trimethoprim-sulfamethoxazole uses

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Trimethoprim-Sulfamethoxazole (TMP-SMX / Cotrimoxazole)

Mechanism of Action

TMP-SMX blocks two sequential steps in bacterial folate synthesis, creating a synergistic (often bactericidal) effect:

Sulfamethoxazole inhibits dihydropterate synthetase, blocking incorporation of PABA into dihydrofolic acid
Trimethoprim inhibits dihydrofolate reductase, blocking conversion of dihydrofolate to tetrahydrofolate

The combination is formulated in a 1:5 ratio (TMP:SMX), which gives a plasma concentration ratio of 1:20 - optimal for in vitro synergy. Neither drug alone is reliably bactericidal; together, they usually are.

TMP-SMX Therapeutic Applications - Lippincott

Antibacterial Spectrum

Category	Organisms Covered
Gram-positive cocci	S. aureus (MSSA and CA-MRSA)
Gram-positive bacilli	Listeria monocytogenes
Gram-negative cocci	Neisseria gonorrhoeae (resistance now common)
Gram-negative rods	E. coli, H. influenzae, Proteus mirabilis, Shigella, Salmonella/S. typhi, Legionella pneumophila
Other gram-negatives	Stenotrophomonas maltophilia, Nocardia spp.
Fungi/opportunists	Pneumocystis jirovecii, Toxoplasma gondii

Not active against: anaerobes, Pseudomonas aeruginosa, Mycoplasma, Chlamydia, spirochetes.

Clinical Uses

1. Urinary Tract Infections (UTIs)

Most common use - treats uncomplicated and complicated UTIs caused by susceptible E. coli, Klebsiella, Proteus
Standard dose: 1 DS tablet (160/800 mg) every 12 hours
Prophylaxis for recurrent UTIs in women: 1 SS tablet (80/400 mg) three times weekly
Trimethoprim concentrates in prostatic and vaginal fluids (being more lipid-soluble) - effective for bacterial prostatitis

2. Pneumocystis jirovecii Pneumonia (PCP)

Drug of choice for both treatment and prophylaxis
Treatment: High-dose IV or oral TMP 15-20 mg/kg/d (dosed on trimethoprim component)
IV formulation used for moderate-to-severe PCP
Prophylaxis: 1 DS tablet daily or three times weekly; indicated in HIV patients with CD4 < 200 cells/mL

3. Skin and Soft Tissue Infections (SSTIs)

Effective for community-acquired MRSA SSTIs (furunculosis, cellulitis, abscesses)
Standard DS dosing every 12 hours
Bone and joint MRSA infections: 8-10 mg/kg/d of the TMP component

4. Respiratory Tract Infections

Haemophilus influenzae, Moraxella catarrhalis, susceptible K. pneumoniae
Alternative treatment for Legionella pneumophila
Not active against Mycoplasma pneumoniae or Streptococcus pyogenes (unreliable)

5. Gastrointestinal Infections

Shigellosis (bacillary dysentery) - treatment of choice if susceptible
Typhoid fever / Salmonella carriers - alternative agent
Nontyphoid Salmonella infections
Cyclospora cayetanensis and Cystoisospora belli (Isospora) infections - TMP-SMX is the drug of choice for both treatment and long-term suppression in immunocompromised patients

6. Nocardiosis

Drug of choice for Nocardia spp. infections (pulmonary, disseminated, CNS)
High-dose, prolonged treatment required

7. Stenotrophomonas maltophilia

One of the few reliable agents against this intrinsically multidrug-resistant organism

8. Listeriosis

Alternative to ampicillin for Listeria monocytogenes septicemia and meningitis, especially in penicillin-allergic patients

9. Other Uses

Traveler's diarrhea (where susceptibility is maintained)
Toxoplasmosis prophylaxis in HIV/immunocompromised patients (TMP-SMX covers this at PCP prophylaxis doses)
Whipple's disease (alternative)
Chronic granulomatous disease - long-term prophylaxis against bacterial infections
Wegener's granulomatosis (GPA) - used for relapse prevention

Formulations and Doses

Formulation	Composition	Common Use
Single-strength (SS) tablet	TMP 80 mg + SMX 400 mg	UTI prophylaxis
Double-strength (DS) tablet	TMP 160 mg + SMX 800 mg	Most adult infections
IV solution	TMP 80 mg + SMX 400 mg per 5 mL	Severe PCP, bacteremia
Pediatric tablet	TMP 20 mg + SMX 100 mg	Pediatric dosing

Pediatric dose: TMP 8 mg/kg/day + SMX 40 mg/kg/day divided every 12 hours (for shigellosis, UTI, otitis media).

Dose adjustment: Reduce by half when creatinine clearance is 15-30 mL/min. Avoid if CrCl < 15 mL/min (if alternatives exist).

Adverse Effects

Category	Effects
GI	Nausea, vomiting, diarrhea (most common)
Hypersensitivity	Rash, urticaria, Stevens-Johnson syndrome (sulfonamide component)
Hematologic	Leukopenia, thrombocytopenia, granulocytopenia, megaloblastic anemia (with prolonged use or folate deficiency)
Renal/Electrolytes	Nephrotoxicity, hyperkalemia, hyponatremia (more common at high doses; TMP blocks potassium secretion in collecting duct)
Hepatic	Elevated transaminases (uncommon)

Key Drug Interactions

Warfarin - TMP-SMX inhibits CYP2C9, potentiating anticoagulant effect
Phenytoin - increased phenytoin levels (reduced metabolism)
Methotrexate - additive folate antagonism, increased toxicity
ACE inhibitors/potassium-sparing diuretics - additive hyperkalemia risk (TMP blocks renal K+ secretion)
Cyclosporine - may increase nephrotoxicity

Resistance

TMP resistance: due to reduced cell permeability, overproduction of dihydrofolate reductase, or plasmid-encoded resistant enzymes spread via transposons
Combined resistance is less common than resistance to either drug alone (requires simultaneous resistance to both)
E. coli resistance now ~25-30% in many regions - limits empiric use for upper UTIs and pneumonia
Resistance in pneumococci is also significant

Sources: Harrison's Principles of Internal Medicine 22E, p. 1221 | Katzung's Basic and Clinical Pharmacology, 16th Ed., pp. 1301-1302 | Lippincott Illustrated Reviews: Pharmacology, pp. 1037-1039 | Goodman & Gilman's Pharmacological Basis of Therapeutics

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