Sulfonamides and Cotrimoxazole

• Sulfadoxine is used with pyrimethamine for malaria in chloroquine-resistant cases.
• Sulfonamides are a prophylactic option for streptococcal pharyngitis in penicillin-allergic patients with rheumatic fever.
• Sulfacetamide eye drops treat bacterial conjunctivitis and penetrate the aqueous humor.
• Mafenide and silver sulfadiazine ointments are used to prevent infection in burn patients
• Sulfasalazine is effective for ulcerative colitis and rheumatoid arthritis.

Cotrimoxazole Details

• Cotrimoxazole is a combination of trimethoprim and sulfamethoxazole.
• Trimethoprim is effective against gram-positive and gram-negative organisms.
• Resistance develops rapidly with trimethoprim is used a sole agent.

Antibacterial Spectrum

• Effective against Staph. aureus, streptococci, meningococci, C. diphtheriae, E. coli, Proteus, H. influenzae, Salmonella, Shigella, and Pneumocystis jiroveci.

Mechanism of Action

• Sulfonamides inhibit PABA conversion to dihydrofolic acid (DHF).
• Trimethoprim inhibits dihydrofolate reductase (DHFR), preventing DHF reduction to tetrahydrofolic (THF) acid.
• Together, the drugs sequentially block folic acid synthesis.
• Trimethoprim and sulfonamides are bacteriostatic alone but bactericidal when combined.
• Trimethoprim has a high selective affinity for bacterial DHFR.
• The ratio of trimethoprim to sulfamethoxazole used is 1:5.
• The optimal peak plasma concentration of the combination is in the ratio 1:20.
• Sulfamethoxazole is chosen due to its pharmacokinetic properties closely matching trimethoprim.

Resistance

• Resistance develops more slowly to the combination than to the individual drugs.
• Bacteria may acquire resistance through mutation or a plasmid coding for altered DHFR.

Pharmacokinetics

• Trimethoprim and sulfamethoxazole have similar half-lives.
• They can be administered orally or intravenously.
• They are well absorbed from the gut.
• They are widely distributed in the body.
• Trimethoprim has good distribution into tissues, including prostatic and vaginal fluids.
• Trimethoprim concentrates in acidic fluids due to its basic nature.
• Both drugs are excreted by the kidneys, so the dose should be reduced in renal failure.

Adverse Effects

• Nausea, vomiting, headache, glossitis, stomatitis, and allergic skin rashes are relatively common.
• Cotrimoxazole may precipitate megaloblastic anemia in patients with folate deficiency.

Additional Information

• Hematological reactions like anemia and granulocytopenia are rare.
• AIDS patients are more prone to adverse effects of cotrimoxazole.
• Patients with renal disease may develop uremia.
• Cotrimoxazole should not be given in pregnancy as it is an antifolate drug and could be teratogenic.

Preparations

• Trimethoprim: 80 mg, 160 mg
• Sulfamethoxazole: 400 mg, 800 mg (double strength - DS)
• Common brands: CIPLIN, SEPTRAN, SEPMAX, BACTRIM
• Usual dose: Single to double strength 1 tab BD.

Uses

• Uncomplicated acute UTI treated for 7-10 days with cotrimoxazole (DS, twice a day).
• Chronic and recurrent UTI can be treated with small doses for prophylaxis (1 tab single strength thrice a week).
• Bacterial prostatitis can be treated with Trimethoprim, which attains high concentration in prostatic fluid or Cotrimoxazole DS twice daily.
• Cotrimoxazole can be used for respiratory tract infections.
• Bacterial gastroenteritis responds to cotrimoxazole due to Shigella and E. coli.
• Cotrimoxazole is used as an alternative for typhoid, but to fluoroquinolones.
• For Pneumocystis jiroveci infection, cotrimoxazole is used for prophylaxis, and high doses, for treatment of Pneumocystis jiroveci pneumonia in neutropenic and AIDS patients.
• Cotrimoxazole (DS, BD for 7 days) is the drug of choice for chancroid.
• Cotrimoxazole may be used as an alternative to pyrimethamine + sulfadiazine for use in toxoplasmosis.
• Cotrimoxazole has use in melioidosis, but severe infection requires combination antibiotics.

Intravenous Cotrimoxazole

• It is used when not able to be taken orally as in pneumocystis pneumonia, typhoid, and UTI caused by susceptible microbes.

Clinical Pharmacology

• Cotrimoxazole is restricted to the treatment of pneumocystosis and toxoplasmosis.
• It is the first-line treatment in UTI before a culture report is available.
• Gram +ve organisms have demonstrated resistance to cotrimoxazole because of extensive use.
• Use of sulfonamide monotherapy is uncommon.

Quinolones Overview

• Quinolones are a group of synthetic antimicrobial agents.
• Nalidixic acid is the older agent in the group.
• Oxalinic acid and cinoxacin are other quinolones.

Nalidixic Acid

• Nalidixic acid is bactericidal against various gram-negative organisms.
• Effective against E. coli, Shigella, Enterobacter, Proteus and Klebsiella.
• Shares the same mechanism as fluoroquinolones by inhibition of DNA gyrase in the bacteria.