Quinolones

 

Quinolones

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Quinolones are a group of synthetic antibacterial agents. Nalidixic acid was the first member of Quinolone family introduced in 1964. Oxolinic acid was introduced in 1970s. This was followed by the introduction of Fluoroquinolones (having extended spectrum and systemic antibacterial action) in 1980s. Currently available Quinolones contain the basic structure of 4-quinolone with a carboxylic acid moity at position 3. Various modifications on the basic ring structure have produced compounds with differing physical, chemical, pharmacokinetic and antibacterial properties.

On the basis of chemical structure, following generalizations can be made.

 

 

1. Carboxyl group at position 3 and ketone group at position 4 are essential for the antibacterial activity of Quinolones.

2. Substitution at position 6 with fluoride moity markedly enhances the activity against gram negative and gram positive bacteria as well as Mycoplasma and Chlamydia.

3. Addition of piperazine ring at position 7 on Fluoroquinolones significantly increases tissue and bacterial penetration and improves spectrum of activity to include Pseudomonas (e.g., Ciprofloxacin and Enrofloxacin).

4. Substitution with an oxygen atom at position 8 improves activity against gram positive and anerobic bacteria without affecting the bactericidal profile.

5. Change to a carbon from a nitrogen at position 8 decreases some adverse CNS effects and increases the activity against Staphylococci.

 

Properties: Quinolones are amphoteric compounds and they exist as zwitter ions at physiological P_H. Therefore they exhibit poor water solubility (high lipid solubility). In concentrated acidic urine some Quinolones form needle shaped crystals.

 

Classification: Quinolones are classified on the basis of their evolution pattern (chronology).

1^st generation Quinolones: Nalidixic acid, Oxolinic acid and Pipemidic acid

2^nd generation Quinolones (1^st generation Fluoroquinolones): Ofloxacin, Norfloxacin, Enrofloxacin, Ciprofloxacin and Flumequine

2^nd generation Fluoroquinolones: Levofloxacin and Gatifloxacin

 

Mechanism of action: Quinolones are bactericidal drugs that inhibit replication of bacterial DNA by interfering with the action of DNA-gyrase (Topoisomerase-II) enzyme. They enter the susceptible micro-organisms (via passive diffusion) and target the enzyme DNA-gyrase that is responsible for supercoiling (negative supercoiling) of DNA. Supercoiling is a process of coiling of double-stranded DNA molecule on itself so that a DNA upto 1.3mm length can be tightly and compactly packed inside the bacterial cell. When DNA-gyrase is inhibited by Quinolones, a reduction in the supercoiling occurs with consequent disruption of DNA replication. Inhibition of supercoiling may also lead to degradation of DNA into small fragments by the action of exonucleases. Mammalian Topoisomerases are fundamentally different from bacterial gyrases and are not susceptible to Quinolones.

 

Antimicrobial spectrum: 1^st generation Quinolones tend to have only a moderately extended gram negative spectrum. The spectrum of activity of Fluoroquinolones might be considered broad with efficacy against a wide range of gram negative and gram positive bacteria, Mycoplasma and Chlamydia. Common bacteria susceptible to them include E. coli, Salmonella, Compylobacter, Shigella, Brucella, Pseudomonas, Vibrio, Staphylococcus but Streptococcus tends to be resistant them. 1^st generation Fluoroquinolones are not effective against anaerobic bacteria. 2^nd generation Fluoroquinolones also cover the bacteria (such as Streptococci and anaerobic bacteria) that are not susceptible to 1^st generation Fluoroquinolones. The antibacterial activity of Quinolones appears to correlate more closely with the peak concentration (dose) than with the duration of plasma-drug concentration above MIC. The efficacy of Fluoroquinolones occurs, in part, due to their long post-antibiotic effect, which is also concentration-dependent. Quinolones are less active against susceptible bacteria in anaerobic and acid (abscesses) environment.

 

Bacterial resistance: Resistance noted so far is either due to chromosomal mutation producing alteration in bacterial DNA-gyrase enzyme with a decreased affinity for Quinolones or due to reduced permeability of bacterial membranes to Quinolones. Cross-resistance among closely related Fluoroquinolones has also been reported.

 

Pharmacokinetics: In general, Quinolones have a good rate and extent of absorption after oral administration in monogastric animals and pre-ruminating calves. Mg⁺² and Ca⁺² ions decrease the absorption of Quinolones after oral administration. Food delays the rate but not extent of drug absorption. The Quinolones distribute well into all body tissues and fluids including CNS, bones and prostrate. They accumulate in macrophages and leucocytes thus being effective against intracellular pathogens. Metabolites of few Quinolones are active i.e., Enrofloxacin undergoes de-ethylation to form Ciprofloxacin. Renal excretion is the major route of elimination for most Quinolones. The alkaline urine increases re-absorption of Quinolones from the renal tubules and may prolong elimination half life. Fluoroquinolones appear in the milk of lactating animals in high concentration.

 

Adverse effects: Side effects with older Quinolones are relatively common, but the newer Quinolones are generally well tolerated. Fluoroquinolones can lower the threshold to seizures with chance of convulsions at high doses. They can cause crystalluria in dogs due to their low solubility in acidic urine. The cartilage deformities, chondrodestruction, and joint growth disorders have been documented in young animals, particularly dogs and foals, after the administration of Fluoroquinolones. In heavy-breed dogs the weight-bearing joints are specifically susceptible often leading to permanent damage. This occurs mainly due to chelation of Mg⁺² in cartilages that affects selected proteins.

 

Contraindications: Quinolones are not recommended in growing dogs under 12 (small/medium breeds) to 18 (heavy breeds) months of age due to inhibition of the growth of load-bearing articular cartilage. They should be used with extreme care in patients suffering from seizure disorders. As Quinolones have the tendency to cause crystalluria in acidic urine, animals should not be allowed to become dehydrated. Patients with renal insufficiency may require dose adjustment to prevent drug accumulation.  Their use in lactating animals should be avoided or an optimal milk withdrawal time should be followed.

 

Drug interactions: Quinolones have few but important drug interactions. They are potent chelators of Mg⁺², Ca⁺² and Al⁺³ ions, so non-systemic antacids may interfere with their absorption. Probenicid is reported to block renal tubular excretion of some Quinolones and may enhance their plasma levels and half lives. The combination of Fluorinated Quinolones with NSAID_S increases the potential of Fluroquinolones to lower the seizure threshold level. A synergistic effect of Quinolones with β-lactams, Aminoglycosides, Clindamycin and Metronidazole has been reported.

 

 

Clinical uses: Older Quinolones are primarily used as urinary antiseptics. Fluoroquinolones are usually used against intra-cellular pathogens and to treat deep-seated infections. Fluoroquinolones are useful in the treatment of meningo-encephalitis, osteomyelitis and arthritis. Nalidixic acid is considered useful in the treatment of Ampicillin-resistant Shigella enteritis in humans. Oxolinic acid is occasionally used for the treatment of certain bacterial diseases of fish. Enrofloxacin is commonly used to treat respiratory infection such as Mycoplasmosis and Pasteurellosis. Ciprofloxacin is used for the treatment of typhoid in human medicine. Flumequine is used to treat gram negative enteric infections (such as Colibacillosis) in poultry and livestock.