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PHARMACOLOGY 3 > 10 – Fluoroquinolones > Flashcards

10 – Fluoroquinolones Flashcards

1
Q

What are the fluroquinolones (FQ) licensed for vet med?

A
  • Enrofloxacin (Baytril): small animal and food animal
  • Marbofloxacin
  • Pradofloxacin
  • (Danofloxacin)
  • (Ciprofloxacin: human formulation, ‘cheaper’)
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2
Q

Enrofloxacin (Baytril): small animal

A
  • Oral tablets for dogs/cats
  • Injectable (IM) solution for dogs
  • Otic solution
  • *indicated for treatment of infections associated with bacteria susceptible to enrofloxacin (broad spectrum)
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3
Q

Enrofloxacin and humans

A
  • NONE: for good reasons
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4
Q

Enrofloxacin (Baytril 100): food animal

A
  • Injectable (SC) solution in cattle and swine
  • *respiratory disease claims
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5
Q

Marbofloxacin formulations

A
  • Oral tablets: dogs and cats (Zeniquin)
  • Otic solution (Aurizon)
  • Injectable solution for BRD in cattle (Forcyl)
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6
Q

Pradofloxacin formulation and indications

A
  • Oral tablet (dog) and suspension (cat) (Veraflox)
  • Indicated for skin infections and wounds
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7
Q

What enzymes are needed to change coiling for bacterial DNA replication or transcription?

A
  • Topoisomerase enzymes
    o Topoisomerase II (aka DNA gyrase) binds to dsDNA and supercoils it
    o First cuts it and then re-seals it
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8
Q

What is the mechanism of action of fluroquinolones?

A
  • bind to DNA-DNA gyrase complex
    o Inhibits re-sealing of cut DNA
    o Damaged DNA then destroyed by exonucleases (half unravelled DNA)
  • Also inhibit topoisomerase IV (normally relaxes the DNA supercoils)
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9
Q

FQ length and type of effect

A
  • Long post-antibiotic effect (similar to aminoglycosides)
    o Still inhibits the bacteria even after the drug is gone=allows longer dosing intervals
  • Good evidence of bactericidal effect
  • **concentration (dose) dependent
    o Higher Cmax or AUC to MIC = better efficacy
    o CMax:MIC >10
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10
Q

**Concentration-dependent effect: AUC/MIC

A
    1. Maximize efficacy
      o If not getting high enough exposure=don’t get enough bacterial kill
      o If >250: most patients will be culture negative quickly
    1. Minimize AMR
      o Probability of remaining susceptible remains higher if have a greater exposure (greater AUC/MIC)
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11
Q

FQ are generally effective against

A
  • Some Gram + (Staph): not a go to
  • Most gram –
    o Usually BRD and SRD pathogens
    o *enteric pathogens
  • Some anaerobes: Pradofloxacin
  • Pseudomonas
  • Some mycoplasma, Chlamydia, Rickettsia
  • **REALLY DOES WORK ON A LOT OF BACTERIA
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12
Q

FQ are generally NOT/LESS effective against

A
  • Strep and Enterococcus
  • Most anaerobes: except PRADO
  • Resistance has emerged for many isolates: historical MICs not always accurate
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13
Q

FQ and MICs

A
  • All similar
  • *not like beta-lactams: widely different MICs between different pathogens
  • Lower MIC for some anaerobes to Pradofloxacin (still wont use if first, but good to know)
  • If MIC 1 or less=very achievable
  • *get out of date very fast: so has less value
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14
Q

What are some of the mechanisms of resistance to FQs?

A
  • Chromosomal mechanism (not transferred, but emerge over time)
  • Plasmid-mediated (transferable)
  • *cross-resistance is common (really in most except beta-lactams)
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15
Q

Chromosomal resistance mechanism

A
  • Mutations in topoisomerase genes
    o Single point mutation=minor increase in resistance
    o Subsequent mutations=significant resistance
  • Decreased permeability or increase efflux
  • *occur with selective pressure
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16
Q

What type of exposure or therapy promotes chromosomal resistance?

A
  • Prolonged exposure (chronic low-dose therapy)
  • *do NOT do this
17
Q

What type of dose or therapy is best for FQs? 2 reasons.

A
  • *high dose, short course therapy is most rational
    1. Increase efficacy (concentration-dependent effect)
    2. Minimize emergence of FQ resistance
18
Q

Plasmid-mediated resistance mechanism

A
  • qnr gene: protects DNA gyrase from FQ binding
19
Q

3d Baytril (FQ) vs. 14d Clavamox for an UTI infection

A
  • all the dogs did good, close to 90% success rate
    o no real difference between them
  • *argue=not using either of dosing regimens
    o Not Baytril for a simple infection
    o Clavamox: 7d would be fine
20
Q

What are some FQ warning statements?

A
  • Food withdrawal
    o 36d cattle
    o 8d swine
  • Do NOT use in female dairy cattle 20+ months or older
  • Do NOT use in veal calves
    o Unsure of withdrawal period in preruminating calves
21
Q

What are some warning statements to limit the development of AMR of FQs?

A
  • Baytril 100
    o *should not be used as mass medication in cattle or swine (try to minimize resistance)
    o **only used after first choice treatment has failed (doesn’t like it)
    o Needs to be used with clinical experience and susceptibility testing
    o Do NOT use extra label (large animal products, NOT on small animal but likely should)
22
Q

Fluoroquinolone PK: absorption

A
  • Good oral bioavailability in most (small animal) species
    o Cipro generally lower than Enro
  • Chelation with divalent cations=decrease oral bioavailability (different than with tetracyclines)
    o Not usually an issue, unless mixed/stored with other substances
23
Q

Oral fluoroquinolones in other mixtures (compounding)

A
  • Not as much an issue anymore
  • Mostly compatible in mixtures and generally very stable
  • Ex. Enrofloxacin: actually wasn’t too bad
24
Q

Fluroquinolone PK: distribution

A
  • Not as high as macrolides
  • Lipophilic drug + low protein binding = high distribution to tissues
    o Vd=1-5 L/kg
    o [tissue] generally >/equal to [plasma] (look at LABELS)
  • Taken up by phagocytic cells: antimicrobial activity persists, good for intracellular pathogens (like macrolides)
25
Q

Horses and fluroquinolones

A
  • Used a lot (likely too much)
  • Septicemia/meningitis
  • Pseudomonas ulcers (eye): very good choice
  • pleuropneumonia
26
Q

Fluroquinolone PK: elimination

A
  • Hepatic metabolism
    o ENRO metabolized to CIPRO in dogs, cats, horses
    o Generally comparable antimicrobial activity
    o C&S data usually on has ENRO or CIPRO
  • Excretion:
    o Mostly renal
    o Some biliary
  • *don’t need to change dosing if kidney failure or liver disease
27
Q

FQ half-life

A
  • Typically 4-10hr (slightly longer than other classes)
  • *Once daily dosing is sufficient=very nice
28
Q

Enrofloxacin PK and reptiles

A
  • Reasonable Enro levels, only a little bit of Cipro produced
  • *only for the one specific species the research was one on
29
Q

*PK parameters and efficacy and safety

A
  • PK parameters do not predict efficacy and safety
30
Q

FQ adverse events: association with Streptococcal Shock syndrome and Necrotizing Fasciitis

A
  • When Strep canis is infected by bacteriophage=transfer of genetic material occurs
  • If Enrofloxacin therapy started
    o Enro-mediated bacterial DNA upregulates transcription of proteins to fix the damaged DNA (SOS response)
    o BUT phage genes encode a toxin which is also upregulated
    o *toxic shock response occurs
    o May exacerbated by concurrent NSAID or steroid use
  • *likely just wouldn’t be using FQ to treat Strep (but it also isn’t guaranteed to happen)
31
Q

**FQ adverse events: arthropathies

A
  • Chronic, high dose FQ can cause articular cartilage lesions (juvenile, large breed, dogs and foals)
  • Likely due to chelation of Mg2+
  • *labels: don’t use during rapid growth phase in dogs (1-1.5+ years)
32
Q

FQ adverse events: drug interactions

A
  • CYP enzyme inhibition (Enro/Cipro)
  • P-gp substances
  • *likely not a big deal as wouldn’t be treating FQ with something else for a long period of time
33
Q

Feline ABCG2 transporter genes

A
  • Several AA differences at conserved sites compared to other mammalian species
    o Feline AA sequence appears CONSISTENT in all cats, not just a subpopulation
  • Differences in ABCG2 result in DECREASED transport function
34
Q

**FQ adverse events: retinopathy in cats

A
  • ABCG2 expressed in retinal capillaries
    o Blood-retinal barrier=pumps drugs away
  • Cats have accumulation of ENRO/CIPRO at retina
    o Retinal degeneration or atrophy
    o At SUPRA-therapeutic doses
  • Does NOT occur with Prado
  • Probably does NOT occur with Marbo/Orbi
35
Q

FQ adverse events: bone marrow suspension

A
  • US: Prado suspension approved in cats, contraindicated in dogs
  • Canada: Prado tablets approved for dogs, suspension for cats
  • *varying degrees of leukopenia, anemia and thrombocytopenia
36
Q

FQ adverse events: GI and neuro

A
  • GI: relatively mild irritation
  • Neuro: seizures in dogs, cats, horses
    o IV injection in horses: administer slowly
37
Q

Baythrill: ENRO in humans AE (why we do not use it for humans)

A
  • Causes hallucinations
    o No published incidence or evidence

PHARMACOLOGY 3 (15 decks)

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