y may be initiated prior to obtaining the results of these tests.

e to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibiotic use. careful medical history is necessary since cdad has been reported to occur over two months after the administration of antibacterial agents. if cdad is suspected or confirmed, ongoing antiobiotic use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of c. difficile , and surgical evaluation should be instituted as clinically indicated.

enia, megaloblastic anemia, and methemoglobinemia. metabolic hyperkalemia, hyponatremia. neurologic aseptic meningitis has been rarely reported. miscellaneous fever, and increases in bun and serum creatinine levels.

eived trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter. because trimethoprim may interfere with folic acid metabolism, trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nonteratogenic effects the oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.

administration ). during a 13 week study of trimethoprim administered at a daily dosage of 200 mg (50 mg q.i.d.), the mean minimum steady-state concentration of the drug was 1.1 mcg/ml. steady-state concentrations were achieved within 2 to 3 days of chronic administration and were maintained throughout the experimental period. excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion. urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood. after a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/ml during the 0 to 4 hour period and declined to approximately 18 to 91 mcg/ml during the 8 to 24 hour period. a 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high. after oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim. since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. concentrations of trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. sufficient trimethoprim is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora. trimethoprim also passes the placental barrier and is excreted in human milk. microbiology mechanism of action trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. this binding is very much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins. resistance resistance to trimethoprim may be conferred by a variety of mechanisms including cell wall impermeability, overproduction of the chromosomal dihydrofolate reductase (dhfr) enzyme, production of a resistant chromosomal dhfr enzyme or production of a plasmid-mediated trimethoprim-resistant dhfr enzyme. acinetobacter baumannii/acinetobacter calcoaceticus complex, burkholderia cepacia complex, pseudomonas aeruginosa, stenotrophomonas maltophilia are intrinsically resistant to trimethoprim. non- enterobacteriaceae fecal organisms, bacteroides spp. and lactobacillus spp. are not susceptible to trimethoprim at the concentrations obtained with the recommended dosage. enterococcus spp, (e. faecalis, e. faecium, e. gallinarum/e. casseliflavus ) may appear active in vitro to trimethoprim but are not effective clinically and should not be reported as susceptible. moraxella catarrhalis isolates were found consistently resistant to trimethoprim. antimicrobial activity trimethoprim has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the indications and usage section. aerobic gram-positive bacteria staphylococcus species (coagulase-negative strains, including s. saprophyticus ) aerobic gram-negative bacteria enterobacter species escherichia coli klebsiella pneumoniae proteus mirabilis susceptibility test methods when available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. these reports should aid the physician in selecting an antibacterial drug for treatment. dilution techniques quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (mic's). these mic's provide estimates of the susceptibility of bacteria to antimicrobial compounds. the mic's should be determined using a standardized procedure (broth and/or agar) 1,7 . the mic values should be interpreted according to the criteria provided in table 1. diffusion techniques quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. the zone size should be determined using a standardized test method.2,7 this procedure uses paper disks impregnated with 5 mcg trimethoprim to test the susceptibility of bacteria to trimethoprim. the disc diffusion breakpoints are provided in table 1. table 1. susceptibility test interpretive criteria for trimethoprim pathogen minimum inhibitory concentrations (mcg) zone diameters (mm) s i r s i r enterobacteriaceae ≤ 8 - ≥ 16 ≥ 16 11-15 ≤ 10 coagulase negative staphylococci (including s. saprophyticus ) ≤ 8 - ≥ 16 ≥ 16 11-15 ≤ 10 a report of susceptible (s) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. a report of intermediate (i) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. this category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. this category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. a report of resistant (r) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. quality control standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test 1,2,7 . standard trimethoprim powder should provide the following range of mic values noted in table 2. for the diffusion technique using the 5 mcg disk, the criteria in table 2 should be achieved. table 2: quality control parameters for trimethoprim qc strain minimum inhibitory concentrations (mcg/ml) zone diameters (mm) enterococcus faecalis atcc 29212 0.12 - 0.5 -- escherichia coli atcc 25922 0.5 - 2 21 - 28 haemophilus influenzae atcc 49247 0.06 - 0.5 27 - 33 staphylococcus aureus atcc 29213 1 - 4 -- staphylococcus aureus atcc 25923 -- 19 - 26 streptococcus pneumoniae atcc 49619 1 - 4 -- pseudomonas aeruginosa atcc 27853 > 64 --

general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.

as late as two or more months after having taken the last dose of the antibiotic. if this occurs, patients should contact their physician as soon as possible.