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CASE STUDY

CASE STUDY

A 59-year-old woman presents to an urgent care clinic with a 4-day history of frequent and painful urination. She has had fevers, chills, and flank pain for the past 2 days. Her physician advised her to come immediately to the clinic for evaluation. In the clinic, she is febrile (38.5°C [101.3°F]) but otherwise stable and states she is not experiencing any nausea or vomiting. Her urine dipstick test is positive for leukocyte esterase. Urinalysis and urine culture are ordered. Her past medical history is significant for three urinary tract infections in the past year. Each episode was uncomplicated, treated with trimethoprim-sulfamethoxazole, and promptly resolved. She also has osteoporosis for which she takes a daily calcium supplement. The decision is made to treat her with oral antibiotics for a complicated urinary tract infection with close follow-up. Given her history, what would be a reasonable empiric antibiotic choice? Depending on the antibiotic choice, are there potential drug interactions?

ANTIFOLATE DRUGS

SULFONAMIDES

Chemistry

The basic formulas of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) are shown in Figure 46–1. Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (—SO2—NH—R) or the amino group (—NH2) of the sulfanilamide nucleus.* Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration.

FIGURE 46–1

Structures of some sulfonamides and p-aminobenzoic acid.

Mechanism of Action & Antimicrobial Activity

Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway (Figure 46–2) is thus essential for production of purines and nucleic acid synthesis. As structural analogs of PABA, sulfonamides inhibit dihydropteroate synthase and folate production. Sulfonamides inhibit both gram-positive bacteria, such as Staphylococcus sp, and gram-negative enteric bacteria, such as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Enterobacter sp, as well as Nocardia sp, Chlamydia trachomatis, and some protozoa. Rickettsiae are not inhibited by sulfonamides but instead may be stimulated in their growth. Activity is poor against anaerobes. Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics.

FIGURE 46–2

Actions of sulfonamides and trimethoprim.

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (see Figure 46–2).

Resistance

Some bacteria lack the enzymes required for folate synthesis from PABA and, like mammals, depend on exogenous sources of folate; therefore, they are not susceptible ...

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