Urinary Tract Anti-infective Agents

Urinary Tract Anti-infective Agents

Urinary tract anti-infective agents are drugs used to treat bacterial infections of the urinary tract, such as cystitis, pyelonephritis, and urethritis. These agents either kill the bacteria (bactericidal) or inhibit their growth (bacteriostatic).

Classes of Urinary Tract Anti-Infective Agents

1. Sulfonamides
   • Mechanism: Inhibit bacterial folic acid synthesis by acting as competitive inhibitors of para-aminobenzoic acid (PABA).
   • Examples: Sulfamethoxazole (often used in combination with Trimethoprim).
   • Uses: Treatment of uncomplicated urinary tract infections (UTIs).
   • Side effects: Crystalluria, hypersensitivity reactions.
2. Quinolones and Fluoroquinolones
   • Mechanism: Inhibit bacterial DNA gyrase and topoisomerase IV, essential for DNA replication.
   • Examples: Ciprofloxacin, Norfloxacin, Levofloxacin.
   • Uses: Effective against Gram-negative organisms and recurrent UTIs.
   • Side effects: Nausea, photosensitivity, tendonitis.
3. Nitrofurans
   • Mechanism: Reduced by bacterial enzymes to form reactive intermediates that damage bacterial DNA and proteins.
   • Examples: Nitrofurantoin, Furazolidone.
   • Uses: Treatment and prevention of lower UTIs.
   • Side effects: Nausea, pulmonary reactions, hepatotoxicity.
4. Fosfomycin
   • Mechanism: Inhibits bacterial cell wall synthesis by blocking the formation of peptidoglycan.
   • Example: Fosfomycin tromethamine.
   • Uses: Used for uncomplicated UTIs and multidrug-resistant infections.
   • Side effects: Diarrhea, headache, dizziness.
5. Methenamine
   • Mechanism: Decomposes in acidic urine to release formaldehyde, which is bactericidal.
   • Examples: Methenamine mandelate, Methenamine hippurate.
   • Uses: Used for chronic suppression of UTIs.
   • Side effects: GI upset, bladder irritation.

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 of Quinolones

• 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

• 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

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

• 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