Low-dose polymyxin: an option for therapy of Gram-negative sepsis

Stephan Harm1, Franz Gabor2, Jens Hartmann3

  • 1Department for Health Sciences and Biomedicine, Danube University Krems, Krems, Austria Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria stephan.harm@donau-uni.ac.at.

Innate Immunity
|March 20, 2016
PubMed

Insights

Polymyxin B (PMB) effectively inactivates endotoxins (lipopolysaccharides) in vitro, reducing their inflammatory potential in blood. This endotoxin inactivation, combined with cytokine removal, shows promise for treating sepsis and liver failure.

Area of Science:

  • Microbiology
  • Immunology
  • Pharmacology

Background:

  • Endotoxins, components of Gram-negative bacteria, trigger severe immune responses like septic shock.
  • Current treatments for endotoxin-related conditions are limited.

Purpose of the Study:

  • To investigate the in vitro inactivation of endotoxins by polymyxin B (PMB).
  • To assess the inflammatory activity of the lipopolysaccharide-PMB complex in blood.
  • To determine optimal PMB levels for endotoxin inactivation.

Main Methods:

  • In vitro inactivation of endotoxins using PMB.
  • Examination of LPS-PMB complex inflammatory activity in human blood.
  • Measurement of PMB plasma protein binding and clearance during dialysis.
  • Assessment of cytokine secretion and inflammatory markers.

Main Results:

  • The LPS-PMB complex exhibited significantly reduced inflammatory activity in vitro.
  • Optimal plasma PMB levels for endotoxin inactivation were determined to be 100-200 ng/ml.
  • Combined PMB treatment and cytokine removal strongly suppressed inflammatory effects in an in vitro model.

Conclusions:

  • PMB effectively inactivates endotoxins, reducing their inflammatory impact in blood.
  • Low-dose intravenous PMB or extracorporeal infusion shows potential for endotoxin elimination in sepsis and liver failure.
  • Combining endotoxin inactivation with cytokine removal offers a potent strategy against inflammatory diseases.

Related Concept Videos

Acute Pyelonephritis II: Diagnostic Studies and Management01:28

Acute Pyelonephritis II: Diagnostic Studies and Management

Introduction:For diagnosing acute pyelonephritis, a comprehensive patient history is collected to identify symptoms such as dysuria, frequent or urgent urination, flank pain, or costovertebral angle (CVA) tenderness that may suggest a kidney infection.Physical ExaminationDuring the physical examination, CVA tenderness is assessed. This involves gentle percussion over the costovertebral angle, where tenderness often indicates a kidney infection.Diagnostic TestsUrinalysis: Used to identify white...
618
Inhibitors of Gram-positive Cell Wall Synthesis01:23

Inhibitors of Gram-positive Cell Wall Synthesis

Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
21
Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence01:22

Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence

Generic intravenous (IV) drugs are considered bioequivalent to their branded counterparts due to their 100% bioavailability upon administration. However, variations in stability among different drug products can significantly influence their therapeutic performance, even if they are pharmaceutically equivalent.Cefuroxime, a prophylactic antimicrobial, is often used as a single-dose IV injection for patients undergoing coronary artery bypass grafting surgery. A 3 g dose typically provides...
238
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
19
Combined Effects of Drugs: Synergism01:27

Combined Effects of Drugs: Synergism

Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...
7.3K
Determination of Multiple Dosing Parameters: Steady-State, Minimum and Maximum Concentrations01:15

Determination of Multiple Dosing Parameters: Steady-State, Minimum and Maximum Concentrations

Gentamicin, an aminoglycoside antibiotic, is commonly administered via intermittent intravenous infusion to treat severe infections. An intermittent one-hour infusion of gentamicin, administered at eight-hour intervals, allows for precise control of plasma drug concentrations, minimizing toxicity while ensuring therapeutic efficacy. Pharmacokinetic principles govern the dynamics of plasma concentrations and can be mathematically described using specific equations.The plasma drug concentration...
317