14 Quinolones and fluoroquinolones

Question 1

What is the mechanism of action of fluoroquinolones and quinolones?

Answer 1

• They enter bacteria through porin channels and exhibit antimicrobial effects on DNA gyrase and bacterial topoisomerase IV
  
  • The inhibition of DNA gyrase prevents relaxation of supercoiled DNA, promoting DNA strand breakage
  • Inhibition of topoisomerase IV impacts the chromosomal stabilization during cell division ==> inhibition of separation of newly replicated DNA
• In gram (-) the inhibition of DNA gyrase is more significant than that of topoisomerase IV, in gram (+) it is the opposite
• Concentration-dependent bactericidal effect
• Long PAE

Question 2

What are the characteristics of non-fluorinated quinolones?

Drugs?

Pharmacokinetics?

Spectrums?

…

Answer 2

• E.g. nalidixic acid (oxolinic acid)
• Weak antibacterial action

Pharmacokinetics:

• Too rapid excretion into the urine ==> don’t achieve systemic antibacterial levels
  
  • Possible use in lower urinary tract infections only
• Interactions:
  
  • Inhibition of CYP1A2
  • Binding to di- or trivalent ions (Ca, Al, Mg, Fe, Zn)
  • Antacids, meal may reduce bioavailability
  • Glucocorticoids increase the risk for tendon rupture, convulsions

Spectrum:

• Narrow spectrum: gram (-) aerobic
• Resistance:
  
  • Point mutations in the quinolone-binding site of the target enzyme
  • Change in permeability
  • Non-fluorinated quinolones: resistance is common
  • Fluorinated quinolones: resistance develops more slowly, but streptococcus pneumoniae is more and more often resistant

Indications:

• UTIs, but not recommended anymore

Adverse effects:

• GI disturbances
• CNS disturbances
• Contraindications:
  
  • Pregnancy, nursing women
  • Children under 18 years of age (not absolute!)
  • Quinolones allergy
  • CNS disease (e.g. epilepsy)

Question 3

What are the general characteristics of fluoroquinolones?

Answer 3

• 4 generations with common precursor: Nalidixic acid
• Greatly improved antibacterial activity, broader spectrum, less resistant
• Better pharmacokinetics: achieving high levels (bactericidal levels) in blood and tissue

Pharmacokinetics (gen. 2-4):

• High oral bioavailability (70-95%)
  
  • Oral absorption is impaired by divalent cations (meal, antacids)
• Wide distribution in tissues, low CNS penetration
• Elimination mostly by renal mechanism (dose adjustment in renal failure)
  
  • Ciprofloxacin: in part, extra-renal routes of elimination
    
    • Dose adjustment in renal failure is not needed
  • Gemifloxacin in part, moxifloxacin mostly by non-renal elimination
• AUC/MIC-dependent killing:
  
  • When drug concentration ­ to 30-fold of MIC bactericidal activity is more pronounced

Clinical use:

• UTI (1^st and 2^nd generation, not moxifloxacin)
• Bacterial diarrhea, skin and soft tissue infections, intra-abdominal infections
• RTI (against multiresistant pseudomonas and enterobacter)
• Gonococcal infection (ciprofloxacin and ofloxacin now has high resistance)
• Anthrax (ciprofloxacin), mycobacterial (atypical) infections (ciprofloxacin, levofloxacin, moxifloxacin)
• Chronic or nosocomial respiratory tract infections (3^rd generation)
  
  • 1^st and 2^nd generation not recommended in acute community acquired infections (pneumococcus)
  • Levofloxacin (4^th generation) and mocifloxacin (3^rd generation) has excellent effect against S. pneumoniae

Adverse effects:

• Well tolerated drugs
• May damage growing cartilage (generally not given under age of 18 years, exception – pseudomonas infection in cystic fibrosis)
• Tendinitis (rarely)
• Photosensitivity
• GI symptoms
  
  • Pseudomembranous colitis
• Neurological/psychic:
  
  • Nervousness, sleep disturbances, rarely hallucinations, convulsions, psychotic states (interactions with GABA and NMDA receptor)
• Cardiotoxicity:
  
  • QT-prolongation ==> risk of arrhythmias (most with sparfloxacin, may occur with levofloxacin and moxifloxacin)
• Combination with class a1 and II anti-arrhythmic, erythromycin, TCA is dangerous, normal potassium level is important

Question 4

What are the 1st generation fluoroquinolones?

Answer 4

Norfloxacin:

• Spectrum:
  
  • Good activity against most gram (-) aerobe bacteria (E.coli, K. pneumoniae, P. mirabilis, shigella, Neisseria, H. influenza)
  • No or limited activity against Pseudomonas, gram (+) cocci, anaerobe, intracellular and atypical bacteria
• Pharmacokinetics:
  
  • Lower bioavailability or too rapid renal excretion ==> dose not achieved adequate systemic concentration, but high level in the urinary tract
  • Short half-life
  • Administration:
    
    • Oral, 2x/day
• Clinical use:
  
  • UTI (including prostatitis)
  • Enteritis
• Adverse effects:
  
  • GI disturbances
  • CNS disturbances

Question 5

What are the 2nd generation fluoroquinolones?

Answer 5

• Ciprofloxacin, enoxacin, ofloxacin, pefloxacin, lomefloxacin:
  
  • Spectrum:
    
    • Excellent activity against gram (-) aerobe bacteria (only ciprofloxacin – even against Pseudomonas, used in CF)
      
      • B. Antracis (ciprofloxacin)
    • Better (moderate to good) activity against gram (+) cocci (mainly penicillin resistant staphylococci (but MRSA uncertain))
    • Good action against legionella
    • Less action (but still active in higher concentration) against atypical bacteria (e.g. mycoplasma, Chlamydia – especially ofloxacin)
    • Mycobacterium
    • Anaerobes are resistant
  • Clinical use:
    
    • Mostly ciprofloxacin and ofloxacin
      
      • 2x daily oral (also topical solutions)
    • UTIs, often even when caused by multidrug-resistant bacteria
      
      • E.g. pseudomonas (especially ciprofloxacin)
    • Bacterial diarrhea caused by shigella, salmonella (typhus), E. coli, campylobacter
    • Soft tissue, bone, joint and systemic infections (including sepsis)
    • Gram (-) nosocomial infections (ciprofloxacin - cystic fibrosis or other bronchopulmonal Pseudomonas infections)
    • Acute exacerbation in chronic suppurative otitis, chronic sinusitis (alternative)
    • Pelvic infections (Neisseria Gonorrhea)
    • Used as 2^nd line treatment for tuberculosis
  • Pharmacokinetics:
    
    • High serum concentration
    • Good absorption and distribution, but no entry in CNS
    • Ofloxacin is completely excreted via kidney without inactivation
    • Ciprofloxacin is partly eliminated via the kidney
    • Administration:
      
      • Oral, parenteral and topical
  • Adverse effects:
    
    • GI disturbances
    • CNS disturbances
    • Bone, cartilage disturbances in adolescents
    • Drug interactions

Question 6

What are the 3rd generation fluoroquinolones?

Answer 6

• Levofloxacin, sparfloxacin:
  
  • Levofloxacin is the L-isomer of ofloxacin
    
    • Twice as potent, superior activity against some microbes
  • Spectrum:
    
    • Similar to the 2^nd generation
      
      • Less activity against Pseudomonas aeruginosa
    • Better activity against some gram (+) (streptococcus pneumonia) and atypical (mycoplasma) bacteria
    • Mycobacteria
  • Clinical use:
    
    • Indications: more respiratory orientation
      
      • Due to enhanced gram (+) activity and activity against atypical pneumonia agents (Chlamydia, mycoplasma, legionella)
      • Superior in upper and lower respiratory tract infections (compared with group II)
    • Not as active against gram (-) bacteria as ciprofloxacin
  • Pharmacokinetics:
    
    • Same as 2^nd generation
  • Adverse effects:
    
    • GI disturbances
    • QT interval prolongation
    • Phototoxicity

Question 7

What are the 4th generation fluoroquinolones?

Answer 7

• Moxifloxacin, gemifloxacin, prulifloxacin:
  
  • Spectrum:
    
    • Similar to the 3^rd group
    • Further improved activity against some gram (+) (streptococcus pneumoniae)
    • Moxifloxacin has some activity against anaerobes as well
    • Intracellular pathogens
  • Clinical use:
    
    • Moxifloxacin:
      
      • Home acquired pneumonia (even aspiration)
      • Intraabdominal infections
      • Complicated skin and soft tissue infections
    • Prulifloxacin (prodrug of ulifloxacin)
      
      • Complicated low UTI
      • Exacerbation of chronic bronchitis
  • Pharmacokinetics:
    
    • Moxifloxacin, prulifloxacin has long half-life
      
      • 1x/day dosage
    • Moxifloxacin is mainly metabolized in the liver and is not excreted through the kidney
      
      • Oral, parenteral
    • Prulifloxacin is eliminated through the kidneys
      
      • Oral
    • Good absorption
    • Low elimination
  • Adverse effect:
    
    • GI disturbances
    • CNS disturbances
    • Selection of C. difficile