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

treatment of an established deep infection. Superinfection with
Candida occasionally may be a problem. The cream is applied once
or twice daily to a thickness of 1-2 mm over the burned skin.
Cleansing of the wound and removal of debris should be carried out
before each application of the drug. Therapy is continued until skin
grafting is possible. Mafenide is rapidly absorbed systemically and
converted to para-carboxybenzenesulfonamide. Studies of absorption
from the burn surface indicate that peak plasma concentrations
are reached in 2-4 hours. Adverse effects include intense pain at sites
of application, allergic reactions, and loss of fluid by evaporation
from the burn surface because occlusive dressings are not used. The
drug and its primary metabolite inhibit carbonic anhydrase, and the
urine becomes alkaline. Metabolic acidosis with compensatory
tachypnea and hyperventilation may ensue; these effects limit the
usefulness of mafenide.
Long-Acting Sulfonamides
Sulfadoxine. This agent, N1-[5,6-dimethoxy-4-pyrimidiny] sulfanilamide,
has a particularly long plasma t 1/2
(7-9 days). It is used in
combination with pyrimethamine (500 mg sulfadoxine plus 25 mg
pyrimethamine as FANSIDAR) for the prophylaxis and treatment of
malaria caused by mefloquine-resistant strains of Plasmodium falciparum
(Chapter 49). However, because of severe and sometimes
fatal reactions, including the Stevens-Johnson syndrome, and the
emergence of resistant strains, the drug has limited usefulness for
the treatment of malaria.
Sulfonamide Therapy
The number of conditions for which the sulfonamides
are therapeutically useful and constitute drugs of first
choice has been reduced sharply by the development of
more effective antimicrobial agents and by the gradual
increase in the resistance of a number of bacterial
species to this class of drugs. However, the combination
of sulfamethoxazole and trimethoprim is widely
employed.
Urinary Tract Infections. Because a significant percentage of urinary
tract infections in many parts of the world are caused by
sulfonamide-resistant microorganisms, sulfonamides are no longer
a therapy of first choice. Trimethoprim-sulfamethoxazole, a
quinolone, trimethoprim, fosfomycin, or ampicillin are the preferred
agents. However, sulfisoxazole may be used effectively in areas
where the prevalence of resistance is not high or when the organism
is known to be sensitive. The usual dosage is 2-4 g initially followed
by 1-2 g, orally four times a day for 5-10 days. Patients with acute
pyelonephritis with high fever and other severe constitutional manifestations
are at risk of bacteremia and shock and should not be
treated with a sulfonamide.
Nocardiosis. Sulfonamides are of value in the treatment of infections
due to Nocardia spp. A number of instances of complete
recovery from the disease after adequate treatment with a sulfonamide
have been recorded. Sulfisoxazole or sulfadiazine may be
given in dosages of 6-8 g daily. Concentrations of sulfonamide in
plasma should be 80-160 μg/mL. This schedule is continued for
several months after all manifestations have been controlled. The
administration of sulfonamide together with a second antibiotic
has been recommended, especially for advanced cases, and ampicillin,
erythromycin, and streptomycin have been suggested for this
purpose. The clinical response and the results of sensitivity testing
may be helpful in choosing a companion drug. Notably, there are
no clinical data to show that combination therapy is better than
therapy with a sulfonamide alone. Trimethoprim-sulfamethoxazole
also has been effective, and some authorities consider it to be the
drug of choice.
Toxoplasmosis. The combination of pyrimethamine and sulfadiazine
is the treatment of choice for toxoplasmosis (Montoya et al., 2005)
(Chapter 50). Pyrimethamine is given as a loading dose of 75 mg
followed by 25 mg orally per day, with sulfadiazine 1 g orally every
6 hours, plus folinic acid (leucovorin) 10 mg orally each day for at
least 3-6 weeks. Patients should receive at least 2 L of fluid intake
daily to prevent crystalluria during therapy.
Use of Sulfonamides for Prophylaxis. The sulfonamides are as efficacious
as oral penicillin in preventing streptococcal infections and
recurrences of rheumatic fever among susceptible subjects. Despite
the efficacy of sulfonamides for long-term prophylaxis of rheumatic
fever, their toxicity and the possibility of infection by drug-resistant
streptococci make sulfonamides less desirable than penicillin for this
purpose. They should be used, however, without hesitation in
patients who are hypersensitive to penicillin. If untoward responses
occur, they usually do so during the first 8 weeks of therapy; serious
reactions after this time are rare. White blood cell counts should be
carried out once weekly during the first 8 weeks.
Untoward Reactions to Sulfonamides
The untoward effects that follow the administration of
sulfonamides are numerous and varied; the overall incidence
of reactions is ~5%.
Disturbances of the Urinary Tract. Although the risk of crystalluria
was relatively high with the older, less soluble sulfonamides,
the incidence of this problem is very low with more soluble agents
such as sulfisoxazole. Crystalluria has occurred in dehydrated
patients with acquired immune deficiency syndrome (AIDS) who
were receiving sulfadiazine for Toxoplasma encephalitis. Fluid
intake should be sufficient to ensure a daily urine volume of at least
1200 mL (in adults). Alkalinization of the urine may be desirable if
urine volume or pH is unusually low because the solubility of sulfisoxazole
increases greatly with slight elevations of pH.
Disorders of the Hematopoietic System.
Acute Hemolytic Anemia. The mechanism of the acute hemolytic anemia
produced by sulfonamides is not always readily apparent. In
some cases, it may be a sensitization phenomenon; in other
instances, the hemolysis is related to an erythrocytic deficiency of
glucose-6-phosphate dehydrogenase activity. Hemolytic anemia is
rare after treatment with sulfadiazine (0.05%); its exact incidence
following therapy with sulfisoxazole is unknown.
Agranulocytosis. Agranulocytosis occurs in ~0.1% of patients who
receive sulfadiazine; it also can follow the use of other sulfonamides.
Although return of granulocytes to normal levels may be delayed for
weeks or months after sulfonamide is withdrawn, most patients
recover spontaneously with supportive care.
1467
CHAPTER 52
SULFONAMIDES, TRIMETHOPRIM-SULFAMETHOXAZOLE, QUINOLONES, AND AGENTS FOR URINARY TRACT INFECTIONS