Topical Antibiotics - Dr. Arhin PDF

# Topical antibiotics Stephen Mensah Arhin (PhD, RN) Department of Pharmacology UCCSMS 10/15/ ## Structure of the skin - Shunt diffusion - Permeation - Penetration - Vehicle reservoir - Str corneum - 20 µm - Viable epidermis - ~100 µm - Reservoir function - Barrier function - Binding - Dermis - ~12...

# Topical antibiotics Stephen Mensah Arhin (PhD, RN) Department of Pharmacology UCCSMS 10/15/ ## Structure of the skin - Shunt diffusion - Permeation - Penetration - Vehicle reservoir - Str corneum - 20 µm - Viable epidermis - ~100 µm - Reservoir function - Barrier function - Binding - Dermis - ~1200 µm - Hypo - Binding - Resorption - Lymph vessels - Permeation - Cutaneous vasculature ## Target Bacteria - Most topical antibiotics are directed against - *Staphylococcus aureus* - *Streptococcus pyogenes* - *Propionibacterium acnes* - The anaerobic Gram-positive bacterial species ## Advantages - Avoids the GIT and hepatic first pass metabolism - Reduce systemic side effect - Higher [C] of drug at site of application - Improve compliance - Plasma concentration of <10 compared to oral route ## Side effects - Itching - Burning - Rash - Allergic reaction ## Examples - Bactroban, Polysporin, and Triple Antibiotic Ointment or Cream - Neosporin ## Classes of topical antibiotics - Cell wall synthesis inhibitors - Protein synthesis inhibitors - Folate inhibitors (Sulfa drugs) - Miscellaneous ## Cell wall synthesis inhibitors ## Polymyxin B - Daptomycin - Polymyxin B - Member of the **lipopeptide** class of antibiotics, similar to daptomycin - Bactericidal ## Polymyxin: Antibacterial activity - Polymyxins only active against gram negative bacteria (*P. aeruginosa*, *E. coli*, *K. pneumoniae*) - Daptomycin is used to treat gram positive bacteria - The polymyxins are highly **nephrotoxic** and are only used topically ## Polymyxins: Mechanism of action - Bind 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 - Neosporin - Triple Antibiotic Ointment ## Bacitracin: History - Isolated by John T. Goorley in 1943 - Found in the infected compound fracture 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 - Used for cuts, burns, ocular infections, diaper rash ## Bacitracin: Mechanism - Bacitracin interferes with bacterial cell wall synthesis - Interferes with **peptidoglycan** transport across the cell membrane - Acts by blocking a step in the process whereby the key subunits are transferred from the cytoplasm ## Bacitracin: Mechanism of action - Specifically, bacitracin tightly binds **undecaprenyl pyrophosphate**, preventing the hydrolysis into **undecaprenyl phosphate**. - This step is essential for recycling of the carrier. ## Products containing Bacitracin - Bacitracin Ophthalmic Ointment USP - Neosporin ## Protein synthesis inhibitors - **Mupirocin** (90% Pseudomonic acid A) ## Mupirocin - Isolated from *Pseudomonas fluorescens* - Antibacterial activity 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). - Used for impetigo, folliculitis, boils, eczema, etc ## Mupirocin: Mechanism of action - Ester linkage is rapidly **hydrolyzed** hepatically, thus precluding utility as an oral or intravenous antibiotic ## Mupirocin: Mechanism of action - Mupirocin inhibits bacterial **isoleucyl-tRNA synthetase** - Leads to inhibition of protein synthesis - By depleting isoleucyl-tRNA, indirectly disrupts cell wall integrity - Isoleucyl-tRNA is necessary for bacterial protein synthesis, maintains cell wall integrity ## Gramicidin - Gramicidin S ## Gramicidins - Gramicidins - small peptides (15 amino acids) - *Gramicidin S*, are cyclic - *Gramicidin A, B, C*, and *D*, are linear. - Commercial gramicidin is a mixture of compounds, with *gramicidin A* being major ## Gramicidins - Gramicidin S - powerful antibacterial agent - With broad range against a number of Gram positive and Gram negative microorganisms. ## Gramicidin S: Mechanism of action - 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 ## 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 ## Neomycin: Mechanism of action - Like other aminoglycosides, neomycin works by binding to the bacterial 30S ribosomal subunit, thus inhibiting protein synthesis. ## Folate inhibitors - Silver sulfadiazine ## Folate inhibitors: 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 ## Products containing silver sulfadiazine - SILVADENE® CREAM 1% (silver sulfadiazine) ## 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 ## What causes Acne? - 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. ## How Acne develops: 3 steps - Healthy pore - Clogged pore - Bacteria spreading within sebaceous gland - Swollen pore (acne) - Step 1 - The healthy pore - Step 2 - The clogged pore - Step 3 - The swollen pore ## 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. ## Clindamycin: Mechanism of action - Lincomycin (Lincocin) - Natural product - Note rare octose 8C sugar - Not really used clinically - Clindamycin (Cleocin) - Semisynthetic lincomycin derivative (CI) - Clindamycin is a lincosamide antibacterial agents and acts at the bacterial ribosome. - Clindamycin is commonly used to treat aerobic Gram-positive bacteria. ## Oral antibiotics effective against skin infections | Antibiotic | Route | Recommended Dosing in Adults | | ------------------------ | ------ | ------------------------------ | | Vancomycin | IV | 15 mg/kg every 12 hours | | Linezolid | IV/oral | IV: 600 mg every 12 hours | | | | Oral: 600 mg twice a day | | Clindamycin | IV/oral | IV: 600 mg every 8 hours | | | | Oral: 300-450 mg 4 times a day | | Daptomycin | IV | 4 mg/kg daily | | Ceftaroline | IV | 600 mg every 12 hours | | Doxycycline, minocycline | Oral | 100 mg twice a day | | Trimethoprim-sulfamethoxazole | Oral | 1-2 double strength tablets twice a day | ## Summary of Recently Approved Antibiotics for the Treatment of Acute Bacterial Skin and Structure Infection | Product | Indications | Microbiology | Formulations | Dosing | | :--------------- | :---------------------------------------------------------- | :---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | :------------ | :----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | | Dalbavancin | ABSSSI caused by susceptible strains of gram-positive microorganisms | In vitro and clinical activity against the following aerobic and facultative gram-positive bacteria: *Staphylococcus aureus* (including MRSA) *Streptococcus pyogenes* *Streptococcus agalactiae* *Staphylococcus dysgalactiae* *Staphylococcus anginosus group* (including *Staphylococcus anginosus*, *Staphylococcus intermedius*, *Staphylococcus constellatus*) *Enterococcus faecalis* (vancomycin-susceptible isolates only) | IV | Single-dose regimen: 1500 mg IV over 30 min. Two-dose regimen: 1000 mg IV over 30 min followed 1 week later by 500 mg IV over 30 min | | Oritavancin | ABSSSI caused by susceptible strains of gram-positive microorganisms | In vitro and clinical activity against: *S. aureus*, (including MRSA) *S. pyogenes* *S. agalactiae* *S. anginosus group* (including *S. anginosus*, *S. intermedius*, *S. constellatus*) *E. faecalis* | IV | Single-dose regimen: 1200 mg IV over 3 hours | | Tedizolid | ABSSSI caused by susceptible strains of gram-positive microorganisms | In vitro and clinical activity against gram-positive bacteria including *S. aureus* (including MRSA) *S. agalactiae* *S. anginosus group* (including *S. anginosus*, *S. intermedius*, *S. constellatus*) *S. dysgalactiae* *S. pyogenes* *E. faecalis* (vancomycin-susceptible isolates only) | IV/oral | 200 mg IV/oral tablet daily for 6 days; IV infusion over 1 hour or 450 mg oral tablet every 12 hours for 6-14 days | | Delafloxacin | ABSSSI caused by susceptible strains of gram-positive and gram-negative microorganisms | In vitro and clinical activity against the following aerobic gram-positive and gram-negative bacteria: *S. aureus* (including MRSA) *Staphylococcus haemolyticus* *Staphylococcus lugdunensis* *S. pyogenes* *S. agalactiae* *S. dysgalactiae* *S. anginosus group* (including *S. anginosus*, *S. intermedius*, *S. constellatus*) *E. faecalis* *Escherichia coli* *Klebsiella pneumoniae* *Enterobacter cloacae* *Pseudomonas aeruginosa* | IV/oral | 300 mg IV over 60 min every 12 hours for 5-14 days or 450 mg oral tablet every 12 hours for 5-14 days | ## The End Thank you