginosa.

scholarly journals A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

2011 ◽  
Vol 79 (8) ◽  
pp. 3366-3376 ◽  
Author(s):  
Charles V. Rosadini ◽  
Jeffrey D. Gawronski ◽  
Daniel Raimunda ◽  
José M. Argüello ◽  
Brian J. Akerley
Keyword(s):  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Pathogen ◽  
Lung Infection ◽  
Lung Model ◽  
Mouse Lung ◽  
Infection Model ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
Lung Colonization

ABSTRACTNontypeableHaemophilus influenzae(NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence ofH. influenzae. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the “zinc bindingessential forvirulence” (zev) locus consisting ofzevA(HI1249) andzevB(HI1248). NTHI mutants ofzevAandzevBgrew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate thatzevABis a novel virulence factor important for zinc utilization ofH. influenzaeunder conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.

scholarly journals In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Yu-Feng Zhou ◽  
Meng-Ting Tao ◽  
Wei Huo ◽  
Xiao-Ping Liao ◽  
Jian Sun ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Species ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Content Type ◽  
Murine Lung ◽  
Tract Infections

ABSTRACT Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The E max Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0–24)/MIC ratio was the PD index most closely linked to efficacy (R 2 = 0.96). The mean free-drug AUC0–24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae.

scholarly journals Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Catharine C. Bulik ◽  
Ólanrewaju O. Okusanya ◽  
Elizabeth A. Lakota ◽  
Alan Forrest ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Drug Plasma ◽  
Infection Models

ABSTRACT Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log10 CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (C max) to the MIC (C max/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r 2 = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log10 CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

scholarly journals In Vivo Pharmacodynamic Target Determination for Delafloxacin against Klebsiella pneumoniae and Pseudomonas aeruginosa in the Neutropenic Murine Pneumonia Model

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
David R. Andes
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Phase 3 ◽  
Content Type ◽  
Target Determination

ABSTRACT Delafloxacin is a broad-spectrum anionic fluoroquinolone that has completed a phase 3 study for community-acquired bacterial pneumonia. We investigated the pharmacodynamic target for delafloxacin against 12 Klebsiella pneumoniae and 5 Pseudomonas aeruginosa strains in the neutropenic murine lung infection model. The median 24-h free-drug area under the curve (fAUC)/MIC values associated with net stasis and 1-log kill were 28.6 and 64.1 for K. pneumoniae, respectively. The 24-h fAUC/MIC values associated with net stasis and 1-log kill for P. aeruginosa were 5.66 and 14.3, respectively.

scholarly journals Elucidation of the Pharmacokinetic/Pharmacodynamic Determinant of Colistin Activity against Pseudomonas aeruginosa in Murine Thigh and Lung Infection Models

2009 ◽  
Vol 54 (3) ◽  
pp. 1117-1124 ◽  
Author(s):  
Rajesh V. Dudhani ◽  
John D. Turnidge ◽  
Kingsley Coulthard ◽  
Robert W. Milne ◽  
Craig R. Rayner ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Dose Range ◽  
Lung Infection ◽  
Dose Fractionation ◽  
Maximum Effect ◽  
Infection Model ◽  
Infection Models

ABSTRACT Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC max]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R 2 = 87%) and the lung infection model (R 2 = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.

scholarly journals Eravacycline (TP-434) Is Efficacious in Animal Models of Infection

2015 ◽  
Vol 59 (5) ◽  
pp. 2567-2571 ◽  
Author(s):  
Trudy H. Grossman ◽  
Timothy M. Murphy ◽  
Andrew M. Slee ◽  
Denene Lofland ◽  
Joyce A. Sutcliffe
Keyword(s):  
Lung Infection ◽  
Mouse Lung ◽  
Infection Model ◽  
Murine Models ◽  
Bacterial Burden ◽  
Content Type ◽  
E Coli ◽  
Serious Infections ◽  
Infection Models ◽  
Wide Range

ABSTRACTEravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD50) values of ≤1 mg/kg of body weight once a day (q.d.) againstStaphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistantS. aureus(MRSA), andStreptococcus pyogenes. The PD50values againstEscherichia coliisolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitiveS. aureus(MSSA) andS. pyogenes, eravacycline produced 2 log10reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistantStreptococcus pneumoniaein a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log10CFU reduction in kidney bacterial burden in a model challenged with a uropathogenicE. coliisolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens.

scholarly journals In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Brian VanScoy ◽  
Daniel S. Taylor ◽  
Evelyn Ellis-Grosse ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Gram Negative ◽  
Content Type ◽  
E Coli

ABSTRACT Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC0–∞) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R 2 = 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

Sign in / Sign up

Export Citation Format

Share Document