phenicols, sulfas, tetracyclines Flashcards
Florfenicol
FOOD ANIMAL PRODUCTS:
– Nuflor: injectable solution in cattle (IM/SC) & swine (IM)
* Cattle indications: Respiratory disease, footrot, pinkeye DONT USE FOR SIMPLE PINK EYE OR FOOTROT
– Resflor: florfenicol + flunixin (NSAID) injectable solution (SC)
– Zeleris: florfenicol + meloxicam (NSAID) injectable solution (SC
– Aquaflor: medicated premix for salmon
* Indications include Aeromonas & Vibrio infections
-small animal products:
– Osurnia, Claro: ear medications with terbinafine (antifungal) 1/week ear med
Chloramphenicol
– Chlor®Palm 250, Chlor-palmitate (oral suspensions)
* Label claim for various infections in dogs & cats
– Human generic formulations widely used as well
* Oral tablets and suspension
* Injectable (sodium succinate solutions
-banned in food animal, causes aplastic anemia in humans
Phenicols: Mechanism of Action
- Binds to bacterial ribosomal 50S sub-unit
– Causes incorrect tRNA translation
– Disrupts bacterial protein synthesis
BUT: also inhibits mitochondrial protein synthesis in mammalian bone marrow
– Will impact blood cell production
– dose-dependent effect
Phenicols: Spectrum of Activity
- Many Gram (+) species
– Including some MRSA/P - Many Gram (-) bacteria (not gram neg enteric they are usually resistant)
- Many anaerobes, protozia
- Some Mycoplasma
- Some Rickettsia & Chlamydia**
-Enterococcus & E coli MICs may be too high for phenicols to work.
phenicols resistance
Enzymes adding acetyl group
– chloramphenicol acetyltransferases, CAT
– Prevents binding to ribosome 50S subunit
– FLOR less vulnerable to acetylation
- Other resistance mechanisms:
– ↓ phenicol permeability
– ↑ efflux pumps (floR gene in Gram - enterics)
– Mutations to 50S binding sites - Resistance genes are typically mobile
– Plasmids, transposons, etc.
Chlorampheicol
Florfenicol
PK of phenicols bioavailability
Bioavailability:
* Chloramphenicol: Overall good oral
* Florfenicol:
– Prolonged (but variable) absorption after IM/SC
injection
– Flip-flop kinetics: slower rate of elimination but absorption still occurring during elimination phase.
-moderate/ high VD
phenicol’s elimination
- Hepatic metabolism & glucuronide conjugation
– Poor in cats! So longer half-life and dosing interval
– Much longer T1/2 elim in young animals - Primarily renal excretion of inactive metabolites
phenicol pk-pd
Bacteriostatic:
* Very difficult to reach MBC (not safe)
* Considered “time-dependent”
– Limited proof?
– Recommended T>MIC for >50% of dosing interval
Phenicol Drug Interactions
- May be antagonistic with other antibiotics. recommended not to be given with other antimicrobials
Hepatic metabolism interactions:
– Microsomal enzyme inhibitor (CYP)
* Can prolong barbiturate anesthesia (not relevant now)
* Can inhibit metabolism of phenobarb & other CYP-mediated
drugs
- Florfenicol is not known to cause hepatic drug
interactions
phenicols AE and warnings
Blood dyscrasias (aplastic anemia, pancytopenia)
* Decreased production of RBC, WBC, platelets
* Dose-dependent: Can be caused by CPHC or FLOR
– Cause: mitochrondrial protein inhibition in bone marrow
– Occurs in both humans & animal
Related to total phenicol exposure (AUC)
* Both dose and duration are important
– Cats more likely to develop toxicity
- Dose-independent (idiosyncratic)
– Humans – can be fatal
GI adverse events:
* Chloramphenicol: vomit, diarrhea, inappetence:
* FLOR:
– Change in GI normal flora, leads to diarrhea in calves
– Nuflor label: cause diarrhea, anal inflammation.
potentiated sulfonamides
Sulfadiazine (with trimethoprim – aka TMS)
* Uniprim (oral powders/granules)
– Indicated in horses for respiratory / soft tissue infections
Sulfadimethoxine (with ormetoprim)
* Romet 30 (medicated feed for furunculosis in salmon
- Sulfaquinoxaline: oral solution coccidostat for poultry (not antibacterial use)
Sulfonamide Mechanism of Action
Sulfas:
* Structure similar to para-aminobenzoic
acid (PABA)
* Competitive inhibition for enzyme
dihydropteroate synthase (PABA
incorporation into folate pathway)
Diaminopyrimidines mechanism of action
- Trimethoprim, ormetoprim,
pyrimethamine - Inhibits dihydrofolate reductactase
(next step in folate synthesis
-End result: No folate, no bacterial DNA synthesis
Sulfonamides uses
-medicated feeds
-scour boluses
-water soluable preperations
Sulfonamide Mechanism of Action
Sulfas:
* Structure similar to para-aminobenzoic
acid (PABA)
* Competitive inhibition for enzyme
dihydropteroate synthase (PABA
incorporation into folate pathway)
End result: No folate, no bacterial DNA synthesis.
-bacteriastatic
-mammels need folate too but they can utilize dietary folate (vitamin B9) so sulfas arnt toxic to mammels.
-If lots of PABA present bacteria are resistant to sulfa drugs, ex abcesses
Diaminopyrimidines (added with sulfas) mechanism of action
- Trimethoprim, ormetoprim,
pyrimethamine - Inhibits dihydrofolate reductactase
(next step in folate synthesis) blocks both steps, as synergism with sulfa drugs. very effective. bacteriacidal
Sulfonamides: Spectrum of Activity
Highly variable for individual isolates! labeled for many conditions but doesnt mean it will work.
-Gram Positives
-Gram negatives
-anarbobes
-protozoa, coccidia
sulfa not/ less effective agaisnt
Resistance emerges rapidly in
many bacterial species
– Many/most Strep equi, E. coli,
Salmonella isolates now resistant
* Pseudomonas
* Enterococcus
sulfas mechanisms of resistance
Very common!
* May be chromosomal or plasmid-mediated
* Hyper-production of PABA (or in environment)
* Altered dihydropteroic synthase (sulfa) or DHFR
(trimethoprim) enzymes
* Increased production of DHFR
* Reduced drug penetration into bacteria
Notes on resistance:
– Cross resistance between sulfas is typical
– Emerges more slowly with potentiated sulfas than with sulfas alone
Sulfonamide PK
Not uniform between sulfa drugs and species!
* Generally good oral bioavailability
* Distributes into many tissues (Vd = 0.3 – 0.7 L/kg)
– Including CSF, synovial fluid, urine
* Differences in protein binding between sulfas & species
- Elimination:
– Hepatic metabolism (to inactive metabolites)
– Renal excretion (glomerular filtration) - Tubular reabsorption can occur
- ↓ reabsorption with alkaline urine (ion-trapping of acidic sulfa)
PK between sulfas
and diaminopyrimidines!
significant differences in PK Makes optimizing the sulfa:TMP ratio challenging
* Makes C & S results more difficult to interpret
* Differences between vet & human formulations
Sulfonamide Adverse Events hypersensitivity
. Hypersensitivity reactions: * N1 position: associated with type I
hypersensitivity (IgE) reactions
* N4 position: forms reactive metabolites
that can cause direct cytotoxicity or
stimulate an immunologic response
-different types are: blood dysrasisas (hemolytic anemia in horses), arthritis, skin eruptions, hepatic nectosis.
Sulfonamide Adverse Events occular
Keratoconjunctivitis sicca (KCS)
* “Dry-eye” due to ↓ tear production
– Sulfa component toxic to lacrimal acinar cells
– Easy to confirm with Schirmer Tear Test
* Occurs in ~ 15% of dogs treated with sulfas
-resolves when therapy stops.
Sulfonamide Adverse Events renal
Renal damage
* Sulfas are poorly soluble – can precipitate in urine
– Especially with ↓tubular flow (dehydration) or acidic
urine (↓ sulfa solubility)
* Can lead to crystalluria, hematuria, and tubule
blockage
* Not a big problem now, make sure patient is hydrated
