ArticleAntimicrobial agents and chemotherapy2012
Novel modeling framework to guide design of optimal dosing strategies for β-lactamase inhibitors.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it.
- What are the optimal pharmacokinetic/pharmacodynamic targets for β-lactamase inhibitors? A systematic review.The Journal of antimicrobial chemotherapy · 2024Pooled it
- Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.Journal of clinical pharmacology · 2016Trial
- Preclinical Pharmacokinetics and Pharmacodynamics of Antibiotic Adjuvants.ACS infectious diseases · 2026Review
- Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis.The Journal of antimicrobial chemotherapy · 2025Article
- Revisiting the Checkerboard to Inform Development of β-Lactam/β-Lactamase Inhibitor Combinations.Antibiotics (Basel, Switzerland) · 2024Article
- Pharmacokinetic/pharma-codynamic study of pralurbactam (FL058) combined with meropenem in a neutropenic murine thigh infection model.Frontiers in microbiology · 2024Article
- Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-ProducingAntibiotics (Basel, Switzerland) · 2023Article
- In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept.Pharmaceutical research · 2023Article
- Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.The Journal of antimicrobial chemotherapy · 2023Article
- Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae.The Journal of antimicrobial chemotherapy · 2023Article
- All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches.Antibiotics (Basel, Switzerland) · 2023Review
- Pharmacokinetic/Pharmacodynamic Index Linked toAntimicrobial agents and chemotherapy · 2023Article
- New Perspectives on Antimicrobial Agents: Imipenem-Relebactam.Antimicrobial agents and chemotherapy · 2022Review
- Biochemical exploration of β-lactamase inhibitors.Frontiers in genetics · 2022Review
- New β-Lactam-β-Lactamase Inhibitor Combinations.Clinical microbiology reviews · 2020Review
- Clinical Pharmacokinetics and Pharmacodynamics of Imipenem-Cilastatin/Relebactam Combination Therapy.Clinical pharmacokinetics · 2020Review
- Article
- What the Clinical Microbiologist Should Know About Pharmacokinetics/Pharmacodynamics in the Era of Emerging Multidrug Resistance: Focusing on β-Lactam/β-Lactamase Inhibitor Combinations.Clinics in laboratory medicine · 2019Review
- A novel framework to compare the effectiveness of β-lactamase inhibitors against extended-spectrum β-lactamase-producing Enterobacteriaceae.Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2019Article
- Generating Robust and Informative NonclinicalAntimicrobial agents and chemotherapy · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MIC(i)]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (E(max))-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MIC(i) values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MIC(i) values. In addition, different dosing regimens of MK-7655 achieving a similar T>MIC(i) (69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitro activity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.