Cotrimoxazole

The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole.

Adverse Drug Reaction, Spectrum, Resistance and Use of Cotrimoxazole.

1. Cotrimoxazole Mr. Vijay Kevlani

2. The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole . Trimethoprim is a diaminopyrimidine related to the antimalarial drug pyrimethamine which selectively inhibits bacterial dihydrofolate reductase ( DHFRase ). Cotrimoxazole introduced in 1969 causes sequential block of folate metabolism.

3. Pteridine + PABA ↓ Dihydropteroic Acid + Glutamic Acid × ↓ Folate Synthase Dihydrofolic acid × ↓ Dihydrofolate Reductase Tetrahydrofolic Acid Sulfa Drug Trimethoprime

4. Trimethoprim is >50,000 times more active against bacterial DHFRase than against the mammalian enzyme. Thus, human folate metabolism is not interfered at antibacterial concentrations of trimethoprim. individually, both sulfonamide and trimethoprim are bacteriostatic , but the combination becomes cidal against many organisms.

5. Maximum synergism is seen when the organism is sensitive to both the components , But even when it is moderately resistant to one component, the action of the other may be enhanced.

6. Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (- 10 hr ) . Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim I . The MIC of each component may be reduced by 3-6 times .

7. This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : I , because trimethoprim is more lipid soluble, enters many tissues, has a larger volume of distribution than sulfamethoxazole and attains lower plasma concentration.

8. However, trimethoprim crosses blood-brain barrier and placenta, while sulfamethoxazole has a poorer entry. Moreover, trimethoprim is more rapidly absorbed than sulfamethoxazole hence concentration ratios may vary with time.

9. Trimethoprim is 40% plasma protein bound, while sulfamethoxazole is 65% bound.

10. Spectrum of action Antibacterial spectra of trimethoprim and sulfonamides overlap considerably. Additional organisms covered by the combination are- Salmonella typhi , Serratia , Klebsiella , Enterobacte r , Y ersinia enterocolitica , Pneumocystis jiroveci

11. Many sulphonamide resistant strains Staph . aureus, Strep . pyogenes Shigella , E teropathogenic E. coli, H.inftuenzae , Gonococci and Meningococci .

12. Resistance Bacteria are capable of acquiring resistance to trimethoprim mostly through plasmid mediated acquisition of a DHFRase having lower affinity for the inhibitor. Resistance to the combination has been slow to develop compared to either drug alone, but widespread use of the combination over a long period has resulted in reduced responsiveness of over 30% originally sensitive strains .

13. Adverse effects All adverse effects seen with sulfonamides can be produced by cotrimoxazole . Nausea, vomiting, stomatitis, headache and rashes are the usual manifestations. Folate deficiency (megaloblastic anaemia) is infrequent, occurs only in patients with marginal folate levels.

14. Blood dyscrasia occurs rarely. Cotrimoxazole should not be given during pregnancy. Trimethoprim being an antifolate , there is theoretical teratogenic risk. Neonatal haemolysis and methaemoglobinaemia can occur

15. Patients with renal disease may develop uremia. Dose should be reduced in moderately severe renal impairment. A high incidence ( upto 50%) of fever, rash and bone marrow hypoplasia has been reported among AIDS patients with Pneumocystis jiroveci infection when treated with high dose cotrimoxazole

16. The elderly are also at greater risk of bone marrow toxicity from cotrimoxazole . Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia.

17. Uses Urinary tract infections 2. Respiratory tract infections 3. Bacterial diarrhoeas and dysentery 4. Pneumocystis jiroveci 5. Chancroid 6. Typhoid

18. Thank You