Quinolones Flashcards
Quinolones in general
•Quinolone carboxylic acid derivatives are synthetic anti-microbial agents
A. Aminoquinolines: e.g. chloroquine, primaquine (antimalarial drugs)
B. Hydroxy-(halogenated-) quinolones e.g. chlorquinadole
C. Isoquinoline derivatives (e.g. papverine, paraziquantel)
D. Quinolone carboxylic acids (ketone group)
•Known generically as fluroquinolones or 4-quinolones, these drugs are derived from several closely related ring structures that have certain common features
•OBS! CIA and very imp. in human med. –> only use them when there are no other options available! 2 exceptions:
1. Life threatening infections
2. Prostatitis in dog (FQ and Sulphonamides are only drugs with outstanding activity – but FQ are better)
Structure - effect relationship
•Quinolones: (4-quinolones or fluoroquinolones)
•Quinolin- (or Naphtyridine-) structure
•Antibacterial effect:
3. Position: carboxyl –> attaching to
4. Position: ketone –> site of action
•Broader spectrum:
6. Position: flour
1. Position: cyclopropyl, ethyl, fluorophenyl
5. Position: NH2, CH3, flour
7. Position: piperazine, diazabicyclonil
8. Position: flour, methoxi, cyano (8-ciano-quinolones)
Drugs
- st generation: (Nalidixic acid, Oxalinic acid, Cinoxcin)
- generation: (Flumequine, Norfloxacin)
- generation: Enrofloxacin, Marbofloxacin, Danofloxacin, Dinofloxacin, (Iblafloxacin, Pefloxacin, Ciprofloxacin, Oflaxacin, Orbifloxacin, Sarafloxacin)
3rd. generation: (Balofloxacin, Levofloxacin, Sparfloxacin, Temafloxacin)
4th. generation: (Pradofloxacin, Gatifloxacin, Gemifloxacin, Moxifloxacin, Trovafloxacin)
- generation: Enrofloxacin, Marbofloxacin, Danofloxacin, Dinofloxacin, (Iblafloxacin, Pefloxacin, Ciprofloxacin, Oflaxacin, Orbifloxacin, Sarafloxacin)
Mechanism of action
•Inhibition of DNA synthesis by promoting cleavage of bacterial DNA in the DNA-enzyme complexes of DNA gyrase (type II Topoisomerase, Gr-) & type IV Topoisomerase (Gr+), resulting in rapid bacterial death.
Mode of action
- Bactericidal, conc. dependent! + PAE
* AUC : MIC should be at least 125, Cmax: MIC should be 10x bigger – if too low ratio = resistance.
Antibacterial spectrum
-4-quinolones - 1st gen: rel. small antibac. spectrum
o Gr- bacteria – Enterobacteriacae family
-FQ - 2.1st gen.
o Mainly Gr- bacteria
o Enterobacteriacae family, Aeromonas spp. (fish farming)
-FQ - 2.2nd gen
o Mainly Gr- bacteria: Enterobacteriaceae family, Klebsiella spp., Bordatella bronchiseptica & Actinobacillus pleuropneumoniae, Haemophilus somnus & Pasteurella spp., Mycoplasma spp, Ureaplasma spp., Pseudomonas spp. (P. aeruginosa - 1st. choice: Ciprofloxacin, 2.best: Marbo, 3rd.best: Enro.), Brucella sp.
o Some Gr+ bacteria: Staph spp. (S. aureus, S. pseudointermedius), Mycobacterium spp
-FQ - 3rd & 4th gen.: mainly used in hu med
-3rd gen
o Enterobacteriaceae
o Atypical pathogens (Chlamydia pneumoniae, Mycoplasma pneumoniae)
o Strept (only Hu, we use Penicillins instead)
-4th gen
o Pradofloxacin: v. valuable drug –> prohibited in food prod. animals.
o Improved Gr+ coverage & added anaerobic coverage (intra-abd. infections)
o Enterobacteriaceae, atypical pathogens, MRSA, Strep, anaerobes (Porphyromonas & Prevotella spp)
o BUT – P. aeruginosa reduced or absent*
Resistance
•Significant!
•Chromosomal mutation. Developing rel. fast, when drugs are used “heavily”, due to selection pressure or using sublethal concentrations.
•Mechanisms:
o Changes in DNA-gyrase A gene
o Membrane proteins (inhibited penetration)
o Increased bacterial efflux
•Frequent among zoonotic E. coli, Salmonella & Campylobacter strains & Mycoplasma
•Cross resistance is complete within the groups (generations!) limitations?
•Changes in gyrase A gene (gry-A) resistance against 1st gen
•Changes in both gyrase A & B gene - full resistance
•CVMP (committee for medical products for veterinary use) – public statement on the use of FQ in food-prod animals in EU: development of resistance & impact on human & animal health
Pharmacokinetics
•Excellent (lipophilic): one shot of injection can cure the animal – very good against resistance!
•Absorption: excellent abs after PO, good bioavail. in monogastrics (very pure in adult cattle). Food delays time to peak!
* Divalent or trivalent cations (e.g. Ca, Fe, Mg, Zn or Al) may reduce abs..
* SC, IM good absorption
•Distribution: excellent, very high Vd, high conc. in bile, urine, prostate. Quinolones appear in milk.
o Good penetration through special barriers (CSF, ocular fluids!) - meningitis, prostatitis, mastitis (IV)
o Penetrate IC - Mycoplasma, Chlamydia, Rickettsia
o FQ are conc. within phagocytic cells
•Metabolism: partially (1st generation more completely)
o Metabolites may also be active e.g. Enrofloxacin –> Ciprofloxacin
•Elimination: mainly kidneys (tubular secretion) as active drug, partially with bile (e.g. inactive glucuronide ester).
o Enterohepatic recirculation, reduction of metabolite by gut bacteria –> prolonged action
o In active form –> UTI - E. coli, Klebsiella, Proteus, Pseudomonas, Staphylococcus spp. (outstanding – best drugs but CIA – so 1st choice is Amoxicillin)
Safety and side effects
•Majority of “modern” FQ are safe - large TI, wide therapeutic margin But 1st gen. FQs are more toxic!
•When therapeutic doses are applied, side effects are uncommon.
•Long lasting adm. &/or too large doses may increase the possibility of unwanted side-effects.
•Recent FQ are neither mutagenic nor teratogenic.
•Inhibition of load-bearing cartilage (NOT in growing dogs, rat, humans, horses! – label off use - dogs below one year, giant breeds below 1,5 year, foals below 6 mnd)
o For horses it can be given with own responsibility only.
o For puppies that has not started walking, it is not toxic to the cartilage
•Retinopathy leading to blindness (Fe! Enrofloxacin. In higher doses/long term, in Fe: max 5mg/kg or 2-3 weeks)
•CNS-signs - Epilepsy!
•Dysbacteriosis (according to label-not for horses)
•IV adm. can lead to excitation, tremors and convulsion – slowly given, and never to cats!
•Others (observed mainly in humans):
o GI: nausea, vomiting, diarrhoea, abdominal pain
o CNS: headache, dizziness, drowsiness, confusion, insomnia, fatigue, malaise, depression, somnolence, vertigo, light-headedness, restlessness, tremor
o Dermatologic: rash, photosensitivity reactions, pruritus
o Cardiac toxicity or QTc prolongation, delayed repolarisation
o Hepatotoxicity
o Abnormal/bitter taste
o Tendon rupture
Interactions
•FQ are synergistic with:
o Beta-lactams
o Aminoglycosides
o Vancomycin
o E.g.:
-Staph. Aureus (Ciprofloxacin + Azlocillin; Lefoloxacin + Oxacillin)
-P. aeruginosa (Ciprofloxacin + Imipenem or Azlocillin or Amikacin)
-Enterococci (Ciprofloxacin + Imipenem or Ampicillin or Vancomycin)
o Expanded antibacterial spectrum & metronidazole
o Antagonistic interactions (Ciprofloxacin with): chloramphenicol, rifampin
• May increase:
o Anticoagulant effect of warfarin
o Caffeine levels (liver)
o Theophylline levels (liver)
o Cyclosporine levels
•May prolong QTc if used concomitantly with anti-arrhythmics (e.g. class 1A ^ £ agents) or with Cisapride
•May incr. risk of CNS stimulation & convulsions if used concomitantly with NSAIDs
•May lead to hypoglycaemia &/or hyperglycaemias if used concomitantly with anti-diabetic agents
•Gatifloxacin: increased serum Digoxin levels
•Probenicid may increase Ciprofloxacin levels (kidney)
Indications
•1st gen only: UTI (quickly eliminated from body) – only Gr-, (GI infections – but resistance!)
•Danofloxacin: cattle only, Difloxacin: birds only
•RT infections - Including Mycoplasmosis – in all species, with single shot dosage (very frequent in Ru and swine)
•Soft tissue infections
•Pyoderma
•Osteomyelitis
•Prostatitis – FQ is primary choice!
•Eye infections – mostly Ciprofloxacin - eyedrops
•Periodontitis, gingivitis –
o Dogs and cats: oral cavity infections and bite wounds - Pradafloxacin good (orally)
•Meningitis, meningioencephalitis
•Systemic infections/septicaemia (IV preferred, usually combined with Cephalosporins or Amoxiclav)
•Acute mastitis (IV)
•Ear infections – Pseudomonas, Staph, Strep – mostly Marbofloxacin used
Doses
2.5-10 mg/BWkg SID/BID, PO/injection
•Enrofloxacin: 7,5 mg/kg BW
•Marbofloxacin: 8-10 mg/kg BW
