Antibiotic GroupsSulfonamides

History

The sulfonamides were the first effective chemotherapeutic agents to be employed systemically for the prevention and cure of bacterial infections in humans.

History

1933 Foerster reported the first clinical case study of prontosil.

1935 Prontosil was shown to be a pro-drug of sulfanilamide.

1939 Domagk was awarded the Nobel Prize in Physiology or

Medicine for discovering the chemotherapeutic value of prontosil.

Description

The sulfonamide class contains a large number of antibacterial drugs, including:1. Sulfadiazine2. Sulfamethazine (sulfadimidine)3. Sulfathiazole4. Sulfamethoxazole

Cont. …

There are what is called “Potentiated sulfonamides” which are combinations of sulfonamide and an antibacterial diaminopyrimidine such as trimethoprim.

Potentiated sulfonamides demonstrate improved efficacy compared with sulfonamides alone.

Mechanism of Action

1. Sulfonamides are the structural analogues of PABA paraaminobenzoic acid.

2. Sulfonamides competitively inhibit dihydropteroate synthetase, which is an enzyme that catalyzes the synthesis of dihydrofolic acid (folic acid)

Mechanism of Action

3. The decreased synthesis of dihydrofolic acid (folic acid) lead to decreased synthesis of tetrahydrofolic acid (folinic acid), which is required for the synthesis of DNA.

Cont. …

A variety of effects may result in susceptible organisms, including:1. Suppression of protein synthesis.2. Impairment of metabolic processes.3. Inhibition of growth and multiplication.

Cont. …

Potentiated sulfonamides They inhibit dihydrofolate reductase which catalyzes the

synthesis of folic acid. This enzyme is present in both bacteria and mammals. The antibacterial diaminopyrimidines such as trimethoprim

and ormetoprim inhibit this enzyme more efficiently in bacteria than in mammalian cells.

Cont. …

Notre that; Before such activity is exhibited, existing stores of folic acid,

folinic acid, purines, thymidine and amino acids are utilized by bacteria.

Spectrum

Organisms susceptible to sulfonamides must synthesize their own folic acid, unlike mammalian cells, which utilize preformed folic acid.

Sulfonamides are not efficacious in the presence of purulent material

Spectrum

Sulfonamides are bacteriostatic Sulfonamides inhibit:

1. Gram positive 2. Gram negative3. Some chlamydia, Nocardia, and Actinomyces species4. Some protozoa including coccidia and Toxoplasma species

Cont. …

Potentiated sulfonamides Diaminopyrimidines such as trimethoprim and ormetoprim

are bacteriostatic when used alone. When combined with sulfonamides, the sequential blockade

of dihydropteroate synthetase and dihydrofolate reductase elicits a bactericidal effect.

Cont. …

Potentiated sulfonamide are active against Gram positive and Gram negative organisms, including:

- Actinomyces - Bordetella- Clostridium - Corynebacterium- Fusobacterium - Haemophilus- Klebsiella - Pasteurella- Proteus - Salmonella- Shigella - Campylobacter species- E. coli - Streptococci- Staphylococci

Resistance

Organisms resistant to sulfonamides include:1. Pseudomonas2. Klebsiella3. Proteus4. Clostridium5. Leptospira species

Organisms resistant to potentiated sulfonamides include:1. Pseudomonas 2. Mycobacterium species

Cont. …

Resistance to sulfonamides is widespread in bacteria isolated from animals, and may involve:1. Chromosomal mutations 2. Plasmid-mediated mechanisms

Cont. …

Chromosomal mutations cause:1. Impaired drug penetration.2. production of altered forms of dihydropteroate synthetase for which

sulfonamides have a lowered affinity.3. production of excessive PABA that overcomes the metabolic block

imposed by the inhibition of dihydropteroate synthetase.

Plasmid-mediated mechanisms, may result in; 4. Impaired drug penetration. 5. Synthesis of sulfonamide-resistant dihydropteroate synthetase.

There is cross-resistance among sulfonamides.

Cont. …

Resistance potentiated sulfonamides develops very rapidly and results from:1. Chromosomal mutations

• It allows bacteria to utilize exogenous sources of folinic acid or thymidine, thereby overcoming the drug-imposed blockade.

2. Plasmid-mediated mechanisms• It result in the synthesis of dihydrofolate reductase

characterized by a reduced affinity for antibacterial diaminopyrimidines.

Indications

Compared to most classes of antimicrobial drugs, the usage of sulfonamides and potentiated sulfonamides in veterinary medicine is high.

Cont. …

Sulfonamides are used to treat or prevent acute systemic or local infections, including:1. Actinobacillosis2. Coccidiosis3. Mastitis4. Metritis5. Colibacillosis6. Pododermatitis7. Polyarthritis8. Respiratory infections9. Toxoplasmosis

Cont. …

Sulfonamides in combination with pyrimethamine are used to treat protozoal diseases such as leishmaniasis and toxoplasmosis.

Administration

Sulfonamides are most effective in the early stages of acute infections when organisms are rapidly multiplying.

Sulfonamides are administered as:– Additives to feed – In drinking water– Controlled release oral boluses– Intrauterine infusions

Highly insoluble sulfonamides such as phthalylsulfathiazole are absorbed from the gastrointestinal tract very slowly and are used to treat enteric infections.

Side Effects

The majority of adverse effects to sulfonamides are mild in nature and reversible; 1. Urinary tract disturbances, including sulfonamide

crystalluria and hematuria which can be minimized by maintaining an adequate water intake to maintain a high urine flow.

2. Bone marrow depression and dermatologic.