ArticleAntimicrobial agents and chemotherapy2015
Novel approach to optimize synergistic carbapenem-aminoglycoside combinations against carbapenem-resistant Acinetobacter baumannii.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 2 of them syntheses that pooled it.
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Who cites it
38 citing papers in PubMed, 2 syntheses or guidelines pooled it, 59 citations in OpenAlex.
- Bibliometric analysis of global research on the clinical applications of aminoglycoside antibiotics: improving efficacy and decreasing risk.Frontiers in microbiology · 2025Pooled it
- Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials.Antimicrobial agents and chemotherapy · 2019Pooled it
- Synergistic Effects of Amikacin With Imipenem and Ciprofloxacin Against Multidrug-Resistance UropathogenicThe Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale · 2026Article
- Current progress in antibacterial agents for carbapenem-resistant enterobacterales.Frontiers in pharmacology · 2026Review
- Genomic Analysis of Carbapenem-ResistantAntibiotics (Basel, Switzerland) · 2024Article
- 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
- Comprehensive stability analysis of 13 β-lactams and β-lactamase inhibitors inAntimicrobial agents and chemotherapy · 2024Article
- Characterization ofAntimicrobial agents and chemotherapy · 2023Article
- Insights into Carbapenem Resistance inInternational journal of molecular sciences · 2022Review
- Carbapenem resistance associated with coliuria among outpatient and hospitalised urology patients.New microbes and new infections · 2022Article
- Efficient simulation of clinical target response surfaces.CPT: pharmacometrics & systems pharmacology · 2022Article
- Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin againstAntibiotics (Basel, Switzerland) · 2022Article
- PKPD Modeling of the Inoculum Effect ofFrontiers in pharmacology · 2022Article
- Combating Multidrug-Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling.Clinical pharmacology and therapeutics · 2021Article
- A review on bacterial resistance to carbapenems: epidemiology, detection and treatment options.Future science OA · 2020Review
- Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients.Antimicrobial agents and chemotherapy · 2019Article
- Can phenotypic data complement our understanding of antimycobacterial effects for drug combinations?The Journal of antimicrobial chemotherapy · 2019Article
- Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against HypermutablePharmaceutics · 2019Article
- Pharmacodynamic Drug-Drug Interactions.Clinical pharmacology and therapeutics · 2019Review
- Generating Robust and Informative NonclinicalAntimicrobial agents and chemotherapy · 2019Review
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
Acinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize β-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii. We studied combinations of 10 β-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (≤2.3 log10) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other β-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/liter combined with an aminoglycoside yielded synergistic killing (>5 log10) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log10 killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.
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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.