46

C H A P T E R

Sulfonamides,
Trimethoprim, &
Quinolones
*
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD

C ASE STUDY

A 59-year-old woman presents to an urgent care clinic with tract infections in the past year. Each episode was uncom-
a 4-day history of frequent and painful urination. She has plicated, treated with trimethoprim-sulfamethoxazole, and
had fevers, chills, and flank pain for the past 2 days. Her promptly resolved. She also has osteoporosis for which she
physician advised her to come immediately to the clinic for takes a daily calcium supplement. The decision is made to
evaluation. In the clinic she is febrile (38.5°C [101.3°F]) treat her with oral antibiotics for a complicated urinary
but otherwise stable and states she is not experiencing any tract infection with close follow-up. Given her history,
nausea or vomiting. Her urine dipstick test is positive for what would be a reasonable empiric antibiotic choice?
leukocyte esterase. Urinalysis and urine culture are ordered. Depending on the antibiotic choice are there potential drug
Her past medical history is significant for three urinary interactions?

■ ANTIFOLATE DRUGS Mechanism of Action & Antimicrobial

Activity
SULFONAMIDES Sulfonamide-susceptible organisms, unlike mammals, cannot
use exogenous folate but must synthesize it from PABA. This
Chemistry pathway (Figure 46–2) is thus essential for production of
The basic formulas of the sulfonamides and their structural simi- purines and nucleic acid synthesis. As structural analogs of
larity to p-aminobenzoic acid (PABA) are shown in Figure 46–1. PABA, sulfonamides inhibit dihydropteroate synthase and folate
Sulfonamides with varying physical, chemical, pharmacologic, production. Sulfonamides inhibit both Gram-positive bacteria,
and antibacterial properties are produced by attaching sub- such as Staphylococcus sp and Gram-negative enteric bacteria such
stituents to the amido group (  SO2  NH  R) or the amino as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and
group (  NH2) of the sulfanilamide nucleus. Sulfonamides tend Enterobacter sp, as well as Nocardia sp, Chlamydia trachomatis, and
to be much more soluble at alkaline than at acid pH. Most can some protozoa. Rickettsiae are not inhibited by sulfonamides but
be prepared as sodium salts, which are used for intravenous are instead stimulated in their growth. Activity is poor against
administration. anaerobes. Pseudomonas aeruginosa is intrinsically resistant to
sulfonamide antibiotics.
Combination of a sulfonamide with an inhibitor of dihy-
∗
The authors thank Henry F. Chambers, MD and Daniel H. Deck, for drofolate reductase (trimethoprim or pyrimethamine) provides
their contributions to previous editions.

834
 CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 835

synthase with low sulfonamide affinity is often encoded on a plas-

SO2NH2 COOH mid that is transmissible and can disseminate rapidly and widely.
Sulfonamide-resistant dihydropteroate synthase mutants also can
emerge under selective pressure.

NH2 NH2
Pharmacokinetics
Sulfanilamide p-Aminobenzoic acid (PABA) Sulfonamides can be divided into three major groups: (1)
oral, absorbable; (2) oral, nonabsorbable; and (3) topical.
SO2NH Oral absorbable sulfonamides are absorbed from the stomach
SO2NH and small intestine and distributed widely to tissues and body
N N
N fluids (including the central nervous system and cerebrospinal
O CH3 fluid), placenta, and fetus. Protein binding varies from 20%
to over 90%. Therapeutic concentrations are in the range of
NH2 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours
NH2 after oral administration.
Sulfadiazine Sulfamethoxazole A portion of absorbed drug is acetylated or glucuronidated in
the liver. Sulfonamides and inactive metabolites are then excreted
FIGURE 46–1 Structures of some sulfonamides and in the urine, mainly by glomerular filtration. The dosage of
p-aminobenzoic acid. sulfonamides must be reduced in patients with significant renal
failure.

synergistic activity because of sequential inhibition of folate

synthesis (Figure 46–2). Clinical Uses
Sulfonamides are infrequently used as single agents. Many
Resistance strains of formerly susceptible species, including meningococci,
pneumococci, streptococci, staphylococci, and gonococci, are
Some bacteria lack the enzymes required for folate synthesis from now resistant. The fixed-drug combination of trimethoprim-
PABA and, like mammals, depend on exogenous sources of folate; sulfamethoxazole is the drug of choice for infections such
therefore, they are not susceptible to sulfonamides. Sulfonamide as Pneumocystis jiroveci (formerly P carinii) pneumonia,
resistance may also occur as a result of mutations that (1) cause toxoplasmosis, and nocardiosis.
overproduction of PABA, (2) cause production of a folic acid-
synthesizing enzyme that has low affinity for sulfonamides, or
A. Oral Absorbable Agents
(3) impair permeability to the sulfonamide. Dihydropteroate
Sulfamethoxazole is a commonly used absorbable agent; however,
in the USA, it is available only as the fixed-dosed combination
trimethoprim-sulfamethoxazole. Typical dosing and indications
are discussed below.
p-Aminobenzoic acid
Administration of sulfadiazine with pyrimethamine is first-
line therapy for treatment of acute toxoplasmosis. Using sulfa-
Sulfonamides
Dihydropteroate − (compete diazine plus pyrimethamine, a potent inhibitor of dihydrofolate
synthase
with PABA) reductase, is synergistic because these drugs block sequential steps
in the folate synthesis pathway (Figure 46–2). However, since
Dihydrofolic acid 2015, there have been challenges with manufacturing, supply,
and pricing of pyrimethamine in the USA. In some cases, clini-
cians have obtained a compounded product through specialty
Dihydrofolate − Trimethoprim pharmacies or prescribed alternate agents, such as trimethoprim-
reductase
sulfamethoxazole. Sulfadoxine is a long-acting sulfonamide that is
coformulated with pyrimethamine (Fansidar). This combination
Tetrahydrofolic acid
is no longer commercially available in the USA but may be found
in other parts of the world where it is used as a second-line treat-
ment for malaria (see Chapter 52).
Purines

B. Oral Nonabsorbable Agents

DNA Sulfasalazine (salicylazosulfapyridine) is widely used in ulcer-
ative colitis, enteritis, and other inflammatory bowel disease (see
FIGURE 46–2 Actions of sulfonamides and trimethoprim. Chapter 62).
836 SECTION VIII Chemotherapeutic Drugs

C. Topical Agents and sulfamethoxazole is often bactericidal, compared with the

Sodium sulfacetamide ophthalmic solution or ointment is effec- bacteriostatic activity of a sulfonamide alone.
tive in the treatment of bacterial conjunctivitis and as adjunctive NH2 OCH3
therapy for trachoma. Another sulfonamide, mafenide acetate, is N
used topically but can be absorbed from burn sites. The drug and
H2N CH2 OCH3
its primary metabolite inhibit carbonic anhydrase and can cause
metabolic acidosis, a side effect that limits its usefulness. Silver N

sulfadiazine is a less toxic topical sulfonamide and is preferred to OCH3

mafenide for prevention of infection of burn wounds. Trimethoprim

Adverse Reactions NH2

N
Historically, drugs containing a sulfonamide moiety, including
antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypo- H2N CI
glycemic agents, were considered to be cross-allergenic. However, N
more recent evidence suggests cross-reactivity is uncommon and C2H5
many patients who are allergic to nonantibiotic sulfonamides toler- Pyrimethamine
ate sulfonamide antibiotics. The most common adverse effects are
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria,
nausea, vomiting, diarrhea, and difficulties referable to the urinary Resistance
tract (see below). Stevens-Johnson syndrome, although relatively Resistance to trimethoprim can result from reduced cell perme-
uncommon (<1% of treatment courses), is a particularly serious ability, overproduction of dihydrofolate reductase, or production
and potentially fatal type of skin and mucous membrane eruption of an altered reductase with reduced drug binding. Resistance
associated with sulfonamide use. Other unwanted effects include can emerge by mutation, although more commonly it is due to
stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see plasmid-encoded trimethoprim-resistant dihydrofolate reductases.
below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. These resistant enzymes may be coded within transposons on con-
jugative plasmids that exhibit a broad host range, accounting for
A. Urinary Tract Disturbances rapid and widespread dissemination of trimethoprim resistance
Sulfonamides may precipitate in urine, especially at neutral or acid among numerous bacterial species.
pH, producing crystalluria, hematuria, or even obstruction. This is
rarely a problem with the more soluble sulfonamides (eg, sulfisoxa- Pharmacokinetics
zole). Sulfadiazine and sulfamethoxazole are relatively insoluble in Trimethoprim is usually given orally, alone or in combination with
acidic urine and can cause crystalluria, particularly when given in sulfamethoxazole, which has a similar half-life. Trimethoprim-
large doses or if fluid intake is poor. Crystalluria is treated by admin- sulfamethoxazole can also be given intravenously. Trimethoprim is
istration of sodium bicarbonate to alkalinize the urine and fluids well absorbed from the gut and distributed widely in body fluids
to increase urine flow. Sulfonamides have also been implicated in and tissues, including cerebrospinal fluid.
various types of nephrosis and in allergic nephritis. Because trimethoprim is more lipid-soluble than sulfamethoxa-
zole, it has a larger volume of distribution than the latter drug.
B. Hematopoietic Disturbances Therefore, when 1 part of trimethoprim is given with 5 parts of
Sulfonamides can cause hemolytic or aplastic anemia, granulocy- sulfamethoxazole (the ratio in the formulation), the peak plasma con-
topenia, thrombocytopenia, or leukemoid reactions. Sulfonamides centrations are in the ratio of 1:20, which is optimal for the combined
may provoke hemolytic reactions in patients with glucose- effects of these drugs in vitro. About 30–50% of the sulfonamide and
6-phosphate dehydrogenase deficiency. Sulfonamides taken near 50–60% of the trimethoprim (or their respective metabolites) are
the end of pregnancy increase the risk of kernicterus in newborns. excreted in the urine within 24 hours. The dose should be reduced by
half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and
TRIMETHOPRIM & TRIMETHOPRIM- in vaginal fluid, which are more acidic than plasma. Therefore, it
SULFAMETHOXAZOLE MIXTURES has more antibacterial activity in prostatic and vaginal fluids than
many other antimicrobial drugs.
Mechanism of Action
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhib-
Clinical Uses
its bacterial dihydrofolic acid reductase, which converts dihy- A. Oral Trimethoprim
drofolic acid to tetrahydrofolic acid, a step leading to the Trimethoprim can be given alone (100 mg twice daily) in acute
synthesis of purines and ultimately to DNA (Figure 46–2). urinary tract infections. Many community-acquired organisms are
Trimethoprim is a much less efficient inhibitor of mammalian susceptible to the high concentrations that are found in the urine
dihydrofolic acid reductase. The combination of trimethoprim (200–600 mcg/mL).
 CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 837

B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ) acid, 10 mg orally each day, should be administered to minimize
A combination of trimethoprim-sulfamethoxazole is effective bone marrow suppression seen with pyrimethamine. Some clini-
treatment for a wide variety of infections including P jiroveci cians recommend using trimethoprim-sulfamethoxazole as an
pneumonia, urinary tract infections, prostatitis, and some alternate option if pyrimethamine is not available.
infections caused by susceptible strains of Shigella, Salmonella, In falciparum malaria, the combination of pyrimethamine
and nontuberculous mycobacteria. It is active against most with sulfadoxine (Fansidar) has been used (see Chapter 52); how-
Staphylococcus aureus strains, both methicillin-susceptible and ever, it is no longer commercially available in the USA.
methicillin-resistant, and against respiratory tract pathogens such
as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but Adverse Effects
not Mycoplasma pneumoniae). However, the increasing prevalence Trimethoprim produces the predictable adverse effects of an
of strains of E coli (up to 30% or more) and pneumococci that are antifolate drug, especially megaloblastic anemia, leukopenia, and
resistant to trimethoprim-sulfamethoxazole must be considered granulocytopenia. The combination trimethoprim-sulfamethox-
before using this combination for empiric therapy of upper uri- azole may cause all of the untoward reactions associated with
nary tract infections or pneumonia. Trimethoprim-sulfamethoxa- sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal
zole is commonly used for the treatment of uncomplicated skin damage, and central nervous system disturbances occasionally
and soft tissue infections. occur. Patients with AIDS and pneumocystis pneumonia have
One double-strength tablet (each tablet contains trimethoprim a particularly high frequency of untoward reactions to trime-
160 mg plus sulfamethoxazole 800 mg) given every 12 hours is thoprim-sulfamethoxazole, especially fever, rashes, leukopenia,
effective treatment for urinary tract infections, prostatitis, uncom- diarrhea, elevations of hepatic aminotransferases, hyperkalemia,
plicated skin and soft tissue infections, and infections caused by and hyponatremia. Trimethoprim inhibits secretion of creatinine
susceptible strains of Shigella and Salmonella. Bone and joint at the distal renal tubule, resulting in mild elevation of serum
infections caused by S. aureus can be effectively treated, typically creatinine without impairment of glomerular filtration rate. This
at doses of 8–10 mg/kg per day of the trimethoprim component. nontoxic effect is important to distinguish from true nephrotoxic-
One single-strength tablet (containing trimethoprim 80 mg plus ity that may be caused by sulfonamides.
sulfamethoxazole 400 mg) given three times weekly may serve as
prophylaxis in recurrent urinary tract infections of some women.
The dosage for children treated for shigellosis, urinary tract infec-
tion, or otitis media is trimethoprim 8 mg/kg per day and sulfa-
■ DNA GYRASE INHIBITORS
methoxazole 40 mg/kg per day divided every 12 hours.
Infections with P jiroveci and some other pathogens, such as
FLUOROQUINOLONES
Nocardia or Stenotrophomonas maltophilia, can be treated with high The clinically relevant quinolones are synthetic fluorinated ana-
doses of the either the oral or intravenous combination (dosed on logs of nalidixic acid (Figure 46–3). They are active against a
the basis of the trimethoprim component at 15–20 mg/kg/d). variety of Gram-positive and Gram-negative bacteria.
P jiroveci can be prevented in immunosuppressed patients by a
number of low dose regimens such as one double-strength tablet
daily or three times weekly. Mechanism of Action
Quinolones block bacterial DNA synthesis by inhibiting bacterial
C. Intravenous Trimethoprim-Sulfamethoxazole topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition
A solution of the mixture containing 80 mg trimethoprim plus of DNA gyrase prevents the relaxation of positively supercoiled
400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% DNA that is required for normal transcription and replication.
dextrose in water can be administered by intravenous infusion Inhibition of topoisomerase IV interferes with separation of repli-
over 60–90 minutes. It is the agent of choice for moderately cated chromosomal DNA into the respective daughter cells during
severe to severe pneumocystis pneumonia. It has been used for cell division.
Gram-negative bacterial sepsis, but has largely been replaced by
extended spectrum β-lactams and fluoroquinolones. It may be Antibacterial Activity
an effective alternative for infections caused by some multidrug- Earlier quinolones such as nalidixic acid did not achieve systemic
resistant species such as Enterobacter and Serratia; shigellosis; or antibacterial levels and were useful only in the treatment of lower
typhoid. It is the preferred alternate therapy for serious Listeria urinary tract infections. Fluorinated derivatives (ciprofloxacin,
infections in patients unable to tolerate ampicillin. The dosage is levofloxacin, and others; Figure 46–3 and Table 46–1) have
10–20 mg/kg/d of the trimethoprim component. greatly improved antibacterial activity compared with nalidixic
acid and achieve bactericidal levels in blood and tissues.
D. Oral Pyrimethamine with Sulfonamide Fluoroquinolones were originally developed because of their
Pyrimethamine and sulfadiazine are used in the treatment of toxo- excellent activity against Gram-negative aerobic bacteria; the ear-
plasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily, liest agents had limited activity against Gram-positive organisms.
with pyrimethamine given as a 200-mg loading dose followed by Subsequent members of the group have improved activity against
a once-daily dose of 50–75 mg. Leucovorin, also known as folinic Gram-positive cocci. The relative activity against Gram-negative
838 SECTION VIII Chemotherapeutic Drugs

O
O
COOH F COOH

CH3 N N HN N N
C2H5
C2H5
Nalidixic acid Norfloxacin

O O
F COOH F COOH

HN N N CH3 N N N
O
CH3
Ciprofloxacin Levofloxacin

O
O
F COOH
CH2O F CO2H
H N N
N N
N N N
O
H3C H2N

Moxifloxacin Gemifloxacin

FIGURE 46–3 Structures of nalidixic acid and some fluoroquinolones.

versus Gram-positive species is useful for differentiating these typically used in combination with a second active agent, such
agents. Norfloxacin, which is no longer available in the USA, as rifampin, to prevent emergence of resistance while on therapy.
is the least active of the fluoroquinolones against both Gram- Enterococci tend to be less susceptible than staphylococci, limit-
negative and Gram-positive organisms, with minimum inhibitory ing the efficacy of fluoroquinolones in infections caused by these
concentrations (MICs) fourfold to eightfold higher than those organisms. Ciprofloxacin is the most active agent of this group
of ciprofloxacin. Ciprofloxacin, enoxacin, lomefloxacin, levo- against Gram-negative organisms, particularly P aeruginosa. Levo-
floxacin, ofloxacin, and pefloxacin comprise a second group floxacin, the l-isomer of ofloxacin, has superior activity against
of similar agents possessing excellent Gram-negative activity and Gram-positive organisms, especially Streptococcus pneumoniae.
moderate to good activity against Gram-positive bacteria. Cip- Gatifloxacin, gemifloxacin, and moxifloxacin make up a third
rofloxacin and levofloxacin are the two agents from this group group of fluoroquinolones with improved activity against Gram-
that are used systemically in the USA. MICs for Gram-negative positive organisms, particularly S pneumoniae and some staphylo-
cocci and bacilli, including Enterobacter sp, P aeruginosa, Neis- cocci. Gemifloxacin is active in vitro against ciprofloxacin-resistant
seria meningitidis, Haemophilus sp, and Campylobacter jejuni, are strains of S pneumoniae, but in vivo efficacy is unproven. Although
1–2 mcg/mL and often less. Methicillin-susceptible strains of S MICs of these agents for staphylococci are lower than those of cip-
aureus are generally susceptible to these fluoroquinolones, but rofloxacin (and the other compounds mentioned in the paragraph
methicillin-resistant strains of staphylococci are often resistant. above), it is not known whether the enhanced activity is sufficient
When treating staphylococcal infections, fluoroquinolones are to permit use of these agents for treatment of infections caused by

TABLE 46–1 Pharmacokinetic properties of some fluoroquinolones.

Oral Peak Serum Primary Route of
Drug Half-Life (h) Bioavailability (%) Concentration (mcg/mL) Oral Dose (mg) Excretion

Ciprofloxacin 3–5 70 2.4 500 twice daily Renal

Gemifloxacin 8 70 1.6 320 once daily Renal and nonrenal
Levofloxacin 5–7 95 5.7 500 once daily Renal
Moxifloxacin 9–10 >85 3.1 400 once daily Nonrenal
Norfloxacin 3.5–5 80 1.5 400 twice daily Renal
Ofloxacin 5–7 95 2.9 400 twice daily Renal
 CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 839

ciprofloxacin-resistant strains. In general, none of these agents is as agents are also effective for bacterial diarrhea caused by Shigella,
active as ciprofloxacin against Gram-negative organisms. Fluoro- Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones
quinolones also are active against agents of atypical pneumonia (eg, (except norfloxacin, which does not achieve adequate systemic
mycoplasmas and chlamydiae) and against intracellular pathogens concentrations) are used in infections of soft tissues, bones, and
such as Legionella and some mycobacteria, including Mycobacterium joints and in intra-abdominal and respiratory tract infections,
tuberculosis and Mycobacterium avium complex. Moxifloxacin has including those caused by multidrug-resistant organisms such as
modest activity against anaerobic bacteria but lacks appreciable Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice
activity against P aeruginosa. Because of toxicity when systemically for prophylaxis and treatment of anthrax; the newer fluoroquino-
administered, gatifloxacin is available only as an ophthalmic solu- lones are active in vitro, and levofloxacin is also approved by the
tion in the USA. U.S. Food and Drug Administration (FDA) for prophylaxis.
Ciprofloxacin and levofloxacin are no longer recommended
Resistance for the treatment of gonococcal infection in the USA, as resis-
tance is now common; however, gemifloxacin may be used in
During fluoroquinolone therapy, resistant organisms emerge in combination with azithromycin as an alternate to ceftriaxone.
7 9
about 1 of every 10 –10 organisms, especially among staphylo- Levofloxacin and ofloxacin are recommended by the Centers for
cocci, P aeruginosa, and Serratia marcescens. Emerging resistance Disease Control and Prevention as alternative treatment options
is due to one or more point mutations in the quinolone binding for chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin,
region of the target enzyme or to a change in the permeability of or moxifloxacin is occasionally used as part of a treatment regimen
the organism. However, additional mechanisms seem to account for tuberculosis and non-tuberculous mycobacterial infections.
for the relative ease with which resistance develops in highly sus- These agents are suitable for eradication of meningococci from
ceptible bacteria. Two types of plasmid-mediated resistance have carriers and for prophylaxis of bacterial infection in neutropenic
been described. The first type utilizes Qnr proteins, which protect cancer patients.
DNA gyrase from the fluoroquinolones. The second is a variant With their enhanced Gram-positive activity and activity
of an aminoglycoside acetyltransferase capable of modifying cip- against atypical pneumonia agents (chlamydiae, Mycoplasma,
rofloxacin. Both mechanisms confer low-level resistance that may and Legionella), levofloxacin, gemifloxacin, and moxifloxacin—
facilitate the point mutations that confer high-level resistance and so-called respiratory fluoroquinolones—are effective for treatment
also may be associated with resistance to other antibacterial drug of lower respiratory tract infections.
classes. Resistance to one fluoroquinolone, particularly if it is of
high level, generally confers cross-resistance to all other members
of this class. Adverse Effects
Fluoroquinolones are generally well tolerated. The most common
Pharmacokinetics effects are nausea, vomiting, and diarrhea. Occasionally, headache,
After oral administration, the fluoroquinolones are well absorbed dizziness, insomnia, skin rash, or abnormal liver function tests
(bioavailability of 80–95%) and distributed widely in body fluids develop. Photosensitivity has been reported with lomefloxacin
and tissues (Table 46–1). Serum half-lives range from 3 to 10 and pefloxacin. Prolongation of the QTc interval may occur with
hours. The relatively long half-lives of levofloxacin, gemifloxacin, gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin; these
and moxifloxacin permit once-daily dosing. Oral absorption is drugs should be avoided or used with caution in patients with
impaired by divalent and trivalent cations, including those in ant- known QTc interval prolongation or uncorrected hypokalemia;
acids. Therefore, oral fluoroquinolones should be taken 2 hours in those receiving class 1A (eg, quinidine or procainamide) or
before or 4 hours after any products containing these cations. class 3 antiarrhythmic agents (sotalol, ibutilide, amiodarone);
Serum concentrations of intravenously administered drug are sim- and in patients receiving other agents known to increase the QTc
ilar to those of orally administered drug. Most fluoroquinolones, interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin
moxifloxacin being an important exception, are eliminated by has been associated with hyperglycemia in diabetic patients and
renal mechanisms, either tubular secretion or glomerular filtration with hypoglycemia in patients also receiving oral hypoglycemic
(Table 46–1). Dosage adjustment is required for patients with agents. Because of these serious effects (including some fatalities),
creatinine clearances less than 50 mL/min, the exact adjustment gatifloxacin was withdrawn from sale in the United States in 2006.
depending on the degree of renal impairment and the specific In animal models, fluoroquinolones may damage growing car-
fluoroquinolone being used. Dosage adjustment for renal failure is tilage and cause an arthropathy. Thus, these drugs have not been
not necessary for moxifloxacin since it is metabolized in the liver; recommended as first-line agents for patients under 18 years of
it should be used with caution in patients with hepatic failure. age. However, there is a growing consensus that fluoroquinolones
may be used in children if needed (eg, for treatment of pseu-
domonal infections in patients with cystic fibrosis). Tendinitis,
Clinical Uses a complication in adults, can be serious because of the risk of
Fluoroquinolones (other than moxifloxacin, which achieves rela- tendon rupture. Risk factors for tendinitis include advanced age,
tively low urinary levels) are effective in urinary tract infec- renal insufficiency, and concurrent steroid use. Fluoroquinolones
tions caused by many organisms, including P aeruginosa. These should be avoided during pregnancy in the absence of specific
840 SECTION VIII Chemotherapeutic Drugs

data documenting their safety. Oral or intravenously adminis- many potential adverse effects are uncommon, the FDA called for
tered fluoroquinolones have also been associated with peripheral updated warnings for all fluoroquinolones in 2016, stating that
neuropathy. Neuropathy can occur at any time during treatment these agents should be reserved for patients who do not have alter-
with fluoroquinolones and may persist for months to years after native options, particularly in less severe infections such as upper
the drug is stopped. In some cases it may be permanent. Although respiratory infections or uncomplicated cystitis.

SUMMARY Sulfonamides, Trimethoprim, and Fluoroquinolones

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

FOLATE ANTAGONISTS
Synergistic combination of Bactericidal activity
sulfamethoxazole folate antagonists blocks against susceptible
purine production and bacteria P jiroveci 5:1 ratio of sulfamethoxazole to
nucleic acid synthesis Toxicity: Rash, fever, bone
marrow suppression, hyperkalemia,
nephrotoxicity

Sulfadiazine: Oral; first-line therapy for toxoplasmosis when combined with pyrimethamine
Trimethoprim: Oral; used alone only for lower urinary tract infections; may be safely prescribed to patients with sulfonamide allergy
Pyrimethamine: Oral; first-line therapy for toxoplasmosis when combined with sulfadiazine; coadminister with leucovorin to limit bone marrow toxicity
Pyrimethamine-sulfadoxine: Oral; second-line malaria treatment

FLUOROQUINOLONES
Inhibits DNA replication by Bactericidal activity Urinary tract infections
binding to DNA gyrase and against susceptible
topoisomerase IV bacteria Toxicity:
Gastrointestinal upset, neurotoxicity,
tendonitis

Levofloxacin: Oral, IV; L-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus
Moxifloxacin: Oral, IV; “respiratory” fluoroquinolone; once-daily dosing; improved activity versus anaerobes and M tuberculosis; hepatic clearance results in lower urinary
levels so use in urinary tract infections is not recommended
Gemifloxacin: Oral; “respiratory” fluoroquinolone

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

GENERAL-PURPOSE SULFONAMIDES PYRIMETHAMINE
Sulfadiazine Generic Pyrimethamine Daraprim
SULFONAMIDES FOR SPECIAL APPLICATIONS Pyrimethamine-sulfadoxine Generic, Fansidar
Mafenide Generic, Sulfamylon QUINOLONES & FLUOROQUINOLONES
Silver sulfadiazine Generic, Silvadene Ciprofloxacin Generic, Cipro, Cipro I.V., Ciloxan
Sulfacetamide sodium Generic
Gemifloxacin Factive
TRIMETHOPRIM Levofloxacin
Generic, Proloprim, Moxifloxacin Generic, Avelox, others
Norfloxacin Noroxin
Generic, Bactrim, Septra, others Ofloxacin Generic, Floxin, Ocuflox
 CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 841

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Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of
Talan DA et al: Prevalence of and risk factor analysis of trimethoprim-sulfamethox-
bacterial infections. Drugs 2004;64:2347.
azole- and fluoroquinolone-resistant E. coli infection among emergency
Mandell LA et al: Infectious Disease Society of America/American Thoracic department patients with pyelonephritis. Clin Infect Dis 2008;47:1150.
Society consensus guidelines on the management of community-acquired
Workowski KA et al: Sexually Transmitted Diseases Treatment Guidelines, 2015.
pneumonia. Clin Infect Dis 2007;44:S27.
MMWR Recomm Rep 2015;64(RR-03):1.
Mwenya DM et al: Impact of cotrimoxazole on carriage and antibiotic resistance
Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug
of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected
sensitive). Cochrane Database Syst Rev 2013;(6):CD004795.
children in Zambia. Antimicrob Agents Chemother 2010;54:3756.
Nouira S et al: Standard versus newer antibacterial agents in the treatment of severe
acute exacerbation of chronic obstructive pulmonary disease: A randomized

C ASE STUDY ANSWER

A fluoroquinolone that achieves good urinary and systemic susceptibility. Her recent exposure to multiple courses of
levels (ciprofloxacin or levofloxacin) would be a reasonable trimethoprim-sulfamethoxazole increases her chances of
choice for empiric treatment of this patient’s complicated having a urinary tract infection with an isolate that is resis-
urinary tract infection. Given the possibility of a fluoroqui- tant to this antibiotic. The patient should be told to take the
nolone-resistant organism, one dose of a parenteral agent oral fluoroquinolone 2 hours before or 4 hours after her
such as ceftriaxone (given IV or IM) would be reason- calcium supplement, as divalent and trivalent cations can
able pending culture results confirming fluoroquinolone significantly impair the absorption of oral fluoroquinolones.
 46
C H A P T E R

Sulfonamides,
Trimethoprim,
& Fluoroquinolones

Sulfonamides and trimethoprim are antimetabolites that are Fluoroquinolones, which selectively inhibit microbial
selectively toxic to microorganisms because they interfere with nucleic acid metabolism, also have a broad spectrum of anti-
folic acid synthesis. Sulfonamides continue to be used selectively microbial activity that includes many common pathogens.
as individual antimicrobial agents, although resistance is common. Resistance has emerged to the older antibiotics in this class,
The combination of a sulfonamide with trimethoprim causes but has been offset to some extent by the introduction of newer
a sequential blockade of folic acid synthesis. This results in a fluoroquinolones with expanded activity against common
synergistic action against a wide spectrum of microorganisms; pathogenic organisms.
resistance occurs but has been relatively slow in development.

Sulfonamides, trimethoprim, & fluoroquinolones

Antimetabolites Fluoroquinolones

Sulfonamides Narrow spectrum Wide spectrum

1st generation
(eg, norfloxacin)
Trimethoprim

Trimethoprim- 2nd generation

sulfamethoxazole (eg, ciprofloxacin)

3rd generation
(eg, levofloxacin)

ANTIFOLATE DRUGS 1. Sulfonamides—The sulfonamides are weakly acidic compounds

that have a common chemical nucleus resembling p-aminobenzoic
A. Classification and Pharmacokinetics acid (PABA). Members of this group differ mainly in their pharmaco-
The antifolate drugs used in the treatment of infectious diseases kinetic properties and clinical uses. Pharmacokinetic features include
are the sulfonamides, which inhibit dihydropteroate synthase, modest tissue penetration, hepatic metabolism, and excretion of both
a microbial enzyme involved in folic acid synthesis, and trim- intact drug and acetylated metabolites in the urine. Solubility may
ethoprim, a selective inhibitor of dihydrofolate reductase. be decreased in acidic urine, resulting in precipitation of the drug or

390

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 CHAPTER 46 Sulfonamides, Trimethoprim, & Fluoroquinolones 391

High-Yield Terms to Learn

Antimetabolite A drug that, through chemical similarity, interferes with the role of an endogenous compound in cellular
metabolism
Sequential blockade The combined action of 2 drugs that inhibit sequential steps in a pathway of bacterial metabolism
DNA gyrase Bacterial topoisomerase responsible for negative supercoiling of double-stranded DNA that balances the
positive supercoiling of DNA replication, preventing damage to the DNA strand
Topoisomerase IV Bacterial topoisomerase initiating decatenation, the mechanism by which 2 daughter DNA molecules are
separated at the conclusion of DNA replication

its metabolites. Because of the solubility limitation, a combination of synthesize folic acid; they must use preformed folic acid that is
3 separate sulfonamides (triple sulfa) has been used to reduce the present in the diet.
likelihood that any one drug will precipitate. The sulfonamides may
be classified as short-acting (eg, sulfisoxazole), intermediate-acting 2. Trimethoprim—Trimethoprim is a selective inhibitor of
(eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bacterial dihydrofolate reductase that prevents formation of the
bind to plasma proteins at sites shared by bilirubin and by other active tetrahydro form of folic acid (Figure 46–1). Bacterial
drugs. dihydrofolate reductase is 4–5 orders of magnitude more sensitive
to inhibition by trimethoprim than the mammalian enzyme.
2. Trimethoprim—This drug is structurally similar to folic acid.
It is a weak base and is trapped in acidic environments, reach- 3. Trimethoprim plus sulfamethoxazole—When the 2 drugs
ing high concentrations in prostatic and vaginal fluids. A large are used in combination, antimicrobial synergy results from the
percentage of trimethoprim is excreted unchanged in the urine. sequential blockade of folate synthesis (Figure 46–1). The drug
The half-life of this drug is similar to that of sulfamethoxazole combination is bactericidal against susceptible organisms.
(10–12 h).
C. Resistance
B. Mechanisms of Action Bacterial resistance to sulfonamides is common and may be
1. Sulfonamides—The sulfonamides are bacteriostatic inhibi- plasmid-mediated. It can result from decreased intracellular accu-
tors of folic acid synthesis. As antimetabolites of PABA, they are mulation of the drugs, increased production of PABA by bacteria,
competitive inhibitors of dihydropteroate synthase (Figure 46–1). or a decrease in the sensitivity of dihydropteroate synthase to the
They can also act as substrates for this enzyme, resulting in the sulfonamides. Clinical resistance to trimethoprim most commonly
synthesis of nonfunctional forms of folic acid. The selective toxicity results from the production of dihydrofolate reductase that has a
of sulfonamides results from the inability of mammalian cells to reduced affinity for the drug.

D. Clinical Use
p-Aminobenzoic acid (PABA)
1. Sulfonamides—The sulfonamides are active against Gram-
positive and Gram-negative organisms, Chlamydia, and Nocardia.
Dihydropteroate Sulfonamides
Specific members of the sulfonamide group are used by the fol-
−
synthase (compete with PABA)
lowing routes for the conditions indicated:
Dihydrofolic acid a. Simple urinary tract infections—Oral (eg, triple sulfa,
sulfisoxazole).
Dihydrofolate − Trimethoprim b. Ocular infections—Topical (eg, sulfacetamide).
reductase
c. Burn infections—Topical (eg, mafenide, silver sulfadiazine).
Tetrahydrofolic acid d. Ulcerative colitis, rheumatoid arthritis—Oral (eg,
sulfasalazine).
Purines e. Toxoplasmosis—Oral sulfadiazine plus pyrimethamine
(a dihydrofolate reductase inhibitor) plus folinic acid.
DNA
2. Trimethoprim-sulfamethoxazole (TMP-SMZ)—This drug
FIGURE 46–1 Inhibitory effects of sulfonamides and combination is effective orally in the treatment of urinary tract
trimethoprim on folic acid synthesis. Inhibition of 2 successive infections and in respiratory, ear, and sinus infections caused by
steps in the formation of tetrahydrofolic acid constitutes sequential Haemophilus influenzae and Moraxella catarrhalis. In the immuno-
blockade and results in antibacterial synergy. compromised patient, TMP-SMZ is used for infections due to

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 392 PART VIII Chemotherapeutic Drugs

Aeromonas hydrophila and is the drug of choice for prevention and mycobacteria, and agents of atypical pneumonia (Mycoplasma
treatment of pneumocystis pneumonia. An intravenous formula- pneumoniae, Chlamydophila pneumoniae). Third-generation fluo-
tion is available for patients unable to take the drug by mouth roquinolones (levofloxacin, gemifloxacin, and moxifloxacin)
and is used for treatment of severe pneumocystis pneumonia and are slightly less active than ciprofloxacin and ofloxacin against
for Gram-negative sepsis. TMP-SMZ is also the drug of choice in Gram-negative bacteria but have greater activity against Gram-
nocardiosis, a possible backup drug for cholera, typhoid fever, and positive cocci, including S pneumoniae and some strains of entero-
shigellosis, and has been used in the treatment of infections caused cocci and methicillin-resistant Staphylococcus aureus (MRSA).
by methicillin-resistant staphylococci and Listeria monocytogenes. Third-generation drugs are commonly referred to as “respira-
tory fluoroquinolones.” The most recently introduced drugs
E. Toxicity of Sulfonamides (eg, gemifloxacin, moxifloxacin) are the broadest-spectrum fluo-
1. Hypersensitivity—Allergic reactions, including skin rashes roquinolones introduced to date, with enhanced activity against
anaerobes.
and fever, occur commonly. Cross-allergenicity between the
individual sulfonamides should be assumed and may also occur
with chemically related drugs (eg, oral hypoglycemics, thiazides). B. Pharmacokinetics
Exfoliative dermatitis, polyarteritis nodosa, and Stevens-Johnson All the fluoroquinolones have good oral bioavailability (antacids
syndrome have occurred rarely. containing multivalent cations may interfere) and penetrate most
body tissues. However, norfloxacin does not achieve adequate
2. Gastrointestinal—Nausea, vomiting, and diarrhea occur plasma levels for use in most systemic infections. Elimination of
commonly. Mild hepatic dysfunction can occur, but hepatitis is most fluoroquinolones is through the kidneys via active tubular
uncommon. secretion, which can be blocked by probenecid. Dosage reductions
are usually needed in renal dysfunction except for moxifloxacin
3. Hematotoxicity—Although such effects are rare, sulfon- which is eliminated partly by hepatic metabolism and also by
amides can cause granulocytopenia, thrombocytopenia, and biliary excretion. Use of moxifloxacin in urinary tract infections
aplastic anemia. Acute hemolysis may occur in persons with is not recommended. Half-lives of fluoroquinolones are usually in
glucose-6-phosphate dehydrogenase deficiency. the range of 3–8 h.

4. Nephrotoxicity—Sulfonamides may precipitate in the urine C. Mechanism of Action

at acidic pH, causing crystalluria and hematuria. The fluoroquinolones interfere with bacterial DNA synthesis by
inhibiting topoisomerase II (DNA gyrase), especially in Gram-
5. Drug interactions—Competition with warfarin and negative organisms, and topoisomerase IV, especially in Gram-
methotrexate for plasma protein binding transiently increases the positive organisms. They block the relaxation of supercoiled
plasma levels of these drugs. Sulfonamides can displace bilirubin DNA that is catalyzed by DNA gyrase, a step required for normal
from plasma proteins, with the risk of kernicterus in the neonate transcription and duplication. Inhibition of topoisomerase IV
if used in the third trimester of pregnancy. by fluoroquinolones interferes with the separation of replicated
chromosomal DNA during cell division. Fluoroquinolones are
usually bactericidal against susceptible organisms. Like amino-
F. Toxicity of Trimethoprim
glycosides, the fluoroquinolones exhibit postantibiotic effects,
Trimethoprim can cause the predictable adverse effects of an whereby bacterial growth continues to be inhibited even after the
antifolate drug, including megaloblastic anemia, leukopenia, plasma concentration of the drug has fallen below the minimum
and granulocytopenia. These effects are usually ameliorated by inhibitory concentration of the bacterium (see Chapter 45).
supplementary folinic acid. The combination of TMP-SMZ may
cause any of the adverse effects associated with the sulfonamides.
D. Resistance
AIDS patients given TMP-SMZ have a high incidence of adverse
effects, including fever, rashes, leukopenia, and diarrhea. Resistance to second-generation fluoroquinolones has emerged
rapidly, especially in Campylobacter jejuni and gonococci, but
also in Gram-positive cocci (eg, MRSA), Pseudomonas aeruginosa,
FLUOROQUINOLONES and Serratia species. Mechanisms of resistance include decreased
intracellular accumulation of the drug via the production of efflux
A. Classification pumps or changes in porin structure (in Gram-negative bacteria).
Fluoroquinolones are classified by “generation” based on their Efflux mechanisms appear to be responsible for resistance in strains of
antimicrobial spectrum of activity. Norfloxacin, a first-generation M tuberculosis, S aureus, and S pneumoniae. Changes in the sensi-
fluoroquinolone derived from nalidixic acid, has activity against tivity of the target enzymes via point mutations in the antibiotic
the common pathogens that cause urinary tract infections. binding regions are also established to confer resistance against
Ciprofloxacin and ofloxacin (second-generation fluoroquino- specific fluoroquinolones. Mutations in the quinolone resistance-
lones) have greater activity against Gram-negative bacteria and determining region of the gyrA gene that encodes DNA gyrase is
are also active against the gonococcus, many Gram-positive cocci, responsible for resistance in gonococci.

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 CHAPTER 46 Sulfonamides, Trimethoprim, & Fluoroquinolones 393

E. Clinical Use 2. A 65-year-old woman has returned from a vacation abroad

Fluoroquinolones are effective in the treatment of infections of the suffering from traveler’s diarrhea, and her problem has not
responded to antidiarrheal drugs. A pathogenic Gram-negative
urogenital and gastrointestinal tracts caused by Gram-negative organ-
bacillus is suspected. Which drug is most likely to be effective
isms, including gonococci, E coli, Klebsiella pneumoniae, C jejuni, in the treatment of this patient?
Enterobacter, P aeruginosa, Salmonella, and Shigella species. They have (A) Ampicillin
been used widely for respiratory tract, skin, and soft tissue infections, (B) Ofloxacin
but their effectiveness is now variable because of the emergence of (C) Sulfadiazine
resistance. Ciprofloxacin and ofloxacin in single oral doses have been (D) Trimethoprim
used as alternatives to ceftriaxone or cefixime in gonorrhea, but they (E) Vancomycin
are not currently recommended because resistance is now common. 3. Which statement about the clinical use of sulfonamides is
Ofloxacin eradicates Chlamydia trachomatis, but a 7-d course of treat- correct?
ment is required. Levofloxacin has activity against most organisms asso- (A) Cannot be used topically for treatment of chlamydial
ciated with community-acquired pneumonia, including chlamydiae, infections of the eye
mycoplasma, and legionella species. Gemifloxacin and moxifloxacin (B) Effective as sole agents in the treatment of prostatitis
(C) Effective in Rocky Mountain spotted fever
have the widest spectrum of activity, which includes both Gram-
(D) In some bacterial strains resistance occurs via reduced
positive and Gram-negative organisms, atypical pneumonia agents, PABA formation
and some anaerobic bacteria. Fluoroquinolones have also been used (E) Reduced intracellular uptake is a mechanism of sulfonamide
in the meningococcal carrier state, in the treatment of tuberculosis, resistance in some bacterial strains
and in prophylactic management of neutropenic patients.
4. A 31-year-old man has gonorrhea. He has no drug allergies,
but a few years ago acute hemolysis followed use of an anti-
F. Toxicity malarial drug. The physician is concerned that the patient
Gastrointestinal distress is the most common adverse effect. The has an accompanying urethritis caused by C trachomatis,
fluoroquinolones may cause skin rashes, headache, dizziness, although no cultures or enzyme tests have been performed.
insomnia, abnormal liver function tests, phototoxicity, neurotoxicity, Which of the following drugs will be reliably effective against
and both tendinitis and tendon rupture. Opportunistic infections both gonococci and C trachomatis and safe to use in this
patient?
caused by C albicans and streptococci have occurred. The fluoro- (A) Cefixime
quinolones are not recommended for children or pregnant women (B) Ciprofloxacin
because they may damage growing cartilage and cause arthropathy. (C) Spectinomycin
Fluoroquinolones may increase the plasma levels of theophylline (D) Sulfamethoxazole-trimethoprim
and other methylxanthines, enhancing their toxicity. Newer fluo- (E) None of the above
roquinolones (gemifloxacin, levofloxacin, moxifloxacin) prolong 5. Which statement about the fluoroquinolones is accurate?
the QTc interval. They should be avoided in patients with known (A) Antacids increase their oral bioavailability
QTc prolongation and those taking certain antiarrhythmic drugs (B) Contraindicated in patients with hepatic dysfunction
(Chapter 14) or other drugs that increase the QTc interval. (C) Fluoroquinolones are drugs of choice in a 6-year-old
child with a urinary tract infection
(D) Gonococcal resistance to fluoroquinolones may involve
SKILL KEEPER: PROLONGATION OF THE changes in DNA gyrase
QT INTERVAL (SEE CHAPTER 14) (E) Modification of moxifloxacin dosage is required in
patients when creatinine clearance is less than 50 mL/min
Grepafloxacin was withdrawn from clinical use in the United 6. A 40-year-old man complains of periodic bouts of diarrhea
States because of serious cardiotoxicity. The currently available with lower abdominal cramping and intermittent rectal
fluoroquinolones are contraindicated in patients taking drugs bleeding. Seen in the clinic, he appears well nourished,
that prolong the QT interval. What other drugs increase the with blood pressure in the normal range. Examination
duration of the ventricular action potential? reveals moderate abdominal pain and tenderness. His cur-
The Skill Keeper Answer appears at the end of the chapter.
rent medications are limited to loperamide for his diarrhea.
Sigmoidoscopy reveals mucosal edema, friability, and some
pus. Laboratory findings include mild anemia and decreased
serum albumin. Microbiologic examination via stool cultures
QUESTIONS and mucosal biopsies do not reveal any evidence for bacterial,
amebic, or cytomegalovirus involvement. The most appropri-
1. Trimethoprim-sulfamethoxazole is established to be effective ate drug to use in this patient is
against which of the following opportunistic infections in the (A) Ampicillin
AIDS patient? (B) Doxycycline
(A) Cryptococcal meningitis (C) Norfloxacin
(B) Herpes simplex (D) Sulfasalazine
(C) Oral candidiasis (E) Trimethoprim-sulfamethoxazole
(D) Toxoplasmosis
(E) Tuberculosis

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 394 PART VIII Chemotherapeutic Drugs

7. Which adverse effect is most common with sulfonamides? urogenital chlamydial infection. Although ciprofloxacin
(A) Fanconi’s aminoaciduria syndrome might be effective in both gonorrhea and chlamydial urethri-
(B) Hematuria tis, it is no longer recommended for treatment of gonorrhea
(C) Kernicterus in the newborn in the United States, since resistance is now common. This
(D) Neurologic dysfunction patient could be treated by single oral doses of cefixime plus
(E) Skin rash azithromycin (not listed). Sulfamethoxazole or TMP-SMZ
would not be useful and may cause acute hemolysis in this
8. Which drug is effective in the treatment of nocardiosis and, patient. The answer is E.
in combination with pyrimethamine, is prophylactic against
Pneumocystis jirovecii infections in AIDS patients? 5. Antacids can decrease oral bioavailability of fluoroquinolones.
(A) Amoxicillin Neither hepatic nor renal dysfunction is a contraindication to
(B) Erythromycin the use of fluoroquinolones. Most fluoroquinolones undergo
(C) Levofloxacin renal elimination and dosage should be modified with creati-
(D) Sulfadiazine nine clearance <50 mL/min. Moxifloxacin elimination occurs
(E) Trimethoprim mainly via the liver. The fluoroquinolones should not be used
to treat uncomplicated first-time urinary tract infections in
9. Which statement about ciprofloxacin is accurate? children because of possible effects on cartilage development.
(A) Antagonism occurs if used with dihydrofolate reductase Uncomplicated urinary tract infections in children are usually
inhibitors due to a strain of E coli that is sensitive to many other drugs,
(B) Ciprofloxacin is active against MRSA strains of including beta-lactam antibiotics. The answer is D.
staphylococci 6. In the absence of any evidence pointing toward a definite
(C) Most “first-time” urinary tract infections are resistant to microbial cause for the colitis in this patient, a drug that
ciprofloxacin decreases inflammation is indicated. Sulfasalazine has sig-
(D) Organisms that commonly cause ear infections are nificant anti-inflammatory action, and its oral use results in
highly resistant symptomatic improvement in 50–75% of patients suffering
(E) Tendinitis may occur during treatment from ulcerative colitis. The drug is also used for its anti-
10. Supplementary folinic acid may prevent anemia in folate- inflammatory effects in rheumatoid arthritis. The answer is D.
deficient persons who use this drug; it is a weak base achiev- 7. The most common adverse effect of the sulfonamides is a
ing tissue levels similar to those in plasma. skin rash caused by hypersensitivity. Neurologic dysfunction
(A) Ciprofloxacin and hematuria occur less frequently. Sulfonamides are usually
(B) Levofloxacin avoided in the third trimester of pregnancy or in neonates, so
(C) Linezolid kernicterus is rare. Fanconi’s syndrome is associated with the
(D) Sulfamethoxazole use of outdated tetracyclines. The answer is E.
(E) Trimethoprim 8. Sulfadiazine and TMP-SMZ are drugs of choice in nocar-
diosis. In combination with pyrimethamine (an effective
dihydrofolate reductase inhibitor in protozoa), sulfadiazine
ANSWERS is effective in toxoplasmosis and is prophylactic against
pneumocystis pneumonia in the AIDS patient. However,
1. Trimethoprim-sulfamethoxazole is not effective in the treat- TMP-SMZ is more commonly used for the latter purpose.
ment of infections caused by viruses, fungi, or mycobacte- The answer is D.
ria. However, the drug combination is active against certain
protozoans, including Toxoplasma, and can be used for both 9. Ciprofloxacin is commonly used for the treatment of urinary
prevention and treatment of toxoplasmosis in the severely tract infections and is active against most strains of common
immunocompromised AIDS patient. The answer is D. causative agents of otitis media, including H influenzae and
pneumococci. However, up to 50% of strains of MRSA are
2. The second-generation fluoroquinolones are very effective now resistant to ciprofloxacin. No clinical antagonism has
in diarrhea caused by bacterial Gram-negative pathogens, been reported between fluoroquinolones and inhibitors of
including E coli, Shigella, and Salmonella. None of the other folic acid synthesis. Fluoroquinolones are not recommended
drugs listed would be appropriate. Many coliforms are now for use in pregnancy or for children less than 10 years of age
resistant to amoxicillin and ampicillin. Although trime- because they may damage growing cartilage. Tendonitis and
thoprim is available as a single drug, resistance emerges rapidly tendon rupture are adverse effects of the fluoroquinolones.
during treatment unless it is used for urinary tract infections, The answer is E.
in which high concentrations can be achieved. Vancomycin
has no activity against Gram-negative bacilli. The answer is B. 10. Trimethoprim is the only weak base listed (fluoroquinolones
and sulfonamides are acidic compounds), and its high lipid
3. Reduced uptake of sulfonamides is one way organisms can solubility at blood pH allows penetration of the drug into
become resistant. All of the other statements about sulfonamide prostatic and vaginal fluid to reach levels similar to those in
antimicrobial drugs are incorrect. The answer is E. plasma. Leukopenia and thrombocytopenia may occur in
4. Cefixime in a single oral dose is effective in gonorrhea folate deficiency when the drug is used alone or in combi-
(Chapter 43), but it has no activity against organisms caus- nation with sulfamethoxazole. Fluoroquinolones and line-
ing nongonococcal urethritis. Spectinomycin (Chapter 45) zolid do not exacerbate symptoms of folic acid deficiency.
is active against most gonococci, but does not eradicate a The answer is E.

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 CHAPTER 46 Sulfonamides, Trimethoprim, & Fluoroquinolones 395

SKILL KEEPER ANSWER: PROLONGATION OF THE QT INTERVAL

(SEE CHAPTER 14)

The most important drugs that prolong the QT interval are antiarrhythmics. These include
drugs from group 1A and group 3, including amiodarone, disopyramide, dofetilide, ibutilide,
procainamide, quinidine, and sotalol. Recall that although group 1A drugs are classified as
Na+ channel blockers, they also block K+ channels and prolong the duration of the ventricular
action potential. Other drugs implicated in QT prolongation include erythromycin, mefloquine,
pentamidine, thioridazine and possibly other tricyclic antidepressants, and ziprasidone.

CHECKLIST

When you complete this chapter, you should be able to:

❑ Describe how sulfonamides and trimethoprim affect bacterial folic acid synthesis and
how resistance to the antifolate drugs occurs.
❑ Identify major clinical uses of sulfonamides and trimethoprim, singly and in combina-

❑ Describe how fluoroquinolones inhibit nucleic acid synthesis and identify mechanisms
involved in bacterial resistance to these agents.
❑ List the major clinical uses of fluoroquinolones and describe their characteristic

DRUG SUMMARY TABLE: Sulfonamides, Trimethoprim, & Fluoroquinolones

Activity & Clinical Pharmacokinetics
Subclass Mechanism of Action Uses & Interactions Toxicities

Trimethoprim- Synergistic inhibition Urinary tract, respiratory, Rash, fever, bone marrow
sulfamethoxazole of folic acid synthesis ear, and sinus infections half-life ∼10 h suppression, hyperkalemia
P jirovecii pneumonia
bactericidal by sequential effects in AIDS patients
blockade

Other folate antagonists

Sulfonamides inhibit Simple urinary tract Hepatic and renal Oral sulfonamides cause
dihydropteroate synthase infections (oral) and GI upsets, acute hemolysis in
(+/– pyrimethamine) Trimethoprim and topical in burn or eye plasma protein binding G6PDH deficiency, possible
Trimethoprim pyrimethamine inhibit infections (sulfonamides) of sulfonamides (displace crystalluria and rash (assume
Pyrimethamine dihydrofolate reductase - cross-hypersensitivity)
and warfarin)

pyrimethamine)

(Continued )

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 396 PART VIII Chemotherapeutic Drugs

DRUG SUMMARY TABLE: Sulfonamides, Trimethoprim, & Fluoroquinolones (Continued )

Activity & Clinical Pharmacokinetics
Subclass Mechanism of Action Uses & Interactions Toxicities

Ciprofloxacin Inhibits DNA replication Effective in urogenital, GI upsets, CNS effects

via binding to DNA gyrase GI tract, and some clearance, half-life 4 h
(Gram-negative organ- respiratory infections Oral absorption impaired
isms) and topoisomerase by cations on cartilage (avoid in young
IV (Gram-positive children and pregnancy)
use in tuberculosis

Other fluoroquinolones
Mechanism identical Oral and IV forms of levo-
used mainly for urinary

via changes in target -

- with use of group 1A and
and possibly formation of respiratory infections with 3 antiarrhythmics
enhanced activity against permit once-daily dosing
Gram-positive cocci and
atypicals (chlamydia, by cations
mycoplasma)

G6PDH, glucose-6-phosphate dehydrogenase.

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