Chapter 46: Sulfonamides, Trimethoprim, & Fluoroquinolones

A. Classification and Pharmacokinetics

The antifolate drugs used in the treatment of infectious diseases are the sulfonamides, which inhibit microbial enzymes involved in folic acid synthesis, and trimethoprim, a selective inhibitor of dihydrofolate reductase.

1. Sulfonamides

The sulfonamides are weakly acidic compounds that have a common chemical nucleus resembling p-aminobenzoic acid (PABA). Members of this group differ mainly in their pharmacokinetic properties and clinical uses. Pharmacokinetic features include modest tissue penetration, hepatic metabolism, and excretion of both intact drug and acetylated metabolites in the urine. Solubility may be decreased in acidic urine, resulting in precipitation of the drug or its metabolites. Because of the solubility limitation, a combination of 3 separate sulfonamides (triple sulfa) has been used to reduce the likelihood that any one drug will precipitate. The sulfonamides may be classified as short-acting (eg, sulfisoxazole), intermediate-acting (eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs.

2. Trimethoprim

This drug is structurally similar to folic acid. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal fluids. A large percentage of trimethoprim is excreted unchanged in the urine. The half-life of this drug is similar to that of sulfamethoxazole (10–12 h).

B. Mechanisms of Action

1. Sulfonamides

The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. As antimetabolites of PABA, they are competitive inhibitors of dihydropteroate synthase (Figure 46–1). They can also act as substrates for this enzyme, resulting in the synthesis of nonfunctional forms of folic acid. The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet.

2. Trimethoprim

Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase that prevents formation of the active tetrahydro form of folic acid (Figure 46–1). Bacterial dihydrofolate reductase is 4–5 orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme.

3. Trimethoprim plus sulfamethoxazole

When the 2 drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis (Figure 46–1). The drug combination is bactericidal against susceptible organisms.

C. Resistance

Bacterial resistance to sulfonamides is common and may be plasmid-mediated. It can result from decreased intracellular accumulation of the drugs, increased production of PABA by bacteria, or a decrease in the sensitivity of dihydropteroate synthase to the sulfonamides. Clinical resistance to trimethoprim most commonly results from the production of dihydrofolate reductase that has a reduced affinity for the drug.

D. Clinical Use

1. Sulfonamides

The sulfonamides are active against gram-positive and gram-negative organisms, Chlamydia, and Nocardia. Specific members of the sulfonamide group are used by the following routes for the conditions indicated:

a. Simple urinary tract infections

Oral (eg, triple sulfa, sulfisoxazole).

b. Ocular infections

Topical (eg, sulfacetamide).

c. Burn infections

Topical (eg, mafenide, silver sulfadiazine).

d. Ulcerative colitis, rheumatoid arthritis

Oral (eg, sulfa-salazine).

e. Toxoplasmosis

Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) plus folinic acid.

2. Trimethoprim-sulfamethoxazole (TMP-SMZ)

This drug combination is effective orally in the treatment of urinary tract infections and in respiratory, ear, and sinus infections caused by Haemophilus influenzae and Moraxella catarrhalis. In the immuno­compromised patient, TMP-SMZ is used for infections due to Aeromonas hydrophila and is the drug of choice for prevention and treatment of pneumocystis pneumonia. An intravenous formulation is available for patients unable to take the drug by mouth and is used for treatment of severe pneumocystis pneumonia and for gram-negative sepsis. TMP-SMZ is also the drug of choice in nocardiosis, a possible backup drug for cholera, typhoid fever, and shigellosis, and has been used in the treatment of infections caused by methicillin-resistant staphylococci and Listeria monocytogenes.

E. Toxicity of Sulfonamides

1. Hypersensitivity

Allergic reactions, including skin rashes and fever, occur commonly. Cross-allergenicity between the individual sulfonamides should be assumed and may also occur with chemically related drugs (eg, oral hypoglycemics, thiazides). Exfoliative dermatitis, polyarteritis nodosa, and Stevens-Johnson syndrome have occurred rarely.

2. Gastrointestinal

Nausea, vomiting, and diarrhea occur commonly. Mild hepatic dysfunction can occur, but hepatitis is uncommon.

3. Hematotoxicity

Although such effects are rare, sulfonamides can cause granulocytopenia, thrombocytopenia, and aplastic anemia. Acute hemolysis may occur in persons with glucose-6-phosphate dehydrogenase deficiency.

4. Nephrotoxicity

Sulfonamides may precipitate in the urine at acidic pH, causing crystalluria and hematuria.

5. Drug interactions

Competition with warfarin and methotrexate for plasma protein binding transiently increases the plasma levels of these drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of kernicterus in the neonate if used in the third trimester of pregnancy.

F. Toxicity of Trimethoprim

Trimethoprim can cause the predictable adverse effects of an antifolate drug, including megaloblastic anemia, leukopenia, and granulocytopenia. These effects are usually ameliorated by supplementary folinic acid. The combination of TMP-SMZ may cause any of the adverse effects associated with the sulfonamides. AIDS patients given TMP-SMZ have a high incidence of adverse effects, including fever, rashes, leukopenia, and diarrhea.

A. Classification

Fluoroquinolines are classified by “generation” based on their antimicrobial spectrum of activity. Norfloxacin, a first-generation fluoroquinolone derived from nalidixic acid, has activity against the common pathogens that cause urinary tract infections. Ciprofloxacin and ofloxacin (second-generation fluoroquinolones) have greater activity against gram-negative bacteria and are also active against the gonococcus, many gram-positive cocci, mycobacteria, and agents of atypical pneumonia (Mycoplasma pneumoniae, Chlamydophila pneumoniae). Third-generation fluoroquinolones (levofloxacin, gemifloxacin, and moxifloxacin) are slightly less active than ciprofloxacin and ofloxacin against gram-negative bacteria but have greater activity against gram-positive cocci, including S pneumoniae and some strains of enterococci and methicillin-resistant Staphylococcus aureus (MRSA). Third-generation drugs are commonly referred to as “respiratory fluoroquinolones.” The most recently introduced drugs (eg, gemifloxacin, moxifloxacin) are the broadest-spectrum fluoroquinolones introduced to date, with enhanced activity against anaerobes.

B. Pharmacokinetics

All the fluoroquinolones have good oral bioavailability (antacids containing multivalent cations may interfere) and penetrate most body tissues. However, norfloxacin does not achieve adequate plasma levels for use in most systemic infections. Elimination of most fluoroquinolones is through the kidneys via active tubular secretion, which can be blocked by probenecid. Dosage reductions are usually needed in renal dysfunction except for moxifloxacin which is eliminated partly by hepatic metabolism and also by biliary excretion. Use of moxifloxacin in urinary tract infections is not recommended. Half-lives of fluoroquinolones are usually in the range of 3–8 h.

C. Mechanism of Action

The fluoroquinolones interfere with bacterial DNA synthesis by inhibiting topoisomerase II (DNA gyrase), especially in gram-negative organisms, and topoisomerase IV, especially in gram-positive organisms. They block the relaxation of supercoiled DNA that is catalyzed by DNA gyrase, a step required for normal transcription and duplication. Inhibition of topoisomerase IV by fluoroquinolones interferes with the separation of replicated chromosomal DNA during cell division. Fluoroquinolones are usually bactericidal against susceptible organisms. Like aminoglycosides, the fluoroquinolones exhibit postantibiotic effects, whereby bacterial growth continues to be inhibited even after the plasma concentration of the drug has fallen below the minimum inhibitory concentration of the bacterium (see Chapter 45).

D. Resistance

Fluoroquinolone resistance has emerged rapidly in the case of second-generation fluoroquinolones, especially in Campylobacter jejuni and gonococci, but also in gram-positive cocci (eg, MRSA), Pseudomonas aeruginosa, and Serratia species. Mechanisms of resistance include decreased intracellular accumulation of the drug via the production of efflux pumps or changes in porin structure (in gram-negative bacteria). Efflux mechanisms appear to be responsible for resistance in strains of M tuberculosis, S aureus, and S pneumoniae. Changes in the sensitivity of the target enzymes via point mutations in the antibiotic binding regions are also established to confer resistance against specific fluoroquinolones. Mutations in the quinolone resistance-determining region of the gyrA gene that encodes DNA gyrase is responsible for resistance in gonococci.

E. Clinical Use

Fluoroquinolones are effective in the treatment of infections of the urogenital and gastrointestinal tracts caused by gram-negative organisms, including gonococci, E coli, Klebsiella pneumoniae, C jejuni, Enterobacter, P aeruginosa, Salmonella, and Shigella species. They have been used widely for respiratory tract, skin, and soft tissue infections, but their effectiveness is now variable because of the emergence of resistance. Ciprofloxacin and ofloxacin in single oral doses have been used as alternatives to ceftriaxone or cefixime in gonorrhea, but they are not currently recommended because resistance is now common. Ofloxacin eradicates Chlamydia trachomatis, but a 7-d course of treatment is required. Levofloxacin has activity against most organisms associated with community-acquired pneumonia, including chlamydiae, mycoplasma, and legionella species. Gemifloxacin and moxifloxacin have the widest spectrum of activity, which includes both gram-positive and gram-negative organisms, atypical pneumonia agents, and some anaerobic bacteria. Fluoroquinolones have also been used in the meningococcal carrier state, in the treatment of tuberculosis, and in prophylactic management of neutropenic patients.

F. Toxicity

Gastrointestinal distress is the most common adverse effect. The fluoroquinolones may cause skin rashes, headache, dizziness, insomnia, abnormal liver function tests, phototoxicity, and both tendinitis and tendon rupture. Opportunistic infections caused by C albicans and streptococci have occurred. The fluoroquinolones are not recommended for children or pregnant women because they may damage growing cartilage and cause arthropathy. Fluoroquinolones may increase the plasma levels of theophylline and other methylxanthines, enhancing their toxicity. Newer fluoroquinolones (gemifloxacin, levofloxacin, moxifloxacin) prolong the QTc interval. They should be avoided in patients with known QTc prolongation and those on certain antiarrhythmic drugs (Chapter 14) or other drugs that increase the QTc interval.

Grepafloxacin was withdrawn from clinical use in the United States because of serious cardiotoxicity (See Chapter 14). The currently available fluoroquinolones are contraindicated in patients taking drugs that prolong the QT interval. What other drugs increase the duration of the ventricular action potential?

The Skill Keeper Answer appears at the end of the chapter.

1. Trimethoprim-sulfamethoxazole is established to be effective against which of the following opportunistic infections in the AIDS patient?

   • (A) Cryptococcal meningitis

   • (B) Herpes simplex

   • (C) Oral candidiasis

   • (D) Toxoplasmosis

   • (E) Tuberculosis

2. A 65-year-old woman has returned from a vacation abroad suffering from traveler’s diarrhea, and her problem has not responded to antidiarrheal drugs. A pathogenic gram-negative bacillus is suspected. Which drug is most likely to be effective in the treatment of this patient?

   • (A) Ampicillin

   • (B) Ofloxacin

   • (C) Sulfadiazine

   • (D) Trimethoprim

   • (E) Vancomycin

3. Which statement about the clinical use of sulfonamides is false?

   • (A) Active against C trachomatis and can be used topically for treatment of chlamydial infections of the eye

   • (B) Are not effective as sole agents in the treatment of prostatitis

   • (C) Effective in Rocky Mountain spotted fever

   • (D) In some bacterial strains resistance occurs via increased PABA formation

   • (E) Reduced intracellular uptake is a mechanism of sulfonamide resistance in some bacterial strains

4. A 31-year-old man has gonorrhea. He has no drug allergies, but a few years ago acute hemolysis followed use of an antimalarial drug. The physician is concerned that the patient has an accompanying urethritis caused by C trachomatis, although no cultures or enzyme tests have been performed. Which of the following drugs will be reliably effective against both gonococci and C trachomatis and safe to use in this patient?

   • (A) Cefixime

   • (B) Ciprofloxacin

   • (C) Spectinomycin

   • (D) Sulfamethoxazole-trimethoprim

   • (E) None of the above

5. Which statement about the fluoroquinolones is accurate?

   • (A) Antacids increase their oral bioavailability

   • (B) Contraindicated in patients with hepatic dysfunction

   • (C) Fluoroquinolones are drugs of choice in a 6-year-old child with a urinary tract

   • (D) Gonococcal resistance to fluoroquinolones may involve changes in DNA gyrase

   • (E) Modification of moxifloxacin dosage is required in patients when creatinine clearance is less than 50 mL/min

6. A 40-year-old man complains of periodic bouts of diarrhea with lower abdominal cramping and intermittent rectal bleeding. Seen in the clinic, he appears well nourished, with blood pressure in the normal range. Examination reveals moderate abdominal pain and tenderness. His current medications are limited to loperamide for his diarrhea. Sigmoidoscopy reveals mucosal edema, friability, and some pus. Laboratory findings include mild anemia and decreased serum albumin. Microbiologic examination via stool cultures and mucosal biopsies do not reveal any evidence for bacterial, amebic, or cytomegalovirus involvement. The most appropriate drug to use in this patient is

   • (A) Ampicillin

   • (B) Doxycycline

   • (C) Norfloxacin

   • (D) Sulfasalazine

   • (E) Trimethoprim-sulfamethoxazole

7. Which adverse effect is most common with sulfonamides?

   • (A) Fanconi’s aminoaciduria syndrome

   • (B) Hematuria

   • (C) Kernicterus in the newborn

   • (D) Neurologic dysfunction

   • (E) Skin rash

8. Which drug is effective in the treatment of nocardiosis and, in combination with pyrimethamine, is prophylactic against Pneumocystis jirovecii infections in AIDS patients?

   • (A) Amoxicillin

   • (B) Erythromycin

   • (C) Levofloxacin

   • (D) Sulfadiazine

   • (E) Trimethoprim

9. Which statement about ciprofloxacin is accurate?

   • (A) Antagonism occurs if used with dihydrofolate reductase inhibitors

   • (B) Ciprofloxacin is active against MRSA strains of staphylococci

   • (C) Most “first-time” urinary tract infections are resistant to ciprofloxacin

   • (D) Organisms that commonly cause ear infections are highly resistant

   • (E) Tendinitis may occur during treatment

10. Supplementary folinic acid may prevent anemia in folate-deficient persons who use this drug; it is a weak base achieving tissue levels similar to those in plasma

    • (A) Ciprofloxacin

    • (B) Levofloxacin

    • (C) Linezolid

    • (D) Sulfamethoxazole

    • (E) Trimethoprim

1. Trimethoprim-sulfamethoxazole is not effective in the treatment of infections caused by viruses, fungi, or mycobacteria. However, the drug combination is active against certain protozoans, including Toxoplasma, and can be used for both prevention and treatment of toxoplasmosis in the severely immunocompromised AIDS patient. The answer is D.

2. The second-generation fluoroquinolones are very effective in diarrhea caused by bacterial gram-negative pathogens, including E coli, Shigella, and Salmonella. None of the other drugs listed would be appropriate. Many coliforms are now resistant to amoxicillin and ampicillin. Although trimethoprim is available as a single drug, resistance emerges rapidly during treatment unless it is used for urinary tract infections, in which high concentrations can be achieved. Vancomycin has no activity against gram-negative bacilli. The answer is B.

3. Sulfonamides have minimal therapeutic actions in rickettsial infections. Chloramphenicol may be used for Rocky Mountain spotted fever in patients with established allergy or other contraindication to tetracyclines. All of the other statements about sulfonamide antimicrobial drugs are accurate. The answer is C.

4. Cefixime in a single oral dose is effective in gonorrhea (Chapter 43), but it has no activity against organisms causing nongonococcal urethritis. Spectinomycin (Chapter 45) is active against most gonococci, but does not eradicate a urogenital chlamydial infection. Although ciprofloxacin might be effective in both gonorrhea and chlamydial urethritis, it is no longer recommended for treatment of gonorrhea in the United States, since resistance is now common. This patient could be treated by single oral doses of cefixime plus azithromycin (not listed). Sulfamethoxazole or TMP-SMZ would not be useful and may cause acute hemolysis in this patient. The answer is E.

5. Antacids can decrease oral bioavailability of fluoroquinolones. Neither hepatic or renal dysfunction is a contraindication to the use of fluoroquinolones. Most fluoroquinolones undergo renal elimination and dosage should be modified with creatinine clearance <50 mL/min. Moxifloxacin elimination occurs mainly via the liver. The fluoroquinolones should not be used to treat uncomplicated first-time urinary tract infections in children because of possible effects on cartilage development. Uncomplicated urinary tract infections in children are usually due to a strain of E coli that is sensitive to many other drugs, including beta-lactam antibiotics. The answer is D.

6. In the absence of any evidence pointing toward a definite microbial cause for the colitis in this patient, a drug that decreases inflammation is indicated. Sulfasalazine has significant anti-inflammatory action, and its oral use results in symptomatic improvement in 50–75% of patients suffering from ulcerative colitis. The drug is also used for its anti-inflammatory effects in rheumatoid arthritis. The answer is D.

7. The most common adverse effect of the sulfonamides is a skin rash caused by hypersensitivity. Neurologic dysfunction and hematuria occur less frequently. Sulfonamides are usually avoided in the third trimester of pregnancy or in neonates, so kernicterus is rare. Fanconi’s syndrome is associated with the use of outdated tetracyclines. The answer is E.

8. Sulfadiazine and TMP-SMZ are drugs of choice in nocardiosis. In combination with pyrimethamine (an effective dihydrofolate reductase inhibitor in protozoa), sulfadiazine is effective in toxoplasmosis and is prophylactic against pneumocystis pneumonia in the AIDS patient. However, TMP-SMZ is more commonly used for the latter purpose. The answer is D.

9. Ciprofloxacin is commonly used for the treatment of urinary tract infections and is active against most strains of common causative agents of otitis media, including H influenzae and pneumococci. However, up to 50% of strains of MRSA are now resistant to ciprofloxacin. No clinical antagonism has been reported between fluoroquinolones and inhibitors of folic acid synthesis. Fluoroquinolones are not recommended for use in pregnancy or for children less than 10 years of age because they may damage growing cartilage. Tendonitis and tendon rupture are adverse effects of the fluoroquinolones. The answer is E.

10. Trimethoprim is the only weak base listed (fluoroquinolones and sulfonamides are acidic compounds), and its high lipid solubility at blood pH allows penetration of the drug into prostatic and vaginal fluid to reach levels similar to those in plasma. Leukopenia and thrombocytopenia may occur in folate deficiency when the drug is used alone or in combination with sulfamethoxazole. Fluoroquinolones and linezolid do not exacerbate symptoms of folic acid deficiency. The answer is E.

The most important drugs that prolong the QT interval are antiarrhythmics (See Chapter 14). These include drugs from group 1A and group 3, including amiodarone, bretylium, disopyramide, procainamide, quinidine, and sotalol. Recall that although group 1A drugs are classified as Na⁺ channel blockers, they also block K⁺ channels and prolong the duration of the ventricular action potential. Other drugs implicated in QT prolongation include erythromycin, mefloquine, pentamidine, thioridazine and possibly other tricyclic antidepressants, and ziprasidone.

When you complete this chapter, you should be able to:

• ❑ Describe how sulfonamides and trimethoprim affect bacterial folic acid synthesis and how resistance to the antifolate drugs occurs.

• ❑ Identify major clinical uses of sulfonamides and trimethoprim, singly and in combination, and describe their characteristic pharmacokinetic properties and toxic effects.

• ❑ Describe how fluoroquinolones inhibit nucleic acid synthesis and identify mechanisms involved in bacterial resistance to these agents.

• ❑ List the major clinical uses of fluoroquinolones and describe their characteristic pharmacokinetic properties and toxic effects.