___________________________________________________________________________ Antibiotics Review
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. SIDE EFFECTS/TOXICITY Allergic reactions with rash and itching are relatively common. Nausea, vomiting, diarrhea, headache, and photosensitivity may occur. Rare but severe hypersensitivity reactions, including vasculitis, anaphylaxis, serum sickness, and Stevens-Johnson syndrome, may occur [131]. Sulfacetamide lotion also contains metabisulfite, which may cause an allergic reaction in patients allergic to sulfites [6]. Sulfonamide ophthalmic preparations may cause local irri- tation. The topical mafenide may cause pain or burning locally. Systemic reactions may develop during treatment with ophthalmic and topical preparations of sulfonamides due to systemic absorption. Less common reactions include metabolic acidosis that may occur with absorption of mafenide due to a byproduct, (rho) carboxybenzenesulfonamide, that inhibits carbonic anhydrase. Very rare reactions with sulfonamides include blood dyscra- sias (agranulocytosis, aplastic anemia, thrombocytopenia, hemolytic anemia), hepatitis and hepatocellular necrosis, and toxic nephrosis due to crystalluria. Hemolysis is more likely to develop in patients with G6PD deficiency [131]. Sulfonamides are contraindicated in patients who are known to be allergic to sulfa drugs and in cases where there have been previous adverse effects to sulfonamides [6]. DRUG INTERACTIONS Warfarin, phenytoin, and sulfonylureas may all be potentiated due to displacement of the drugs from serum albumin by the sulfonamides [6]. Cyclosporine levels may be decreased, and levels should be monitored [6]. Administration of PABA may antagonize the effects of sulfa drugs.
SPECIAL POPULATIONS Sulfa drugs should be avoided in pregnancy near term due to the increased potential for kernicterus in the newborn [131]. Animal studies with sulfamethoxazole show bone abnormali- ties and a higher incidence of cleft palate. Adequate studies have not been done in pregnant women [131]. Mafenide, sulfacetamide ophthalmic drops, and sulfadiazine are pregnancy category C. Sulfacetamide lotion has not been studied in pregnancy. Adverse events were not observed in animal reproduction studies of silver sulfadiazine; nevertheless, it is contraindicated for use near term in pregnant women [6]. Sulfonamides are excreted in breast milk. Sulfamethoxazole and sulfisoxazole are considered compatible with breastfeeding by the AAP, although they should be avoided if hyperbilirubi- nemia or G6PD deficiency is present [57]. Sulfacetamide lotion and silver sulfadiazine have not been studied in breastfeeding but would presumably also be excreted in breast milk; use with caution in breastfeeding women [6]. The manufacturer considers the use of sulfadiazine to be contraindicated in breastfeeding women [6]. Because of the risk of neonatal kernicterus, use of sulfonamides should be avoided in the newborn. Sulfacetamide eye drops have not been studied in children younger than 2 months of age [6]. TETRACYCLINES Chlortetracycline, the first tetracycline, was developed in 1948 as a product of Streptomyces aureofaciens . Chlortetracycline was altered to produce tetracycline. Doxycycline and minocycline are semisynthetic derivatives. Tetracyclines bind to the 30S ribosomal subunit (and possibly the 50S ribosomal subunits of susceptible bacteria), blocking the binding of aminoacyl transfer-RNA [6; 138]. This results in inhibition of protein synthesis, with bacteriostatic effects. Bacterial resistance is typically the result of mutations that either prevent entrance of tetracyclines into the cell or increase the export of tetracycline out of the cell [139]. The resistance may be transmitted by plasmids [140].
MECHANISMS OF ACTION AND PHARMACOKINETICS
The tetracyclines have a broad spectrum of activity that includes aerobic gram-positive and gram-negative bacilli, atypical bacteria (such as Chlamydia trachomatis , Chlamydia psittaci , and Mycoplasma pneumoniae ), and spirochetes (such as Borrelia burgdorferi ). Tetracycline is also a second-line agent for T. pallidum . It is approved by the FDA for treatment of rickettsial infections, typhus, Rocky Mountain spotted fever, trachoma, nongonococcal urethritis, and lymphogranuloma venereum [6].
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