Quinolones and Fluoroquinolones

Bacterial Nucleic Acid Inhibitors: 1-Quinolones

Lecture objectives

• List examples of hepatotoxic and nephrotoxic antimicrobials
• Explain why quinolones are not used in pregnancy
• List choices of antimicrobials for staph, anaerobes, gram-negative, and gram-positive infections
• Explain the rationale for combining sulphonamide and trimethoprim
• List antibiotics used in atypical organisms
• Understand why rifampicin is used in specific infections
• Explain why some antibiotics are restricted in pregnancy and specific ages
• Discuss the pharmacokinetic parameters of antibiotics

Quinolones and Fluoroquinolones (FQs)

• Nalidixic acid was the first quinolone to be introduced and is the predecessor to all fluoroquinolones
• The addition of Fluorine at position-6 of the quinolone nucleus was found to increase antimicrobial activity and improve pharmacokinetics during the 1980s through numerous structural modifications

Mechanism Of Action

• The main target of quinolones is DNA gyrase (topoisomerases II & topoisomerase IV)
• DNA gyrase is responsible for cutting one of the chromosomal DNA strands at the beginning of the supercoiling process
• The nick is only introduced temporarily and the two ends are later joined back together
• The quinolone molecule forms a stable complex with DNA gyrase, thus inhibiting its activity, and preventing the repair of DNA cuts

Spectrum

• Broad spectrum effective against gram-positive and gram-negative organisms, atypical organisms (Legionella, Chlamydia), and some mycobacteria (Mycobacterium tuberculosis)
• Fluoroquinolones are typically not used for the treatment of Staphylococcus aureus or enterococcal infections

Fluoroquinolone Generations

• Nalidixic acid is considered first generation, has a narrow spectrum of susceptible organisms
• Ciprofloxacin, ofloxacin, and norfloxacin are second generation and mainly active against aerobic gram-negative, atypical bacteria, and mycobacteria
• Levofloxacin (l-isomer of ofloxacin) has largely replaced ofloxacin and is classified as third generation due to increased activity against gram-positive bacteria
• Moxifloxacin is fourth generation due to its activity against anaerobic and gram-positive organisms
• Levofloxacin and moxifloxacin are referred to as "respiratory fluoroquinolones" because they have excellent activity against S. pneumoniae, a common cause of community-acquired pneumonia (CAP)
• Fluoroquinolones accumulate significantly in macrophages and polymorphonuclear leukocytes, thus therapy for infections in which a bacterium spends part of its life cycle inside a host cell
• Levofloxacin and moxifloxacin have the longest half-lives, permitting once-daily dosing

Pharmacokinetics

• Absorption: Fluoroquinolones can form a complex with (chelate) sucralfate, aluminum- or magnesium-containing antacids, or dietary supplements containing iron or zinc (multivitamins), which reduces absorption
• Milk, calcium, and other divalent cations also interfere with absorption
• Separate these agents by at least 2 hours
• Distribution: Fluoroquinolones distribute well into all tissues and body fluids, with high levels found in bone, urine (except moxifloxacin), lungs, kidney, and prostatic tissue
• Penetration into cerebrospinal fluid is relatively low (except for ofloxacin)
• Elimination: Most fluoroquinolones are excreted renally, therefore, dosage adjustments are needed in renal dysfunction (except moxifloxacin)
• Moxifloxacin is excreted primarily by the liver, and no dose adjustment is required for renal impairment

Uses of Specific Fluoroquinolones

• Norfloxacin: Infrequently prescribed due to poor oral bioavailability and short half-life
• it is effective in treating non-systemic infections, such as urinary tract infections (UTIs), prostatitis, and infectious diarrhea
• Levofloxacin: Has broad spectrum activity and is used in a wide range of infections including: Prostatitis, skin infections, community-acquired pneumonia (CAP), and nosocomial pneumonia
• excellent activity against S. pneumoniae respiratory infections and is dosed once daily
• Ciprofloxacin: Effective in treating many systemic infections caused by gram-negative bacilli
• has the best activity against P. aeruginosa
• effective for traveler's diarrhea caused by E. coli, typhoid fever caused by Salmonella typhi, and tuberculosis (second-line agent)
• Moxifloxacin: Has poor activity against P. aeruginosa, is not indicated for the treatment of UTIs
• Fluoroquinolones used in bone and joint infections caused by gram-negative organisms
• Also used in ophthalmic infections
• Gonorrhea, chlamydia & Prostatitis
• PU (H.Pylori) only Levofloxacin
• Used in cystic fibrosis in adolescents and UTI
• Fluoroquinolones are alternatives for patients with a documented severe β-lactam allergy, if other antibiotics fail

Adverse Reactions

• Several fluoroquinolones have been removed from the market due to serious side effects (trovafloxacin and gatifloxacin)
• Nausea, vomiting, diarrhea, headache, dizziness, or light-headedness
• Patients with central nervous system (CNS) disorders, such as epilepsy, should be treated cautiously (seizure-inducing potential), also, peripheral neuropathy and visual disturbances
• Patients should use sunscreen and avoid excess exposure to sunlight due to phototoxicity
• If phototoxicity occurs, discontinuation of the drug is advisable
• Articular cartilage erosion (arthropathy) affects immature animals exposed to fluoroquinolones, thus 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 those taking corticosteroids
• Tendonitis usually precedes rupture, so complaints of tendon pain should be taken seriously
• Vigorous exercise should be avoided during fluoroquinolone therapy, particularly in patients receiving corticosteroids
• Can exacerbate muscle weakness in patients with myasthenia gravis
• Interstitial nephritis and crystalluria and pseudomembranous colitis
• Moxifloxacin and other fluoroquinolones may prolong the QTc interval, contraindicated for patients predisposed to arrhythmias or those taking other medications that cause QT prolongation
• Trovafloxacin was rapidly removed from the market after release due to cardiac arrhythmias, liver destruction, and phototoxicity
• Quinolones may raise the serum levels of warfarin, caffeine, cyclosporine, and theophylline by inhibiting their metabolism (cytochrome oxidase enzymes in the liver)
• Gatifloxacin was removed from the market for causing diabetes
• Can result in allergy and resistance
• G.I.T upset (early diarrhea)
• Superinfection -CDAD (late diarrhea)

2-Metronidazole

• MOA: The drug must be activated to work
• Metronidazole (contains a nitro group) is a prodrug reduced (accepts electrons) intracellularly by anaerobic bacteria and protozoa to its active form
• Anaerobic bacteria and protozoa (not aerobic bacteria) activate the nitroimidazole molecule, which forms free radicals that damage DNA and lead to cell death

Spectrum

• The small molecule can passively diffuse into protozoa and bacteria
• Active against G+ve and G-ve anaerobes, including C. difficile and H. pylori

3-Rifampicin

• Bactericidal and inhibits DNA-dependent RNA polymerase (inhibits m-RNA synthesis)

4-Fidaxomicin

• Inhibitions of nucleic acid synthesis
  • DNA synthesis: Metronidazole
  • DNA Gyrase & Topoisomerase IV: Quinolones
  • RNA Polymerase: Rifampicin

Lecture on quinolones and fluoroquinolones including mechanism of action and antimicrobial activity. Quinolones target bacteria by inhibiting DNA gyrase and topoisomerase IV, enzymes essential for DNA replication, repair, and transcription. Adding fluorine enhances antimicrobial activity.