Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e

Chapter 56: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents

for Urinary Tract Infections

Conan MacDougall

ABBREVIATIONS
Abbreviations

AIDS: acquired immunodeficiency syndrome

CSF: cerebrospinal fluid

FDA: Food and Drug Administration

GABA: γ-aminobutyric acid

GI: gastrointestinal

G6PD: glucose-6-phosphate dehydrogenase

HIV: human immunodeficiency virus

IV: intravenous

MIC: minimal inhibitory concentration

MRSA: methicillin-resistant Staphylococcus aureus

NADP: nicotinamide adenine dinucleotide phosphate

NADPH: reduced NADP

NSAID: nonsteroidal anti-inflammatory drug

PABA: para-aminobenzoic acid

PO: by mouth

TMP: trimethoprim

UTI: urinary tract infection

SULFONAMIDES
History

The sulfonamide drugs were the first e!ective chemotherapeutic agents used systemically for the prevention and cure of bacterial infections in humans. Investigations in
1932 at the I. G. Farbenindustrie in Germany resulted in the patenting of prontosil and several other azo dyes containing a sulfonamide group. Because 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). The advent of penicillin and other antibiotics diminished the usefulness of the sulfonamides, but
the introduction of the combination of trimethoprim and sulfamethoxazole in the 1970s increased the use of sulfonamides for the prophylaxis and treatment of specific
microbial infections.

Sulfonamides are derivatives of para-aminobenzenesulfonamide (sulfanilamide; Figure 56–1) and are congeners of PABA. 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 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 e!ects on antibacterial activity of the molecule; substitution of heterocyclic
aromatic nuclei at N1 yields highly potent compounds.

Figure 56–1
Sulfanilamide and PABA. 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 Chapters 60 and 70) also bears a resemblance to PABA and sulfanilamide.

Mechanism of Action

Sulfonamides are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of PABA into dihydropteroic acid, the
immediate precursor of folic acid (Figure 56–2). Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can use preformed folate are not
a!ected. Sulfonamides administered as single agents are bacteriostatic; cellular and humoral defense mechanisms of the host are essential for final eradication of the
infection. 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 (Grayson, 2010).

Figure 56–2
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 e!ective than either agent alone.

Synergists of Sulfonamides

Trimethoprim exerts a synergistic e!ect 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 one-carbon transfer reactions. Coadministration of a sulfonamide and trimethoprim (as in trimethoprim-
sulfamethoxazole) introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate (see Figure 56–2); the combination is much more e!ective than either
agent alone (Bushby and Hitchings, 1968). Similar complementary activity is seen with pyrimethamine, which is generally used in combination with agents such as
sulfadoxine, sulfadiazine, or dapsone. The predominant systemic use of sulfonamides is now in such combinations.

Antibacterial Spectrum

On their original introduction to therapeutic use, sulfonamides had a wide range of antimicrobial activity against both gram-positive and gram-negative bacteria; a high
percentage of isolates of Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae were susceptible to systemically
achievable concentrations of sulfonamides. However, the increase in sulfonamide resistance in these agents is such that sulfonamide activity against these pathogens in
serious infections cannot be assumed, and they play little part in empiric therapy (Grayson, 2010). Potent activity remains against most isolates of Haemophilus ducreyi,
Nocardia, and Klebsiella granulomatis. Isolates of Neisseria meningitidis and Shigella are generally resistant, as are many strains of Escherichia coli isolated from patients
with UTIs (Olson et al., 2009). Sulfonamides also possess important activity against a number of parasites (see Chapters 53 and 54).

Bacterial Resistance
Bacterial resistance to sulfonamides can originate by random mutation and selection or by transfer of resistance by plasmids (see Chapter 52); it usually does not involve
cross-resistance to other classes of antibiotics. Resistance to sulfonamide can result from (1) a lower a!inity of dihydropteroate synthase for sulfonamides, (2) decreased
bacterial permeability or active e!lux of the drug, (3) an alternative metabolic pathway for synthesis of an essential metabolite, or (4) increased production of an essential
metabolite or drug antagonist (e.g., PABA) (Gold and Moellering, 1996). Plasmid-mediated resistance is due to plasmid-encoded, drug-resistant dihydropteroate
synthetase.

ADME

Except for sulfonamides especially designed for their local e!ects in the bowel (see Chapter 51), 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. Peak plasma drug concentrations achievable in vivo are about 100–200 μg/mL. 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 su!icient 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. Sulfonamides are distributed throughout all tissues of the body. 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 body fluids usually is low, the drug is present in the unbound active form. A"er systemic administration
of adequate doses, sulfadiazine and sulfisoxazole attain concentrations in CSF that may be e!ective 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 e!ects.

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

Sulfonamides for Systemic Use

Sulfisoxazole

Sulfisoxazole is a rapidly absorbed and excreted sulfonamide. 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 about 30% in the urine is in the acetylated form. The kidney excretes about 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 tasteless and hence
preferred for oral use in children. Sulfisoxazole acetyl in combination with erythromycin ethylsuccinate is used in children with otitis media.

The untoward e!ects produced by this agent are similar to those that follow the administration of other sulfonamides, as discussed further in the chapter. 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 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 (t1/2 of 11 h). It is administered orally and
employed for both systemic and UTIs. 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, with a t1/2 of 10 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. 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.

Sulfadoxine

This agent has a particularly long plasma t1/2 of 7–9 days. Although no longer marketed in the U.S., its combination with pyrimethamine (500 mg sulfadoxine plus 25 mg
pyrimethamine) is listed as WHO essential medicine and is used for the prophylaxis and treatment of malaria caused by mefloquine-resistant strains of Plasmodium
falciparum (see Chapter 53). 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.

Sulfonamides for Topical Use

Sulfacetamide

Sulfacetamide is the N1-acetyl-substituted derivative of sulfanilamide. Its aqueous solubility is about 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 e!ective 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 69 and 70 for ocular and dermatological uses.

Silver Sulfadiazine

Silver sulfadiazine 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

The sulfonamide mafenide 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 e!ects include intense pain at sites of application and allergic reactions. Application of the drug over a large burn
surface can lead to appreciable systemic absorption. The drug and its primary metabolite inhibit carbonic anhydrase, and the urine becomes alkaline. Metabolic acidosis
with compensatory tachypnea and hyperventilation may ensue; these e!ects limit the usefulness of mafenide.

Therapeutic Uses

Urinary Tract Infections

Because a significant percentage of UTIs are caused by sulfonamide-resistant microorganisms, sulfonamides are no longer a therapy of first choice; trimethoprim-
sulfamethoxazole is preferred (although resistance to this agent is increasing as well). Sulfisoxazole may be used e!ectively for cystitis in areas where the prevalence of
resistance is not high. The usual dosage is 2–4 g initially, followed by 1–2 g orally four times a day for 5–10 days.

Nocardiosis

Trimethoprim-sulfamethoxazole is most commonly used for infections due to Nocardia spp., but sulfisoxazole or sulfadiazine are alternative agents, given in dosages of 6–8
g daily. For serious infections, addition of a second agent, such as imipenem, amikacin, or linezolid, is recommended.

Toxoplasmosis

The combination of pyrimethamine and sulfadiazine is the treatment of choice for toxoplasmosis (see Chapter 54). Pyrimethamine is given as a loading dose of 2000 mg
followed by 50–75 mg orally per day, with sulfadiazine 1–1.5 g orally every 6 h, plus folinic acid (leucovorin) 10–25 mg orally each day for at least 6 weeks (Panel on
Opportunistic Infections, 2016). Patients should receive at least 2 L of fluid intake daily to prevent crystalluria.

Adverse Reactions

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 o"en a"er 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 e!ects is about 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 a"er several days of sulfonamide therapy.
Drug fever is a common untoward manifestation of sulfonamide treatment; the incidence approximates 3% with sulfisoxazole.

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 HIV who were receiving
sulfadiazine for Toxoplasma encephalitis. Crystalluria can be prevented by maintaining daily urine volume of at least 1200 mL (in adults) or alternatively urine alkalinization
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 G6PD activity. Agranulocytosis occurs in about 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 a"er 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 e!ect 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).

Miscellaneous Reactions

Anorexia, nausea, and vomiting occur in 1%–2% of persons receiving sulfonamides. Focal or di!use necrosis of the liver owing to direct drug toxicity or sensitization occurs
in less than 0.1% of patients. Headache, nausea, vomiting, fever, hepatomegaly, jaundice, and laboratory evidence of hepatocellular dysfunction usually appear 3–5 days
a"er sulfonamide administration is started, and the syndrome may progress to acute yellow atrophy and death. 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 mainly with the oral anticoagulants, the sulfonylurea hypoglycemic agents, and the hydantoin anticonvulsants. In each
case, sulfonamides can potentiate the e!ects 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-SULFAMETHOXAZOLE
Trimethoprim inhibits bacterial dihydrofolate reductase, an enzyme downstream from the one that sulfonamides inhibit in the same biosynthetic sequence (see Figure 56–
2). The combination of trimethoprim with sulfamethoxazole was an important advance in the development of clinically e!ective 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,
trimethoprim is available as a single-entity preparation.

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 56–2). Tetrahydrofolate is essential for one-carbon transfer reactions (e.g., the synthesis of thymidylate from deoxyuridylate). Selective
toxicity for microorganisms is achieved in two 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: About 100,000 times more drug is required to inhibit human reductase than the
bacterial enzyme. The optimal ratio of the concentrations of the two agents equals the ratio of the MICs of the drugs acting independently. Although this ratio varies for
di!erent bacteria, the most e!ective 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 two drugs will thus be relatively constant in the body over a long period. Although each agent alone usually exerts bacteriostatic activity, when the
organism is sensitive to both agents, bactericidal activity may be achieved.

Antibacterial Spectrum

The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole, although trimethoprim is 20–100 times more potent. Pseudomonas aeruginosa,
Bacteroides fragilis, and enterococci are clinically resistant. There is significant variation in the susceptibility of Enterobacteriaceae to trimethoprim in di!erent geographic
locations because of the spread of resistance mediated by plasmids and transposons (see Chapter 52).

Spectrum of Trimethoprim-Sulfamethoxazole in Combination

Although most S. pneumoniae are susceptible, there has been a disturbing increase in resistance (paralleling the rise in penicillin resistance), and its value for empiric
therapy/use in respiratory tract infections is questionable. Most strains of S. aureus and Staphylococcus epidermidis remain susceptible, even among methicillin-resistant
isolates, although geographic variation exists. Streptococcus pyogenes is usually sensitive when proper testing procedures (media with low thymidine content) are
followed (Bowen et al., 2012). The viridans group of streptococci is typically susceptible, although susceptibility among penicillin-resistant strains is low (Diekema et al.,
2001). Susceptibility in E. coli varies by geographic region, although it has been declining in general. Proteus mirabilis, Klebsiella spp., Enterobacter spp., Salmonella,
Shigella, Pseudomonas pseudomallei, Serratia, and Alcaligenes spp. are typically susceptible. Also sensitive are Brucella abortus, Pasteurella haemolytica, Yersinia
pseudotuberculosis, Yersinia enterocolitica, and Nocardia asteroides.

Bacterial Resistance

Bacterial resistance to trimethoprim-sulfamethoxazole is a rapidly increasing problem, although resistance is lower than it is to either of the agents alone. Resistance o"en
is due to the acquisition of a plasmid that codes for an altered dihydrofolate reductase.

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. A"er 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 a"er 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 (one “double-strength” tablet; “single strength” ratio is 400 mg to 80 mg, maintaining the same ratio)
twice daily, the peak concentrations of the drugs in plasma are about 40 and 2 μg/mL, the optimal ratio. Peak concentrations are similar (46 and 3.4 μg/mL) a"er
intravenous infusion of 800 mg sulfamethoxazole and 160 mg trimethoprim over a period of 1 h.

Trimethoprim is distributed and concentrated rapidly in tissues; about 40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of
trimethoprim is almost nine 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% to 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.

Therapeutic Uses

Urinary Tract Infections

Treatment of an uncomplicated lower UTI with trimethoprim-sulfamethoxazole is highly e!ective for sensitive bacteria, although some authorities avoid empiric use for
UTIs when local resistance among E. coli exceeds 20% (Gupta et al., 2010). Single-dose therapy (320 mg trimethoprim plus 1600 mg sulfamethoxazole in adults) has been
e!ective in some cases for the treatment of acute uncomplicated UTI, but longer courses of therapy are less likely to be associated with recurrence. Most treatment
guidelines recommend 160/800 mg administered twice daily for 3 days for uncomplicated cystitis and for 10–14 days for complicated disease or pyelonephritis.
Trimethoprim also is found in therapeutic concentrations in prostatic secretions, and trimethoprim-sulfamethoxazole is o"en e!ective for the treatment of bacterial
prostatitis.

Bacterial Respiratory Tract Infections

Trimethoprim-sulfamethoxazole is e!ective for mild acute exacerbations of chronic bronchitis. Administration of 800–1200 mg sulfamethoxazole plus 160–240 mg
trimethoprim twice a day appears to be e!ective 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 e!ective for acute otitis media in children and acute maxillary
sinusitis in adults that are caused by susceptible strains of H. influenzae and S. pneumoniae.

GI Infections

The combination is an alternative to a fluoroquinolone for treatment of shigellosis caused by susceptible strains, which are becoming less common worldwide.
Trimethoprim and trimethoprim/sulfamethoxazole are no longer recommended for prevention or treatment of traveler’s diarrhea because of increasing resistance
worldwide among likely pathogens (Hill et al., 2006).

Infection by Pneumocystis jiroveci

High-dose therapy (trimethoprim 15–20 mg/kg/d plus sulfamethoxazole 75–100 mg/kg/d in three or four divided doses; typical maximum dose is 20 mg/kg/d of
trimethoprim) is e!ective for Pneumocystis jiroveci pneumonia (Panel on Opportunistic Infections, 2016). Adjunctive corticosteroids should be given at the onset of anti-
Pneumocystis therapy in patients with a PO2 less than 70 mm Hg or an alveolar-arterial gradient less than 35 mm Hg. Prophylaxis with 800 mg sulfamethoxazole and 160
mg trimethoprim once daily or three times a week is e!ective in preventing pneumonia caused by this organism in patients with HIV as well as other
immunocompromising conditions (such as neutropenia and solid-organ transplantation). Adverse reactions are less frequent with the lower prophylactic doses of
trimethoprim-sulfamethoxazole.

Methicillin-Resistant Staphylococcus aureus Infections

The increasing incidence of community-acquired infections due to MRSA has provided a role for trimethoprim-sulfamethoxazole as an adjunctive therapy to incision and
drainage of complicated abscesses. However, it is less e!ective than standard therapy in the treatment of invasive MRSA infections, including bacteremia (Paul et al., 2015).

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 the treatment of choice for brucellosis, trimethoprim-sulfamethoxazole may be an e!ective substitute for the doxycycline combination.
Trimethoprim-sulfamethoxazole also has been used successfully for infection by Stenotrophomonas maltophilia and infection by the intestinal parasites Cyclospora and
Isospora. Wegener granulomatosis may respond, depending on the stage of the disease.

Adverse E!ects

Trimethoprim-sulfamethoxazole may extend the toxicity of the sulfonamides. 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. Hematological
reactions include various anemias, coagulation disorders, granulocytopenia, agranulocytosis, purpura, Henoch-Schönlein purpura, and sulfhemoglobinemia.
Trimethoprim-sulfamethoxazole reportedly causes up to three times as many dermatological reactions as does sulfisoxazole alone (5.9% vs. 1.7%). Mild and transient
jaundice has been noted and appears to have the histological features of allergic cholestatic hepatitis. Permanent impairment of renal function may follow the use of
trimethoprim-sulfamethoxazole in patients with renal disease due to sulfamethoxazole crystalluria; liberal fluid intake should be encouraged to dilute the urine during
therapy. An increase in serum creatinine without decrement in glomerular filtration rate may be observed with high-dose therapy due to trimethoprim’s inhibition of
creatinine secretion. Hyperkalemia can also be observed, as trimethoprim has a similar structure to potassium-sparing diuretics such as triamterene. Patients with HIV
frequently have hypersensitivity reactions to trimethoprim-sulfamethoxazole (rash, neutropenia, Stevens-Johnson syndrome, Sweet syndrome, and pulmonary infiltrates).
Rapid and slow desensitization protocols have been established for patients intolerant to medically necessary therapy (Gluckstein and Ruskin, 1995).

THE QUINOLONES
The first quinolone, nalidixic acid, was isolated as a by-product of the synthesis of chloroquine and made available for the treatment of UTIs. The introduction of
fluorinated 4-quinolones (fluoroquinolones), such as norfloxacin, ciprofloxacin, and levofloxacin (Table 56–1), represents a particularly important therapeutic advance:
These agents have broad antimicrobial activity and are e!ective a"er oral administration for the treatment of a wide variety of infectious diseases (Mitscher and Ma, 2003).
However, due to potentially fatal side e!ects, many quinolones had to be withdrawn from the U.S. market: lomefloxacin and sparfloxacin (phototoxicity, QTc prolongation);
gatifloxacin (systemic forms only; hypoglycemia); temafloxacin (immune hemolytic anemia); trovafloxacin (hepatotoxicity); grepafloxacin (cardiotoxicity); and clinafloxacin
(phototoxicity). In all cases, the side e!ects were discovered during postmarketing surveillance (Sheehan and Chew, 2003).

Table 56–1
Structural Formulas of Selected Quinolones and Fluoroquinolones

Mechanism of Action

The quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria, topoisomerase IV is the primary target (Alovero et al., 2000).
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 56–3) (Cozzarelli, 1980). 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 a target for quinolones.

Figure 56–3
Model of the formation of negative DNA supercoils by DNA gyrase. DNA gyrase binds to two 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. (Reprinted with
permission from AAAS. Cozzarelli NR. DNA gyrase and the supercoiling of DNA. Science, 1980
1980, 207:953–960.)
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 Proteus, E. coli, Klebsiella, and various species of Salmonella, Shigella, Enterobacter, and Campylobacter.
While once a standard therapy for N. gonorrhoeae infections, resistance has increased to the point these agents are no longer recommended in many countries for empiric
therapy of gonorrhea (Centers for Disease Control and Prevention, 2015). Some fluoroquinolones are active against Pseudomonas spp., with ciprofloxacin and levofloxacin
having substantial enough activity for use in systemic infections. Fluoroquinolones have good in vitro activity against staphylococci, but they are less active against
methicillin-resistant strains, and there is concern over development of resistance during therapy. Activity against streptococci is significantly greater with the newer agents,
including levofloxacin, gemifloxacin, and moxifloxacin. 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, ofloxacin, and
moxifloxacin have MIC90 values from 0.5 to 3 μg/mL for Mycobacterium fortuitum, Mycobacterium kansasii, and M. tuberculosis. Moxifloxacin also has useful activity
against anaerobes.

Bacterial Resistance

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). Less commonly, plasmid-mediated resistance develops through proteins that bind to and protect the topoisomerases
from quinolone e!ects. Resistance has increased a"er the introduction of fluoroquinolones, especially in Pseudomonas and staphylococci. Escherichia coli, Campylobacter
jejuni, Salmonella, N. gonorrhoeae, and S. pneumoniae are also increasingly fluoroquinolone resistant (Olson et al., 2009).

ADME

Most quinolones are well absorbed a"er oral administration. Peak serum levels of the fluoroquinolones are obtained within 1–3 h of an oral dose. The volume of
distribution of quinolones is high, with concentrations in urine, kidney, lung, and prostate tissue and stool, bile, and macrophages and neutrophils higher than serum
levels. Food may delay the time to peak serum concentrations. Ciprofloxacin, ofloxacin, and levofloxacin have been detected in human breast milk; because of their
excellent bioavailability, the potential exists for substantial exposure of nursing infants. Except for moxifloxacin, quinolones are cleared predominantly by the kidney, and
dosages must be adjusted for renal failure. Moxifloxacin should not be used in patients with hepatic failure.

Pharmacological Properties of Individual Quinolones

Norfloxacin

Norfloxacin’s gram-negative activity is similar to, but somewhat less potent than, that of ciprofloxacin. However, relatively low serum levels are reached with norfloxacin
and limit its usefulness in the treatment of UTIs and gastrointestinal infections. The serum t1/2 is 3–5 h for norfloxacin; approximately 25% of the drug is eliminated
unchanged in the urine, with hepatic metabolism also occurring.

Ciprofloxacin

Ciprofloxacin’s bioavailability is approximately 70%. Typical oral doses are 250–750 mg and intravenous doses are 200–400 mg twice daily (maximum dose 1.5 g/d). The
elimination t1/2 is about 5 h, and the drug is typically dosed twice daily, with the exception of an extended-release formulation, which can be dosed once daily.

Ofloxacin/Levofloxacin

Ofloxacin has somewhat more potent gram-positive activity; separation of the more active S- or levorotatory isomer yields levofloxacin, which has even better
antistreptococcal activity. Bioavailability of both of these agents is excellent, such that intravenous and oral doses are the same; levofloxacin is dosed once daily (250–750
mg) as opposed to twice-daily dosing for ofloxacin (200–400 mg daily divided every 12 h).

Moxifloxacin

Moxifloxacin improves further on the gram-positive potency of levofloxacin, typically having MICs one to two dilutions lower against S. pneumoniae. It also has expanded
activity against anaerobic pathogens but is substantially less active than ciprofloxacin or levofloxacin against P. aeruginosa. Moxifloxacin is well absorbed, with equivalent
intravenous and oral doses; the t1/2 is about 12 h, allowing for daily dosing (usual dose 400 mg daily). Moxifloxacin undergoes hepatic sulfation and glucuronidation. Less
than a quarter of systemic moxifloxacin is excreted unchanged via the kidneys, and because high concentrations are not achieved in the urine, it is not recommended for
UTIs.

Gatifloxacin and Gemifloxacin

The agents gatifloxacin and gemifloxacin have a similar spectrum of activity to moxifloxacin, with enhanced potency against gram-positive organisms and poor activity
versus Pseudomonas. They are less active than moxifloxacin against B. fragilis. Both have high bioavailability and renal elimination. Gatifloxacin is no longer available for
systemic use in the U.S. due to toxicity concerns, but an ophthalmic preparation is licensed for the treatment of bacterial conjunctivitis.

Therapeutic Uses

Urinary Tract Infections

Nalidixic acid is useful only for UTIs caused by susceptible microorganisms. The fluoroquinolones are significantly more potent and are a mainstay of treatment of upper
and lower UTIs (Fihn, 2003). They are more e!icacious than trimethoprim-sulfamethoxazole or oral β-lactams for the treatment of UTIs. Because of their broad spectrum of
activity, however, recent guidelines suggest reserving their use for complicated cystitis or pyelonephritis when possible. Moxifloxacin does not accumulate in the urine and
is not approved for treatment of UTIs. Typical treatment durations for the other quinolones are 3 days for uncomplicated cystitis and 5–7 days for uncomplicated
pyelonephritis.

Prostatitis

Norfloxacin, ciprofloxacin, ofloxacin, and levofloxacin are e!ective in the treatment of prostatitis caused by sensitive bacteria. Fluoroquinolones administered for 4–6
weeks appear to be e!ective in patients not responding to trimethoprim-sulfamethoxazole.

Sexually Transmitted Diseases

Fluoroquinolones lack activity for Treponema pallidum but have activity in vitro against Chlamydia trachomatis and Haemophilus ducreyi. For chlamydial
urethritis/cervicitis, a 7-day course of ofloxacin or levofloxacin is an alternative to a 7-day treatment with doxycycline or a single dose of azithromycin; other available
quinolones have not been reliably e!ective. Previously, a single oral dose of a fluoroquinolone such as ciprofloxacin had been e!ective treatment of sensitive strains of N.
gonorrhoeae, but increasing resistance to fluoroquinolones has led to ce"riaxone 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

Norfloxacin, ciprofloxacin, ofloxacin, and levofloxacin given for 1–3 days all have been e!ective in the treatment of patients with traveler’s diarrhea, reducing the duration
of loose stools by 1–3 days. Ciprofloxacin in a single daily dose is also e!ective for prophylaxis of traveler’s diarrhea. Ciprofloxacin and ofloxacin can cure most patients
with enteric fever caused by Salmonella typhi, as well as bacteremic nontyphoidal infections in patients with HIV, and clears chronic fecal carriage. Ciprofloxacin, ofloxacin,
and levofloxacin, when combined with metronidazole, may be useful in the management of intra-abdominal infections when Enterococcus is not a likely pathogen.
Moxifloxacin as a single agent was shown to have similar e!icacy to piperacillin/tazobactam for complicated intra-abdominal infection, although there are concerns over
increasing resistance in B. fragilis.

Respiratory Tract Infections

Many newer fluoroquinolones, including levofloxacin, moxifloxacin, and gemifloxacin, have excellent activity against S. pneumoniae, H. influenzae, and the atypical
respiratory pathogens. Thus, these agents are frequently used in the management of community-acquired pneumonia and for upper respiratory tract infections such as
sinusitis that are not responsive to more narrow-spectrum agents. Mild-to-moderate respiratory exacerbations owing to P. aeruginosa in patients with cystic fibrosis have
responded to oral fluoroquinolone therapy with ciprofloxacin or levofloxacin.

Bone, Joint, and So" Tissue Infections

The treatment of chronic osteomyelitis may require prolonged (weeks to months) antimicrobial therapy with agents active against S. aureus or gram-negative rods.
Failures are associated with the development of resistance, particularly in S. aureus. Combination therapy with a fluoroquinolone and rifampin has been e!ective at
reducing the development of resistance and providing good cure rates, especially in the management of early prosthetic joint infections. In diabetic foot infections, the
fluoroquinolones in combination with an agent with antianaerobic activity are a reasonable choice.

Other Infections

Ciprofloxacin and levofloxacin are used for the prophylaxis of anthrax and are e!ective for the treatment of tularemia (Hendricks et al., 2014). The quinolones, especially
moxifloxacin, may be used as part of multiple-drug regimens for the treatment of multidrug-resistant tuberculosis and atypical mycobacterial infections as well as
Mycobacterium avium complex infections in AIDS (see Chapter 60) (American Thoracic Society, 2003). Quinolones, when used as prophylaxis in neutropenic patients, have
decreased the incidence of gram-negative rod bacteremias (Hughes et al., 2002). Levofloxacin and ciprofloxacin are approved to treat and prevent anthrax as well as plague
due to Yersinia pestis.

Adverse E!ects

Gastrointestinal Adverse E!ects

Common adverse reactions involve the GI tract, with 3%–17% of patients reporting mild nausea, vomiting, and abdominal discomfort. Fluoroquinolones have emerged as
a common cause of Clostridium di!icile colitis due to the spread of quinolone-resistant strains.

Neurologic Adverse E!ects

Side e!ects (1%–11%) of the CNS include mild headache and dizziness. Rarely, hallucinations, delirium, and seizures have occurred, predominantly in patients who were
also receiving theophylline or NSAIDs. Patients with a history of epilepsy are at higher risk for fluoroquinolone-induced convulsions. Recently, the fluoroquinolones have
been recognized as a rare cause of peripheral neuropathy, which in some cases has been irreversible.

Musculoskeletal Adverse E!ects

Arthralgias and joint pain are occasionally reported with fluoroquinolones. Tendon rupture or tendinitis (usually of the Achilles tendon) is a recognized adverse e!ect,
especially in those more than 60 years old, in patients taking corticosteroids, and in solid-organ transplant recipients. Early animal studies suggested an increased risk of
cartilage damage and malformation among young animals (Burkhardt et al., 1997). Subsequent human studies have not noted a substantially increased risk of these
e!ects in children or among the o!spring of pregnant women who received fluoroquinolones. Nevertheless, the agents are typically avoided in pregnancy and among
young children (Sabharwal and Marchant, 2006).

Other Adverse E!ects

Among the quinolones available in the U.S., moxifloxacin carries the highest risk for QT interval prolongation and torsades de pointes arrhythmias; gemifloxacin,
levofloxacin, and ofloxacin appear to have lower risk; and ciprofloxacin has the lowest risk. However, the overall risk of torsades de pointes is small with the use of
fluoroquinolones. Gatifloxacin’s propensity to cause both hypo- and hyperglycemia, especially in older adults, led to its removal for systemic use in the U.S. (Park-Wyllie et
al., 2006). Other agents such as levofloxacin may rarely be associated with dysglycemias among at-risk patients. Rashes, including photosensitivity reactions, also can
occur; patients with frequent sun exposure should be advised to protect themselves with clothing or sunscreen.

Drug Interactions

All quinolones form complexes with divalent and trivalent cations (e.g., calcium, iron, aluminum). When coadministered orally with quinolones, these cations can chelate
the quinolone and reduce systemic bioavailability. Thus, a separation of at least 2 h between oral administration of quinolones and these cations is recommended.
Ciprofloxacin inhibits the metabolism of theophylline, and toxicity from elevated concentrations of the methylxanthine may occur (Schwartz et al., 1988). NSAIDs may
augment displacement of GABA from its receptors by the quinolones, enhancing neurologic adverse e!ects (Halliwell et al., 1993). Due to risk for QT prolongation,
quinolones should be used with caution in patients on class III (amiodarone) and class IA (quinidine, procainamide) antiarrhythmics (see Chapter 30).

ANTISEPTIC 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 e!ective concentrations are not achieved in plasma with safe doses; however, they can be administered orally to treat UTIs.

Methenamine

Methenamine (hexamethylenamine) is a urinary tract antiseptic and prodrug that acts by generating formaldehyde via the following reaction:

N4(CH2)6 + 6H2O + 4H+ → 6HCHO + 4NH+4

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 formaldehyde-dependent antibacterial action. The decomposition reaction is fairly slow, and 3 h are required to reach 90% completion.

Antimicrobial Activity

Nearly all bacteria are sensitive to free formaldehyde at concentrations of about 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 insu!iciency. 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. GI distress frequently is caused by doses more than 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/d given for longer
than 3–4 weeks. Renal insu!iciency is not a contraindication to the use of methenamine alone, but the acids given concurrently may be detrimental; methenamine
mandelate is contraindicated in renal insu!iciency. 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 o!enders and o"en S. aureus and S. epidermidis as well. Enterobacter aerogenes and Proteus
vulgaris are usually resistant. A urinary pH less than 5 is typically necessary for methenamine to be active; some clinicians recommend monitoring of the urinary pH and
even urinary acidification with ammonium chloride or ascorbic acid.

Nitrofurantoin

Nitrofurantoin 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 or more. The antibacterial activity is higher in acidic urine.

Pharmacology, Toxicity, and Therapeutic Uses

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; about 40% is excreted unchanged into the urine. The average dose of nitrofurantoin yields a
concentration in urine of about 200 μg/mL. This concentration is soluble at pH greater than 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 e!icacy 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 four times a day with meals and at bedtime, less for the macrocrystalline formulation (100 mg every 12 h for 7
days). A single 50- to 100-mg dose at bedtime may be su!icient 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 less than 60 mL/min), and children younger than 1 month should not receive nitrofurantoin.

Nitrofurantoin is approved for the treatment of lower UTIs. It is not recommended for treatment of pyelonephritis or prostatitis.

The most common untoward e!ects 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 and in newborns
exhibiting low levels of reduced glutathione in their red blood cells), cholestatic jaundice, and hepatocellular damage. 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 a"er
discontinuation of the drug. Interstitial pulmonary fibrosis can occur in patients (especially the elderly) taking the drug chronically. 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.

Fosfomycin

Fosfomycin is a phosphonic acid derivative that is used primarily for the prevention and treatment of UTIs.

Antimicrobial Activity

Fosfomycin inhibits MurA, an enolpyruvyl transferase that catalyzes the initial step in bacterial cell wall synthesis. This mechanism is unique among antibacterials; thus,
cross-resistance to other agents is rarely seen. Optimal testing of fosfomycin activity requires supplementation of the media with glucose-6-phosphate. Fosfomycin’s usual
spectrum of activity includes the uropathogens E. coli, Proteus, Enterococcus, and Staphylococcus saphrophyticus. Activity against Klebsiella, Enterobacter, and Serratia
spp. is variable, and Pseudomonas and Acinetobacter are typically resistant. Staphylococcus aureus is frequently susceptible, although emergence of resistance during
therapy has been reported.

Pharmacology, Toxicity, and Therapeutic Uses

Outside the U.S., fosfomycin is available as an intravenous formulation that can achieve adequate levels to treat some systemic infections. However, in the U.S. it is only
available as a powder (fosfomycin tromethamine) that is dissolved in water and taken orally. Bioavailability of the oral formulation is approximately 40%, with a t1/2 of 5–8
h. With oral administration of 3 g, systemic concentrations are low, but urinary concentrations are as high as 1000–4000 μg/mL. The FDA-approved dosing regimen is a
single 3-g dose for uncomplicated UTI; some investigators have administered 3 g every other day for three doses for complicated UTI or 3 g every 10 days for UTI
prophylaxis.

Overall, fosfomycin is well tolerated. Adverse e!ects are uncommon and usually consist of GI distress, vaginitis, headache, or dizziness.

Acknowledgment
William A. Petri, Jr contributed to this chapter in the previous editions of this book. We have retained some of his text in the current edition.

DRUG SUMMARY TABLE

Favorite Table | Download (.pdf) | Print
Drug Facts for Your Personal Formulary: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections

Drug Therapeutic Uses Clinical Pharmacology and Tips

Sulfonamides: Competitive inhibitors of bacterial dihydropteroate synthase, thereby disrupting folate synthesis
General: Bacteriostatic; limited e!icacy as monotherapy, renal elimination, hypersensitivity reactions

Sulfisoxazole (PO) Lower UTIs Some activity vs. Streptococcus pyogenes, S. pneumoniae, Staphylococcus aureus,
Otitis media (with erythromycin) Haemophilus influenzae, Escherichia coli, Nocardia
Rapid renal excretion

Sulfadiazine (PO) Toxoplasmosis (with pyrimethamine) Similar to sulfisoxazole, with good activity against Toxoplasma gondii
Reasonable CSF penetration
Higher risk of crystalluria, requires hydration

Sulfadoxine (PO) Prophylaxis and treatment of malaria (with Similar to sulfisoxazole, with some activity vs. Plasmodium falciparum
pyrimethamine) Long t1/2

Sulfacetamide Treatment of ocular infections Activity similar to sulfisoxazole

(ophthalmic) High penetration into ocular fluids

Silver sulfadiazine Prevention of infection in burn patients Activity similar to sulfisoxazole

(topical) Burning and itching at application site
Mafenide (topical) Application over large surface may lead to systemic absorption and adverse e!ects

Sulfonamide and Dihydrofolate Reductase Inhibitor Combination: Sequential inhibition of folate synthesis

Trimethoprim- UTI Excellent activity vs. S. aureus, Staphylococcus epidermidis, Streptococcus pyogenes
sulfamethoxazole (IV, PO) Upper respiratory tract infections Good activity vs. Proteus, E. coli, Klebsiella, Enterobacter, Serratia, Nocardia, Brucella
Shigellosis Some activity vs. S. pneumoniae
Pneumocystis jiroveci pneumonia Formulated in 5:1 (sulfa:TMP) ratio, giving 20:1 serum levels
Skin/so" tissue infections due to S. aureus Well absorbed on oral administration
Infections due to Nocardia, Stenotrophomonas Good penetration into CSF
maltophila, Cyclospora, Isospora Metabolized and renally eliminated
Hypersensitivity reactions (i.e., rash) common
Dose-related bone marrow suppression, hyperkalemia

Quinolones: Bactericidal inhibitors of bacterial gyrase and topoisomerase, prevent DNA unwinding
General: Drug interactions with cations, neurologic adverse e!ects, tendonitis/tendon rupture, photosensitivity; typically avoided in children and
pregnant women

Norfloxacin (PO) UTI, prostatitis Good activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella
Traveler’s diarrhea Some activity vs. Pseudomonas
E!ective concentrations only achieved in GI and urinary tracts

Ciprofloxacin (IV, PO) UTI, prostatitis Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella
Traveler’s diarrhea Good activity vs. Pseudomonas
Intra-abdominal infections (with metronidazole) Some activity vs. S. aureus, streptococci
Pseudomonas infections Good bioavailability and tissue distribution
Anthrax, tularemia Renal and nonrenal elimination

Levofloxacin (IV, PO) Respiratory tract infections Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, Salmonella, Shigella, streptococci,
 UTI, prostatitis H. influenzae, Legionella, Chlamydia
Chlamydia Good activity vs. Pseudomonas, S. aureus
Traveler’s diarrhea Good bioavailability and tissue distribution
Intra-abdominal infections (with metronidazole) Renal elimination
Pseudomonas infections S-isomer of ofloxacin

Moxifloxacin (IV, PO) Respiratory tract infections Excellent activity vs. E. coli, Klebsiella, Proteus, Serratia, streptococci, H. influenzae,
Intra-abdominal infections Legionella, Chlamydia
Mycobacterial infections Good activity vs. S. aureus, Bacteroides fragilis
Good bioavailability and tissue distribution
Renal and nonrenal elimination; not for UTI
QT prolongation

Urinary Agents: Diverse mechanisms, e!ective concentrations reached only in urine

Methenamine (PO) Chronic suppression of cystitis Forms formaldehyde in urine

Requires acidic urine for activity
Excellent activity against most uropathogens except for Proteus and Enterobacter
GI distress at high doses

Nitrofurantoin (PO) Cystitis treatment DNA damage through reactive intermediates

Cystitis prophylaxis Excellent activity vs. E. coli, Enterococcus
Some activity vs. Klebsiella, Enterobacter
Rapid absorption and elimination
Colors urine brown
Acute pneumonitis and chronic interstitial pulmonary fibrosis

Fosfomycin (PO) Cystitis treatment Inhibits early cell wall synthesis

Excellent activity vs. E. coli, Proteus, Enterococcus
Some activity vs. Klebsiella, Enterobacter
Single-dose treatment of acute uncomplicated cystitis

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