Cotrimoxazole D.S 800/160 (Sulfamethoxazole 800 mg + Trimethoprim 160 mg) – EU

Cotrimoxazole D.S (Double Strength) 800/160 is a fixed-dose combination oral tablet containing Sulfamethoxazole 800 mg and Trimethoprim 160 mg​. The combination, commonly known as co-trimoxazole​, pairs a sulfonamide antibiotic with a diaminopyrimidine folate antagonist to produce synergistic bactericidal activity against a broad spectrum of Gram-positive, Gram-negative, and certain protozoal organisms. It is one of the most widely prescribed antibiotic combinations globally and is included on the WHO Model List of Essential Medicines​.

The synergy arises from sequential blockade of two consecutive enzymatic steps in bacterial tetrahydrofolate (folate) synthesis — a pathway essential for nucleic acid and protein synthesis in susceptible organisms but absent in mammalian cells, which obtain folate from dietary sources.

Cotrimoxazole D.S is manufactured by multiple Indian generic pharmaceutical companies, making it widely available and cost-effective. The D.S (double strength) formulation provides a convenient single-tablet adult dose, improving compliance compared with the earlier two-tablet standard-strength regimen. Primary indications include urinary tract infections, respiratory tract infections (including Pneumocystis jirovecii pneumonia prophylaxis and treatment), gastrointestinal infections, and certain opportunistic infections in immunocompromised patients.

Chemical Information

Sulfamethoxazole:

• Chemical Name: 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide
• Molecular Formula: C₁₀H₁₁N₃O₃S
• Molecular Weight: 253.28 g/mol
• CAS Number: 723-46-6
• Chemical Class: Sulfonamide antibiotic
• Structural Characteristics: Contains a para-aminobenzenesulfonamide core with a methylisoxazole substituent. It is structurally analogous to para-aminobenzoic acid (PABA), enabling competitive inhibition of dihydropteroate synthase.

Trimethoprim:

• Chemical Name: 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
• Molecular Formula: C₁₄H₁₈N₄O₃
• Molecular Weight: 290.32 g/mol
• CAS Number: 738-70-5
• Chemical Class: Diaminopyrimidine antifolate
• Structural Characteristics: Consists of a 2,4-diaminopyrimidine ring linked to a trimethoxybenzyl group. It acts as a competitive inhibitor of bacterial dihydrofolate reductase.

Both compounds are white to off-white crystalline powders, practically insoluble in water. The 5:1 ratio (800 mg Sulfamethoxazole to 160 mg Trimethoprim) in the D.S tablet achieves optimal synergistic plasma concentration ratios.

Mechanism of Action

Cotrimoxazole blocks two sequential steps in bacterial tetrahydrofolate biosynthesis​, a critical pathway for the synthesis of purines, thymidine, and ultimately DNA.

Step 1: Sulfamethoxazole – Dihydropteroate Synthase Inhibition

Sulfamethoxazole is a structural analogue of para-aminobenzoic acid (PABA). It competitively inhibits dihydropteroate synthase​, the enzyme that catalyses the condensation of PABA with dihydropteridine diphosphate to form dihydropteroic acid. This prevents the synthesis of dihydrofolic acid, the immediate precursor of tetrahydrofolic acid.

Step 2: Trimethoprim – Dihydrofolate Reductase Inhibition

Trimethoprim is a potent, selective competitive inhibitor of bacterial dihydrofolate reductase (DHFR). DHFR catalyses the reduction of dihydrofolate to tetrahydrofolate, the active coenzyme form required for one-carbon transfer reactions. Trimethoprim binds with 100,000-fold greater affinity to bacterial DHFR than to mammalian DHFR, providing the basis for selective toxicity.

Synergy

The sequential blockade produces synergistic bactericidal activity​. When used alone, sulfonamides are bacteriostatic; the addition of Trimethoprim converts the effect to bactericidal in many species. Synergy is expressed as a fractional inhibitory concentration (FIC) index of ≤0.5 for susceptible organisms. The 5:1 ratio produces peak plasma concentrations of approximately 20:1 (Sulfamethoxazole:Trimethoprim), which has been determined as optimal for synergy against most target pathogens.

Spectrum of Activity

Susceptible organisms include:

• Gram-positive: Staphylococcus aureus (including some community-acquired MRSA), Streptococcus pneumoniae​, Streptococcus pyogenes
• Gram-negative: Escherichia coli​, Klebsiella pneumoniae​, Proteus mirabilis​, Salmonella species, Shigellaspecies, Haemophilus influenzae​, Moraxella catarrhalis
• Protozoal and atypical: Pneumocystis jirovecii​, Toxoplasma gondii​, Nocardia species, Stenotrophomonas maltophilia​, Isospora belli

Resistance is increasing globally, mediated by acquired mutations in the target enzymes or by plasmid-mediated acquisition of resistant DHFR variants.

Pharmacological Effects

In-Vitro Findings

• Checkerboard synergy testing confirms synergistic bactericidal activity against susceptible organisms when combined at the 5:1 ratio.
• Time-kill studies demonstrate ≥3-log reduction in viable bacterial counts within 6–8 hours for E. coli and S. aureus at clinically achievable concentrations.
• Pneumocystis jirovecii is highly susceptible, though routine in-vitro susceptibility testing is not standardised for this organism.

Animal Findings

• Animal models of pyelonephritis, pneumonia, and intra-abdominal sepsis demonstrate the efficacy of cotrimoxazole, with results generalisable to human clinical settings.
• In the rat model of Pneumocystis pneumonia, cotrimoxazole was shown to be the most effective treatment compared with pentamidine and other antifolates.

Human Clinical Evidence

Cotrimoxazole has extensive clinical validation:

• Urinary tract infections: Clinical cure rates of 90–95% for uncomplicated UTIs caused by susceptible E. coliand other Enterobacteriaceae. Declining susceptibility in community uropathogens is a concern.
• Pneumocystis pneumonia (PCP): Cotrimoxazole is first-line therapy for PCP in immunocompromised patients (HIV/AIDS, transplant recipients). High-dose treatment (15–20 mg/kg/day of the Trimethoprim component) achieves response rates of 70–85%. Low-dose prophylaxis (one D.S tablet daily or three times weekly) reduces the incidence of PCP by >90%.
• Acute infective exacerbations of chronic bronchitis: Clinical cure in 80–85% of cases.
• Travellers’ diarrhoea and shigellosis: Reduces symptom duration and pathogen excretion, though resistance in Campylobacter and Shigella is prevalent in some regions.
• Toxoplasmosis: Used as an alternative second-line agent (in combination with pyrimethamine).
• Nocardiosis: First-line treatment for most Nocardia species infections.

Dosage

The D.S tablet (800/160 mg) is the standard adult formulation.Export

Indication	Adult Dose	Duration	Notes
Uncomplicated UTI	1 D.S tablet twice daily	3 days	Shorter course than older 7–10 day regimens.
Acute exacerbation of chronic bronchitis	1 D.S tablet twice daily	5–7 days	Alternative to amoxicillin-clavulanate or doxycycline.
Travellers’ diarrhoea	1 D.S tablet twice daily	3–5 days	Reduced efficacy if resistant Campylobacter​.
Pneumocystis pneumonia (treatment)	15–20 mg/kg/day Trimethoprim component in 4 divided doses	21 days	High-dose regimen; typically 2 D.S tablets every 6 hours for a 60 kg patient.
Pneumocystis pneumonia (prophylaxis)	1 D.S tablet once daily or 1 D.S tablet 3 times weekly	Indefinite while immunosuppressed	First-line prophylaxis in HIV (when CD4 <200 cells/μL).
Nocardiosis	2 D.S tablets twice daily	6–12 months	Prolonged therapy required.

Administration: Take with a full glass of water. May be taken with or without food, though food may reduce gastrointestinal upset. Maintain adequate fluid intake during therapy to reduce the risk of crystalluria.

Pharmacokinetics

• Absorption: Both components are rapidly and well absorbed after oral administration, with bioavailability of approximately 90–100%. Peak plasma concentrations are reached within 1–4 hours.
• Distribution: Both components distribute widely into body tissues and fluids, including cerebrospinal fluid, sputum, middle ear fluid, and prostatic fluid. Trimethoprim achieves particularly high concentrations in prostatic and vaginal secretions. Both cross the placenta and are excreted in breast milk. Plasma protein binding: Sulfamethoxazole ~70%, Trimethoprim ~45%.
• Metabolism: Sulfamethoxazole undergoes hepatic acetylation and glucuronidation; genetic variation in acetylator status (slow vs. fast acetylators) affects plasma half-life. Trimethoprim undergoes partial hepatic metabolism but is primarily renally excreted unchanged.
• Half-life: Both components have an elimination half-life of approximately 9–11 hours, making the combination amenable to twice-daily dosing.
• Elimination: Both components are excreted primarily via the kidneys, both by glomerular filtration and tubular secretion. Dose adjustment is required in renal impairment.

Side Effects and Safety

Cotrimoxazole is generally well tolerated but has a well-characterised adverse effect profile.

Common

• Gastrointestinal: Nausea, vomiting, anorexia (occurring in 5–10% of patients). Taking with food may help.
• Dermatological: Maculopapular rash, urticaria, photosensitivity. Mild rashes occur in 3–5% of patients; severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) are rare but life-threatening.
• Renal: Crystalluria (particularly with inadequate fluid intake in patients receiving high doses). Reversible increase in serum creatinine due to Trimethoprim inhibition of renal tubular creatinine secretion (does not reflect a true reduction in GFR).

Serious

• Haematological: Leucopenia, thrombocytopenia, megaloblastic anaemia (due to folate antagonism; more common in folate-deficient patients and with prolonged high-dose therapy). Agranulocytosis and aplastic anaemia are very rare.
• Hepatotoxicity: Cholestatic hepatitis, transaminase elevation (typically reversible).
• Hyperkalaemia: Trimethoprim, structurally similar to the potassium-sparing diuretic amiloride, blocks distal tubular sodium channels and can cause hyperkalaemia, particularly in elderly patients, those with renal impairment, or those on other potassium-elevating medications (ACE inhibitors, ARBs, potassium-sparing diuretics).
• Severe hypersensitivity: Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Higher risk in HIV-positive patients.

Contraindications

• Known hypersensitivity to sulfonamides, trimethoprim, or any excipient.
• Severe hepatic impairment, severe renal failure (CrCl <15 mL/min without dose adjustment — high-dose PCP treatment is an exception, with monitoring).
• Pregnancy (first trimester, risk of neural tube defects from folate antagonism) and breastfeeding in neonates (risk of kernicterus from sulfonamide).
• Porphyria (sulfonamides may precipitate acute attacks).
• Concomitant use with dofetilide (risk of ventricular arrhythmias).

Drug Interactions

• Warfarin: Sulfamethoxazole potentiates the anticoagulant effect, increasing INR. Close monitoring is required.
• Methotrexate: Both components can increase methotrexate toxicity by protein binding displacement and additive anti-folate effects.
• Phenytoin: Sulfamethoxazole may increase phenytoin levels.
• ACE inhibitors, ARBs, potassium-sparing diuretics: Additive risk of hyperkalaemia with Trimethoprim.
• Hyperkalaemia risk: Monitor serum potassium in elderly patients and those with renal impairment or on interacting medications.

Dependence, Tolerance and Withdrawal

Cotrimoxazole has no abuse potential, no dependence, and no withdrawal syndrome​. Antimicrobial resistance, however, is an increasing problem globally. Resistance in Enterobacteriaceae has reduced the utility of cotrimoxazole for empirical therapy in many settings. This is not patient tolerance but microbial resistance driven by widespread antibiotic use.

Legal and Regulatory Status

• India: Cotrimoxazole D.S 800/160 is typically a Schedule H prescription drug​. However, in some states, it may be dispensed by pharmacists without prescription, depending on local regulations. Standard practice is prescription-based, especially for prolonged or high-dose courses.
• Global: Prescription-only in most countries. Included on the WHO Model List of Essential Medicines.

Research Applications

• Antifolate pharmacology: Cotrimoxazole serves as a model for studying sequential enzyme inhibition, synergy, and the development of resistance.
• Pneumocystis biology: Used in research to understand P. jirovecii metabolism and to screen for novel therapies.
• Opportunistic infection prophylaxis in HIV: Ongoing research into optimal prophylaxis regimens and cessation criteria in the era of early antiretroviral therapy.
• Antibiotic resistance surveillance: Cotrimoxazole susceptibility patterns are widely monitored as an indicator of resistance trends in Enterobacteriaceae.

Conclusion

Cotrimoxazole D.S 800/160 is a fixed-dose combination of Sulfamethoxazole and Trimethoprim that produces synergistic bactericidal activity through sequential blockade of bacterial folate synthesis. It is a WHO Essential Medicine, widely indicated for urinary tract infections, respiratory tract infections, and as the first-line agent for Pneumocystis jirovecii pneumonia prophylaxis and treatment. The D.S tablet provides a convenient twice-daily adult dose with reliable oral absorption. Clinicians must monitor for hyperkalaemia, renal and haematological effects, and severe dermatological reactions, particularly in immunocompromised patients. Rising antimicrobial resistance limits empirical utility in some settings. Cotrimoxazole D.S 800/160 is a prescription medicine and should be used under appropriate clinical assessment.