Sulfamethoxazole

Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis.

Mechanism of resistance

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.

Many common pathogenic bacteria are susceptible in vitro to sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Susceptibility testing breakpoints:

EUCAST

Enterobacteriaceae: S≤2 R>4
S. maltophilia: S≤4 R>4
Acinetobacter: S≤2 R>4
Staphylococcus: S≤2 R>4
Enterococcus: S≤0.032 R>1
Streptococcus ABCG: S≤1 R> 2
Streptococcus pneumoniae: S≤1 R>2
Hemophilus influenza: S≤0.5 R>1
Moraxella catarrhalis: S≤0.5 R>1
Psuedomonas aeruginosa and other non-enterobacteriaceae: S≤2* R>4*

S = susceptible, R = resistant.
* These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to sulfamethoxazole or not.

Sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species

Gram-positive aerobes:

Staphylococcus aureus
Staphylococcus saprophyticus
Streptococcus pyogenes

Gram-negative aerobes:

Enterobacter cloacae
Haemophilus influenzae
Klebsiella oxytoca
Moraxella catarrhalis
Salmonella spp.
Stenotrophomonas maltophilia
Yersinia spp.

Species for which acquired resistance may be a problem

Gram-positive aerobes:

Enterococcus faecalis
Enterococcus faecium
Nocardia spp.
Staphylococcus epidermidis
Streptococcus pneumoniae

Gram-negative aerobes:

Citrobacter spp.
Enterobacter aerogenes
Escherichia coli
Klebsiella pneumoniae
Klebsiella pneumonia
Proteus mirabilis
Proteus vulgaris
Providencia spp.
Serratia marcesans

Inherently resistant organisms

Gram-negative aerobes:

Pseudomonas aeruginosa
Shigella spp.
Vibrio cholera

Absorption

After oral administration sulfamethoxazole is 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.

Peak plasma levels of sulfamethoxazole are higher and achieved more rapidly after one hour of intravenous infusion of 80 mg per ml for infusion than after oral administration of an equivalent dose of a sulfamethoxazole oral presentation. Plasma concentrations, elimination half-life and urinary excretion rates show no significant differences following either the oral or intravenous route of administration.

Distribution

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) fluids is of the order of 20 to 50% of the plasma concentration.

Biotransformation

Renal excretion of intact sulfamethoxazole accounts for 15-30% of the dose. This drug is extensively metabolised 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.

Elimination

The half-life of sulfamethoxazole in man is approximately 9 to 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 25 ml /minute.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form.

The pharmacokinetics of sulfamethoxazole in the paediatric population with normal renal function is age dependent. Elimination of sulfamethoxazole is reduced in neonates, during the first two months of life, thereafter sulfamethoxazole showes 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.

In elderly patients there is a reduced renal clearance of sulfamethoxazole.

Special patient population

Hepatic impairment

Caution should be exercised when treating patients with severe hepatic parenchymal damage as there may be changes in the absorption and biotransformation of sulfamethoxazole.

Elderly patients

In elderly patients, a slight reduction in renal clearance of sulfamethoxazole has been observed.

At doses in excess of recommended human therapeutic dose, sulfamethoxazole has been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist.