340 Antibacterials

InteractionsAs for Sulfamethoxazole, p.341.

Antimicrobial ActionAs for Sulfamethoxazole, p.341.

PharmacokineticsSulfamethizole is readily absorbed from the gastroin-testinal tract; about 90% has been reported to be boundto plasma proteins. Its half-life has been reported torange from about 1.5 to 3 hours. It is only slightlyacetylated in the body and is rapidly excreted, about60% of a dose being eliminated in the urine in 5 hoursand around 90% within 10 hours. Sulfamethizole andits acetyl derivative are readily soluble in urine over awide pH range. Only low concentrations are achievedin blood and tissues because of its rapid excretion.

Uses and AdministrationSulfamethizole is a short-acting sulfonamide that isgiven orally in the treatment of infections of the urinarytract, sometimes with other antibacterials; it is unsuita-ble for the treatment of systemic infection since onlyrelatively low concentrations of drug are achieved inthe blood and tissues. It is given in adult doses of 1.5 to 4 g daily in 3 or 4divided doses. A usual dose for children is 30 to45 mg/kg daily in 4 divided doses. Sulfamethizole monoethanolamine has also been used.PreparationsUSP 31: Sulfamethizole Oral Suspension; Sulfamethizole Tablets.Proprietary Preparations (details are given in Part 3)Denm.: Lucosil; Fr.: Rufol; Norw.: Lucosil†; Thai.: Luco-Oph†.Multi-ingredient: Spain: Micturol Sedante; USA: Urobiotic-250; Ven-ez.: Bacteval.

Sulfamethoxazole (BAN, USAN, rINN)

Ro-4-2130; Sulfamethoxazol; Sulfaméthoxazole; Sulfamethoxa-zolum; Sulfametoksatsoli; Sulfametoksazol; Sulfametoksazolas;Sulfametoxazol; Sulfisomezole; Sulphamethoxazole; Szulfame-toxazol. N1-(5-Methylisoxazol-3-yl)sulphanilamide.СульфаметоксазолC10H11N3O3S = 253.3.CAS — 723-46-6.ATC — J01EC01.ATC Vet — QJ01EQ11.

NOTE. Compounded preparations of sulfamethoxazole may berepresented by the following names: • Co-trimoxazole (BAN)—sulfamethoxazole 5 parts and tri-

methoprim 1 part (see p.258) • Co-trimoxazole (PEN)—sulfamethoxazole and trimethoprim.Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, andViet. Ph. Eur. 6.2 (Sulfamethoxazole). A white or almost white, crys-talline powder. Practically insoluble in water; sparingly solublein alcohol; freely soluble in acetone. It dissolves in dilute solu-tions of sodium hydroxide and in dilute acids. Protect from light. USP 31 (Sulfamethoxazole). A white to off-white, practicallyodourless, crystalline powder. Soluble 1 in 3400 of water, 1 in 50of alcohol, and 1 in 1000 of chloroform and of ether; slowly andusually incompletely soluble 1 in 2 of carbon disulfide; freelysoluble in acetone and in dilute solutions of sodium hydroxide.Protect from light.

Adverse Effects and TreatmentNausea, vomiting, anorexia, and diarrhoea are relative-ly common after use of sulfamethoxazole and othersulfonamides. Hypersensitivity reactions to sulfonamides haveproved a problem. Fever is relatively common, and re-actions involving the skin may include rashes, pruritus,photosensitivity reactions, exfoliative dermatitis, anderythema nodosum. Severe, potentially fatal, skin reac-

tions including toxic epidermal necrolysis and theStevens-Johnson syndrome have occurred in patientstreated with sulfonamides. Dermatitis may also occurfrom contact of sulfonamides with the skin. SLE, par-ticularly exacerbation of pre-existing disease, has alsobeen reported. Nephrotoxic reactions including interstitial nephritisand tubular necrosis, which may result in renal failure,have been attributed to hypersensitivity to sulfameth-oxazole. Lumbar pain, haematuria, oliguria, and anuriamay also occur due to crystallisation in the urine of sul-famethoxazole or its less soluble acetylated metabolite.The risk of crystalluria can be reduced by giving fluidsto maintain a high urine output. If necessary, alkalini-sation of the urine with sodium bicarbonate may in-crease solubility and aid the elimination of sulfona-mides. Blood disorders have occasionally occurred duringtreatment with the sulfonamides including sulfameth-oxazole, and include agranulocytosis, aplastic anae-mia, thrombocytopenia, leucopenia, hypoprothrombi-naemia, and eosinophilia. Many of these effects on theblood may result from hypersensitivity reactions. Sul-fonamides may rarely cause cyanosis due to methaem-oglobinaemia. Acute haemolytic anaemia is a rarecomplication which may be associated with G6PD de-ficiency. Other adverse effects that may be manifestations of ageneralised hypersensitivity reaction to sulfonamidesinclude a syndrome resembling serum sickness, hepat-ic necrosis, hepatomegaly and jaundice, myocarditis,pulmonary eosinophilia and fibrosing alveolitis, andvasculitis including polyarteritis nodosa. Anaphylaxishas been reported only very rarely. Other adverse reactions reported after sulfamethoxa-zole or other sulfonamides include hypoglycaemia,hypothyroidism, neurological reactions includingaseptic meningitis, ataxia, benign intracranial hyper-tension, convulsions, dizziness, drowsiness, fatigue,headache, insomnia, mental depression, peripheral oroptic neuropathies, psychoses, tinnitus, vertigo, andpancreatitis. Sulfonamides may displace serum-bound bilirubin, re-sulting in kernicterus in premature neonates. As with other antimicrobials, sulfamethoxazole maycause alterations of the bacterial flora in the gastroin-testinal tract. There is, therefore, the possibility, al-though it appears to be small, that pseudomembranouscolitis may occur. Slow acetylators of sulfamethoxazole may be at great-er risk of adverse reactions than fast acetylators. For further information on the adverse effects of sul-famethoxazole when used with trimethoprim, see Co-trimoxazole, p.258.

PrecautionsIn patients given sulfamethoxazole, adequate fluid in-take is necessary to reduce the risk of crystalluria; thedaily urine output should be 1200 mL or more. Com-pounds that render the urine acidic may increase therisk of crystalluria; the risk may be reduced with alka-line urine. Treatment with sulfonamides should be stopped imme-diately a rash appears because of the danger of severeallergic reactions such as the Stevens-Johnson syn-drome. Sulfamethoxazole should be given with care to patientswith renal or hepatic impairment and is contra-indicat-ed in patients with severe impairment or with blooddisorders. Dosage reduction may be necessary in renalimpairment. Complete blood counts and urinalyseswith microscopic examination should be carried outparticularly during prolonged therapy. Sulfamethoxa-zole should not be given to patients with a history ofhypersensitivity to sulfonamides as cross-sensitivitymay occur between drugs of this group. Care is gener-ally advisable in patients with a history of allergy or

asthma. Caution is also needed in the elderly, who maybe more likely to have other risk factors for reactions.Some consider sulfamethoxazole to be contra-indicat-ed in lupus erythematosus as it may exacerbate thecondition. Patients with glucose 6-phosphate dehydro-genase deficiency may be at risk of haemolytic reac-tions. Sulfamethoxazole and other sulfonamides are not usu-ally given to infants within 1 to 2 months of birth be-cause of the risk of producing kernicterus; for the samereason, they are generally contra-indicated in womenprior to delivery (see below). Patients with AIDS may be particularly prone to ad-verse reactions, especially when sulfamethoxazole isgiven with trimethoprim as co-trimoxazole. Sulfonamides have been reported to interfere withsome diagnostic tests, including those for urea, creati-nine, and urinary glucose and urobilinogen.Breast feeding. Sulfonamides are excreted into breast milk inlow concentrations and, although they are generally contra-indi-cated in the USA in breast-feeding women because of the risk ofkernicterus, they are usually thought to pose a negligible risk tohealthy neonates. However, sulfonamides should be used withcaution in breast-feeding mothers of ill, stressed, or prematureinfants and of infants with jaundice, hyperbilirubinaemia orG6PD deficiency. The American Academy of Pediatrics considers sulfamethoxa-zole, when given with trimethoprim, to be compatible withbreast feeding.11. American Academy of Pediatrics. The transfer of drugs and oth-

er chemicals into human milk. Pediatrics 2001; 108: 776–89.Correction. ibid.; 1029. Also available at: h t tp: / /aappol icy.aappublica tions.org/cgi /content /ful l /pediatrics%3b108/3/776 (accessed 28/05/04)

Immunocompromised patients. Sulfamethoxazole ismainly conjugated in the liver to the N4-acetyl derivative, but isalso oxidised, to a limited extent, to the hydroxylamine metabo-lite.1-5 Although this metabolite was originally implicated6 in thedevelopment of adverse reactions to sulfonamides, recent work7

has cast some doubt on this hypothesis. The metabolite appearsto be produced through cytochrome P450 oxidative metabolism,and it has been suggested that slow acetylators of sulfamethoxa-zole exhibit increased oxidation compared with other metabolicroutes.1 AIDS patients also exhibit increased oxidation, sincethey may be depleted of substrates such as acetylcoenzyme A orglutathione necessary for acetylation or detoxification, and thismay explain their susceptibility to sulfamethoxazole toxicity.2,3 There have been attempts to inhibit the formation of the hydrox-ylamine metabolite by competitive inhibition of cytochromeP450 enzymes, notably with fluconazole and ketoconazole.4,5

Encouraging results have been obtained with fluconazole inhealthy subjects, but the potential for clinical benefit in AIDSpatients requires further study.5 However, one successful method of overcoming adverse effectsin AIDS patients has been desensitisation. Desensitisation byuse of initial doses of 4 mg of sulfamethoxazole or 5 mg of sul-fadiazine every 6 hours, doubled at 24-hour intervals until thedesired dose was reached, was uneventful in 9 of 13 patients withAIDS requiring sulfonamide treatment for opportunistic infec-tions.8 The remaining 4 had cutaneous reactions with fever, butin 2 of these the reactions were successfully managed with anantihistamine. Although there is a risk of anaphylaxis, patientswith AIDS can be successfully treated with sulfonamides afterdesensitisation. See also Immunocompromised Patients under Precautions ofCo-trimoxazole, p.258.1. Cribb AE, Spielberg SP. Sulfamethoxazole is metabolized to the

hydroxylamine in humans. Clin Pharmacol Ther 1992; 51:522–6.

2. Lee BL, et al. The hydroxylamine of sulfamethoxazole and ad-verse reactions in patients with acquired immunodeficiency syn-drome. Clin Pharmacol Ther 1994; 56: 184–9.

3. van der Ven AJA, et al. Urinary recovery and kinetics of sul-phamethoxazole and its metabolites in HIV-seropositive patientsand healthy volunteers after a single oral dose of sulphamethox-azole. Br J Clin Pharmacol 1995; 39: 621–5.

4. Mitra AK, et al. Inhibition of sulfamethoxazole hydroxylamineformation by fluconazole in human liver microsomes andhealthy volunteers. Clin Pharmacol Ther 1996; 59: 332–40.

5. Gill HJ, et al. The effect of fluconazole and ketoconazole on themetabolism of sulphamethoxazole. Br J Clin Pharmacol 1996;42: 347–53.

6. van der Ven AJAM, et al. Adverse reactions to co-trimoxazole inHIV infection. Lancet 1991; 338: 431–3.

7. ter Hofstede HJM, et al. Drug reactions to cotrimoxazole in HIVinfection: possibly not due to the hydroxylamine metabolites ofsulphamethoxazole. Br J Clin Pharmacol 1999; 47: 571–3.

8. Torgovnick J, Arsura E. Desensitization to sulfonamides in pa-tients with HIV infection. Am J Med 1990; 88: 548–9.

Porphyria. Sulfonamides have been associated with acute at-tacks of porphyria and are considered unsafe in porphyric pa-tients.

H2N

SNH

O O ONCH3

Sulfamethoxazole 341

The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)

Pregnancy. Some sulfonamides have been shown to cause fetalabnormalities including cleft palate in animals, but fears of tera-togenic effects in humans do not appear to be substantiated. Sul-fonamides are probably safe in the first trimester of pregnancy,although throughout pregnancy they should be used only in theabsence of a suitable alternative drug.1 Sulfonamides may dis-place serum-bound bilirubin and they should be avoided close todelivery because of the risk of kernicterus in the neonate. Therisk of drug-induced bilirubin displacement has been reviewed.2The initial evidence suggesting a kernicterus-promoting effect ofdrugs in neonates was reported for sulfafurazole, and this drugnow serves as a standard displacing agent against which otherdrugs are evaluated. Although all sulfonamides are highly pro-tein bound, each has a different capacity to displace bilirubin.Sulfadiazine and sulfanilamide have been found to be the leastdisplacing of the sulfonamides and the effects of sulfadiazine onbilirubin may not be clinically significant; an increased incidenceof hyperbilirubinaemia and kernicterus has not been shown afteruse for prophylaxis of rheumatic fever during pregnancy. Sul-fasalazine should theoretically cause significant bilirubin dis-placement, but studies suggest that the drug may be given to pa-tients with Crohn’s disease who are pregnant or breast feeding.Metabolites of sulfonamides have also been evaluated for ker-nicterus-promoting effects; glucuronide metabolites are expect-ed to compete for binding sites less effectively than the parentcompound, whereas acetylated metabolites of some sulfona-mides appear to be more potent bilirubin displacers.1. Wise R. Prescribing in pregnancy: antibiotics. BMJ 1987; 294:

42–4. 2. Walker PC. Neonatal bilirubin toxicity: a review of kernicterus

and the implications of drug-induced bilirubin displacement.Clin Pharmacokinet 1987; 13: 26–50.

InteractionsThe action of sulfonamides may be antagonised by p-aminobenzoic acid and its derivatives, particularly po-tassium aminobenzoate and the procaine group of localanaesthetics. Sulfamethoxazole and other sulfonamides may poten-tiate the effects of some drugs, such as oral anticoagu-lants (p.1428), methotrexate (p.748), and phenytoin(p.498); this may be due to displacement of the drugfrom plasma protein binding sites or to inhibition ofmetabolism. However, the clinical significance ofthese interactions appears to depend on the particularsulfonamide involved. The possibility of interactionswith other highly protein-bound drugs, such asNSAIDs, should be considered. High doses of sulfonamides have been reported to havea hypoglycaemic effect; the antidiabetic effect of thesulfonylurea compounds may be enhanced by sulfona-mides (p.462). Some sulfonamides have been associat-ed with a decrease in plasma-ciclosporin concentra-tions when used together (p.1826). Isolated reportshave described possible failures of hormonal contra-ceptives resulting in pregnancy in patients given sul-fonamides (p.2068). The use of compounds which render the urine acidicmay increase the risk of crystalluria.

Antimicrobial ActionSulfamethoxazole and other sulfonamides have a sim-ilar structure to p-aminobenzoic acid and interfere withthe synthesis of nucleic acids in sensitive micro-organ-isms by blocking the conversion of p-aminobenzoicacid to the coenzyme dihydrofolic acid, a reduced formof folic acid; in man, dihydrofolic acid is obtained fromdietary folic acid so sulfonamides do not affect humancells. Their action is primarily bacteriostatic, althoughthey may be bactericidal where concentrations ofthymine are low in the surrounding medium. The sul-fonamides have a broad spectrum of action, but the de-velopment of widespread resistance (see below) hasgreatly reduced their usefulness, and susceptibility of-ten varies widely even among nominally sensitivepathogens. Gram-positive cocci, particularly the Group A strepto-cocci and some strains of Streptococcus pneumoniae,are usually sensitive and staphylococci also demon-strate sensitivity but to a lesser extent. Enterococci andmany of the clostridia are more or less resistant, al-though strains of Clostridium perfringens are moder-ately susceptible. Among other Gram-positive organ-isms that have been reported to be sensitive are

Bacillus anthracis and many strains of Nocardia, espe-cially N. asteroides. The Gram-negative cocci Neisseria meningitidis andN. gonorrhoeae were formerly extremely susceptibleto sulfonamides, but many strains are now resistant.Susceptibility is often seen in Haemophilus influenzaealthough resistance in H. ducreyi is increasingly com-mon. Susceptibility varies widely among the Entero-bacteriaceae: strains of Escherichia coli, Klebsiella,Proteus, Salmonella, and Serratia are sometimes sen-sitive, but few strains of Shigella are now susceptible.Vibrio cholerae may be sensitive. Other organisms that have been reported to be sensitiveinclude Actinomyces spp., Brucella, Klebsiella granu-lomatis, Legionella, and Yersinia pestis. Chlamydiace-ae are sensitive, but not mycoplasmas, rickettsias, orspirochaetes, nor in general the mycobacteria. Pseu-domonas aeruginosa is resistant, although sulfona-mides may be effective against Burkholderia pseu-domallei (Pseudomonas pseudomallei). Sulfonamides have some activity against the protozoaPlasmodium falciparum and Toxoplasma gondii. Theyare also active against Pneumocystis jirovecii, but areineffective against most fungi. Sulfamethoxazole and other sulfonamides demon-strate synergy with the dihydrofolate reductase inhibi-tors pyrimethamine and trimethoprim which inhibit alater stage in folic acid synthesis. For reports of the an-timicrobial activity of sulfamethoxazole with trimeth-oprim, see Co-trimoxazole, p.259. The in-vitro antimicrobial activity of sulfamethoxazoleis very dependent on both the culture medium and sizeof inoculum used. Resistance. Acquired resistance to sulfonamides iscommon and widespread among formerly susceptibleorganisms, particularly Neisseria spp., Shigella andsome other enterobacteria, staphylococci, and strepto-cocci. There appear to be several mechanisms of resistanceincluding alteration of dihydropteroate synthetase, theenzyme inhibited by sulfonamides, to a less sensitiveform, or an alteration in folate biosynthesis to an alter-native pathway; increased production of p-aminoben-zoic acid; or decreased uptake or enhanced metabolismof sulfonamides. Resistance may result from chromosomal alteration, ormay be plasmid-mediated and transferable, as in manyresistant strains of enterobacteria. High-level resist-ance is usually permanent and irreversible. There iscomplete cross-resistance between the different sulfon-amides.

PharmacokineticsSulfamethoxazole is readily absorbed from the gas-trointestinal tract and peak plasma concentrations arereached after about 2 hours. Following a single 2-g oraldose , b lood concentra t ions of up to100 micrograms/mL are achieved. About 70% isbound to plasma proteins. The plasma half-life is about6 to 12 hours; it is prolonged in patients with severerenal impairment. Sulfamethoxazole, like most sulfonamides, diffusesfreely throughout the body tissues and may be detectedin the urine, saliva, sweat, and bile, in the cerebrospi-nal, peritoneal, ocular, and synovial fluids, and in pleu-ral and other effusions. It crosses the placenta into thefetal circulation and low concentrations have been de-tected in breast milk. Sulfamethoxazole undergoes conjugation mainly inthe liver, chiefly to the inactive N4-acetyl derivative;this metabolite represents about 15% of the totalamount of sulfamethoxazole in the blood. Metabolismis increased in patients with renal impairment and de-creased in those with hepatic impairment. Eliminationin the urine is dependent on pH. About 80 to 100% ofa dose is excreted in the urine, of which about 60% is

in the form of the acetyl derivative, with the remainderas unchanged drug and glucuronide. Sulfamethoxazole is also oxidised to the hydroxy-lamine, a metabolite that has been implicated in ad-verse reactions to sulfonamides (see also Immunocom-promised Patients, under Precautions, above),although some doubt has been cast upon this hypothe-sis.

Uses and AdministrationThe use of sulfamethoxazole and other sulfonamideshas been limited by the increasing incidence of resist-ant organisms. Their main use has been in the treat-ment of acute, uncomplicated urinary-tract infections,particularly those caused by Escherichia coli. Theyhave also been used in nocardiosis, and in some otherbacterial infections such as otitis media, Chlamydiaand Chlamydophila infections, and prophylaxis ofmeningococcal meningitis, but have largely been re-placed by other drugs: even where pathogens retainsome sensitivity to sulfonamides, a combination suchas co-trimoxazole (sulfamethoxazole with trimetho-prim) has often been preferred. The usual treatment ofthese infections is discussed under Choice of Antibac-terial, p.162. Sulfonamides are also used, often withpyrimethamine or trimethoprim, in the treatment ofprotozoal infections, particularly malaria (p.594) andtoxoplasmosis (p.826). They are also used similarly inpneumocystis pneumonia (p.521). Sulfamethoxazole is an intermediate-acting sulfona-mide that has been given orally in a usual dose of 2 ginitially, followed by 1 g twice daily. In severe infec-tions 1 g three times daily has been given. Children have been given a dose of 50 to 60 mg/kg in-itially, followed by 25 to 30 mg/kg twice daily, up to amaximum daily dose of 75 mg/kg. Reduction of dosage may be required in patients withrenal impairment. For the uses and dosage of sulfamethoxazole with tri-methoprim, see Co-trimoxazole, p.259. Sulfamethoxazole lysine has also been used.Administration. US licensed product information for a formerproduct of sulfamethoxazole recommended that blood concen-trations be measured in patients receiving sulfonamides for seri-ous infections. The following concentrations of free sulfonamidein the blood were considered to be therapeutically effective: • for most infections, 50 to 150 micrograms/mL • for serious infections, 120 to 150 micrograms/mL Concentrations of 200 micrograms/mL should not be exceededsince the incidence of adverse reactions might be increased.

PreparationsBP 2008: Co-trimoxazole Intravenous Infusion; Co-trimoxazole Oral Sus-pension; Co-trimoxazole Tablets; Dispersible Co-trimoxazole Tablets; Pae-diatric Co-trimoxazole Oral Suspension; Paediatric Co-trimoxazole Tablets; USP 31: Sulfamethoxazole and Trimethoprim Injection; Sulfamethoxazoleand Trimethoprim Oral Suspension; Sulfamethoxazole and TrimethoprimTablets; Sulfamethoxazole Oral Suspension; Sulfamethoxazole Tablets.Proprietary Preparations (details are given in Part 3)Multi-ingredient: Arg.: Adrenol; Bacti-Uril; Bacticel; Bactrim; BactrimBalsamico; Cotrizol-G; Danferane; Diocla†; Dosulfin Bronquial; DosulfinFuerte; Enterobacticel; Netocur ; Netocur Balsamico; Neumobacticel;Novidrine; Sulfagrand; Tritenk; Urisept NF; Uro-Bactrim†; Austral.:Bactrim; Cosig†; Resprim; Septrin; Trimoxazole; Austria: Bactrim; Cot-ribene; Eusaprim; Oecotrim; Trimetho comp; Belg.: Bactrim; Cotrim; Eus-aprim; Steroprim†; Braz.: Assepium; Assepium Balsamico; Bac-Sulfitrin;Bacfar; Bacprotin; Bacris†; Bacteracin; Bactrim; Bactrisan; Bactrizol; Bactro-pin; Batrox; Baxapril†; Benectrin; Benectrin Balsamico; Binoctrin†; Clotri-zol†; Diazol; Dientrin; Dispeptrin; Duoctrin†; Ectrin; Ectrin Balsamico; Espe-ctrin†; Espectroprima†; Gamactrin; Imuneprim; Infectrin; Lifactrin†; Linurin†;Lupectrim†; Metoprin; Metoprin Balsamico; Neotrin; Pulkrin; Qiftrin†;Quimio-Ped†; Roytrin†; Selectrin; Selectrin Balsamico; Septiolan†; Teutrin;Tricban; Trimexazol; Trimezol†; Uro-Baxapril†; Uroctrin; Uropol; Canad.:Apo-Sulfatrim; Novo-Trimel; Nu-Cotrimox; Septra; Chile: Bacterol; Bactri-mel; Entero Micinovo; Introcin†; Septrin; Trelibec; Uro-Micinovo; Cz.: Apo-Sulfatrim†; Berlocid†; Biseptol; Bismoral; Nopil†; Oriprim†; Primotren;Sumetrolim; Supracombin†; Denm.: Sulfotrim†; Fin.: Cotrim; Fr.: Bactrim;Eusaprim†; Ger.: Bactoreduct†; Berlocid; Cotrim; Cotrim-Diolan; Cotrim-Hefa; Cotrimhexal; Cotrimox-Wolff; Cotrimstada; Drylin; Eusaprim; Kepi-nol; Microtrim†; Sigaprim†; Supracombin†; TMS; Gr.: Bactrimel; Bioprim†;Septrin; Hong Kong: Chemitrim†; Chemoprim; Cotrim; Dhatrin; Letus;Septrin; Hung.: Cotripharm; Sumetrolim; India: Bactrim; Ciplin; Colizole;Cotrimol†; Oriprim; Pyramet; Sepmax; Septran; Tabrol; Trisulfose; Indon.:Bactoprim Combi; Bactricid; Bactrim; Bactrizol; Cotrim; Cotrimol; Dumot-rim; Erphatrim; Ikaprim; Infatrim; Kaftrim; Lapikot; Licoprima; Meditrim; Me-protrin; Nufaprim; Ottoprim; Primadex; Primazole; Primsulfon; Sanprima;Septrin; Spectrem; Sulprim; Sultrimmix; Trimezol; Triminex; Trimoxsul; Trix-zol; Trizole; Ulfaprim; Wiatrim; Xepaprim; Zoltrim; Zultrop; Irl.: Duobact†;Septrin; Israel: Diseptyl; Resprim; Septrin; Ital.: Abacin†; Bactrim;Chemitrim; Eusaprim; Gantrim†; Jpn: Bactramin; Malaysia: Bacin; Baser-in†; Chemix; Cotrim; Resprim; Trimexazole; Virin†; Mex.: Andoprim; Ani-trim; Apo-Trinelax; Bacpiryl; Bactelan; Bacteric; Bactide; Bactilen; Bactiver;

342 AntibacterialsBactrim; Bactrim Compositum; Bactropin; Bateral; Batrizol; Bioprim; Bi-sultrim; Brogamax; Dertrin; Dibaprim; Ectaprim; Esteprim; Eutrim; Fartro-pin; Fectri; Guayaprin; Kaltrim; Maxtrim; Metoxiprim; Microbactim†; Mix-ange; Octex; Octiban; Pisatrina; Polibatrin; Pribac; Protaxol; Protrim;Sadocin; Septrin; Servitrim; Soltrim; Sulfawal; Sulfoid Trimetho; Sulfort; Sul-prim; Sultiprim†; Syraprim†; Thriazol; Tribakin; Trime/Sulfa†; Trimetoger;Trimetox; Trimexazol; Trimexole; Trimexole Compositum; Trimzol; Trine-lax†; Trisufin†; Vanadyl; Neth.: Bactrimel; Eusaprim†; Sulfotrim; Norw.:Bactrim; Trimetoprim-Sulfa†; NZ: Apo-Sulfatrim; Trisul; Philipp.: Bacidal;Bactille; Bactrim; Bacxal; Baczole; Bantizol; Chromo-Z; Combi-Methoxan;Costazole; Cozole; Drilozole; Fedimed; Forteprim; Globaxol; Ivatrim; Kasse-mox; Lictora; Macromed; Moxadden; Moxzole; Neotrim; Onetrim; Opri-zole; Prizogen; Procor; Renatrim; Rimezone; Rotrace; Scribcin; Septrin; Su-prex; Syltrifil; Synermed; Triforam; Trim-S; Trimephar; Trimocom; Trimoxis;Triphimox; Trizole; Xanazole; Zamboprim; Zolmed; Pol.: Bactrim; Biseptol;Groseptol†; Septrin; Two-Septol; Port.: Bactrim; Cotrim†; Metomide†; Mi-crocetim; Septrin; Rus.: Biseptol (Бисептол); Oriprim (Ориприм); Rancot-rim (Ранкотрим); S.Afr.: Acuco; Bactrim; Bencole; Casicot; Cocydal; Coz-ole; Durobac; Fabubac†; Lagatrim; Meditrim; Mezenol†; Purbac; Septran;Spectrim; Trimethox; Trimzol; Xerazole; Xeroprim†; Singapore: Apo-Sul-fatrim; Bacin; BS†; Chemix; Chemoprim; Co-Trimexazole; Dhatrin; Sep-trin†; Suprim; Trimaxazole; Trimezole†; Spain: Bactopumon; Balsoprim;Bronco Aseptilex Fuerte; Broncomega†; Broncovir ; Bronquicisteina; Bron-quidiazina CR; Bronquimar; Bronquimucil†; Busetal†; Cotrazol; EduprimMucolitico; Eduprim†; Gobens Trim; Momentol; Neumopectolina†; PulmoMenal†; Pulmosterin Duo; Septrin; Soltrim; Swed.: Bactrim; Eusaprim;Switz.: Agoprim†; Bactrim; Cotrim; Escoprim; Groprim; Lagatrim;Mediprim; Nopil; Sigaprim†; Supracombin†; Thai.: Actin; Bacin; Bacta†;Bactrim; Baczole; Chemoprim†; Co-Tasian; Co-Trimed; Conprim; Cota-mox; Ko-Cap; Ko-Kure; Ladar; Lastrim; Letus; M-Trim; Mano-Trim; Med-Sultrim†; Mega-Prim; Metrim; Metxaprim; Mycosamthong; Po-Trim; Pul-vicin†; Septrin†; Spectrim; Sulbacta; Sulfometh; Suntrim; Tampo†; Toprim†;Trimexazole; Triprim; Trixzol; Zoleprim†; Turk.: Bactrim; Bakton; Kemo-prim; Metoprim; Mikrosid; Septrin; Trifen; Trimoks; UAE: Trimol; UK:Fectrim; Septrin; USA: Bactrim; Cotrim; Septra; SMZ-TMP; Sulfatrim; Ven-ez.: Bactrimel; Bactron†; Co-Sultrin; Forcrim; Trimecor; Trimetoprim Sulfa†;Tripur.

Sulfamethoxypyridazine (BAN, rINN)

Solfametossipiridazina; Sulfamethoxypyridazin; Sulfaméthoxypy-ridazine; Sulfamethoxypyridazinum; Sulfamethoxypyridazinum adusum veterinarium; Sulfametoksipyridatsiini; Sulfametoxipiridazi-na; Sulfametoxipyridazin; Sulphamethoxypyridazine; Szulfame-toxipiridazin. N1-(6-Methoxypyridazin-3-yl)sulphanilamide.СульфаметоксипиридазинC11H12N4O3S = 280.3.CAS — 80-35-3.ATC — J01ED05.ATC Vet — QJ01EQ15.

Pharmacopoeias. In Int. and Viet. In Eur. (see p.vii) for veter-inary use only. Ph. Eur. 6.2 (Sulfamethoxypyridazine for Veterinary Use; Sul-fametoxypyridazine BP(Vet) 2008). A white or slightly yellowishcrystalline powder which colours slowly on exposure to light.Practically insoluble in water; slightly soluble in alcohol; spar-ingly soluble in acetone; very slightly soluble in dichlorometh-ane; dissolves in dilute mineral acids and solutions of alkali hy-droxides. Protect from light.ProfileSulfamethoxypyridazine is a long-acting sulfonamide with prop-erties similar to those of sulfamethoxazole (p.340) and has beenused for the treatment of susceptible infections. It is rapidly ab-sorbed from the gastrointestinal tract and excreted slowly inurine, partly as the N4-acetyl metabolite; it remains detectable forup to 7 days after a dose. It has also been used with trimethoprimsimilarly to co-trimoxazole. Acetyl sulfamethoxypyridazine, which is hydrolysed in the gas-trointestinal tract forming sulfamethoxypyridazine, and sulfam-ethoxypyridazine sodium have also been used.Skin disorders. Reference to the use of sulfamethoxypyri-dazine in the treatment of pemphigoid.1 Sulfamethoxypyridazinehas also been used in the treatment of dermatitis herpetiformis.21. Thornhill M, et al. An open clinical trial of sulphamethoxypyri-

dazine in the treatment of mucous membrane pemphigoid. Br JDermatol 2000; 143: 117–26.

2. Fry L. Dermatitis herpetiformis. Baillieres Clin Gastroenterol1995; 9: 371–93.

PreparationsProprietary Preparations (details are given in Part 3)Multi-ingredient: Braz.: Urofen†; Uropac.

SulfamethylthiazoleMethylsulfathiazole; Sulfametiltiazol. 4-Amino-N-(4-methyl-2-thi-azolyl)benzenesulfonamide.C10H11N3O2S2 = 269.3.CAS — 515-59-3.

ProfileSulfamethylthiazole is a sulfonamide with properties similar tothose of sulfamethoxazole (p.340). It is applied topically with tet-racycline in the treatment of eye infections.PreparationsProprietary Preparations (details are given in Part 3)Multi-ingredient: Ital.: Pensulvit.

Sulfametopyrazine (BAN)

Sulfalene (USAN, pINN); AS-18908; NSC-110433; Solfametopirazi-na; Solfametossipirazina; Sulfaleeni; Sulfalen; Sulfalène; Sulfaleno;Sulfalenum; Sulfamethoxypyrazine; Sulfapirazinmetossina; Sul-fapyrazin Methoxyne; Sulphalene. N1-(3-Methoxypyrazin-2-yl)sulphanilamide.СульфаленC11H12N4O3S = 280.3.CAS — 152-47-6.ATC — J01ED02.

Pharmacopoeias. In It.Adverse Effects, Treatment, and PrecautionsAs for Sulfamethoxazole, p.340. If adverse effects occur, sulfametopyrazine has the disadvantagethat several days are required for its elimination from the body.InteractionsAs for Sulfamethoxazole, p.341.Antimicrobial ActionAs for Sulfamethoxazole, p.341.PharmacokineticsSulfametopyrazine is readily absorbed from the gastrointestinaltract; 60 to 80% is bound to plasma proteins. Only about 5% ofa dose is metabolised to the acetyl derivative. It is slowly excret-ed in the urine. The biological half-life has been reported to beabout 60 to 65 hours.Uses and AdministrationSulfametopyrazine is a long-acting sulfonamide that has beenused orally in the treatment of respiratory- and urinary-tract in-fections due to sensitive organisms. Sulfametopyrazine is given with pyrimethamine (p.611) in thetreatment of malaria. It has also been given in the ratio 4 parts of sulfametopyrazine to5 parts of trimethoprim as a combination with uses similar tothose of co-trimoxazole (p.259).PreparationsProprietary Preparations (details are given in Part 3)Ger.: Longum†.Multi-ingredient: Belg.: Co-Arinate; Dafrafin; Ital.: Metakelfin; Mex.:Kelfiprim†.

Sulfametrole (BAN, rINN)

Sulfametrol; Sulfamétrole; Sulfametrolum. N1-(4-Methoxy-1,2,5-thiadiazol-3-yl)sulphanilamide.СульфаметролC9H10N4O3S2 = 286.3.CAS — 32909-92-5.

ProfileSulfametrole is a sulfonamide with properties similar to those ofsulfamethoxazole (p.340). It is given in the ratio of 5 parts ofsulfametrole to 1 part of trimethoprim as a combination with usessimilar to those of co-trimoxazole (p.259). Usual oral doses are960 mg (800 mg of sulfametrole and 160 mg of trimethoprim)twice daily. It has also been given as the sodium salt by intrave-nous infusion.

Preparations

Proprietary Preparations (details are given in Part 3)

Multi-ingredient: Austria: Lidaprim; Gr.: Lidaprim; Hong Kong: Lid-aprim; Ital.: Lidaprim†; Neth.: Lidatrim; Rus.: Lidaprim (Лидаприм);Thai.: Lidaprim†.

Sulfamonomethoxine (BAN, USAN, rINN)

DJ-1550; DS-36; ICI-32525; Ro-4-3476; Sulfamonométhoxine;Sulfamonomethoxinum; Sulfamonometoxina. N1-(6-Methoxypy-rimidin-4-yl)sulphanilamide monohydrate.

Сульфамонометоксин

C11H12N4O3S,H2O = 298.3.

CAS — 1220-83-3 (anhydrous sulfamonomethoxine).

(anhydrous sulfamonomethoxine)

Pharmacopoeias. In Jpn.

ProfileSulfamonomethoxine is a sulfonamide antibacterial with proper-ties similar to those of sulfamethoxazole (p.340). It is used in vet-erinary medicine.

Sulfamoxole (BAN, USAN, rINN)

Sulfamoksoli; Sulfamoxol; Sulfamoxolum; Sulphadimethyloxazole;Sulphamoxole. N1-(4,5-Dimethyloxazol-2-yl)sulphanilamide.

Сульфамоксол

C11H13N3O3S = 267.3.

CAS — 729-99-7.

ATC — J01EC03.

NOTE. Compounded preparations of sulfamoxole may be repre-sented by the following name:

• Co-trifamole (BAN)—sulfamoxole 5 parts and trimethoprim 1part (see p.257).

Pharmacopoeias. In Fr.

ProfileSulfamoxole is a sulfonamide antibacterial with properties simi-lar to those of sulfamethoxazole (p.340). It has been used withtrimethoprim as co-trifamole (p.257).

Preparations

Proprietary Preparations (details are given in Part 3)

Multi-ingredient: S.Afr.: Supristol†.

H2N

SNH

NN

OCH3OO

SO

ONHS

NH3C

NH2

SNH

O ON

N

H2NO

CH3

NH

SO

O

H2NSN

N

O CH3

NHS

O

O

NH2

NN

OH3C

SNH

H2N

OO

N

O

CH3

CH3