Urinary Tract Anti-infective Agents
Quinolones
• Synthetic substances
possessing in common an N-1-alkylated 3-carboxypyrid-4-one ring fused to
another aromatic ring, which itself carries other substituents
• First
quinolone to be marketed was nalidixic acid
• Spectrum
of activity was limited to a small number of gram negative organisms
• Quinolones
were of little clinical significance until the discovery that addition of a
fluoro group to 6 position of basic nucleus greatly increased the biologic
activity
• Agents
that contain the 6-fluoro substitution are referred to as fluoroquinolones-
important therapeutic class of antimicrobials
• Norfloxacin
was approved for use in 1986 and represents the first of the second-generation
quinolones
• Broad
spectrum and equivalent in potency to many of the fermentation derived
antibiotics
• Intense
research ensued, and over a thousand analogs have now been made
• Ciprofloxacin,
gemifloxacin, norfloxacin, ofloxacin, levofloxacin, and moxifloxacin are
currently marketed for systemic use
• In
addition, ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin along with
besifloxacin and gatifloxacin are available for ophthalmic use
Second-, third-, and
fourth-generation quinolones
Therapeutic Classification of Quinolones
Mechanism of action
• Quinolones
are rapidly bactericidal, largely as a consequence of inhibition of DNA gyrase
and topoisomerase IV
• Key
bacterial enzymes that dictate the conformation of DNA
• Using
the energy generated by adenosine triphosphate (ATP) hydrolysis, DNA progressively
wound about itself in a positive supercoil
• In
the absence of ATP, the process is reversed, relaxing the molecule
• DNA
gyrase alters the conformation of DNA by catalyzing transient double-strand
cuts, passing the uncut portion of the molecule through the gap, and resealing
the molecule back together
• DNA
topoisomerase IV- unties enchained daughter DNA molecules produced through
replication of circular DNA
• Inhibition
of DNA gyrase and topoisomerase IV makes a cell’s DNA inaccessible and leads to
cell death
• Different
quinolones inhibit these essential enzymes to different extents
• Topoisomerase
IV seems more important to some gram-positive organisms
• DNA
gyrase seems more important to some gram-negative organisms
• Humans
shape their DNA with topoisomerase II, an analogous enzyme to DNA gyrase
• Quinolones
doesn’t bind at normally achievable doses and do not kill host cells
Nalidixic Acid
• Pale buff crystalline
powder that is sparingly soluble in water and ether, but soluble in most polar
organic solvents
• Useful
in the treatment of urinary tract infections in which Gram-negative bacteria
predominate
• Particularly
active against indole-positive Proteus spp. is
• Rapidly
absorbed, extensively metabolized, and rapidly excreted after oral
administration
• 7-hydroxymethyl
metabolite is significantly more active than the parent compound
Norfloxacin
• Pale yellow crystalline
powder that is sparingly soluble in water
• Has
broad-spectrum activity against Gram-negative and Gram-positive aerobic
bacteria
• Fluorine
atom provides increased potency against Gram-positive organisms
• Piperazine
moiety improves antipseudomonal activity
• Indicated
for the treatment of urinary tract infections caused by E. coli, K.
pneumoniae, Enterobacter cloacae, Proteus mirabilis,
indole-positive Proteus spp., including P. vulgaris, Providencia
rettgeri, Morganella morganii, P. aeruginosa, S.
aureus, and S. epidermidis, and group-D streptococci
• Generally
not effective against obligate anaerobic bacteria
• Oral
absorption of norfloxacin is about 40%, 15% protein bound and is metabolized in
the liver
• Significant
biliary excretion, with about 30% of the original drug appearing in the feces
Enoxacin
• Broad-spectrum
antibacterial activity
• Used
primarily for the treatment of urinary tract infections and sexually
transmitted diseases
• Approved
for the treatment of uncomplicated gonococcal urethritis and has also been
shown to be effective in chancroid caused by Haemophilus ducreyi
• Also approved for the
treatment of acute (uncomplicated) and chronic (complicated) urinary tract
infections
• Oral
bioavailability approaches 98%
• More
than 50% of the unchanged drug is excreted in the urine
• Relatively
short elimination half-life of enoxacin dictates twice-a-day dosing
• Has
been reported to decrease theophylline clearance, causing increased plasma
levels and increased toxicity
• Forms
insoluble chelates with divalent metal ions present in antacids and hematinics,
which reduce its oral bioavailability
Ciprofloxacin
• Higher
potency against most Gram-negative bacterial species, including P. aeruginosa,
than other quinolones
• Ciprofloxacin
is widely distributed to virtually all parts of the body, including the CSF
• Agent
of choice for the treatment of bacterial gastroenteritis caused by
Gram-negative bacilli such as enteropathogenic E. coli, Salmonella
spp. (including S. typhi), Shigella spp., Vibrio spp.,
and Aeromonas hydrophilia
• It
is widely used for the treatment of respiratory tract infections and is
particularly effective for controlling bronchitis and pneumonia caused by Gram-negative
bacteria
• Also
used for combating infections of the skin, soft tissues, bones, and joints
• Both
uncomplicated and complicated urinary tract infections caused by Gram-negative
bacteria can be treated effectively
• Particularly
useful for the control of chronic infections characterized by renal tissue
involvement
• Has important
applications in controlling venereal diseases
• A
combination of ciprofloxacin with the cephalosporin antibiotic ceftriaxone is
recommended as the treatment of choice for disseminated gonorrhea
• Single-dose
treatment with ciprofloxacin plus doxycycline, a tetracycline antibiotic, can
usually eradicate gonococcal urethritis
• Has
also been used for chancroid
• Approved
for postexposure treatment of inhalational anthrax
• Injectable
forms of ciprofloxacin are incompatible with drug solutions that are alkaline
because of the reduced solubility of the drug at pH 7
• May
also induce crystalluria under the unusual circumstance that urinary pH above 7
Ofloxacin
• Quinolone
class of antibacterial drugs wherein the 1- and 8-positions are joined in the
form of a 1,4-oxazine ring
• Resembles
ciprofloxacin in its antibacterial spectrum and potency
• Has
been approved for the treatment of infections of the lower respiratory tract,
including chronic bronchitis and pneumonia, caused by Gram-negative bacilli
• Used
for the treatment of pelvic inflammatory disease and is highly active against
both gonococci and chlamydia
• Not
effective in the treatment of syphilis
• A
single 400-mg oral dose of ofloxacin in combination with the tetracycline
antibiotic doxycycline for the outpatient treatment of acute gonococcal
urethritis
• Used
for the treatment of urinary tract infections caused by Gram-negative bacilli
and for prostatitis caused by E. coli
• Infections
of the skin and soft tissues caused by staphylococci, streptococci, and
Gram-negative bacilli may also be treated
• Has
an asymmetric carbon atom in its structure, it is obtained and supplied
commercially as a Racemate
• 3S(–)
isomer is substantially more active (8–125 times, depending on the bacterial
species) than the 3R(+) isomer and has recently been marketed as
levofloxacin (Levaquin) for the same indications as the racemate
Lomefloxacin
• Difluorinated quinolone
with a longer elimination half-life (7–8 hours)
• Only
quinolone for which once-daily oral dosing suffices
• Food
slows, but does not prevent, its oral absorption
• Extent
of biotransformation of lomefloxacin is only about 5%
• High
concentrations of unchanged drug, ranging from 60%- 80%, excreted in urine
• Has
been approved for two primary indications
• First,
acute bacterial exacerbations of chronic bronchitis caused by H. influenzae
or Moraxella (Branhamella) catarrhalis, but not if Streptococcus
pneumonia is the causative organism
• Second,
it is used for prophylaxis of infection following transurethral surgery
• Treatment
of acute cystitis and chronic urinary tract infections caused by Gram-negative
bacilli
• Causes
the highest incidence of phototoxicity (photosensitivity) of the currently
available quinolones
• Presence
of a halogen atom (fluorine, in this case) at the 8-position has been
correlated with an increased chance of phototoxicity in the quinolones
Sparfloxacin
• Exhibits
higher potency against Grampositive bacteria, especially staphylococci and
streptococci, than the fluoroquinolones currently marketed
• More
active against chlamydia and the anaerobe Bacteroides fragilis
• Activity
of sparfloxacin against Gram-negative bacteria is also very impressive, and it
compares favorably with ciprofloxacin and ofloxacin in potency against Mycoplasma
spp., Legionella spp., Mycobacteria spp., and Listeria
monocytogenes
• Has
a long elimination half-life of 18 hours, which permits once-a-day dosing
• Recommended
for the treatment of bacterial gastroenteritis and cholecystitis
• Incidence
of phototoxicity of sparfloxacin is the lowest of the fluoroquinolones, because
of the presence of the 5-amino group, which counteracts the effect of the
8-fluoro substituent
Gatifloxacin
• Substitution
of a methoxy group at C-8 reduces the photosensitivity
• Used
in the treatment of bacterial exacerbation of chronic bronchitis and
community-acquired pneumonia
Moxifloxacin
• Substitution
of a methoxy group at C-8 reduces the photosensitivity
• Pyrrolidinyl
ring represent the most signify cant antimicrobial improvement
• Have
a spectrum of activity that includes Bacteroides fragilis
• Also
recommended as second-line agents for tuberculosis as an off-label use
SAR of Quinolones
• Structural
features of the quinolones strongly influence the antimicrobial and
pharmacokinetic properties of this class of drugs
• Essential
pharmacophore for activity is the carboxy-4-pyridone nucleus
• Apparently,
the carboxylic acid and the ketone are involved in binding to the
DNA/DNA-gyrase enzyme system
• Reduction
of the 2,3-double bond or the 4-keto group inactivates the molecule
• Substitution
at C-2 interferes with enzyme–substrate complexation
• Fluoro
substitution at the C-6 position greatly improves antimicrobial activity by
increasing the lipophilicity of the molecule
• Also
improves the drug’s penetration through the bacterial cell wall
• C-6
fluoro also increases the DNA gyrase/topoisomerase IV inhibitory action
• An
additional fl uoro group at C-8 further improves drug absorption and half-life,
but also increases drug-induced photosensitivity
• Substitution
of a methoxy group at C-8 reduces the photosensitivity
• (moxifloxacin
and gatifloxacin)
• Heterocyclic
substitution at C-7 improves the spectrum of activity especially against
gramnegative organisms
• Piperazinyl
(ciprofloxacin) and pyrrolidinyl (moxifloxacin) represent the most significant
antimicrobial improvement
• Unfortunately,
piperazinyl group at C-7 also increases binding to CNS γ-aminobutyric acid
(GABA) receptors, which accounts for CNS side effects
• Alkyl
substitution on the piperazine nitrogen (ofloxacin and
• levofloxacin)
is reported to decrease binding to GABA
• Cyclopropyl
substitution at N-1 appears to broaden activity of the quinolones to include
activity against atypical bacteria including Mycoplasma, Chlamydia, and Legionella
species
• Substitution
of a 2,4-difluorophenyl at N-1 also improves antimicrobial potency, but agents
with this substitution (trovafloxacin and temafloxacin) have been withdrawn
from the market due to serious adverse effects
• Introduction
of a third ring to the nucleus of the quinolones gives rise to ofloxacin
• Additionally,
ofloxacin has an asymmetric carbon at the C-3′ position
• S
-(−)-isomer (levofloxacin) is twice as active as ofloxacin and 8 to 128
times more potent than the R-(+)-isomer resulting from increased binding
to the DNA gyrase
• A
chemical incompatibility common to all of the quinolones involves the ability
of these drugs to chelate polyvalent metal ions (Ca2+, Mg2+, Zn2+, Fe2+, Al3+)
• Resulting
in decreased solubility and reduced drug absorption
• Chelation
occurs between the metal and the 3-carboxylic acid and 4-keto groups
• Agents
containing polyvalent metals should be administered separately from the
quinolones
Miscellaneous
• Nitrofurans-
first nitroheterocyclic compounds to be introduced into chemotherapy
• Three
of these compounds- Nitrofurazone, furazolidone, and nitrofurantoin
• Have
been used for the treatment of bacterial infections of various kinds for nearly
50 years
• A
fourth nitrofuran, nifurtimox, is used as an antiprotozoal agent to treat
trypanosomiasis and leishmaniasis
• Another
nitroheterocyclic of considerable importance is metronidazole, which is an
amebicide (a trichomonicide) and is used for the treatment of systemic
infections caused by anaerobic bacteria
• Derivatives
of 5-nitro-2-furaldehyde, formed on reaction with the appropriate hydrazine or
amine derivative
• Antimicrobial
activity is present only when the nitro group is in the 5-position
• Mechanism
of antimicrobial action- not fully understood
• Known
to be mutagenic and carcinogenic under certain conditions
• It
is thought that DNA damage caused by metabolic reaction products may be
involved in these cellular effects
Furazolidine
• Yellow
crystalline powder with a bitter after taste
• It
is insoluble in water or alcohol
• Has
bactericidal activity against a relatively broad range of intestinal pathogens,
including S. aureus, E. coli, Salmonella, Shigella,
Proteus spp., Enterobacter, and Vibrio cholera
• It
is also active against the protozoan Giardia lamblia
• It
is recommended for the oral treatment of bacterial or protozoal diarrhea caused
by susceptible organisms
• Only
a small fraction of an orally administered dose of furazolidone is absorbed
• Approximately
5% of the oral dose is detectable in the urine in the form of several
metabolites
• Some
gastrointestinal distress has been reported with its use
• Alcohol
should be avoided when furazolidone is being used because the drug can inhibit
aldehyde dehydrogenase
Nitrofurantoin
• Nitrofuran
derivative that is suitable for oral use
• It
is recommended for the treatment of urinary tract infections caused by
susceptible strains of E. coli, enterococci, S. aureus,
Klebsiella, Enterobacter, and Proteus spp
• Most
common side effects are gastrointestinal- anorexia, nausea, and vomiting
• Hypersensitivity
reactions- pneumonitis, rashes, hepatitis, and hemolytic anemia have
occasionally been observed
Methenamine
• Activity
of hexamethylenetetramine depends on the liberation of formaldehyde
• Compound
is prepared by evaporating a solution of formaldehyde and strong ammonia water
to dryness
• Free
base exists as odorless, white crystalline powder that sublimes at about 260°C
• It
dissolves in water to form an alkaline solution and liberates formaldehyde when
warmed with mineral acids
• Weak base with a pKa of
4.9
• Used
internally as a urinary antiseptic for the treatment of chronic urinary tract
infections
• Free
base has practically no bacteriostatic power
• Formaldehyde
release at the lower pH of the kidney is required
• To
optimize the antibacterial effect, an acidifying agent such as sodium
biphosphate or ammonium chloride generally accompanies the administration of
methenamine
• Certain
bacterial strains are resistant to the action of methenamine because they
liberate urease, an enzyme that hydrolyzes urea to form ammonia
• Resultant
high urinary pH prevents the activation of methenamine, rendering it
ineffective
• This
problem can be overcome by the co-administration of the urease inhibitor
acetohydroxamic acid
Ciprofloxacin- Synthesis
Nitrofurantoin- Synthesis
