Polymyxin B

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Polymyxin B
Polymyxin B1.svg
Polymyxin B2.svg
Clinical data
Trade names Poly-Rx, others
AHFS/Drugs.com Monograph
Pregnancy
category
Routes of
administration
Topical, intramuscular, intravenous, intrathecal, eye drops
ATC code
Legal status
Legal status
Identifiers
  • N-[4-amino-1-[[1-[[4-amino-1-oxo-1-[[6,9,18-tris(2-aminoethyl)-15-benzyl-3-(1-hydroxyethyl)-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide
CAS Number
PubChem CID
DrugBank
UNII
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.014.340 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C56H100N16O17S
Molar mass 1301.57 g·mol−1
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Polymyxin B, sold under the brand name Poly-Rx among others, is an antibiotic used to treat meningitis, pneumonia, sepsis, and urinary tract infections. [1] While it is useful for many Gram negative infections, it is not useful for Gram positive infections. [1] It can be given by injection into a vein, muscle, or cerebrospinal fluid or inhaled. [1] The injectable form is generally only used if other options are not available. [2] It is also available as the combinations bacitracin/polymyxin B and neomycin/polymyxin B/bacitracin for use on the skin. [3] [4]

Contents

Common side effects when given by injection include kidney problems, neurological problems, fever, itchiness, and rash. [1] Injections into muscle may result in significant pain. [1] Other serious side effects may include fungal infections, anaphylaxis, and muscle weakness. [1] It is unclear if use during pregnancy is safe for the baby. [1] Polymyxin B works by breaking down the cytoplasmic membrane which generally results in bacterial cell death. [1]

Polymyxin B was approved for medical use in the United States in 1964. [1] It is on the World Health Organization's List of Essential Medicines. [5] It is available as a generic medication. [1] In Europe it is only approved to be applied to the skin as of 2015. [6] It is derived from the bacterium Paenibacillus polymyxa (formerly known as Bacillus polymyxa ). [2]

Medical uses

Spectrum of susceptibility

Polymyxin B has been used to treat urinary tract infections and meningitis caused by Pseudomonas aeruginosa and Haemophilus influenzae, respectively. The following represents MIC susceptibility data for a few medically significant microorganisms.

Endotoxin adsorption

An effective use of polymyxin B is found in patients with refractory septic shock, that is, without positive outcome to the administration of standard treatments (increase in volemia and other antibiotics). The obstacle of the toxicity of polymyxin B is bypassed by extracorporeal circulation with perfusion of venous blood through a cartridge on whose fibers polymyxin B is covalently fixed; in this way the antibiotic exerts its bactericidal function but is not released into the blood since it remains fully attached to the fiber. Through this perfusion the cartridge retains the endotoxin, recognized as the trigger of septic shock. The treatment of the cartridge to polymyxin B (Toraymyxin, medical device designed and produced by the Japanese Toray), takes place in two sessions of two hours each, carried out at a distance of 24 hours. [8]

Mechanism of action

  1. Alters bacterial outer membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer, which has an electrostatic attraction for the positively charged amino groups in the cyclic peptide portion [9] (this site normally is a binding site for calcium and magnesium counter ions); the result is a destabilized outer membrane
  2. Fatty acid portion dissolves in hydrophobic region of cytoplasmic membrane and disrupts membrane integrity
  3. Leakage of cellular molecules, inhibition of cellular respiration
  4. Binds and inactivates endotoxin [10]
  5. Relative absence of selective toxicity: nonspecific for cell membranes of any type, highly toxic.

Removal of the hydrophobic tail of polymyxin B yields polymyxin nonapeptide (PMBN), which still binds to LPS, but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating that it still causes some degree of membrane disorganization. [11]

Mixture composition

Polymyxin B is composed of polymyxins B1, B1-I, B2, B3, and B6. Polymyxins B1 and B2 are considered major components. These related components are structurally identical with the exception of a variable fatty acid group on each fraction. Results from in vitro studies have shown marginal differences in MIC data when comparing the fractions. [12]

Research application

Polymyxin B is also used to induce envelope stress in order to study the organisms response to such stress. Polymyxin envelope stress assays such as this have been used for the study of small RNA (sRNA) responses in Salmonella enterica. [13]

See also

Related Research Articles

<span class="mw-page-title-main">Gram-negative bacteria</span> Group of bacteria that do not retain the Gram stain used in bacterial differentiation

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner cytoplasmic cell membrane and a bacterial outer membrane.

<span class="mw-page-title-main">Streptomycin</span> Aminoglycoside antibiotic

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<span class="mw-page-title-main">Neomycin</span> Type of antibiotic

Neomycin is an aminoglycoside antibiotic that displays bactericidal activity against gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against gram-positive bacilli and anaerobic gram-negative bacilli. Neomycin comes in oral and topical formulations, including creams, ointments, and eyedrops. Neomycin belongs to the aminoglycoside class of antibiotics that contain two or more amino sugars connected by glycosidic bonds.

<span class="mw-page-title-main">Lipopolysaccharide</span> Class of molecules found in the outer membrane of Gram-negative bacteria

Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by covalent bonds, and are found in the outer membrane of Gram-negative bacteria, such as E. coli and Salmonella. Today, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.

<span class="mw-page-title-main">Aminoglycoside</span> Antibacterial drug

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

<span class="mw-page-title-main">Polymyxin</span> Group of antibiotics

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Colistin</span> Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

<span class="mw-page-title-main">Bacitracin</span> Polypeptide Antibiotic (Gram Positive Bacteriacide)

Bacitracin is a polypeptide antibiotic. It is a mixture of related cyclic peptides produced by Bacillus licheniformis bacteria, that was first isolated from the variety "Tracy I" in 1945. These peptides disrupt gram-positive bacteria by interfering with cell wall and peptidoglycan synthesis.

<i>Haemophilus influenzae</i> Species of bacterium

Haemophilus influenzae is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacteria are mesophilic and grow best at temperatures between 35 and 37 °C.

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Neomycin/polymyxin B/bacitracin, also known as triple antibiotic ointment, is an antibiotic medication used to reduce the risk of infections following minor skin injuries. It contains the three antibiotics neomycin, polymyxin B, and bacitracin. It is for topical use.

<span class="mw-page-title-main">Kanamycin A</span> Antibiotic

Kanamycin A, often referred to simply as kanamycin, is an antibiotic used to treat severe bacterial infections and tuberculosis. It is not a first line treatment. It is used by mouth, injection into a vein, or injection into a muscle. Kanamycin is recommended for short-term use only, usually from 7 to 10 days. As with most antibiotics, it is ineffective in viral infections.

<span class="mw-page-title-main">Tobramycin</span> Chemical compound

Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

<i>N</i>-Acetylneuraminic acid Chemical compound

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<span class="mw-page-title-main">Pathogenic bacteria</span> Disease-causing bacteria

Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number of these pathogenic species in humans is estimated to be fewer than a hundred. By contrast, several thousand species are part of the gut flora present in the digestive tract.

<span class="mw-page-title-main">Polypeptide antibiotic</span> Class of antibiotics

Polypeptide antibiotics are a chemically diverse class of anti-infective and antitumor antibiotics containing non-protein polypeptide chains. Examples of this class include actinomycin, bacitracin, colistin, and polymyxin B. Actinomycin-D has found use in cancer chemotherapy. Most other polypeptide antibiotics are too toxic for systemic administration, but can safely be administered topically to the skin as an antiseptic for shallow cuts and abrasions.

Haemophilus meningitis is a form of bacterial meningitis caused by the Haemophilus influenzae bacteria. It is usually associated with Haemophilus influenzae type b. Meningitis involves the inflammation of the protective membranes that cover the brain and spinal cord. Haemophilus meningitis is characterized by symptoms including fever, nausea, sensitivity to light, headaches, stiff neck, anorexia, and seizures. Haemophilus meningitis can be deadly, but antibiotics are effective in treating the infection, especially when cases are caught early enough that the inflammation has not done a great deal of damage. Before the introduction of the Hib vaccine in 1985, Haemophilus meningitis was the leading cause of bacterial meningitis in children under the age of five. However, since the creation of the Hib vaccine, only two in every 100,000 children contract this type of meningitis. Five to ten percent of cases can be fatal, although the average mortality rate in developing nations is seventeen percent, mostly due to lack of access to vaccination as well as lack of access to medical care needed to combat the meningitis.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Polymyxin B Sulfate topical Monograph for Professionals". Drugs.com. Retrieved 11 November 2019.
  2. 1 2 Bennett JE, Dolin R, Blaser MJ, Mandell GL (2009). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book. Elsevier Health Sciences. p. 469. ISBN   9781437720600.
  3. "Neomycin, bacitracin, polymyxin b ointment". DailyMed. U.S. National Library of Medicine. Retrieved 19 April 2019.
  4. Woo TM, Robinson MV (2015). Pharmacotherapeutics For Advanced Practice Nurse Prescribers. F.A. Davis. p. 651. ISBN   9780803645813.
  5. "World Health Organization model list of essential medicines: 21st list 2019" (PDF). World Health Organization. 2019. hdl:10665/325771.
  6. "Polymyxin-based products" (PDF). Assessment report. European Medicines Agency. Retrieved 11 November 2019.
  7. "Polymyxin B sulfate : Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). Toku-e.com. Retrieved 2017-04-02.
  8. Shoji H (February 2003). "Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin)". Therapeutic Apheresis and Dialysis. 7 (1): 108–114. doi:10.1046/j.1526-0968.2003.00005.x. PMID   12921125. S2CID   41911308.
  9. Khondker A, Dhaliwal AK, Saem S, Mahmood A, Fradin C, Moran-Mirabal J, Rheinstädter MC (February 2019). "Membrane charge and lipid packing determine polymyxin-induced membrane damage". Communications Biology. 2: 67. doi:10.1038/s42003-019-0297-6. PMC   6379423 . PMID   30793045.
  10. Cardoso LS, Araujo MI, Góes AM, Pacífico LG, Oliveira RR, Oliveira SC (January 2007). "Polymyxin B as inhibitor of LPS contamination of Schistosoma mansoni recombinant proteins in human cytokine analysis". Microbial Cell Factories. 6: 1. doi: 10.1186/1475-2859-6-1 . PMC   1766364 . PMID   17201926.
  11. Tsubery H, Ofek I, Cohen S, Fridkin M (2000-01-01). "Structure activity relationship study of polymyxin B nonapeptide". The Biology and Pathology of Innate Immunity Mechanisms. Advances in Experimental Medicine and Biology. Vol. 479. pp. 219–222. doi:10.1007/0-306-46831-X_18. ISBN   978-0-306-46409-6. PMID   10897422.
  12. Orwa JA, Govaerts C, Busson R, Roets E, Van Schepdael A, Hoogmartens J (April 2001). "Isolation and structural characterization of polymyxin B components". Journal of Chromatography A. 912 (2): 369–373. doi:10.1016/S0021-9673(01)00585-4. PMID   11330807.
  13. Hébrard M, Kröger C, Srikumar S, Colgan A, Händler K, Hinton JC (April 2012). "sRNAs and the virulence of Salmonella enterica serovar Typhimurium". RNA Biology. 9 (4): 437–445. doi:10.4161/rna.20480. PMC   3384567 . PMID   22546935.