Developing combinations of CO-ACTIVE antimicrobials and non-antimicrobials
Therapeutics
- Joseph Meletiadis, Erasmus MC University Medical Center, Netherlands (Coordinator)
- Lena Friberg, Uppsala University, Sweden (Partner)
- Francoise Van Bambeke, Katholieke Universiteit Leuven, Belgium (Partner)
- Thomas Tängdén, Uppsala University, Sweden (Partner)
- William Couet, Université de Poitiers, France (Partner)
- Alain Bousquet-Melou, INRAE, French National Institute for Agriculture, Food and Environment, France (Partner)
Increasingly, patients with infections are difficult to treat because the bacteria that cause the infection have become resistant to antibiotics. There is therefore an increasing demand for new antimicrobials to overcome resistance. However, there are few new antibiotics in development. An alternative strategy to overcome resistance that has been insufficiently explored is a more efficient use of existing antibiotics (AB) by combining them, in particular Neglected and Disused AB (ND-AB). Also, the combination of antibiotics and other drugs -non-antibiotics (NA) might be efficacious but has not been well explored. CO-ACTION project identified several AB+ND-AB combinations with increased activity against multidrug resistant gram negative bacteria Acinetobacter baumannii, Klebsiella pneuoniae and Pseudomonas aeruginosa. Polymyxin B with rifampicin and minocycline was the most promising combinations in in vitro extracellular and intracellular studies verified in several animal models (murine thigh and lung infection models, pig model) where pharmacokinetics, pharmacodynamics and resistance development was studied. Furthermore, in search of effective ND-AB+NA combinations, synergism was found between polymyxin B and some NA with spironolactone identified as a potential candidate for further studies. In addition, a high throughput model for screening multiple ND-AB+AB combinations against large set of isolates was developed whereas a method for testing AB+NA combinations was assessed. Finally, PK-PD models were developed by associating drug concentrations with antimicrobial activity and clinical doses for the combined drugs were proposed.
- Clinical Microbiology and Infection, 2018. Automated time-lapse microscopy a novel method for screening of antibiotic combination effects against multidrug-resistant Gram-negative bacteria
- Clinical Microbiology and Infection, 2018. Semi-mechanistic pharmacokinetic–pharmacodynamic modelling of antibiotic drug combinations
- Clinical Microbiology and Infection, 2018. PK/PD characterization of combined antimicrobial agents: a real challenge and an urgent need
- International Journal of Antimicrobial Agents, 2019. An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics
- Journal of Antimicrobial Chemotherapy, 2019. Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen
- Antimicrobial Agents and Chemotherapy, 2020, Extension of Pharmacokinetic/Pharmacodynamic Time-Kill Studies To Include Lipopolysaccharide/Endotoxin Release from Escherichia coli Exposed to Cefuroxime
- Molecular Pharmaceutics, 2020, Model-Informed Drug Development in Pulmonary Delivery: Semimechanistic Pharmacokinetic–Pharmacodynamic Modeling for Evaluation of Treatments against Chronic Pseudomonas aeruginosa Lung Infections
- Antimicrobial Agents and Chemotherapy, 2020. Efficacy of Antibiotic Combinations against MultidrugResistant Pseudomonas aeruginosa in Automated Time-Lapse
- Clinical Microbiology and Infection, 2020. Evaluation of polymyxin B in combination with 13 other antibiotics against carbapenemase-producing Klebsiella pneumoniae in time-lapse microscopy and time-kill experiments
- International Journal of Antimicrobial Agents, 2020. Combination of polymyxin B and minocycline against multidrug-resistant Klebsiella pneumoniae: interaction quantified by pharmacokinetic/pharmacodynamic modelling from in vitro data
- Clinical Microbiology and Infection, 2020. Semi-mechanistic PK/PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii
- Clinical Microbiology and Infection, 2020. Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria
- International Journal of Antimicrobial Agents, 2020. Pharmacodynamics of immune response biomarkers of interest for evSaluation of treatment effects in bacterial infections