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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