8b – Sulfonamides Flashcards
1
Q
Sulfa formulations (potentiated and non-potentiated)
A
- Companies use different components based on what is available and will depend on the formulation they want
- NO crazy big differences
- *sometimes use a human generic TMS tablet formulation
- *some NOT used as an antibiotic
- Medicated feed, boluses, water preparations
2
Q
Used in large animal
A
Trimidox
Borgal
*IM or SC
3
Q
What are sulfas mechanism of action?
A
- Structure is similar to para-aminobenzoic acid (PABA)
o Competitive inhibition for enzyme dihydropteroate synthase (PABA incorporation into folate pathway - *not going after bacterial cell wall, or bacterial protein synthesis
- **BLOCK SYNTHEISIS OF dihydrofolate (pre-cursor steps): bacteriostatic
4
Q
Diaminopyrimidines (what is added to potentiated sulfas): things ending in ‘oprim’
A
- Trimethoprim, ormetoprim, pyrimethamine
- *inhibits dihydrofolate reductase (next step in folate synthesis)
- **do not get tetra-hydrofolic acid=NO DNA synthesis
- **BOTH: block DNA synthesis (more bacteriocidal)=A LOT MORE POTENT
5
Q
So why aren’t sulfa drugs toxic to us?
A
- Utilize dietary folate (Vitamin B9)
o *don’t need to SYNTHESIZE IT - SAFE for us in terms of folate production
6
Q
What are some implications with sulfas being a competitive inhibitor of PABA?
A
- If lots of PABA available in local environment, bacteria will be RESISTANT to sulfa drugs
o Ex. abscess=sulfas NOT effective
7
Q
What is generally susceptible to sulfonamides?
A
- Some gram + isolates
- Some gram – isolates
- Many anaerobes: likely NOT the best choice (penicillin’s or cephalosporins used more likely)
- *Some protozoa and coccidia (ex. in poultry)
8
Q
What is generally NOT/LESS effective to sulfonamides?
A
- Resistance emerges RAPIDLY in many bacterial species
o Many/most Strep equi, E. coli, Salmonella - Pseudomonas
- Enterococcus
9
Q
Synergism of sulfas and trimethoprim
A
- Makes them very potent when used together
o POTENTIATION - *sum of both drugs together is much GREATER than if you just ‘added’ them
10
Q
Sulfas spectrum of activity
A
- Many of the labels are OLD and are labelled for lots of infectious condition
- *highly variable for individual isolates
11
Q
What are some mechanisms of resistance against sulfonamides?
A
- Chromosomal or plasmid-mediated
- Hyper-production of PABA (or in environment)
- Altered dihydropteroic synthase or FHFR (trimethoprim) ENZYMES
- Increased production of DHFR
- Reduced drug penetration into bacteria
12
Q
What are some important notes with resistance?
A
- Cross resistance between sulfas is typical
o If resistant to one=likely RESISTANT to the OTHERS - *emerges more slowly with potentiated sulfas then with sulfas alone
13
Q
Sulfas oral bioavailability, distribution, elimination half life)
A
- *not uniform between drugs and species
- Generally good oral bioavailability
- Distributes into many tissue
- *difference in protein binding=subsequent differences in elimination half-lives
14
Q
Sulfas elimination
A
- Hepatic metabolism (to inactive metabolites)
o NOT worried about hepatic disease - Renal excretion (glomerulation filtration)
o Tubular reabsorption can occur
o Decrease reabsorption with ALKALINE URINE (ion-trapping of acidic sulfa)
o *worried about renal disease
15
Q
Sulfonamides when potentiate and PK
A
- DIFFERENCES
o Makes optimizing the sulfa:TMP ratio challenging
o Makes C&S results more difficult to interpret (test may have used a different ratio to the drug formulation we will use)
o Differences between vet and human formulations - Ex. TMP eliminated quickly and sulfa eliminated slowly=sulfa is hanging around for longer by itself
16
Q
Label dose: OLD, how many doses a day?
A
- Label: once daily
- Vets say: BID instead
o Likely time-dependent (longer concentrations remain above MIC=better likelihood to get efficacy)
o Especially with TMP component eliminating faster (do not have TMP to give it on its own)
17
Q
What are some sulfa AEs?
A
- Hypersensitivity
- Keratoconjunctivitis sicca (KCS)
- Renal damage
- Hypothyroidism
- GI: diarrhea, vomiting, salivation
- Anemia from chronic sulfa use (rare)
- Injection reactions
18
Q
Hypersensitivity AE of sulfas: side chains (shown in people) and reason
A
- *different reactions based on where/which side chain the hypersensitivity is too
- In people: these only happen to the antibiotic sulfas and NOT the drugs that are derivatives of sulfonamides (non-antibiotics)
19
Q
Hypersensitivity of sulfas AE: what is seen
A
- Blood dyscrasis
o IMHA: horses
o Thrombocytopenia and epistaxis (DECREASED PLATELETS) - Skin eruptions: (especially Dobermans)
- *Hepatic necrosis
20
Q
***Keratoconjunctivitis sicca (KCS): AE of sulfas
A
- ‘dry-eye’ due to DECREASED tear production
o Sulfa component TOXIC to lacrimal acinar cells
o *confirm with Schirmer Tear Test - Occurs in 15% of dogs treated with sulfas
o Maybe higher incidence in small dogs - Typically RESOLVES when sulfa therapy STOPPED (if not=do eye drops)
21
Q
Renal damage: AE of sulfas
A
- Sulfas are poorly soluble: can PRECIPITATE in urine
o Can lead to crystalluria, hematuria, tubule blockage - NOT a big problem as TMS mostly used
o Lower sulfa need when used with TMP
o But need to make sure patients are hydrated!
22
Q
Why does Sulectim contain 4 different sulfas?
A
- *each sulfa has different solubility
- 4x 1 sulfa=increased change of precipitation in renal tubules
- **1x 4 sulfas=same antimicrobial effect, but less likely all precipitate at ONCE
23
Q
Hypothyroidism: AE of sulfas
A
- Inhibition of thyroid enzyme activity
o Generally reversible
o *likely not to see if using for appropriate amount of time (~1 week), different with chronic use - Rodents: thyroid follicular hyperplasia/adenocarcinomas
24
Q
Anemia from chronic sulfa use (rare): AE of sulfas
A
- *not likely to occur or be worried about it
- Folate-related (not hypersensitivity mediated)
- Decrease folate production from intestinal bacteria
- If worried: supplement folic acid=VitB9
25
Q
What are some injection AE reactions with sulfas?
A
- Lesions after IM injection
- Rapid IV (extralabel) has caused thrombophlebitis or anaphylaxis in horses
26
Q
What are the drug interactions of sulfas?
A
- NONE that are highly relevant
o Procaine (PPG) is a PABA analogue =NO clinical effect though
o Often not using with other antimicrobials
