Sulfonamides, Trimethoprim, & Fluoroquinolones: Introduction
Sulfonamides and trimethoprim are antimetabolites selectively toxic to microorganisms because they interfere with folic acid synthesis. Sulfonamides continue to be used selectively as individual antimicrobial agents, although resistance is common. The combination of a sulfonamide with trimethoprim causes a sequential blockade of folic acid synthesis. This results in a synergistic action against a wide spectrum of microorganisms; resistance occurs but has been relatively slow in development.
Fluoroquinolones, which selectively inhibit microbial nucleic acid metabolism, also have a broad spectrum of antimicrobial activity that includes many common pathogens. Resistance has emerged to the older antibiotics in this class, but has been offset to some extent by the introduction of newer fluoroquinolones with expanded activity against common pathogenic organisms.
High-Yield Terms to Learn
Antimetabolite A drug that, through chemical similarity, is able to interfere with the role of an endogenous compound in cellular metabolism. Sequential blockade The combined action of 2 drugs that inhibit sequential steps in a pathway of bacterial metabolism DNA gyrase Bacterial topisomerase responsible for negative supercoiling of double-stranded DNA that balances the positive supercoiling of DNA replication and acts as a "swivel," preventing damage to the DNA strand Topoisomerase IV Bacterial topisomerase initiating decatenation, the mechanism by which 2 daughter DNA molecules are separated at the conclusion of DNA replication
Antifolate Drugs
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.
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.
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).
Mechanisms of Action
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.
FIGURE 46-1
Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis. Inhibition of 2 successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy.
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.
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.
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.
Clinical Use
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:
Simple Urinary Tract Infections
Oral (eg, triple sulfa, sulfisoxazole).
Ocular Infections
Topical (eg, sulfacetamide).
Burn Infections
Topical (eg, mafenide, silver sulfadiazine).
Ulcerative Colitis, Rheumatoid Arthritis
Oral (eg, sulfasalazine).
Toxoplasmosis
Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) plus folinic acid.
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.
Toxicity of Sulfonamides
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.
Gastrointestinal
Nausea, vomiting, and diarrhea occur commonly. Mild hepatic dysfunction can occur, but hepatitis is uncommon.
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.
Nephrotoxicity
Sulfonamides may precipitate in the urine at acidic pH, causing crystalluria and hematuria.
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.
Toxicity of Trimethoprim
Trimethoprim may 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.
Fluoroquinolones
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.
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.
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).
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.
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, Campylobacter jejuni, Enterobacter, Pseudomonas 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.
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.
Skill Keeper: Prolongation of the QT Interval
(See Chapter 14)
Grepafloxacin was withdrawn from clinical use in the United States because of serious cardiotoxicity. The currently available fluoroquinolones are contraindicated in patients taking drugs that prolong the QT interval. What other drugs can you recall that have this characteristic effect to increase the duration of the ventricular action potential? The Skill Keeper Answer appears at the end of the chapter.
Skill Keeper Answer: Prolongation of the QT Interval
(See Chapter 14)
The most important drugs that prolong the QT interval are antiarrhythmics. These include drugs from class IA and class III, including amiodarone, bretylium, disopyramide, procainamide, quinidine, and sotalol. You may recall that although group IA 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.
Checklist
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.
Drug Summary Table: Sulfonamides, Trimethoprim, & Fluoroquinolones
Subclass Mechanism of Action Activity & Clinical Uses Pharmacokinetics & Interactions Toxicities Trimethoprim-sulfamethoxazole Synergistic inhibition of folic acid synthesis; the combination is bactericidal-"sequential blockade" Urinary tract, respiratory, ear, and sinus infections; P jiroveci pneumonia; toxoplasmosis; nocardiosis Oral, IV; renal clearance, half-life ~8 h Rash, fever, bone marrow suppression, hyperkalemia; high incidence of adverse effects in AIDS Other folate antagonists Sulfisoxazole Sulfadiazine (+/- pyrimethamine) Trimethoprim Pyrimethamine (+/- sulfadoxine) Sulfonamides inhibit dihydropteroate synthase Trimethoprim and pyrimethamine inhibit dihydrofolate reductase Simple urinary tract infections (oral) and topical in burn or eye infections (sulfonamides); toxoplasmosis (sulfadiazine + pyrimethamine); malaria (sulfadoxine + pyrimethamine) Hepatic and renal clearance and extensive plasma protein binding of sulfonamides (displace bilirubin, methotrexate, and warfarin) Common—oral dose of sulfonamides cause GI upsets, acute hemolysis in G6PDH deficiency, possible crystalluria and rash (assume cross-hypersensitivity Ciprofloxacin Inhibits DNA replication via binding to DNA gyrase (gram-negative organisms) and topoisomerase IV (gram-positive organisms); bactericidal Resistance: see below Effective in urogenital, GI tracts, and some respiratory infections; activity versus gonococci rapidly declining; limited use in tuberculosis Oral, IV; mostly renal clearance, half-life 4 h Oral absorption impaired by cations GI upsets, CNS effects (dizziness, headache); tendinitis due to effects on cartilage (try to avoid in young children and pregnancy) Other fluoroquinolones Norfloxacin Ofloxacin Levofloxacin Moxifloxacin Gemifloxacin Mechanism identical to that of ciprofloxacin; bactericidal Resistance via changes in target enzymes (eg DNA gyrase) and possibly formation of inactivating enzymes Norfloxacin and ofloxacin used mainly for urinary tract infections; levofloxacin and moxifloxacin are "respiratory" fluoroquinolones with enhanced activity against gram-positive cocci and atypicals (chlamydia, mycoplasma) Oral and IV forms of levofloxacin and moxifloxacin; mostly renal clearance (not moxifloxacin—hepatic) Long half-lives of gemifloxacin and moxifloxacin permit once-daily dosing Like ciprofloxacin (see above) QTc prolongation (levofloxacin, gemifloxacin, and moxifloxacin) Caution with use of class 1A and III antiarrhythmics
G6PDH, glucose-6-phosphate dehydrogenase.