ArticleAntimicrobial agents and chemotherapy2012
Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa.
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 33 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- 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
- A freely accessible, adaptable hollow-fiber setup to reproduce first-order absorption: illustration with linezolid cerebrospinal fluid pharmacokinetic data.Microbiology spectrum · 2025Article
- DynamicAntibiotics (Basel, Switzerland) · 2024Review
- Article
- Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen ofPharmaceuticals (Basel, Switzerland) · 2023Review
- The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Review
- Combating Multidrug-Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling.Clinical pharmacology and therapeutics · 2021Article
- Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting-Focus on ICU Patients and Gram-Negative Strains.Antibiotics (Basel, Switzerland) · 2020Review
- Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in anAntimicrobial agents and chemotherapy · 2020Article
- Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections.Clinical microbiology reviews · 2019Review
- Generating Robust and Informative NonclinicalAntimicrobial agents and chemotherapy · 2019Review
- Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.Clinical pharmacokinetics · 2019Review
- Efficacy of Human-Simulated Exposures of Ceftolozane-Tazobactam Alone and in Combination with Amikacin or Colistin against Multidrug-Resistant Pseudomonas aeruginosa in anAntimicrobial agents and chemotherapy · 2018Article
- Review
- Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward 'molecularly targeted' therapy.Expert review of anti-infective therapy · 2018Review
- Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy.Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia · 2018Review
- Combination of Epicatechin 3-Gallate fromEvidence-based complementary and alternative medicine : eCAM · 2018Article
- Multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus: Three major threats to hematopoietic stem cell transplant recipients.Transplant infectious disease : an official journal of the Transplantation Society · 2017Review
- Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.Antimicrobial agents and chemotherapy · 2017Article
- Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The panoply of resistance mechanisms in Pseudomonas aeruginosa makes resistance suppression difficult. Defining optimal regimens is critical. Cefepime is a cephalosporin whose 3' side chain provides some stability against AmpC β-lactamases. We examined the activity of cefepime against P. aeruginosa wild-type strain PAO1 and its isogenic AmpC stably derepressed mutant in our hollow-fiber infection model. Dose-ranging studies demonstrated complete failure with resistance emergence (both isolates). Inoculum range studies demonstrated ultimate failure for all inocula. Lower inocula failed last (10 days to 2 weeks). Addition of a β-lactamase inhibitor suppressed resistance even with the stably derepressed isolate. Tobramycin combination studies demonstrated resistance suppression in both the wild-type and the stably derepressed isolates. Quantitating the RNA message by quantitative PCR demonstrated that tobramycin decreased the message relative to that in cefepime-alone experiments. Western blotting with AmpC-specific antibody for P. aeruginosa demonstrated decreased expression. We concluded that suppression of β-lactamase expression by tobramycin (a protein synthesis inhibitor) was at least part of the mechanism behind resistance suppression. Monte Carlo simulation demonstrated that a regimen of 2 g of cefepime every 8 h plus 7 mg/kg of body weight of tobramycin daily would provide robust resistance suppression for Pseudomonas isolates with cefepime MIC values up to 8 mg/liter and tobramycin MIC values up to 1 mg/liter. For P. aeruginosa resistance suppression, combination therapy is critical.
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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.