Topical%20Antibiotics

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Topical Antibiotics
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• Topical antibiotics help prevent infections
  caused by bacteria that get into minor cuts,
  scrapes, and burns.
• Treating minor wounds with antibiotics allows
  quicker healing.
• If the wounds are left untreated, the bacteria
  will multiply, causing pain, redness, swelling,
  itching, and oozing.
• Untreated infections can eventually spread and
  become much more serious.

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Which bacteria?

• Most topical antibiotics are directed against
  Staphylococcus aureus and Streptococcus pyogenes.
• The anaerobic Gram-positive bacterial species
  Propionibacterium acnes has been linked to acne.

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Which topical antibiotics are common?

• Some widely used topical antibiotics are
  bacitracin, neomycin, mupirocin, and polymyxin B.

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• Among the products that contain one or more of
  these ingredients are Bactroban (a prescription
  item), Neosporin, Polysporin, and Triple
  Antibiotic Ointment or Cream.

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Classes of topical antibiotics

• Cell wall synthesis inhibitors
• Ribosome function inhibitors
• Sulfa drugs
• Burn treatment agents
• Miscellaneous

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Mupirocin (90 Pseudomonic acid A)

• Isolated from Pseudomonas fluorescens
• Antibacterial activity of substance from P.
  fluorescens noted in 1887
• Purified in the 1960s.
• Mupirocin works against Gram-positive bacteria
  only
• Can be used to treat MRSA (although resistance is
  rising)

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• Ester linkage is rapidly hydrolyzed hepatically,
  thus precluding utility as an oral or intravenous
  antibiotic

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• Mupirocin inhibits bacterial isoleucyl-tRNA
  synthetase.

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Products containing Mupirocin
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Polymyxin B
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Polymixin B
Daptomycin
Polymixin B

• Member of the lipopeptide class of antibiotics,
  similar to daptomycin

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Polymyxin Antibacterial activity

• However, the polymyxins are only active against
  gram negative bacteria (P. aeruginosa, E. coli,
  K. pneumoniae), while daptomycin is used to treat
  gram positive bacteria
• The polymyxins are highly nephrotoxic and are
  thus only used topically

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Polymyxins Mechanism of action

• Bind the the lipopolysaccharide in the outer
  membrane, thus destroying OM integrity.
• Bind to the cytoplasmic membrane (to the
  phosphatidylethanolamine) and make the membrane
  more permeable.

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Products containing polymyxin B
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Bacitracin A
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Bacitracin History

• Isolated by John T. Goorley in 1943
• Found in the infected compound fracture of the
  patient Margaret Tracy

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Bacitracin Antibacterial Activity

• Primarily used against gram positive bacteria S.
  aureus and Streptococci spp.
• Most gram negative organisms are resistant

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Bacitracin Mechanism

• Bacitracin interferes with bacterial cell wall
  synthesis
• Acts by blocking a step in the process whereby
  the key subunits are transferred from the
  cytoplasm

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• Specifically bacitracin tightly binds
  undecaprenyl pyrophosphate, preventing the
  hydrolysis into undecaprenyl phosphate
• This step is essential for recycling of the
  carrier
• Link

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Products containing Bacitracin
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Gramicidin
Gramicidin S
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Gramicidins

• The Gramicidins are small peptides (15 amino
  acids)
• Some, such as gramicidin S, are cyclic
• Others, including Gramicidin A, B, C, and D, are
  linear
• Commercial gramicidin is a mixture of compounds,
  with gramicidin A being major

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Gramicidins

• Gramicidin S is a powerful antibacterial agent,
  with broad range against a number of Gram
  positive and Gram negative microorganisms.

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• Unfortunately, Gramicidin S is hemolytic, and
  thus is limited to topical use.
• Mechanism of action is believed to be at the
  cytoplasmic membrane.

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Gramicidins Mechanism of action
A gramicidin channel

• The gramicidins behave as ionophoric substances
• The gramicidins self associate, thus forming
  small pores that cause leakage of essential
  cations from the cytoplasm

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• Gramicidin is an unusual peptide, with
  alternating D L amino acids.
• In lipid bilayer membranes, gramicidin dimerizes
  folds as a right-handed b-helix.
• The dimer just spans the bilayer.
• Primary structure of gramicidin (A)

HCO-L-Val-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-
L-Trp-D-Leu-L-Trp-D-Leu-L-Trp-D-Leu-L-Trp- NHCH2CH
2OH Note The amino acids are all
hydrophobic both peptide ends are modified
(blocked).
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• The outer surface of the gramicidin dimer, which
  interacts with the core of the lipid bilayer, is
  hydrophobic.
• Ions pass through the more polar lumen of the
  helix.
• Ion flow through individual gramicidin channels
  can be observed if a small number of gramicidin
  molecules is present in a lipid bilayer
  separating 2 compartments containing salt
  solutions.

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Neomycin
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Historical Aminoglycosides

• Waksman and Schatz demonstrated the antibacterial
  activity of Streptomyces griseus in 1943
• Streptomycin isolated in 1944
• Neomycin isolated from Streptomyces fradiae in
  1949

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Neomycin

• Neomycin is extremely nephrotoxic, thus limiting
  its use to a topical antibiotic
• Neomycin has excellent activity against gram
  negative bacteria and partial activity against
  gram positive strains
• Some people have allergies to neomycin

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• Like other aminoglycosides, neomycin works by
  binding to the bacterial 30S ribosomal subunit,
  thus inhibiting protein synthesis.

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Silver sulfadiazine
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• Sulfa drug works by normal mechanism of
  interfering with the biosynthesis of folic acid
• Heavy metals, like silver, seem to be toxic to
  bacteria, probably due to their ability to
  denature proteins through reaction with disulfide
  bonds

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Uses

• Used to treat burn patients

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Treatment of Acne Vulgaris
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What Causes Acne?

• Acne is a result of clogging of a hair follicle,
  and simultaneous activation of the sebaceous
  gland (thus producing more sebum).

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• A commensal bacterium, Propionibacterium acnes,
  which lives on the skin, but is also present in
  the follicle, causes inflammation and thus
  contributes to the problem.

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Propionibacterium acnes

• Killing the bacteria can help with treatment of
  acne

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Benzoyl Peroxide

• Exact antibacterial mechanism is unknown, but
  presumably involves oxidation of essential
  bacterial structures.

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Clindamycin
The antibiotic clindamycin is commonly used
topically in the treatment of acne
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• Recall that clindamycin is a member of the
  lincosamide class of antibacterial agents and
  acts at the bacterial ribosome.
• Clindamycin is commonly used to treat aerobic
  Gram-positive bacteria.

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Assigned Reading

• Noah Scheinfeld A primer on topical antibiotics
  for the skin and eyes. Journal of drugs in
  dermatology JDD (2008), 7(4), 409-15.

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Homework Question

• List the primary target organism and the
  mechanism of action of the topical antibiotics
  discussed in this presentation.