DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

The synergistic interaction between sulfonamide and trimethoprim
is predictable from their respective mechanisms. There is an optimal
ratio of the concentrations of the two agents for synergism that
equals the ratio of the minimal inhibitory concentrations of the drugs
acting independently. Although this ratio varies for different bacteria,
the most effective ratio for the greatest number of microorganisms is
20 parts sulfamethoxazole to 1 part trimethoprim. The combination is
thus formulated to achieve a sulfamethoxazole concentration in vivo
that is 20 times greater than that of trimethoprim. The pharmacokinetic
properties of the sulfonamide chosen to be in combination with
trimethoprim are critical because relative constancy of the concentrations
of the two compounds in the body is desired.
Bacterial Resistance. Bacterial resistance to trimethoprimsulfamethoxazole
is a rapidly increasing problem, although resistance
is lower than it is to either of the agents alone. Resistance often
is due to the acquisition of a plasmid that codes for an altered dihydrofolate
reductase. Resistance to trimethoprim-sulfamethoxazole
is reportedly formed in almost 30% of urinary isolates of E. coli
(Olson, et al., 2009).
Absorption, Distribution, and Excretion. The pharmacokinetic profiles
of sulfamethoxazole and trimethoprim are closely but not perfectly
matched to achieve a constant ratio of 20:1 in their
concentrations in blood and tissues. The ratio in blood is often >20:1,
and that in tissues is frequently less. After a single oral dose of the
combined preparation, trimethoprim is absorbed more rapidly than
sulfamethoxazole. The concurrent administration of the drugs
appears to slow the absorption of sulfamethoxazole. Peak blood concentrations
of trimethoprim usually occur by 2 hours in most
patients, whereas peak concentrations of sulfamethoxazole occur by
4 hours after a single oral dose. The half-lives of trimethoprim and
sulfamethoxazole are ~11 and 10 hours, respectively.
When 800 mg sulfamethoxazole is given with 160 mg
trimethoprim (the conventional 5:1 ratio) twice daily, the peak concentrations
of the drugs in plasma are ~40 and 2 μg/mL, the optimal
ratio. Peak concentrations are similar (46 and 3.4 μg/mL) after intravenous
infusion of 800 mg sulfamethoxazole and 160 mg trimethoprim
over a period of 1 hour.
Trimethoprim is distributed and concentrated rapidly in tissues,
and ~40% is bound to plasma protein in the presence of sulfamethoxazole.
The volume of distribution of trimethoprim is almost
nine times that of sulfamethoxazole. The drug readily enters cerebrospinal
fluid and sputum. High concentrations of each component
of the mixture also are found in bile. About 65% of sulfamethoxazole
is bound to plasma protein.
About 60% of administered trimethoprim and from 25% to
50% of administered sulfamethoxazole are excreted in the urine in
24 hours. Two-thirds of the sulfonamide is unconjugated.
Metabolites of trimethoprim also are excreted. The rates of excretion
and the concentrations of both compounds in the urine are reduced
significantly in patients with uremia.
Therapeutic Uses.
Urinary Tract Infections. Treatment of uncomplicated lower urinary
tract infection (UTI) with trimethoprim-sulfamethoxazole often is
highly effective for sensitive bacteria. The preparation has been shown
to produce a better therapeutic effect than does either of its components
given separately when the infecting microorganisms are of the family
Enterobacteriaceae. Single-dose therapy (320 mg trimethoprim plus
1600 mg sulfamethoxazole in adults) has been effective in some
cases for the treatment of acute uncomplicated UTI, but a minimum
of 3 days of therapy is more likely to be effective (Fihn, 2003; Zinner
and Mayer, 2005).
The combination appears to have special efficacy in chronic
and recurrent infections of the urinary tract. Small doses (200 mg
sulfamethoxazole plus 40 mg trimethoprim per day and postcoitally
or 2-4 times these amounts once or twice per week) effectively
reduce the number of recurrent urinary tract infections in women.
This effect may be related to the presence of therapeutic concentrations
of trimethoprim in vaginal secretions. Enterobacteriaceae surrounding
the urethral orifice may be eliminated or markedly reduced
in number, thus diminishing the chance of an ascending reinfection.
Trimethoprim also is found in therapeutic concentrations in prostatic
secretions, and trimethoprim-sulfamethoxazole is often effective
for the treatment of bacterial prostatitis.
Bacterial Respiratory Tract Infections. Trimethoprim-sulfamethoxazole
is effective for acute exacerbations of chronic bronchitis.
Administration of 800-1200 mg sulfamethoxazole plus 160-240 mg
trimethoprim twice a day appears to be effective in decreasing fever,
purulence and volume of sputum, and sputum bacterial count.
Trimethoprim-sulfamethoxazole should not be used to treat streptococcal
pharyngitis because it does not eradicate the microorganism.
It is effective for acute otitis media in children and acute maxillary
sinusitis in adults caused by susceptible strains of H. influenzae
and S. pneumoniae.
GI Infections. The combination is an alternative to a fluoroquinolone
for treatment of shigellosis because many strains of the causative agent
now are resistant to ampicillin; however, resistance to trimethoprimsulfamethoxazole
is increasingly common. It also is a second-line drug
(ceftriaxone or a fluoroquinolone is the preferred treatment) for
typhoid fever, but resistance is an increasing problem. In adults,
trimethoprim-sulfamethoxazole appears to be effective when the dose
is 800 mg sulfamethoxazole plus 160 mg trimethoprim every 12 hours
for 15 days. The same regimen has been used for 5 days for Travelers’
diarrhea.
Trimethoprim-sulfamethoxazole appears to be effective in the
management of carriers of sensitive strains of Salmonella typhi and
other Salmonella spp. One proposed schedule is the administration
of 800 mg sulfamethoxazole plus 160 mg trimethoprim twice a day
for 3 months; however, failures have occurred. The presence of
chronic disease of the gallbladder may be associated with a high
incidence of failure to clear the carrier state. Acute diarrhea owing
to sensitive strains of enteropathogenic E. coli can be treated or prevented
with either trimethoprim or trimethoprim plus sulfamethoxazole
(Hill et al., 2006). However, antibiotic treatment (either
trimethoprim-sulfamethoxazole or cephalosporin) of diarrheal
illness owing to enterohemorrhagic E. coli O157:H7 may increase
the risk of hemolytic-uremic syndrome, perhaps by increasing the
release of Shiga toxin by the bacteria (Wong et al., 2000).
Infection by Pneumocystis jiroveci. High-dose therapy (trimethoprim
15-20 mg/kg per day plus sulfamethoxazole 75-100 mg/kg per day
in three or four divided doses) is effective for this severe infection
in patients with AIDS (Thomas and Limper, 2004). This combination
compares favorably with pentamidine for treatment of this disease.
Adjunctive corticosteroids should be given at the onset of
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CHAPTER 52
SULFONAMIDES, TRIMETHOPRIM-SULFAMETHOXAZOLE, QUINOLONES, AND AGENTS FOR URINARY TRACT INFECTIONS