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.

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

6. Classes of topical antibiotics
Cell wall synthesis inhibitors
Ribosome function inhibitors
Sulfa drugs
Burn treatment agents
Miscellaneous

7. Mupirocin (90% Pseudomonic acid A)
Isolated from Pseudomonas fluorescens
Antibacterial activity of substance from P. fluorescens noted in 1887
Purified in the 1960’s.
Mupirocin works against Gram-positive bacteria only
Can be used to treat MRSA (although resistance is rising)

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

9. Mupirocin inhibits bacterial isoleucyl-tRNA synthetase.

10. Products containing Mupirocin

11. Polymyxin B

12. Polymixin B
Daptomycin
Polymixin B
Member of the lipopeptide class of antibiotics, similar to daptomycin

13. 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

14. 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.

15. Products containing polymyxin B

16. Bacitracin A

17. Bacitracin: History Isolated by John T. Goorley in 1943
Found in the infected compound fracture of the patient Margaret Tracy

18. Bacitracin: Antibacterial Activity
Primarily used against gram positive bacteria S. aureus and Streptococci spp.
Most gram negative organisms are resistant

19. 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

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

22. Products containing Bacitracin

23. Gramicidin
Gramicidin S

24. 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

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

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

27. 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

29. 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-
NHCH2CH2OH Note: The amino acids are all hydrophobic; both peptide ends are modified (blocked).

30. 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.

31. Neomycin

32. 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

33. 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

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

36. Silver sulfadiazine

37. 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

38. Uses
Used to treat burn patients

40. Treatment of Acne Vulgaris

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

42. 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.

44. Propionibacterium acnes
Killing the bacteria can help with treatment of acne

45. Benzoyl Peroxide
Exact antibacterial mechanism is unknown, but presumably involves oxidation of essential bacterial structures.

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

47. 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.

48. Assigned Reading
Noah Scheinfeld A primer on topical antibiotics for the skin and eyes. Journal of drugs in dermatology : JDD (2008), 7(4),

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