Folate Inhibitors (Anti-Biotics)

Question 1

What are the three classes of ABX that fall under the category of “folate inhibitors?”

Answer 1

Sulfonamides, Sulfones, and Trimethoprims.

Question 2

What are the precursors of the folate inhibitors?

Answer 2

Para-amino benzoic acid, aka PABA, and this is the precursor to folic acid synthesis.

Question 3

What is the general idea of using folate inhibitors to attack bacteria?

Answer 3

Bacteria can make their own folate whereas humans need to consume it, thus if we inhibit the synthesis of folate we mess with bacteria and not with humans (who will just ingest folate).

Question 4

General PK of all Sulfonamides?

Answer 4

Seems to be all oral (some topical), well distributed in the CSF and urine, however we cannot use Sulfonamides to tx meningitis due to increased resistance.

Question 5

How are sulfonamides metabolized?

Answer 5

They are hepatically metabolized via the N-4 acetylation pathway, and the inactive drug is actually implicated in some of the drug tox. Dapsone is metabolized by CYPs instead.

Question 6

How are sulfonamides excreted?

Answer 6

Glomerular filtration of the unchanged drug (which is why it has an effect in the UTIs).

Question 7

How is Dapsone metabolized?

Answer 7

Via 2C9 and 3A4.

Question 8

What are the CYP interactions with Trimethoprims?

Answer 8

Substrates of 2C9 and 3A4, and also inhibitor of 2C9 (moderate).

Question 9

What is the ratio of the TMP-SMX drug?

Answer 9

1:5 TMP to SMX, because TMP is lipid soluble so it is more widely distributed in the first place.

Question 10

How are all these drugs of folate inhibition generally excreted?

Answer 10

Renal excretion.

Question 11

What are the 4 general classes of sulfonamides?

Answer 11

1. Agents absorbed and excreted quickly.
2. Poorly absorbed when taken orally but active in the bowel lumen.
3. Rapidly absorbed but slow excretion (long acting).
4. Stuff used topically.

Question 12

Name 3 of the sulfonamides that have rapid absorption and which of this is long acting?

Answer 12

Sulfamethoxazole (SMX), Sulfadoxine, Trimethoprim (TMP). Sulfadoxine is the long acting drug (5-9 day half life).
**TMX is not a sulfa but it is a folate inhibitor so its lumped in this group.

Question 13

What’s special about Sulfasalazine that allows it to be used for IBS?

Answer 13

Its poorly absorbed from the gut lumen, so it stays in the lumen and is active there. Useful for IBS, but can also be used for RA tx as an adjunct.

Question 14

What is the MOA of Sulfonamides and Sulfones?

Answer 14

They compete with PABA for dihydropteroate synthase and thus no conversion of PABA into dihydrofolic acid.
** Humans do not have the dihydropteroate synthase enzyme.

Question 15

What is the MOA of Trimethoprim aka TMP?

Answer 15

It inhibits dihydrofolate reductase (DHFR) and prevents the conversion of Dihydro folic acid into the active tetrahydrofolic acid (TH4)
** Dihydrofolic acid needs to be activated into the TH4 via the enzyme DHFR.

Question 16

What does no active folate (TH4) result in for the bacteria?

Answer 16

No purine or thymidine synthesis, so no amino acids or proteins. And as a result, no DNA or RNA.

Question 17

Are sulfa or the TMX drugs bacteriostatic or cidal?

Answer 17

On their own they are static, but if given in combo like the TMP-SMX combo, then it becomes bacteriocidal.

Question 18

What gram + organisms do TMP and sulfa drugs hit?

Answer 18

Aerobic organisms, strep, staph (including caMRSA), pneumococci.

Question 19

What gram neg organisms do Sulfa and TMP hit?

Answer 19

Aerobes and some enterobacteriaceae, some protozoa.

Question 20

Activity of Dapsone?

Answer 20

Mycobacterium Leprae, Plasmodium, Toxoplasma Gondii, Pneumocystis Jirovecii.

Question 21

What is the acquired and intrinsic resistance of Folate inhibitors?

Answer 21

Acquired is through plasmids and the usual suspects such as increased efflux pumps, decreased binding sites, etc. Intrinsic includes anarobes, enterococci (which can get their thymadine from other sources instead of just making it),P. Aeruginosa, Rickettsia, Mycobacteria, Mycoplasma, Chlamydia, and spirochetes (syphilis, lyme disease, etc).

Question 22

Can we use Sulfa for Rickettsia?

Answer 22

No, and in fact using sulfa’s might induce Rickettsia to grow.

Question 23

TMP-SMX can be used for UTI’s?

Answer 23

Yes, usually by uncomplicated E. coli and others.

Question 24

TMP-SMX for uncomplicated G+ MRSA?

Answer 24

Yes, for skin or skin structure infections.

Question 25

TMP-SMX for strep pharyngitis?

Answer 25

No, the organism is not susceptible to this drug.

Question 26

Other uses for TMP-SMX besides UTIs and MRSA?

Answer 26

Acute URI to strep pneumo or H. Influenza, Nocardiosis, P. Jirovecii pneumonia tx and px, toxoplasmosis tx and px.

Question 27

For what can you use TMP alone?

Answer 27

Uncomplicated UTIs.

Question 28

What’s special about the use of Sulfisoxazole tx?

Answer 28

Lower UTI, acute otitis media (w/ erythromycin) against M. Catarrhalis, and beta lactamase producing H. Influenza.

Question 29

2 uses for Sulfasalazine?

Answer 29

RA adjunctive tx and and IBS.

Question 30

What is one of the glaring AE’s of sulfa drugs?

Answer 30

Extreme HS reactions that are potentially fatal, HIV/AIDS patients have increased incidence of developing this. This includes rashes, SJS, photosensitivity, toxic epidermal necoriss, exfoliative dermatitis, erethema multiform.

Question 31

Besides the skin HS reactions what are the other AE’s of sulfa drugs?

Answer 31

Hepatic necrosis (which is also a HS rxn), hematopoetic related problems including bone marrow suppression (more evident in pt’s already with issues or prolonged use of sulfas).

Question 32

Why can’t patients with G6PD Dehydrogenase deficiency not take sulfas? Why?

Answer 32

It can cause hemolytic anemia, but this hemolytic anemia can be caused in normal patients without G6PD deficiency. In this deficiency, pt’s cannot make glutathione, and as a result you cannot detoxify the RBCs and they die.

Question 33

Why do we have to use caution when prescribing sulfas in pt’s with folate deficiency?

Answer 33

It can cause or exacerbate Agranulocytosis, apalastic anemia.

Question 34

Why is it recommended to take sulfa drugs with a lot of water all the time?

Answer 34

Due to the probability of developing crystalluria, esp the older agents and this will precipitate in acidic urine. Drinking excess water helps flush it out.

Question 35

What is Kernicteris and why do Sulfa’s cause this?

Answer 35

Kernicteris is the accumilation of bilirubin in the brain of neonates, sulfas can cause this because it can displace the binding site of biliruben from albumin.

Question 36

C. diff and sulfa?

Answer 36

Possible.

Question 37

What is the Dapsone HS reaction triad with rash?

Answer 37

Eosinophilia, fever, and internal organ involvement.

Question 38

Other specific AE’s of Dapsone besides the HS reaction?

Answer 38

Hemolytic anemia w/ G6PD DH deficiency, reversible Peripheral Neuropathy, Methemoglobinemia (a form of hemoglobin that is produced in an abnormal amount, thus O2 cannot be released properly).

Question 39

Folate Inhbitors and Preggos? Peds?

Answer 39

Contraindicated in late pregnancy and breast feeding, and contraindicated in children smaller than 2 months.

Question 40

What are some DDI’s with Sulfas?

Answer 40

It can displace protein binding sites from other drugs like MTX, phenytoin and other drugs with narrow thereupatic window. TMP is a substrate of 2C9 and 3A4 and inhibits the 2C family. Increased risk of bleeding with warfarin.