Resistance sulfonamides, potentiated

Typical maximum residue hmit (MRL) for sulfonamides is 100 pg/kg in meat and 10 pg/kg in milk. Sulfonamide residues are of concern because of the possible development of antibiotic resistance and their potential carcinogenic properties. 

The sulfonamides are a group of organic compounds with chemotherapeutic activity they are antimicrobial agents and not antibiotics. They have a common chemical nucleus that is closely related to PABA, an essential component in the folic acid pathway of nucleic acid synthesis. The sulfonamides are synergistic with the diaminopyrim-idines, which inhibit an essential step further along the folate pathway. The combination of a sulfonamide and a diaminopyrimidine is advantageous because it is relatively non-toxic to mammalian cells (less sulfonamide is administered) and is less likely to select for resistant bacteria. Only these so-called potentiated sulfonamides are used in equine medicine. These drugs are formulated in a ratio of one part diaminopyrimidine to five parts sulfonamide, but the optimal antimicrobial ratio at the tissue level is 1 20, which is achieved because the diaminopyrimidines are excreted more rapidly than the sulfonamides. 

Resistance to the diaminopyrimidines usually occurs by plasmid-encoded production of diaminopyrimidine-resistant DHFR. Excessive bacterial production of DHFR and a reduction in the ability of the drug to penetrate the bacterial cell wall also results in resistance. There is less resistance to the potentiated sulfonamides than to the individual agents. 

It warrants mention that resistance to a particular antimicrobial agent in vitro may not preclude successful treatment with the drug as long as high concentrations are achieved in urine. Similarly, demonstrable susceptibility in vitro does not always guarantee a successful response to treatment. For example. Enterococcus spp. is often found to be susceptible to the potentiated sulfonamide combinations in vitro however, this pathogen is inherently resistant to these combinations in vivo (Jose-Cunilleras Hinchcliff 1999, Schott 1998). Antimicrobial therapy should be continued for at least 1 week for the treatment of lower UTIs and for 2-6 weeks for upper UTls in horses. Ideally, a voided, midstream urine sample should be submitted for bacterial culture 2-4 days after the initiation of therapy and again 1-2 weeks after treatment has been discontinued. 

The cephalosporins and tetracyclines are commonly used for treatment of UTIs in other species. However, in horses, the cephalosporins are rarely more advantageous than the penicillins or potentiated sulfonamides. However, ceftiofur has broad-spectrum antimicrobial activity and may be indicated when urinary pathogens are resistant to... 

Even though the synergism observed with antifolate-sulfonamide combinations appears real, whether or not the mechanism is truly a sequential blockade is questionable. For example, it was shown that a potent DHFR inhibitor, 2,4-diaminopteroyl aspartate, is not synergistic with sulfamethoxazole. In addition, it was found that DHFR isolated from E. coli could be inhibited by sulfonamides, suggesting a multiple simultaneous inhibition of DHFR by both drugs. Curiously, it was also found that the TM potentiates sulfonamides that alone are resistant to the bacterium tested. 

It Is easier to demonstrate synergy in vitro than in vivo, and concerns about the toxic contribution of the sulfonamide (and, doubtless, commercial considerations as well) have led to a recent vogue for the use of trimethoprim alone. Trimethoprim has a broad spectrum in vitro, so it Is potentially useful against many microorganisms. Combined with sulfamethoxazole, it Is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler s diarrhea, methicillin-resistant Staphylococcus aureus (MRSA), Legionella infection, and bronchitis. 

Trimethoprim, however, is a competitive inhibitor of dihydrofolate reductase . The accumulation of dihydrofolate, through continuing biosynthesis and reoxidation of tetrahydrofolate, tends to increase the metabolite antimetabolite ratio and diminishes the effectiveness of the blockade. Conjoint application of a sulfonamide, however, removes the source of new dlhydrofolate and Improves the effectiveness of the inhibition. In practice the simultaneous use of the 2 inhibitors results in a 5-10-fold potentiation, broadening of the spectrum of action, a decreased liability to the development of resistance, and a conversion of bacteriostatic to bactericidal effects . 

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