Antibiotics Review _ __________________________________________________________________________
The Short- to Medium-Acting Sulfonamides This group of agents includes sulfadiazine and sulfamethoxa- zole. Sulfadiazine is readily diffused into CSF and excreted largely in urine, 15% to 40% as metabolites and 43% to 60% as unchanged drug [6]. It is indicated for use in treating chan- croid, trachoma, inclusion conjunctivitis, nocardiosis, UTIs, toxoplasmosis encephalitis, and malaria and for prophylaxis of rheumatic fever [6]. Sulfamethoxazole is combined with trim- ethoprim and is indicated for Pneumocystis jiroveci prophylaxis and treatment, upper respiratory tract infections, and urinary tract infections [6]. Sulfonamides Limited to Gastrointestinal Tract Activity The agents limited to the GI tract are very poorly absorbed and have been used for reducing bacterial flora in the bowel before surgery. The only available agent in this class is sul- fasalazine, which is used in the treatment of ulcerative colitis and for juvenile and rheumatoid arthritis in patients who have responded inadequately to salicylates or other NSAIDs [6]. Although absorption of sulfasalazine from the intact intestine is very low, inflammation in the bowel may result in significant absorption of the metabolite sulfapyridine [6]. Topical Sulfonamides The topical sulfonamides include mafenide acetate and sil- ver sulfadiazine, which are used in the treatment of burns. Mafenide is used less often because it may cause a metabolic acidosis as a result of carbonic anhydrase inhibition. An additional topical agent is sulfacetamide, which is used in ophthalmic and lotion formulations. Topical sulfonamides may be absorbed systemically, and if large burn areas are treated, absorption may be significant [6]. ABSORPTION/ELIMINATION The sulfonamides are quickly absorbed after administration unless they have been altered to stay in the lumen of the intes- tine (e.g., sulfasalazine). After absorption, they are acetylated in the liver into a toxic but inactive form. The acetylated form is mostly excreted in the urine, with a small amount excreted in bile. These drugs are widely distributed throughout body tissue and fluids, including the CSF and peritoneal fluid [137]. The sulfonamides undergo acetylation and glucuronidation in the liver. Both the unchanged and metabolized forms are excreted in the urine through glomerular filtration and renal tubular secretion. Mafenide may be used in renal failure, but monitoring of acid-base balance is recommended. Dosage and frequency of administration of other sulfonamides must be adjusted in renal failure based on serum levels. No data is available on dosing in hepatic insufficiency.
Quinolones are not routinely used as first-line therapy for pedi- atric patients but may be considered a reasonable alternative in situations where no safe and effective substitute is available (e.g., multi-drug resistance) [6].
SULFONAMIDES Sulfonamides, the first true antibiotics, are derived from azo dyes. The first agent was sulfachrysoidine, used in 1935, which released sulfanilamide in vivo [130]. Modifications were made to the sulfanilamide to reduce side effects, resulting in the development of the modern sulfonamides. Many of the sulfonamides are no longer used as parenteral agents, but they continue to be used as topical agents or for treatment in specific conditions (e.g., prophylaxis for drug-resistant malaria). Some of these agents are no longer available in the United States but are still commonly used in other countries. MECHANISM OF ACTION The sulfonamides are bacteriostatic, exerting their effect as competitive antagonists of para-aminobenzoic acid (PABA). They inhibit dihydropteroate synthase from using PABA to synthesize dihydropteroic acid, a precursor of folic acid. The lack of folic acid intermediates ultimately results in impaired synthesis of nucleotides. Bacteria that use pre-formed folate are not susceptible to the bacteriostatic action. Silver sulfadiazine is one exception, as it exerts its effects on the cell membrane and cell wall and is bactericidal. Unfortunately, bacterial resistance to sulfonamides is com- mon, with cross-resistance between agents frequently occur- ring [131]. Mutations that result in additional production of PABA or changes in the enzyme binding sites for sulfonamides are responsible for the resistance [132; 133]. Genes for these resistant mutations may be carried on plasmids, allowing rapid transfer to other similar bacteria and resulting in more rapid development of resistance patterns than through random mutation alone [133; 134]. One method for improving bacterial activity against poten- tially resistant strains is the addition of trimethoprim [135]. Trimethoprim is a competitive inhibitor of dihydrofolate reductase, another enzyme active in the synthesis of folate [6]. Trimethoprim resistance is also common [136]. PHARMACOKINETICS The sulfonamides can be divided into groups based on absorp- tion and excretion characteristics. They are classified as short- to medium-acting agents, agents limited to activity in the GI tract, and topical agents.
84
MDTX2026
Powered by FlippingBook