Folate Antagonists

Agents: trimethoprim/sulfamethoxazole (TMP/SMX), dapsone, pyrimethamine,  sulfadiazine, sulfadoxine These drugs inhibit steps in the folate-synthesis pathway, ultimately leading to inhibition of DNA synthesis in susceptible organisms. In this class  of drugs, the combination drug TMP/SMX is the most widely used, for both bacterial and parasitic/ fungal infections. TMP/SMX was once considered a broad-spectrum drug that has since fallen victim to the relentless march of antibiotic resistance; how-ever, it is still a drug of choice for a number of indications. Resistance varies considerably by geo-graphic region, so consider your local antibiogram before using TMP/SMX as empiric therapy. The other agents are used against parasitic/fungal infections. The information below refers to TMP/SMX except where noted.

Spectrum

Good: Staphylococcus aureus (including many MRSA strains),  H. influenzae,  Stenotrophomonas maltophilia, Listeria, Pneumocystis jirovecii  (formerly known as  P. carinii),  Toxoplasma gondii (pyrimethamine and sulfadiazine)

Moderate: enteric GNRs,  S. pneumoniae, Salmonella, Shigella, Nocardia

Poor : Pseudomonas, enterococci,  S. pyogenes, anaerobes

Adverse Effects

Dermatologic: TMP/SMX frequently causes rash,  usually because of the sulfamethoxazole component. Rash is much more common in HIV/ AIDS patients. Although these rashes are usually not severe, life-threatening dermatologic reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been documented.

Hematologic: A primarily dose-dependent bone-marrow suppression can be seen with TMP/ SMX, especially at the higher doses used to treat Pneumocystis infections.

Renal: Confusingly, TMP/SMX can cause both true and pseudo-renal failure. Crystalluria and AIN caused by the SMX component can lead to acute renal failure; however, the blockade of creatinine secretion by TMP can cause an increase in serum creatinine without a true decline in glomerular filtration rate. TMP can also cause hyperkalemia in a fashion similar to the potassium-sparing diuretics (e.g., triamterene).

Important Facts

• For years, TMP/SMX was standard first-line therapy for treatment of acute uncomplicated cystitis in women. Guidelines suggest, how-ever, that in areas with local resistance rates of less than 15–20% in E. coli, an alternative drug  (e.g., ciprofloxacin or nitrofurantoin) should be used. This recommendation is somewhat controversial because of the increasing rate of fluoroquinolone resistance. Certainly, at a minimum TMP/SMX should not be used for empiric therapy of complicated UTI (pyelonephritis or urosepsis).

• TMP/SMX comes in a fixed 1:5 ratio of the two components. Dosing is based on the TMP component. The oral form comes in two strengths:  single-strength (80:400 mg TMP:SMX) and double-strength (160:800 mg TMP:SMX). TMP/ SMX has excellent oral bioavailability, allowing for conversion to oral therapy when patients are tolerating oral medications.

• TMP/SMX has a significant drug interaction with warfarin, leading to higher-than-anticipated prothrombin times. TMP/SMX should be avoided in patients on warfarin if possible. If co-administration is absolutely necessary, careful monitoring of the patient’s inter-national normalized ratio is required.

• TMP/SMX is fairly insoluble in IV solutions,  and relatively large volumes of diluent are needed for it to go into solution. Be aware that this fluid may be considerable, particularly for volume-overloaded patients such as those with heart failure.

What They’re Good For

Treatment of uncomplicated lower UTIs (in areas with low local resistance), prophylaxis against re-current UTIs, treatment of listerial meningitis,  treatment of and prophylaxis for  Pneumocystis jirovecii pneumonia, and treatment of Toxoplasma encephalitis. TMP/ SMX is also an alternative therapy for bacterial prostatitis, typhoid fever,  and methicillin-resistant  Staphylococcus aureus infections.

Don’t Forget!

Patients allergic to TMP/SMX may have cross-reactions to other drugs containing sulfonamide  moieties, such as furosemide, sulfadiazine, acetazolamide, hydrochlorothiazide, and glipizide.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.