Chapter 52: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections

History. Investigations in 1932 at the I. G. Farbenindustrie resulted in the patenting of prontosil and several other azo dyes containing a sulfonamide group. Prompted by the knowledge that synthetic azo dyes had been studied for their action against streptococci, Domagk tested the new compounds and observed that mice with streptococcal and other infections could be protected by prontosil. In 1933, Foerster reported giving prontosil to a 10-month-old infant with staphylococcal septicemia and achieving a dramatic cure. Favorable clinical results with prontosil and its active metabolite, sulfanilamide, in puerperal sepsis and meningococcal infections awakened the medical profession to the new field of antibacterial chemotherapy, and experimental and clinical articles soon appeared in profusion. The development of the carbonic anhydrase inhibitor–type diuretics and the sulfonylurea hypoglycemic agents followed from observations made with the sulfonamide antibiotics. For discovering the chemotherapeutic value of prontosil, Domagk was awarded the Nobel Prize in Medicine for 1938 (Lesch, 2007).

Chemistry. The term sulfonamide is employed herein as a generic name for derivatives of para-aminobenzenesulfonamide (sulfanilamide); the structural formulas of selected members of this class are shown in Figure 52–1. Most of them are relatively insoluble in water, but their sodium salts are readily soluble. The minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself. The SO₂NH₂ group is not essential as such, but the important feature is that the sulfur is linked directly to the benzene ring. The para-NH₂ group (the N of which has been designated as N4) is essential and can be replaced only by moieties that can be converted in vivo to a free amino group. Substitutions made in the amide NH₂ group (position N1) have variable effects on antibacterial activity of the molecule. However, substitution of heterocyclic aromatic nuclei at N1 yields highly potent compounds.

Resistance to sulfonamide probably is the consequence of an altered enzymatic constitution of the bacterial cell; the alteration may be characterized by (1) a lower affinity of dihydropteroate synthase for sulfonamides, (2) decreased bacterial permeability or active efflux of the drug, (3) an alternative metabolic pathway for synthesis of an essential metabolite, or (4) an increased production of an essential metabolite or drug antagonist. For example, some resistant staphylococci may synthesize 70 times as much PABA as do the susceptible parent strains. Nevertheless, an increased production of PABA is not a constant finding in sulfonamide-resistant bacteria, and resistant mutants may possess enzymes for folate biosynthesis that are less readily inhibited by sulfonamides. Plasmid-mediated resistance is due to plasmid-encoded drug-resistant dihydropteroate synthetase.

All sulfonamides are bound in varying degree to plasma proteins, particularly to albumin. The extent to which this occurs is determined by the hydrophobicity of a particular drug and its pK_a; at physiological pH, drugs with a high pK_a exhibit a low degree of protein binding, and vice versa.

Sulfonamides are distributed throughout all tissues of the body. The diffusible fraction of sulfadiazine is distributed uniformly throughout the total-body water, whereas sulfisoxazole is confined largely to the extracellular space. The sulfonamides readily enter pleural, peritoneal, synovial, ocular, and similar body fluids and may reach concentrations therein that are 50-80% of the simultaneously determined concentration in blood. Because the protein content of such fluids usually is low, the drug is present in the unbound active form.

After systemic administration of adequate doses, sulfadiazine and sulfisoxazole attain concentrations in cerebrospinal fluid that may be effective in meningeal infections. At steady state, the concentration ranges between 10% and 80% of that in the blood. However, because of the emergence of sulfonamide-resistant microorganisms, these drugs are used rarely for the treatment of meningitis.

Sulfonamides pass readily through the placenta and reach the fetal circulation. The concentrations attained in the fetal tissues are sufficient to cause both antibacterial and toxic effects.

The sulfonamides undergo metabolic alterations in vivo, especially in the liver. The major metabolic derivative is the N4-acetylated sulfonamide. Acetylation, which occurs to a different extent with each agent, is disadvantageous because the resulting products have no antibacterial activity and yet retain the toxic potential of the parent substance.

Sulfonamides are eliminated from the body partly as the unchanged drug and partly as metabolic products. The largest fraction is excreted in the urine, and the t_1/2 of sulfonamides in the body thus depends on renal function. In acid urine, the older sulfonamides are insoluble and may precipitate, forming crystalline deposits that can cause urinary obstruction. Small amounts are eliminated in the feces, bile, milk, and other secretions.

Rapidly Absorbed and Eliminated Sulfonamides

Sulfisoxazole. Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with excellent antibacterial activity. Because its high solubility eliminates much of the renal toxicity inherent in the use of older sulfonamides, it has essentially replaced the less soluble agents.

Sulfisoxazole is bound extensively to plasma proteins. Following an oral dose of 2-4 g, peak concentrations in plasma of 110-250 μg/mL are found in 2-4 hours. From 28-35% of sulfisoxazole in the blood and ~30% in the urine is in the acetylated form. The kidney excretes ~95% of a single dose in 24 hours. Concentrations of the drug in urine thus greatly exceed those in blood and may be bactericidal. The concentration in cerebrospinal fluid averages about a third of that in the blood.

Sulfisoxazole acetyl is tasteless and hence preferred for oral use in children. Sulfisoxazole acetyl is marketed in combination with erythromycin ethylsuccinate for use in children with otitis media.

Fewer than 0.1% of patients receiving sulfisoxazole suffer serious toxic reactions. The untoward effects produced by this agent are similar to those which follow the administration of other sulfonamides, as discussed later. Because of its relatively high solubility in the urine as compared with sulfadiazine, sulfisoxazole only infrequently produces hematuria or crystalluria (0.2-0.3%). Despite this, patients taking this drug should ingest an adequate quantity of water. Sulfisoxazole and all sulfonamides that are absorbed must be used with caution in patients with impaired renal function. Like all sulfonamides, sulfisoxazole may produce hypersensitivity reactions, some of which are potentially lethal. Sulfisoxazole currently is preferred over other sulfonamides by most clinicians when a rapidly absorbed and rapidly excreted sulfonamide is indicated.

Sulfamethoxazole. Sulfamethoxazole is a close congener of sulfisoxazole, but its rates of enteric absorption and urinary excretion are slower. It is administered orally and employed for both systemic and urinary tract infections. Precautions must be observed to avoid sulfamethoxazole crystalluria because of the high percentage of the acetylated, relatively insoluble form of the drug in the urine. The clinical uses of sulfamethoxazole are the same as those for sulfisoxazole. In the U.S., it is marketed only in fixed-dose combinations with trimethoprim.

Sulfadiazine. Sulfadiazine given orally is absorbed rapidly from the GI tract, and peak blood concentrations are reached within 3-6 hours after a single dose. Following an oral dose of 3 g, peak concentrations in plasma are 50 μg/mL. About 55% of the drug is bound to plasma protein at a concentration of 100 μg/mL when plasma protein levels are normal. Therapeutic concentrations are attained in cerebrospinal fluid within 4 hours of a single oral dose of 60 mg/kg.

Sulfadiazine is excreted quite readily by the kidney in both the free and acetylated forms, rapidly at first and then more slowly over a period of 2-3 days. It can be detected in the urine within 30 minutes of oral ingestion. About 15-40% of the excreted sulfadiazine is in acetylated form. This form of the drug is excreted more readily than the free fraction, and the administration of alkali accelerates the renal clearance of both forms by further diminishing their tubular reabsorption.

In adults and children who are being treated with sulfadiazine, every precaution must be taken to ensure fluid intake adequate to produce a urine output of at least 1200 mL in adults and a corresponding quantity in children. If this cannot be accomplished, sodium bicarbonate may be given to reduce the risk of crystalluria.

Poorly Absorbed Sulfonamides

Sulfasalazine. Sulfasalazine (azulfidine, others) is very poorly absorbed from the GI tract. It is used in the therapy of ulcerative colitis and regional enteritis (Chapter 47). Intestinal bacteria break sulfasalazine down to sulfapyridine, an active sulfonamide that is absorbed and eventually excreted in the urine, and 5-aminosalicylate (5-ASA, mesalamine; Figures 47–2, 47–3, 47–4), which reaches high levels in the feces. Whereas sulfapyridine is responsible for most of the toxicity 5-ASA is the effective agent in inflammatory bowel disease. Toxic reactions include Heinz-body anemia, acute hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and agranulocytosis. Nausea, fever, arthralgias, and rashes occur in up to 20% of patients treated with the drug; desensitization has been an effective treatment. Sulfasalazine can cause a reversible infertility in males owing to changes in sperm number and morphology.

Sulfonamides for Topical Use

Sulfacetamide. Sulfacetamide is the N1-acetyl-substituted derivative of sulfanilamide. Its aqueous solubility (1:140) is ~90 times that of sulfadiazine. Solutions of the sodium salt of the drug are employed extensively in the management of ophthalmic infections. Although topical sulfonamide for most purposes is discouraged because of lack of efficacy and a high risk of sensitization, sulfacetamide has certain advantages. Very high aqueous concentrations are not irritating to the eye and are effective against susceptible microorganisms. A 30% solution of the sodium salt has a pH of 7.4, whereas the solutions of sodium salts of other sulfonamides are highly alkaline. The drug penetrates into ocular fluids and tissues in high concentration. Sensitivity reactions to sulfacetamide are rare, but the drug should not be used in patients with known hypersensitivity to sulfonamides. See Chapters 64 and 65 for ocular and dermatogical uses.

Silver Sulfadiazine. Silver sulfadiazine (silvadene, others) inhibits the growth in vitro of nearly all pathogenic bacteria and fungi, including some species resistant to sulfonamides. The compound is used topically to reduce microbial colonization and the incidence of infections from burns. It should not be used to treat an established deep infection. Silver is released slowly from the preparation in concentrations that are selectively toxic to the microorganisms. However, bacteria may develop resistance to silver sulfadiazine. Although little silver is absorbed, the plasma concentration of sulfadiazine may approach therapeutic levels if a large surface area is involved. Adverse reactions—burning, rash, and itching—are infrequent. Silver sulfadiazine is considered by most authorities to be an agent of choice for the prevention of burn infections.

Mafenide. This sulfonamide (α-amino-p-toluene-sulfonamide) is marketed as mafenide acetate (sulfamylon). When applied topically, it effectively prevents colonization of burns by a large variety of gram-negative and gram-positive bacteria. It should not be used in 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.

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.

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.

Aplastic Anemia. Complete suppression of bone marrow activity with profound anemia, granulocytopenia, and thrombocytopenia is an extremely rare occurrence with sulfonamide therapy. It probably results from a direct myelotoxic effect and may be fatal. However, reversible suppression of the bone marrow is quite common in patients with limited bone marrow reserve (e.g., patients with AIDS or those receiving myelosuppressive chemotherapy).

Hypersensitivity Reactions. The incidence of other hypersensitivity reactions to sulfonamides is quite variable. Among the skin and mucous membrane manifestations attributed to sensitization to sulfonamide are morbilliform, scarlatinal, urticarial, erysipeloid, pemphigoid, purpuric, and petechial rashes, as well as erythema nodosum, erythema multiforme of the Stevens-Johnson type, Behçet's syndrome, exfoliative dermatitis, and photosensitivity. These hypersensitivity reactions occur most often after the first week of therapy but may appear earlier in previously sensitized individuals. Fever, malaise, and pruritus frequently are present simultaneously. The incidence of untoward dermal effects is ~2% with sulfisoxazole, although patients with AIDS manifest a higher frequency of rashes with sulfonamide treatment than do other individuals. A syndrome similar to serum sickness may appear after several days of sulfonamide therapy. Drug fever is a common untoward manifestation of sulfonamide treatment; the incidence approximates 3% with sulfisoxazole.

Focal or diffuse necrosis of the liver owing to direct drug toxicity or sensitization occurs in <0.1% of patients. Headache, nausea, vomiting, fever, hepatomegaly, jaundice, and laboratory evidence of hepatocellular dysfunction usually appear 3-5 days after sulfonamide administration is started, and the syndrome may progress to acute yellow atrophy and death.

Miscellaneous Reactions. Anorexia, nausea, and vomiting occur in 1-2% of persons receiving sulfonamides, and these manifestations probably are central in origin. The administration of sulfonamides to newborn infants, especially if premature, may lead to the displacement of bilirubin from plasma albumin. In newborn infants, free bilirubin can become deposited in the basal ganglia and subthalamic nuclei of the brain, causing an encephalopathy called kernicterus. Sulfonamides should not be given to pregnant women near term because these drugs pass through the placenta and are secreted in milk.

Drug Interactions. The most important interactions of the sulfonamides involve those with the oral anticoagulants, the sulfonylurea hypoglycemic agents, and the hydantoin anticonvulsants. In each case, sulfonamides can potentiate the effects of the other drug by mechanisms that appear to involve primarily inhibition of metabolism and, possibly, displacement from albumin. Dosage adjustment may be necessary when a sulfonamide is given concurrently.

Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell's syndrome) are rare, occurring primarily in older individuals. Nausea and vomiting constitute the bulk of GI reactions; diarrhea is rare. Glossitis and stomatitis are relatively common. Mild and transient jaundice has been noted and appears to have the histological features of allergic cholestatic hepatitis. Central nervous system reactions consist of headache, depression, and hallucinations, manifestations known to be produced by sulfonamides. Hematological reactions, in addition to those just mentioned, are various anemias (including aplastic, hemolytic, and macrocytic), coagulation disorders, granulocytopenia, agranulocytosis, purpura, Henoch-Schönlein purpura, and sulfhemoglobinemia. Permanent impairment of renal function may follow the use of trimethoprim-sulfamethoxazole in patients with renal disease, and a reversible decrease in creatinine clearance has been noted in patients with normal renal function.

Patients with AIDS frequently have hypersensitivity reactions to trimethoprim-sulfamethoxazole (rash, neutropenia, Stevens-Johnson syndrome, Sweet's syndrome, and pulmonary infiltrates). It may be possible to continue therapy in such patients following rapid oral desensitization (Gluckstein and Ruskin, 1995).

Chemistry. The compounds that are currently available for clinical use in the U.S. are quinolones containing a carboxylic acid moiety at position 3 of the primary ring structure. Many of the newer fluoroquinolones also contain a fluorine substituent at position 6 and a piperazine moiety at position 7 (Table 52–2).

The DNA gyrase of E. coli is composed of two 105,000 Da A subunits and two 95,000 Da B subunits encoded by the gyrA and gyrB genes, respectively. The A subunits, which carry out the strand-cutting function of the gyrase, are the site of action of the quinolones (Figure 52–3). The drugs inhibit gyrase-mediated DNA supercoiling at concentrations that correlate well with those required to inhibit bacterial growth (0.1-10 μg/mL). Mutations of the gene that encodes the A subunit polypeptide can confer resistance to these drugs (Hooper, 2005a).

Topoisomerase IV is also composed of four subunits encoded by the parC and parE genes in E. coli (Hooper, 2005a). Topoisomerase IV separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication. Eukaryotic cells do not contain DNA gyrase, but they do contain a conceptually and mechanistically similar type II DNA topoisomerase that removes positive supercoils from DNA to prevent its tangling during replication. This enzyme is the target for some antineoplastic agents (Chapters 60 and 61). Quinolones inhibit eukaryotic type II topoisomerase only concentrations (100-1000 μg/mL) much higher than those that inhibit bacterial DNA gyrase (Mitscher and Ma, 2003).

Antibacterial Spectrum. The fluoroquinolones are potent bactericidal agents against E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria (Hooper, 2005a). MICs of the fluoroquinolones for 90% of these strains (MIC₉₀) usually are <0.2 μg/mL. Ciprofloxacin is more active than norfloxacin (noroxin) against P. aeruginosa; values of MIC₉₀ range from 0.5-6 μg/mL. Fluoroquinolones also have good activity against staphylococci, but not against methicillin-resistant strains (MIC₉₀ = 0.1-2 μg/mL).

Activity against streptococci is limited to a subset of the quinolones, including levofloxacin (levaquin), gatifloxacin, and moxifloxacin (avelox) (Hooper, 2005a). Several intracellular bacteria are inhibited by fluoroquinolones at concentrations that can be achieved in plasma; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis) (American Thoracic Society, 2003). Ciprofloxacin (cipro, others), ofloxacin (floxin), and pefloxacin have MIC₉₀ values from 0.5-3 μg/mL for M. fortuitum, M. kansasii, and M. tuberculosis; ofloxacin and pefloxacin (not available in U.S.) are active in animal models of leprosy (Hooper, 2005a). However, clinical experience with these pathogens remains limited.

Several fluoroquinolones, including garenoxacin (not available in U.S.) and gemifloxacin, have activity against anaerobic bacteria (Medical Letter, 2000, 2004).

Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria (Oethinger et al., 2000). No quinolone-modifying or -inactivating activities have been identified in bacteria (Gold and Moellering, 1996). Resistance has increased after the introduction of fluoroquinolones, especially in Pseudomonas and staphylococci. Increasing fluoroquinolone resistance also is being observed in C. jejuni, Salmonella, N. gonorrhoeae, and S. pneumoniae.

As mentioned in Chapter 48, the pharmacokinetic and pharmacodynamic parameters of antimicrobial agents are important in preventing the selection and spread of resistant strains and have led to description of the mutation-prevention concentration, which is the lowest concentration of antimicrobial that prevents selection of resistant bacteria from high bacterial inocula. β-Lactams are time-dependent agents without significant post-antibiotic effects, resulting in bacterial eradication when unbound serum concentrations exceed MICs of these agents against infecting pathogens for >40-50% of the dosing interval. By contrast, fluoroquinolones are concentration- and time-dependent agents, resulting in bacterial eradication when unbound serum area under the curve-to-MIC ratios exceed 25-30. An extended release formulation of ciprofloxacin (proquin xr) exemplifies this principle.

Absorption, Fate, and Excretion. The quinolones are well absorbed after oral administration and are distributed widely in body tissues. Peak serum levels of the fluoroquinolones are obtained within 1-3 hours of an oral dose of 400 mg, with peak levels ranging from 1.1 μg/mL for sparfloxacin to 6.4 μg/mL for levofloxacin. Relatively low serum levels are reached with norfloxacin and limit its usefulness to the treatment of urinary tract infections. Food does not impair oral absorption but may delay the time to peak serum concentrations. Oral doses in adults are 200-400 mg every 12 hours for ofloxacin, 400 mg every 12 hours for norfloxacin and pefloxacin, and 250 to 750 mg every 12 hours for ciprofloxacin. Bioavailability of the fluoroquinolones is >50% for all agents and >95% for several. The serum t_1/2 is 3-5 hours for norfloxacin and ciprofloxacin. The volume of distribution of quinolones is high, with concentrations of quinolones in urine, kidney, lung and prostate tissue, stool, bile, and macrophages and neutrophils higher than serum levels. Quinolone concentrations in cerebrospinal fluid, bone, and prostatic fluid are lower than in serum. Pefloxacin and ofloxacin levels in ascites fluid are close to serum levels, and ciprofloxacin, ofloxacin, and pefloxacin have been detected in human breast milk.

Most quinolones are cleared predominantly by the kidney, and dosages must be adjusted for renal failure. Exceptions are pefloxacin and moxifloxacin, which are metabolized predominantly by the liver and should not be used in patients with hepatic failure. None of the agents is removed efficiently by peritoneal dialysis or hemodialysis.

Therapeutic Uses.

Urinary Tract Infections. Nalidixic acid is useful only for UTI caused by susceptible microorganisms. The fluoroquinolones are significantly more potent and have a much broader spectrum of antimicrobial activity. Norfloxacin is approved for use in the U.S. only for urinary tract infections. Comparative clinical trials indicate that the fluoroquinolones are more efficacious than trimethoprim-sulfamethoxazole for the treatment of UTI (Hooper, 2005b). Ciprofloxacin XR is FDA-approved only for UTI.

Prostatitis. Norfloxacin, ciprofloxacin, and ofloxacin all have been effective in uncontrolled trials for the treatment of prostatitis caused by sensitive bacteria. Fluoroquinolones administered for 4-6 weeks appear to be effective in patients not responding to trimethoprim-sulfamethoxazole.

Sexually Transmitted Diseases. The quinolones are contraindicated in pregnancy. Fluoroquinolones lack activity for Treponema pallidum but have activity in vitro against C. trachomatis and H. ducreyi. For chlamydial urethritis/cervicitis, a 7-day course of ofloxacin is an alternative to a 7-day treatment with doxycycline or a single dose of azithromycin; other available quinolones have not been reliably effective. A single oral dose of a fluoroquinolone such as ofloxacin or ciprofloxacin had been effective treatment for sensitive strains of N. gonorrhoeae, but increasing resistance to fluoroquinolones has led to ceftriaxone being the first-line agent for this infection (Newman et al., 2004). Chancroid (infection by H. ducreyi) can be treated with 3 days of ciprofloxacin.

GI and Abdominal Infections. For traveler's diarrhea (frequently caused by enterotoxigenic E. coli), the quinolones are equal to trimethoprim-sulfamethoxazole in effectiveness, reducing the duration of loose stools by 1-3 days (Hill et al., 2006). Norfloxacin, ciprofloxacin, and ofloxacin given for 5 days all have been effective in the treatment of patients with shigellosis, with even shorter courses effective in many cases. Ciprofloxacin and ofloxacin treatment cures most patients with enteric fever caused by S. typhi, as well as bacteremic nontyphoidal infections in AIDS patients, and it clears chronic fecal carriage. Shigellosis is treated effectively with either ciprofloxacin or azithromycin. The in vitro ability of the quinolones to induce the Shiga toxin stx2 gene (the cause of the hemolytic-uremic syndrome) in E. coli suggests that the quinolones should not be used for Shiga toxin–producing E. coli (Miedouge et al., 2000). Ciprofloxacin and ofloxacin have been less effective in treating episodes of peritonitis occurring in patients on chronic ambulatory peritoneal dialysis likely owing to the higher MICs for these drugs for the coagulase-negative staphylococci that are a common cause of peritonitis in this setting.

Respiratory Tract Infections. The major limitation to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis had been the poor in vitro activity of ciprofloxacin, ofloxacin, and norfloxacin against S. pneumoniae and anaerobic bacteria. However, newer fluoroquinolones, including gatifloxacin (available only for ophthalmic use in U.S.) and moxifloxacin, have excellent activity against S. pneumoniae. The fluoroquinolones have in vitro activity against the rest of the commonly recognized respiratory pathogens, including H. influenzae, Moraxella catarrhalis, S. aureus, M. pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Either a fluoroquinolone (ciprofloxacin or levofloxacin) or azithromycin is the antibiotic of choice for L. pneumophila (Edelstein & Cianciotto, 2005). Fluoroquinolones have been very effective at eradicating both H. influenzae and M. catarrhalis from sputum. Mild to moderate respiratory exacerbations owing to P. aeruginosa in patients with cystic fibrosis have responded to oral fluoroquinolone therapy. Emerging clinical data are demonstrating a clear role for the newer fluoroquinolones as single agents for treatment of community-acquired pneumonia (Hooper, 2005b). However, on the horizon is a decreasing susceptibility of S. pneumoniae to fluoroquinolones (Chen et al., 1999; Wortmann and Bennett, 1999).

Bone, Joint, and Soft Tissue Infections. The treatment of chronic osteomyelitis requires prolonged (weeks to months) antimicrobial therapy with agents active against S. aureus and gram-negative rods. The fluoroquinolones, by virtue of their oral administration and appropriate antibacterial spectrum for these infections, may be used appropriately in some cases; recommended doses are 500 mg every 12 hours or, if severe, 750 mg twice daily. Bone and joint infections may require treatment for 4-6 weeks or more. Dosage should be reduced for patients with severely impaired renal function. Clinical cures have been as high as 75% in chronic osteomyelitis in which gram-negative rods predominated (Hooper, 2005b). Failures have been associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens. In diabetic foot infections, which are commonly caused by a mixture of bacteria including gram-negative rods, anaerobes, streptococci, and staphylococci, the fluoroquinolones in combination with an agent with antianaerobic activity are a reasonable choice.

Adverse Effects. Quinolones and fluoroquinolones generally are well tolerated (Mandell, 2003). The most common adverse reactions involve the GI tract, with 3-17% of patients reporting mostly mild nausea, vomiting, and/or abdominal discomfort. Ciprofloxacin is the most common cause of C. difficile colitis. Gatifloxacin is associated with both hypo- and hyperglycemia in older adults (Park-Wyllie et al., 2006). CNS side effects, predominantly mild headache and dizziness, have been seen in 0.9-11% of patients. Rarely, hallucinations, delirium, and seizures have occurred, predominantly in patients who were also receiving theophylline or a nonsteroidal anti-inflammatory drug. Ciprofloxacin and pefloxacin inhibit the metabolism of theophylline, and toxicity from elevated concentrations of the methylxanthine may occur (Schwartz et al., 1988). Nonsteroidal anti-inflammatory drugs may augment displacement of γ-aminobutyric acid (GABA) from its receptors by the quinolones (Halliwell et al., 1993). Rashes, including photosensitivity reactions, also can occur. Achilles tendon rupture or tendinitis is a recognized adverse effect, especially in those >60 years old, patients taking corticosteroids, and in solid organ transplant recipients (Mandell, 2003). All these agents can produce arthropathy in several species of immature animals. Traditionally, the use of quinolones in children has been contraindicated for this reason. However, children with cystic fibrosis given ciprofloxacin, norfloxacin, and nalidixic acid have had few, and reversible, joint symptoms (Burkhardt et al., 1997; Sabharwal & Marchant, 2006). Therefore, in some cases the benefits may outweigh the risks of quinolone therapy in children. Ciprofloxacin should not be given to pregnant women.

Leukopenia, eosinophilia, and mild elevations in serum transaminases occur rarely. QT_c interval (QT interval corrected for heart rate) prolongation has been observed with sparfloxacin and to a lesser extent with gatifloxacin and moxifloxacin. Quinolones probably should be used only with caution in patients on class III (amiodarone) and class IA (quinidine, procainamide) antiarrhythmics (Chapter 29).

Chemistry. Methenamine is hexamethylenetetramine (hexamethylenamine). The compound decomposes in water to generate formaldehyde, according to the following reaction:

At pH 7.4, almost no decomposition occurs; the yield of formaldehyde is 6% of the theoretical amount at pH 6 and 20% at pH 5. Thus, acidification of the urine promotes formaldehyde formation and the formaldehyde-dependent antibacterial action. The decomposition reaction is fairly slow, and 3 hours are required to reach 90% completion.

Antimicrobial Activity. Nearly all bacteria are sensitive to free formaldehyde at concentrations of ~20 μg/mL. Urea-splitting microorganisms (e.g., Proteus spp.) tend to raise the pH of the urine and thus inhibit the release of formaldehyde. Microorganisms do not develop resistance to formaldehyde.

Pharmacology and Toxicology. Methenamine is absorbed orally, but 10-30% decomposes in the gastric juice unless the drug is protected by an enteric coating. Because of the ammonia produced, methenamine is contraindicated in hepatic insufficiency. Excretion in the urine is nearly quantitative. When the urine pH is 6 and the daily urine volume is 1000-1500 mL, a daily dose of 2 g will yield a urine concentration of 18-60 μg/mL of formaldehyde; this is more than the MIC for most urinary tract pathogens. Various poorly metabolized acids can be used to acidify the urine. Low pH alone is bacteriostatic, so acidification serves a double function. The acids commonly used are mandelic acid and hippuric acid (urex, hiprex).

GI distress frequently is caused by doses >500 mg four times a day, even with enteric-coated tablets. Painful and frequent micturition, albuminuria, hematuria, and rashes may result from doses of 4 to 8 g/day given for longer than 3-4 weeks. Once the urine is sterile, a high dose should be reduced. Because systemic methenamine has low toxicity at the typically used doses, renal insufficiency does not constitute a contraindication to the use of methenamine alone, but the acids given concurrently may be detrimental; methenamine mandelate is contraindicated in renal insufficiency. Crystalluria from the mandelate moiety can occur. Methenamine combines with sulfamethizole and perhaps other sulfonamides in the urine, which results in mutual antagonism; therefore, these drugs should not be used in combination.

Therapeutic Uses and Status. Methenamine is not a primary drug for the treatment of acute urinary tract infections, but it is of value for chronic suppressive treatment (Fihn, 2003). The agent is most useful when the causative organism is E. coli, but it usually can suppress the common gram-negative offenders and often S. aureus and S. epidermidis as well. Enterobacter aerogenes and Proteus vulgaris are usually resistant. Urea-splitting bacteria (mostly Proteus) make it difficult to control the urine pH. The physician should strive to keep the pH <5.5.

Antimicrobial Activity. Enzymes capable of reducing nitrofurantoin appear to be crucial for its activation. Highly reactive intermediates are formed, and these seem to be responsible for the observed capacity of the drug to damage DNA. Bacteria reduce nitrofurantoin more rapidly than do mammalian cells, and this is thought to account for the selective antimicrobial activity of the compound. Bacteria that are susceptible to the drug rarely become resistant during therapy. Nitrofurantoin is active against many strains of E. coli and enterococci. However, most species of Proteus and Pseudomonas and many species of Enterobacter and Klebsiella are resistant. Nitrofurantoin is bacteriostatic for most susceptible microorganisms at concentrations of ≤32 μg/mL or less and is bactericidal at concentrations of ≥100 μg/mL. The antibacterial activity is higher in an acidic urine.

Pharmacology and Toxicity. Nitrofurantoin is absorbed rapidly and completely from the GI tract. The macrocrystalline form of the drug is absorbed and excreted more slowly. Antibacterial concentrations are not achieved in plasma following ingestion of recommended doses because the drug is eliminated rapidly. The plasma t_1/2 is 0.3-1 hour; ~40% is excreted unchanged into the urine. The average dose of nitrofurantoin yields a concentration in urine of ~200 μg/mL. This concentration is soluble at pH >5, but the urine should not be alkalinized because this reduces antimicrobial activity. The rate of excretion is linearly related to the creatinine clearance, so in patients with impaired glomerular function, the efficacy of the drug may be decreased and the systemic toxicity increased. Nitrofurantoin colors the urine brown.

The most common untoward effects are nausea, vomiting, and diarrhea; the macrocrystalline preparation is better tolerated than traditional formulations. Various hypersensitivity reactions occur occasionally. These include chills, fever, leukopenia, granulocytopenia, hemolytic anemia (associated with G6PD deficiency), cholestatic jaundice, and hepatocellular damage. Chronic active hepatitis is an uncommon but serious side effect. Acute pneumonitis with fever, chills, cough, dyspnea, chest pain, pulmonary infiltration, and eosinophilia may occur within hours to days of the initiation of therapy; these symptoms usually resolve quickly after discontinuation of the drug. More insidious subacute reactions also may be noted, and interstitial pulmonary fibrosis can occur in patients taking the drug chronically. This appears to be due to generation of oxygen radicals as a result of redox cycling of the drug in the lung. Elderly patients are especially susceptible to the pulmonary toxicity of nitrofurantoin. Megaloblastic anemia is rare. Various neurological disorders are observed occasionally. Headache, vertigo, drowsiness, muscular aches, and nystagmus are readily reversible, but severe polyneuropathies with demyelination and degeneration of both sensory and motor nerves have been reported; signs of denervation and muscle atrophy result. Neuropathies are most likely to occur in patients with impaired renal function and in persons on long-continued treatment.

The oral dosage of nitrofurantoin for adults is 50-100 mg four times a day with meals and at bedtime, less for the macrocrystalline formulation (100 mg every 12 hours for 7 days). Alternatively, the daily dosage is better expressed as 5-7 mg/kg in four divided doses (not to exceed 400 mg). A single 50-100-mg dose at bedtime may be sufficient to prevent recurrences. The daily dose for children is 5 to 7 mg/kg but may be as low as 1 mg/kg for long-term therapy. A course of therapy should not exceed 14 days, and repeated courses should be separated by rest periods. Pregnant women, individuals with impaired renal function (creatinine clearance <40 mL/minute), and children <1 month of age should not receive nitrofurantoin.

Nitrofurantoin is approved only for the treatment of urinary tract infections caused by microorganisms known to be susceptible to the drug. Currently, bacterial resistance to nitrofurantoin is more frequent than resistance to fluoroquinolones or trimethoprim-sulfamethoxazole, making nitrofurantoin a second-line agent for treatment of urinary tract infections (Fihn, 2003). Nitrofurantoin is not recommended for treatment of pyelonephritis or prostatitis.

The usual dose is 200 mg three times daily. The compound is an azo dye, which colors urine orange or red; the patient should be so informed. GI upset is seen in up to 10% of patients and can be reduced by administering the drug with food; overdosage may result in methemoglobinemia. Phenazopyridine has been marketed since 1925 and has had dual prescription/over-the-counter (OTC) marketing status since 1951. As part of their ongoing review of OTC drug products, the Food and Drug Administration (FDA) is currently in the process of evaluating products containing <200 mg phenazopyridine to determine whether these products generally are recognized as safe and effective as urinary analgesics. The outcome of this evaluation will determine the continued availability of OTC phenazopyridine products in the U.S. Products containing 200 mg phenazopyridine are sold by prescription, but their long-term availability in the marketplace also may be affected by the FDA's final OTC ruling. Phenazopyridine is no longer available in Canada.