Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic Group: ANTIBACTERIALS FOR SYSTEMIC USE – SULFONAMIDES AND TRIMETHOPRIM – Combinations of sulphonamides and trimethoprim, incl. derivatives
ATC Code: J01EE0l
Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate. Depending on the conditions the effects may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.
Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less for the corresponding bacterial enzyme.
In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.
Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.
Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.
Testing of trimethoprim-sulfamethoxazole was performed using the common dilution series to assess the Minimum Inhibitory Concentration (MIC). The MIC breakpoints for resistance are those recommended by CLSI (Clinical and Laboratory Standards Institute – formerly the National Committee for Clinical Laboratory Standards (NCCLS) and EUCAST guidelines.
The majority of common pathogenic bacteria are sensitive in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antimicrobial agents in vitro activity does not necessarily imply that clinical efficacy had been demonstrated. These organisms include:
Gram Negative:
Brucella spp.
Citrobacter spp.
Escherichia coli (including ampicillin-resistant strains)
Haemophilus ducreyi
Haemophilus influenzae (including ampicillin-resistant strains)
Klebsiella/Enterobacter spp.
Legionella pneumophila
Morganella morganii (previously Proteus morganii)
Neisseria spp.
Proteus spp.
Providencia spp. (including previously Proteus rettgeri)
Certain Pseudomonas spp. except aeruginosa
Salmonella spp. including S. typhi and paratyphi.
Serratia marcescens
Shingella spp.
Vibrio cholerae
Yersinia spp.
Gram positive:
Listeria monocytogenes
Nocardias pp.
Staohylococcus aureus
Staphylococcus epidermidis and saprophyticus
Enterococcus faecalis
Streptococcus pneumoniae
Many strains of Bacteroides fragilis are sensitive. Some strains of Campylobacter fetus subsp. Jejuni and chlamydia are sensitive without evidence of synergy. Some varieties of non-tuberculous mycobacteria are sensitive to sulfamethoxazole but not trimethoprim. Mycoplasmas, Ureaplasma urealyticum, Mycobacterium tuberculosis and Treponema pallidum are insensitive.
Satisfactory sensitivity testing is achieved only with recommended media free from inhibitory substances especially thymidine and thymine.
After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect in the concentrations achieved in the blood by the other.
Approximately 50% of trimethoprim in the plasma is protein bound.
Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, salvia, sputum and vaginal secretions. Levels in the aqueous humour, breast milk, cerebrospinal; middle ear fluid synovial fluid and tissue (interstitial) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and fetal tissue reaching concentrations approximately those of maternal serum.
Approximately 66% of sulfamethoxazole in the plasma is protein bound. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humour, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluid is of the order of 20-50% of the plasma concentration.
Renal excretion of intact sulfamethoxazole accounts for 15-30% of the dose. This drug is more extensively metabolised than trimethoprim, via acetylation, oxidation or glucuronidation. Over a 72 hour period, approximately 85% of the dose can be accounted for in the urine as unchanged drug plus the major (N4-acetylated) metabolite.
The half-life of trimethoprim in man is in the range 8.6 to 17 hours in the presence of normal renal function. There appears to be no significant difference in the elderly compared with young patients. The principle route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.
The half-life of sulfamethoxazole in man is approximately 9-11 hours in the presence of normal renal function.
There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25ml/minute. The principle route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form.
When the creatinine clearance falls below 30 mL/min the dosage of Septrin should be reduced (see section 4.2).
Caution should be exercised when treating patients with severe hepatic impairment as there may be changes in the absorption and biotransformation of trimethoprim and sulfamethoxazole.
In older patients, a slight reduction in renal clearance of sulfamethoxazole but not trimethoprim has been observed.
The pharmacokinetics in the paediatric population with normal renal function of both components of Septrin, trimethoprim and sulfamethoxazole are age dependent. Elimination of trimethoprim – sulfamethoxazole is reduced in neonates, during the first two months of life, thereafter both trimethoprim and sulfamethoxazole show a higher elimination with a higher body clearance and a shorter elimination half-life. The differences are most prominent in young infants (>1.7 months up to 24 months) and decrease with increasing age, as compared to young children (1 year up to 3.6 years), children (7.5 years and <10 years) and adults (see section 4.2).
At doses generally in excess of the recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, finding typical of a folate antagonist. Effects with trimethoprim were preventable by co-administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.
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