Unique Applications for Topical Anti-Infectives in the Treatment of Nail and Foot Infections Andrew Orwick, Pharm.D. Precision Compounding Pharmacy April 26 th , 2019
Disclosure Presenter has no financial or non-financial interest to disclose Status of medications and devices mentioned in this presentation are off-label use and for informational purposes only
The Food and Drug Administration (FDA) does not review any compound from any pharmacy for safety and efficacy Disclaimer to Any Compound It is recommended to utilize a pharmacy that strictly follows USP guidelines
A pharmacy can promote that it follows USP guidelines, but it cannot claim that the compounds are safe or effective Disclaimer to The compounds discussed herein have not Any Compound been approved by the FDA and, therefore, should not be promoted as safe or effective for any use
Identify potential uses for unique applications of topical anti-infectives including bath irrigation, topical sprays, nail soaks, and topical gels Explain specialized delivery devices utilized for topical Objectives delivery Discuss topical anti-infectives available for use and their mechanism of action Review specific patient cases and outcomes with the use of topical anti-infectives Discuss the role of the pharmacist in culture review, product selection, and patient education
How do we categorize different anti-biotics? By Mechanisms of Action By type of bacterial coverage? • Cell wall • Gram-positive (MRSA) • Cell membrane • Gram-negative (Pseudomonas) • DNA/RNA • Anaerobe • Ribosomal 50s/30s • Atypical
Bacterial structure and Antibiotic MoA
Potential Benefits of Topical Anti-Infectives Low systemic effect of the drug on patients High concentration of Anti-Infectives at the site of infection Combination treatment of bacterial and fungal infections when it is suspected to be polymicrobial
Potential Benefits of Topical Anti-Infectives Alternative option when desired outcomes have not been achieved using standard oral antibiotics and/or antifungals Patient has failed treatment using one or more commercially available topically delivered medication Avoid using oral or IV medications Concomitant delivery with oral or IV medications
Available dosage forms Capsules Powders Gels Ointments Sprays
Topical Powders Combination of an antibiotic, antifungal, antiviral, and/or an anesthetic can be compounded in a powder delivery form Patient then sprinkles/spreads the dry powder directly onto the wound site or can be mixed into bath irrigation Examples – Gentamicin 5%, Mupirocin 5% powder Levofloxacin 3%, Tobramycin 5% powder Powder treatment can be followed by an ointment to occlude the wound if desired
Topical Ointments Combination of an antibiotic, antifungal, and/or antiviral can be compounded into an ointment Patient directly applies ointment to the wound site or can be mixed in bath irrigation Example – Tobramycin 2.5%, Doxycycline 2.5%, Mupirocin 1.855%, Itraconazole 1% ointment
Topical Spray Combination of an antibiotic, antifungal, antiviral, and/or an anesthetic can be compounded into a spray delivery form Patient sprays the medication directly on the wound site or patient make soak gauze in the solution then apply to wound For extremely painful wounds, patient is able to avoid any direct contact
Anti-Infective Bath Irrigation System Foot Spa with Bubbles & Heat Medications to be mixed into solution just prior to treatment Detailed instructions by a pharmacist on how to step up and use their bath irrigation system, along with a mixing jar. Patients will soak their feet in the medicated solution for up to 10 minutes two times a day
Bacteria Resistance Mechanisms Bacteria can mutate to change or protect the structure of the antibiotic target site whilst maintaining function Gram-negative cells can mutate and/or block the target site of fluoroquinolones (DNA gyrase) which reduces drug binding and provides resistance Bacteria are able to produce enzymes, which can inactivate or modify the antibiotic rendering it ineffective. Extended spectrum β -lactamases (ESBLs) are more commonly being found in Gram- negative species globally reducing the efficacy of penicillins, cephalosporins and aztreonam Bacteria can prevent effective concentrations of the antibiotics to their target site By up-regulating the normal level of efflux activity of the cell Reducing the permeability of the cell membrane by repressing porin production. P . aeruginosa and E. coli are capable of efflux pumps to export multiple drugs Hughes, G., and Webber, M. A. (2017) Novel approaches to the treatment of bacterial biofilm infections. British Journal of Pharmacology , 174: 2237 – 2246. doi: 10.1111/bph.13706. Ciofu, O, Rojo‐Molinero , E, Macià, MD, Oliver, A. Antibiotic treatment of biofilm infections. APMIS 2017;125: 304 – 319.
Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all bacterial infections and 90% of all chronic wounds Biofilms allow bacteria to demonstrate up to 1000-fold increase in antibiotic tolerance This is due to physical impedance and enzymatic inactivation of the drugs, coupled with lowered metabolic rates in many biofilm-associated cells Altered environment and growth kinetics of bacteria in biofilms Bacteria at the lower end of the gradient exist in a stationary phase, with limited diffusion of oxygen, glucose and other nutrients. Metabolically dormant and highly antibiotic resistant Can survive antibiotic exposure and occasionally come out of dormancy and act to re- populate the biofilm Bacteria in the upper end of the gradient have better access to nutrients and are more susceptible to antibiotics Fleming D, Rumbaugh KP . Approaches to Dispersing Medical Biofilms. Microorganisms . 2017; 5(2):15. Hughes, G., and Webber, M. A. (2017) Novel approaches to the treatment of bacterial biofilm infections. British Journal of Pharmacology , 174: 2237 – 2246. doi: 10.1111/bph.13706.
Biofilms and Topical Treatments Systemic antibiotics are useful during early stages of infection However chronic biofilm wound infections will likely be treated most efficiently with local antibiotics Local administration of antibiotics Allows for delivery of antibiotics at significantly higher doses Allowing the minimal biofilm inhibitory concentration to be obtained Without the risk of toxicity encountered during systemic delivery of high dose antibiotics Combined antimicrobial therapies maybe be required Biofilms are bacterial communities that exhibit not only different structural areas but also different metabolic states Combining some agents that attack metabolically active layers Tobramycin, Ciprofloxacin, or the beta-lactams With antibiotics that preferentially kill biofilm cells with low metabolic activity provides a framework for combination therapy Colistimethate Blanchette KA, Wenke JC. Current therapies in treatment and prevention of fracture wound biofilms: why a multifaceted approach is essential for resolving persistent infections. J Bone Jt Infect . 2018;3(2):50 – 67. Published 2018 Apr 12. doi:10.7150/jbji.23423 Ciofu, O, Rojo‐Molinero , E, Macià, MD, Oliver, A. Antibiotic treatment of biofilm infections. APMIS 2017;125: 304 – 319.
Biofilms and Topical Treatments Acetic acid: A weak organic acid (WOA) Applied topically within dressings (at concentrations between 2% and 5%) Higher hydrophobicity and lipid permeability allows them to diffuse into the bacterial cell cytoplasm before dissociation occurs Lower the internal cytoplasmic pH of the bacteria in a process known as ion trapping This can then lead to a disruption of metabolic activities, and as the dissociated acid components do not readily pass across membranes There is an intracellular accumulation of the breakdown products of the WOA. As cytoplasmic WOA accumulates there is an increase in turgor pressure causing an osmotic effect The decrease the internal cytoplasmic pH, it can also increase the osmolality resulting in an influx of water Hughes, G., and Webber, M. A. (2017) Novel approaches to the treatment of bacterial biofilm infections. British Journal of Pharmacology , 174: 2237 – 2246. doi: 10.1111/bph.13706.
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