Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 48 Bacterial Folate Antagonists, Fluoroquinolones, and Other Antibacterial Agents

MAJOR DRUG CLASSES

Sulfonamides and Trimethoprim

Fluoroquinolones

Nitrofurans

Polymyxins

Therapeutic Overview

The sulfonamides such as sulfamethoxazole (SMX) and trimethoprim (TMP) act by inhibiting synthesis of folic acid in bacteria. Most bacteria must synthesize folic acid derivatives, whereas humans can rely on dietary sources. Thus inhibition of folate synthesis constitutes a route for selective antibiotic development. Many sulfonamide derivatives have been synthesized and tested in humans, but because of the development of widespread bacterial resistance to these drugs, only a few are still in clinical use. Sulfonamides are useful in treatment of nocardiosis (usually administered in the combination form of TMP-SMX) and are also administered topically to burn wounds. Sulfadiazine is used in combination with the antimalarial drug pyrimethamine to treat toxoplasmosis. The TMP-SMX combination has many therapeutic applications, which are summarized in the Therapeutic Overview Box.

Several other types of antimicrobial agents act by inhibiting or damaging bacterial deoxyribonucleic acid (DNA) (fluoroquinolones and nitrofurans) or by disrupting bacterial cell membranes (polymyxins). Quinolones were first developed in the 1960s and can be classified into generations based on antimicrobial activity. Fluoroquinolones (second- and third-generation) are the only quinolones in current use. Norfloxacin (an older second-generation fluoroquinolone) and the nitrofurans are not effective for systemic infections and are used primarily to treat urinary tract infections. Another second-generation fluoroquinolone, ciprofloxacin, is also effective against gonorrhea, diarrhea, prostatitis, and osteomyelitis. Ciprofloxacin is the fluoroquinolone with the highest activity against Pseudomonas aeruginosa. The third-generation fluoroquinolones have increased activity against gram-positive pathogens including the important respiratory pathogen S. pneumoniae. Most fluoroquinolones are available in both oral and intravenous (IV) formulations and can be used to treat a broad range of serious infections. Polymyxin B is an older agent that has been used with

Abbreviations

AIDS

Acquired immunodeficiency syndrome

CNS

Central nervous system

CSF

Cerebrospinal fluid

DNA

Deoxyribonucleic acid

GI

Gastrointestinal

IV

Intravenous

SMX

Sulfamethoxazole

TMP

Trimethoprim

Therapeutic Overview

Sulfonamides

Treatment of nocardiosis and toxoplasmosis

Topical agents for burn wounds

 

Trimethoprim-sulfamethoxazole Combination

No longer drugs of choice for upper respiratory tract infections

Urinary tract infections

Resistant bacteria

Treatment and prevention of Pneumocystic carinii infections and toxoplasma gondii encephalitis in AIDS patients (significant side effects)

Prevention of spontaneous bacterial peritonitis in patients with cirrhosis

Fluoroquinolones

Urinary tract infections

Prostatitis

Sexually transmitted diseases (increasing resistance in N. gonorrhea)

Bacterial diarrheal infections

Community-acquired pneumonia (third-generation agents only)

Osteomyelitis

Agents of biowarfare

Mycobacterial infections

Nitrofurans

Urinary tract infections

Polymyxins

Mainly topical uses

IV treatment only as therapeutic alternative for serious nosocomial infections caused by multi-resistant gram-negative organisms

some frequency in the past few years for treatment of multidrug-resistant gram-negative infections.

Mechanisms of Action

Folic Acid Synthesis and Regeneration

The bacterial synthesis of folic acid involves a multistep enzyme-catalyzed reaction sequence (Fig. 48-1). Tetrahydrofolic acid is the physiologically active form of folic acid and is required as a cofactor in synthesis of thymidine, purines, and bacterial DNA. Sulfonamides are structural analogs of p-aminobenzoic acid and competitively inhibit dihydropteroate synthase. TMP blocks the production of tetrahydrofolate from dihydrofolate by reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus these two drugs block the synthesis of tetrahydrofolate at different steps in the synthetic pathway and result in a bactericidal synergistic effect.

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FIGURE 48–1 Folate synthesis pathway and sites of action of trimethoprim and sulfamethoxazole.

From Masters PA, et al. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med 2003; 163:402. Copyright 2003 American Medical Association. All rights reserved.

Sulfonamides

The sulfonamides are bacteriostatic because microorganisms must synthesize their own folic acid, whereas mammalian cells do not. When folate synthesis is inhibited, bacterial cell growth is halted. This inhibition can be reversed by addition of purines, thymidine, methionine, and serine. Resistance to sulfonamides is widespread, and its incidence continues to increase among all major bacterial pathogens. One mechanism is reduced cellular uptake of the drug, which can be chromosomal or plasmid in origin. A second mechanism is altered dihydropteroate synthetase, which can result from a point mutation or the presence of a plasmid that causes synthesis of a new enzyme. Replacement of a single amino acid in the enzyme alters its affinity for sulfonamides. In enteric species, plasmid-propagated resistance is the common form. A final mechanism of resistance is the production of increased amounts of p-aminobenzoic acid. This mechanism is exhibited by some staphylococci but is not common. Resistance stemming from an altered enzyme can develop during therapy.

Trimethoprim

TMP was used initially as an antimalarial drug but has been replaced by pyrimethamine, which acts by a similar mechanism. The antimalarial and antibacterial actions of TMP stem from its high affinity for bacterial dihydrofolate reductase. TMP binds competitively and inhibits this enzyme in bacterial and mammalian cells. Approximately 100,000 times higher concentrations of drug are needed to inhibit the human enzyme as compared with the bacterial enzyme. This enzyme is also inhibited by methotrexate, discussed in Chapter 54. TMP thus prevents conversion of dihydrofolate to tetrahydrofolate and blocks formation of thymidine, some purines, methionine, and glycine in bacteria, leading to rapid death of the microorganisms.

TMP and SMX are used effectively in combination to achieve synergistic effects, which they accomplish by blocking different steps in folic acid synthesis. Moreover, sulfamethoxazole potentiates the action of TMP by reducing the dihydrofolate competing with TMP for binding to dihydrofolate reductase. The combination of the two drugs is bactericidal.

Resistance to TMP and to the combination of TMP-SMX stems from permeability changes and from the presence of an altered dihydrofolate reductase. Production of this enzyme can be modified by a chromosomal mutation or by a plasmid. There is an increasing incidence of resistance to TMP-SMX by the plasmid mechanism. A mutation to thymine dependence has also been found, as has an overproduction of dihydrofolate reductase.

Fluoroquinolones

The fluoroquinolones include norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin. Fluoroquinolones all have a fluorine at position 6 in the 2 ring structure (Fig. 48-2). Gatifloxacin was recently withdrawn from the market in the United States.

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FIGURE 48–2 Basic 2-ring structure of fluoroquinolones. All fluoroquinolones have a fluorine at position 6 in the 2-ring structure. Other substitutions at positions 1 to 5 and 7 to 8 are associated with changes in antibacterial spectrum and pharmacokinetics.

The fluoroquinolones act by inhibiting type 2 bacterial DNA topoisomerases, DNA gyrase, and topoisomerase IV. These topoisomerases are enzymes that consist of α- and β-subunits (encoded for bygyrA and gyrB or parC and parE, respectively) and catalyze the direction and extent of supercoiling and other topological reactions of DNA chains. Fluoroquinolones act by binding to and trapping the enzyme-DNA complex. This trapped complex blocks DNA synthesis and cell growth and ultimately has a lethal effect on the cell, possibly by releasing lethal double-strand DNA breaks from the complex. The primary target for the quinolones is determined by the differing sensitivities of DNA gyrase and topoisomerase IV to the particular quinolone in each organism (Fig. 48-3).

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FIGURE 48–3 Mechanism of cytotoxicity by quinolones. Topoisomerases bind to DNA in a noncovalent fashion followed by formation of transient cleavage complexes. In these complexes, type 2 topoisomerase (DNA gyrase or topoisomerase IV) creates double-stranded breaks. In the presence of quinolones, levels of cleavage complexes (shown in brackets) increase dramatically. After traversal by replication complexes or helicases, transient topoisomerase-mediated breaks become permanent double-stranded fractures, triggering events that ultimately culminate in cell death.

Data from Froelich-Ammon SJ, Osheroff N. Increased drug affinity as the mechanistic basis for drug hypersensitivity of a mutant type II topoisomerase. J Biological Chem 1995; 270[47]:28018-28021.

Bacterial resistance is the most common and serious problem confronting the clinical use of fluoroquinolones. Mutations in the type 2 topoisomerases DNA gyrase or topoisomerase IV account for most bacterial resistance to fluoroquinolones. Stepwise increases in resistance are associated with sequential mutations in gyrA (or gyrB) and parC (or parE). Decreased permeability, active efflux, and plasmid-mediated resistance have also been described. Fluoroquinolone resistance of clinical significance occurs in Staphylococcus aureus, Pseudomonas aeruginosa, Campylobacter spp., E. coli and other Enterobacteriaceae, N. gonorrhea and, more recently, Streptococcus pneumoniae. Higher rates of fluoroquinolone resistance in a population are often associated with high rates of fluoroquinolone use, implicating selection of spontaneous mutants. However, community spread of single clones of fluoroquinolone-resistant S. pneumoniae has recently been observed.

Nitrofurans

Nitrofurantoin is a member of a group of synthetic nitrofuran compounds that also includes nitrofurazone. The precise mechanism of action of the nitrofurans is not established. They inhibit many bacterial enzyme systems, most probably through DNA damage. A nitroreductase bacterial enzyme converts the compounds to short-lived intermediates, including oxygen free radicals, which interact with DNA to cause strand breakage and bacterial damage.

Resistance develops infrequently. It is not plasmid-mediated, but appears to result from a mutation associated with a loss of bacterial nitroreductase activity.

Polymyxins

Polymyxins are detergents with both lipophilic and lipophobic groups that interact with phospholipids and disrupt bacterial cell membranes. The initial damage is to the cell wall, with a subsequent loss of periplasmic enzymes. The divalent cationic sites on the lipopolysaccharide component of the outer membrane of gram-negative organisms interact with the amino groups of the cyclic polymyxin peptide. The fatty acid tail portion of the drug molecule penetrates into the hydrophobic areas of the outer wall to produce holes in the membrane, through which intracellular constituents leak out of the bacteria (Fig. 48-4). A bacterium is rendered susceptible to the agent as a result of phospholipids in the bacteria cell wall interacting with the drug. The cell walls of resistant bacteria restrict the transport of polymyxin and prevent access of the drug to the cell membrane. Elevated concentrations of Ca++ or Mg++ reduce the activity of the polymyxins.

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FIGURE 48–4 Mechanism of action of polymyxins. Microbial cell in absence (A) and presence (B) of polymyxin.

Pharmacokinetics

Relevant pharmacokinetic parameters are summarized in Tables 48-1 and 48-2.

TABLE 48–1 Pharmacokinetic Properties for Sulfonamides and Trimethoprim

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TABLE 48–2 Pharmacokinetic Properties of Fluoroquinolones, Nitrofurantoins, and Polymyxins

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Sulfonamides

Sulfonamides are generally well absorbed from the gastrointestinal (GI) tract, with most absorption occurring in the small intestine. There is minimal absorption from topical application.

Sulfonamides differ in their protein-binding capacity, from a low of 45% for sulfadiazine to >90% for sulfisoxazole, sulfasalazine, and sulfadoxine, with less protein binding in renal failure. The drugs enter most body compartments, including ocular, pleural, peritoneal, synovial, and cerebrospinal fluid (CSF). Highest concentrations in the CSF are achieved with sulfadiazine, reaching 30% to 80% of plasma concentrations. Sulfonamides cross the placenta and enter the fetal circulation.

Acetylation in the liver is a major mechanism of inactivation of sulfonamides. These compounds are also metabolized by glucuronidation. All metabolites are excreted in the urine. Renal elimination is by filtration, with some tubular reabsorption but only slight tubular secretion. Some sulfonamides are poorly soluble and precipitate in acidic urine.

Rapid-acting sulfonamides, including sulfisoxazole, SMX, and sulfadiazine, are rapidly absorbed and eliminated. Sulfadoxine is well absorbed and has an extraordinarily long half-life. Sulfadoxine is combined with pyrimethamine in treatment of falciparum malaria (see Chapter 52).

Sulfasalazine is poorly absorbed from the GI tract and therefore can be used to treat GI infections. It is metabolized by intestinal bacteria to sulfapyridine, which is absorbed from the intestine and excreted in the urine, and in turn to a second metabolite, 5-aminosalicylate, which is the active agent.

Trimethoprim

TMP is well absorbed from the GI tract, with peak plasma concentrations reached in approximately 2 hours. Absorption is not influenced by SMX.

TMP is rapidly and widely distributed to body tissues and compartments, entering pleural, peritoneal, and synovial fluids, as well as the aqueous fluid of the eye, the CSF, and brain. Because of its high lipid solubility, TMP crosses biological membranes and enters bronchial secretions, prostate and vaginal fluids, and bile. Both TMP and SMX cross the placenta.

Only 10% to 20% of TMP is metabolized by oxidation and conjugation to inactive oxide and hydroxyl derivatives. It is excreted in the urine, with 60% of the dose excreted in 24 hours in patients with normal renal function. There is a linear relationship between the serum creatinine concentration and the half-life of TMP. The half-life of 11 hours in normal adults and children is shortened to approximately 6 hours in young children. Urinary concentrations of TMP are high, even in the presence of decreased renal function, and a small amount of TMP is excreted in the bile.

Fluoroquinolones

Fluoroquinolones are well absorbed from the upper GI tract, with absorption decreased in the presence of Ca++, Al++, Ca++, Zn++, or Fe++. The fluoroquinolones have good tissue penetration, with levels that exceed serum concentrations in prostate, stool, bile, lung, and neutrophils. Urine and kidney tissue concentrations are also usually high when renal elimination is high. Concentrations of fluoroquinolones in bone are usually lower than in serum but are still adequate for treatment of osteomyelitis. CSF penetration is not usually sufficient for treatment of meningitis.

The half-lives of norfloxacin and ciprofloxacin require twice-a-day dosing, but levofloxacin, moxifloxacin, and ofloxacin can be given once daily. The principal route of elimination for most of these agents is via the kidney, and dose adjustments are required for patients with compromised renal function. Moxifloxacin is excreted hepatically.

Nitrofurans

Nitrofurantoin is well absorbed from the GI tract, and absorption is not altered in the presence of food. No drug accumulation occurs except in urine and bile. The drug is excreted into bile, after which it is reabsorbed and eliminated through glomerular filtration and tubular secretion to yield brown urine. It has a short t1/2 in normal people as the result of rapid excretion and metabolism in tissues. Less drug enters the urine in patients with declining renal function, making this drug ineffective in the treatment of urinary tract infections in patients with creatinine clearances of less than 40 mL/min. The drug accumulates and can cause neurotoxicity in patients with severely depressed renal function.

Polymyxins

Polymyxins are not well absorbed after oral or topical administration. Polymyxin B has been given by oral, topical, endobronchial, intramuscular, and IV routes. Colistin, an analog with a structure similar to that of polymyxin E, is given by the IV and oral routes. The drug may be found in urine for up to 3 days after an IV dose. Polymyxins are distributed poorly to tissues and do not enter the CSF. They are excreted by glomerular filtration and accumulate to toxic concentrations in anuric patients.

Relationship of Mechanisms of Action to Clinical Response

Sulfonamides

Sulfonamides have activity against a broad range of gram-positive and negative bacteria as well as parasites (Plasmodia and Toxoplasma). However, there are few indications for the use of sulfonamides because of the many other agents available with fewer side effects or better therapeutic profiles.

Of the sulfonamides, sulfadiazine achieves the highest concentrations in CSF and brain and is used for treatment of central nervous system (CNS) toxoplasmosis (an opportunistic infection in acquired immunodeficiency syndrome [AIDS]) in combination with pyrimethamine. However, when it is used, fluid intake must be high or bicarbonate must be administered to alkalinize the urine and reduce the risk of renal crystalluria. The only long-acting sulfonamide used today is sulfadoxine, which is available in combination with pyrimethamine to treat malaria.

Of the poorly absorbed sulfonamides, sulfasalazine is used to treat ulcerative colitis and regional enteritis; it has no effect on intestinal flora.

Sulfacetamide, a topical agent, is used in ophthalmic preparations because it penetrates into ocular tissues and fluids. Allergic reactions are rare, although it should not be used in patients with a known sulfonamide allergy.

Both silver sulfadiazine and mafenide are active against many bacterial species, including Pseudomonas aeruginosa, and are used topically in burn patients to reduce the bacterial population in the burn eschar to concentrations low enough to prevent wound sepsis and hasten healing. The activity of silver sulfadiazine probably results from slow release of silver into the surrounding medium. Mafenide is absorbed and converted to p-carboxybenzene sulfonamide. Mafenide and its breakdown products are carbonic anhydrase inhibitors, which can cause metabolic acidosis.

Sulfonamides are drugs of choice for the treatment of nocardiosis, but clinicians usually prefer to use the TMP-SMX combination for this indication. Most sulfonamide use is in the form of TMP-SMX (see following text).

Trimethoprim

TMP inhibits many different bacteria, and in combination with SMX, several parasites. Because of increasing resistance and the availability of alternative agents, TMP is rarely used alone to treat infection.

TMP-SMX inhibits many Staphylococcus aureus (most methicillin-susceptible S. aureus and some methicillin-resistant S. aureus, especially community-acquired strains); coagulase-negative staphylococci, including Staphylococcus saprophyticus; hemolytic streptococci; some S. pneumoniae; H. influenzae; N. meningitidis; N. gonorrhoeae; Listeria monocytogenes; aerobic gram-negative bacteria such as E. coli and Klebsiella; and some more difficult species to inhibit such as Enterobacter, Citrobacter, Serratia and Stenotrophomonas. Salmonella, Shigella, Aeromonas, and Yersinia species may be susceptible, but enterococci and Campylobacter species are resistant.

TMP-SMX is active against many Enterobacteriaceae and has been the drug of choice in the United States for the treatment of uncomplicated urinary tract infections. The prevalence of resistance in E. coli now threatens the empiric use of TMP-SMX. Recent guidelines recommend that once the local prevalence of E. coli resistant to TMP-SMX exceeds 20%, quinolones replace TMP-SMX for empiric treatment of urinary tract infections. TMP-SMX is considered an alternative to quinolones for prostatitis resulting from Enterobacteriaceae.

Although TMP-SMX has been used in treatment of upper and lower respiratory tract infections because of its activity against H. influenzae, Moraxella species, and S. pneumoniae, emerging resistance among S. pneumoniae and also H. flu and Moraxella in the United States, Canada, and Europe has changed recommendations for use in these settings. TMP-SMX is now considered an alternative to high-dose amoxicillin in patients allergic to β-lactam antibiotics (adults and children) for treatment of mild acute bacterial sinusitis. TMP-SMX is also no longer recommended as empiric therapy for community-acquired pneumonia. Furthermore TMP-SMX is no longer recommended for treatment of traveler’s diarrhea or for most identified bacterial diarrhea because of the high prevalence of resistance in Shigellaand enterotoxigenic E. coli.

TMP-SMX provides effective prophylaxis against P. carinii pneumonia in patients with cell-mediated immune defects, such as those seen in patients with AIDS and in some solid organ transplant recipients. This combination has also proved useful in preventing spontaneous bacterial peritonitis in patients with underlying cirrhosis. An oral regimen of TMP in combination with dapsone is one of several alternatives to oral high-dose TMP-SMX in mild to moderate P. carinii pneumonia. TMP-SMX is also used for the treatment of Whipple’s disease caused by Trophermyma whippleii.

Fluoroquinolones

Fluoroquinolones are broadly active against aerobic gram-negative bacilli, including Pseudomonas aeruginosa. Third-generation quinolones have increased activity against gram-positive pathogens including S. pneumoniae. Fluoroquinolones are also active against many agents causing zoonotic infection and against mycobacteria.

Fluoroquinolones are effective for treatment of uncomplicated and complicated urinary tract infections caused by Enterobacteriaceae and have become drugs of choice in areas where the prevalence of TMP-SMX resistance is over 20% (Table 48-3). Because of activity against N. gonorrheaC. trachomatis, and Enterobacteriaceae, fluoroquinolones are drugs of choice for both acute and chronic prostatitis.

TABLE 48–3 Clinical Uses of Fluoroquinolones

Disease

Recommendations

Respiratory Tract Infections

Pharyngitis, otitis media

Not appropriate

Necrotizing otitis

Ciprofloxacin for Pseudomonas aeruginosa

Sinusitis

Third-generation fluoroquinolone

Community-acquired pneumonia

Third-generation fluoroquinolone

Hospital-acquired pneumonia

Ciprofloxacin, for susceptible gram-negative pathogens

Urinary Tract Infections

Cystitis, uncomplicated

All effective (second generation most appropriate)

Pyelonephritis

All effective (second generation most appropriate)

Prostatitis

All effective

Skin Structure Infections

Primary cellulitis

Not appropriate as first-line therapy

Anaerobic soft-tissue infections

Not appropriate

Osteomyelitis

Gram-negative bacterial infections

Ciprofloxacin

Bacterial Diarrheal Diseases

 

Ciprofloxacin used most commonly; all considered likely to be effective

Sexually Transmitted Diseases

Gonorrhea

Resistance testing required

Chlamydia

Ofloxacin, levofloxacin

Chancroid

All likely to be effective

Mycoplasma

Ofloxacin, levofloxacin

Syphilis

Not appropriate

Mycobacterial Diseases

Disseminated M. avium complex

Ciprofloxacin, ofloxacin as fourth agent if needed

M. tuberculosis

Ofloxacin, levofloxacin for drug resistance or intolerance to first-line agents

Data from Neu HC. The crisis in antibiotic resistance. Science 1992; 257:1054.

In treating sexually transmitted diseases, fluoroquinolones in a single dose are considered possible alternatives to ceftriaxone for gonorrhea in patients with β-lactam allergy, and in multi-day dosing as alternative agents to azithromycin (single dose) or doxycycline (multi-day dosing) for chlamydia treatment. Fluoroquinolones are used in combination with other agents in treatment of pelvic inflammatory disease. Fluoroquinolone-resistant N. gonorrhea limits the efficacy of these drugs in Asia, the Pacific (including Hawaii), and more recently, California. Resistance of N. gonorrhea to fluoroquinolones is expected to spread, and resistance testing should be pursued when gonorrhea is diagnosed.

Fluoroquinolones are efficacious for treating diarrhea caused by Shigella organisms, toxigenic E. coli, Campylobacter, Salmonella, and typhoid and are drugs of choice in the empiric treatment of traveler’s diarrhea.

Fluoroquinolones are useful in treatment of osteomyelitis, and in particular, ciprofloxacin is effective therapy for susceptible Pseudomonas osteomyelitis. The potential for rapid development of quinolone resistance in staphylococci during quinolone therapy limits the role of fluoroquinolones in the treatment of skin and soft tissue infections, especially if S. aureus is suspected. In combination with a gram-positive agent such as clindamycin, fluoroquinolones may be used for the treatment of complicated diabetic foot infections. In addition, a single dose of ciprofloxacin constitutes an alternative to rifampin for eradication of Neisseria meningitidis in asymptomatic carriers.

Because of their enhanced activity against gram-positive organisms, including pneumococci (both penicillin-susceptible and penicillin-resistant S. pneumoniae), levofloxacin and moxifloxacin are drugs of choice for treating community-acquired pneumonia. They, like other fluoroquinolones, are also active against atypical causes of pneumonia, such as Chlamydia species, Mycoplasma pneumoniae, andLegionella pneumophila. Ciprofloxacin is effective in treatment of susceptible Pseudomonas respiratory infections in cystic fibrosis.

Fluoroquinolones are drugs of choice for treatment of and post-exposure prophylaxis against several agents that could be used in biowarfare, including treatment of anthrax, cholera, plague, brucellosis, and tularemia.

Fluoroquinolones are also useful in the treatment of mycobacterial infections. Multidrug treatment of Mycobacterium avium complex infections may include a fluoroquinolone as a third or fourth agent. Ofloxacin and levofloxacin are commonly used in the treatment of multidrug-resistant tuberculosis and for tuberculosis patients intolerant to first-line therapies. Moxifloxacin pharmacokinetics and potency predict that it may be useful as an additional first-line therapy for tuberculosis.

Nitrofurans

Nitrofurans are used to treat urinary tract infections, whereas nitrofurazone is used only for topical applications. Both inhibit a variety of gram-positive and gram-negative bacteria, including most E. coli, staphylococci, many Klebsiella species, enterococci, Neisseriae, SalmonellaeShigella organisms, and Proteus bacteria.

Polymyxins

The polymyxins are used topically as a single agent to treat Pseudomonas infections of the mucous membranes, eye, and ear and also in combination with other antimicrobials (commonly neomycin and bacitracin) for minor skin, ear, and eye infections. Gram-positive and anaerobic organisms generally are resistant to polymyxins. However, E. coli, Klebsiella, Enterobacter, Shigella, Pseudomonas, andAcinetobacter are susceptible. In recent years systemic IV Polymyxin B has been used to treat serious infections caused by multidrug-resistant gram-negative bacilli with over 85% efficacy and a 14% rate of nephrotoxicity (lower than reported in the older literature).

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The major clinical problems for these drugs are summarized in the Clinical Problems Box.

Sulfonamides

Sulfonamides cause many adverse effects, the most important of which are hypersensitivity reactions. Allergic rashes are frequent, occurring in approximately 2% to 3% of patients receiving these drugs. Rashes may be maculopapular, urticarial, or, rarely, exfoliative, as in the Stevens-Johnson syndrome. Most rashes occur after 1 week of therapy but can occur earlier in previously sensitized individuals. A serum sickness-like illness also is seen, with fever, joint pains, and rash, which can be of the erythema nodosum type. Drug fever occurs in approximately 3% of patients given sulfonamides. Arteritis of a periarteritis, or a systemic lupus erythematosus type, has also been reported.

Several hematological toxicities are seen with sulfonamides. These include agranulocytosis, megaloblastic anemia, aplastic anemia, hemolytic anemia, and thrombocytopenia. Hemolytic anemia can occur in patients deficient in glucose-6-phosphate dehydrogenase, in which the sulfonamide serves as an oxidant. Hemolysis can also occur in patients who have normal glucose-6-phosphate dehydrogenase concentrations.

Hepatotoxicity occurs in less than 0.1% of patients receiving sulfonamides, and renal damage is rare in patients receiving the newer sulfonamides; however, sulfadiazine can precipitate in the kidneys, ureters, and bladder and lead to renal failure.

Drug interactions include potentiation of the action of sulfonylurea hypoglycemic agents, orally administered anticoagulants, phenytoin, and methotrexate. Mechanisms include displacement of albumin-bound drug and competition for drug-metabolizing enzymes.

Trimethoprim

TMP alone can cause nausea, vomiting, and diarrhea but rarely causes a rash. TMP can increase creatinine concentrations, because both compounds compete for the same renal clearance pathways. Hyperkalemia has been associated with the use of high-dose TMP-SMX and is now known to result from a TMP-induced decrease in K+ secretion in the distal tubule.

Side effects encountered with TMP-SMX include all those associated with both agents. Hematological toxicity in the form of megaloblastic anemia, thrombocytopenia, and leukopenia occurs more often in patients receiving the combination than in those receiving single agents and can be dose-related. Other toxicity-related conditions include glossitis, stomatitis, and occasional pseudomembranous enterocolitis. CNS effects include headache, depression, and hallucinations.

The incidence of rash and neutropenia is greater in patients with AIDS than in other patients treated with TMP-SMX. The importance of TMP-SMX in the prevention of P. carinii pneumonia has prompted an investigation of ways to manage allergic reactions to TMP-SMX in AIDS patients. Both symptomatic treatment (antihistamines or steroids) of the effect and oral desensitization have been effective.

Fluoroquinolones

Fluoroquinolones can cause GI reactions such as nausea, vomiting, and abdominal pain. Outbreaks of pseudomembranous colitis have been reported in hospitals following the introduction of a third-generation fluoroquinolone on the formulary. CNS effects including dizziness, headache, restlessness, depression, and insomnia are infrequent but tend to occur more commonly in the elderly and may be potentiated by the concomitant use of nonsteroidal antiinflammatory drugs; seizures are a rare problem. Dermatologic reactions including rash, photosensitivity reactions, and pruritus are common. In addition, hepatotoxicity occasionally occurs in association with these agents. High rates of these adverse events observed in postmarketing surveillance have caused several other fluoroquinolones to be removed from the market.

Quinolones produce damage to cartilage in immature animals and are not recommended for use in children, and quinolone therapy has been associated with multiple reports of tendon rupture (usually the Achilles tendon). Theophylline concentrations become elevated in patients treated with ciprofloxacin.

Nitrofurans

The most common adverse reactions to the nitrofurans are GI in nature, with anorexia, nausea, and vomiting most prevalent. Hypersensitivity reactions involving the skin, lungs, liver, or blood also occur and are often associated with fever and chills. Cutaneous effects include maculopapular, erythematous, urticarial, and pruritic reactions.

Two major types of pulmonary reactions occur in patients receiving nitrofuran. An acute immunologically mediated reaction, characterized by fever, cough, and dyspnea, begins approximately 10 days into treatment. A second form occurs in patients receiving long-term therapy. The onset is insidious, with patients exhibiting cough, shortness of breath, and radiological signs of interstitial fibrosis. Patients’ conditions improve when the drug is stopped, but many have residual effects, which are believed to be caused by peroxidative destruction of pulmonary membrane lipids arising from the reactive oxygen derivatives produced by the action of reductase on the nitrofurans. The nitrofurans also cause cholestatic and hepatocellular liver disease and granulomatous hepatitis.

Hematological reactions related to the nitrofurans include granulocytopenia, leukopenia, and megaloblastic anemia, with acute hemolytic anemia occurring in patients deficient in glucose-6-phosphate dehydrogenase. Several neurological reactions including headache, drowsiness, dizziness, nystagmus, and peripheral neuropathy of an ascending sensorimotor type are also observed.

Polymyxins

The polymyxins have few adverse effects when used topically. IV administration of polymyxins can cause nephrotoxicity and neurotoxicity, but recent experience suggests that the incidence of these side effects is not high enough to prohibit use when clinically indicated (serious infection with a polymyxin-susceptible organism and no alternative therapy). The mechanism of

CLINICAL PROBLEMS

Trimethoprim-sulfamethoxazole

Numerous side effects

Hypersensitivity: rashes, fever

Stevens-Johnson syndrome (with long-acting agents)

Hematological reactions

Increased serum creatinine concentration (Trimethoprim)

Drug interactions

Protein binding displacement

Competition for metabolizing enzymes

Fluoroquinolones

Gastrointestinal effects

CNS agitation (rarely seizures)

Damage to growing cartilage (not recommended for use in children)

Theophylline interaction (with ciprofloxacin)

Nitrofurans

Gastrointestinal effects

Hypersensitivity

Cutaneous reactions

Pulmonary reactions

Polymyxins

Nephrotoxicity and neurotoxicity

polymyxin-induced nephrotoxicity is not established but appears to result from polymyxin binding to renal tubule cell membranes. This produces proteinuria, casts, and a loss of brush border enzymes and can progress to renal failure. Renal function usually returns when the drug is discontinued.

The polymyxins may damage some mammalian cell membranes and can cause neuromuscular blockade and respiratory paralysis. They can also produce persistent blockade of the action of acetylcholine at the neuromuscular junction, which is not reversed by neostigmine.

New Horizons

Sulfonamides and trimethoprim have been mainstays of antibiotic therapy for years; however, emerging widespread resistance has resulted in loss of effectiveness of these antibiotics. The fluoroquinolones have proven very useful in treatment of a variety of other diseases, but bacterial resistance has become an increasing problem for these drugs as well. The search for new antibiotics to replace the older compounds to which bacteria have

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Fluoroquinolones

Ciprofloxacin (Cipro)

Enoxacin (Penetrex)

Gemifloxicin (Factive)

Levofloxacin (Levaquin)

Lomefloxacin (Maxaquin)

Norfloxacin (Noroxin)

Ofloxacin (Floxin)

Sulfonamides and Trimethoprim

Mafenide (Sulfamylon)

Sulfacetamide (Sulamyd)

Sulfadiazine

Silver sulfadiazine (Silvadene)

Sulfadoxine (Fansidar)

Sulfamethizole (Thiosulfil Forte)

Sulfamethoxazole (Gantanol)

Sulfanilamide (AVC)

Sulfisoxazole (Gantrisin)

Trimethoprim (Proloprim, Trimpex)

Trimethoprim-sulfamethoxazole (Co-trimoxazole, TMP-SMZ, Bactrim, Septra)

Pyrimethamine-sulfadoxine (Fansidar)

Nitrofurans

Nitrofurantoin (Macrobid, Macrodantin)

Nitrofurazone (Furacin)

Polymyxins

Polymyxin B (Polymyxin B sulfate)

Polymyxin E (Colistin)

become increasingly resistant has become a matter of grave concern. Fortunately, with the newfound ability to rapidly sequence and compare genomes of specific bacteria, new targets for antibiotics are rapidly emerging. Hopefully, development of such new compounds will be successful before a crisis occurs in which strains of bacteria emerge that are resistant to all known antibiotics.

FURTHER READING

Anonymous. Choice of antibacterial drugs. Treat Guidel Med Lett. 2007;5:33-50.

Masters et al. 2003 Masters PA, O’Bryan TA, Zurlo J, et al. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med. 2003;163:402-410.

Scheld WM. Maintaining fluoroquinolone class efficacy: Review of influencing factors. Emerg Infect Dis. 2003;9:1-9.

SELF-ASSESSMENT QUESTIONS

1. A 27-year-old white woman develops an exfoliative rash along with painful joints, anemia, and nephritis while being treated for a first episode of a urinary tract infection. Which of the following drugs is responsible for these effects?

A. Ciprofloxacin

B. Nitrofurantoin

C. Norfloxacin

D. Polymyxin B

E. Trimethoprim-Sulfamethoxazole

2. A 20-year-old woman presents to the University Student Health Care center with a 2-day history of painful urination, dysuria, frequency, and urgency. She had been in good health before the abrupt onset of these symptoms. Physical examination reveals moderate suprapubic tenderness and a normal vaginal exam. Which of the following is the best empiric therapy while awaiting culture results?

A. Azithromycin

B. Cefepime

C. Levofloxacin

D. Trimethoprim/sulfamethoxazole

E. Vancomycin

3. Which if the following agents exerts a bacteriostatic action by inhibiting folate synthesis by microorganisms?

A. Ciprofloxacin

B. Nitrofurantoin

C. Polymyxin B

D. Sulfamethoxazole

D. Azithromycin

4. A chromosomal mutation in dihydrofolate reductase may lead to resistance to which antibacterial agent?

A. Ciprofloxacin

B. Trimethoprim

C. Sulfamethoxazole

D. Nitrofurantoin

D. Polymyxin B