Sulfonamides

Sulfonamides were the first effective antibacterial agents to be used systemically in man. They were introduced by Domagk in 1935 and in the next few years several of them were synthesized and widely used. Currently, their role in therapeutics is limited because of their toxicity, development of resistance and availability of safer drug.

 

ANTIBACTERIAL  SPECTRUM 

Sulfonamides inhibit many gram-positive and also some gram-negative bacteria including streptococci, Haemophilus influenzae, Haremopilus ducreyi, Nocardia, Escherichia coli, Salmonella, Shigella, Proteus, Vibrio cholerae, a few strains of staphylococci, gonococci, meningococci and pneumococci. They are also effective against chlamydiae, Plasmodium falciparum and Toxoplasma gondii.

PREPARATION OF SULFONAMIDES

1. Sulfadiazine; 0.5–2 g BD

      Sulphadiazine–500 mg tab

       Silver sulfadiazine, BURN AID CREAM 1%,

        SILVERINE CREAM 1%, SILVINDON CREAM 1%

2. Sulfasalazine: 0.5–1 g BD, SAAZ 500 mg tab,

       SALAZAR EC tab 500 mg

3. Sulfamethoxazole 0.5–1 g BD, GANTANOL 500mg tab

4. Sulfacetamide, ALEKTRA 20% eye drops,

         ALBUCID 10, 20, 30% eyedrops, 6% eye ointment.

Uses of sulfonamides

sulfonamides are not commonly used now except in a few cases, because of the development of resistance and availability of better antimicrobials which are more effective and less toxic. It should be noted Sulfonamides are given in combination with other drugs like trimethoprim and pyrimethamine.

1. Urinary tract infections:

• Uncomplicated acute UTI can be treated with sulfonamides in areas where resistance is not high. Sulfisoxazole (1 g QID) or sulfamethoxazole (1 g TDS).

2. Nocardiosis:

• High doses of sulfonamides can be used as alternatives.

3. Toxoplasmosis:

• Sulfadoxine with pyrimethamine is the treatment of choice in Toxoplasma gondii infection. They block sequential steps in folate synthesis and are synergistic. Sulfadoxine is given in the dose of 4 g/day while pyrimethamine is given as a bolus dose of 75 mg followed by 25 mg daily. The treatment is continued for 4–6 weeks. Such doses require leucovorin rescue (10 mg folinic acid daily) to prevent severe folic acid deficiency .

4. Trachoma, inclusion conjunctivitis, lymphogranuloma venereum and chancroid:

• Sulfonamides are used as alternatives to tetracyclines.

5. Malaria:

• Sulfadoxine is used with pyrimethamine in chloroquine-resistant malaria.

6. Prophylactic use:

• In patients allergic to penicillins, sulfonamides may be used for prophylaxis of streptococcal pharyngitis in rheumatic fever.

7. Topical:

• Sulfacetamide eye drops are used in bacterial conjunctiviti sulfacetamide also readily penetrates into the aqueous humour; mafenide and silver sulfadiazine (preferred) ointments are used in burns to prevent infection.

8. Ulcerative colitis:

• Sulfasalazine is useful in ulcerative colitis and rheumatoid arthritis.

Side effects of sulfonamides 

1. Renal irritation, haematuria, albuminuria and crystalluria—due to precipitation of the drug in acidic urine. This can be avoided by intake of large volumes of fluids and by alkalinising the urine with sodium bicarbonate. Nephrosis and allergic nephritis can also occur.

2. Allergic reactions: Sulfonamides can produce a range of hypersensitivity reactions like rashes, fever, anaphylactoid reactions, urticaria, photosensitivity and rarely, Stevens-Johnson syndrome (SJS) and exfoliative dermatitis. Stevens-Johnson syndrome can be fatal and should be watched for. Nephritis may also be of allergic aetiology.

3. Anorexia, nausea, stomatitis, abdominal pain, conjunctivitis and arthritis can occur.

4. Sulfonamides can cause haemolytic anaemia and decreased granulocyte and thrombocyte count. Haemolytic anaemia may be precipitated in patients with G6PD deficiency.

5. Kernicterus: Sulfonamides displace bilirubin from the plasma protein binding sites which crosses the BBB and may cause kernicterus in the newborn. Hence, sulfonamides are contraindicated in pregnancy and in infants.

COTRIMOXAZOLE

The combination of trimethoprim and sulfamethoxazole is cotrimoxazole. Trimethoprim is effective against several gram-positive and gram-negative organisms. However, when used as a sole agent, resistance develops rapidly.

Antibacterial spectrum:

Cotrimoxazole is effective against several gram-positive and gram-negative organisms like Staph. aureus, streptococci, meningococci, C. diphtheriae, E. coli, Proteus, H. influenzae, Salmonella, Shigella, and Pneumocystis jiroveci.

Uses of COTRIMOXAZOLE 

1. Urinary tract infection

• Uncomplicated acute UTI: It is treated for 7–10 days with cotrimoxazole (DS, twice a day). Both drugs attain good concentration in the urine.

• Chronic and recurrent UTI: Small doses are given for prophylaxis (1 tab single strength thrice a week).

• Bacterial prostatitis: Trimethoprim attains high concentration in prostatic fluid. Cotrimoxazole DS twice daily.

2. Respiratory tract infections: Upper and lower respiratory infections including bronchitis, sinusitis and otitis media respond.

3. Bacterial gastroenteritis: Due to Shigella and E. coli respond to cotrimoxazole.

4. Typhoid: Cotrimoxazole is used as an alternative to fluoroquinolones.

5. Pneumocystis jiroveci infection: Cotrimoxazole is used for the prophylaxis and high doses (trimethoprim 20 mg/kg + sulfamethoxazole 100 mg/kg daily) for the treatment of Pneumocystis jiroveci pneumonia in neutropenic and AIDS patients. It also protects against infections with other gram-negative bacteria.

6. Chancroid: Cotrimoxazole (DS, BD for 7 days) is the drug of choice.

7. Melioidosis: It is caused by Burkholderia pseudomallei. An outbreak has been reported recently in South India. Cotrimoxazole may be tried in mild infection but severe infection and septicaemia requires combination of antibiotics. Initial intensive phase needs 2 weeks of ceftazidime or meropenem and eradication requires 3 months of cotrimoxazole + doxycycline.

8. Toxoplasmosis: As an alternative to pyrimethamine + sulfadiazine.

9. Intravenous cotrimoxazole: Generally cotrimoxazole is used orally. In serious illness and when it cannot be taken orally as in pneumocystis pneumonia, typhoid, and UTI caused by susceptible microbes, cotrimoxozole may be given intravenously.

Adverse Effects of COTRIMOXAZOLE 

• Nausea, vomiting, headache, glossitis, stomatitis and allergic skin rashes are relatively common.

• In patients with folate deficiency, cotrimoxazole may precipitate megaloblastic anaemia.

• Haematological reactions like anaemia and granulocytopenia are rare.

• AIDS patients are more prone to adverse effects of cotrimoxazole.

• Patients with renal disease may develop uraemia.

• Cotrimoxazole should not be given in pregnancy as it is an antifolate drug and could be teratogenic.

                        Clinical Pharmacology

 • Cotrimoxazole is inexpensive and hence has been widely used.

             • Currently cotrimoxazole use is restricted to the treatment of                          pneumocystosis and toxoplasmosis.It is the first-line treatment                    in UTI before culture report is available.

            • Gram +ve organisms have demonstrated resistance to                      cotrimoxazole because of extensive use and its use has declined in the last few years. It is likely to make a ‘come back’ as many cultures are now sensitiveto cotrimoxazole.

           • Use of sulfonamide monotherapy is uncommon.

           • Allergic reactions must be borne in mind while using        sulfonamides.