Chapter: Modern Pharmacology with Clinical Applications: Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine


Chemistry, Structure, and Mechanism of Action



Chemistry, Structure, and Mechanism of Action


Trimethoprim (Trimpex, Proloprim) is a structural ana-logue of the pteridine portion of dihydrofolic acid. It dif-fers from the sulfonamides in that it acts at a second step in the folic acid synthetic pathway; that is, it competitively inhibits dihydrofolate reductase. This is the enzyme that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, the active form of folate. Dihydrofolate reductase is present in both mammalian tissue and bacteria, but 20,000 to 60,000 times more drug is required to inhibit the mammalian enzyme; this accounts for its selective toxicity against bacteria.


Trimethoprim–sulfamethoxazole (TMP-SMX) was in-troduced as a fixed dose combination in 1968. Tri-methoprim was added to sulfamethoxazole to synergisti-cally and sequentially inhibit bacterial synthesis of tetrahydrofolic acid.The combination was also designed to delay development of bacterial resistance. Sulfameth-oxazole was selected in part because it is a congener of the frequently used sulfisoxazole but exhibits slower enteric absorption and urinary excretion. Sulfamethoxazole has a half-life similar to that of trimethoprim.


Antibacterial Spectrum and Resistance


Trimethoprim exhibits broad-spectrum activity. It is most commonly used in combination with sulfamethoxazole and is active against most gram-positive and gram-negative organisms, especially the Enterobacteriaceae. There is little activity against anaerobic bacteria; P. aerug-inosa, enterococci, and methicillin-resistant staphylo-cocci should be considered resistant to trimethoprim.


Resistance can develop from alterations in dihydro-folate 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.


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


Absorption, Metabolism, and Excretion


Trimethoprim is well absorbed from the GI tract, and peak blood levels are achieved in about 2 hours. Tissue levels often exceed those of plasma, and the urine con-centration of trimethoprim may be 100 times that of the plasma. Trimethoprim readily enters the CSF if inflam-mation is present. The half-life of the drug is approxi-mately 11 hours. Sulfamethoxazole (t1/2 10 hours) is frequently coadministered with trimethoprim in a fixed dose ratio of 1:5 (trimethoprim to sulfamethoxazole).

Peak drug levels in plasma are achieved in 1 to 4 hours following oral administration and 1 to 1.5 hours after IV infusion. At this time, the TMP-SMX plasma ratio is 1:20, which is the ratio most effective for producing a synergistic effect against most susceptible pathogens. The ratio is also influenced by the greater lipid solubil-ity of trimethoprim, which results in its larger volume of distribution. Both trimethoprim and sulfamethoxazole bind to plasma protein (45 and 66% respectively) and both are metabolized in the liver. Approximately 40 to 60% of both parent drugs and their metabolites is ex-creted by the kidney within 24 hours; in moderate to se-vere renal dysfunction the dose should be reduced by approximately one-half. Only the parent compounds are excreted in the bile. Both drugs cross the placenta and are found in breast milk (see adverse effects).


Clinical Use of Trimethoprim–Sulfamethoxazole


TMP-SMX (Septra, Bactrim) is used in the treatment of genitourinary, GI, and respiratory tract infections caused by susceptible bacteria. E. coli, enterococci, P. mirabilis, some indole-positive strains of Proteus spp., and Klebsiella pneumoniae are usually sensitive to this combination therapy for both chronic and recurrent UTIs. Trimethoprim is present in vaginal secretions in high enough levels to be active against many of the or-ganisms found in the introital area that are often re-sponsible for recurrent UTIs. In some patients with re-current UTIs, most notably women of childbearing age, the long-term use of one tablet taken at night is an ef-fective form of chemoprophylaxis. The drug is approved for use by the U. S. Food and Drug Administration (FDA) for treating UTIs in both children and adults.


TMP-SMX is also used in the treatment of infection caused by ampicillin-resistant Shigella spp. and for antibiotic-resistant Salmonella spp.. The combination is also effective for covering the carrier state of Salmonella typhi, the agent of typhoid fever, and other Salmonella spp.. Successful treatment of traveler’s diar-rhea due to susceptible E. coli is another advantage of the use of this combination. The combination is not in-dicated in the therapy of enterohemorrhagic E. coli strains such as O157:H7 because of the risk of develop-ing hemolytic–uremic syndrome associated with the re-lease of the cytotoxic enterotoxin by the drugs.


Because trimethoprim accumulates in the prostate, TMP-SMX is used to treat prostatitis caused by sensi-tive organisms. Therapy can be prolonged (4–6 weeks) and repeat courses of therapy may be necessary. Trimethoprim alone, because of its lipid solubility, can be effectively used when patients exhibit an allergic re-sponse to the sulfonamide component.


Otitis media in children and purulent exacerbations of chronic bronchitis respond well to TMP-SMX because of its activity against both susceptible Streptococcus pneumoniae and Haemophilus influenzae type b (Hib); the latter organism is now a much less frequent pathogen in otitis because of the use of the Hib vaccine.


Gonorrhea, typhoid fever, and brucellosis have been treated with TMP-SMX with cure rates comparable to those attained by standard therapy. It also has been used in the treatment of nocardial infections.


TMP-SMX remains the antimicrobial therapy of choice in both the treatment and prevention of infec-tions caused by P. carinii, a protozoan that produces se-rious pneumonitis in patients with hematological malig-nancies and AIDS. In those with AIDS, treatment is more prolonged and relapse is common. These patients are at increased risk for untoward effects such as fever, hepatitis, rash, and leukopenia.


Adverse Effects and Drug Interactions


Serious adverse effects are rare except in AIDS patients. TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration, including skin rashes, central nervous system (CNS) disturbances, and blood dyscrasias. Blood dyscrasias, hepatotoxicity, and skin rashes are particularly common in patients with AIDS. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Tri-methoprim may increase the hematological toxicity of sulfamethoxazole. Long-term use of trimethoprim in per-sons with borderline folic acid deficiency, such as alco-holics and the malnourished, may result in megaloblastic anemia, thrombocytopenia, and granulocytopenia.


Trimethoprim has been reported to decrease the therapeutic effect of cyclosporine with a concomitant increased risk of nephrotoxicity. Increased levels of dapsone, warfarin, methotrexate, zidovudine, and sul-fonylureas may occur when given together with tri-methoprim; dosages of these drugs should be modified and the patient monitored accordingly.


Because both drugs may interfere with folic acid metabolism, their use during pregnancy is usually con-traindicated by the potential for effects on the fetus, such as the development of neural tube defects associ-ated with folate deficiency. The use of trimethoprim is contraindicated in patients with blood dyscrasias, he-patic damage, and renal impairment.


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Modern Pharmacology with Clinical Applications: Synthetic Organic Antimicrobials: Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine : Trimethoprim |

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