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Andrew Orwick, Pharm.D. Precision Compounding Pharmacy April 26 th , 2019 Unique Applications for Topical Anti-Infectives in the Treatment of Nail and Foot Infections

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Page 1: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Andrew Orwick, Pharm.D.

Precision Compounding PharmacyApril 26th, 2019

Unique Applications for Topical Anti-Infectives in the Treatment

of Nail and Foot Infections

Page 2: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 3: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Disclaimer to

Any Compound

The Food and Drug Administration (FDA) does

not review any compound from any pharmacy

for safety and efficacy

It is recommended to utilize a pharmacy that

strictly follows USP guidelines

Page 4: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Disclaimer to

Any Compound

A pharmacy can promote that it follows USP

guidelines, but it cannot claim that the

compounds are safe or effective

The compounds discussed herein have not

been approved by the FDA and, therefore,

should not be promoted as safe or effective

for any use

Page 5: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Objectives

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

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

Page 6: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

How do we categorize different anti-biotics?

By Mechanisms of Action

• Cell wall

• Cell membrane

• DNA/RNA

• Ribosomal 50s/30s

By type of bacterial coverage?

• Gram-positive (MRSA)

• Gram-negative(Pseudomonas)

• Anaerobe

• Atypical

Page 7: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Bacterial structure and Antibiotic MoA

Page 8: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 9: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 10: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Available dosage forms

Capsules

Powders

Gels

Ointments

Sprays

Page 11: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 12: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 13: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 14: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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

Page 15: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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.

Page 16: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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.

Page 17: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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.

Page 18: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

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.

Page 19: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Biofilms and Topical TreatmentsUrea: An amide that is theorized to break down biofilms by disrupting the

hydrogen bonds that are vital for extracellular polymeric substance(EPS)

mechanical stability.

Exhibited dispersal ability against biofilms from

P. aeruginosa

S. epidermidis

K. pneumoniae

Biofilms formed by S. epidermidis that were treated with urea became more

deformed and exhibited significant biofilm loss(71% reduction) during the

post-treatment flow challenge.

During the treatment soak phase, biofilms exposed to urea swelled

Potentially allowing great access of antibiotics

Fleming D, Rumbaugh KP. Approaches to Dispersing Medical Biofilms. Microorganisms. 2017; 5(2):15.

Brindle, E.R.; Miller, D.A.; Stewart, P.S. Hydrodynamic deformation and removal of Staphylococcus epidermidis biofilms

treated with urea Biotechnol. Bioeng. 2011, 108, 2968–2977.

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

Page 20: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Potential uses and advantages

in Diabetic Foot Infections Most DFI are polymicrobial

Aerobic gram-positive cocci, MRSA is present in 10% to 32%

Including gram-negative bacteria

Anaerobic pathogens are more commonly present in necrotic wounds and infections of

the ischemic foot.

Common Treatment of Mild to Moderate DFI

Treated with oral antibiotics in an outpatient setting for 1-3 weeks depending on

severity

No single antibiotic regimen is clearly superior

Up to 40% of patients with DFI also have peripheral arterial disease

Reduced effectiveness of oral and IV therapies

Broader spectrum coverage recommended

In patients with ABX-Resistant infection, Chronic and/or previously treated

Gemechu FW, Seemant F, Curley CA. Diabetic foot infections. Am Fam Physician 2013;88(3):177-184.

IDSA Guideline for Diabetic Foot Infections; 2012

Page 21: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Potential uses and advantages

in Chronic Non Healing Wounds

Constant state of inflammation

From repeated tissue trauma, infection, and/or ischemia/hypoxia

Chronic wounds had increased activation and expression of MMPs

MMPs degrade new formed tissue/ECM

Delays/stops the normal healing process

Need to change the wound environment to a non-inflammatory state

This can be achieved pharmacologically with topical doxycycline

Stechmiller J, Cowan L, Schultz G. The role of doxycycline as a matrix metalloproteinase inhibitor for the treatment of chronic wounds. Biol Res Nurs 2010. April;11(4):336–344.

Iqbal A, Jan A, Wajid MA, Tariq S. Management of Chronic Nonhealing Wounds by Hirudotherapy. World J Plast Surg 2017;6(1):9-17.

Patel S, Maheshwari A, Chandra A. Biomarkers for wound healing and their evaluation. Journal of Wound Care 2016;25(1):46-55.

Page 22: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Potential uses and advantages in Fungal

Nail Infections

Difficult to treat

Complete cures can take up to 18 months

20-25% of patient fail to reach cure

High Prevalence and Recurrence Rate

Contagious, with potential to spread

Other nails, web spaces, toes, and the whole foot

Increased susceptibility in patients with chronic comorbidities

Increased likelihood of polypharmacy (no oral antifungals)

Christenson JK, Peterson GM, Naunton M, Bushell M, Kosari S, Baby KE, Thomas J. Challenges and Opportunities in the Management of Onychomycosis. Journal of Fungi. 2018; 4(3):87.

Page 23: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Vancomycin

Mechanism of action – inhibits cell wall synthesis in gram positive bacterial (can conceivably have activity against gram negative – but typically very minimal)

Considered by many healthcare practitioners as the “end-all-save-all” for gram-positive infections

Examples:

Vancomycin 50mg capsule

Vancomycin 5% ointment

Page 24: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Mupirocin

Mechanism of action – strongly inhibits protein and RNA synthesis in Staphylococcus aureus while DNA and cell wall formation are also minimally impacted

Specifically FDA-indicated against MRSA when reviewing Mupirocin 2% Ointment insert

• Referencing commercially available medication only

No oral or IV options are commercially availableX

Page 25: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review -

Penicillin(s)/Cephalosporin(s)

Mechanism of action – inhibits the formation of

peptidoglycan cross-links in the bacterial cell wall (less

resistance historically seen with cephalosporin(s))

Penicillin(s)

Examples – Piperacillin-Tazobactam powder

Page 26: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review -

Cephalosporin(s)

As one transitions from 1st Generation to 4th Generation, one generally sees increased coverage of gram-negative bacteria and decreased coverage of gram-positive bacteria

1st Generation Example – Cephalexin

2nd Generation Example – Cefoxitin

3rd Generation Example – Ceftriaxone 1 gram powder

4th Generation Example – Cefepime 1 gram powder

Page 27: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Carbapenems

Example – Meropenem 500mg powder

Mechanism of action-inhibits bacterial cell wall synthesis through disruption of normal protein utilization

Drug structure historically renders them resistant to most beta-lactamases

Page 28: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Polymyxin(s)

Mechanism of action – Surface active agent (detergent) which penetrates into and disrupts the bacterial cell membrane

Example – Colistimethate 150mg powder

Page 29: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Aminoglycoside(s)

Mechanism of action of aminoglycosides is to inhibit bacterial

biosynthesis by binding reversibly to bacterial subunits 30s of the

bacterial ribosome thereby inhibiting translocation of transfer-RNA

(tRNA)

Examples –

Tobramycin 100mg capsule, 2.5% ointment

Gentamicin 80mg capsule, 2.5% ointment

Streptomycin 1 gram powder

Page 30: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Aminoglycoside(s)

Tobramycin, as a drug, often shows activity against a wide

variety of gram-negative bacteria (typically including

numerous Pseudomonas species) as well as a few gram-positive

(including Staphylococcus aureus)

Gentamicin, as a drug, often shows activity against a wide

variety of gram-positive bacteria (occasionally including MRSA) and gram-negative bacteria

(occasionally including certain Pseudomonas species)

Streptomycin, as a drug, often shows activity against a wide variety of gram-positive and

gram-negative bacteria (typically including E. coli, Enterococcus, and Proteus)

Page 31: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Quinolone(s)

Mechanism of action of quinolones is to inhibit DNA

replication and transcription

Newer medications typically have higher number of generation (the

higher the generation, the less resistance is typically seen)

1st Generation Example – Ofloxacin

2nd Generation Example – Ciprofloxacin 90mg capsule

3rd Generation Example – Levofloxacin 3% ointment

4th Generation Example – Moxifloxacin

Page 32: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Quinolone(s)

Ciprofloxacin, as a drug, often shows activity against a limited number of

gram-positive bacteria (typically excluding MRSA) and gram-negative

bacteria (typically excluding certain Pseudomonas species)

Levofloxacin, as a drug, often shows activity against a wide variety of gram-

positive bacteria (typically excluding MRSA) and gram-negative bacteria

Page 33: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Tetracycline(s)

Mechanism of action – inhibit bacterial protein biosynthesis by binding reversibly to the bacterial subunit 30s of the bacterial ribosome thereby inhibiting translocation of peptidyl transfer RNA

Examples – Doxycycline 2.5% ointment, 100mg capsule

Tetracycline 250mg capsule

Topical doxycycline, a synthetic MMP inhibitor (MMPI), to enhance healing of chronic wounds.

Beneficial effects were independent of the antimicrobial effect

Stechmiller J, Cowan L, Schultz G. The role of doxycycline as a matrix metalloproteinase inhibitor for the treatment of chronic wounds. Biol Res Nurs 2010. April;11(4):336–344.

Dixon H. Xu, Ziwen Zhu and Yujiang Fang*, “The Effect of a Common Antibiotics Doxycycline on Non-Healing Chronic Wound”, Current Pharmaceutical Biotechnology (2017) 18: 360. https://doi.org/10.2174/1389201018666170519095339

Page 34: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Lincosamide(s)

Mechanism of action – inhibit bacterial protein biosynthesis by binding reversibly to the bacterial subunit 50s of the bacterial ribosome thereby inhibiting translocation of peptidyl transfer RNA

Example – Clindamycin 1% solution, 300mg capsule

Anaerobic coverage, possesses activity against Staphylococcus aureus

No activity against aerobic gram-negative bacteria

Page 35: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review – Folic Acid Metabolism

• Example –

Sulfamethoxazole 80 mg capsule

Mechanism of action is to inhibit bacterial utilization of PABA (para-

aminobenzoic acid) for the synthesis of folic acid which is an important

metabolite in DNA synthesis

• Example –

Trimethoprim 50mg capsule

Mechanism of action is to block the production of tetrahydrofolic acid

from dihydrofolic acid by binding to and reversibly inhibiting the required

enzyme, dihydrofolate reductase.

Page 36: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review – Nitrofuran(s)

Nitrofurantoin inhibits bacterial DNA, RNA, and cell wall protein synthesis. The mechanism of action is unusual among antibacterial medications, it activated by the bacterial flavoproteins to intermediates that exhibit the anti-infective properties

Example – Nitrofurantoin 25mg capsule

Page 37: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Linezolid

Mechanism of action is to bind to the site on the bacterial 23S ribosomal RNA of the 50s subunit and prevent the formation of a functional 70s initiation complex – which is essential for bacterial reproduction

Active against

VRE

MRSA

Example –

Linezolid 600mg powder

Page 38: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review

– Azole(s)

Clotrimazole, as a drug, often shows activity against a variety of fungi (more limited than Itraconazole/Voriconazole)

Ketoconazole, as a drug, often shows activity against a variety of fungi (more limited than Itraconazole/Voriconazole)

Itraconazole, as a drug, often shows activity against a wide variety of fungi (occasionally including 2 species of Aspergillus)

Voriconazole, as a drug, often shows activity against a wide variety of fungi (typically including all primary species of Aspergillus including niger and terreus)

Page 39: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review – Azole(s)

IV or Oral Azole(s) Problems

Inhibitors of CYP3A4

Estimated up to 50% of all commonly

prescribed drugs are metabolized by

the CYP3A4 enzyme

Elewski B, Tavakkol A. Safety and tolerability of oral antifungal agents

in the treatment of fungal nail disease: a proven reality. Therapeutics

and Clinical Risk Management. 2005;1(4):299-306.

Page 40: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Azoles vs Amphotericin B

Ampho B: Mechanism of action is to bind to the sterol component of a cell membrane

which leads to alterations in cell permeability and cell death although it has a high

affinity for both fungal and mammalian cells thereby often causing redness and

irritation when it comes in contact with human skin

Amphotericin B will not be used in topical deliver systems

Because of Ampho B lack of selectivity towards fungal cells there is a high likelihood of an

adverse reaction following treatment

Page 41: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Drug Review - Naltrexone

Approved for oral use by the FDA for the treatment of opioid addiction

and alcoholism

Naltrexone is a non-selective pure opioid antagonist

Highest affinity for the mu-opioid receptors

Also binds to the kappa, delta, and zeta opioid receptors

For this presentation we are going to focus on Naltrexone’s effects on

the zeta-opioid receptor(opioid growth factor receptor, [OGFr])

Example – Naltrexone 1mg/ml gel

Applied directly onto wound site

Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization. Medical Sciences. 2018; 6(4):82

Li, Z.; You, Y.; Griffin, N.; Feng, J.; Shan, F. Low-dose naltrexone (LDN): A promising treatment in immune-related

diseases and cancer therapy. Int. Immunopharmacol. 2018, 61, 178–184.

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Topical Naltrexone in Wound Healing

Opioid growth factor (OGF), and its unique receptor (OGFr)

OGF is produced by the body tonically (continuous or sustained)

Alterations to this system can increase or decrease cell division

Autocrine and Paracrine effects

OGF is a naturally occurring opioid (chemical name Met5-enkephalin)

Its physiologically effect is to depress cell division when bound to its receptor

OGFr has no resemblance to classic opioid receptors

OGF-OFGr system has been conserved from bacteria to humans

Joseph W. Sassani, Patricia J. Mc Laughlin, and Ian S. Zagon, “The Yin and Yang of the Opioid Growth Regulatory System: Focus

on Diabetes—The Lorenz E. Zimmerman Tribute Lecture,” Journal of Diabetes Research, vol. 2016, Article ID 9703729, 23

pages, 2016. https://doi.org/10.1155/2016/9703729.

Immonen, J. A., Zagon, I. S., & McLaughlin, P. J. (2014). Featured Article: Selective blockade of the OGF–OGFr pathway by

naltrexone accelerates fibroblast proliferation and wound healing. Experimental Biology and Medicine, 239(10), 1300–

1309. https://doi.org/10.1177/1535370214543061

Page 43: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Topical Naltrexone in Wound Healing

OGF is an inhibitory growth factor

When OGF is bound to OGFr cell division is suppressed

Naltrexone blocks OGF from binding to OGFr

Antagonism of the inhibitory effect causes increased cell proliferation

Topically applied Naltrexone increases cell proliferation in diabetic wound models

Increased expression of PDGF, VEGF

Accelerated DNA synthesis

Joseph W. Sassani, Patricia J. Mc Laughlin, and Ian S. Zagon, “The Yin and Yang of the Opioid Growth Regulatory System: Focus on

Diabetes—The Lorenz E. Zimmerman Tribute Lecture,” Journal of Diabetes Research, vol. 2016, Article ID 9703729, 23 pages,

2016. https://doi.org/10.1155/2016/9703729.

McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS. Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment

of Diabetic Wounds. Adv Wound Care (New Rochelle). 2017;6(9):279-288.

Ondrovics M, Hoelbl-Kovacic A, Fux DA. Opioids: Modulators of angiogenesis in wound healing and cancer. Oncotarget.

2017;8(15):25783-25796.

Page 44: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Patient Case #1 69 y.o. Female

Patient has a wound on the lateral plantar area of her right foot

Size: 1cm2

Chronic non-healing wound

IV antibiotics 2 months prior to her getting an Rx from the pharmacy

The wound has a history of MRSA colonization per physician

Culture results showed

MRSA and Pseudomonas Aeruginosa

Page 45: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Patient Case #1

Physician sent over a request for a recommendation for the patient

based on the patient’s Culture and Susceptibility Report

Pharmacist to interpret the results from the C&S Report and identify

therapeutic options that will treat the infection

Spray application was requested

C&S Results:

MRSA: Vancomycin (S), Levofloxacin(S), Tetracycline(S), Methicillin(R),

Penicillin(R)

Pseudomonas Aeruginosa: Tobramycin(S), Gentamicin(S), Ceftazidime(S),

Levofloxacin(S), Ciprofloxacin(S)

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Patient Case #1 Based off C&S report the pharmacist found options that were pharmacologically

effective and covered by the patient’s insurance

Treatment Plan

Linezolid 600mg powder → Protein synthesis (23s of the 50s)

Tobramycin 100mg powder → Protein synthesis (30s)

Ceftriaxone 1gram powder → Cell wall synthesis

Patient would mix all three powders with sterile sodium chloride

The solution was then applied onto sterile gauze to saturate

Medication to be reapplied daily for 1 month

Patient had a follow up in the office 2 weeks out

The wound had completely healed with no remaining signs of infection

Page 47: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Patient Case #2

62 y.o. Male

Chronic venous stasis with ulcerations, peripheral edema, DM, HTN, Morbid obesity, Hyperlipidemia

Patient has had wound care treatment at multiple facilities with little to no success

Powder treatment followed by an ointment was requested

Broad Spectrum coverage was requested

5 wounds on lower left leg

Wound #1: 1.5 x 3.5 x 0.2 cm → Medial ankle

Wound #2: 1 x 2 x 0.2 cm → Anterior shin

Wound #3: 2 x 4 x 0.2 cm → Anterior lateral shin

Wound #4: 1 x 2 x 0.2 cm → Lateral calf

Wound #5: 1 x 2 x 0.2 cm → Lateral calf

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Patient Case #2

Pharmacist to interpret the results from the C&S Report and identify

therapeutic options that will treat the infection

The options need to be affordable to the patient, finding options that are

covered by the patient’s insurance is important

Culture results showed

Staphylococcus Aureus (MRSA)

Pseudomonas Aeruginosa

Enterococcus Faecalis

Morganella Morganii

Proteus Mirabilis

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Patient Case #2

C&S Results:

Staphylococcus Aureus (MRSA): Gentamicin(S), Tetracycline(S), Levofloxacin(R), Oxacillin(R)

Pseudomonas Aeruginosa: Ciprofloxacin(S), Gentamicin(S), Levofloxacin(S), Ceftazidime(S)

Enterococcus Faecalis: Vancomycin(S), Ampicillin(S), Penicillin(S), Gentamicin(R)

Morganella Morganii: Ceftriaxone(S), Ciprofloxacin(S), Gentamicin(S), Levofloxacin(S), Ampicillin(R)

Proteus Mirabilis: Ampicillin(S), Ciprofloxacin(S), Gentamicin(S), Levofloxacin(S),

Treatment Plan

Powder followed by occlusive ointment

Powders

Gentamicin: Protein synthesis(30s)

Doxycycline: Protein synthesis(30s)/MMPI

Levofloxacin: DNA gyrase

Linezolid: Protein synthesis (23s)

Ointment

Mupirocin: Protein synthesis (tRNA)/ Cell wall synthesis

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PAR Form

Patient Assessment Request

(PAR)

Page 51: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Involved Pharmacist improve patient

outcomes Pharmacist will select appropriate anti-infective therapy based off the culture

and susceptibility report

The most effective therapy is selected individually per patient

Pharmacist will find the best therapeutic option for the patient based off their

insurance coverage

Medication that is affordable to the patient is more likely to be filled

Pharmacist will educate the patient on the importance of the treatment and

how to properly use the prescription

Increases patient compliance

Page 52: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

THE TRIAD

Patient

Pharmacist Physician

Relationship

Page 53: Unique Applications for Topical Anti-Infectives in the Treatment of Nail … · Biofilms and Topical Treatments Bacteria capable of forming biofilm are present in up to 80% of all

Andrew Orwick, Pharm.D.

[email protected]

(812) 941-9300