Bacteria Trimethoprim

Resistance to trimethoprim can be due to the acquisition of plasmid encoded non-allelic variants of the chromosomal DHFR enzyme that are antibiotic unsusceptible. The genes may be part of transposons that then insert into the chromosome. For instance, in gram-negative bacteria the most widespread gene is dhfrl on transposon Tn7. 

Trimethoprim (Trimpex) interferes with the ability of bacteria to metabolize folinic acid, thereby exerting bacteriostatic activity. Trimethoprim is used for UTIs that are caused by susceptible microorganisms. Trimethoprim administration may result in rash, pruritus, epigastric distress, nausea, and vomiting. When trimethoprim is combined with sulfamethoxazole (Septra), the adverse effects associated with a sulfonamide may also occur. The adverse reactions seen with other anti-infectives, such as ampicillin, the sulfonamides, and cephalosporins, are given in their appropriate chapters. 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Initial therapy with trimethoprim-sulfamethoxazole appears to be effective for CA-MRSA and should be considered in geographic areas in which CA-MRSA are commonly encountered. Alternative agents for documented infections with resistant gram-positive bacteria such as methicil-lin-resistant staphylococci and vancomycin-resistant enterococci include linezolid, quinupristin/dalfopristin, daptomycin, and tigecycline. 

Uncomplicated coli Gram-positive bacteria 1. Quinolone x 14 days (A, II)0 2. Trimethoprim-sulfamethoxazole (if susceptible) x 14 days (B, II)0 1. Amoxicillin or amoxicillin-clavulanic acid x 14 days (B, III)0 Can be managed as outpatient... 

If gram-negative bacteria are presumed, trimethoprim-sulfamethoxazole or a fluoroquinolone is a preferred agent. Initial therapy is for 10 to 14... 

Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

Trimethoprim has a broad spectrum of antimicrobial activity. It is 20-100 times more active than sulfamethoxazole with respect to most bacterial forms. Trimethoprim is active with respect to Gram-positive, aerobic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, and various types of Streptococcus and Listeria monocytogenes. Trimethoprim is inferior to sulfonamides against forms of Nocardia. It is active... 

Haemophilus influenzae and H. ducreyi are sensitive to trimethoprim. Pathogenic Neisseria (meningococci and gonococci) and Branhamella catarrhalis are moderately resistant to trimethoprim, although they are very sensitive to a combination of trimethoprim and sulfamethoxazole. Anaerobic bacteria in general are resistant to trimethoprim, although a combination of trimethoprim-sulfamethoxazole does have an effect on them. Pneumocystis carinii is also sensitive to that combination. 

The frequency of relapse and the risk of renal damage determine the need for on-demand therapy or prophylactic therapy. In intercourse-related UTI in sexually active women single dose prophylactic therapy was shown to be effective. One dose of trimethoprim ( sulfamethoxazole) or nitrofurantoin is effective, inexpensive and unlikely to allow the emergence of resistant bacteria. 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Trimethoprim exhibits broad-spectrum activity. It is most commonly used in combination with sulfamethoxazole and is active against most gram-positive and gramnegative organisms, especially the Enterobacteriaceae. There is little activity against anaerobic bacteria P. aeruginosa, enterococci, and methiciUin-resistant staphylococci should be considered resistant to trimethoprim. 

Because trimethoprim and sulfamethoxazole have their effects at different points in the folic acid synthetic pathway, a synergistic effect results when the two are administered together. The incidence of bacterial resistance to the combination is less than that observed when the drugs are used individually. Resistance is an increasing problem in a number of bacteria, but is especially problematic in the Enterobacteriaceae, against which the combination is used in AIDS patients for Pneumocystis carinii pneumonia prophylaxis. 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Nitrofurantoin is bacteriostatic and bactericidal for many gram-positive and gram-negative bacteria but P aeruginosa and many strains of proteus are resistant. There is no cross-resistance between nitrofurantoin and other antimicrobial agents and resistance emerges slowly. As Escherichia coli resistant to trimethoprim-sulfamethoxazole and fluoroquinolones has become more common, nitrofurantoin has become an important alternative oral agent for treatment of uncomplicated urinary tract infection. 

The sulfonamide antibiotics were the first synthetic antibiotics to have general utility in human therapy (B-79MI10806). Of the numerous compounds thus developed, comparatively few are presently used in veterinary practice. They include sulfapyridine (40), sulfamethazine (41) and sulfadimethoxine (42). They are much less potent than the /3-lactams (dose 100-200 mg kg-1), and have a bacteriostatic effect. They are commonly used in combination with trimethoprim (43), when a synergistic effect is observed, i.e. the combination is more potent than either drug alone, and species of bacteria which are unaffected by the drugs individually are susceptible to the combination. 

Trimethoprim (Proloprim, Trimpex) interferes with the bacterial folic acid pathway by inhibiting the dihydrofolate reductase enzyme in susceptible bacteria (see Fig. 33-2). This enzyme converts dihydrofolic acid to tetrahydrofolic acid during the biosynthesis of folic acid cofactors. By inhibiting this enzyme, trimethoprim directly interferes with the production of folic acid cofactors, and subsequent production of vital bacterial nucleic acids is impaired. 

In acute and chronic urinary tract infection, the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra) exerts a truly synergistic effect on bacteria. The sulfonamide inhibits the utilization of p-amino-benzoic acid in the synthesis of folic acid (Figure 2.3), whereas trimethoprim, by inhibiting dihydrofolic acid reductase, blocks the conversion of dihydrofolic acid to tetrahydrofolic acid, which is essential to bacteria in the denovo synthesis of purines, pyrimidines, and certain amino acids. Because mammalian organisms do not synthesize folic acid and therefore need it as a vitamin in their daily diets, trimethoprim-sulfamethoxazole does not interfere with the metabolism of mammalian cells. 

A wide range of compounds also inhibit a number of the enzyme systems that are involved in the biosynthesis of purines and pyrimidines in bacteria. For example, sulphonamide bacteriostatics inhibit dihydropteroate synthetase, which prevents the formation of folic acid in both humans and bacteria. However, although both mammals and bacteria synthesize their folic acid from PABA (Figure 7.12), mammals can also obtain it from their diet. In contrast, trimethoprim specifically inhibits bacterial DHF, which prevents the conversion... 

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