Cotrimoxazole
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Cotrimoxazole is a combination antibiotic of sulfamethoxazole (SMX) + trimethoprim (TMP) in a 5:1 ratio, acting synergistically to block folate synthesis. It covers a broad range of organisms and is used for UTIs, PCP prophylaxis, Pneumocystis pneumonia treatment, and more.
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cotrimoxazole trimethoprim sulfamethoxazole
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Cotrimoxazole (Trimethoprim-Sulfamethoxazole, TMP-SMX)
Cotrimoxazole is the fixed-dose combination of trimethoprim (TMP) + sulfamethoxazole (SMX) in a 1:5 ratio by weight (TMP 80 mg : SMX 400 mg in a single-strength tablet; 160 mg : 800 mg in a double-strength tablet). The combination is widely known as cotrimoxazole in much of the world.
Chemical Structure
The trimethoprim component is a trimethoxybenzylpyrimidine:
Sulfamethoxazole is a sulfonamide - a derivative of para-aminobenzenesulfonamide and a congener of para-aminobenzoic acid (PABA).
Mechanism of Action
The combination blocks two sequential, essential steps in bacterial tetrahydrofolate (THF) synthesis:
| Step | Drug | Target |
|---|---|---|
| 1 | Sulfamethoxazole | Dihydropteroate synthase - competes with PABA, blocks dihydropteroic acid synthesis |
| 2 | Trimethoprim | Dihydrofolate reductase (DHFR) - blocks conversion of dihydrofolic acid → tetrahydrofolic acid |
THF is required for one-carbon transfer reactions (e.g., thymidylate synthesis from deoxyuridylate) - ultimately essential for DNA synthesis in bacteria. TMP is ~100,000 times more selective for bacterial DHFR than for mammalian DHFR.
Key point: Each drug alone is largely bacteriostatic; together they are often bactericidal due to synergistic sequential blockade. The optimal in vitro ratio of SMX:TMP is 20:1 - which is what the formulation achieves in plasma.
Pharmacokinetics
| Parameter | TMP | SMX |
|---|---|---|
| Absorption | Well absorbed orally | Well absorbed orally |
| Peak plasma (oral DS tablet) | ~2 μg/mL at ~2 h | ~40 μg/mL at ~4 h |
| Peak plasma (IV) | ~3.4 μg/mL | ~46 μg/mL |
| Protein binding | ~40% | ~65% |
| Volume of distribution | Large (9× that of SMX) | Smaller |
| Half-life | ~11 h | ~10 h |
| CNS/CSF penetration | Good | Good |
| Excretion (24 h urine) | ~60% | 25-50% |
- TMP is more lipid-soluble and concentrates in prostatic fluid and vaginal fluid (both more acidic than plasma), which is why it is particularly effective for prostatitis.
- High concentrations in bile.
- Dose adjustment required when CrCl is 15-30 mL/min (halve the dose). Excretion rates are significantly reduced in uremia.
Antimicrobial Spectrum
Susceptible organisms:
- E. coli, Proteus mirabilis, Klebsiella spp., Enterobacter spp., Serratia spp., Salmonella, Shigella
- Staphylococcus aureus (>90%, including many MRSA strains - though geographic variation)
- H. influenzae, Moraxella catarrhalis, S. pneumoniae (though increasing resistance)
- Nocardia asteroides, Stenotrophomonas maltophilia, Brucella abortus
- Pneumocystis jirovecii
- Yersinia spp., Pasteurella haemolytica
Intrinsically resistant (clinically resistant):
- Pseudomonas aeruginosa
- Bacteroides fragilis
- Enterococcus spp.
- Mycoplasma pneumoniae
Note: E. coli resistance rates have increased significantly (up to 30% or more in some regions). Guidelines recommend avoiding empiric TMP-SMX for UTIs when local E. coli resistance exceeds 20% or if the patient has received TMP-SMX recently.
Formulations & Dosing
| Formulation | TMP | SMX |
|---|---|---|
| Single-strength (SS) tablet | 80 mg | 400 mg |
| Double-strength (DS) tablet | 160 mg | 800 mg |
| IV solution | 80 mg/5 mL | 400 mg/5 mL |
Standard Doses
| Indication | Dose | Duration |
|---|---|---|
| Uncomplicated UTI/cystitis | 1 DS tablet (160/800 mg) PO q12h | 3 days |
| Complicated UTI/pyelonephritis | 1 DS tablet q12h | 10-14 days |
| Prostatitis | 1 DS tablet q12h | 4-6 weeks (chronic) |
| Skin & soft tissue infections (MRSA) | 1-2 DS tablets q12h | 5-7 days |
| Shigellosis/Salmonella | 1 DS tablet q12h | 3-5 days |
| UTI prophylaxis (recurrent) | 1 SS tablet 3× weekly | Long-term |
| Bone & joint infections (S. aureus) | 8-10 mg/kg/day TMP component | - |
| Children (UTI/otitis media/shigellosis) | TMP 8 mg/kg/day + SMX 40 mg/kg/day divided q12h | - |
PCP (Pneumocystis jirovecii Pneumonia)
| Purpose | Dose |
|---|---|
| Treatment (moderate-severe) | TMP 15-20 mg/kg/day + SMX 75-100 mg/kg/day in 3-4 divided doses IV or oral |
| Prophylaxis | 1 DS tablet daily or 3× weekly |
- IV route: 80 mg TMP + 400 mg SMX per 5 mL, diluted in 125 mL D5W, infused over 60-90 minutes.
- Adjunctive corticosteroids should be given with treatment of moderate-severe PCP (PaO₂ <70 mmHg or A-a gradient >35 mmHg).
Therapeutic Uses (Summary)
- Urinary tract infections - uncomplicated cystitis, complicated UTI, pyelonephritis
- Prostatitis (acute and chronic) - TMP concentrates well in prostatic secretions
- PCP treatment and prophylaxis (drug of choice)
- Skin and soft tissue infections (MRSA, community-acquired)
- Respiratory tract infections - acute exacerbations of chronic bronchitis, otitis media, sinusitis (H. influenzae, S. pneumoniae - where susceptible)
- GI infections - shigellosis (alternative to fluoroquinolones), typhoid (alternative)
- Nocardiosis
- Stenotrophomonas maltophilia infections
- Listeria infections (in penicillin-allergic patients)
- Toxoplasmosis prophylaxis in immunosuppressed patients
- Traveler's diarrhea - no longer recommended due to widespread resistance
Not effective for:
- Streptococcal pharyngitis (does not eradicate organism from the pharynx)
- Pseudomonas infections
- Enterococcal infections
Resistance
Two mechanisms operate:
To sulfonamides:
- Mutations in dihydropteroate synthase (reduced drug binding)
- Overproduction of PABA
- Decreased uptake of drug
To trimethoprim:
- Point mutations in DHFR gene (reduced binding)
- Plasmid-encoded alternative DHFR (most common - via transposons on conjugative plasmids with broad host range, accounting for rapid spread among many species)
- Reduced cell permeability
- Overproduction of DHFR
Resistance to the combination is generally lower than resistance to either agent alone.
Adverse Effects
| Category | Effects |
|---|---|
| Hematologic | Megaloblastic anemia, leukopenia, thrombocytopenia (folate deficiency, especially in folate-deficient patients); hemolytic anemia in G6PD deficiency |
| Hypersensitivity | Rashes (including urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis - especially sulfonamide component) |
| Renal | Crystalluria (sulfonamide precipitation), interstitial nephritis, hyperkalemia (TMP blocks ENaC - potassium-sparing effect like amiloride), elevated serum creatinine (TMP inhibits tubular creatinine secretion - spurious rise) |
| GI | Nausea, vomiting, diarrhea, hepatitis (rare), cholestasis |
| CNS | Headache, aseptic meningitis (rare) |
| HIV patients | Particularly high rate of adverse reactions (rash, fever, cytopenias) - up to 50-60% |
| Photosensitivity | Sulfonamide component |
Key metabolic effects of TMP:
- Hyperkalemia - blocks aldosterone-sensitive sodium channels (ENaC) in collecting duct, similar to amiloride
- Spurious creatinine rise - blocks tubular creatinine secretion; GFR is not actually affected
Contraindicated in:
- Pregnancy (especially 1st trimester - folate antagonism; 3rd trimester - neonatal hyperbilirubinemia/kernicterus)
- Neonates and infants <2 months (risk of kernicterus and hemolytic anemia)
- Severe renal or hepatic impairment (unless adjusted)
- Known sulfonamide hypersensitivity
Drug Interactions
| Drug | Interaction |
|---|---|
| Warfarin | TMP-SMX potentiates anticoagulant effect (inhibits CYP2C9 metabolism of warfarin S-enantiomer) |
| Methotrexate | Increased toxicity (additive folate antagonism) |
| Phenytoin | Increased phenytoin levels |
| Cyclosporine | Increased nephrotoxicity; reduced cyclosporine levels |
| ACE inhibitors/ARBs, potassium-sparing diuretics | Additive hyperkalemia risk (with TMP's ENaC-blocking effect) |
| Azathioprine/6-mercaptopurine | Myelosuppression |
| Digoxin | Increased digoxin levels (in elderly) |
Recent Evidence
Recent systematic reviews (2024-2026) have examined:
- PCP treatment - A 2025 network meta-analysis (PMID 39732393) confirmed that high-dose TMP-SMX remains the standard of care for P. jirovecii pneumonia in HIV patients, with superior outcomes compared to alternatives.
- Complicated UTIs - A 2026 systematic review (PMID 41693075) comparing oral beta-lactams vs TMP-SMX and fluoroquinolones for complicated UTIs found TMP-SMX remains a first-line option where susceptibility is confirmed.
- Recurrent UTI prophylaxis in children - A 2024 systematic meta-analysis (PMID 39492618) evaluated prophylaxis options including TMP-SMX in children with recurrent UTIs.
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics (14th Ed.), p. 1159-1160; Katzung's Basic and Clinical Pharmacology (16th Ed.), pp. 1301-1302; Smith and Tanagho's General Urology (19th Ed.)
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