Multi-omics informed mathematical model for meropenem and tobramycin against hypermutable Pseudomonas aeruginosa.

Hypermutable P. aeruginosa isolates frequently display resistance emergence during treatment. Mechanisms of such resistance emergence have not been explored using dynamic hollow-fiber studies and multi-omics-informed mathematical modeling.

Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients.

Determining an effective dosing regimen for piperacillin-tazobactam in critically ill patients is challenging due to substantial pharmacokinetic variability caused by complex pathophysiological changes. To address this need, a prospective clinical study was conducted, which enrolled 112 critically ill patients and employed an opportunistic sampling strategy. Population modeling and simulation were performed to characterize the pharmacokinetics (PK) and probability of target attainment (PTA) of piperacillin-tazobactam under various dosing regimens.

Population Pharmacokinetic Modeling of Cefepime, Meropenem, and Piperacillin-Tazobactam in Patients With Cystic Fibrosis.

Background: Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to β-lactam antibiotics. The pharmacokinetics (PK) of these agents are inadequately characterized in patients with CF.

The effects of single and multiple resistance mechanisms on bacterial response to meropenem.

Objectives: Meropenem is commonly used against Pseudomonas aeruginosa. Traditionally, the time unbound antibiotic concentration exceeds the MIC (fT) is used to select carbapenem regimens. We aimed to characterize the effects of different baseline resistance mechanisms on bacterial killing and resistance emergence; evaluate whether fT can predict these effects; and, develop a novel Quantitative and Systems Pharmacology (QSP) model to describe the effects of baseline resistance mechanisms on the time-course of bacterial response.

Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

Objective: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P.

Identifying and mathematically modeling the time-course of extracellular metabolic markers associated with resistance to ceftolozane/tazobactam in .

Extracellular bacterial metabolites have potential as markers of bacterial growth and resistance emergence but have not been evaluated in dynamic studies. We investigated the dynamic metabolomic footprint of a multidrug-resistant hypermutable isolate exposed to ceftolozane/tazobactam as continuous infusion (4.5 g/day, 9 g/day) in a hollow-fiber infection model over 7-9 days in biological replicates ( = 5).

Distinguishing Inducible and Non-Inducible Resistance to Colistin in Pseudomonas aeruginosa by Quantitative and Systems Pharmacology Modeling at Low and Standard Inocula.

Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled.

Ceftolozane-Tazobactam against Pseudomonas aeruginosa Cystic Fibrosis Clinical Isolates in the Hollow-Fiber Infection Model: Challenges Imposed by Hypermutability and Heteroresistance.

Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM).

Ceftolozane/tazobactam plus tobramycin against free-floating and biofilm bacteria of hypermutable Pseudomonas aeruginosa epidemic strains: Resistance mechanisms and synergistic activity.

Objective: Acute exacerbations of biofilm-associated Pseudomonas aeruginosa infections in cystic fibrosis (CF) have limited treatment options. Ceftolozane/tazobactam (alone and with a second antibiotic) has not yet been investigated against hypermutable clinical P. aeruginosa isolates in biofilm growth.

A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients.

Objectives: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients.

Methods: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS).

Population pharmacokinetics and target attainment analyses to identify a rational empirical dosing strategy for cefepime in critically ill patients.

Objectives: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis.

Patients And Methods: A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method.

Clinical pharmacological considerations in an early intravenous to oral antibiotic switch: are barriers real or simply perceived?

Background: Traditionally, there has been a common belief that ongoing i.v. antibiotic therapy is superior to an early i.

Evaluation of Empirical Dosing Regimens for Meropenem in Intensive Care Unit Patients Using Population Pharmacokinetic Modeling and Target Attainment Analysis.

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting.

Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach.

Arthroplasty is a healthcare priority and represents high volume, high cost surgery. Periprosthetic joint infection (PJI) results in significant mortality, thus it is vital that the risk for PJI is minimized. Vancomycin is recommended for surgical prophylaxis in total joint arthroplasty (TJA) by current clinical practice guidelines endorsed by the Infectious Diseases Society of America.

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

Antimicrobial resistance is a global threat. As "proof-of-concept," we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CR) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients ( = 49) and CR isolates ( = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016.

Research priorities towards precision antibiotic therapy to improve patient care.

Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections.

Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling.

Background: Acute rheumatic fever (ARF), an autoimmune reaction to Group A Streptococcus (Streptococcus pyogenes; Strep A) infection, can cause rheumatic heart disease (RHD). New formulations of long-acting penicillins are being developed for secondary prophylaxis of ARF and RHD.

Objectives: To evaluate the penicillin G concentrations required to suppress growth of Strep A.

A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens.

The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility.

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model.

We evaluated piperacillin-tazobactam and tobramycin regimens against isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MIC 4 mg/L, MIC 0.

Simulated Intravenous versus Inhaled Tobramycin with or without Intravenous Ceftazidime Evaluated against Hypermutable Pseudomonas aeruginosa via a Dynamic Biofilm Model and Mechanism-Based Modeling.

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ). Two hypermutable P.

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients.

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility.

Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward.

Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids.

Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model.

Objectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination.

Methods: Pseudomonas aeruginosa PAOΔmutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill (SCTK) studies (inoculum ~10 CFU/mL); four strains were also studied in a dynamic in vitro model (IVM) (inoculum ~10 CFU/mL).

Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Is Predominately Driven by Chloramphenicol.

Carbapenem-resistant has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing . However, the mechanism(s) underpinning their synergistic killing are not well studied.