Resistance to 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. 

Detecting evolutionary hot spots of antibiotic resistance in Europe Disc diffusion method Genes encoding dihydrofolate reductases confers resistance to trimethoprim... 

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. 

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. 

Resistance can develop from alterations in dihydrofolate reductase, bacterial impermeability to the drug, and by overproduction of the dihydrofolate reductase. The most important mechanism of bacterial resistance to trimethoprim clinically is the production of plasmid-encoded trimethoprim-resistant forms of dihydrofolate reductase. 

A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, shigellosis, systemic salmonella infections, urinary tract infections, prostatitis, and some nontuberculous mycobacterial infections. It is active against most Staphylococcus aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as the pneumococcus, Haemophilus sp, Moraxella catarrhalis, and Klebsiella pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empirical therapy of upper urinary tract infections or pneumonia. 

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. 

Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. 

Modification of target sites Alteration of the target site through mutation can confer resistance as occurs with the penicillin binding proteins in methicillin-resistant aureus, or the enzyme dihydrofolate reductase, which is less sensitive to inhibition in organisms resistant to trimethoprim. 

As a result of the urethral catheter she had inserted in the intensive care unit, CM develops a urinary tract infection, with an E. coli that is resistant to trimethoprim and amoxicillin, but is sensitive to gentamicin. She is prescribed a dose of gentamicin, 7 mg/kg intravenously once daily for 5 days. 

Plasmid- and transposon-mediated resistance to trimethoprim involves a by-pass of the sensitive step by duplication of the chromosomally-encoded dihydrofolate reductase (DHFR) target enzyme [203]. Several trimethoprim-resistant bacterial DHFRs have been identified, resistance ensuing because of altered enzyme target sites [204], Low-level resistance to tetracyclines arises in E. coli as a result of chromosomal mutations leading to loss of the outer membrane porin OmpF through which these drugs normally pass [6, 193],... 

Bacteria have developed several mechanisms that make them resistant to trimethoprim. Resistance can occur rapidly, and has been reported in Europe, the USA, Asia, and South America, which may account for the fact that trimethoprim is usually used in combination (1,167,168). However, the clinical significance of resistance to trimethoprim has been debated (1,7,16,169). 

Urinary tract infection—Acnte nncomplicated cystitis in women can be effectively and inexpensively treated, before the infecting organism is known, with a three-day course of oral trimethoprim-sulfamethoxazole in areas where the prevalence of E. coli resistant to trimethoprim-sulfamethoxazole exceeds 15 to 20%, a fluoroquinolone can be substituted. 

The combination is an alternative to fluoroquinolone for treatment of shigellosis, but resistance to trimethoprim—sulfamethoxazole is increasingly common. 

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. 

Bacterial resistance to trimethoprim is increasingly common. In pneumococcal infections, it can result from a single amino acid mutation (lie-100 to Leu) in the dihydrofolate reductase enzyme. Overexpression of dihydrofolate reductase by Staphylococcus aureus has been reported in resistant strains as well. 

No activity observed, E. coli isolates (resist to trimethoprim-sulfamethoxazole, cefepime, tazobactam), P. aeruginosa isolates (resist to Trimethoprim-Sulfamethoxazole, tazobactam), P.mirabilis isolates (resist to trimethoprim-sulfamethoxazole, cefepime, tazobactam), K. pneumoniae isolates (resist to trimethoprim-sulfamethoxazole, amoxicillin clavulonate, ceftriaxone, cefepime, aztreonam)... 

A. baumannii isolates (resist to trimethoprim-sulfamethoxazole, cefepime). 

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