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    Urinary Antiseptics & Quinolones

    Dr. Aliena Edun, BPharm, M.D.


    Introduction
    • Urinary tract infection (UTI) is an infection caused by pathogenic
    microorganisms of one or more structures of the urinary tract.
    • Common UTIs:
    Cystitis—inflammation of the bladder
    Urethritis—inflammation of the urethra
    Prostatitis—inflammation of the prostate gland
    Pyelonephritis—inflammation of the kidney and renal pelvis
    • Clinical manifestations of UTIs: urgency, frequency, burning and pain on
    urination (dysuria), and pain caused by spasm in the region of the bladder and
    the suprapubic area.
    • Some drugs used in the treatment of UTIs do not belong to the antibiotic or
    sulfonamide groups of drugs.
    Classification of Drugs Used To Treat UTIs
    1) Urinary Antiseptics:
    • Nitrofurantoin (Furadantin)
    • Fosfomycin (Monurol)
    • Methenamine mandelate (Mandelamine)
    2) Quinolones
    3) Penicillins
    4) Cephalosporins
    5) Sulphonamides & Trimethoprim ( Co-Trimoxazole)
    Urinary Antiseptics:

    Urinary antiseptics are the antimicrobial drugs that are excreted mainly in the
    urine and perform it antiseptic action in the bladder.
    These drugs have no action on the body system.
    These drugs may be given before examination or surgery on the urinary tract or
    to treat UTI.

    Action:
    Urinary Antiseptic are concentrated in the Kidney tubules which are mainly
    useful in lower urinary tract only.
    Nitrofurantoin (Furadantin)
    • M.O.A: Inactivates or alters bacterial ribosomal proteins and other macromolecules that may
    interfere with metabolism and cell wall synthesis.

    • An agent that is both bacteriostatic and bactericidal (at high doses against gram positive and
    gram negative bacteria ( except Proteus and pseudomonas).

    • It is metabolized and excreted so rapidly that no systemic antibacterial action is achieved.

    • The drug is excreted into the urine by both glomerular filtration and tubular secretion.

    • Hence, Nitrofurantoin is contraindicated in patients with significant renal insufficiency.


    Nitrofurantoin (Furadantin)
    • Nitrofurantoin antagonizes the action of Nalidixic Acid.

    • Side Effects: Anorexia, nausea, vomiting, brown discoloration of the urine, and
    hypersensitivity reactions.

    • Neuropathies and hemolytic anemia occur in patients with glucose-6-phosphate


    dehydrogenase deficiency.
    Fosfomycin (Monurol)
    • Fosfomycin is used for UTIs that are caused by susceptible microorganisms.

    • M.O.A: Blocks bacterial cell wall synthesis by inactivating enolpyruvyl


    transferase; also reduces bacterial adherence to uroepithelial cells
    (Bateriocidal)

    • Side Effects: headache, dizziness, nausea, abdominal cramps, and vaginitis.


    Methenamine mandelate (Mandelamine)
    • M.O.A: Methenamine and Methenamine salts break down and form ammonia
    and formaldehyde, which are bactericidal.
    • These drugs are used for UTIs that are caused by susceptible microorganisms.
    • This drug do not exert any antimicrobial action in the blood and body tissue and
    kidneys.

    • Side Effect: Gastrointestinal disturbances such as anorexia, nausea, vomiting,


    stomatitis, and cramps.

    • The drug is used cautiously in patients with renal or hepatic impairment or gout
    (Crystalluria).
    Quinolones
    Quinolones
    • M.O.A: Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II
    (DNA gyrase) and topoisomerase IV.

    • In gram negative bacteria, DNA gyrase (Topoisomerase II) is the primary target.

    • In gram positive bacteria, Topoisomerase IV is the primary target (newer quinolones).

    • Dual MOA:
    1. Inhibition of bacterial DNA Gyrase (Topoisomerase II)
    a) Formation of quinolone-DNA-Gyrase complex
    b) Induced cleavage of DNA

    2. Inhibition of bacterial Topoisomerase IV


    c) Mechanism poorly understood
    Quinolones

    • DNA Gyrase comprises bacterial DNA into supercoils 🡪 Inhibition of DNA


    gyrase leads to the unwinding of the supercoils which leads to cell death.

    • Inhibition of topoisomerase IV is blocked by Flouroquionlones which is


    required by bacteria for cell division.

    • They are primarily used in the treatment of susceptible microorganisms in


    lower respiratory infections, infections of the skin, urinary tract infections, and
    sexually transmitted diseases.
    Mechanism of Action
    Classification of Quinolones
    • First Generation: Nalidixic Acid QUINOLONE

    • Second Generation:
    • Ciprofloxacin
    • Norfloxacin
    • Ofloxacin
    • Enoxacin
    • Lomefloxacin

    • Third Generation:
    • Gatifoxacin FLUOROQUINOLONES
    • Levofloxacin
    • Moxifloxacin
    • Sparfloxacin

    • Fourth Generation:
    • Trovafloxacin
    Quinolones
    Agents Trade Name Availability
    Ciprofloxacin Cipro® PO/IV/GUTT/Eye
    oint./Ear drop
    Ofloxacin Floxin® PO/IV
    Norfloxacin Noroxin® PO
    Enoxacin Penetrex® PO

    Lomefloxacin Maxaquin® PO
    Levofloxacin Levaquin® PO/IV/GUTT
    Sparfloxacin Zagam® PO
    Moxifloxacin Avelox®, PO/IV/GUTT
    Vigamox®
    Nalidixic Acid
    • Non-fluorinated quinolone.

    • Effective against → gram (-)/gram(+) .

    • 1st quinolone with antibacterial activity 🡪 Parent drug

    • Nalidixic Acid does not achieve systemic antibacterial levels therefore usage is
    restricted to uncomplicated UTIs.
    Fluoroquinolones
    •First fluorinated quinolone – Norfloxacin.

    •Newer fluorinated quinolones offer greater potency & broader


    spectrum of antimicrobial activity. (3rd and 4th Generation)

    •Bactericidal

    •Exhibit concentration dependent killing


    Pharmacokinetics:
    Quinolone (1st generation):
    Highly protein bound
    Mostly used in UTIs
    Fluoroquinolones (2nd, 3rd and 4th generation):
    Modified 1st generation quinolone
    Not highly protein bound
    Wide distribution to urine and other tissues; limited CSF penetration.
    Newer 3rd and 4th generation FQ’s have very good activity against
    gram-positive organisms.
    Norfloxacin 🡪 35% to 70% is orally absorbed
    All other Fluoroquinolones 🡪 80% to 99%
    Pharmacokinetics:
    Well distributed into body tissues 🡪 bones, urine (except Moxifloxacin),
    Kidneys, and Prostatic tissue (but not Prostatic fluid.

    Concentrations in the lungs exceed those in serum.

    Penetration into cerebrospinal fluid is relatively low except for Ofloxacin.

    Most fluoroquinolones are excreted renally. Therefore, dosage adjustments are


    needed in renal dysfunction.

    Moxifloxacin is excreted primarily by the liver 🡪 doesn’t require renal dosing


    Flouroquinolones: Spectrum of Activity
    • Gram-positive (Fair)
    • Moderate activity against Staphylococci (MRSA/MRSE)
    • Ofloxacin, Levofloxacin & Sparfloxacin has best in vitro activity against S.
    aureus
    • Poor to moderate activity against streptococci and enterococci
    • Useful in uncomplicated enterococcal UTIs

    • Gram-negative (Excellent)
    • Ciprofloxacin most potent against P. aeruginosa, however there is recent
    development of resistance.
    • Excellent activity against Enterobacteriaceae.
    • Used in gram negative osteomyelitis, bacteremia, gastroenteritis & UTIs
    Flouroquinolones: Spectrum of Activity
    • Anaerobes
    • Only Moxifloxacin has coverage against Anaerobes

    • Atypical
    • Levofloxacin & Sparfloxacin active against Chlamydia and Mycoplasma
    pneumoniae

    • Other pathogens
    • Mycobacteria: M. avium complex (ciprofloxacin), M. tuberculosis MDRTB
    (Ofloxacin)
    • STD pathogens: C. trachomatis (Ofloxacin), N. gonorrhoeae (many as
    single dose)
    • Enteric pathogen: E. coli, Campylobacter, Salmonella, Shigella
    Flouroquinolones: Spectrum of Activity
    Ciprofloxacin
    • Good gram-negative coverage

    • N. gonorrhea, H. influenzae

    • UTI, Traveler’s diarrhea caused by E. coli and Typhoid fever caused by Salmonella Typhi

    • Best activity against P. aeruginosa and is commonly used in Cystic Fibrosis

    Levofloxacin
    • L-enantiomer of Ofloxacin

    • Better gram-positive coverage (mainly Streptococcus) than Ciprofloxacin

    • Used for LRTI

    Moxifloxacin
    • Quite broad-spectrum

    • Activity against Strep/Staph plus gram-negatives


    • Anaerobic coverage
    • Minimal to no Anti-pseudomonal activity
    Clinical uses of Fluoroquinolones:
    Disease Recommendations
    RESPIRATORY TRACT INFECTIONS/ENT
    Pharyngitis, otitis media Not appropriate
    Necrotizing otitis Ciprofloxacin for Pseudomonas aeruginosa
    Sinusitis Third-generation fluoroquinolone
    Community-acquired pneumonia Third-generation fluoroquinolone
    Hospital-acquired pneumonia Ciprofloxacin, for susceptible gram-negative
    pathogens
    URINARY TRACT INFECTIONS
    Cystitis, uncomplicated All effective (second generation most appropriate)

    Pyelonephritis All effective (second generation most appropriate)


    Prostatitis All effective
    SKIN STRUCTURE INFECTIONS
    Primary cellulitis Not appropriate as first line therapy
    Anaerobic soft-tissue infections Not appropriate
    Clinical uses of Fluoroquinolones:
    Disease Recommendations
    OSTEOMYELITIS
    Gram-negative bacterial infections Ciprofloxacin
    BACTERIAL DIARRHEAL DISEASES Ciprofloxacin used most commonly; all considered
    likely to be effective
    SEXUALLY TRANSMITTED DISEASES
    Gonorrhea Resistance testing required
    Chlamydia Ofloxacin, levofloxacin
    Chancroid All likely to be effective
    Mycoplasma Ofloxacin, levofloxacin
    Syphilis Not appropriate
    MYCOBACTERIAL DISEASES
    Disseminated M. avium complex Ciprofloxacin, ofloxacin as fourth agent if needed
    M. tuberculosis Ofloxacin, levofloxacin for drug-resistance or
    intolerance to first-line agents
    Adverse Effects:
    1.GI Disturbances (< 4%): Vomiting, Nausea, Diarrhea.
    2. CNS disturbances (< 3%) : Insomnia, Confusion, Convulsions, Dizziness.
    (Enoxacin)
    3. Nephrotoxicity → Crystalluria in patients receiving high dose, Interstitial
    Nephritis
    4. Photosensitivity (< 2-4%) - Sparfloxacin--sunlight or artificial UV light
    5. Articular Cartilage Erosion 🡪 Damage in growing cartilage (Adolescent
    Arthropathy.
    • Contraindicated in pregnancy, lactation and in children under 18 years.
    6. Tendonitis or Tendon rupture
    7. Prolongation of the QT interval 🡪 Arrhythmias
    8. Hypoglycemia and hyperglycemia
    Drug Interaction
    1. Antacid containing Aluminium & Magnesium/Sucralfate/Dietary supplements
    containing Iron or Zinc/Calcium and other divalent and multivalent cations =
    Decreased absorption of Fluoroquinolones

    2. Fluoroquinolones + Theophylline/Caffeine/Warfarin/Cyclosporine = Increased


    Plasma Concentration of those drugs
    • Cytochrome P 450:
    Enoxacin>Ciprofloxacin>Ofloxacin>Lomefloxacin
    • Theophylline/caffeine- no interaction with Norfloxacin, Ofloxacin,
    Lomefloxacin and Fleroxacin.
    • Enoxacin- most potent effect on theophylline metabolism (~60% reduction)
    3. NSAIDS- possibility increases CNS excitation 🡪 Seizures

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