Sulfonamide and TMP-SMZ Antibiotics

1. Main mechanism of action of the antibiotics:

• Inhibition of folic acid synthesis: This is the main mechanism of sulfonamides and TMP-SMZ.

• Bacteria use para-aminobenzoic acid (PABA) to synthesize dihydrofolic acid, the precursor of tetrahydrofolic acid, a coenzyme essential for the synthesis of purine, pyrimidine, and DNA.

• Sulfonamides compete with PABA to bind to the enzyme dihydropteroate synthetase, preventing the synthesis of dihydrofolic acid.

• Trimethoprim (TMP) inhibits the enzyme dihydrofolate reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid.

• Combining TMP-SMZ creates a synergistic effect, inhibiting both steps in the synthesis of tetrahydrofolic acid, significantly reducing bacterial growth.

2. Learning objectives:

• Key mechanism of action of the antibiotics: Understand the mechanism of inhibition of folic acid synthesis by sulfonamides and TMP-SMZ.

• Mechanism of antibiotic resistance: The mechanisms of bacterial resistance to sulfonamides and TMP-SMZ.

• Adverse reactions of the group: Side effects and contraindications of using sulfonamides and TMP-SMZ.

3. How are sulfonamides currently used?

• Due to the high rate of antibiotic resistance, sulfonamides are now often combined with TMP-SMZ.

• TMP-SMZ is an effective therapy for treating many types of infections, including respiratory tract infections, urinary tract infections, skin infections, and infections caused by Pneumocystis jirovecii.

4. Mechanism of action of sulfonamides and the reason for using them in combination with TMP-SMZ:

• Bacteria use PABA to synthesize dihydrofolic acid, the precursor of tetrahydrofolic acid, which is essential for DNA synthesis.

• Sulfonamides inhibit step 1: They compete with PABA to bind to the enzyme dihydropteroate synthetase, preventing the synthesis of dihydrofolic acid.

• Trimethoprim inhibits step 2: It inhibits the enzyme dihydrofolate reductase, preventing the conversion of dihydrofolic acid to tetrahydrofolic acid.

• Bacteria can develop resistance to sulfonamides by:

• Increasing PABA production: Bacteria produce more PABA to compete with sulfonamides.

• Altering the dihydropteroate synthetase enzyme: Bacteria may alter the structure of the enzyme, making it difficult for sulfonamides to bind.

• Producing dihydrofolate reductase with low affinity for TMP: Bacteria may produce dihydrofolate reductase with low affinity for TMP, reducing the effectiveness of TMP inhibition.

• Combining TMP-SMZ:

• Inhibits both consecutive steps in the folic acid synthesis cycle.

• Reduces the risk of bacterial resistance.

• Increases treatment effectiveness.

5. TMP-SMZ:

• Trimethoprim sulfamethoxazole

• Brand name: Co-trimoxazole, Bactrim

6. Are sulfonamides bacteriostatic or bactericidal?

• Bacteriostatic: Sulfonamides inhibit bacterial growth by preventing folic acid synthesis.

7. Spectrum of action of sulfonamides:

• Mostly Gram +: Streptococcus, Staphylococcus, Enterococcus.

• Gram -: Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella.

• Protozoa: Pneumocystis jirovecii (atypical pneumonia), Toxoplasma gondii, Chlamydia.

• No effect on Pseudomonas aeruginosa: This bacterium does not use PABA for growth.

8. What drugs are commonly used in combination with sulfonamides?

• Trimethoprim:

• Treatment of respiratory tract infections, urinary tract infections, skin infections, and infections caused by Pneumocystis jirovecii.

• Pyrimethamine:

• Treatment of malaria, especially malaria caused by Plasmodium falciparum.

• Treatment of Toxoplasma gondii infections.

9. Pharmacokinetics of sulfonamides:

• Oral:

• Sulfamethoxazole, sulfadiazine, sulfadozin.

• Pyrimethamine (Fansidar).

• TMP-SMZ:

• Penetrates fluids such as cerebrospinal fluid, lungs, bronchi, prostate, vagina…

• Sulfacetamide: Eye drops.

10. Note the substances when combined with sulfonamides:

• Combined with acetyl (10-50%):

• Creates a substance that is easily precipitated.

• When excreted through the kidneys, it can be precipitated again.

• Need to drink plenty of water (1g/0.5l) to increase urine volume and reduce precipitation.

• Combined with glucuronide:

• Good solubility.

• Combined with TMP-SMZ:

• Increases treatment effectiveness.

11. Sulfonamide preparations:

• Trimethoprim/sulfamethoxazole:

• Brand name: Co-trimoxazole, Bactrim.

• Strong: 160/800 mg.

• Common: 80/400 mg.

12. Side effects of sulfonamides:

• Folate antagonism: Megaloblastic anemia, leukopenia, thrombocytopenia.

• Skin reactions: Stevens-Johnson syndrome, dermatitis, photosensitivity.

13. Note when using high doses of sulfonamides:

• May affect both bacteria and human cells.

• Closely monitor patients.

14. Contraindications of sulfonamides:

• Megaloblastic anemia due to folate deficiency.

• Pregnancy and lactation: May cause kernicterus.

• Children under 2 months old.

• Caution: Liver disease, kidney disease.

15. Why does sulfonamide use cause kernicterus in pregnant women and breastfeeding mothers?

• Mechanism:

• Sulfonamides compete with bilirubin for binding sites on albumin.

• Albumin, secreted by the liver, binds to bilirubin to prevent jaundice.

• Bilirubin then accumulates and enters the brain and central nervous system, causing kernicterus.

Note:

• This information is for informational purposes only and does not replace the advice of a doctor.

• Consult your doctor before using any medication.

Additional information:

• Mechanism of TMP-SMZ resistance:

• Bacteria can increase the production of dihydrofolate reductase to compensate for the inhibited enzyme.

• Bacteria may alter the structure of the dihydrofolate reductase enzyme, making it difficult for TMP to bind.

• Note when using TMP-SMZ:

• Monitor blood counts, liver function, and kidney function during treatment.

• Supplement with folate to prevent anemia.

• Use medication as prescribed by your doctor; do not self-medicate or stop medication.

• Combining TMP-SMZ with other drugs:

• Be aware of drug interactions between TMP-SMZ and other drugs.

• Inform your doctor of any medications you are taking.

Conclusion:

Sulfonamides and TMP-SMZ are important antibiotics in the treatment of many types of infections. Understanding the mechanism of action, side effects, contraindications, and how to use these drugs is essential to ensure treatment effectiveness and minimize side effects.