Sulfonamides bacterial resistance

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.]... 

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%. 

Because of bacterial resistance and unacceptable side effects in some patients, the antibacterial sulfonamides no longer enjoy the clinical vogue they once had. Still, their cheapness, undeniable efficacy in susceptible infections, and the hope of overcoming their deficiencies leads to a continuing interest despite thousands having been synthesized to date. 

Among pharmaceuticals, antibiotics have become of special concern in recent years. The reason is that these substances are continuously being introduced into the environment and may spread and maintain bacterial resistance in the different compartments. Sulfonamides are very commonly used antimicrobials in humans but mainly in veterinary medicine, due to their broad spectrum of activity and low cost, being the second most widely used veterinary antibiotic in the EU. Their occurrence has been reported in all kinds of water matrices their high excretion rates (after their intake by humans of livestock) and high water solubility make them very ubiquitous and persistent pollutants in the environment. 

Keywords Bacterial resistance, Environmental risk assessment. Soil, Sulfonamide, Surface waters, Toxicity... 

Much of the debate concerning the use of antibiotics in livestock feeds has centered on bacterial resistance. One of the first observations made early in the 1950s, was that the bacterial count in animal feces increased after a temporary decrease when antibiotics, such as tetracyclines, were fed (12). This was in contrast to the effect of sulfonamides, which reduce the count. Obviously, resistance had occurred because the intestinal bacteria were thriving in the presence of antibiotics. Simultaneously, the growth of the animals was increased. Therefore the resistance in itself was not harmful. 

The sulfonamides can be classified according to their therapeutic utility and pharmacokinetic parameters (table 9.1.2). However, because of bacterial resistance and discovery of many safer and more effective antibiotics, the utility of sulfonamides is limited to few infections which are of clinical interest. 

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. 

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. 

Describe the mechanisms of antibacterial action of sulfonamides and trimethoprim on bacterial folic acid synthesis and the mechanisms involved in bacterial resistance to the antifolate drugs. 

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. 

Trimethoprim frequently is used as a single agent clinically for the oral treatment of uncomplicated urinary tract infections caused by susceptible bacteria (predominantly community acquired Escherichia coli and other Gram-negative rods). It is, however, most commonly used in a 1 5 fixed concentration ratio with the sulfonamide sulfamethoxazole (Bactrim, Septra). This combination is not only synergistic in vitro but also is less likely to induce bacterial resistance than either agent alone. It is rationalized that microorganisms not... 

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. 

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. 

Resistance occurs as the result of one or more alterations in the cellular metabolism of the bacteria both mutation and plasmid-mediated resistance occurs. These changes, which can be irreversible, include alterations in the physical or enzymatic characteristics of the enzyme or enzymes that metabolize PABA and participate in the cellular synthesis of tetrahydrofolic acid. The appearance of alternative pathways for PABA synthesis within the bacteria or the development of an increased capacity to inactivate or eliminate the sulfonamide also may contribute to bacterial cell resistance. Bacteria that can use preformed folate are not inhibited by sulfonamides. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

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. 

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. 

R-plasmid-mediated resistance is almost invariably associated with crossresistance to a number of related and unrelated antibiotics. The reasons for the association lie in the resistance mechanism to related compounds that have been coded, the usual presence of more than one R determinant in the same plasmid, and the frequent coexistence of several different plasmids in the same bacterial cell. As a result, use of any antibiotic can lead to development of resistance to itself and to other related and unrelated antibiotics. If, for example, a plasmid is encoded for resistance to ampicillin, tetracycline, sulfonamide, and streptomycin, exposure to any of these antibiotics results in resistance to all the others, whereas the use of a -lactamase-containing strain results in resistance to other members of this group. 

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis and depend upon exogenous sources of folate therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that cause overproduction of PABA, cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or cause a loss of permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant cells may be present in susceptible bacterial populations and can emerge under selective pressure. 

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