ArticleAntimicrobial agents and chemotherapy2013
Quantifying subpopulation synergy for antibiotic combinations via mechanism-based modeling and a sequential dosing design.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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46 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Guideline
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- Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents.Antimicrobial agents and chemotherapy · 2024Article
- Translational PK/PD for the Development of Novel Antibiotics-A Drug Developer's Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in anMicrobiology spectrum · 2024Article
- Influence of β-lactam pharmacodynamics on the systems microbiology of gram-positive and gram-negative polymicrobial communities.Frontiers in pharmacology · 2024Article
- Mechanism of Action of Isopropoxy Benzene Guanidine against Multidrug-Resistant Pathogens.Microbiology spectrum · 2023Article
- A mechanism-based pathway toward administering highly active N-phage cocktails.Frontiers in microbiology · 2023Article
- A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.Antimicrobial agents and chemotherapy · 2022Article
- The area under the effect curve as an efficacy determinant for anti-infectives.CPT: pharmacometrics & systems pharmacology · 2022Article
- Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling.The Journal of antimicrobial chemotherapy · 2022Article
- Generating Genotype-Specific Aminoglycoside Combinations with Ceftazidime/Avibactam for KPC-ProducingAntimicrobial agents and chemotherapy · 2021Article
- Combating Multidrug-Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling.Clinical pharmacology and therapeutics · 2021Article
- Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model.Clinical pharmacology and therapeutics · 2021Article
- Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward.Frontiers in pharmacology · 2021Review
- Resveratrol enhances the antimicrobial effect of polymyxin B on Klebsiella pneumoniae and Escherichia coli isolates with polymyxin B resistance.BMC microbiology · 2020Article
- In pursuit of the triple crown: mechanism-based pharmacodynamic modelling for the optimization of three-drug combinations against KPC-producing Klebsiella pneumoniae.Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2020Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum, 10(8) CFU/ml). A sequential design (initial dosing of 8 or 32 mg/liter nisin, switched to amikacin or linezolid at 1.5 h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles comodeled in S-ADAPT and NONMEM. A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise (r = 0.99, slope = 1.00; S-ADAPT) individual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 liter/(mg · h). For amikacin, the maximum killing rate constants were 10.1 h(-1) against its susceptible and 0.771 h(-1) against its less-susceptible populations, with 14.7 mg/liter amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin. Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.
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