Folate Synthesis Inhibtors

Question 1

What are the two actives in co-trimoxazole?

Answer 1

Sulphonamides and Trimethoprim

Question 2

What is the MOA of sulfonamides?

Answer 2

1. PABA and Pteridine (Dihydropteroate synthase)
2. Dihydropteroic acid (Dihydrofolate synthase)
3. Dihydrofolic acid (Dihydrofolate reductase)
4. Tetrahydrofolic acid

Question 3

What are some mechanisms of resistance?

Answer 3

Mutations
1. Lower affinity of dihydropteroate synthase enzyme for sulfonamide
2. Reduced bacterial cell permeability
3. Active efflux pump
4. Alternative pathway for essential metabolite synthesis
5. Enhanced production of essential metabolites or antagonists

Question 4

What is the spectrum of activity?

Answer 4

Retained Potent Activity
Klebsiella granulomatis
Haemophilus ducreyi
Chlamydia trachomatis
Nocardia spp.
Actinomyces
Important Activity
Parasites
Fungi (Pneumocystis jiroveccii – Co-trimoxazole = DOC)

Question 5

What are the gaps in the spectrum

Answer 5

Pseudomonas aeruginosa
Anaerobes
Enterococci
Resistant pathogens
Rickettsiae

Question 6

Classify the sulfonamides

Answer 6

Oral Absorbable
1.Sulfamethoxazole
2. Sulfadoxine

Oral Non-absorbable
Sulfasalazine

Topical
1. Sulfacetamide
2. Silver Sulfadiazine

Question 7

What the pharmacokinetics of the oral absorbable agents?

Answer 7

A - Well absorbed. Stomach and intestine

D - Widely distributed. Includes CNS, placenta, foetus, body fluids. Variable protein binding (20% - 90%)

M - Acetylation. Glucuronidation.

E - Active and inactive metabolites excreted in urine (glomerular filtration)

Question 8

What type of killing does it exhibit?

Answer 8

Single Therapy usually Time-dependent
Combination (Co-trimoxazole) also has concentration-dependent effects

Question 8

What are the clinical uses for oral absorbable agents?

Answer 8

PJP - Co-trimoxazole Drug of Choice

Nocardiosis - Co-trimoxazole drug of choice in some countries. Severe cases: + second agent

Toxoplasmosis
Sulfadiazine + pyrimethamine

Question 9

What are expected adverse effects?

Answer 9

Allergic reactions - Fever
Skin rashes
Exfoliative dermatitis
Photosensitivity
Urticaria
Stevens-Johnson’s syndrome (rare).

UTI-
Crystalluria
Haematuria
Obstruction

Haematotoxicity -
Haemolytic anaemia
Granulocytopenia
Thrombocytopenia
Be cautious in patients with G6PD deficiencies
If taken near end of pregnancy, can cause kernicterus

Question 10

What are some drug interactions?

Answer 10

Warfarin
Methotrexate
Bilirubin

Question 11

What about trimethoprim?

Answer 11

Similar structure to folic acid
Reaches high concentrations in prostatic and vaginal fluids
Excreted mostly unchanged in urine
Resistance due mostly due to production of enzyme with low affinity for trimethoprim
Similar t1/2 to sulfamethoxazole
Thus co-formulated (i.e. co-trimoxazole)
Comparable adverse effects to sulfonamides
HIV positive patients have higher risk of adverse effects