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    • Topical Antibiotics
      • 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.
    • 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.
    • 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.
    • Classes of topical antibiotics
      • Cell wall synthesis inhibitors
      • Ribosome function inhibitors
      • Sulfa drugs
      • Burn treatment agents
      • Miscellaneous
    • 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)
      • Ester linkage is rapidly hydrolyzed hepatically, thus precluding utility as an oral or intravenous antibiotic
      • Mupirocin inhibits bacterial isoleucyl-tRNA synthetase.
    • Products containing Mupirocin
    • Polymyxin B
    • Polymixin B
      • Member of the lipopeptide class of antibiotics, similar to daptomycin
      Daptomycin Polymixin B
    • 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
    • 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.
    • Products containing polymyxin B
    • Bacitracin A
    • Bacitracin: History
      • Isolated by John T. Goorley in 1943
      • Found in the infected wound of the patient Margaret Tracy
    • Bacitracin: Antibacterial Activity
      • Primarily used against gram positive bacteria S. aureus and Streptococci spp.
      • Most gram negative organisms are resistant
    • 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
    •  
    • Products containing Bacitracin
    • Gramicidin Gramicidin S
    • 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
    • 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.
    • Gramicidins: Mechanism of action
      • The gramicidins behave as ionophoric substances
      • The gramicidins self associate, thus forming small pores that cause leakage of essential cations from the cytoplasm
      A gramicidin channel
    •  
      • Gramicidin is an unusual peptide, with alternating D & L amino acids.
      • In lipid bilayer membranes, gramicidin dimerizes & folds as a right-handed  -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).
      • 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.
    • Neomycin
    • 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
    • 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
    • Mechanism of action
      • Like other aminoglycosides, neomycin works by binding to the bacterial 30S ribosomal subunit, thus inhibiting protein synthesis.
    •  
    • Silver sulfadiazine
    • 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
    • Uses
      • Used to treat burn patients
    •  
    • Treatment of Acne Vulgaris
    • 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.
    • Propionibacterium acnes
      • Killing the bacteria can help with treatment of acne
    • Benzoyl Peroxide
      • Exact antibacterial mechanism is unknown, but presumably involves oxidation of essential bacterial structures.
    • 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.
    • 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.
    • Homework Question
      • List the primary target organism and the mechanism of action of the topical antibiotics discussed in this presentation.