trimethoprim-sulfamethoxazole

**Mechanism of action** - Bacteria must synthesize folate (humans get it from diet), so this pathway is selectively toxic. - Sulfamethoxazole: a PABA structural analog. It competitively inhibits dihydropteroate synthase, blocking conversion of PABA to dihydropteroic acid (dihydrofolate precursor). - Trimethoprim: inhibits bacterial dihydrofolate reductase (DHFR), blocking DHF to THF. THF is needed for purine, thymidine, and DNA synthesis. - Sequential blockade makes the combination synergistic and usually bactericidal. Each drug alone is bacteriostatic. - Mnemonic: "TMP: Treats Marrow Poorly" (antifolate effects), "Sulfa = PABA antimetabolite". - Trimethoprim is structurally similar to methotrexate and pyrimethamine, but it is far more selective for bacterial DHFR than human DHFR.

**Spectrum and indications (high-yield)** - Uncomplicated UTI/cystitis (E. coli, Klebsiella, Proteus) and prostatitis. Resistance is rising, so local resistance is >20% in some areas, and this limits empiric use. - Pneumocystis jirovecii pneumonia: first-line treatment (high dose) and prophylaxis when CD4 <200/µL in HIV. Steroids are added if PaO2 <70 mmHg or A-a gradient ≥35. - Toxoplasma gondii prophylaxis in HIV when CD4 <100/µL. - Community-acquired MRSA skin and soft tissue infections, such as abscesses and cellulitis. Poor coverage of Streptococcus pyogenes, so add beta-lactam coverage for non-purulent cellulitis. - Nocardia (first-line), Stenotrophomonas maltophilia (first-line), Listeria (alternative in penicillin allergy), Shigella, Salmonella (some), traveler's diarrhea, and Burkholderia. - Not effective for anaerobes or Pseudomonas.

**Adverse effects** - Hyperkalemia: trimethoprim blocks ENaC in the collecting duct (amiloride-like). Risk is higher with ACE inhibitors, ARBs, spironolactone, and renal impairment. - Creatinine rise without a true GFR drop: trimethoprim blocks tubular creatinine secretion. - Bone marrow suppression: megaloblastic anemia, leukopenia, granulocytopenia. This is worse in folate deficiency and in HIV. It is treated or prevented with leucovorin (folinic acid). - Hypersensitivity: rash, fever, Stevens-Johnson syndrome/toxic epidermal necrolysis (sulfonamide cross-reactivity is a classic concern), and photosensitivity. - Hemolysis in G6PD deficiency. - Kernicterus in neonates: sulfonamides displace bilirubin from albumin. Avoid in the third trimester and in infants under 2 months. - Teratogenic in the first trimester (folate antagonism causing neural tube defects, cardiac defects, and cleft palate). - Tubulointerstitial nephritis and crystalluria (sulfonamides are less soluble in acidic urine, so hydrate). - Methemoglobinemia (less common). - Others: nausea and vomiting, aseptic meningitis, and hypoglycemia (sulfonamide, sulfonylurea-like effect) in renal failure.

**Drug interactions** - Potentiates warfarin: CYP2C9 inhibition plus protein-binding displacement raises INR and bleeding risk. - Increases phenytoin and methotrexate levels, with a risk of severe pancytopenia with methotrexate. - Hyperkalemia risk with ACE inhibitors, ARBs, and potassium-sparing diuretics. - Sulfonylureas: hypoglycemia.

**Resistance** - Altered DHFR (plasmid-encoded, with decreased trimethoprim affinity). - Overproduction of PABA. - Altered dihydropteroate synthase. - Decreased drug permeability or efflux. - Enterococci take up exogenous folate, so they are effectively resistant.

**Clinical pearls** - Folate supplementation does not reliably reverse the bacterial effect, but leucovorin rescues the human marrow. - High-dose TMP-SMX for PJP commonly causes hyperkalemia, rash, and cytopenias. In HIV, hypersensitivity rates are high, and desensitization may be tried. - Sulfa allergy: a classic board question is the cross-reactivity of sulfonamide antibiotics with non-antibiotic sulfonamides, which is low in practice. Sulfonamide antibiotics have an N4 arylamine group that non-antibiotic sulfonamides lack. - Dose adjustment is needed for CrCl <30 mL/min.