Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, preferably in models which mimic the intended clinical indication. A method for inducing robust lung infections in immunocompetent rats and mice is described which allows for the assessment of treatments in a model of serious pneumonia caused by S. pneumoniae, H. influenzae, P. aeruginosa, K. pneumoniae or A. baumannii. Animals are anesthetized, and an agar-based inoculum is deposited deep into the lung via nonsurgical intratracheal intubation. The resulting infection is consistent, reproducible, and stable for at least 48 h and up to 96 h for most isolates. Studies with marketed antibacterials have demonstrated good correlation between in vivo efficacy and in vitro susceptibility, and concordance between pharmacokinetic/pharmacodynamic targets determined in this model and clinically accepted targets has been observed. Although there is an initial time investment when learning the technique, it can be performed quickly and efficiently once proficiency is achieved. Benefits of the model include elimination of the neutropenic requirement, increased robustness and reproducibility, ability to study more pathogens and isolates, improved flexibility in study design and establishment of a challenging infection in an immunocompetent host.
BackgroundGEP, a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens implicated in a range of infections, including drug-resistant strains of E. coli associated with acute cystitis.MethodsPK and PD studies were conducted in murine (male CD-1 mice) thigh and kidney infections. The administered doses ranged from 1 to 200 mg/kg SC every 6 hours starting 1-hour post-infection. Infected tissues were evaluated for bacterial burden at 24-h post-infection (baseline controls at 1-hour post-infection). Plasma and tissue samples (kidney or thigh homogenates) were collected at 15, 30, 60, 120, 240 and 360 minutes. A population PK (PopPK) model was built in NONMEM using plasma exposures. Efficacy was determined against E. coli ALL, 997577, ATCC25922, IR5 and NCTC13441 (MICs of 1 to 4 µg/mL) in thigh-infected neutropenic (I-) mice and against E. coli ALL in kidney-infected immunocompetent (I+) and I- mice. The PopPK model was used to determine GEP exposures associated with efficacy. PK-PD analyses were conducted using Phoenix WinNonLin 6.3 (Pharsight). The change in log10 colony-forming units (CFU) from baseline were correlated with free drug (f) AUC:MIC using an inhibitory model from the Phoenix library, and model parameter values for each isolate were used to calculate the plasma fAUC:MIC associated with stasis, 1- or 2-log10 reductions in CFU.ResultsPlasma PK data were best fit by a 1-compartment IV model with first-order elimination and were similar in I+ vs. I- and thigh- vs. kidney-infected mice. The AUC0-6 of GEP in kidney was approximately 4- to 5-fold higher than in plasma while the AUC0-6 in thigh was approximately half of plasma. In the I- thigh model, median plasma fAUC:MIC ratios for stasis, 1- or 2-log10 reductions in CFU were 11, 16, and 25 (ranges 3–17, 4–25 and 7–40), respectively. Efficacy vs. E. coli ALL was similar in I- mice infected in thigh or kidney. In I+ mice, the PK-PD target was reduced by half.ConclusionMedian plasma fAUC:MIC targets ranged from 11 to 25. Higher drug levels in kidney vs. plasma or thigh did not translate into improved efficacy in pyelonephritis vs. thigh-infection models.Disclosures All authors: No reported disclosures.
Liposomes are promising targeted drug delivery systems with the potential to improve the efficacy and safety profile of certain classes of drugs. Though attractive, there are unique analytical challenges associated with the development of liposomal drugs including human dose prediction given these are multi-component drug delivery systems. In this study, we developed a multimodal imaging approach to provide a comprehensive distribution assessment for an antibacterial drug, GSK2485680, delivered as a liposomal formulation (Lipo680) in a mouse thigh model of bacterial infection to support human dose prediction. Positron emission tomography (PET) imaging was used to track the in vivo biodistribution of Lipo680 over 48h post-injection providing a clear assessment of the uptake in various tissues and, importantly, the selective accumulation at the site of infection. In addition, a pharmacokinetic model was created to evaluate the kinetics of Lipo680 in different tissues. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was then used to analyze and quantify the distribution of GSK2485680 and a liposomal lipid throughout sections of infected and non-infected thigh tissues at high spatial resolution. Through the combination of both PET and MALDI images, we observed an excellent correlation between the Lipo680-radionuclide signal from PET with GSK2485680 and lipid component signals from MALDI IMS. This multimodal translational method can reduce drug attrition by providing comprehensive biodistribution profiles of drug delivery systems to provide mechanistic insight and elucidate safety concerns. Liposomal formulations have broad potential to deliver therapeutics for other indications, and this work serves as a template to aid in delivering future liposomal drugs to the clinic.
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