Unique Applications for Topical Anti-Infectives in the Treatment of - - PowerPoint PPT Presentation
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
Andrew Orwick, Pharm.D. Precision Compounding Pharmacy April 26th, 2019
Presenter has no financial or non-financial interest to disclose Status of medications and devices mentioned in this presentation are
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
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
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
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
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
Capsules Powders Gels Ointments Sprays
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
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%
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
Foot Spa with Bubbles & Heat Medications to be mixed into solution
just prior to treatment
Detailed instructions by a pharmacist
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 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.
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.
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.
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
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.
Urea: 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
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
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.
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.
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
No oral or IV options are commercially available
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
As one transitions from 1st Generation to 4th Generation,
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
Drug structure historically renders them resistant to most beta-lactamases
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
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)
Mechanism of action of quinolones is to inhibit DNA
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
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
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
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
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
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
Sulfamethoxazole 80 mg capsule Mechanism of action is to inhibit bacterial utilization of PABA (para- aminobenzoic acid) for the synthesis
metabolite in DNA synthesis
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.
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
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
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)
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.
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
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.
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
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–
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,
McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS. Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment
Ondrovics M, Hoelbl-Kovacic A, Fux DA. Opioids: Modulators of angiogenesis in wound healing and cancer. Oncotarget. 2017;8(15):25783-25796.
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
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)
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
62 y.o. Male
Chronic venous stasis with ulcerations, peripheral edema, DM, HTN, Morbid
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
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
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
Patient Assessment Request (PAR)
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
Patient Pharmacist Physician Relationship