Podcast
Questions and Answers
What is the primary mechanism of action of polymyxins against Gram-negative bacteria?
What is the primary mechanism of action of polymyxins against Gram-negative bacteria?
- Disruption of the bacterial cell membrane (correct)
- Inhibition of protein synthesis
- Inhibition of DNA replication
- Inhibition of cell wall synthesis
What is the main reason for the limited use of polymyxins in treating CRAB infections?
What is the main reason for the limited use of polymyxins in treating CRAB infections?
- Development of resistance to polymyxins
- Higher cost compared to other antibiotics
- Lack of in vitro activity against CRAB
- Unavailability for target attainment and toxicity constraint (correct)
What is the primary characteristic of polymyxin that allows it to penetrate the outer cell membrane of bacteria?
What is the primary characteristic of polymyxin that allows it to penetrate the outer cell membrane of bacteria?
- Tripeptide core
- N-terminal fatty acid acyl side chain
- Cationic charge
- Fatty acid chain (correct)
What is the main concern associated with the prolonged use of polymyxins?
What is the main concern associated with the prolonged use of polymyxins?
What is the term used to describe the process by which polymyxins disrupt the bacterial cell membrane?
What is the term used to describe the process by which polymyxins disrupt the bacterial cell membrane?
What is the primary reason for the need to modify polymyxin dosing in patients with impaired kidney function?
What is the primary reason for the need to modify polymyxin dosing in patients with impaired kidney function?
What is the primary mechanism by which Acinetobacter baumannii acquires carbapenem resistance?
What is the primary mechanism by which Acinetobacter baumannii acquires carbapenem resistance?
What is the primary concern associated with using higher doses of polymyxins to achieve target attainment?
What is the primary concern associated with using higher doses of polymyxins to achieve target attainment?
What is the term used to describe the process by which polymyxins bind to the lipopolysaccharide of Gram-negative bacteria?
What is the term used to describe the process by which polymyxins bind to the lipopolysaccharide of Gram-negative bacteria?
What is the primary limitation of using polymyxins in patients receiving ECMO?
What is the primary limitation of using polymyxins in patients receiving ECMO?
What is the mechanism of action of injectable polymyxins?
What is the mechanism of action of injectable polymyxins?
What is the primary indication for the use of I.V. fosfomycin?
What is the primary indication for the use of I.V. fosfomycin?
What type of bacteria is fosfomycin active against?
What type of bacteria is fosfomycin active against?
What is the primary reason for the increased use of colistin in recent times?
What is the primary reason for the increased use of colistin in recent times?
What is the role of fosfomycin in the prevention and treatment of chronic obstructive pulmonary conditions?
What is the role of fosfomycin in the prevention and treatment of chronic obstructive pulmonary conditions?
What is a major concern associated with the use of colistin?
What is a major concern associated with the use of colistin?
What is the effect of fosfomycin on the production of N-acetylmuramic acid?
What is the effect of fosfomycin on the production of N-acetylmuramic acid?
What is the primary benefit of combining colistin with intravenous fosfomycin?
What is the primary benefit of combining colistin with intravenous fosfomycin?
What is a major gap in the understanding of polymyxin use?
What is a major gap in the understanding of polymyxin use?
What is the result of fosfomycin's inhibition of the enolpyruvate transferase enzyme?
What is the result of fosfomycin's inhibition of the enolpyruvate transferase enzyme?
What is the primary concern associated with the use of polymyxin B?
What is the primary concern associated with the use of polymyxin B?
What is the significance of fosfomycin's broad-spectrum activity?
What is the significance of fosfomycin's broad-spectrum activity?
What is the usual dosage of I.V. fosfomycin?
What is the usual dosage of I.V. fosfomycin?
What is a major consequence of the global spread of multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa?
What is a major consequence of the global spread of multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa?
What is the primary goal of interventions involving polymyxin use?
What is the primary goal of interventions involving polymyxin use?
What is the significance of polymyxins being amphipathic compounds?
What is the significance of polymyxins being amphipathic compounds?
What is the primary association of multidrug-resistant Acinetobacter baumannii (MDRAB)?
What is the primary association of multidrug-resistant Acinetobacter baumannii (MDRAB)?
What is the result of the emergence of drug resistance to polymyxins?
What is the result of the emergence of drug resistance to polymyxins?
What is the primary reason for the adjustment of the dosage scheme of polymyxin B?
What is the primary reason for the adjustment of the dosage scheme of polymyxin B?
What is the therapeutic range of colistin in animal models of infection?
What is the therapeutic range of colistin in animal models of infection?
What is the key parameter for polymyxins to effectively exert their anti-infection effects?
What is the key parameter for polymyxins to effectively exert their anti-infection effects?
How is colistin primarily administered in clinical cases of gastrointestinal infections?
How is colistin primarily administered in clinical cases of gastrointestinal infections?
What is the primary mechanism of fosfomycin resistance in Escherichia coli?
What is the primary mechanism of fosfomycin resistance in Escherichia coli?
What is the function of FosA family proteins in mediating resistance to fosfomycin?
What is the function of FosA family proteins in mediating resistance to fosfomycin?
What is the primary reason for the increase in clinical bacterial strains resistant to polymyxin?
What is the primary reason for the increase in clinical bacterial strains resistant to polymyxin?
How is the plasma colistin concentration typically measured?
How is the plasma colistin concentration typically measured?
What is the primary route of excretion of polymyxin?
What is the primary route of excretion of polymyxin?
What is the effective concentration of colistin in blood plasma to cure an infected patient?
What is the effective concentration of colistin in blood plasma to cure an infected patient?
What is the primary function of the Fos family proteins in relation to antimicrobial resistance?
What is the primary function of the Fos family proteins in relation to antimicrobial resistance?
What is the most common mechanism of resistance to polymyxin in Gram-negative bacteria?
What is the most common mechanism of resistance to polymyxin in Gram-negative bacteria?
What is the primary advantage of using combination therapy with polymyxin and fosfomycin?
What is the primary advantage of using combination therapy with polymyxin and fosfomycin?
What is the effect of the combination of polymyxin and fosfomycin on the expression of biomarkers associated with drug resistance?
What is the effect of the combination of polymyxin and fosfomycin on the expression of biomarkers associated with drug resistance?
What is the primary concern associated with the use of polymyxin in combination with other nephrotoxic agents?
What is the primary concern associated with the use of polymyxin in combination with other nephrotoxic agents?
What is the primary mechanism of synergy between polymyxin and fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary mechanism of synergy between polymyxin and fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary advantage of using polymyxin in combination with fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary advantage of using polymyxin in combination with fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary concern associated with the use of polymyxin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary concern associated with the use of polymyxin in treating carbapenem-resistant Acinetobacter baumannii?
What is the primary mechanism of resistance to fosfomycin in Gram-negative bacteria?
What is the primary mechanism of resistance to fosfomycin in Gram-negative bacteria?
What is the primary advantage of using combination therapy with polymyxin and fosfomycin in treating MDR-GNB infections?
What is the primary advantage of using combination therapy with polymyxin and fosfomycin in treating MDR-GNB infections?
What is the primary advantage of polymyxin analogs over traditional polymyxins?
What is the primary advantage of polymyxin analogs over traditional polymyxins?
What is the primary benefit of using CSP conglomerates in treating pathogenic bacteria?
What is the primary benefit of using CSP conglomerates in treating pathogenic bacteria?
What is the primary goal of optimizing PK-PD-based dosing regimens for CSP therapy?
What is the primary goal of optimizing PK-PD-based dosing regimens for CSP therapy?
What is the primary concern associated with using polymyxin combination therapy in critically ill patients?
What is the primary concern associated with using polymyxin combination therapy in critically ill patients?
What is the primary characteristic of polymyxin-fosfomycin combination therapy?
What is the primary characteristic of polymyxin-fosfomycin combination therapy?
What is the primary benefit of combining polymyxin with rifampicin?
What is the primary benefit of combining polymyxin with rifampicin?
What is the primary concern associated with the emergence of mcr genes in Acinetobacter baumannii?
What is the primary concern associated with the emergence of mcr genes in Acinetobacter baumannii?
What is the primary benefit of using polymyxin-rifampicin combination therapy in critically ill patients?
What is the primary benefit of using polymyxin-rifampicin combination therapy in critically ill patients?
Study Notes
Polymyxins and Fosfomycin in Treating Multidrug-Resistant Infections
- Rise of Multidrug-Resistant Infections: The global spread of multidrug-resistant (MDR) pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa, has increased the use of colistin and polymyxin B.
- Limitations of Polymyxins: Despite their effectiveness, polymyxins have limitations, including systemic toxicity, which remains a significant concern, and the potential for resistance.
Mechanism of Action and Clinical Use of Polymyxins
- Mechanism of Action: Polymyxins are cationic detergents that disrupt the outer and inner membranes of bacterial cells, leading to cell death.
- Selective Binding: Polymyxins exhibit preferential binding to lipopolysaccharide on the cell membrane of Gram-negative bacteria, disrupting the cell membrane and ultimately leading to cell death.
- Clinical Use: Polymyxins are used to treat nosocomial infections caused by MDR pathogens, such as A. baumannii, due to their potent in vitro antibacterial activity.
Structure and Classification of Polymyxins
- Cyclic Cationic Peptide Antibiotics: Polymyxins consist of a tripeptide core with an N-terminal fatty acid acyl side chain, which anchors the molecule to the lipid A motif of endotoxins.
- Amphipathic Compounds: Polymyxins are categorized into ten different structural types (A-J) and possess cationic and hydrophobic chemical properties.
Antibacterial Activity and Spectrum of Polymyxins
- Broad-Spectrum Activity: Polymyxins exhibit antibacterial activity against a broad range of Gram-negative bacteria, including MDR and extensively drug-resistant pathogens.
- Limited Use: The antibacterial spectrum of polymyxins is restricted to Gram-negative bacteria, and their use is limited due to the emergence of drug resistance.
Fosfomycin: Mechanism of Action and Clinical Use
- Mechanism of Action: Fosfomycin obstructs the production of N-acetylmuramic acid, a compound required for bacterial cell wall synthesis, by covalently bonding to the enolpyruvate transferase enzyme (MurA).
- Clinical Use: Fosfomycin is used to treat urinary tract infections, prosthetic joint infections, and chronic obstructive pulmonary disease exacerbations.
Pharmacokinetics and Pharmacodynamics of Polymyxins and Fosfomycin
- Pharmacokinetics: The pharmacokinetics of polymyxins and fosfomycin are critical in determining their antibacterial efficacy and minimizing toxicity.
- Pharmacodynamics: The pharmacodynamic indices of polymyxins and fosfomycin, such as peak concentration/minimum inhibitory concentration (Peak/MIC) and AUC_0–24/MIC, are essential in understanding their antibacterial effects.
Combination Therapy: Rationale and Evidence
- Rationale: Combination therapy with polymyxins and fosfomycin can prevent the emergence of resistance, enhance bactericidal activity, and improve clinical outcomes.
- Evidence: Combination therapy with polymyxins and fosfomycin has shown synergistic effects, repressed the expression of biomarkers associated with drug resistance, and demonstrated therapeutic effects in treating carbapenem-resistant A. baumannii-infected pneumonia.
Future Perspectives and Conclusion
- Future Directions: Alternative CSP drugs, such as polymyxin analogs, and emerging CSP conglomerates may provide potential therapeutic options for treating MDR pathogens.
- Optimized Dosing Regimens: PK-PD-based dosing regimens should be optimized for polymyxins and fosfomycin to maximize their antibacterial effects and minimize adverse effects.
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Description
This quiz assesses knowledge on the resurgence of colistin, its relation to multi-drug resistant bacteria, and its effectiveness in modern medicine. It covers the limitations and benefits of colistin usage, including adverse events and clinical effectiveness.
