Sulfonamides drug resistance

The phenomenon of bacterial resistance to antibiotics was already known by the pioneers of the era of antibiotics, like Paul Ehrlich, who coined the term selective toxicity as the basic principle of antimicrobial therapeutics, as well as Gerhard Domagk, the inventor of the sulfonamide drugs, and Sir Alexander Fleming, the discoverer of the penicillins. When penicillin G was introduced into clinical practice in 1944, as many as 5% of the isolates of Staphylococcus aureus were resistant to penicillin, while 5 years later the percentage was 50%. 

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

Numerous episodes have occurred in which humans have developed drug-resistant nontyphoid Salmonella infections that have been traced to animal sources (23). These bacteria can be transmitted to humans in food or through direct contact with animals. Antimicrobial resistance limits the tlierapeutic options available to veterinarians and physicians for the subset of clinical cases of nontyphoid Salmonella that require treatment. A recent example is a clone of Salmonella typhimurium DT 104 with chromosomally encoded resistance to ampicillin, tetracycline, streptomycin, chloramphenicol and sulfonamides, which has become increasingly common in humans in England and Wales since 1990 (24). Since 1992, only Salmonella enteritidis has accounted for more cases of human salmonellosis than Salmonella typhimurium DT 104 (25, 26). Multiresistant DT 104 has currently emerged in several European countries (27-29) outbreaks have been also reported in the United States in both cattle (30) and humans (31). 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

The gene encoding 7,8-dihydropteroate synthase was cloned from P falciparum and found to encode a bifunctional enzyme that includes the pyrophosphokinase at the amino terminal of the protein. Discrepancies were observed in the sequences of 7,8-dihydropteroate synthase portion of the genes from sulfadoxine-sensitive versus sulfadoxine-resistant P falciparum, thus confirming that this enzyme is the target for the antimalarial sulfonamide drugs. 

Only organisms that synthesize their own folate are sensitive to the sulfonamides. Bacterial resistance to the sulfas can arise from plasmid transfers or random mutations. The resistance is generally irreversible and may be due to any of the following three possibilities. [Note Organisms resistant to one member of this drug family are resistant to all, but they may be susceptible to co-trimoxazole.]... 

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. 

Consider quinolonc for suspected shigellosis in adults (fever, inflammation) macrolidc for suspected resistant Campylobacter avoid antimotility drugs, sulfonamides or quinolones if suspected EHEC (afebrile, bloody diarrhea). 

Resistance to the sulfonamides can be the result of decreased bacterial permeability to the drug, increased production of PABA, or production of an altered dihydropteroate synthetase that exhibits low affinity for sulfonamides. The latter mechanism of resistance is plasmid mediated. Active efflux of the sulfonamides has also been reported to play a role in resistance. The inhibitory effect of the sulfonamides also can be reversed by the presence of pus, tissue fluids, and drugs that contain releasable PABA. 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

Ultra long acting sulfonamides in combination with pyrimethamine are used. The effect is supraadditive due to sequential block. It may be employed as a clinical curative. Another advantage of the drug combination is that the development of resistance is retarded. 

Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprim-sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections. 

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