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After reading this article you will learn about:- 1. Meaning of Fluoroquinolones 2. Classifications of Fluoroquinolones 3. Pharmacological Features 4. Pharmacokinetics 5. Pharmacokinetic Parameters 6. Mechanism of Action 7. Antimicrobial Activity 8. Post -Antibiotic Effect 9. Resistance and Other Details.
Contents:
- Meaning of Fluoroquinolones
- Classifications of Fluoroquinolones
- Pharmacological Features of Fluoroquinolones
- Pharmacokinetics of Fluoroquinolones
- Pharmacokinetic Parameters
- Mechanism of Action
- Antimicrobial Activity
- Post -Antibiotic Effect of Fluoroquinolones
- Resistance to Fluoroquinolones
- Clinical Uses of Fluoroquinolones
- Formulations and Dosage of Fluoroquinolones
- Toxicity and Adverse Effects of Fluoroquinolones
- Drug Interactions
1. Meaning of Fluoroquinolones:
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It will not be a matter of exaggeration to call decades after 1980’s as an era of fluoroquinolones when their use increased both in human as well as veterinary medicine. They are synthetic anti-bacterials having primary activity against gram (- ve) negative bacteria and with advancement, having broad spectrum.
The first member of quinolone anti-bacterials to be introduced was Nalidixic acid in mid sixties and its congener oxalones were introduced in 1970s. Increased spectrum was achieved by introduction of fluoroquinolones in 1980s.
Fluoroquinolones are produced by fluorination of the basic quinolone structure at 6th position (Fig. 32.1) whereas introduction of a piperazine substitution at 7th position results in production of different derivatives having higher potency, expanded spectrum and better penetration and slow development of resistance.
Enrofloxacin is the privileged member of the fluoroquinolone group to get developed exclusively for use in veterinary clinics. Subsequently Danofloxacin was also introduced for exclusive use in animals.
2. Classifications of Fluoroquinolones:
Fluoroquinolones have been classified either based on their chemical structure or as per the chronological development into different generations viz.,
First Generation:
Nalidixic acid, Oxalinic acid, Cinoxacin, Piromidic acid, Flumequine
Second Generation:
Norfloxacin, Ciprofloxacin, Ofloxacin, Enrofloxacin, Danofloxacin
Third Generation:
Pefloxacin, Marbofloxacin, Sarafloxacin
New Generation Fluoroquinolones:
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Gatifloxacin, Moxifloxacin, Levofloxacin, Premafloxacin, Sparfloxacin
3. Pharmacological Features of Fluoroquinolones:
(i) Broad spectrum of activity
(ii) Can be used in majority of domesticated species of animals.
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(iii) Can be administered by variety of routes
(iv) Have wide margin of safety
(v) Large volume of distribution
(vi) Concentration dependent effect
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(vii) Biphasic effect
(viii) Post-antibiotic effect
(ix) Efficacy at low therapeutic doses
4. Pharmacokinetics of Fluoroquinolones:
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General dispositional characteristics of fluoroquinolones.
(i) Variable but good oral absorption
(ii) Complete parenteral absorption
(iii) Good tissue distribution
(iv) Volume of distribution 2-4 L/kg.
(v) Renal excretion by glomerular filtration and tubular secretion
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(vi) Hepatic metabolism via oxidation and glucuronidation
(vii) Possibility of enterohepatic recycling
(viii) Terminal phase half-life of 2-4 hrs.
Absorption:
In general absorption of fluoroquinolones is satisfactory after oral administration in nonruminants and poultry, Food does not affect the extent of absorption though, the time required for absorption may increase. Administration of drug in a prey can produce therapeutic concentration in a predator. Absorption after nonvascular route (I.M.,S.C.) is complete but slow compared to intravenous route.
Distribution:
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Fluoroquinolones are distributed extensively to all body tissues. They penetrate well in bronchial secretions, prostatic fluid organs of excretion, milk, bone and cartilage , intestinal tract tissue and skin. Fluoroquinolones also accumulate in leukocytes but are not detected in body fat.
Concentration of norfloxacin and Enrofloxacin was reported lower in mastitis milk than the normal milk. Protein-binding of fluoroquinolones ranges from 10-70 % which varies with species and individual fluoroquinolone.
Metabolism:
Fluoroquinolones are extensively metabolized in general by phase I metabolic reactions; primarily through hydroxylation and oxidation. The glucuronide conjugates of fluoroquinolones may be excreted in urine or bile depending on the individual fluoroquinolone and the species involved.
A fluoroquinolone may get bio-transformed to other fluoroquinolone molecule viz; Enrofloxacin to Ciprofloxacin, Pefloxacin to Norfloxacin and Difloxacin to Sarafloxacin. There are indications that enterohepatic circulation of fluoroquinolones may occur principally through action of β-glucuronidases in the gastrointestinal tract that may liberate the parent drug or biologically active metabolite.
Excretion:
Renal excretion of fluoroquinolones is variable and fluoroquinolones are excreted by glomerular filtration and tubular secretion. Concentration in urine is several times the plasma concentration except for difloxacin of which renal excretion accounts for less than 5%. Faecal excretion is also reported as major route of elimination for pefloxacin.
5. Pharmacokinetic Parameters:
Pharmacokinetics of fluoroquinolones has been extensively studied in farm animals, pet animals, poultry, fish and exotic animal species after administration by various routes and their half- life varies from 1.5 to 9 hr. Fluoroquinolones have large volume of distribution (0.1 to 10 L/kg).
Bioavailability is satisfactory after oral and parenteral administration and sometimes may exceed cent per cent after administration by nonvascular route. Fluoroquinolones exhibit ‘Flip-Flop Kinetics’.
After intravenous administration the drug is eliminated faster and hence the levels are maintained for shorter period whereas parenteral administration results in maintenance of levels for longer period and better availability due to slower absorption.
6. Mechanism of Action:
Fluoroquinolones act as bactericidal agents by interfering with nucleic acid synthesis. During DNA / RNA synthesis, message is received from the double helix structure; DNA. For DNA replication, the two strands of DNA helix must be separated for transcription of message.
The separation results into an excessive over-winding (positive supercoiling) of strands beyond the point of separation. To sustain the mechanical pressure due to the excessive over-winding, an enzyme DNA gyrase, introduces negative supercoils continuously.
For introduction of the negative supercoils, both the strands are required to be cut to permit the passage of a DNA segment through the break and the break is then resealed. This is an ATP dependent process where DNA gyrase plays an important role. DNA gyrase is composed of two subunits (‘A’ and ‘B’) Subunit ‘A’ is responsible for cutting and sealing DNA strands whereas subunit ‘B’ is meant for introducing negative supercoiling.
Fluoroquinolones inhibit DNA gyrase enzyme and thereby prevent the nicking and resealing resulting in inhibition of synthesis of nucleic acids. The bactericidal action results from degradation of DNA by exonucleases, the production of which is signaled by DNA damage.
Fluor quinolones are selectively toxic to bacteria as eukaryotic cells do not contain DNA gyrase. In eukaryotic cells, the same function is carried out by type II topoisomerase which are affected by quinolones at very high concentrations.
Topoiomerse II in mammalian cells is inhibited only when drug concentration exceeds 100-1000 µg/ml whereas bacteria are inhibited at concentration as low as 0.1-10 µ/ml. Thus fluoroquinolones are selectively toxic to prokaryotic cells. Topomerse IV enzyme is the target for fluoroquinolones in some gram – positive bacteria.
7. Antimicrobial Activity:
Fluor quinolones have activity against major pathogens of veterinary importance. MIC value for gram positive bacteria are higher than for gram negative bacteria. In general, they have an excellent activity against Enterobacteriaceae, fastidious gram-negative bacteria (E.coli, Klebsiella, Proteus spp. Salmonella sp. Enterobacter spp) and Pseudomonas aeruginosa (Ciprofloxacin most active against P.aeruginosa) and good to moderate activity against Staphylococci, Mycobacteria, Chlamydia and Mycoplasma. Newest fluoroquinolones are also active against anaerobes.
Fluoroquinolones are more active in alkaline environment for gram-negative bacteria but susceptibility to gram-positive bacteria is not affected by pH. Their activity is unaffected in the presence of serum. In general the MIC values of fluoroquinolones are 0.2 µg/ml for gram-negative organisms and 0.1-2 µg/ml for gram – positive organisms.
Fluoroquinolones are said to be having ‘biphasic effects’. Their activity is absent below the MICs as well as at concentrations above the MIC values. The absence of activity at concentrations higher than the MIC values is attributed to the ability of fluoroquinolones to inhibit bacterial RNA polymerase, an enzyme essential for nucleic acid synthesis, a process which is the prime target of fluoroquinolones.
8. Post-Antibiotic Effect of Fluoroquinolones:
Post-antibiotic effect is the persistent suppression of bacterial growth following removal of antibacterial agent. The bacterial action persists even after serum concentration of fluoroquinolones falls below MIC. The suppression of bacterial growth induced by fluoroquinolones is concentration dependent.
The therapeutic success of fluoroquinolones depends on achieving concentration many fold MIC (within the therapeutic window). The effect is independent of the time for which levels are maintained. Owing to this effect, “higher doses for the shorter period” is the practice adopted on many farms.
9. Resistance to Fluoroquinolones:
Resistance to fluoroquinolones develops via the single step or multi step mutation in the genes those code for specific bacterial enzyme (DNA-gyrase or topoisomerase IV) due to which, enzyme with reduced affinity towards fluoroquinolones is produced. Such a resistance occurs at a low frequency, is usually unstable and of low lev
Other mechanisms proposed are the reduced affinity for fluoroquinolones or reduction in bacterial permeability for these agents. There may be change in the membrane protein resulting in reduced accumulation of drug in bacterial cell. Bacteria have not been shown to develop fluoroquinolones inactivating mechanisms.
Use of Fluor quinolones as growth promoter is discouraged owing to the concern of residues in animal products and thence the spread of resistance. Continued use of fluoroquinolones in livestock can lead to resistant mutants of Salmonella being passed on to human beings through food chain.
Resistance to Fluor quinolones has been reported in E. coli, Enterobacteriaceae, Proteus and other gram negative bacteria. However, the data on resistance profile in India is needed to be generated.
10. Clinical Uses of Fluoroquinolones:
Fluoroquinolones are used widely in farm animals, pet animals, birds and fish for treating susceptible infections.
Indications:
Dog and Cats:
Infections of skin ,soft tissue, oral cavity, urinary tract, prostate, respiratory tract and bone, wound, otitis
Cattle Buffalo, Sheep, Goat:
Upper respiratory tract infections, gastrointestinal infections, anthrax, enterotoxaemia, mastitis, uterine infections, meningitis, skin and bone infections, Black quarter, wooden tongue.
Poultry:
Colisepticaemia, Infectious coryza, salmonellosis, CRD, fowl cholera, pasturellosis, mixed bacterial infections.
11. Formulations and Dosage of Fluoroquinolones:
In western countries specific fluoroquinolone is available only for certain species of animal; viz. enrofloxacin, difloxacin, orbifloxacin and marbofloxacin for small animals. Danofloxacin, enrofloxacin and ciprofloxacin for poultry.
Ciprofloxacin, enoxancin, lomefloxacin and ofloxacin are available for human use. However, their extra label use is observed in animals. In India, however there are no such demarcations and some of the fluoroquinolones formulations (ciprofloxacin, norfloxacin) that are available for human use have also been introduced for animal use.
New generation fluoroquinolones that have been introduced in human use include levofloxacin, moxifloaxacin, gatifloxacin and premafloxacin. Some of these molecules probably would be available for veterinary use in near future.
The formulations of fluoroquinolones that are currently available for veterinary use in India are as follows:
Ciprofloxacin:
Injection (2mg/ml, 40mg/ml, 100mg/ml), Tablet(250mgl)
Eye ointment (0.3%), Eye/Eardrops(0.3%)
Poultry Products:
Ciprofloxacin powder 10%
Combination Products:
Ciprofloxacin-20g+ Norfloxacin 20 g soluble powder for poultry
Ciprofloxacin 250mg+ Tinidazole 300mg as tablet form for small animals-
Ciprofloxacin 1500mg+ Tinidazole 1800mg bolus for large animals
Dose:
Cattle, Buffalo, Sheep and Goat-4-5mg/Kg b.w. once a day for 3-5 days
Dogs and Cats:
15mg/Kg b.w. once a day for 3-5 days
Poultry:
50 mg ciprofloxacin/L drinking water.
Enrofloxacin:
Injection 5%, 10% or 20% Tablets 50 mg, 150 mg (for small animals) Dose in all species: 2.5 to 5.0 mg/kg body weight. Poultry: 5% or 10% solution to be added in water.
Prophylactic dose:
5 mg/kg body weight. Curative dose: 10 mg/kg body weight.
Flumequine:
10% powder for use in poultry and large animals.
Dose:
Cattle, Horse and Buffalo: 6 mg/Kg body weight. Dogs and cats: 0.5mg/Kg body weight.
Poultry:
Chicks:
50mg/L water
Adults:
100mg/L water.
Combination:
Bolus:
Norfloxacin 1200 mg + Tinidazole 1800 mg for large animals and small animals.
Dose:
Cats and dogs; 22 mg norfloxacin/kg body weight B. I. D. for 3-5 days
Poultry:
5%, 10% or 20% powder through water.
Norfloxacin + Metronidazole (Each 25mg/500 gm. powder) Prophylactic dose: 5 mg Norfloxacin/Kg body weight. Curative dose: 10 mg Norfloxacin/Kg body weight.
Pefloxacin:
Tablet: 400 mg, Bolus: 1 g
Infusion:
400 mg/100 ml
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Dose:
Cattle, sheep and goat: Oral 10 mg/kg B.I.D for 3-5 days Or 5 mg/kg intravenous
Dogs:
10-40 mg/kg (B.I.D. for 3-5 days orally or i.v.
Owing to the post-antibiotic effect, flip-flop kinetics and concentration dependent effect, high doses of fluoroquinolones for short period are recommended by subcutaneous route.
Recently enrofloxacin is recommended at 7.5 -12 mg/kg body weight S.C as a single dose administration. Taking into consideration the concentration dependent effect of fluoroquinolones, plus dose administration appears to be a preferred option over continuous administration in poultry.
12. Toxicity and Adverse Effects of Fluoroquinolones:
Fluoroquinolones have very high margin of safety and are well tolerated. Acute toxicity studies of fluoroquinolones in laboratory animals have assured their high safety and no reproduction toxicity or teratogenicity was observed. The toxicity of clinical relevance is the arthropathic effect observed in immature pups (dogs below 1 year of age) due to the damage to the cartilage of weight bearing joints.
Dogs between 4 to 21 weeks of age are most susceptible to these toxic effects. Owing to these effects, use of fluoroquinolones in horses has remained a matter of debate. Affected animals exhibit lameness and joint swelling; however, these are reversible symptoms if drug is discontinued.
In young dogs and horses, fluoroquinolones cause toxicity to chondrocytes leading to vesicle formation on articular surfaces. The mechanism involves chelation by the drug of magnesium which is essential for development of cartilage mostly in young and growing animals. Magnesium chelation leads to its deficiency causing loss of proteoglycans in the cartilage.
High dose of fluoroquinolones have shown to cause ocular problems from drug induced changes in the retina. To avoid the enrofloxacin induced blindness in cats, doses higher than 5mg/kg per day are not recommended.
Occasionally ciprofloxacin causes CNS toxicity in the form of restlessness, tremors, dizziness and seizures which is attributed to inhibition of binding of GABA to its receptors. Sparfloxacin is prone to cause phototoxic effects. In human beings, Enrofloxacin is not used due to its CNS effects.
13. Drug Interactions:
Plasma concentrations of theophylline, caffeine and warifarin are increased if administered along with ciprofloxacin, norfloxacin and pefloxacin. The increase in plasma concentrations is as a result of inhibition of metabolism of these drugs which might cause toxic effects.
Antacids, iron salts and sucralfate reduce the absorption of fluoroquinolones if given concomitantly orally. NSAIDS are reported to enhance CNS toxicity of fluoroquinolones resulting in seizures. Fluoroquinolones are excreted by an active secretion process reported to be sensitive to inhibition by probenecid.
