Antimicrobial Therapy: Aminoglycosides, Aminocyclitols, and Fluoroquinolones Flashcards
Aminoglycosides
originally isolated form Streptomyces or Mircomonospora
Aminoglycosides:
Spectrum
Gram negative aerobes, some gram positive, NOT streptococcus, NOT anaerobes
Oxygen dependent pathway for bacterial uptake
Pseudomonas - YES
Aminoglycosides:
Concentration
Peak dependent, rapidly bactericidal
Aminoglycosides:
Elimination
Renal
Aminoglycosides:
Use
parenteral only for systemic effects
Often incorporated into topical medications
Oral aminoglycoside only are effective to treat enteric bacteria
Intra-articular, intravenous regional perfusion ot treat joints
Aminoglycosides:
MOA
30s ribosomal inhibitor
Aminoglycosides:
Conditions decreaseing Efficacy
Needs active uptake due to hydrophilicity
Cellular debris, low pH anaerobic conditions decrease bacterial uptake and efficacy
Can be inactivated in vitro by mixing with other antimicrobials, especially beta lactams
Aminoglycosides:
Distribution
excluded from protected environments
Vd larger in neonates = increased doses compared to adults
Low plasma protein binding
Aminoglycosides:
Resistance
inactivating enzymes
Aminoglycosides:
Toxicity
- Renal, otic, could enhance neuromuscular blockade of neuromuscular blockers
- renal toxicity may be reversible if caught early; prior to basement membrane loss of tubules
- renal tubular casts appear first
- If azotemia develops, too late, nephrons lost, will get worse
- Therapeutic Drug monitoring and icrease in half-life is the best indicator of renal toxicity
- renal toxicity may be reversible if caught early; prior to basement membrane loss of tubules
- Minimization of Toxicity
- only administer to hydrated animals
- Drug free intervals
- Minimize duration of therapy
Aminoglycosides:
Gentamicin
- IV, IM, SQ, Intra-articular, Intravenouse regional perfusion and Topicals
- Is actually a mixture of 3 active components, but expressed as a sum on the label
- They are essentially equally active and toxic
- once daily to maximize efficacy / minimize toxicity
- Most commonly used in horses systemically
- Do not administer intra-abdomen for peritonitis
- Intramammary administration results in systemic absorption and violative residues
- Commonly included in otic/opthalmic traetments
- Oral administration results in little systemic absorption
Aminoglycosides:
Amikacin
Same as gentamicin except less susceptible to inactivating enzymes
Therefore you can have a gentamicin resistanct, amikacin susceptible bacteria
No Substantial difference in nephrotoxicity risk
Aminoglycosides:
Neomycin
oral/topical ONLY
PO administration only for enteric infections
With enteritis some drug will be asborded systemically
Labels for food animal use (PO only)
Aminocyclitols:
Spectinomycin
Similar to aminoglycosides, BUT
- not nephrotoxic
- Bacteriostatic
- Less active agianst gram negative
- No efficacy for Pseudomonas
- Effective for Mycoplasma, but many other drugs are too
Poor PO bioavailability
Hydrophilic, does not penetrate protected tissues well
Injection no longer available
DO NOT COMPOUND INJECTION FROM SPECTINOMYCIN POWDER
Fluoroquinolones
Synthetic antimicrobials, not naturally occurring
Spectrum very similar to aminoglycosides
Gram negative aerobes, Pseudomonas, Staphylococcus, Most also have activity against Brucella, Chlamydophila, Rickettsia, +/- mycoplasma
Essentially no Streptococcus and no anaerobes
Newer FQs added anaerobes, and Streptococcus
Rapidly bactericidal, concentration dependent
Fluoroquinolones:
Absorption
PO yes,
Also IV, IM, SQ topical
Fluoroquinolones:
Distribution
widely distributed including protected environments
Fluoroquinolones:
Metabolism
most species vairable metabolize enrofloxacin to ciprofoxacin contributing to its activity
Fluoroquinolones:
Elimination
most elimination by renal mechanisms, marbofloxacin mixed
Fluoroquinolones:
Pharmacokinetic Interactions
most chelate to di- and trivalent cations and cause inactivation
Enrofloxacin appears to be the exception with similar PK with concurrent sucralfate - not assessed with other drugs
Most FQs inhibit some CYP.
Major interaction is with theophyline
Fluoroquinolones:
Mechanism
Bacterial Topoisomerase inhibition
DNA gyrase: introduces negative supercoiling
Topoisomerase: IV, also allows DNA to uncoil
Fluoroquinolones:
Resistance
- No mutaiton = normal
- 1 step topoisomerase 2 mutation:
- MIC increase, but still may be effective dose if appropriate drug/dose used
- 2 step also topoisomerase 4 mutation
- MIC increased further = complete resistance
Fluoroquinolones:
Adverse Effects
- In general, well tolerated
- High doses/concentrations can cuase CNS toxicity and seizures
- avoid in patients prone to seizures
- Young growing animals are susceptible to cartilage damage which can result in permanent damage
- foals and young growing large breed dogs are susceptible
- Retinal toxicity and blindness reported in cats with high doses / concentrations
- Rarely vomiting / diarrhea with high doses
- In humans, tendon injuries are reported
Fluoroquinolones:
Vet label:
Enrofloxacin
dogs, cats, cattle (including non-lactating dairy), swine
Fluoroquinolones:
Vet Label:
Orbifloxacin
dogs and cats
Fluoroquinolones:
Vet Label:
Marbofloxacin
dogs and cats
Extra label: for cattle, horses
Fluoroquinolones:
Vet Label:
Danofloxacin
cattle
Fluoroquinolones:
Vet Label:
Pradofloxacin
cats
Fluoroquinolones:
Human Label:
Ciprofoxacin
not ideal ….
Fluoroquinolones:
Human Label:
Levofloxacin
humans
Food Animal Use
Enrofloxacin:
Cattle for respiratory disease
Swine for respiratory disease and colibacillosis
Danofloxacin:
Cattle not intended for dairy or veal for respiratory disease
NO EXTRALABEL DRUG USE IN FOOD ANIMALS
Enrofloxacin
- Small animal injection, tabs, chewables
- Food animal injection
- Generics available
- Enrofloxacin injection may percipitate in IV fluid line if not diluted
- Large animal formulation is basic and can cause tissue damage,
- in horses, causes mucosal damage when administered PO.
- Sterile abscesses in dogs and cats occur regularly
- Once daily administration for small animlas, horses.
- Cattle can also be administered a single high dose
- Swine administered a single dose
- ELDU in food animals is prohibited
- Human ingestion can result in sever neurologic adverse effects
Marbofloxacin
- Available as tablets, once daily admin.
- Mixed hepatic/renal elimination - no need to dose adjust with renal failure
- May be less likely to cause blindness in cats
- Often has greater activity than other FQs against many gram negative and Pseudomonas
- often 1 fold dilution lower
- Therefore some infections may be treated successfully with marbofloxacin, but not enrofloxacin
- Has a better pharmacokinetic profile than enrofloxacin
Orbifloxacin
liquid and tablet formulations
Approved for dogs and cats, once daily admin.
Similar to other FQs
Overall lower activity vs. other FQs
Pradofloxacin
Approved for cats (suspension)
Enhance spectrum against Streptococcus and anaerobes
Used for dental infections
Otherwise similar to other FQs
Danafloxacin
approved for use in cattle with respiratory disease
No advantages/disadvantages compared to enrofloxacin, except indications
Can be administered as a single injection or split inot q48h injections for 2 doses total
Ciprofloxacin
- Approved for use in humans only, extralabel use allowed in non-food animals
- Poor oral bioavailability in most species
- Vary variable in dogs
- inconsistent absorption linits its effectiveness to only highly susceptible bacteria, results in essentially 10x lower potency compared to enrofloxacin
- Ciprofloxacin generic breakpoint for susceptible
- Enrofloxacin breakpoint is 0.5mcg/ml
- Only reason it is used is because of its low cost, otherwise inferior to other FQs
Levofloxacin
- Human approved, extra label use allowed in non-food animals
- available as tablets and injection
- Primarily used orally in veterinary medicine
- Enhanced spectrum agianst gram positive and anaerobes similar to pradofloxacin
- Otherwise is similar to other FQs
- Good oral bioavailability in dogs and cats
- A generic breakpoint of 0.5mcg/ml for Enterobacteriacease adn 1mcg/ml for Pseudomonas
- pradofloxacin can be used as a surrogate marker on cultures
- remember cirpofolxacin generic breakpoint
