Antimicrobials - NC State Veterinary Medicine...Antimicrobials Amy J. Rankin Diplomate ACVO...

Antimicrobials Amy J. Rankin

Diplomate ACVO

Associate Professor Ophthalmology

Kansas State University

Antimicrobial Agents

• Interpretation of efficacy

• Prophylactic vs therapeutic treatment

• Antibacterial agents

• Antifungal agents

“Best” Antimicrobial

• Legal

• Efficacy

• Safe – patient, owner, consumer

• Available

• Readily administered

• Financial constraints

Terminology

• MBC-Minimum Bactericidal Concentration

– Lowest concentration of an antibacterial agent required

to kill a particular bacterium

– Bactericidal -- MBC is no more than 4x the MIC

• MIC-Minimum Inhibitory Concentration

– Lowest concentration of an antimicrobial drug that will

inhibit visible growth of a microorganism

Terminology

• Breakpoint in vitro

– MIC used to indicate susceptible “S”,

intermediate “I” or resistant “R”

• MIC ˂ breakpoint – S

• MIC > breakpoint – I, R

– Chosen concentration of an antibiotic which

defines whether a species of bacteria is

susceptible or resistant to the antibiotic

• Breakpoint in vivo

– PK/PD =

pharmacokinetics (what the body does to the drug)

pharmacodynamics (what the drug does to the body)

– Empirically based

– Individual variation

• Susceptible

– Infection may be appropriately treated with the

dosage regimen of an antimicrobial agent

recommended for that type of infection

• Intermediate

– infection may be appropriately treated in body sites

where the drugs are physiologically concentrated, or

when a high dosage of a drug can be used

• Resistant

– Strains are not inhibited by the usually achievable

concentration of the agent with normal dosage

schedules and/or microbial resistance mechanisms

likely

T>MIC—optimize the duration of exposure (time-dependent)

Cmax/MIC—maximize concentrations (conc.-dependent)

Antimicrobial Agents

• Concentration dependent

– Effects are proportionate to concentration

– Aminoglycosides, fluoroquinolones, &

amphotericin B

– GOAL: maximize concentrations

Antibacterial Agents

• Time-dependent

– Killing capacity directly linked to exposure

time

– Includes bacteriostatic antibiotics

– Beta-lactams & macrolides

– GOAL: optimize duration of exposure

https//u.osu.edu/beef/2017

Classification of Antibiotics

Bacteriostatic

• Chloramphenicol

• Macrolides

• Sulfonamides

• Tetracyclines

• Trimethoprim

Bactericidal

• Aminoglycosides

• Bacitracin

• Cephalosporins

• Fluoroquinolones

• Gramicidin

• Penicillins

• Polymyxin B

• Vancomycin

Antibacterial Agents

• MOA

– Cell wall synthesis

– Cell membrane integrity

– Protein synthesis

– Folate metabolism

– DNA synthesis

• Gram positive

– Thick cell wall

• Gram negative

– Outer membrane of

LPS & phospholipids

– Thinner cell wall

www.onlinebiologynotes.com

Inhibit Cell Wall Synthesis

• Penicillins

• Cephalosporins

• Bacitracin

• Vancomycin

Penicillin • Thiazolidine ring & a β-lactam ring connected to

a side chain

• 1928 Fleming

• 1940 drug isolated

• Side chain

– PK

– Spectrum

– Susceptibility to destruction

• β-lactam ring

– Binds transpeptidase and inhibits formation of

peptidoglycan

Side chain

Thiazolidine ring

β-lactam

Mechanism of Action Penicillins

Resistance to Penicillins • Bacteria

– Alter their transpeptidases (PBP)

– Decreased penetration of outer cell membrane

– **Production of β-lactamases

• Inactivate the β-lactam portion

• Penicillinases subgroup of bacterial β-lactamases

www.antimicrobe.org

Penicillinase-Resistant Agents

• Methicillin, oxacillin,

cloxacillin,

dicloxacillin, &

nafcillin

• Resist bacterial β-

lactamases

“Superbug”

• Methicillin-resistant S. aureus (MRSA)

• Methicillin-resistant S. pseudointermedius (MRSP)

• Oxacillin is used to test for this resistance

• Altered PBP/transpeptides

• MR Staphyloccus in dogs

with keratitis

– 4X more likely to be owned

by healthcare worker

– 23.5% dogs + nasal culture

www.steemkr.com LoPinto et al., Vet Ophthalmol, 2015

β-lactamase Inhibitors

• Bind to β–lactamase enzyme (irreversible/noncompetitive)

• “Suicide inhibitors”

• Always combined with another β-lactam antibiotic

Riviere & Papich, Veterinary Pharmacology and Therapeutics, 10 Ed.

Clavamox®

• Amoxicillin-clavulanate

– Extends spectrum of amoxicillin to include β-

lactamase-producing bacteria

– 4:1 ratio of amoxicillin:clavulanate

– Augmentin 4:1 or 7:1 ratio

Drug Route Spectrum Drawback

Penicillin G parenteral Gm + Susceptible to

organisms that

produce β-

lactamase

S. Aureus

S. epidermidis

Penicillin V po Gm +

Ampicillin Gm + & Gm - Inactivated by β-

lactamase

Amoxicillin Gm + & Gm -

Carbenicillin

Mezlocillin

Piperacillin

Ticarcillin

Pseudomonas

aeruginosa

Some Proteus &

Enterobacter sp.

Gm -

Cephalosporins • Dihydrothiazine and β-lactam ring connected to

a side chain

• Interfere with peptidoglycan cross-linking

• β-lactam

– Antibacterial activity

– Bind transpeptidase

– Inhibit peptidoglycan

formation

• Side chain

– Determines spectrum Side chain

β-lactam Side chain

dihydrothiazine

Cephalosporins

• Resistance

– Destruction by β-lactamases

– Less susceptible than penicillins

• S. aureus produces penicillinases

• Gm – bacteria produce β-lactamases

– Generation classification – Based on spectrum of activity

Cephalosporin Generations

First Second Third Fourth

Cephalexin Cefamandole Cefoperazone Cefquinome

Cephalothin Cefmetazole Cefotaxime Cefepime

Cefadroxil Cefonicid Ceftazidime

Cephapirin Cefprozil Ceftizoxime

Cefazolin Cefotetan Ceftriazone

Cephradine Cefoxitin Moxalactam

Cefaparin Cefuroxime Cefixime

Cefaclor Ceftiofur

Cefpodoxime

Cefovecin

Cephalosporin Generations

First Second Third

Good Gm + activity

(except Enterococcus)

Good Gm + activity Modest Gm + activity

Modest Gm - activity Improved Gm - activity Improved Gm – activity

(enteric bacteria)

Cefazolin has greatest

Gm - activity

Increased resistance to

β-lactamases

Ceftazidime-

Pseudomonas

aeruginosa

Penicillins and Cephalosporins

• Not commercially available

topically

• Compound cefazolin 5%

solution

• Systemic administration

– Adnexal disease

– Orbital disease

• Wang et al, Vet Ophtho, 2009

• 100% canine isolates-ceftiofur,

ticarcillin

• 78.3% canine isolates-Clavamox

• 100% feline isolates-Clavamox,

ampicillin, cefazolin cefpodoxime

Bacitracin • Good Gm+ activity

• Does not penetrate

cornea

• Not administered

systemically due to

nephrotoxicity

• Inhibits movement of

a peptidoglycan

precursor from

cytoplasm to cell wall www.faculty.ccbmd.edu

Vancomycin

• Glycopeptide (vancomycin, teicoplanin (Europe))

• Good Gm+ activity – Staphylococcus spp. (including MRSA),Streptococcus spp.,

Clostridium difficile, Enterococcus faecium & E. faecalis, Neisseria

• Good Gm + anaerobic cocci

– Not Gm – anaerobes

• Increasing resistance to vancomycin among

MRSA isolates

Vancomycin

• Ophthalmic use

– Topical-infectious keratitis

• First 2 hr after administration 0.52 µl/ml detected in AH

• Therapeutic for most Gm + bacteria

• Levels undetectable by 4 hours

• Recommend 1 drop q 2 hr – Huerva et al., J Ocul Pharmacol, 1993

– Cystoid macular edema after cataract surgery

• Vancomycin 10 µg.ml in the BSS irrigating solution

• 55% of patients vs 19% in control group – Axer-Siegel, et al, Ophthalmolol, 1999

– Intravitreal injection-endophthalmitis

Disrupt Cell Membrane

• Polymyxin B

• Gramicidin

• Similarities btwn. bacterial and mammalian

cell membranes limit systemic use

Polymyxin B

• Spectrum limited to Gm –

– All Gm + resistant

– Aerobacter, Escherichia, Histophilus, Klebsiella,

Pasteurella, Pseudomonas, Salmonella, & Shigella

– Proteus spp. and most Serratia spp. not effective

• Not absorbed from GIT- administered IV

• Poor penetration intact epithelium

• Local hypersensitivity

• Anaphylactic reaction-cats

• Neurotoxic, nephrotoxic

Gramicidin

• Gr + spectrum

• Forms membrane channel

• Stable in solution

• Causes hemolytic anemia if

administered systemically www.nature.com

David & Rajasekaran, J Kidney Cancer, 2015

Affect Bacterial Protein Synthesis

• Aminoglycosides

– Gentamicin

– Neomycin

– Tobramycin

– Amikacin

– Kanamycin

• Tetracyclines

• Macrolides

– Erythromycin

– Azithromycin

– Clarithromycin

• Chloramphenicol

• Oxazolidinones

– Linezolid

Aminoglycosides

• Irreversibly bind to

receptor protein on 30S

subunit

• Disrupt initiation complex

btwn mRNA and 30S

subunit

• Incorporation of incorrect

aa in protein www.faculty.ccbcmd.edu

Aminoglycosides

• Poor oral absorption

• Administered topically or parenterally

• Strong Gm – activity

– P. aeruginosa, Proteus, E. coli,

Enterobacter...

• Gm + efficacy restricted to S. aureus

Aminoglycoside Toxicity

• Nephrotoxicity

– Concentrate in proximal tubule

– Initial subclinical phase

• Decreased urinary concentrating

– Followed by azotemic phase

– Risk factors

• Dehydration, fever, old age, preexisting renal disease

– If identified early aminoglycoside-induced renal injury

can be reversed


• Ototoxicity/Vesibulartoxicity

– Systemic aminoglycoside therapy (rarely topical)

– Localization in hair cells, cochlea, spiral ganglion

neurons, organ of Corti


• Neuromuscular blockade

– Decrease the release of Ach

– Decrease sensitivity of the end-plate to ACh

– Increase clinical duration and time to recovery

with neuromuscular blockers (atracurium

vercuronium) with aminoglycosides

Dupuis et al., Canadian J of Anaesthesia, 1989

Forsyth et al., Am J Vet Res, 1990

Aminoglycosides in Ophthalmology

Topical

• Neomycin

• Gentamicin

• Tobramycin

• Effects on cornea

– Delayed re-

epithelialization,

punctate epithelial

erosions, chemosis

Intravitreal

• Gentamicin

– Chemical ablation

• Amikacin

– Endophthalmitis

treatment (may be

combined with

vancomycin to

increase Gm +

coverage)

Plasma Concentration of Gentamicin

• Post chemical ablation

• 25-40 mg gentamicin

• Mean dose 2.57 mg/kg

• Plasma 0.21 - 9.71 µg/mL

mean 2.15 ± 2.03

Rankin et al., Vet Ophthalmol, 2015

Tetracyclines

• Bind to 30S ribosomal subunit

• Interfere with binding of

aminoacyl-tRNA to

mRNA/ribosome complex

• Interferes with bacterial protein

synthesis

• Binding to ribosome is

reversible drug concentrations

must be maintained

throughout the dose interval

• Tetracyclines have less affinity

for mammalian ribosomes

www.antibitoics-info.org

Tetracycline Side Effects

• Phototoxicity

• Teeth staining

• Esophageal stricture

• Retard fetal skeletal development

www.smiledreammaker.com Foxnew.com

Tetracyclines

• Short acting (t½ 6-8 hr)

– Tetracycline

– Oxytetracycline

• Long acting (t½ 16 hr)

– Doxycyline

– Minocycline

Tetracycline

• Effective – Rickettsia, Borrelia,

Chlamydophilia, Mycoplasma,

Moraxella, Brucella spp. some

Staphylococcus and

Streptococcus spp.

• Generally NOT effective – Pseudomonas

Chlamydophila felis pre and post 3 weeks of oral

doxycycline and topical oxytetracycline/polymyxin B ointment

G5

Additional Tetracycline Benefits

• Anticollegenase activity

– Inhibit MMPs

– Chelate zinc (doxycycline)

• Inhibit IL-1 synthesis

• Inhibit activated B cell function

• Anti-apoptotic and anti-inflammatory

properties

D’Agostino et al., Eur J Pharmacol, 1998

Solomon et al., Invest Ophthalmol Vis Sci, 2000

Kuzin et al., Int Immunol, 2001

• Tetracyclines at ≥ 0.5%

– More effective at preventing

corneal degeneration than

serum in dogs and horses

Tear Film

• Horse doxycycline 20 mg/kg q 24 hr for 5 d

– Detected in tears at low levels (8.21-9.83 µg/mL)

• Pony minocycline 4mg/kg q 12 hr for 5 d

– Detected in tears (mean 11.8 µg/mL)

– Level did not inhibit MMP-2 or MMP-9

Baker et al., Vet Ophthalmol, 2008

Monk et al, Vet Ophthalmol, 2018

Macrolides

• Erythromycin, clindamycin, azithromycin...

• Gm + activity (increase Gm – spectrum azithromycin)

• Chlamydophila , Mycoplasma, & Borrelia spp.

• Enterococci resistant

• Accumulate intracellularly

Macrolides • Bind to 50S ribosome subunit

• Inhibit polypeptide chain elongation

• Inhibit protein synthesis

• Results in decreased growth and multiplication

www.faculty.ccbcmd.edu

Chloramphenicol

• Gm + and Gm – activity

• Rickettsia, Chlamydophila, & Mycoplasma spp.

• Pseudomonas spp. are resistant

• Bacteriostatic but at higher doses may be

bactericidal

Chloramphenicol Side Effects-Humans

• Reversible bone marrow depression

– Dose-related toxic effect

– Mitochondrial injury

– Reticulocytopenia, anemia

– Larger does

– Prolonged treatment

– Plasma concentrations

• 25 µg/ml or higher


• Aplastic anemia

– Idiosyncratic reaction

– Possible genetic predisposition

– Not dose related

– Occur weeks to month after therapy

– Reported in 1:25,000 patients on systemic

chloramphenicol

– Higher risk of leukemia for those who recover

Wellerstein et al., JAMA, 1969


• GI flora produce a nitro reduction

derivative of chloramphenicol

• Derivative induces DNA damage in

replication hematopoietic stem cells

• Pancytopenia

Topical Chloramphenicol

• Aplastic anemia

– First reported in 1960’s in US

Lam et al., Hong Kong Med J, 2002

Walker et al., Eye, 1998

Topical Chloramphenicol

• 1 drop 0.5% chloramphenicol QID to one eye

• Chloramphenicol was NOT detected in the serum from

any of the 40 patients (< 1 mg)

• Epidemiological data do NOT support the occurrence of

blood dyscrasias after topical chloramphenicol

• Population-based prospective case-control surveillance

of aplastic anemia

• 4.2 million people 1980-1995

• Risk is less than 1:1,000,000

Walker et al., Eye, 1998

Laporte et al., Br J Clin Pharmacol, 1998

Oxazolidinones

• Not used frequently in VM

• Gm + aerobe & anaerobes activity

• Linezolid (Zyox®), tedizolid (Sivextro®)

• Humans

– Treat MRSA and drug-resistant Enterococcus

Oxazolidinones

• Bind to 23 S ribosomal RNA of the 50S

subunit

• Prevents formation of 70S subunit

• Inhibits protein synthesis

Oxazolidinones in Ophthalmology

• Studied in rabbits

• Topically applied-0.2%

– Levels in AH, conjunctiva and cornea exceeded MIC

of most Gm + that cause keratitis

• Oral multi-dose protocol

– Intraocular levels exceeded MIC of most Gm+ that

cause endophthalmitis

• Intravitreal

– Effective in experimental model of S. aureus

endophthalmitis (30 mg)

– No retinal toxicity Saleh et al., J Ocul Pharmacol Ther, 2011

Saleh et al., J Cataract Refract Surg, 2010

Saleh et al., Invest Ophthalmol Vis Sci, 2012

Alter Bacterial Folate Metabolism

• Sulfonamides

• Trimethoprim

• Gm + and some Gm -

• Folate

– Necessary for DNA/RNA

synthesis

– Mammals acquire folate

or folic acid in food

– Bacteria synthesize folate

www.basicmedicalkey.com

Sulfonamide Toxicity -KCS

• Direct toxic effect on

lacrimal cells by the N

containing rings

• Dose-dependent

• Idiosyncratic

• Estimated incidence is

15-25%

• Other signs of toxicity

– Hepatotoxicity

• May be reversible

Affect Bacterial DNA Synthesis

• First generation fluoroquinolone

– Nalidixic acid

• Moderate Gm – and Gm + activity

• Second generation fluoroquinolones

– Lomefloxacin, norfloxacin, enrofloxacin

ciprofloxacin, & ofloxacin

• Gm – and Gm + activity

• Increasing resistance in human ophthalmology

Affect Bacterial DNA Synthesis

• Third generation fluoroquinolone

– Sparfloxacin, gemifloxacin, & levofloxacin

• Fourth generation fluoroquinolones

– Gatifloxacin, moxifloxacin, & besifloxacin

– Increased Gm + spectrum relative to earlier

fluoroquinolones

Fluoroquinolones

Generation Drug Spectrum

First Nalidix acid Gm-

Second Lomefloxacin, norfloxacin,

enrofloxacin, ciprofloxacin,

ofloxacin

Gm – and some

Gm +

Good activity

Pseudomonas

Third Sparfloxacin, gemifloxacin,

levofloxacin, pradofloxacin

Gm- & increased

Gm + and

anaerobes

Fourth Gatifloxacin, moxifloxacin,

besifloxacin

Gm- & increased

Gm + to earlier

fluoroquinolones

Efficacy for

MRSA, &

resistant

Pseudomonas

strains

Fluoroquinolone Targets • DNA is tightly coiled

• Topoisomerase II (DNA gyrase) Gm -

– Allows the DNA strands to be cut and reconnected

– To facilitate coiling, winding, and unwinding

• Topoisomerase IV- Gm +

– Relaxes supercoils that accumulate ahead of DNA

commons.wikimedia.org

Fluoroquinolone Targets

• Topoisomerase II-DNA gyrase

– Relaxes the supercoiled chromosome

– A and B subunits

– Most common target for quinolones is A subunit coded

by gene gyrA

– Mammals resistant because topoisomerase II inhibited

until drug reaches 100-1000 µg/ml

– Bacteria inhibited concentration of 0.1-1.0 µg.ml or less

– Gm - bacteria


• Topoisomerase IV enzyme

– Consists of subunits parC and parE

– Introduces single-stranded break in chromosome to

release them from each other then reseals the DNA

– Gm + bacteria (not present in all bacteria)

writepass.com


• Newer generation fluoroquinolones

– Gm – bacteria

– Increased Gm + spectrum

– Target DNA-gyrase for Gm+

– Some have dual inhibitors

• Older fluoroquinolones

– High activity against DNA gyrase

– Gm – bacteria

– Less activity against topoisomerase IV of Gm +

Fourth Generation Fluoroquinolones

• Besifloxacin ophthalmic suspension 0.6%

– Inhibits both topoisomerase II and IV

– Low potential for resistance in vitro

– Gm +, Gm -, anaerobes, MRSA, MRSE

• Labeled to treat bacterial conjunctivitis

• Cost

Math & sanfilippo, Ophthalmol Ther, 2016

Fluoroquinolones Vet Ophthalmology

• Moxifloxacin higher AH concentrations than

ciprofloxacin and detectable in plasma in normal

horses

• Moxifloxacin higher in tears, cornea, and AH

than ciprofloxacin in horses

• Ofloxacin higher corneal penetration and ability

to exceed MIC90 than ciprofloxacin in dogs

Clode et al., Am J Vet Res, 2010

Westermeyer et al., Am J Vet Res, 2011

Yu-Speight et al, Vet Ophthalmol, 2005

Fluoroquinolone Side Effects

• Formation of corneal

precipitates

– 17.6% in humans

• Case report-dog

– 13 yo Yorkie

– 2 week levofloxacin

• Corneal cytotoxicity

– In vitro

• Delayed wound healing

– In vivo

Park et al, Vet Ophthalmol, 2015

Fluoroquinolone Side Effects

• In vitro decreased cell proliferation

– 1.5% levofloxacin lowest values

• In vivo delayed wound healing

– 1.5% levofloxacin & 0.5% moxifloxacin

• In vivo effects on cell migration in tissue culture

– Cells treated with ciprofloxacin and cefazolin had the

greatest effects on morphologic characteristics

Fukuda & Sasaki, J Ocul Pharm, 2015

Hendrix et al., Am J Vet Res, 2001

www.tuyenlab.net

Methods of Resistance • Modify the antibiotic

– Enzyme induced acetylation,

adenylation, phosphorylation

of antibiotic

• Prevent antibiotic from

reaching target

– Active efflux pumps

– Alteration of porin channels

• Modification of target

– Binding proteins

– Chromosomes

– Ribosomes

healthbeat.spectrumhealth.org

Mechanism of Resistance

• Transformation

– DNA uptake

• Transduction

– Bacterial DNA

transferred by viruses

• Conjugation

– Transfer DNA between

bacteria

Antifungal Agents

• Inhibit DNA/RNA synthesis

– Pyrimidines

• Alter cell membrane permeability

– Polyenes

• Alter cell membrane stability

– Allylamines

– Azoles

• Alter cell wall stability

– Echinocandins biologydiscussion.com

Researchgate.net

Inhibit DNA/RNA Synthesis

• Pyrimidines

– 5-Fluorocytosine

– Limited spectrum for filamentous organisms

– Better spectrum for yeast organisms

– Not generally appropriate as monotherapy

– Block thymidine synthesis

– Fungistatic

Inhibit DNA/RNA Synthesis • 5-Fluorocytosine 5 fluorouracil by cytosine deaminase

in fungal cell then to 5-fdUMP (inhibits thymidylate

synthase & DNA synthesis) and 5-FUMP (incorporated

into fungal RNA)

• Selective toxicity for fungi

• Resistance is common

• Toxicity

– Dose dependent

– Serum 100 mg/L

– Bone marrow toxicity

– Hepatotoxicity

– GI

drfungus.org

Alter Cell Membrane Permeability

• Polyenes

– Natamycin, Amphotericin B

– Fungistatic/cidal depending on concertation

– Resistance is uncommon

– Broad spectrum

– Poor corneal penetration through intact

epithelium

Polyenes Mechanism of Action

• Bind cell membrane

ergosterol polyene-

sterol complex

increase permeability

cell lysis

step1.medbullets.com

Natamycin

• Only approved topical ophthalmic

– 5% natamycin suspension-Natacyn®

• Expensive!!! ~$ 375

• Rabbits-

– Intracameral

• Corneal decompensation and iridocyclitis

– Intravitreal

• 25 µg nontoxic but unlikely to be therapeutic

• 50 µg marked retinal toxicity

Amphotericin B • Poor bioavailability if administered po

• Deoxycholate colloidal suspension IV

– Renal, hepatic, and hematologic toxicities

• Liposomal, lipid complex, colloidal dispersion

– Reduce systemic toxicities

– Comparable clinical efficacy

• Topical administration

– Ocular surface irritation/discomfort

• Subconjunctival injection

– 0.2 ml 5% solution q48 hr 3 doses

Alter Cell Membrane Stability

• Allylamines

– Terbinafine

• Azoles

– Imidizoles

• Clotrimazole

• Miconazole

• Ketoconazole

– Trizaoles

• Itraconazole

• Fluconazole

• Voriconazole

• Posaconazole

Alter Cell Membrane Stability

• Allylamine

– Inhibits squalene epoxidase

– Decreases ergosterol

synthesis

• Azoles

– Inhibit cytochrome P450-dep

enzyme 14α-sterol

demethylase

– Decreases ergosterol

synthesis

cellpress.com

Terbinafine • Lamisil®

• Highly fungicidal

• High oral bioavailability

• Toxic intracellular accumulation of squalene

• Extremely fungal specific

Terbinafine

• Strong in vitro spectrum of activity

– Aspergillus and Fusarium strains

• Synergism with other antifungals (azoles)

• Lipophilic nature

– Stratum corneum, hair follicles, nails...

– 12 days or therapy concentration 75X higher in

stratum corneum than in plasma

• Dermatophytosis

• Malassezia dermatitis

Topical Ophthalmic Terbinafine

• 0.2% terbinafine in corn oil ointment rabbits

– Measurable AH levels – peak 30 min

• 0.2% terbinafine solution equine

– One eye 0.2 mL q 4 hr for 7 doses

– No detectable AH or plasma levels

• Topical terbinafine human keratomycosis

– Retrospective study 90 patients

– 89% favorable response terbinafine 93% natamycin

• Case report rabbit 1% terbinafine ointment

Sun et al., Ophthalmic Research, 2007

Clode et al., Vet Ophthalmol, 2011

Liang et al., Chin Med J (Engl), 2009

Bourguet et al., Vet Ophthalmol, 2016

Topical Ophthalmic Terbinafine

• 2 yo FS dwarf rabbit

• Aspergillus fumigatus

• 8 week therapy QID

• 1% terbinafine ointment

Azoles

• High safety profile

• Broad spectrum of activity

• Topical, oral, and IV formulations

• Inhibit 14α-sterol demethylase

– Inhibits conversion of lanosterol to ergosterol

• Decrease cytochrome P450 metabolism

– Important for drug interactions

Azoles in Ophthalmology

Azole Spectrum Route Corneal

Penetration

Ketaconazole Good: yeast

Poor: filamentous

Oral

Topical

Good

Miconazole Good: yeast, filamentous Topical

Subconj

Good

Fluconazole Poorer efficacy for yeast

& filamentous compared

to other azoles

Oral

Topical

Good

Itraconazole Good: yeast, filamentous Oral

Topical

Poor

Voriconazole Good: yeast, filamentous Oral

Topical

Intravitreal

Intrastromal

Subconj

Good

Voriconazole in Horse Route Dose Other

Oral 4 mg/kg single dose (Clode)

3 mg/kg q12hr x 10 days (Colitz)

4 mg/kg q24hr x 14 days (Passler)

Measurable AH levels

Measurable PTF levels

Measurable AH levels

Topical 0.5%, 1%, 3% q 4hr x 7 doses (Clode) Measurable AH levels

3% topical irritation

Intrastromal

Subconj

(5%) 22.5mg intrastromal (Smith et al.)

(1%) 0.5mg intrastromal + 4mg SC (Tsujita)

et al.)

(1%)1.5mg intrastromal + 5 mg SC (Tsujita)

Clinical resolution of

stromal abscess

Clode et al., Am J Vet Res, 2006

Colitz et al., Am J Vet Res, 2007

Passler et al., J Vet Pharmacol Ther, 2010

Smith et al, Vet Ophthalmol, 2014

Tsujita et al., Vet Ophthalmol, 2013

Systemic Antifungals Horse Drug Dose Other

Fluconazole 14 mg/kg PO once then

5 mg/kg PO q24 hr

Good intraocular

penetration; spectrum

more limited than other

azoles

Itraconazole 1.5 mg/kg IV q 24 hr IV route preferred-

variable absorption of

drug if administered PO

Good intraocular

penetration

Gilger, Equine Ophthalmology, 3rd Ed

Voriconazole Midwest & Southern US

• In vitro susceptibility of Aspergillus & Fusarium

Pearce et al., Vet Ophthalmol, 2009

V M N I F K

Alter Cell Wall Stability

• Echinocandins

– Caspofungin

– Micafungin

– Anidulafungin

• Fungistatic/cidal

• Inhibit β-1,3-glucan synthase which is

responsible for the formation of the essential

fungal cell wall component glucan

Echinocandins

• Fungicidal activity Candida

• Fungistatic Aspergillus & other filamentous

• Poor activity Fusarium

• Poor bioavailability

• Limited studies using animals

– Reasonable intraocular penetration after IV

administration

Echinocandins in Ocular Therapeutics

• Topical 0. 5% caspofungin was as efficacious as

0.15% amphotericin B C. albicans keratitis rabbits

• Intravitreal 0.1% caspofungin effective for

treatment of fungal endophthalmitis rabbits

• Caspofungin safe and nontoxic at vitreal

concentrations of 5 µg/mL mouse

• Topical micafungin as effective as natamycin

Aspergillus keratitis rabbit

Goldman et al., Antimicrob Agents Chemother, 2005

Kusbeci, Curr Eye Res, 2007

Mojumder et al., Invest Ophthalmol Vis Sci, 2010

Trujillo et al, Invest Ophthalmol Vis Sci, 2004

Antimicrobials - NC State Veterinary Medicine...Antimicrobials Amy J. Rankin Diplomate ACVO...

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