Quinolones: Mechanism and Spectrum

Bacterial Nucleic Acid Inhibitors: 1-Quinolones

• Nalidixic acid was the first quinolone introduced and is the predecessor to all fluoroquinolones.
• Structural modifications in the 1980s showed that adding fluorine at position-6 of the quinolone nucleus increases antimicrobial activity and improves pharmacokinetics.

Mechanism of Action: Quinolones

• The primary quinolone target is DNA gyrase (topoisomerases II & IV) which cuts one chromosomal DNA strand at the beginning of supercoiling.
• The quinolone molecule forms a stable complex with DNA gyrase, inhibiting its activity and prevents the repair of DNA cuts.

Spectrum of Activity

• Quinolones have a broad spectrum against gram-positive and gram-negative organisms, atypical organisms (Legionella, Chlamydia), and some mycobacteria (Mycobacterium tuberculosis).
• Fluoroquinolones are typically not used for treating Staphylococcus aureus or enterococcal infections.

Fluoroquinolone Generations

• Nalidixic acid is considered first generation, with a narrow spectrum of susceptible organisms.
• Ciprofloxacin, ofloxacin, and norfloxacin are second generation, active mainly against aerobic gram-negative, atypical bacteria, and mycobacteria.
• Levofloxacin (l-isomer of ofloxacin) is third generation, with increased activity against gram-positive bacteria.
• Moxifloxacin is fourth generation, effective against anaerobic and gram-positive organisms.
• Levofloxacin and moxifloxacin are referred to as respiratory fluoroquinolones because of their excellent activity against S. pneumoniae, which is a common pneumonia cause. -Fluoroquinolones accumulate in macrophages and polymorphonuclear leukocytes, allowing therapy for infections where bacteria spend part of their life cycle inside a host cell.
• Levofloxacin and moxifloxacin have the longest half-lives, allowing once-daily dosing.

Pharmacokinetics

• Absorption: Fluoroquinolones can form complexes with (chelate) sucralfate, aluminum- or magnesium-containing antacids, or dietary supplements containing iron or zinc, reducing their absorption.
• Milk, calcium, and other divalent cations can also interfere with absorption.
• Absorption interfering agents should be separated by at least 2 hours or cease a week before doses.
• Distribution: Fluoroquinolones distribute well into all tissues and body fluids, with high levels in bone, urine (except moxifloxacin), lungs, kidney, and prostatic tissue.
• Penetration into cerebrospinal fluid is low (except ofloxacin).
• Elimination: Most fluoroquinolones are excreted renally, requiring dosage adjustments in renal dysfunction (except moxifloxacin). -Moxifloxacin is primarily excreted by the liver, and does not require dosage adjustment for renal impairment.

Clinical Uses of Specific Quinolones

• Norfloxacin: infrequently prescribed due to poor oral bioavailability and a short half-life.
  • Effective in treating non-systemic infections like urinary tract infections (UTIs), prostatitis, and infectious diarrhea.
• Levofloxacin: has broad spectrum activity and is used in a wide range of infections.
  • These infections include: prostatitis, skin infections, community-acquired pneumonia (CAP), and nosocomial pneumonia.
  • Levofloxacin has excellent activity against S. pneumoniae respiratory infections and is dosed once daily.
• Ciprofloxacin: effective in treating systemic infections caused by gram-negative bacilli.
  • Ciprofloxacin has the best activity against P. aeruginosa.
  • Effective for traveler's diarrhea caused by E. coli, typhoid fever caused by Salmonella typhi, and tuberculosis (as a second-line agent).
• Moxifloxacin: has poor activity against P. aeruginosa.
  • Moxifloxacin does not concentrate in urine and is not indicated for treating UTIs.
• Quinolones can treat bone and jointinfections caused by gram-negative organisms.
• Quinolones can treat Ophthalmic infections.
• Quinolones can treat Gonorrhea, Chlamydia & Prostatitis.
• Levofloxacin is uswed to treat PU (H.Pylori).
• Quinolones are ued in cystic fibrosis in adolescents and UTI. -Fluoroquinolones are alternatives if other antibiotics failed and for patients with documented severe β-lactam allergy.

Adverse Reactions

• Several fluoroquinolones removed from market for serious side effects include trovafloxacin and gatifloxacin.
• Common adverse reactions include nausea, vomiting, diarrhea, headache, dizziness, or light-headedness.
• Patients with central nervous system (CNS) disorders, such as epilepsy, should be treated cautiously due to seizure-inducing potential and peripheral neuropathy.
• Photosensitivity: patients taking these agents should use sunscreen, and discontinue if phototoxicity occurs.
• Articular cartilage erosion (arthropathy) has been seen in immature animals exposed to fluoroquinolones.
  • Thesedrugs should be avoided in pregnancy and lactation, and in children under 18 years of age.
• Arthralgia and increased risk of tendinitis or tendon rupture is more common in the elderly, with renal dysfunction, or in those taking corticosteroids.
• Tendonitis usually precedes rupture, so tendon pain complaints should be taken seriously.
  • Vigorous exercise should be avoided during fluoroquinolone therapy, especially in patients receiving corticosteroids.
  • Fluoroquinolones can also exacerbate muscle weakness in patients with myasthenia gravis.
• Other adverse reations include:Interstitial nephritis, Crystalluria, Pseudomembranous colitis, and Prolonged QTc internal.
• Patients with predispositions to arrythmias or patients currently taking medications causing QT prelongation should not use Quinolones.
• Trovafloxacin was removed from market due to: cardiac arrhythmias, liver destruction, and phototoxicity
• Quinolones may raise the serum levels of warfarin, caffeine, cyclosporine, and theophylline by inhibiting their metabolism via cytochrome oxidase enzymes in the liver.
• Gatifloxacin was removed from the market because it can cause diabetes.
• Patient may develop Allergy and resistance when treated with Quinolones.
• Possible gastrointestinal issues for some people taking Quinolones.
• Patient may develop Superinfection -CDAD, symptoms include late diarrhea.

Metronidazole

• Metronidazole, an anaerobic infection DOC is a prodrug with a nitro group that accepts electrons intracellularly from anaerobic bacteria and protozoa to its active form.
• Activate nitroimidazole molecule that forms free radicals, damaging DNA and leading to cell death.
• Metronidazole has a small molecule that can passively diffuse into protozoa and bacteria, effective against G+ve and G-ve anaerobes, including C. difficile and H. pylori.

Rifampicin

• Inhibits DNA-dependent RNA polymerase, inhibiting m-RNA synthesis

Inhibitors of Nucleic Acid Synthesis

• DNA Gyrase & Topoisomerase IV: Quinolones
• RNA Polymerase: Rifampicin
• DNA Synthesis: Metronidazole

An overview of quinolones, a type of bacterial nucleic acid inhibitor. It covers their mechanism of action, primarily targeting DNA gyrase, and their broad spectrum of activity against various organisms. Fluoroquinolones are generally not used for Staphylococcus aureus or enterococcal infections.