floro and misc drugs

Question 1

Enrofloxacin

Answer 1

-baytrill Small animal
* Oral tablets for dogs/cats
* Injectable (IM) solution for dogs
* Otic solution
* “Indicated for the treatment of
infections associated with bacteria
susceptible to enrofloxacin

Question 2

Enrofloxacin large animal

Answer 2

– food animal)
* Injectable (SC) solution in cattle &swine (respiratory disease
claims)

Danofloxacin (A180)
* Injectable (SC) solution in cattle
(respiratory disease claims)

Question 3

Marbofloxacin

Answer 3

• Oral tablets for use in dogs & cats (Zeniquin)
• Otic solution (Aurizon)
• Injectable solution for BRD in cattle (Forcyl

Question 4

pradofloxacin

Answer 4

Oral tablet (dog) & suspension (cat) (Veraflox)
* Indicated for skin infections and wounds

Question 5

Ciprofloxacin

Answer 5

-human formulation
– Oral tablets and solution for IV use
– NOTE: Ciprofloxacin is also a metabolite produced from
enrofloxacin metabolism

Question 6

Fluoroquinolones: Mechanism of Action different than any other microbial

Answer 6

inhibits bacterial DNA function:
* Bacterial DNA is tightly wound
(supercoiled) inside cell
– Requires topoisomerase enzymes** to change
coiling for DNA replication or transcription
* Topoisomerase II (aka DNA gyrase) binds
to double-stranded DNA & supercoils it:
– First cuts DNA
– Passes other DNA strand through the break
– Then re-seals the cut DNA

Bacterial DNA inhibition:
* FQs bind to DNA – DNA gyrase complex
– Inhibits re-sealing of cut DNA
– Damaged DNA then destroyed by exonucleases
* FQs also inhibit topoisomerase IV
– Enzymes which relaxes the DNA supercoils

Question 7

Fluoroquinolones: type of drug

Answer 7

• Long post-antibiotic effect (even after drug [ ] drops the bacteria is still inhibited for a period of time)
• Good evidence of bactericidal effect
• Concentration (dose)-dependent*** (like aminoglycosides)
  – Cmax : MIC > 10
  – AUC : MIC > 125
  -use this to maximize efficacy, and reduce AMR

Question 8

Fluoroquinolones: Spectrum of Activity (true broad spectrum)

Answer 8

Generally effective:
* Some Gram (+) species (Staph**) but not a go to gram +

• Most Gram (-) bacteria
  – Usual BRD & SRD pathogens
  – Enteric pathogens best to use floros for from - and these are they are hard to treat with other classes
• Pradofloxacin – some anaerobes
• Pseudomonas (esp. CIPRO)**
• Some Mycoplasma, Chlamydia,
  Rickettsia but need high dose and duration, or chloramphenicol are only ones that may treat mycoplasma, probably use these over floras.

Question 9

Fluoroquinolones: Spectrum of Activity less/not effective

Answer 9

• Less effective against Strep
  and Enterococcus
• Most anaerobes
  – except PRADO
• Resistance has emerged for
  many isolates – historical
  MICs not always accurate

Question 10

FQ: Mechanisms of Resistance

Answer 10

-Chromosomal mechanisms: not transferred between species, but emerge over time DONT LOW DOSE OR UNDERDOSE
* Mutations in topoisomerase genes
– Single point mutation = minor ↑ in resistance
– Subsequent mutations = significant resistance
* ↓ permeability / ↑ efflux

-Plasmid-mediated (transferable):
* qnr gene: protects DNA gyrase from FQ binding

Question 11

important notes on resistance

Answer 11

• Cross-resistance between FQs is common
• Chromosomal mutation occurs with selective pressure:
  Prolonged exposure (chronic low-dose therapy)
  promotes chromosomal resistance
• SO DON’T DO THIS!!
  pp
• High dose, short course therapy is most rational:
  – ↑ efficacy (concentration-dependent effect)
  – Minimize emergence of FQ resistance

Question 12

FQ warning statements

Answer 12

-category 1 antimicrobials, very important in human med. not a last line drug when nothing else works, but use for specific cases.
– don’t use on every animal in the pen or every small animal which comes into your clinic but can work great for individual therapy.
-not good to use them after your first antimicrobial choice has failed, won’ work after treatment failure.
-baytrill 100: should not be used as mass medication cattle/swine. do not use extra label.

Question 13

Fluoroquinolone absorption

Answer 13

Absorption:
* Good oral bioavailability

• Chelation with divalent cations = ↓ F
  – Not usually an issue, unless FQ mixed with other substances

Drug Interactions
* CYP enzyme inhibition (ENRO/CIPRO)
* P-gp substrates

Question 14

Fluoroquinolone PK
Distribution

Answer 14

• Lipophilic drug + low protein binding = high distribution to tissues.
  – [tissue] generally ≥ [plasma]
• Including CSF & prostate (good for meningitis=off label, prostatitis)
  -better than macrolides for vd because high Vd and high in tissues/ plasma, more balanced.
• FQ taken up into phagocytic cells
  – Antimicrobial activity persists, good for intracellular
  pathogens

Question 15

Fluoroquinolone PK
Elimination

Answer 15

• Hepatic metabolism:
  – ENRO metabolized to CIPRO in dogs, cats, and horses. enrofloxacin metabolized to ciprofloxacin, so if you give enro you will get cipro. matters with what susceptibility panel you are sending to, use vet lab not human lab won’t include cipro.
• Excretion:
  – Mostly renal (filtration + tubular secretion)
  – Some biliary excretion
  -safe for kidney failure and hepatic disease.
• T1/2 elim typically between 4 – 10 h
  – dose Once-daily is good. so good compliance.
  -marketing saying new floros are better but they are all good.

Question 16

FQ Adverse Events:
Association with Streptococcal Shock syndrome and necrotizing fasciitis

Answer 16

• When Strep canis is infected by a bacteriophage, transfer of genetic material occurs
• If enrofloxacin therapy is started:
  – Enrofloxacin-mediated bacterial DNA damage upregulates transcription of proteins to fix the damaged DNA (the “SOS” response)
  – BUT: Phage genes encode a toxin which is also upregulated
  – Toxic shock response occurs***
  – May be exacerbated by concurrent NSAID or steroid use

-treating any streptococci with floroquinolones bad idea, if strep canis can treated with enro can lead to TTS, not always.

Question 17

FQ Adverse Events:
Arthropathies

Answer 17

• Chronic, high dose FQ can cause articular cartilage lesions
  – Juvenile dogs (esp. large breed)
  – Foals
• Likely due to chelation of Mg2+
• FQ labels: Don’t use during
  rapid growth phase in dogs
  – Small/medium: 2 – 8 mo
  – Large: up to 1 year
  – Giant: up to 18 months

Question 18

FQ Adverse Events:
Retinopathy in Cats

Answer 18

• Feline ABCG2 transporter gene in ALL CATS:
  – feline ABCG2 result in ↓ transport function

– ABCG2 expressed in retinal capillaries
* Blood-retinal barrier → pumps drugs away

– Cats have accumulation of ENRO/CIPRO at retina
* Retinal degeneration or atrophy, at supra-therapeutic doses (20mg/kg) 8x label dose.

– Does not occur with PRADO (so far) probably not with MARBO / ORBI

Question 19

FQ Adverse Events:
Bone Marrow Suppression

Answer 19

– USA: PRADO suspension approved in cats, contraindicated in dogs.
– CANADA: PRADO tablets approved for dogs, suspension for cats.

-CDN: veraflox tablet overdosing (9x label dose) in dogs caused bone marrow suppression.

• US Veraflox label (cats): DO NOT USE IN DOGS, can show bone marrow suppression.

Question 20

FQ Adverse Events Gi and neuro

Answer 20

• GI: relatively mild irritation
• Neuro: Seizures in dogs, cats, horses
  – IV injection in horses: administer slowly
  – “Baythrill” – ENRO causes hallucinations in people

Question 21

Metronidazole (nitroimidazole class) formulation, label and dose

Answer 21

• Formulations:
  – NEW: Eradia oral suspension, great for dosing
• For the treatment of Giardia duodenalis infection in dogs
• Not licensed (yet) for bacterial infections in animals, lisenced as antiprotozoal but we use off label as antibiotic
  – Dose typically 10 – 15 mg/kg BID
  – Lower dose than label Giardiasis dose

– Human products: Oral tablet,
injectable solution, topical cream

Question 22

Metronidazole mechanism and spectrum

Answer 22

• Mechanism: Intracellular anaerobic**
  metabolism of drug produces reactive
  metabolites, leading to DNA damage
• Spectrum of activity: used for anarobes
  – ANAEROBES! (Clostridium, Bacteroides,
  Brachyspira)
  – Protozoa (Trichomonas, Giardia)

Question 23

Metronidazole resistance and PK

Answer 23

• Resistance:
  – Rare, but can occur with ↓ intracellular drug activation
  – Cross-resistance between nitroimidazoles
• PK:
  – Generally good oral bioavailability (fed or fasted is OK)
  – Vd ~ 1 L/kg, penetrates many tissues (incl. CSF, bone)
  – Elimination:
• Hepatic metabolism
• Elimination in bile and urine

Question 24

metronidazole adverse effects

Answer 24

• Potentially carcinogenic**
• BANNED FOR USE IN FOOD ANIMALS

– May be teratogenic – avoid in pregnant animals

– Minimal GI upset (~15% of dogs); may cause salivation, inappetence

– Neurotoxicity: ataxia, seizures, lethargy
* Mechanism not well understood
* Stop therapy, administer diazepam

– Drug interactions: Caution if used with hepatic enzyme substrate drugs (CYP inducers/inhibitors)

Question 25

Nitrofurans formulation, mechanism, spectrum

Answer 25

• Formulations: Veterinary (nitrofurazone)
  – Topical products (wound dressing, ointment)
  – Solution for intrauterine use in horses
• Formulations: Human (nitrofurantoin) for UTI small animals
• Mechanism:
  – Block bacterial pyruvate metabolism (energy production)
• Spectrum of activity:
  – Broad spectrum, but especially gram-negative enterics
  – But can’t use for systemic infections***: Reaching MIC levels in plasma requires doses that produce systemic toxicity!

Question 26

nitrofurans resistance/ PK

Answer 26

• Resistance: Does occur, but generally no cross-
  resistance with other antimicrobial classes, have to ask lab to test not on panel.
• PK:
  – Good oral absorption
  – Wide distribution in body
  – Excretion: RENAL*** (high concentrations in urine)
• So low oral dose can be used, yet still get high [urine]

Question 27

nitrofurans AE

Answer 27

• Adverse events:
  – Cardiomyopathy (ventricular dilation)
  – Reproductive (endocrine) toxicity

– CARCINOGENICITY:
* BANNED FOR USE IN FOOD ANIMALS

Question 28

Nitrofurans uses

Answer 28

– Nitrofurazone: Found in wound creams & solutions
* Topical or intrauterine/intravaginal use (horses)
* NOT FOR FOOD-PRODUCING ANIMALS

– Nitrofurantoin: has been used to treat E. coli / MDR UTIs in dogs & cats, not first line but if multi drug resistant pathogen this can be a treatment

Question 29

Rifampin mech/ spectrum

Answer 29

-formulation: human tablets

• Mechanism:
  – Inhibits bacterial RNA polymerase
  – Penetrates leukocytes, kills intracellular pathogens ** TUBURCULOSIS
  – Bacteriostatic, time-dependent antimicrobial activity
• Spectrum:
  – Broad spectrum, but resistance is prevalent (esp. Gram -)
  – Uses: Mycobacterium (tuberculosis), Staph isolates, Rhodococcus equi pneumonia in foals*
  – Resistance emerges rapidly***, so typically used along with macrolide (erythromycin) or other antibiotic

Question 30

Rifamycins (Rifampin) resistance and PK

Answer 30

Key points:
* Resistance: A single amino acid change in bacterial
RNA polymerase reduces rifampin binding

• PK:
  – Good oral absorption in most species
  – Wide distribution to variety of tissues
  – Hepatic metabolism
  – Biliary and renal excretion

Question 31

Rifamycins (Rifampin) AE

Answer 31

– Red-tinged fluids (urine, sweat, saliva, etc.)
* Not actually a health concern

– Hepatic CYP and P-gp enzyme induction
* ↑ clearance of other drugs

– Teratogenic (don’t use in pregnant animals)

– Blood dyscrasias (rare) – anemia, ↓ platelets

Question 32

Glycopeptides (vancomycin) formulation, mechanism, spectrum

Answer 32

• Formulations: all human
  – oral tablets, injectable solutions
• Mechanism of action:
  – Inhibit peptidoglycan synthesis needed for cell wall
• Spectrum of activity:
  – Gram (+) rods and cocci
• Especially methicillin-resistant Staph, Enterococcus**
  – Gram (-) bacteria typically resistant
  -should be staying away from this one, leave for human medicine.

Question 33

Glycopeptides (vancomycin) resistance, PK, AE

Answer 33

• Resistance: Major human health concern!**
  – Vancomycin-resistant Enterococci (VRE)
  – MRSA with ↓ susceptibility to vancomycin
  – Plasmid-mediated vanA gene changes target binding site
  -try not to use, leads to AMR, save for human med
• PK:
  – Poor oral absorption, limited tissue distribution
  – Excreted via glomerular filtration
• Dosage adjustments needed for renal failure patients
• Adverse events:
  – Very irritating upon injection – administer slowly IV
  – Potentially nephrotoxic, ototoxic, allergenic

Question 34

Polymyxin B mechanism, spectrum, AE

Answer 34

• Mechanism: “cationic detergents” – bind to cell
  membrane and disrupt its structure
• Spectrum: active against Gram (-) bacteria only*** will see it added to other microbial so it covers the gram -
• Adverse events: Wide range of toxicity with systemic administration, use topically

Question 35

Bacitracin spectrum, mech, formulation

Answer 35

• Active against Gram (+) bacteria**
• Mechanism similar to β-lactam antibiotics
• Found in topical formulations
  – BNP “triple ointment” with Polymyxin B and neomycin
• Also used in feed premixes in poultry & swine
  – Growth promoter, prevention of clostridial enteritis

Question 36

Fusidic Acid mech and uses

Answer 36

-mech: Inhibits bacterial protein synthesis

Isaderm germ (fusidic acid + betamethasone)
* Indicated for superficial pyoderma (hot spots) good local topical therapy.
* Most Staph are susceptible (including MRSP)**

Question 37

Mupirocin mech, spectrum, uses

Answer 37

-mech: Blocks bacterial protein synthesis
* Rapidly metabolized after systemic administration
– So only used topically, typically for Staph infections*
* Intranasal use for nasal MRSA carriers
* Good penetration into infected tissues
* Only human formulations approved in Canada
– Muricin® licensed for pyoderma in dogs in US