floro and misc drugs Flashcards
Enrofloxacin
-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
Enrofloxacin large animal
– food animal)
* Injectable (SC) solution in cattle &swine (respiratory disease
claims)
Danofloxacin (A180)
* Injectable (SC) solution in cattle
(respiratory disease claims)
Marbofloxacin
- Oral tablets for use in dogs & cats (Zeniquin)
- Otic solution (Aurizon)
- Injectable solution for BRD in cattle (Forcyl
pradofloxacin
Oral tablet (dog) & suspension (cat) (Veraflox)
* Indicated for skin infections and wounds
Ciprofloxacin
-human formulation
– Oral tablets and solution for IV use
– NOTE: Ciprofloxacin is also a metabolite produced from
enrofloxacin metabolism
Fluoroquinolones: Mechanism of Action different than any other microbial
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
Fluoroquinolones: type of drug
- 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
Fluoroquinolones: Spectrum of Activity (true broad spectrum)
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.
Fluoroquinolones: Spectrum of Activity less/not effective
- Less effective against Strep
and Enterococcus - Most anaerobes
– except PRADO - Resistance has emerged for
many isolates – historical
MICs not always accurate
FQ: Mechanisms of Resistance
-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
important notes on resistance
- 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
FQ warning statements
-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.
Fluoroquinolone absorption
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
Fluoroquinolone PK
Distribution
- 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
Fluoroquinolone PK
Elimination
- 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.
FQ Adverse Events:
Association with Streptococcal Shock syndrome and necrotizing fasciitis
- 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.
FQ Adverse Events:
Arthropathies
- 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
FQ Adverse Events:
Retinopathy in Cats
- 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
FQ Adverse Events:
Bone Marrow Suppression
– 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.
FQ Adverse Events Gi and neuro
- GI: relatively mild irritation
- Neuro: Seizures in dogs, cats, horses
– IV injection in horses: administer slowly
– “Baythrill” – ENRO causes hallucinations in people
Metronidazole (nitroimidazole class) formulation, label and dose
- 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
Metronidazole mechanism and spectrum
- 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)
Metronidazole resistance and PK
- 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
metronidazole adverse effects
- 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)
