Trimethoprim: Mechanisms of Action, Antimicrobial Activity, Bacterial Resistance, Pharmacokinetics, Adverse Reactions, and Therapeutic Indications

Abstract

Trimethoprim has recently been marketed as a single-entity product for the treatment of initial episodes of uncomplicated symptomatic urinary tract infections; it was previously available only in combination with sulfamethoxazole. Trimethoprim exerts antimicrobial activity by blocking the reduction of dihydrofolate to tetrahydrofolate, the active form of folic acid, by susceptible organisms. It has inhibitory activity for most gram-positive aerobic cocci and some gram-negative aerobic bacilli. Resistance to trimethoprim may be either intrinsic or acquired. Acquired resistance most commonly stems from a chromosomal mutation that results in the production of a dihydrofolate reductase enzyme which is less vulnerable to trimethoprim inhibition. Gastrointestinal intolerance and skin eruptions are the most common untoward reactions resulting from the administration of trimethoprim. Trimethoprim constitutes very effective therapy for women with acute symptomatic urinary tract infections caused by E. coli, and the compound compares favorably with alternative standard agents, such as ampicillin and cephalexin. The safety of trimethoprim in the pregnant woman has not been established. Since indiscriminate use of trimethoprim could foster the emergence of trimethoprim resistance, thereby negating the value of both trimethoprim and trimethoprim-sulfamethoxazole, trimethoprim should only be prescribed for well defined indications. Trimethoprim is currently being investigated as definitive therapy for a wide range of infections, including bacterial exacerbations of chronic bronchitis, bacterial pneumonia, and typhoid fever. Initial reports are encouraging.

In vitro antibacterial activity of norfloxacin (MK-0366, AM-715) and other agents against gastrointestinal tract pathogens

“…(Table 1). Although all the isolates tested in this study were susceptible to the present drug of choice in each case, except for Salmonella enteritidis against ampicillin (MIC90, >128 ,ug/ml), various degrees of bacterial resistance have been reported for virtually all of the marketed compounds tested (3,11,15,16,18,29). Resistance of these various enteric pathogens is defined in vitro by MIC breakpoints of -32 ,g/ml for norfloxacin (submitted for publication), nalidixic acid, ampicillin, co-trimoxazole, and vancomycin; .16 jig/ml for tetracycline and chloramphenicol; -8 jig/ml for erythromycin and clindamycin; and .4 jig/ml for trimethoprim (8,30).…”

“…We regret the inadvertent omission of this compound in the present study. It should be pointed out, however, that in several recent reports (8,13,15) In previous investigations, the quinoline drugs oxolinic and nalidixic acids, to which norfloxa-VOL. 23,1983 on May 12, 2018 by guest http://aac.asm.org/ Downloaded from cin is structurally related, were found to be active both in vitro (6,16) and in vivo (10,17) against antibiotic-resistant shigellae.…”

Trimethoprim and Sulfamethoxazole are Selective Inhibitors of CYP2C8 and CYP2C9, Respectively

“…Although trimethoprim is mainly excreted unchanged in urine, a significant amount (20%) of the dose is metabolized by the hepatic cytochrome P450 (P450 1 ) isoforms (Gleckman et al, 1981). In individuals with severe liver damage, the elimination half-life of trimethoprim can be lengthened up to 2-fold (Rieder and Schwartz, 1975).…”

In Vivo Imaging of Bioluminescent Escherichia coli in a Cutaneous Wound Infection Model for Evaluation of an Antibiotic Therapy

“…The combination of SMX and TMP inhibits E. coli(pRB474) folic acid synthesis. This inhibition is called the "sequential blockade" and produces death of the bacterium (13,35).…”

“…This drug combination has proved to be an effective therapeutic agent with broad-spectrum antibacterial activity against both gram-positive and gram-negative organisms. It is recognized as having excellent activity against staphylococci in the skin (13,35,40). This makes SMX-TMP a good choice for the treatment of skin infections or as a general antibiotic when the actual identity of the infecting organism is not known (10).…”