Antibacterials - Antimicrobials

ANTIMICROBIALS

Antibacterials

Sulfonamides

Sulfonamide drugs are derivatives of para-aminobenzenesul-fonic acid. The sulfonamides were the first ever drugs used systemically for treatment of bacterial infections. Prontosil was the earliest such compound proved to have chemotherapeutic value, the discovery of which in 1935 led to the Nobel prize being awarded (in 1938) to Domagk, a German scientist. This was followed by the development of a profusion of similar compounds which were used extensively in therapeutics till the advent of penicillin in the 1940s.

Examples

Sulfadiazine, sulfacetamide, sulfamethoxazole, sulfanilamide, sulfisoxazole, sulfadoxine, sulfasalazine, sulfacytine, silver sulfadiazine, sulfaguanidine, sulfamethizole, sulfapyridine, sulfisoxazole and mafenide.

Today the only systemic sulfonamide that is still popular as an antibacterial is sulfamethoxazole which is usually combined with trimethoprim (for synergistic effect) in a ratio of 5:1, the combined product being referred to as co-trimoxazole.

Sulfacetamide is used as a topical preparation, as also silver sulfadiazine and mafenide.

Sulfadoxine is a long-acting sulfonamide which is usually used in combination with pyrimethamine in the prophylaxis and treatment of malaria.

Sulfasalazine is a poorly absorbed sulfonamide which is used in the therapy of ulcerative colitis.

Uses

Micro-organisms susceptible to sulfonamides include Streptococcus pyogenes, Strep. pneumoniae, Haemophilus influ­ enzae, H.ducreyi, Nocardia, Actinomyces, Calymmatobacterium granulomatis, and Chlamydia trachomatis.

Toxicokinetics

Except for locally acting preparations, all sulfonamides are rapidly absorbed from the GI tract. Peak plasma levels are achieved in 2 to 6 hours. Binding to plasma proteins (especially albumin) is notable, though variable, depending on the exact compound. Sulfonamides are distributed throughout all tissues and body fluids, and readily pass through placenta. Metabolism occurs by acetylation in the liver, and excretion is mainly through the urine (upto 20% as unchanged parent compound).

Mode of Action

·              Sulfonamides are bacteriostatic in normal doses and bacte- riocidal in extremely high concentrations.

·              They act therapeutically by inhibiting para-aminobenzoic acid or para-aminoglutamic acid required for the biosyn-thesis of folic acid.

Adverse Effects

·      Crystalluria: This is particularly common with oldersulfonamides (such as sulfadiazine) which are insoluble and get precipitated in acid urine, producing crystalline deposits that can cause urinary obstruction. The risk can be minimised by ensuring a minimum daily urine flow of 1200 ml (in adults), and alkalinisation. Table 30.1 provides a list of agents that can cause crystalluria.

·      Acute haemolytic anaemia, aplastic anaemia, and agranu-locytosis.

·              Hypersensitivity reactions are not infrequent and may take the form of dermal or mucous membrane manifestations such as skin rash, erythema nodosum, Stevens-Johnson syndrome (Fig 30.1),* Behcet’s syndrome,** and exfolia-tive dermatitis. Stevens-Johnson and Lyell’s Syndromes are usually associated with the use of a long-acting sulfona-mide, although other sulfonamides have been reported to cause these reactions. This serious reaction has been reported even with the use of ophthalmic preparations. Transient myopia, conjunctivitis, and keratitis may occur in association with hypersensitivity reaction. Table 30.2 lists some common drug-related causes of skin allergy.

·      Headache, depression, and hallucinations have been reported with therapeutic use of sulfonamides. Tremor occurred in one patient following a fixed-dose combination of trimethoprim/sulfamethoxazole.

·      Hepatocellular, cholestatic, or mixed types of hepatitis have been reported with therapeutic doses of sulfonamides.

·      Administration of sulfonamides to premature infants leads to kernicterus.

·      A higher rate of adverse reactions are reported with AIDS patients who receive sulfonamides, which may be because of increased sensitivity to reactive sulfonamide metabolites.

Clinical (Toxic) Features

Cases of overdose involving sulfonamides have rarely been reported. Toxicity is associated with nausea, vomiting, diarrhoea, facial swelling headache, mental confusion, convul-sions, and bone marrow depression. Methaemoglobinaemia can occur. Renal failure has been reported with trimethoprim. Coma and seizures were reported following a large overdose of sulfasalazine in one patient.

Diagnosis

The hepatotoxicity and nephrotoxicity associated with these pharmaceuticals may alter lab tests of liver function and kidney function including alkaline phosphatase, bilirubin, transami- nase, cephalin flocculation, BUN, creatinine, urine protein, etc. Monitor the haematopoietic system in long-term treatment, even at normal doses.

·              Bedside test: Place 1 drop of patient’s urine on wood pulp (lignin) or pulp paper (newspaper), and add to it 1 drop ofconcentrate HCl. Normal urine stains yellow, sulfa deriva-tives stain orange. The test can also be done on pulverisedsulfa tablet directly.

·              Quantitation in serum can be done with HPLC.

Treatment

·              Stomach wash.

·              Haematologic evaluation.

·              Diazepam for convulsions.

·              Determine the methaemoglobin concentration, and evaluate the patient for clinical effects of methaemoglobinaemia (dyspnoea, headache, fatigue, CNS depression, tachycardia,acidosis, etc.). Treat patients with symptomatic methaemo- methaemoglobin levels above 20 to 30%, but may occur at lower methaemoglobin levels in patients with anaemia, or underlying pulmonary or cardiovascular disorders). Dose: 1 to 2 mg/kg/dose (0.1 to 0.2 ml/kg/dose) IV over 5 minutes, as needed every 4 hours.

·              If kidney function is normal, administer 0.45% sodium chloride in D5W, and a diuretic such as furosemide 1 mg/ kg to a maximum of 40 mg/dose to obtain a urine flow of 3 to 6 ml/kg/hr to increase renal excretion. For anuria or agranulocytosis, dialysis and/or isolation should be consid-ered.

·              Supportive measures.

·              For acute allergic reaction: The drug should be immedi-ately discontinued and the patient observed for the possi-bility of anaphylactic shock. In this situation the normaltreatment for anaphylaxis is carried out with the establish-ment of an open airway, adrenaline, and diphenhydramine.

·              Intravenous N-acetylcysteine (24 g over 3 days) was reported to be effective in treating hepatitis cause bysulfasalazine in one reported case.

·              Haemodialysis may be beneficial.