Thomas M Guenthner Ph D Department of Pharmacology E 418 MSA m c 868 996 2558 tmg uic edu SYNTHETIC ANTIBACTERIAL DRUGS SULFONAMIDES TRIMETHOPRIM AND QUINOLONES Antibiotics are by definition natural products biosynthesized by microorganisms that are toxic to other species of microorganisms Sulfonamides trimethoprim and quinolones are manmade drugs and are therefore strictly speaking not antibiotics but synthetic antibacterial agents Sulfonamides were the first successful selectively toxic antibacterial drugs Prontosil see below was discovered by Gerhard Domagk in 1936 and used to successfully treat puerperal sepsis childbirth fever in London Prontosil is converted by cellular enzymes to sulfanilamide the prototype of all sulfonamides MECHANISM OF SULFONAMIDE TOXICITY Sulfonamides interfere with bacterial folic acid synthesis Folic acid is a 1 carbon donor required for the de novo biosynthesis of purines and pyrimidines 1 Sulfonamides prevent synthesis of dihydropteroic acid a folic acid precursor They mimic paraaminobenzoic acid and block dihydropteroate synthetase Sulfonamides are bacteriostatic drugs they stop DNA synthesis and prevent cell division SELECTIVE TOXICITY Sulfonamides are selectively toxic to bacteria because folate synthesis is obligatory in bacteria eukaryots obtain folate preformed in the diet DISPOSITION OF SULFONAMIDES ABSORPTION Normally given orally or applied topically some soluble salts given parenterally Readily absorbed from GI tract achieving peak blood levels in 30 min except for those designed to remain in intestine see below DISTRIBUTION Highly plasma protein bound will displace other bound drugs and bilirubin Sulfonamides given in late term can induce neonatal jaundice Distributed in total body water readily enter CNS synovial and ocular fluid fetal circulation and milk METABOLISM Primarily by acetylation at free amino group some oxygenation of aromatic ring and or side chain Acetylated metabolites inactive 2 ELIMINATION Majority eliminated unchanged Concentrated in urine useful in urinary tract infections older sulfonamides actually formed crystals in tubules and ureter TOXICITY Relatively low CTI relative to most antibiotics toxicity occurs in about 5 of patients 1 Renal toxicity Older sulfonamides crystallized in urine doses of 8 10 grams of drug given daily Risk minimized with advent of newer more soluble forms still prudent to give extra fluids 2 Blood dyscrasias Hemolytic anemia agranulocytosis aplastic anemia thrombocytopenia Immune response to sulfonamide hapten 3 Dermal toxicity rashes pruritus erythema exfoliative dermatitis Stevens Johnson syndrome can be fatal Again probably an immune response 4 Other rare but serious side effects hepatitis drug induced fever 5 Less serious side effects headache gi discomfort nausea loss of appetite BACTERIAL RESISTANCE Bacteria become resistant to sulfonamides by 1 Synthesizing large amounts of PABA It takes 5 000 to 25 000 molecules of sulfonamide to compete with 1 molecule of PABA Resistant cells synthesize PABA at 70x the rate of normal cells PABA from pus can compete with sulfonamides also preformed nucleotides PABA can be produced by hydrolysis of procaine 2 Bacterial dihydropteroate synthetase is altered so that it no longer is inhibitable by sulfonamides 3 Bacteria utilize salvage pathway which bypasses 1 carbon synthesis of bases Genes for sulfonamide resistance are transferred by R plasmids Generally one resistance phenotype will confer resistance to all sulfonamides Cross resistance to sulfonamides and other drugs also occurs multiple genes on same plasmid 3 TRIMETHOPRIM Introduced in 1969 as a combination with sulfonamides synergizes sulfonamide activity and minimizes bacterial resistance Cotrimoxazole Bactrim Septra 1 part trimethoprim 5 parts sulfamethoxazole Cotrimazine 1 trimethoprim 5 sulfadiazine Blocks bacterial dihydrofolate reductase similar to methotrexate acts at a different step of the same folate synthetase pathway inhibited by sulfonamides 100 000x higher affinity for bacterial than mammalian enzyme Not only provides synergy with sulfonamides but because 2 compounds act at different points on same pathway chances of resistance developing are a geometric product much smaller Synergy apparent in treatment of non bacterial respiratory infections but not absolute for uncomplicated UTI trimethoprim alone is just as effective as combination INDIVIDUAL SULFONAMIDES Historically classified as short acting long acting and non absorbed according to their rates of absorption and distribution All structurally similar except for substituents on N1 nitrogen substitution of N4 nitrogen terminates activity acetylation site 4 Sulfisoxazole Sulfamethoxazole Sulfadiazine short acting sulfonamides rapidly absorbed and excreted 3 most commonly prescribed sulfonamides last 2 in combination with trimethoprim Sulfadimethoxine Long acting sulfonamide poorly excreted quite toxic but useful in protozoal infections especially in AIDS patients Silver salt of Sulfadiazine topical use in burns Sulfacetamide topical use in eye due to low irritation Poorly absorbed sulfonamides e g Phthalylsulfathiazole used to sterilize the gut prior to bowel surgery aminoglycosides preferred Non absorbed gut flora cleave N4 group Dapsone Antileprosy drug Not a sulfonamide in strict sense but a related compound sulfone with same mechanism of action CLINICAL USES OF SULFONAMIDES Limited due to resistance problems but addition of trimethoprim has greatly extended their usefulness 5 Useful against most non resistant Gram and many Gram bacteria Commonly used normally as cotrimoxazole in lower urinary tract infections particularly due to E Coli and prostatitis trimethoprim alone also used quinolones are replacing them as drug of choice Once commonly used in bacterial dysentery due to shigella and salmonella resistance limited use but became useful again as combination with trimethoprim Sometimes used in meningococcal infections other antibiotics preferred Topical sulfonamides used in eye conjunctivitis and prophylactically for burns Protozoal infections very important role for sulfonamides and trimethoprim since these infections respond poorly to antibiotics Chlamydia nocardia toxoplasma chloroquine resistant plasmodium falciparum Pneumocystis carinii in immune compromised AIDS patients high incidence of drug toxicity in these patients sometimes trimethoprim alone used Combination used as low dose prophylaxis QUINOLONES The
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