Date of Award

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmacometrics

Research Advisor

Bernd Meibohm

Committee

Amelia Deitchman; Carl Panetta; Glen Palmer; Mercedes Gonzalez-Juarrero

Keywords

Hollow Fiber Infection Model, Human Dose Prediction, Mycobacterium abscessus, Physiologically-based Pharmacokinetics, PK/PD modeling, Tigecycline

Abstract

Prevalence and incidence of Mycobacterium abscessus (Mab) pulmonary infections have increased and been recognized as a major cause of mortality, particularly in certain patient populations, such as cystic fibrosis (CF) patients. Due to the intrinsic multidrug resistance mechanisms and biofilm (BF) formation properties of Mab, effective treatment remains challenging, as these factors significantly diminish the antibacterial activity of drugs. Current treatment guidelines recommend prolonged therapy, generally more than 12 months with a multidrug combination of at least four agents. However, no optimal combination, regimen, or treatment duration has been universally established for Mab pulmonary infections (Mab-PI). Therefore, the selective and strategic use of the most potent agents available against Mab is essential. Although simple and standardized antibacterial susceptibility testing methods are broadly applicable and clinically interpretable, the methods inherently fail to account for drug-specific properties, or the pathophysiological conditions present in actual infections. These limitations raise the risk of inaccurate clinical translation when in vitro results are interpreted without such context. Therefore, there is an urgent need to develop evaluation methodologies that integrate both drug characteristics and pathogen-specific properties to enable successful clinical treatment. Tigecycline (TGC), one of the preferred drugs listed in treatment guidelines for Mab-PI, has demonstrated excellent therapeutic efficacy, including in CF patients. However, its clinical utility is limited by its narrow therapeutic window and chemical instability in aqueous environments. Consequently, identifying clinical strategies to optimize both efficacy and safety, or to determine suitable combination partners for multidrug regimens, remains highly constrained. To address these limitations, we utilized TGC as a model compound and proposed a model-based methodological framework that can overcome the limitations of conventional antibacterial evaluation methods, enabling a quantitative assessment of an intrinsic antibacterial activity of drugs against Mab by incorporating key factors that influence experimental outcomes. Furthermore, a Hollow-Fiber Infection Model (HFIM) was employed to experimentally evaluate drug efficacy under more biologically relevant conditions that account for BF formation and the resulting time-dependent reduction in drug susceptibility. Model-based interpretation of HFIM-based dynamic time-kill curve experiments provided a strong rationale for drug inhalation strategies aimed at maximizing local drug concentrations at the site of infection. The clear therapeutic limitations of current treatments for Mab-PI underscore the importance of developing new agents or novel combination regimens. Since Mab is an opportunistic pathogen, the host immune status plays a critical role in infection, progression and treatment outcomes. Accordingly, drug efficacy evaluation requires immune-deficient models, but the development of a suitable model for this purpose has been challenging. In this regard, a physiologically based infection kinetic model was devised to quantitatively evaluate the contribution of individual immune cell types to bacterial clearance following Mab exposure in immune-deficient mouse models. This approach identified NSG mice, combined with intratracheal inoculation, as an ideal in vivo animal model for assessing antibacterial efficacy of drugs against Mab-PI. Lastly, a human physiologically based pharmacokinetic (PBPK) model for inhaled TGC was developed to predict exposure in the systemic circulation and major organs associated with toxicity. Based on clinically and preclinically established adverse event thresholds, 125 mg Q3D was identified as optimized dosing strategy capable of maximizing bacterial killing efficacy while minimizing toxicity. The model-based approaches introduced here offer novel insights into the use of TGC and are expected to inform treatment strategies for Mab-PI, with potential for broad application to other potent antibiotics, including those recommended in treatment guidelines, and the identification of optimal combination regimens.

ORCID

0009-0004-9842-0552

DOI

10.21007/etd.cghs.2025.0697

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