TRIMETHOPRIM
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.
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.
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).
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.
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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