C.14 Flashcards
Quinolones and Fluoroquinolones
Norfloxacin,
Ciprofloxacin,
Ofloxacin,
Levofloxacin,
Moxifloxacin
MOA of Quinolones and fluoroquinolones
Inhibitors of topoisomerase II (=DNA-gyrase) or IV → inhibit nucleic acid synthesis
Inhibition of topoisomerase II (DNA gyrase)
- in case of G(-) bacteria (e.g. E.Coli) the primary target
- Prevents the relaxation of supercoiled DNA (required for normal transcription and replication
Inhibition of topoisomerase IV
- Staph, Strep - the primary target
- Interferes with separation of replicated chromosomal DNA into the respective daughter cells during division
quinolones
Non-fluorinated
MOA: Inhibitors of topoisomerase II (=DNA-gyrase) or IV → inhibit nucleic acid synthesis;
Resistance development:
1. Point mutations in the quinolone binding region of the target enzyme,
2. Change in permeability,
3.Non-fluorinated quinolones → resistance is common
Fluoroquinolones
MOA: Inhibitors of topoisomerase II (=DNA gyrase) or IV;
Resistance development:
1. Point mutations in the quinolone binding region of the target enzyme,
2. Change in permeability; Fluorinated quinolones → resistance is developing more slowly than non-fluorinated, but e.g. S. pneumonia is more and more often resistant!;
Spectrum & resistance: Has improved antibacterial activity, broader spectrum and less resistance;
Pharmacokinetics: Better, achieve high levels (bactericidal levels) in blood and tissues, metabolized by Cytochrome P450 and eliminated by the kidneys, they also inhibit cytochrome P450;
Classified into 4 groups
Adverse effects of quinolones
Usually well tolerated!
- Neurologic/psychic (→Nervousness, sleep disturbances, dizziness, rarely hallucinations, convulsions, psychotic states (interaction with GABA or NMDA receptors?))
- Photosensitivity;
- Cardiotoxicity (→ QT prolongation: Risk of arrhythmias - may occur with levoflaxcin and moxifloxacin)
- Chondrotoxicity (→ may damage growing cartilage in children, may cause severe tendinitis in adults (esp. pefloxacin))
Interactions of quinolones
- Elevation of coffein and theophyllin level (esp. enoxacin and ciprofloxacin)
- Binding to di or trivalent ions (Ca, Al, Mg, Fe, Zn) → antacids, meal may reduce bioavailability
- Glucocorticoids - increase the risk of tendon rupture, convulsions!
quinolones Contra-ind
- Combination with Class Ia or III anti-arrhytmic drugs, erythromycin, TCA is dangerous, abnormal potassium levels.
- Pregnancy, nursing women
- Children under 18 yo (not absolute!)
- CNS diseases (e.g. epilepsy)
- Quinolone allergy
FLUOROQUINOLONES classification
- Group I (Generation 1)
Norfloxacin - Group II (generation II)
Ciprofloxacin, Ofloxacin - Group III
Levofloxacin - L-isomer of Ofloxacin - Group IV (Genertion IV)
Moxifloxacin
Norfloxacin
Spectrum: Good against most Gram (-) aerob bacteria → E.coli (facultative anaerobe), K.pneumoniae (facultative anaerobe), P.mirabilis (facultative anaerobe), Shigella (facultative anaerobe), neisseria (obligate aerobe), H.influenza (generally aerobe);
No or limited activity: pseudomonas, gram + cocci, anaerobe, intracellular and atypical bacteria;
Pharmacokinetics: high levels in the urinary tract!, Lower bioavailability or too rapid renal excretion → does not achieve adequate systemic concentration. Bioavailability is reduced by divalent cations! Dose adjustment in renal failure!;
IND: UTIs (incl. prostatitis) or in case of enteritis!;
ROA & Times: 2xdaily orally
Ciprofloxacin, Ofloxacin
Spectrum: Excellent activity against Gram (-) aerobes. Better (Moderate-good) activity against Gram + cocci. Good against legionella, less action (but still active in higher concentration against atypical bacteria (e.g. Mycoplasma, chlamydia - especially ofloxacin) Anaerobes are resistant;
Pharmacokinetics: High oral bioavailability (70-95%) - oral absorption is impaired by divalent cations (meal, antacids!). Wide distribution in tissues. Elimination mostly by renal mechanisms. Dose adjustment in renal failure!;
Main differences:
-Ciprofloxacin: Against Pseudomonas! - in part extrarenal routes of elimination - dose adjustment in renal failure is not needed!,
-Ofloxacin: Good against atypical bacteria (mycoplasma, chalmydia);
IND: Mostly ciprofloxacin and ofloxacin; 2x daily. UTIs (often even when caused by multidrug-resistant bacteria e.g. pseudomonas), Bacterial diarrhea (caused by: Shigella, salmonella (typhus), E. Coli, Campylobacter), Soft tissue, bone, joint and systemic infections - sepsis;
Resistanse: Pneumococci are usually resistant/less sensitive → NOT recommended for empirical treatment of pneumonia, Anaerobes are resistant
Levofloxacin
2x potent as Ofloxacin → superior activity against some microbes;
Spectrum: Similar to second group, better activity against some Gram (+) - Str. pneumonia and atypical mycoplasma bacteria, mycobacteria;
Resistance: Anaerobes;
Pharmacokinetics: High oral bioavailability (>90%) - oral absorption is impaired by divalent cations (meal, antacids). Wide distribution in tissues, elimination moslty by kidney → dose adjustment in renal failure!;
IND: respiratory infections, Due to enhanced Gram (+) activity and activity against atypical pneumonia agents (Chlamydia, mycoplasma, legionella), Not as active against Gram (-) as ciprofloxacin (Group II);
ROA: P.O/I.V 1-2xdaily
Moxifloxacin
Spectrum: Similar to 3rd group, more activity against some Gram (+). Some activity against anaerobes as well!;
Pharmacokinetics: absorption impaired by divalent cations. Wide distribution in tissues. Elimated mostly non-renal → Dose adjustment in renal failure is not necessary;
Countra-IND: Hepatic failure;
T1/2: Long - once daily dosage;
IND: Upper and Lower respiratory tract infections + UTIs!, Gram (+) activity and activity against atypical pneumonia agents (Chlamydia, mycoplasma, legionella);
ROA: P.O
