Topical Antibiotics

1
Topical Antibiotics
2

• 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.

3
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.

4
Which topical antibiotics are common?

• Some widely used topical antibiotics are
  bacitracin, neomycin, mupirocin, and polymyxin B.
  
• Among the products that contain one or more of
  these ingredients are Bactroban (a prescription
  item), Neosporin, Polysporin, and Triple
  Antibiotic Ointment or Cream.

5
Classes of topical antibiotics

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

6
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)

7

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

8

• Mupirocin inhibits bacterial isoleucyl-tRNA
  synthetase.

9
Products containing Mupirocin
10
Polymyxin B
11
Polymixin B
Daptomycin
Polymixin B

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

12
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

13
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.

14
Products containing polymyxin B
15
Bacitracin A
16
Bacitracin History

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

17
Bacitracin Antibacterial Activity

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

18
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
• Specifically bacitracin tightly binds
  undecaprenyl pyrophosphate, preventing the
  hydrolysis into undecaprenyl phosphate
• This step is essential for recycling of the
  carrier
• Link

19
(No Transcript)
20
Products containing Bacitracin
21
Gramicidin
Gramicidin S
22
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

23
Gramicidins

• Gramicidin S is a powerful antibacterial agent,
  with broad range against a number of Gram
  positive and Gram negative microorganisms.
• Unfortunately, Gramicidin S is hemolytic, and
  thus is limited to topical use.
• Mechanism of action is believed to be at the
  cytoplasmic membrane.

24
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

25
(No Transcript)
26

• 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).
27

• 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.

28
Neomycin
29
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

30
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

31
Mechanism of action

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

32
(No Transcript)
33
Silver sulfadiazine
34
Mechanism of action

• 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

35
Uses

• Used to treat burn patients

36
(No Transcript)
37
Treatment of Acne Vulgaris
38
What Causes Acne?

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

39
Propionibacterium acnes

• Killing the bacteria can help with treatment of
  acne

40
Benzoyl Peroxide

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

41
Clindamycin
The antibiotic clindamycin is commonly used
topically in the treatment of acne 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.
42
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.

43
Homework Question

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