Resistance to sulfonamides

Accessory DHPS enzymes confer resistance to sulfonamides. Two different types encoded by the genes sull (located on transposons) and sulll (located on plasmids) have been described. These resistance determinants are often genetically linked to trimethoprim resistance genes. Therefore, the combination of sulfonamide antibiotics with trimethoprim does not prevent resistance selection. 

The macrolide erythromycin inhibits protein synthesis and resistance is induced by N -dimethyl-ation of adenine within the 23S rRNA, which results in reduced affinity of ribosomes for antibiotics related to erythromcin (Skinner et al. 1983). Sulfonamides function by binding tightly to chromosomal dihydropteroate synthetase and resistance to sulfonamides is developed in the resistance plasmid through a form of the enzyme that is resistant to the effect of sulfonamides. 

Genes encoding phosphotransferases confer resistance to streptomycin Genes encoding a drug-resistant dihydropteroate synthase enzyme required for folate biosynthesis confer resistance to sulfonamide Tetracycline... 

Acquired resistance to sulfonamides is widespread. Mechanisms of resistance include overproduction of... 

Resistance to the sulfonamides occurs via chromosomal mutation or is plasmid mediated. Chromosomal mutation results in hyperproduction of PABA in bacteria, which overcomes the competitive substitution of the sulfonamides. These mutations are of minor clinical significance. The most common form of bacterial resistance to sulfonamides is via the plasmid-encoded production of altered forms of DPS. More than 50 years of widespread use of the sulfonamides in animal health has resulted in widespread resistance. 

This case concerns a chronic E. coli infection of the urinary tract in a 65 year old male that has been present for 12 years and induced a constant, considerable impairment to his overall well-being, and led to attacks of fever and hypochromic anemia.. . . Tests of the infection revealed that the bacteria were nearly completely resistant to Sulfonamide, penicillin, Streptomycin, and Aureomycin.. .. The response to Terramycin, however, was astonishing.. . . Unfortunately, we only had sufficient supplies for two days... . We would be most appreciative if you [Boehringer] could supply us with additional dosages in such instances.37... 

Bacterial resistance to sulfonamides can originate by random mutation and selection or by plasmid transfer of resistance it usually does not confer cross-resistance to other classes of antibiotics. Resistance to sulfonamide results from altered constitution of the bacterial cell that causes (I) a lower affinity for sulfonamides by dihydropteroate synthase, (2) decreased bacterial permeability or active efflux of the drug, (3) an alternative metabolic pathway for synthesis of an essential metabolite, or (4) an increased production of an essential metabolite or drug antagonist. Plasmid-mediated resistance is due to plasmid-encoded, drug-resistant dihydropteroate synthetase. 

A synergistic interaction between these drugs is apparent even when microorganisms are resistant to sulfonamide, but maximal synergism occurs when microorganisms are sensitive to both drugs. 

Resistance to sulfonamides is now common for N. meningitidiSy as well as in cases of bacillary dysentery. Antibiotics have generally replaced the sulfonamides for these purposes. Sulfonamides, particulady sulfisoxazole and sulfadiazine, are of value in treatment of infections due to Nocardia species, and sulfonamides are effective for trachoma. Inclusion conjunctivitis is also treated with sulfacetamide ointment. Oral administration of a sulfonamide, eg, sulfisoxazole, has been successful for treatment of lymphogranuloma venereum and chancroid Dapsone and sulfonamides have also been used for treatment of the skin disorder dermatitis herpetiformis. Sulfonamides have been used for long term prophylaxis of rheumatic fever, but are being replaced by penicillin for this purpose, except in cases of hypersensitivity to penicillin (19). 

C. Resistance Bacterial resistance to sulfonamides is common and may be plasmid-mediated. It can result from decreased intracellular accumulation of the dmgs, increased production of PABA by bacteria, or a decrease in the sensitivity of dihydropteroate synthase to the sulfonamides. Clinical resistance to trimethoprim most commonly results from the production of dihydrofolate reductase that has a reduced affinity for the dmg. 

Bacteria that are able to take up preformed folic acid into their cells are intrinsically resistant to sulfonamides. 

Resistance to sulfonamides is widespread in bacteria isolated from animals, and may involve chromosomal mutations or plasmid-mediated mechanisms. Chromosomal mutations cause impaired drug penetration, production of altered forms of dihydropteroate synthetase for which sulfonamides have a lowered affinity, or production of excessive PABA that overcomes the metabolic block imposed by the inhibition of dihydropteroate synthetase. A more common cause of bacterial resistance to sulfonamides is plasmid-mediated mechanisms, which may result in impaired drug penetration or the synthesis of sulfonamide-resistant dihydropteroate synthetase. There is cross-resistance among sulfonamides. 

Antibiotics have been used for the treatment of infectious diseases and for a number of non-human applications (agriculture, animal husbandry, and aquaculture) during the past 70 years (Levy and Marshall 2004). Prior to the introduction of antibiotics, natural populations of human/animal bacterial pathogens or commensal bacteria were susceptible to antibiotics (Hughes and Datta 1983). Immediately after the entry of antibiotics in the treatment of infectious diseases, the appearance of antibiotic-resistant bacteria was observed. Today, the overwhelming majority of enterobacteria are resistant to sulfonamides, the first antibacterial chemotherapeutics introduced in clinical practice in 1937. Additionally, a high proportion of bacteria are resistant to a broad range of penicillins, streptomycin, chloramphenicol, and tetracyclines. 

So far these two properties of Citrobacter have not been systematically studied. According to our experience the great majority of newly isolated strains are completely resistant to sulfonamides and for the most part also to coUimycin [97]. Recently Washington et al. [98] have found fresh cultures of C. intermedins (25 strains) to be highly susceptible to polymyxin B, kana-mycin, gentamycin, nalidixic acid and nitrofurantoin. The susceptibility to chloramphenicol, tetracycline and streptomycin was intermediate. Practically all strains were resistant to cephalodrin. On the other hand, 80 % of strains were inhibited by carbenicillin (10 mcg/ml). 

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