Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial.

Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria.

Objectives: Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria.

What the Clinical Microbiologist Should Know About Pharmacokinetics/Pharmacodynamics in the Era of Emerging Multidrug Resistance: Focusing on β-Lactam/β-Lactamase Inhibitor Combinations.

As a class, β-lactamase inhibitors have proved successful in extending the clinical utility of β-lactam antibiotics by circumventing β-lactamase-mediated resistance. However, the rapid evolution of these β-lactamases calls for a critical reevaluation of the relationships between susceptibility, drug exposures, and bacterial response. The existing paradigm for in vitro susceptibility testing and development of β-lactam/β-lactamase inhibitor combinations may not optimally facilitate clinical use.

Resistance to Ceftolozane/Tazobactam in Arising by AmpC- and Non-AmpC-Mediated Pathways.

Two pairs of ceftolozane/tazobactam susceptible/resistant were isolated from 2 patients after exposure to -lactams. The genetic basis of ceftolozane/tazobactam resistance was evaluated, and -lactam-resistant mechanisms were assessed by phenotypic assays. Whole genome sequencing identified mutations in AmpC including the mutation (V213A) and a deletion of 7 amino acids (P210-G216) in the Ω-loop.

Optimal Piperacillin-Tazobactam Dosing Strategies against Extended-Spectrum-β-Lactamase-Producing .

Piperacillin-tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin-tazobactam to efficacy, using a modified pharmacokinetic/pharmacodynamic index. Using a clinical isolate expressing CTX-M-15, piperacillin MIC values were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory maximum effect () model.

Prevalence of extended-spectrum beta-lactamase and carbapenemase-producing bloodstream isolates of Klebsiella pneumoniae in a tertiary care hospital.

To improve prescribing of empiric therapy, the local molecular epidemiology of extended-spectrum beta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs) in bloodstream isolates of K. pneumoniae were evaluated. Isolates resistant to third generation cephalosporins were screened phenotypically for ESBLs and carbapenemases, and subsequently confirmed by PCR for the presence of ESBL (bla, bla and bla) and carbapenemase (bla, bla, bla and bla) genes.

Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model.

Multidrug-resistant (MDR) is increasingly more prevalent in nosocomial infections. Although susceptibility of to minocycline is promising, the efficacy of minocycline has not been well established. In this study, the activity of minocycline was evaluated in a neutropenic murine pneumonia model.

Analytical and functional determination of polymyxin B protein binding in serum.

To enhance our understanding of the pharmacological properties of polymyxin B, serum protein binding for polymyxin B1, B2, and B3 and for isoleucine-polymyxin B1 was evaluated. Using equilibrium dialysis and ultrafiltration, comparable protein binding was found in all 4 components of polymyxin B (92% to 99%). Protein binding in human serum was further assessed using a functional assay, the results of which were in general agreement with previous findings (approximately 90%).