Page 851 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 837

B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ) acid, 10 mg orally each day, should be administered to minimize
A combination of trimethoprim-sulfamethoxazole is effective bone marrow suppression seen with pyrimethamine. Some clini-
treatment for a wide variety of infections including P jiroveci cians recommend using trimethoprim-sulfamethoxazole as an
pneumonia, urinary tract infections, prostatitis, and some alternate option if pyrimethamine is not available.
infections caused by susceptible strains of Shigella, Salmonella, In falciparum malaria, the combination of pyrimethamine
and nontuberculous mycobacteria. It is active against most with sulfadoxine (Fansidar) has been used (see Chapter 52); how-
Staphylococcus aureus strains, both methicillin-susceptible and ever, it is no longer commercially available in the USA.
methicillin-resistant, and against respiratory tract pathogens such
as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but Adverse Effects
not Mycoplasma pneumoniae). However, the increasing prevalence Trimethoprim produces the predictable adverse effects of an
of strains of E coli (up to 30% or more) and pneumococci that are antifolate drug, especially megaloblastic anemia, leukopenia, and
resistant to trimethoprim-sulfamethoxazole must be considered granulocytopenia. The combination trimethoprim-sulfamethox-
before using this combination for empiric therapy of upper uri- azole may cause all of the untoward reactions associated with
nary tract infections or pneumonia. Trimethoprim-sulfamethoxa- sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal
zole is commonly used for the treatment of uncomplicated skin damage, and central nervous system disturbances occasionally
and soft tissue infections. occur. Patients with AIDS and pneumocystis pneumonia have
One double-strength tablet (each tablet contains trimethoprim a particularly high frequency of untoward reactions to trime-
160 mg plus sulfamethoxazole 800 mg) given every 12 hours is thoprim-sulfamethoxazole, especially fever, rashes, leukopenia,
effective treatment for urinary tract infections, prostatitis, uncom- diarrhea, elevations of hepatic aminotransferases, hyperkalemia,
plicated skin and soft tissue infections, and infections caused by and hyponatremia. Trimethoprim inhibits secretion of creatinine
susceptible strains of Shigella and Salmonella. Bone and joint at the distal renal tubule, resulting in mild elevation of serum
infections caused by S. aureus can be effectively treated, typically creatinine without impairment of glomerular filtration rate. This
at doses of 8–10 mg/kg per day of the trimethoprim component. nontoxic effect is important to distinguish from true nephrotoxic-
One single-strength tablet (containing trimethoprim 80 mg plus ity that may be caused by sulfonamides.
sulfamethoxazole 400 mg) given three times weekly may serve as
prophylaxis in recurrent urinary tract infections of some women.
The dosage for children treated for shigellosis, urinary tract infec- ■ DNA GYRASE INHIBITORS
tion, or otitis media is trimethoprim 8 mg/kg per day and sulfa-
methoxazole 40 mg/kg per day divided every 12 hours. FLUOROQUINOLONES
Infections with P jiroveci and some other pathogens, such as
Nocardia or Stenotrophomonas maltophilia, can be treated with high The clinically relevant quinolones are synthetic fluorinated ana-
doses of the either the oral or intravenous combination (dosed on logs of nalidixic acid (Figure 46–3). They are active against a
the basis of the trimethoprim component at 15–20 mg/kg/d). variety of Gram-positive and Gram-negative bacteria.
P jiroveci can be prevented in immunosuppressed patients by a
number of low dose regimens such as one double-strength tablet Mechanism of Action
daily or three times weekly.
Quinolones block bacterial DNA synthesis by inhibiting bacterial
C. Intravenous Trimethoprim-Sulfamethoxazole topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition
A solution of the mixture containing 80 mg trimethoprim plus of DNA gyrase prevents the relaxation of positively supercoiled
400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% DNA that is required for normal transcription and replication.
dextrose in water can be administered by intravenous infusion Inhibition of topoisomerase IV interferes with separation of repli-
over 60–90 minutes. It is the agent of choice for moderately cated chromosomal DNA into the respective daughter cells during
severe to severe pneumocystis pneumonia. It has been used for cell division.
Gram-negative bacterial sepsis, but has largely been replaced by
extended spectrum β-lactams and fluoroquinolones. It may be Antibacterial Activity
an effective alternative for infections caused by some multidrug- Earlier quinolones such as nalidixic acid did not achieve systemic
resistant species such as Enterobacter and Serratia; shigellosis; or antibacterial levels and were useful only in the treatment of lower
typhoid. It is the preferred alternate therapy for serious Listeria urinary tract infections. Fluorinated derivatives (ciprofloxacin,
infections in patients unable to tolerate ampicillin. The dosage is levofloxacin, and others; Figure 46–3 and Table 46–1) have
10–20 mg/kg/d of the trimethoprim component. greatly improved antibacterial activity compared with nalidixic
acid and achieve bactericidal levels in blood and tissues.
D. Oral Pyrimethamine with Sulfonamide Fluoroquinolones were originally developed because of their
Pyrimethamine and sulfadiazine are used in the treatment of toxo- excellent activity against Gram-negative aerobic bacteria; the ear-
plasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily, liest agents had limited activity against Gram-positive organisms.
with pyrimethamine given as a 200-mg loading dose followed by Subsequent members of the group have improved activity against
a once-daily dose of 50–75 mg. Leucovorin, also known as folinic Gram-positive cocci. The relative activity against Gram-negative