Lippincott Chapter 40: Quinolones, Folic Acid Antagonists, and Urinary Tract Antiseptics Flashcards
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Nalidixic acid
Norfloxacin NOROXIN
Ofloxacin
Inhibitors of folate synthesis
Mafenide SULFAMYLON
Silversulfadiazine SILVADENE
Sulfasalazine AZULFIDINE
Inhibitors of folate reduction
Pyrimethamine DARAPRIM
Trimethoprim
COMBINATION OF INHIBITORS OF
FOLATE SYNTHESIS AND REDUCTION
Cotrimoxazole (trimethoprim +
sulfamethoxazole) BACTRIM
URINARY TRACT ANTISEPTICS
Methenamine MANDELAMINE, HIPREX
Nitrofurantoin MACROBID
Fluoroquinolones
Nalidixic acid is the predecessor to all fluoroquinolones, a class of
man-made antibiotics. Over 10,000 fluoroquinolone analogs have been
synthesized, including several with wide clinical applications. Fluoroquin-
olones in use today typically offer greater efficacy, a broader spectrum of
antimicrobial activity, and a better safety profile than their predecessors.
Unfortunately, fluoroquinolone use has been closely tied to Clostridium
difficile infection and the spread of antimicrobial resistance in many
organisms (for example, methicillin resistance in staphylococci). The
unfavorable effects of fluoroquinolones on the induction and spread of
antimicrobial resistance are sometimes referred to as “collateral damage,”
a term which is also associated with third-generation cephalosporins (for
example, ceftazidime). The fluoroquinolones and other antibiotics dis-
cussed in this chapter are listed in Figure 40.1.
A. Mechanism of action
Fluoroquinolones enter bacteria through porin channels and exhibit
antimicrobial effects on DNA gyrase (bacterial topoisomerase II) and
bacterial topoisomerase IV. Inhibition of DNA gyrase results in relax-
ation of supercoiled DNA, promoting DNA strand breakage. Inhibition
of topoisomerase IV impacts chromosomal stabilization during cell
division, thus interfering with the separation of newly replicated DNA.
In gram-negative organisms (for example, Pseudomonas aerugi-
nosa), the inhibition of DNA gyrase is more significant than that of
topoisomerase IV, whereas in gram-positive organisms (for example,
Streptococcus pneumoniae), the opposite is true. Agents with higher
affinity for topoisomerase IV (for example, ciprofloxacin) should not
be used for S. pneumoniae infections, while those with more topoi-
somerase II activity (for example, moxifloxacin) should not be used
for P. aeruginosa infections.
B. Antimicrobial spectrum
Fluoroquinolones are bactericidal and exhibit area under the curve/
minimum inhibitory concentration (AUC/MIC)–dependent killing.
Bactericidal activity is more pronounced as serum drug concentra-
tions increase to approximately 30-fold the MIC of the bacteria. In
general, fluoroquinolones are effective against gram-negative organ-
isms (Escherichia coli, P. aeruginosa, Haemophilus influenzae),
atypical organisms (Legionellaceae, Chlamydiaceae), gram-positive
organisms (streptococci), and some mycobacteria (Mycobacterium
tuberculosis). Fluoroquinolones are typically not used for the treat-
ment of Staphylococcus aureus or enterococcal infections. They
are not effective against syphilis and have limited utility against
Neisseria gonorrhoeae due to disseminated resistance worldwide.
Levofloxacin and moxifloxacin are sometimes referred to as “respira-
tory fluoroquinolones,” because they have excellent activity against
S. pneumoniae, which is a common cause of community-acquired
pneumonia (CAP). Moxifloxacin also has activity against many anaer-
obes. Fluoroquinolones are commonly considered alternatives for
patients with a documented severe β-lactam allergy.
Fluoroquinolones may be classified into “generations” based on their
antimicrobial targets. The nonfluorinated quinolone nalidixic acid is
considered to be first generation, with a narrow spectrum of suscep-
tible organisms. Ciprofloxacin and norfloxacin are second generation
because of their activity against aerobic gram-negative and atypical bac-
teria. In addition, these fluoroquinolones exhibit significant intracellular
penetration, allowing therapy for infections in which a bacterium spends
part or all of its life cycle inside a host cell (for example, chlamydia,
mycoplasma, and mycobacteria). Levofloxacin is classified as third gen-
eration because of its increased activity against gram-positive bacteria.
Lastly, the fourth generation includes only moxifloxacin because of its
activity against anaerobic and gram-positive organisms.
C. Examples of clinically useful fluoroquinolones
1. Norfloxacin: Norfloxacin [nor-FLOX-a-sin] is infrequently prescribed
due to poor oral bioavailability and a short half-life. It is effective in
treating nonsystemic infections, such as urinary tract infections
(UTIs), prostatitis, and infectious diarrhea (unlabeled use).
2. Ciprofloxacin: Ciprofloxacin [sip-row-FLOX-a-sin] is effective in
the treatment of many systemic infections caused by gram-negative
bacilli (Figure 40.2). Of the fluoroquinolones, it has the best activ-
ity against P. aeruginosa and is commonly used in cystic fibrosis
patients for this indication. With 80% bioavailability, the intravenous
and oral formulations are frequently interchanged. Traveler’s diar-
rhea caused by E. coli as well as typhoid fever caused by Salmonella
typhi can be effectively treated with ciprofloxacin. Ciprofloxacin is
also used as a second-line agent in the treatment of tuberculosis.
Although typically dosed twice daily, an extended-release formula-
tion is available for once-daily dosing, which may improve patient
adherence to treatment.
3. Levofloxacin: Levofloxacin [leave-oh-FLOX-a-sin] is the l-isomer
of ofloxacin [oh-FLOX-a-sin] and has largely replaced it clinically.
Due to its broad spectrum of activity, levofloxacin is utilized in a
wide range of infections, including prostatitis, skin infections, CAP,
and nosocomial pneumonia. Unlike ciprofloxacin, levofloxacin has
excellent activity against S. pneumoniae respiratory infections.
Levofloxacin has 100% bioavailability and is dosed once daily.
4. Moxifloxacin: Moxifloxacin [mox-ee-FLOX-a-sin] not only has
enhanced activity against gram-positive organisms (for exam-
ple, S. pneumoniae) but also has excellent activity against many
anaerobes, although resistance to Bacteroides fragilis has been
reported. It has poor activity against P. aeruginosa. Moxifloxacin
does not concentrate in urine and is not indicated for the treatment
of UTIs.
D. Resistance
Although plasmid-mediated resistance or resistance via enzymatic
degradation is not of great concern, high levels of fluoroquinolone
resistance have emerged in gram-positive and gram-negative bacte-
ria, primarily due to chromosomal mutations. Cross-resistance exists
among the quinolones. The mechanisms responsible for this resis-
tance include the following:
1. Altered target: Chromosomal mutations in bacterial genes (for
example, gyrA or parC) have been associated with a decreased
affinity for fluoroquinolones at their site of action. Both topoisomer-
ase IV and DNA gyrase may undergo mutations.
2. Decreased accumulation: Reduced intracellular concentration
is linked to 1) porin channels and 2) efflux pumps. The former
involves a decreased number of porin proteins in the outer membrane of the resistant cell, thereby impairing access of the
drugs to the intracellular topoisomerases. The latter mechanism
pumps drug out of the cell.
E. Pharmacokinetics
1. Absorption: Only 35% to 70% of orally administered norfloxacin
is absorbed, compared with 80% to 99% of the other fluoroquino-
lones (Figure 40.3). Intravenous and ophthalmic preparations of
ciprofloxacin, levofloxacin, and moxifloxacin are available. Ingestion
of fluoroquinolones with sucralfate, aluminum- or magnesium-
containing antacids, or dietary supplements containing iron or zinc
can reduce the absorption. Calcium and other divalent cations also
interfere with the absorption of these agents (Figure 40.4).
2. Distribution: Binding to plasma proteins ranges from 10% to 40%.
The fluoroquinolones distribute well into all tissues and body fluids,
which is one of their major clinical advantages. Levels are high in
bone, urine (except moxifloxacin), kidney, and prostatic tissue (but
not prostatic fluid), and concentrations in the lungs exceed those in
serum. Penetration into cerebrospinal fluid is relatively low except
for ofloxacin. Fluoroquinolones also accumulate in macrophages
and polymorphonuclear leukocytes, thus having activity against
intracellular organisms.
3. Elimination: Most fluoroquinolones are excreted renally. Therefore,
dosage adjustments are needed in renal dysfunction. Moxifloxacin
is excreted primarily by the liver, and no dose adjustment is required
for renal impairment.
Fluoroquinolones adverse effects
Adverse reactions
In general, these agents are well tolerated (Figure 40.5). Like most
antibiotics, the most common adverse effects of fluoroquinolones
are nausea, vomiting, and diarrhea. Headache and dizziness or light-
headedness may occur. Thus, patients with central nervous system
(CNS) disorders, such as epilepsy, should be treated cautiously
with these drugs. Peripheral neuropathy and glucose dysregu-
lation (hypoglycemia and hypoglycemia) have also been noted.
Fluoroquinolones can cause phototoxicity, and patients taking
these agents should be advised to use sunscreen and avoid excess
exposure to sunlight. If phototoxicity occurs, discontinuation of
the drug is advisable. Articular cartilage erosion (arthropathy) has
been observed in immature animals exposed to fluoroquinolones.
Therefore, these agents should be avoided in pregnancy and lacta-
tion and in children under 18 years of age. [Note: Careful monitoring
is indicated in children with cystic fibrosis who receive fluoroqui-
nolones for acute pulmonary exacerbations.] An increased risk of
tendinitis or tendon rupture may also occur with systemic fluoroquin-
olone use. Moxifloxacin and other fluoroquinolones may prolong
the QTc
interval and, thus, should not be used in patients who are
predisposed to arrhythmias or those who are taking other medica-
tions that cause QT prolongation. Ciprofloxacin can increase serum
levels of theophylline by inhibiting its metabolism (Figure 40.6).
Quinolones may also raise the serum levels of warfarin, caffeine,
and cyclosporine.
Folate antagonist
Enzymes requiring folate-derived cofactors are essential for the synthesis
of purines and pyrimidines (precursors of RNA and DNA) and other com-
pounds necessary for cellular growth and replication. Therefore, in the
absence of folate, cells cannot grow or divide. To synthesize the critical
folate derivative, tetrahydrofolic acid, humans must first obtain preformed
folate in the form of folic acid from the diet. In contrast, many bacteria are
impermeable to folic acid and other folates and, therefore, must rely on
their ability to synthesize folate de novo. The sulfonamides (sulfa drugs)
are a family of antibiotics that inhibit de novo synthesis of folate. A sec-
ond type of folate antagonist—trimethoprim—prevents microorganisms
from converting dihydrofolic acid to tetrahydrofolic acid, with minimal
effect on the ability of human cells to make this conversion. Thus, both
sulfonamides and trimethoprim interfere with the ability of an infecting
bacterium to perform DNA synthesis. Combining the sulfonamide sulfa-
methoxazole with trimethoprim (the generic name for the combination is
cotrimoxazole) provides a synergistic combination.
Sulfonamide
The sulfa drugs are seldom prescribed alone except in developing coun-
tries, where they are still employed because of their low cost and efficacy.
A. Mechanism of action
In many microorganisms, dihydrofolic acid is synthesized from
p-aminobenzoic acid (PABA), pteridine, and glutamate (Figure 40.7).
All the sulfonamides currently in clinical use are synthetic analogs of
PABA. Because of their structural similarity to PABA, the sulfonamides
compete with this substrate for the bacterial enzyme, dihydropteroate
synthetase. They thus inhibit the synthesis of bacterial dihydrofolic
acid and, thereby, the formation of its essential cofactor forms. The
sulfa drugs, including cotrimoxazole, are bacteriostatic.
B. Antibacterial spectrum
Sulfa drugs are active against select Enterobacteriaceae in the uri-
nary tract and Nocardia infections. In addition, sulfadiazine [sul-fa-
DYE-a-zeen] in combination with the dihydrofolate reductase inhibitor
pyrimethamine [py-ri-METH-a-meen] is the preferred treatment for
toxoplasmosis. Sulfadoxine in combination with pyrimethamine is
used as an antimalarial drug (see Chapter 43).
C. Resistance
Bacteria that can obtain folate from their environment are naturally
resistant to these drugs. Acquired bacterial resistance to the sulfa
drugs can arise from plasmid transfers or random mutations. [Note:
Organisms resistant to one member of this drug family are resistant
to all.] Resistance is generally irreversible and may be due to 1)
an altered dihydropteroate synthetase, 2) decreased cellular per-
meability to sulfa drugs, or 3) enhanced production of the natural
substrate, PABA.
D. Pharmacokinetics
1. Absorption: After oral administration, most sulfa drugs are well
absorbed (Figure 40.8). An exception is sulfasalazine [sul-fa-
SAL-a-zeen]. It is not absorbed when administered orally or as
a suppository and, therefore, is reserved for treatment of chronic
inflammatory bowel disease (for example, ulcerative colitis). [Note:
Local intestinal flora split sulfasalazine into sulfapyridine and
5-aminosalicylate, with the latter exerting the anti-inflammatory
effect. Absorption of sulfapyridine can lead to toxicity in patients
who are slow acetylators.] Intravenous sulfonamides are gener-
ally reserved for patients who are unable to take oral preparations.
Because of the risk of sensitization, sulfa drugs are not usually
applied topically. However, in burn units, creams of silver sulfa-
diazine [sul-fa-DYE-ah-zeen] or mafenide [mah-FEN-ide] acetate
(α-amino-p-toluenesulfonamide) have been effective in reduc-
ing burn-associated sepsis because they prevent colonization of
bacteria. [Note: Silver sulfadiazine is preferred because mafenide
produces pain on application and its absorption may contribute to
acid–base disturbances.]
2. Distribution: Sulfa drugs are bound to serum albumin in the cir-
culation, where the extent of binding depends on the ionization
constant (pKa
) of the drug. In general, the smaller the pKa
value,
the greater the binding. Sulfa drugs distribute throughout the bodily
fluids and penetrate well into cerebrospinal fluid—even in the
absence of inflammation. They can also pass the placental barrier
and enter fetal tissues.
3. Metabolism: The sulfa drugs are acetylated and conjugated pri-
marily in the liver. The acetylated product is devoid of antimicrobial
activity but retains the toxic potential to precipitate at neutral or
acidic pH. This causes crystalluria (“stone formation”; see below)
and, therefore, potential damage to the kidney.
4. Excretion: Sulfa drugs are eliminated by glomerular filtration
and secretion and require dose adjustments for renal dysfunction.
Sulfonamides may be eliminated in breast milk.
Sulfonamide adverse effects
Adverse effects
1. Crystalluria: Nephrotoxicity may develop as a result of crystal-
luria (Figure 40.9). Adequate hydration and alkalinization of urine
can prevent the problem by reducing the concentration of drug and
promoting its ionization.
2. Hypersensitivity: Hypersensitivity reactions, such as rashes, angio-
edema or Stevens-Johnson syndrome, may occur. When patients
report previous sulfa allergies, it is paramount to acquire a descrip-
tion of the reaction to direct appropriate therapy.
3. Hematopoietic disturbances: Hemolytic anemia is encountered
in patients with glucose-6-phosphate dehydrogenase (G6PD) defi-
ciency. Granulocytopenia and thrombocytopenia can also occur.
Fatal reactions have been reported from associated agranulocyto-
sis, aplastic anemia, and other blood dyscrasias.
Kernicterus: This disorder may occur in newborns, because sulfa
drugs displace bilirubin from binding sites on serum albumin. The
bilirubin is then free to pass into the CNS, because the blood–brain
barrier is not fully developed.
5. Drug potentiation: Transient potentiation of the anticoagulant
effect of warfarin results from the displacement from binding
sites on serum albumin. Serum methotrexate levels may also rise
through its displacement.
6. Contraindications: Due to the danger of kernicterus, sulfa drugs
should be avoided in newborns and infants less than 2 months of
age, as well as in pregnant women at term. Sulfonamides should
not be given to patients receiving methenamine, since they can
crystallize in the presence of formaldehyde produced by this agent
(Figure 40.10).
Trimethoprim
Trimethoprim [try-METH-oh-prim], a potent inhibitor of bacterial dihy-
drofolate reductase, exhibits an antibacterial spectrum similar to that of
the sulfonamides. Trimethoprim is most often compounded with sulfa-
methoxazole [sul-fa-meth-OX-a-zole], producing the combination called
cotrimoxazole.
A. Mechanism of action
The active form of folate is the tetrahydro derivative that is formed
through reduction of dihydrofolic acid by dihydrofolate reductase. This
enzymatic reaction (Figure 40.7) is inhibited by trimethoprim, leading
to a decreased availability of the tetrahydrofolate cofactors required
for purine, pyrimidine, and amino acid synthesis. The bacterial reduc-
tase has a much stronger affinity for trimethoprim than does the mam-
malian enzyme, which accounts for the selective toxicity of the drug.
B. Antibacterial spectrum
The antibacterial spectrum of trimethoprim is similar to that of sul-
famethoxazole. However, trimethoprim is 20- to 50-fold more potent
than the sulfonamides. Trimethoprim may be used alone in the treat-
ment of UTIs and in the treatment of bacterial prostatitis (although
fluoroquinolones are preferred).
C. Resistance
Resistance in gram-negative bacteria is due to the presence of an
altered dihydrofolate reductase that has a lower affinity for trimethoprim.
Efflux pumps and decreased permeability to the drug may play a role.
D. Pharmacokinetics
Trimethoprim is rapidly absorbed following oral administration. Because
the drug is a weak base, higher concentrations of trimethoprim are
achieved in the relatively acidic prostatic and vaginal fluids. The
drug is widely distributed into body tissues and fluids, including penetration into the cerebrospinal fluid. Trimethoprim undergoes some
O-demethylation, but 60% to 80% is renally excreted unchanged.
Trimethoprim adverse effects
Trimethoprim can produce the effects of folic acid deficiency. These
effects include megaloblastic anemia, leukopenia, and granulocyto-
penia, especially in pregnant patients and those having very poor
diets. These blood disorders may be reversed by the simultaneous
administration of folinic acid, which does not enter bacteria.
Cotrimoxazole
The combination of trimethoprim with sulfamethoxazole, called cotrimoxa-
zole [co-try-MOX-a-zole], shows greater antimicrobial activity than equiva-
lent quantities of either drug used alone (Figure 40.11). The combination
was selected because of the synergistic activity and the similarity in the
half-lives of the two drugs.
A. Mechanism of action
The synergistic antimicrobial activity of cotrimoxazole results from its
inhibition of two sequential steps in the synthesis of tetrahydrofolic
acid. Sulfamethoxazole inhibits the incorporation of PABA into dihy-
drofolic acid precursors, and trimethoprim prevents reduction of dihy-
drofolate to tetrahydrofolate (Figure 40.7).
B. Antibacterial spectrum
Cotrimoxazole has a broader spectrum of antibacterial action than
the sulfa drugs alone (Figure 40.12). It is effective in treating UTIs and
respiratory tract infections, as well as Pneumocystis jirovecii pneumo-
nia (PCP), toxoplasmosis, and ampicillin- or chloramphenicol-resistant
salmonella infections. It has activity against MRSA and can be par-
ticularly useful for community-acquired skin and soft tissue infections
caused by this organism. It is the drug of choice for infections caused
by susceptible Nocardia species and Stenotrophomonas maltophilia.
C. Resistance
Resistance to the trimethoprim–sulfamethoxazole combination is less
frequently encountered than resistance to either of the drugs alone,
because it requires that the bacterium have simultaneous resistance
to both drugs. Significant resistance has been documented in a num-
ber of clinically relevant organisms, including E. coli and MRSA.
D. Pharmacokinetics
Cotrimoxazole is generally administered orally (Figure 40.13). Intrave-
nous administration may be utilized in patients with severe pneu-
monia caused by PCP. Both agents distribute throughout the body.
Trimethoprim concentrates in the relatively acidic milieu of prostatic
fluids, and this accounts for the use of trimethoprim–sulfamethoxazole
in the treatment of prostatitis. Cotrimoxazole readily crosses the blood–
brain barrier. Both parent drugs and their metabolites are excreted in
the urine.
Cotrimoxazole adverse effects
Adverse effects
Reactions involving the skin are very common and may be severe in
the elderly (Figure 40.14). Nausea and vomiting are the most common
gastrointestinal adverse effects. Glossitis and stomatitis have been
observed. Hyperkalemia may occur, especially with higher doses.
Megaloblastic anemia, leukopenia, and thrombocytopenia may occur
and have been fatal. The hematologic effects may be reversed by the
concurrent administration of folinic acid, which protects the patient
and does not enter the microorganism. Hemolytic anemia may occur
in patients with G6PD deficiency due to the sulfamethoxazole com-
ponent. Immunocompromised patients with PCP frequently show
drug-induced fever, rashes, diarrhea, and/or pancytopenia. Prolonged
prothrombin times (increased INR) in patients receiving both sulfa-
methoxazole and warfarin have been reported, and increased moni-
toring is recommended when the drugs are used concurrently. The
plasma half-life of phenytoin may be increased due to inhibition of its
metabolism. Methotrexate levels may rise due to displacement from
albumin-binding sites by sulfamethoxazole.
Urinary tract antiseptics and antimicrobials
UTIs are prevalent in women of child-bearing age and in the elderly
population. E. coli is the most common pathogen, causing about 80% of
uncomplicated upper and lower UTIs. Staphylococcus saprophyticus is
the second most common bacterial pathogen causing UTIs. In addition
to cotrimoxazole and the quinolones previously mentioned, UTIs may be
treated with any one of a group of agents called urinary tract antiseptics,including methenamine, nitrofurantoin, and the quinolone nalidixic acid
(not available in the United States). These drugs do not achieve antibac-
terial levels in the circulation, but because they are concentrated in the
urine, microorganisms at that site can be effectively eradicated
