5. Sulfonamides, Benzylpyrimidines, & Ionophores

Sulfonamides (sulfas) pre-date which drug class?

penicillin

What are sulfonamides derived from? What is significant about this?

synthetic dyes (methylene blue); non-mycotic

What were the first sulfonamides developed? Which is inactive in vitro?

prontosil and rubizol; prontosil

What is needed with prontosil and rubizol?

hepatic modification

What were the benzylpyrimidines (diaminopyrimidines) originally developed as? What was their original use? What were they later found to be?

thymidine analogues; antiviral; synergistic with sulfas

What is the mechanism of action for both sulfas and benzylpyrimidines? What do they mimic?

inhibit enzymes in the folate metabolic pathway; PABA

Sulfas ________ inhibit ________ ________, so they are ________.

reversibly; dihydropteroate synthetase; bacteriostatic

What is a specific mechanism of action for the benzylpyrimidines?

inhibit an enzyme that is downstream (2,4-diaminopyrimidines)

The benzylpyrimidines ________ inhibit ________ ________, so they are ________.

reversibly; dihydrofolate reductase; bacteriostatic

While the method of action of benzylpyrimidines pathway is present in eukaryotes, what is significant?

1. M

2. S

3. M

1. most folate is ingested

2. sulfas and benzylpyrimidines cannot bind to eukaryotic enzymes

3. methotrexate will inhibit DHFR in eukaryotes

When sulfas and benzylpyrimidines are used alone, are they bacteriostatic or bacteriocidal?

bacteriostatic

When sulfas and benzylpyrimidines are used together, are they bacteriostatic or bacteriocidal?

bacteriocidal

What is necessary of the immune system if using a bacteriostatic antibiotic?

it needs to be healthy

What is the spectrum of the sulfas and benzylpyrimidines?

broad

What do sulfas and benzylpyrimidines fight against?

aerobes, anaerobes. Gram negative, Gram positive, and protozoa

Which Gram positive bacteria do sulfas and benzylpyrimidines not work against?

enterococcus

Which Gram negative bacteria do sulfas and benzylpyrimidines not work against?

pseudomonas

Which protozoa are susceptible to sulfas and benzylpyrimidines? What is important to know?

coccidia and cryptosporidia; most eukaryotes are not

Sulfas and benzylpyrimidines are useless against what?

M
M
S

• mycobacteria

• mycoplasma

• spirochetes

How does resistance to sulfas and benzylpyrimidines occur?

A
D

• alterations in target enzymes (DHPS and DHFR)

• development of alternate folate synthesis or uptake pathway

True or false: If a bacteria is resistant to a sulfa, then it will be resistant to the sulfa and benzylpyrimidine combination. If a bacteria is sensitive to a sulfa, then it will be sensitive to the sulfa and benzylpyrimidine combination.

true

When will sulfas and benzylpyrimidines be eliminated faster?

in alkaline urine

Which benzylpyrimidine is used against prostatitis in dogs? Why?

trimethoprim; 10X concentrates in the prostate

What toxicity is seen with sulfa and benzylpyrimidines? What does this mean?

keratoconjunctivitis sicca in dogs; owner will have to prophylactically medicate the eyes

In what dog species specifically should sulfas and benzylpyrimidines not be used in? Why? Specifically which sulfa?

dobermans; causes arthritis; sulfasalazine

Which sulfa should not be used in male dogs used for breeding? Why?

sulfasalazine; decreases sperm counts

Sulfas and benzylpyrimidines should not be used with what?

sulfonylureas

Sulfas and benzylpyrimidines should not be used on what type of diseases? Why?

rickettsial diseases; sulfas act as growth promotants and folate has a negative regulatory effect on the metabolism in rickettsia

Should sulfas and benzylpyrimidines be used for abscesses? Why or why not?

no; abscesses have a lot of free folate and the bacteria do not have to synthesize their own folate in an abscess

What clinicopathologic anomaly is seen with the use of benzylpyrimidines?

temporary T3/T4 depression during treatment (pseudohypothyroidism)

What sulfa can be used for ophthalmic conditions?

sulfacetamide

Which sulfa is not absorbed from the intestines?

sulfaguanidine

What happens to sulfasalazine in the intestines? What is the net effect?

cleaved to sulfapyridine and salicylate; antibacterial plus anti-inflammatory

What works well as an antiprotozoal agent?

sulfadoxine + pyrimethamine

What is an example of an oxidized sulfonamide (sulfones)?

dapsone

What are the oxidized sulfonamides useful against?

A
A
A

• anti-protozoal (Leishmania)

• anti-mycobacteria especailly M. leprae

• anti-inflammatory (pemphigus and brown recluse spider bites)

Sulfas and benzylpyrimidines should not be used extra-label in what species?

dairy cattle

What sulfas + benzylpyrimidines combination can be used in exotics? For what?

sulfadimethoxine + ormethoprime (Romet-30); furunculosis aeromonas in catfish and salmon

What is the mechanism of action of ionophores?

insert into the cell wall and bind Na, K, and H, resulting in a lethal drop in pH

What is the spectrum of ionophores?

Gram positive bacteriocidal and coccidiostatic

What toxicities are associated with ionophores? How? Which species specifically?

myopathies; insert into the cell membranes of eukaryotic myocytes; equine

When will you see ionophore-mediated myopathies?

P
O
A

• poultry or swine co-fed tiamulin

• overdosage in cattle

• accidental feeding in horses

Why does co-feeding tiamulin with ionophores cause a myopathy?

tiamulin decreases the metabolism of ionophores

What are the non-infectious uses of ionophores?

G
E

• growth promotant in cattle

• eliminates lactate and methane producing rumen bacteria, giving more proprionate produced for energy and prevents bloat

What are the main indications for sulfas and benzylpyrimidines?

1. C

2. C

3. B

4. B

5. I

6. C

1. canine pyoderma

2. canine and feline coccidiosis

3. bovine diarrhea

4. bovine foot rot

5. inflammatory bowel disease

6. canine prostatitis

What type of sulfa and benzylpyrimidines are used for canine pyoderma?

combo only (sulfa + benzylpyrimidine)

Which sulfa is used for canine and feline coccidiosis?

sulfadimethoxine (Albon)

What sulfa is used for IBD in canine and felines?

sulfasalazine

What sulfa is used for bovine diarrhea?

sulfamethazine (Sustain)

What benzylpyrimidine is used only in canine prostatitis?

trimethoprim

What are the main uses of ionophores?

1. C

2. P

3. T

1. coccidiostats in bovine, poultry, and swine

2. prevention of bloat

3. tryptophan-mediated “fog fever” (pulmonary edema)