The sulfonamide drugs were the first effective chemotherapeutic agents to be employed systemically for the prevention and cure of bacterial infections in humans. The advent of penicillin and other antibiotics diminished the usefulness of the sulfonamides, but the introduction of the combination of trimethoprim and sulfamethoxazole has increased the use of sulfonamides for the prophylaxis and treatment of specific microbial infections. Sulfonamides are derivatives of para- aminobenzenesulfonamide (sulfanilamide; Figure 52–1) and are congeners of para-aminobenzoic acid. Most of them are relatively insoluble in water, but their sodium salts are readily soluble.
Figure 52–1 Sulfanilamide and para-aminobenzoic acid. Sulfonamides are derivatives of sulfanilamide and act by virtue of being congeners of para-aminobenzoate (PABA). The antimicrobial and dermatological anti-inflammatory agent dapsone (4,4’-diaminodiphenyl sulfone; see Figure 56–5 and Chapter 65) also bears a resemblance to PABA and sulfanilamide.
The minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself. The sulfur must be 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; substitution of heterocyclic aromatic nuclei at N1 yields highly potent compounds.
MECHANISM OF ACTION. Sulfonamides are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid, the immediate precursor of folic acid (Figure 52–2). Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can use preformed folate are not affected. Toxicity is selective for bacteria because mammalian cells require preformed folic acid, cannot synthesize it, and are thus insensitive to drugs acting by this mechanism.
Figure 52–2 Steps in folate metabolism blocked by sulfonamides and trimethoprim. Coadministration of a sulfonamide and trimethoprim introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate; the combination is much more effective than either agent alone.
SYNERGISTS OF SULFONAMIDES. Trimethoprim exerts a synergistic effect with sulfonamides. It is a potent and selective competitive inhibitor of microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate, which is required for 1-carbon transfer reactions. Coadministration of a sulfonamide and trimethoprim introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate (see Figure 52–2); the combination is much more effective than either agent alone.
EFFECTS ON MICROBES
Sulfonamides have a wide range of antimicrobial activity against both gram-positive and gram-negative bacteria. Resistant strains have become common and the usefulness of these agents has diminished correspondingly. Sulfonamides are bacteriostatic; cellular and humoral defense mechanisms of the host are essential for final eradication of the infection.
ANTIBACTERIAL SPECTRUM. Resistance to sulfonamides is increasingly a problem. Microorganisms that may be susceptible in vitro to sulfonamides include Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus ducreyi, Nocardia, Actinomyces, Calymmatobacterium granulomatis, and Chlamydia trachomatis. Minimal inhibitory concentrations (MICs) range from 0.1 µg/mL for C. trachomatis to 4-64 µg/mL for Escherichia coli. Peak plasma drug concentrations achievable in vivo are ~100-200 µg/mL. Isolates of Neisseria meningitidis and Shigella are generally resistant, as are many strains of E. coli isolated from patients with urinary tract infections (community acquired).
ACQUIRED BACTERIAL RESISTANCE TO SULFONAMIDES. Bacterial resistance to sulfonamides can originate by random mutation and selection or by transfer of resistance by plasmids (see Chapter 48); it usually does not involve cross-resistance to other classes of antibiotics. Resistance to sulfonamide can result from: (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 (e.g., PABA). Plasmid-mediated resistance is due to plasmid-encoded drug-resistant dihydropteroate synthetase.
ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Except for sulfonamides especially designed for their local effects in the bowel (see Chapter 47), this class of drugs is absorbed rapidly from the GI tract. Approximately 70-100% of an oral dose is absorbed, and sulfonamide can be found in the urine within 30 min of ingestion. Peak plasma levels are achieved in 2-6 h, depending on the drug. The small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Absorption from other sites, such as the vagina, respiratory tract, or abraded skin, is variable and unreliable, but a sufficient amount may enter the body to cause toxic reactions in susceptible persons or to produce sensitization.
All sulfonamides are bound in varying degree to plasma proteins, particularly to albumin. This is determined by the hydrophobicity of a particular drug and its pKa; at physiological pH, drugs with a high pKa 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. Because the protein content of such body 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 CSF that may be effective in meningitis. 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 may cause both antibacterial and toxic effects.
Sulfonamides are metabolized in the liver. The major metabolite is the N4-acetylated sulfonamide. Acetylation results in products that have no antibacterial activity but 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 t1/2 depends on renal function. In acid urine, the older sulfonamides are insoluble and crystalline deposits may form. Small amounts are eliminated in the feces, bile, milk, and other secretions.
PHARMACOLOGICAL PROPERTIES OF INDIVIDUAL SULFONAMIDES
The sulfonamides may be classified on the basis of the rapidity with which they are absorbed and excreted (Table 52–1).
Classes of Sulfonamides
RAPIDLY ABSORBED AND ELIMINATED SULFONAMIDES
Sulfisoxazole. Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with excellent antibacterial activity. Its high solubility eliminates much of the renal toxicity inherent in the use of older sulfonamides. 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 h. Approximately 30% 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 h. Concentrations of the drug in urine thus greatly exceed those in blood and may be bactericidal. The concentration in CSF is about a third of that in the blood. Sulfisoxazole acetyl is marketed in combination with erythromycin ethylsuccinate for use in children with otitis media.
The untoward effects of sulfisoxazole are similar to other sulfonamides. Because of its relatively high solubility in the urine as compared with sulfadiazine, sulfisoxazole rarely produces hematuria or crystalluria (0.2-0.3%). Nonetheless, patients should still ingest an adequate quantity of water. Sulfisoxazole 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.
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. Peak blood concentrations are reached within 3-6 h. About 55% of the drug is bound to plasma protein. Therapeutic concentrations are attained in CSF within 4 h of a single oral dose of 60 mg/kg. Both free and acetylated forms of sulfadiazine are readily excreted by the kidney; 15-40% of the excreted drug is in acetylated form. Alkalinization of the urine accelerates the renal clearance of both forms by diminishing their tubular reabsorption. Every precaution must be taken to ensure fluid intake adequate to produce a daily 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. Intestinal bacteria break sulfasalazine down to 5-aminosalicylate (5-ASA, mesalamine; see Figures 47–2 through 47–4), the active agent in inflammatory bowel disease, and sulfapyridine, a sulfonamide that is absorbed and eventually excreted in the urine.
SULFONAMIDES FOR TOPICAL USE
Sulfacetamide. Sulfacetamide is the N1-acetyl-substituted derivative of sulfanilamide. Its aqueous solubility is ~90 times that of sulfadiazine. Solutions of the sodium salt of the drug are employed extensively in the management of ophthalmic infections. Very high aqueous concentrations are not irritating to the eye and are effective against susceptible microorganisms. 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. 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. See Chapters 64 and 65 for ocular and dermatological uses.
Silver Sulfadiazine. Silver sulfadiazine (SILVADENE, others) is used topically to reduce microbial colonization and the incidence of infections from burns. Silver sulfadiazine 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 an agent of choice for the prevention of burn infections.
Mafenide. This sulfonamide (α-amino-p-toluene-sulfonamide; SULFAMYLON) is applied topically to prevent 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. 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. Mafenide is absorbed from the burn surface, reaching peak plasma concentrations in 2-4 h; the absorbed drug is converted to para-carboxybenzenesulfonamide.
Sulfadoxine. This agent has a particularly long plasma t1/2 (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 (see 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 (UTIs). Because a significant percentage of UTIs 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. Sulfisoxazole may be used effectively in areas where the prevalence of resistance is not high. The usual dosage is 2-4 g initially followed by 1-2 g, orally 4 times a day for 5-10 days. Patients with acute pyelonephritis with high fever 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. Sulfisoxazole or sulfadiazine may be given in dosages of 6-8 g daily and this schedule should be continued for several months after all manifestations have been controlled. Combination of sulfonamide with a second antibiotic has been recommended, especially for advanced cases; ampicillin, erythromycin, and streptomycin have been suggested but there are no clinical data to show that combination therapy is better than therapy with a sulfonamide alone. Trimethoprim-sulfamethoxazole also is effective; some authorities consider this combination to be the treatment of choice.
TOXOPLASMOSIS. The combination of pyrimethamine and sulfadiazine is the treatment of choice for toxoplasmosis (see 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 h, 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.
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. Their toxicity and the possibility of infection by drug-resistant streptococci make sulfonamides less desirable than penicillin for this purpose: however, sulfonamides should be used in patients who are hypersensitive to penicillin. Untoward responses usually occur during the first 8 weeks of therapy. White blood cell counts should be carried out once weekly during the first 8 weeks.
UNTOWARD REACTIONS TO SULFONAMIDES
The untoward effects that follow the administration of sulfonamides are numerous and varied; the overall incidence of reactions is~5%.
DISTURBANCES OF THE URINARY TRACT. The risk of crystalluria is very low with the more soluble agents such as sulfisoxazole. Crystalluria has occurred in dehydrated patients with acquired immunodeficiency 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. Although rare, acute hemolytic anemia may occur. In some cases, it may be due to a sensitization phenomenon; in other instances, the hemolysis is related to an erythrocytic deficiency of glucose-6-phosphate dehydrogenase activity. 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 involving 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. 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. 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 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; 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. The administration of sulfonamides to newborn infants, especially if premature, may lead to the displacement of bilirubin from plasma albumin, potentially causing an encephalopathy called kernicterus. Sulfonamides should not be given to pregnant women near term because these drugs cross the placenta and are secreted in milk.
DRUG INTERACTIONS. Drug interactions of the sulfonamides are seen 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 inhibiting its metabolism or by displacing it from albumin. Dosage adjustment may be necessary when a sulfonamide is given concurrently.
Trimethoprim inhibits bacterial dihydrofolate reductase, an enzyme downstream from the one that sulfonamides inhibit in the same biosynthetic sequence (see Figure 52–2). The combination of trimethoprim with sulfamethoxazole was an important advance in the development of clinically effective and synergistic antimicrobial agents. In much of the world, the combination of trimethoprim with sulfamethoxazole is known as cotrimoxazole. In addition to its combination with sulfamethoxazole (BACTRIM, SEPTRA, others), trimethoprim also is available as a single-entity preparation.
ANTIBACTERIAL SPECTRUM. The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole, although trimethoprim is 20-100 times more potent. Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when the drug is used alone. Pseudomonas aeruginosa, Bacteroides fragilis, and enterococci usually are resistant. There is significant variation in the susceptibility of Enterobacteriaceae to trimethoprim in different geographic locations because of the spread of resistance mediated by plasmids and transposons (see Chapter 48).
Efficacy of Trimethoprim-Sulfamethoxazole in Combination. Chlamydia trachomatis and N. meningitidis are susceptible to trimethoprim-sulfamethoxazole. Although most S. pneumoniae are susceptible, there has been a disturbing increase in resistance. From 50-95% of strains of Staphylococcus aureus, Staphylococcus epidermidis, S. pyogenes, the viridans group of streptococci, E. coli, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Enterobacter spp., Salmonella, Shigella, Pseudomonas pseudomallei, Serratia, and Alcaligenes spp. are inhibited. Also sensitive are Klebsiella spp., Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis, Yersinia enterocolitica, and Nocardia asteroides.
MECHANISM OF ACTION. The antimicrobial activity of the combination of trimethoprim and sulfamethoxazole results from actions on sequential steps of the enzymatic pathway for the synthesis of tetrahydrofolic acid (see Figure 52–2). Tetrahydrofolate is essential for one-carbon transfer reactions (e.g., the synthesis of thymidylate from deoxyuridylate). Selective toxicity for microorganisms is achieved in 2 ways. Mammalian cells use preformed folates from the diet and do not synthesize the compound. Furthermore, trimethoprim is a highly selective inhibitor of dihydrofolate reductase of lower organisms: ~100,000 times more drug is required to inhibit human reductase than the bacterial enzyme. The optimal ratio of the concentrations of the 2 agents equals the ratio of the minimal inhibitory concentrations of the drugs acting independently. Although this ratio varies for different bacteria, the most effective ratio for the greatest number of microorganisms is 20:1, sulfamethoxazole:trimethoprim. The combination is thus formulated to achieve a sulfamethoxazole concentration in vivo that is 20 times greater than that of trimethoprim; sulfamethoxazole has pharmacokinetic properties such that the concentrations of the 2 drugs will thus be relatively constant in the body over a long period.
BACTERIAL RESISTANCE. Bacterial resistance to trimethoprim-sulfamethoxazole is a rapidly increasing problem. Resistance often is due to the acquisition of a plasmid that codes for an altered dihydrofolate reductase. Resistance to trimethoprim-sulfamethoxazole is reportedly formed in almost 30% of urinary isolates of E. coli.
ADME. The pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely but not perfectly matched to achieve a constant ratio of 20:1 in their concentrations in blood and tissues. After a single oral dose of the combined preparation, trimethoprim is absorbed more rapidly than sulfamethoxazole. Peak blood concentrations of trimethoprim usually occur by 2 h in most patients, whereas peak concentrations of sulfamethoxazole occur by 4 h after a single oral dose. The half-lives of trimethoprim and sulfamethoxazole are ~11 and 10 h, respectively.
When 800 mg sulfamethoxazole is given with 160 mg trimethoprim (the conventional 5:1 ratio) twice daily, the peak concentrations of the drugs in plasma are ~40 and 2 µg/mL, the optimal ratio. Peak concentrations are similar (46 and 3.4 µg/mL) after intravenous infusion of 800 mg sulfamethoxazole and 160 mg trimethoprim over a period of 1 h.
Trimethoprim is distributed and concentrated rapidly in tissues; ~40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost 9 times that of sulfamethoxazole. The drug readily enters CSF and sputum. High concentrations of each component of the mixture also are found in bile. About 65% of sulfamethoxazole is bound to plasma protein. About 60% of administered trimethoprim and from 25-50% of administered sulfamethoxazole are excreted in the urine in 24 h. Two-thirds of the sulfonamide is unconjugated. Metabolites of trimethoprim also are excreted. The rates of excretion and the concentrations of both compounds in the urine are reduced significantly in patients with uremia.
Urinary Tract Infections. Treatment of uncomplicated lower UTI with trimethoprim-sulfamethoxazole often is highly effective for sensitive bacteria. Single-dose therapy (320 mg trimethoprim plus 1600 mg sulfamethoxazole in adults) has been effective in some cases for the treatment of acute uncomplicated UTI. Trimethoprim also is found in therapeutic concentrations in prostatic secretions, and trimethoprim-sulfamethoxazole is often effective for the treatment of bacterial prostatitis.
Bacterial Respiratory Tract Infections. Trimethoprim-sulfamethoxazole is effective for acute exacerbations of chronic bronchitis. Administration of 800-1200 mg sulfamethoxazole plus 160-240 mg trimethoprim twice a day appears to be effective in decreasing fever, purulence and volume of sputum, and sputum bacterial count. Trimethoprim-sulfamethoxazole should not be used to treat streptococcal pharyngitis because it does not eradicate the microorganism. It is effective for acute otitis media in children and acute maxillary sinusitis in adults caused by susceptible strains of H. influenzae and S. pneumoniae.
GI Infections. The combination is an alternative to a fluoroquinolone for treatment of shigellosis. Trimethoprim-sulfamethoxazole appears to be effective in the management of carriers of sensitive strains ofSalmonella typhi and other Salmonella spp; however, failures have occurred. Acute diarrhea owing to sensitive strains of enteropathogenic E. coli can be treated or prevented with either trimethoprim or trimethoprim + sulfamethoxazole. However, antibiotic treatment of diarrheal illness owing to enterohemorrhagic E. coli O157:H7 may increase the risk of hemolytic-uremic syndrome, perhaps by increasing the release of Shiga toxin by the bacteria.
Infection by Pneumocystis jiroveci. High-dose therapy (trimethoprim 15-20 mg/kg/day plus sulfamethoxazole 75-100 mg/kg/day in 3 or 4 divided doses) is effective for this severe infection in patients with AIDS. Adjunctive corticosteroids should be given at the onset of anti-Pneumocystis therapy in patients with a PO2 <70 mm Hg or an alveolar-arterial gradient >35 mm Hg. Prophylaxis with 800 mg sulfamethoxazole and 160 mg trimethoprim once daily or 3 times a week is effective in preventing pneumonia caused by this organism in patients with AIDS. Adverse reactions are less frequent with the lower prophylactic doses of trimethoprim-sulfamethoxazole. The most common problems are rash, fever, leukopenia, and hepatitis.
Prophylaxis in Neutropenic Patients. Low-dose therapy (150 mg/m2 of body surface area of trimethoprim and 750 mg/m2 of body surface area of sulfamethoxazole) is effective for the prophylaxis of infection by P. jiroveci. A regimen of 800 mg sulfamethoxazole and 160 mg trimethoprim twice daily to severely neutropenic patients provides significant protection against sepsis caused by gram-negative bacteria.
Miscellaneous Infections. Nocardia infections have been treated successfully with the combination, but failures also have been reported. Although a combination of doxycycline and streptomycin or gentamicin now is considered to be the treatment of choice for brucellosis, trimethoprim-sulfamethoxazole may be an effective substitute for the doxycycline combination. Trimethoprim-sulfamethoxazole also has been used successfully in the treatment of Whipple disease, infection by Stenotrophomonas maltophilia, and infection by the intestinal parasites Cyclospora and Isospora. Wegener granulomatosis may respond, depending on the stage of the disease.
UNTOWARD EFFECTS. The margin between toxicity for bacteria and that for humans may be relatively narrow when the patient is folate-deficient. In such cases, trimethoprim-sulfamethoxazole may cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia. In routine use, the combination appears to exert little toxicity. About 75% of the untoward effects involve the skin. Trimethoprim-sulfamethoxazole reportedly causes up to 3 times as many dermatological reactions as does sulfisoxazole alone (5.9% vs. 1.7%). Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis 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. CNS reactions consist of headache, depression, and hallucinations, manifestations ascribed to sulfonamides. Hematological reactions include various anemias, 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 syndrome, and pulmonary infiltrates). It may be possible to continue therapy in such patients following rapid oral desensitization.
Quinolones are derivatives of nalidixic acid. The fluorinated 4-quinolones, such as ciprofloxacin (CIPRO, others) and moxifloxacin (AVELOX), have broad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious diseases (Table 52–2).
Structural Formulas of Selected Quinolones and Fluoroquinolones
Rare and potentially fatal side effects, however, have resulted in the withdrawal from the U.S. market of lomefloxacin, sparfloxacin (phototoxicity, QTc prolongation), gatifloxacin (hypoglycemia), temafloxacin (immune hemolytic anemia), trovafloxacin (hepatotoxicity), grepafloxacin (cardiotoxicity), and clinafloxacin (phototoxicity).
MECHANISM OF ACTION. The quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria, topoisomerase IV is the primary target. In contrast, DNA gyrase is the primary quinolone target in many gram-negative microbes. The gyrase introduces negative supercoils into the DNA to combat excessive positive supercoiling that can occur during DNA replication (Figure 52–3). The quinolones 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 of the gyrase can confer resistance to these drugs. Topoisomerase IV, which separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication, also is target for quinolones.
Figure 52–3 Model of the formation of negative DNA supercoils by DNA gyrase. DNA gyrase binds to 2 segments of DNA (1), creating a node of positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative (–) supercoil. Quinolones inhibit the nicking and closing activity of the gyrase and, at higher concentrations, block the decatenating activity of topoisomerase IV. (From Cozzarelli NR. DNA gyrase and the supercoiling of DNA. Science, 1980;207:953-960. Reprinted with permission from AAAS.)
Eukaryotic cells do not contain DNA gyrase. They do contain a conceptually and mechanistically similar type II DNA topoisomerase but quinolones inhibit it only at concentrations (100-1000 µg/mL) much higher than those needed to inhibit the bacterial enzymes.
ANTIBACTERIAL SPECTRUM. The fluoroquinolones are potent bactericidal agents against E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria (MIC90usually are <0.2 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). 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). Ciprofloxacin (CIPRO, others), ofloxacin (FLOXIN), and pefloxacin have MIC90 values from 0.5-3 µg/mL for M. fortuitum, M. kansasii, and M. tuberculosis. Several fluoroquinolones, including garenoxacin (not available in U.S.) and gemifloxacin, have activity against anaerobic bacteria.
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. 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.
ADME. The quinolones are well absorbed after oral administration. Peak serum levels of the fluoroquinolones are obtained within 1-3 h of an oral dose of 400 mg. The volume of distribution of quinolones is high, with concentrations in urine, kidney, lung and prostate tissue, stool, bile, and macrophages and neutrophils higher than serum levels. Relatively low serum levels are reached with norfloxacin and limit its usefulness to the treatment of UTIs. Food may delay the time to peak serum concentrations. Oral doses in adults are 200-400 mg every 12 h for ofloxacin, 400 mg every 12 h for norfloxacin and pefloxacin, and 250 to 750 mg every 12 h for ciprofloxacin. Bioavailability of the fluoroquinolones is >50% for all agents and >95% for several. The serum t1/2 is 3-5 h for norfloxacin and ciprofloxacin. Quinolone concentrations in CSF, 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. By contrast, pefloxacin and moxifloxacin 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 or hemodialysis.
Pharmacokinetic Aspects. 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 (see Figure 48–4).
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 and ciprofloxacin XR are approved for use in the U.S. only for UTIs. Fluoroquinolones are more efficacious than trimethoprim-sulfamethoxazole for the treatment of UTI.
Prostatitis. Norfloxacin, ciprofloxacin, and ofloxacin are effective in 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. 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. Norfloxacin, ciprofloxacin, and ofloxacin given for 5 days all have been effective in the treatment of patients with shigellosis. Ciprofloxacin and ofloxacin treatment cures most patients with enteric fever caused by S. typhi, as well as bacteremic nontyphoidal infections in AIDS patients, and clears chronic fecal carriage. 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. Ciprofloxacin and ofloxacin are less effective in treating episodes of peritonitis occurring in patients on chronic ambulatory peritoneal dialysis (likely cause: coagulase- negative staphylococci).
Respiratory Tract Infections. Many 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. Either a fluoroquinolone (ciprofloxacin or levofloxacin) or azithromycin is the antibiotic of choice for L. pneumophila. 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.
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, with an appropriate antibacterial spectrum for these infections, may be used in some cases; recommended doses are 500 mg every 12 h or, if severe, 750 mg twice daily. Dosage should be reduced for patients with severely impaired renal function. Clinical cures are as high as 75% in chronic osteomyelitis in which gram-negative rods predominate. Failures are associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens. In diabetic foot infections, the fluoroquinolones in combination with an agent with anti-anaerobic activity are a reasonable choice.
Other Infections. Ciprofloxacin is used for the prophylaxis of anthrax and is effective for the treatment of tularemia. The quinolones may be used as part of multiple-drug regimens for the treatment of multidrug-resistant tuberculosis and atypical mycobacterial infections as well as Myobacterium avium complex infections in AIDS (see Chapter 56). Quinolones, when used as prophylaxis in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias. Levofloxacin is approved to treat and prevent anthrax as well as plague due to Yersinia pestis.
ADVERSE EFFECTS. Quinolones and fluoroquinolones generally are well tolerated. Common adverse reactions involve the GI tract, with 3-17% of patients reporting mild nausea, vomiting, and abdominal discomfort. Ciprofloxacin is the most common cause of C. difficile colitis. Gatifloxacin is associated with both hypo- and hyperglycemia in older adults. CNS side effects (1-11%) include mild headache and dizziness. Rarely, hallucinations, delirium, and seizures have occurred, predominantly in patients who were also receiving theophylline or NSAIDS. Ciprofloxacin and pefloxacin inhibit the metabolism of theophylline, and toxicity from elevated concentrations of the methylxanthine may occur. NSAIDS may augment displacement of γ-aminobutyric acid (GABA) from its receptors by the quinolones. Rashes, including photosensitivity reactions, also can occur. Achilles tendon rupture or tendinitis is a recognized adverse effect, especially in those >60 years old, inpatients taking corticosteroids, and in solid organ transplant recipients. Ciprofloxacin should not be given to pregnant women and are generally not used in children.
Leukopenia, eosinophilia, and mild elevations in serum transaminases occur rarely. QT interval prolongation has been observed with sparfloxacin and to a lesser extent with gatifloxacin and moxifloxacin. Quinolones should be used with caution in patients on class III (amiodarone) and class IA (quinidine, procainamide) anti-arrhythmics (see Chapter 29).
ANTISEPTIC AND ANALGESIC AGENTS FOR URINARY TRACT INFECTIONS
Urinary tract antiseptics are concentrated in the renal tubules where they inhibit the growth of many species of bacteria. These agents cannot be used to treat systemic infections because effective concentrations are not achieved in plasma with safe doses; however, they can be administered orally to treat UTIs. Furthermore, effective antibacterial concentrations reach the renal pelves and the bladder.
METHENAMINE. Methenamine (hexamethylenamine) is a urinary tract antiseptic and prodrug that acts by generating formaldehyde via 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 h are required to reach 90% completion. Nearly all bacteria are sensitive to free formaldehyde at concentrations of ~20 µg/mL. Microorganisms do not develop resistance to formaldehyde. Urea-splitting microorganisms (e.g., Proteus spp.) tend to raise the pH of the urine and thus inhibit the release of formaldehyde.
Pharmacology, Toxicology, and Therapeutic Uses. 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. 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 4 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. Renal insufficiency is not a contraindication to the use of methenamine alone, but the acids given concurrently may be detrimental; methenamine mandelate is contraindicated in renal insufficiency. 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. Methenamine is not a primary drug for the treatment of acute UTIs but is of value for chronic suppressive treatment of UTIs. 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 andProteus vulgaris are usually resistant. The physician should strive to keep the pH <5.5.
NITROFURANTOIN. Nitrofurantoin (FURADANTIN, MACROBID, others) is a synthetic nitrofuran that is used for the prevention and treatment of UTIs.
Antimicrobial Activity. Nitrofurantoin is activated by enzymatic reduction, with the formation of highly reactive intermediates that 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. 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 acidic urine.
Pharmacology, Toxicity, and Therapy. Nitrofurantoin is absorbed rapidly and completely from the GI tract. Antibacterial concentrations are not achieved in plasma following ingestion of recommended doses because the drug is eliminated rapidly. The plasma t1/2 is 0.3-1 h; ~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 oral dosage of nitrofurantoin for adults is 50-100 mg 4 times a day with meals and at bedtime, less for the macrocrystalline formulation (100 mg every 12 h for 7 days). A single 50-100-mg dose at bedtime may be sufficient to prevent recurrences. The daily dose for children is 5-7 mg/kg but may be as low as 1 mg/kg for long-term therapy. A course of therapy should not exceed 14 days; repeated courses should be separated by rest periods. Pregnant women, individuals with impaired renal function (creatinine clearance <40 mL/min), and children <1 month of age should not receive nitrofurantoin. Nitrofurantoin is approved for the treatment of UTIs. It is not recommended for treatment of pyelonephritis or prostatitis.
The most common untoward effects are nausea, vomiting, and diarrhea; the macrocrystalline preparation is better tolerated than traditional formulations. Various hypersensitivity reactions occur occasionally, including chills, fever, leukopenia, granulocytopenia, hemolytic anemia (associated with G6PD deficiency), cholestatic jaundice, and hepatocellular damage. Chronic active hepatitis is an uncommon. 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. Interstitial pulmonary fibrosis can occur in patients (especially the elderly) taking the drug chronically. Megaloblastic anemia is rare. Headache, vertigo, drowsiness, muscular aches, and nystagmus occur occasionally but are readily reversible. Severe polyneuropathies with demyelination and degeneration of both sensory and motor nerves have been reported; neuropathies are most likely to occur in patients with impaired renal function and in persons on long-continued treatment.
PHENAZOPYRIDINE. Phenazopyridine hydrochloride (PYRIDIUM, others) is not a urinary antiseptic. However, it does have an analgesic action on the urinary tract and alleviates symptoms of dysuria, frequency, burning, and urgency. The usual dose is 200 mg 3 times daily. The compound is an azo dye, which colors urine orange or red. 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. OTC products containing phenazopyridine are under review by the FDA for safety and efficacy.