Bacteria sulfonamide effects

The sulfonamide drugs were the first effective antibacterial agents to be employed systemically in humans. These drugs resemble p-aminobenzoic acid in structure and inhibit utilization of that compound for the synthesis of folate in bacteria. Sulfonamides do not interfere with human metabolism. 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Trimethoprim (Trimpex) interferes with the ability of bacteria to metabolize folinic acid, thereby exerting bacteriostatic activity. Trimethoprim is used for UTIs that are caused by susceptible microorganisms. Trimethoprim administration may result in rash, pruritus, epigastric distress, nausea, and vomiting. When trimethoprim is combined with sulfamethoxazole (Septra), the adverse effects associated with a sulfonamide may also occur. The adverse reactions seen with other anti-infectives, such as ampicillin, the sulfonamides, and cephalosporins, are given in their appropriate chapters. 

Some or all of the events of this sequence are readily thrown out of balance, or even completely inhibited. Thus bacteria, particularly the rod-shaped organisms, may be induced to elongate into filaments by various treatments which apparently inhibit cell division but which do not inhibit growth. Such an effect is produced by various chemical substances, by sub-bacteriostatic concentration of certain antibacterial agents, as, for example, methyl violet, sulfonamides, /w-cresol, penicillin, irradiation, and higher temperatures of incubation. 

Much of the debate concerning the use of antibiotics in livestock feeds has centered on bacterial resistance. One of the first observations made early in the 1950s, was that the bacterial count in animal feces increased after a temporary decrease when antibiotics, such as tetracyclines, were fed (12). This was in contrast to the effect of sulfonamides, which reduce the count. Obviously, resistance had occurred because the intestinal bacteria were thriving in the presence of antibiotics. Simultaneously, the growth of the animals was increased. Therefore the resistance in itself was not harmful. 

Sulfonamides are historically important but have been largely replaced by other newer antibacterials. They are still used in urinary infections and in the treatment of bronchitis. The danger of crystal formation in the kidneys is circumvented by administering a mixture of sulfonamides. This changes the solubility characteristics but still has an effect on the bacteria. 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

The sulfonamide antibiotics were the first synthetic antibiotics to have general utility in human therapy (B-79MI10806). Of the numerous compounds thus developed, comparatively few are presently used in veterinary practice. They include sulfapyridine (40), sulfamethazine (41) and sulfadimethoxine (42). They are much less potent than the /3-lactams (dose 100-200 mg kg-1), and have a bacteriostatic effect. They are commonly used in combination with trimethoprim (43), when a synergistic effect is observed, i.e. the combination is more potent than either drug alone, and species of bacteria which are unaffected by the drugs individually are susceptible to the combination. 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

In acute and chronic urinary tract infection, the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra) exerts a truly synergistic effect on bacteria. The sulfonamide inhibits the utilization of p-amino-benzoic acid in the synthesis of folic acid (Figure 2.3), whereas trimethoprim, by inhibiting dihydrofolic acid reductase, blocks the conversion of dihydrofolic acid to tetrahydrofolic acid, which is essential to bacteria in the denovo synthesis of purines, pyrimidines, and certain amino acids. Because mammalian organisms do not synthesize folic acid and therefore need it as a vitamin in their daily diets, trimethoprim-sulfamethoxazole does not interfere with the metabolism of mammalian cells. 

The pharmacologic properties of parasite 7,8-dihydropteroate synthases may differ from those of the bacterial enzymes. For instance, metachloridine and 2-ethoxy-p-aminobenzoate are both ineffective against sulfonamide-sensitive bacteria, but the former has antimalarial activity and the latter is effective against infection by the chicken parasite Eimeria acervulina both activities can be reversed by p-aminobenzoate. 

Administration Most sulfa drugs are well absorbed after oral administration. Sulfasalazine [sul fa SAL a zeen], when administered orally or as a suppository, is reserved for treatment of chronic inflammatory bowel disease (for example, Crohn s disease or ulcerative colitis), because it is not absorbed. Similarly, succinylsulfathiazole [suks in ill sul fa THI a zole] is used for the treatment of salmonella and shigella carriers. Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations. Because of the risk of sensitization, sulfas are not usually applied topically. In burn units, creams of mafenide acetate (p-aminomethylbenzensulfonamide) or silver sulfadiazine have been effective in reducing burn sepsis. However, superinfections with resistant bacteria or fungi may occur. 

A-2) It is common to combine trimethoprim with mlfonamide in the treatment of certain infections. The sulfonamide acts on bacteria to inhibit folate fonnation in bacteria by competitively inhibiting PABA incorporation (fig. 10.4). The trimethoprim acts on the dihydrofolate reductase step (between 7,8 dihydrofolate and 5,6,7,8 THF). Apparently, trimethoprim has a more damaging effect on bacteria and protozoans than it has on humans. 

Sulfisoxa/oie possesses the action and the uses of other sulfonamides and is used for infections involving sulfon-amidc-.scnsilive bacteria. It is claimed to be effective in the treatment of Gram-negative urinary infections. 

The sulfonamide story began in 1935 when it was discovered that a red dye called prontosil had antibacterial properties in vivo (i.e. when given to laboratory animals). Strangely enough, no antibacterial effect was observed in vitro. In other words, prontosil could not kill bacteria grown in the test tube. This remained a mystery until it was discovered that prontosil was not in fact the antibacterial agent. 

Oral Therapy Sulfonamides Trimethoprim-sulfamethoxazole (TMP-SMX) These agents generally have been replaced by more agents due to resistance. This combination is highly effective against most aerobic enteric bacteria except Pseudomonas aeruginosa. High urinary tract tissue levels and urine levels are achieved, which may be important in complicated infection treatment. Also effective as prophylaxis for recurrent infections. 

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