Trimethoprim and

Overproduction of the chromosomal genes for the dihydrofolate reductase (DHFR) and the dihydroptero-ate synthase (DHPS) leads to a decreased susceptibility to trimethoprim and sulfamethoxazol, respectively. This is thought to be the effect of titrating out the antibiotics. However, clinically significant resistance is always associated with amino acid changes within the target enzymes leading to a decreased affinity of the antibiotics. 

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. 

Huovinen P., Sundstrom L., Swedberg G. Skold O. (1995) Trimethoprim and sulphonamide resistance. 

Among its inhibitors are methotrexate (MTX), trimethoprim, and other derivatives of pyrimidines, triazines, pteridines, and related heterocyclic compounds. Some of these inhibitors, such as MTX, bind more tightly to Escherichia coli enzyme than does the substrate dihydrofolate. This fact has been attributed to ion-pair formation between protonated MTX and a negative carboxyl, presumably Asp-27, as well as to hydrophobic interactions.33... 

Antibiotic resistance profiles of the bacterial communities reflected the effects of deforestation and the land degradation (Fig. 2). The degradation was significant (p=0.05) as a source of variation for the numbers of soil bacterial cells resistant to lasalocid, penicillin, spectinomycin and trimethoprim, and marginally significant (0.50 Significant differences between two average values were observed for some antibiotics. When compared with the BG soil bacterial community, the DEF soil bacterial community had more bacterial cells resistant to dapson, kanamycin, lasalocid, nafcillin, penicillin, spectinomycin, streptomycin and trimethoprim. 

Trimethoprim and sulfamethoxazole 160 mg Irimelhoprim and 800 mg sulfamethoxazole orally or IV four limes daily for 10 days (All)0... 

This data shows a noticeable drop in binding affinity for trimethoprim and chicken liver DHFR. Figure 8 illustrates steric interaction between the 5-OMe of trimethoprim (green) with the sidechain of Tyr 31 of native chicken liver DHFR (red). There is no steric interaction seen between the 5-OMe of trimethoprim (green) and the sidechain of Phe 30 of L. casei DHFR (red). (Right view chicken liver DHFR Left View L. casei DHFR) It is known from x-ray crystallographic results that the sidechain of Tyr 31 of chicken liver DHFR rotates to accommodate trimethoprim. ( ... 

This sol-gel procedure is an elaboration on well established entrapment methods [29], but with the added advantage of stability and better flow properties. Interestingly, none of the examples presented thus far demonstrate competitive behavior between multiple ligands (i.e. displacement) in the FAC analysis of trimethoprim and pyrimethamine a reversed order of elution based on is described, but this could simply be due to the shift towards an on-rate limited situation for higher affinity compounds, as described earlier. Erosion of dynamic competition between ligands could occur if the sol-gel allows convective mixing of the entrapped protein however the bimodal pore structure of these materials would... 

Co-trimoxazole consists of trimethoprim and sulphamethoxazole combined because of their synergistic antimicrobial effects. Trimethoprim is a folate antagonist that poses a teratogenic risk. 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual components. Resistant pathogens are infrequent a bactericidal effect may occur. Adverse effects correspond to those of the components. 

The diaminopyrimidines trimethoprim and pyrimethamine are synthetic, antibacterial drags and inhibitors of dihydrofolate reductase that are used both independently as well as in combination with sulfanilamides, in particular, with sulfamethoxazole (cotrimoxazole, bactrim, biseptol, sulfatrim, and many others). 

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. 

Drugs that may affect zidovudine include acetaminophen, atovaquone, bone marrow suppressive/cytotoxic agents (eg, adriamycin, dapsone), clarithromycin, doxorubicin, fluconazole, ganciclovir, methadone, nelfinavir/ritonavir, phenytoin, probenecid, ribavirin, rifamycins, stavudine, trimethoprim, and valproic acid. 

Oral suspension 40 mg trimethoprim and Various, Bactrim Pediatric 200 mg sulfamethoxazole/5 mL (Rx) (Roche), Septra (GlaxoSmithKline)... 

Sulfamethoxazole/trimethoprim has been shown to be the best agent for both the treatment and prophylaxis of PCP. It is therefore important that, where indicated, as many patients as possible receive sulfamethoxazole/trimethoprim and not other less effective medications. Desensitisation has been used as a method of increasing the number of patients able to tolerate sulfamethoxazole/trimethoprim. 

Patients who have a documented allergy, e.g. rash or itching due to sulfamethoxazole/trimethoprim and have failed rechallenge. 

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. 

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