Model-based learn and confirm: designing effective treatment regimens against multidrug resistant Gram-negative pathogens.

Over the last decade, there has been a growing appreciation for the use of in vitro and in vivo infection models to generate robust and informative nonclinical PK/PD data to accelerate the clinical translation of treatment regimens. The objective of this study was to develop a model-based "learn and confirm" approach to help with the design of combination regimens using in vitro infection models to optimise the clinical utility of existing antibiotics. Static concentration time-kill studies were used to evaluate the PD activity of polymyxin B (PMB) and meropenem against two carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates; BAA2146 (PMB-susceptible) and BRKP67 (PMB-resistant).

Predicting the pharmacokinetics and pharmacodynamics of antisense oligonucleotides: an overview of various approaches and opportunities for PBPK/PD modelling.

Introduction: Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.

Areas Covered: A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023).

International society of Pharmacometrics Mentorship Program (IMP): feedback survey from the first cohort of mentor-mentee pairs.

The International Society of Pharmacometrics (ISoP) Mentorship Program (IMP) aims to help professionals at all career stages to transition into the pharmacometrics field, move to a different role/area within pharmacometrics, or expand their skillsets. The program connects mentees at various stages of their careers with mentors based on established criteria for mentor-mentee matching. Pairing mentees with appropriate mentors ensures strong alignment between mentees' interests and mentors' expertise as this is critical to the success and continuation of the relationship between the mentor and mentee.

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2'-MOE and Phosphorothioate Modified Antisense Oligonucleotides.

The pharmacokinetics (PK) of 2'-O-methoxyethyl and phosphorothioate antisense oligonucleotides (ASOs), with or without N-acetyl galactosamine conjugation, have been well characterized following subcutaneous or intravenous drug administration. However, the effect of organ impairment on ASO PK, primarily hepatic or renal impairment, has not yet been reported. ASOs distribute extensively to the liver and kidneys, where they are metabolized slowly by endo- and exonucleases, with minimal renal excretion as parent drug (<1%-3%).

Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing Klebsiella pneumoniae.

Determining the role of the immune response in preventing antimicrobial resistance and optimising antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamic and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates.

Moving From Point-Based Analysis to Systems-Based Modeling: Integration of Knowledge to Address Antimicrobial Resistance Against MDR Bacteria.

The emerging discipline of Quantitative Systems Pharmacology (QSP) enables the integration of quantitative experimental data describing the interactions between the various biological processes within the system using mathematical modeling to gain better insights into the factors that drive disease pathogenicity and influence antibiotic pharmacokinetics (PKs)/pharmacodynamics (PDs). Through our perspective we consider the evolution from PK/PD models to mechanism-based and systems-based models and then finally QSP. We further emphasize the need to invest in ambitious research that takes into consideration: (i) the antibiotic PK/PD activity, (ii) the time course of the host immune response to understand the progression of the infection, (iii) and a growing appreciation of the cellular and molecular networks using multi-omics analysis to understand the modulation of antimicrobial therapy at a true systems level.

Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model.

Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens.

Comparison of the composition and in vitro activity of polymyxin B products.

A number of companies manufacture polymyxin B using United States Pharmacopeia (USP) metrics, rather than chemical composition, to report biological activity. Given that polymyxin B contains several different components, it is unknown whether pharmacokinetic and pharmacodynamic variability exists between the different brands and whether USP metrics capture this variability. Here we investigated the composition of polymyxin B obtained from four manufacturers (Sigma-Aldrich, AK Scientific, USP and MP Biomedicals) and evaluated their rate and extent of killing against multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae using in vitro static time-kill experiments.

Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia.

The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model.

Evaluation of Activity and Emergence of Resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae.

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing and to assess the rate and extent of emergence of resistance to different antibiotic regimens.

Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae.

The multidrug resistance profiles of carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria.

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes.

Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis.

Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae.

Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates.

Combinatorial pharmacodynamics of polymyxin B and tigecycline against heteroresistant Acinetobacter baumannii.

The prevalence of heteroresistant Acinetobacter baumannii is increasing. Infections due to these resistant pathogens pose a global treatment challenge. Here, the pharmacodynamic activities of polymyxin B (PMB) (2-20 mg/L) and tigecycline (0.