Colistin Resistance and Antibiotic Usage
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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?

  • 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?

  • 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?

    <p>Outbreak of polymyxin-resistant bacteria</p> Signup and view all the answers

    What is the term used to describe the process by which polymyxins disrupt the bacterial cell membrane?

    <p>Dissolution of the outer and inner membranes</p> Signup and view all the answers

    What is the primary reason for the need to modify polymyxin dosing in patients with impaired kidney function?

    <p>To avoid nephrotoxicity</p> Signup and view all the answers

    What is the primary mechanism by which Acinetobacter baumannii acquires carbapenem resistance?

    <p>All of the above</p> Signup and view all the answers

    What is the primary concern associated with using higher doses of polymyxins to achieve target attainment?

    <p>Increased risk of nephrotoxicity</p> Signup and view all the answers

    What is the term used to describe the process by which polymyxins bind to the lipopolysaccharide of Gram-negative bacteria?

    <p>Selective binding</p> Signup and view all the answers

    What is the primary limitation of using polymyxins in patients receiving ECMO?

    <p>Difficulty in optimizing polymyxin dosing</p> Signup and view all the answers

    What is the mechanism of action of injectable polymyxins?

    <p>Disrupting the cytoplasmic membrane integrity</p> Signup and view all the answers

    What is the primary indication for the use of I.V. fosfomycin?

    <p>Urinary and extra-urinary infections</p> Signup and view all the answers

    What type of bacteria is fosfomycin active against?

    <p>Both gram-positive and gram-negative bacteria</p> Signup and view all the answers

    What is the primary reason for the increased use of colistin in recent times?

    <p>The global spread of multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa</p> Signup and view all the answers

    What is the role of fosfomycin in the prevention and treatment of chronic obstructive pulmonary conditions?

    <p>It is used as an inhaled therapy</p> Signup and view all the answers

    What is a major concern associated with the use of colistin?

    <p>Systemic toxicity</p> Signup and view all the answers

    What is the effect of fosfomycin on the production of N-acetylmuramic acid?

    <p>It obstructs the production of N-acetylmuramic acid</p> Signup and view all the answers

    What is the primary benefit of combining colistin with intravenous fosfomycin?

    <p>Enhanced immunomodulatory effects</p> Signup and view all the answers

    What is a major gap in the understanding of polymyxin use?

    <p>All of the above</p> Signup and view all the answers

    What is the result of fosfomycin's inhibition of the enolpyruvate transferase enzyme?

    <p>It obstructs the first stage of bacterial cell wall synthesis</p> Signup and view all the answers

    What is the primary concern associated with the use of polymyxin B?

    <p>Its well-known serious adverse effects</p> Signup and view all the answers

    What is the significance of fosfomycin's broad-spectrum activity?

    <p>It includes multidrug resistant pathogens, including MRSA, VRE, ESBL and carbapenemase producing Enterobacteriaceae</p> Signup and view all the answers

    What is the usual dosage of I.V. fosfomycin?

    <p>4 g every 6 h</p> Signup and view all the answers

    What is a major consequence of the global spread of multi-drug resistant Acinetobacter baumannii and Pseudomonas aeruginosa?

    <p>Escalating colistin consumption</p> Signup and view all the answers

    What is the primary goal of interventions involving polymyxin use?

    <p>To minimize the risk of nephrotoxicity and overdose</p> Signup and view all the answers

    What is the significance of polymyxins being amphipathic compounds?

    <p>They have cationic and hydrophobic chemical properties</p> Signup and view all the answers

    What is the primary association of multidrug-resistant Acinetobacter baumannii (MDRAB)?

    <p>Nosocomial infections</p> Signup and view all the answers

    What is the result of the emergence of drug resistance to polymyxins?

    <p>The restricted use of polymyxins</p> Signup and view all the answers

    What is the primary reason for the adjustment of the dosage scheme of polymyxin B?

    <p>According to the pharmacokinetic and pharmacodynamic index data</p> Signup and view all the answers

    What is the therapeutic range of colistin in animal models of infection?

    <p>2-5 mg/kg body weight</p> Signup and view all the answers

    What is the key parameter for polymyxins to effectively exert their anti-infection effects?

    <p>AUC_0–24/MIC</p> Signup and view all the answers

    How is colistin primarily administered in clinical cases of gastrointestinal infections?

    <p>Intramuscularly, intravenously, or through other vascular access routes</p> Signup and view all the answers

    What is the primary mechanism of fosfomycin resistance in Escherichia coli?

    <p>The expression of murA in low levels</p> Signup and view all the answers

    What is the function of FosA family proteins in mediating resistance to fosfomycin?

    <p>Act as glutathione S-transferases</p> Signup and view all the answers

    What is the primary reason for the increase in clinical bacterial strains resistant to polymyxin?

    <p>The increased and inappropriate use of colistin and polymyxin</p> Signup and view all the answers

    How is the plasma colistin concentration typically measured?

    <p>By the high-performance liquid chromatography-fluorescence detector method</p> Signup and view all the answers

    What is the primary route of excretion of polymyxin?

    <p>Through the kidneys and urine</p> Signup and view all the answers

    What is the effective concentration of colistin in blood plasma to cure an infected patient?

    <p>Between 1 and 3 μg/mL</p> Signup and view all the answers

    What is the primary function of the Fos family proteins in relation to antimicrobial resistance?

    <p>Opening the ring of fosfomycin and forming stable glutathione adducts</p> Signup and view all the answers

    What is the most common mechanism of resistance to polymyxin in Gram-negative bacteria?

    <p>Addition of phosphoethanolamine to the secondary acyl groups of lipid A</p> Signup and view all the answers

    What is the primary advantage of using combination therapy with polymyxin and fosfomycin?

    <p>Improved bactericidal activity</p> Signup and view all the answers

    What is the effect of the combination of polymyxin and fosfomycin on the expression of biomarkers associated with drug resistance?

    <p>Repressed expression of biomarkers</p> Signup and view all the answers

    What is the primary concern associated with the use of polymyxin in combination with other nephrotoxic agents?

    <p>Increased risk of nephrotoxicity</p> Signup and view all the answers

    What is the primary mechanism of synergy between polymyxin and fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?

    <p>Polymyxin and fosfomycin have a synergistic effect on the inhibition of bacterial growth</p> Signup and view all the answers

    What is the primary advantage of using polymyxin in combination with fosfomycin in treating carbapenem-resistant Acinetobacter baumannii?

    <p>Enhanced bactericidal activity against carbapenem-resistant Acinetobacter baumannii</p> Signup and view all the answers

    What is the primary concern associated with the use of polymyxin in treating carbapenem-resistant Acinetobacter baumannii?

    <p>Increased risk of nephrotoxicity</p> Signup and view all the answers

    What is the primary mechanism of resistance to fosfomycin in Gram-negative bacteria?

    <p>Formation of stable glutathione adducts</p> Signup and view all the answers

    What is the primary advantage of using combination therapy with polymyxin and fosfomycin in treating MDR-GNB infections?

    <p>Enhanced bactericidal activity and prevention of the selection of multi-drug resistant strains</p> Signup and view all the answers

    What is the primary advantage of polymyxin analogs over traditional polymyxins?

    <p>Reduced nephrotoxicity and inherent LPS-sequestration</p> Signup and view all the answers

    What is the primary benefit of using CSP conglomerates in treating pathogenic bacteria?

    <p>Reduced lung edema and promotion of macrophage differentiation</p> Signup and view all the answers

    What is the primary goal of optimizing PK-PD-based dosing regimens for CSP therapy?

    <p>To minimize adverse effects and maximize bacterial killing</p> Signup and view all the answers

    What is the primary concern associated with using polymyxin combination therapy in critically ill patients?

    <p>Higher resistance evolution of bacterial antimicrobial compounds</p> Signup and view all the answers

    What is the primary characteristic of polymyxin-fosfomycin combination therapy?

    <p>Synergistic targeting of multidrug-resistant bacteria</p> Signup and view all the answers

    What is the primary benefit of combining polymyxin with rifampicin?

    <p>Synergistic targeting of multidrug-resistant bacteria</p> Signup and view all the answers

    What is the primary concern associated with the emergence of mcr genes in Acinetobacter baumannii?

    <p>Higher resistance evolution of bacterial antimicrobial compounds</p> Signup and view all the answers

    What is the primary benefit of using polymyxin-rifampicin combination therapy in critically ill patients?

    <p>Synergistic targeting of multidrug-resistant bacteria and preventing antimicrobial resistance evolution</p> Signup and view all the answers

    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.

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