Folate Antagonists

Question 1

Folate Antagonists

Answer 1

Trimethoprim/Sulfamethoxazole 
Dapsone
Pyrimethamine
Sulfadiazine
Sulfadoxine

T/S is most common
Active against bacterial and parasitic/fungal infections
Once was broad spectrum; not now due to resistance; still drug of choice for many infections
Resistance varies by geographical region; consider local angiobiogram before using as empiric therapy

Other agents used for parasitic/fungal infections

This section will refer to T/S except when noted

Question 2

Folate Antagonists MOA

Answer 2

These drugs inhibit steps in folate biosynthesis pathway- depletes pool of nucleosides- ultimately leads to inhibition of DNA synthesis in susceptible organisms

Question 3

Folate Antagonists Spectrum

Answer 3

Good 
Staph aureus (including many MRSA)
H. influenzae
Stenotrophomonas maltophilia
Listeria
Pneumocystis jirovecii (formerly P. carinii)
Toxoplasma gondii (pyrith and sulfadiaz)

Moderate
Enteric GNRs
S. pneumo
S. pyogenes 
Salmonella
Shigella
Nocardia

Poor
Pseudomonas
Enterococci
Anaerobes

Question 4

Folate Antagonists Adverse Effects

Answer 4

Dermatologic
T/S frequently causes rash (usually because of sulfamethoxazole component)
Rash more common in HIV/AIDS patients
Usually not severe, life threatening reactions can occur (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Hematologic
Dose dependent bone marrow suppression with T/S (especially at higher doses used for Pneumocystis infections)

Renal
T/S can cause true and pseudo renal failure
SMX component can cause crystalluria and AIN leading to acute renal failure
TMP can increase serum creatinine (by blocking its secretion) without a true decline in glomerular filtration rate
TMP can cause hyperkalemia (MOA similar to potassium sparing diuretics like triamterene)

Question 5

Folate Antagonists Important Facts

Answer 5

T/S was standard first line for acute uncomplicated cystitis in women
In areas with local resistance rates > 15-20% for E. coli, use other drug (like nitrofurantoin); in these cases definitely do not use for empiric therapy of complicated UTIs (pyelonephritis and urosepsis)

T/S comes in a fixed 1:5 ratio
Dosing based on TMP component 
SS- 80:400
DS- 160:800
Excellent oral bioavailability 

Significant drug interaction with warfarin- causing higher than anticipated prothrombin times
Avoid with warfarin if possible; if have to use both, then monitor international normalized ratio

Fairly insoluble in IV solutions; large volumes of diluent needed for it to go into solution
Be careful in volume overloaded patients (like heart failure)

Outpatient MRSA strain very susceptible to T/S; like to cause skin infections with abscesses (often large ones); good choice for staph skin infections but must drain abscess

If allergic to T/S, may have cross reactions to other drugs containing sulfonamide moieties (Furosemide, Sulfadiazine, Acetazolamide, HCTZ, Glipizide)

Question 6

Folate Antagonists Good For

Answer 6

Uncomplicated UTIs (empirically in areas with low local resistance; definitively when susceptible)
Prophylaxis against recurrent UTIs
Treatment Listeria meningitis
Treatment and prophylaxis of P. jirovecii pneumonia
Treatment of Toxoplasma encephalitis

Also alternative therapy for bacterial prostatitis, typhoid fever, MRSA

Sulfadiazine used in treatment of Toxoplasmosis