Quinolones:
- These are synthetic antibacterial agents having a 4-quinolone structure.
- They are primarily active against gram -ve bacteria although fluorinated agents (Fluoroquinolones) also inhibit selected gram +ve bacteria.
- Minimally toxic and important in veterinary medicine
- Nalidixic acid was the first member of quinolone family introduced in 1964. As it is limited to use in urinary and G.I infection, its congeners oxolinic acid and rosoxacin with more potency but limited spectrum were introduced as first generation drugs in 1970s.
Chemistry:
- Quinolones contains a basic structure of 4-quinolone with a carboxylic acid moiety in position 3.
- Majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have fluorine atom attached to central ring system at C-6 or C-7 position.
Classification:
- These groups of drugs are classified in number of ways. Most acceptable form is they are grouped into generation on the basis of their pattern of evolution and antibacterial spectrum.
Mechanism of Action:
They inhibit the replication of bacterial DNA by interfering with action of DNA gyrase (Topoisomerase II).
Quinolones enters microorganism by passive diffusion through porins
Quinolones then targets DNA gyrase. DNA gyrase consist of two subunits: 2A and 2B. Quinolones bind to 2A subunit.
Reduction in negative supercoiling where DNA fragments cannot be sealed after cutting, process carried out by DNA gyrase subunit 2A.
Disruption of DNA replication as cuts or exposed nicks are not resealed
Degradation of DNA into smaller fragments by exonucleases
Disruption of bacteria
Antimicrobial spectrum:
- It varies with type of quinolones
- 1st generation quinolones have moderate gram -ve activity and minimal systemic distribution
- 2nd generation quinolones have expanded gram -ve activity but limited gram +ve activity.
- 3rd generation quinolones retain expanded gram -ve and atypical intracellular activity but have improved gram +ve activity.
- 4th generation shows improved gram +ve activity, maintain gram -ve activity and gain anaerobic coverage.
- Efficacy of fluoroquinolones is due to long post-antibiotic effects which is concentration dependent.
- They are less active against susceptible bacteria in anaerobic and acidic environment.
- They shows greater activity against rapidly growing bacteria.
Bacterial resistance:
- Resistance develops quickly to nalidixic acid and some other quinolones
- Resistance is due to mutation in chromosome producing alteration in DNA gyrase with decreased affinity for quinolones or to reduced permeability of bacterial membranes to quinolones.
Pharmacokinetics:
- They have good rate and extent of absorption after oral administration in monogastric animal.
- Bioavailability is greater than 80%, except ruminants.
- Peak plasma concentration is achieved in 0.5-2 hrs after administration.
- Absorption from IM or SC injection site is rapid.
- Distributed well into body tissues and fluids including CNS, bone and prostrate.
- Also accumulate in macrophages and polymorphonuclear leucocytes
- Elimination of quinolones depend on type of agent. Some are excreted unchanged; some are partially metabolized, and few are completely metabolized.
- Excretion through urine is most important route.
- Half-live ranges from 3-6 hrs.
Side effects/Adverse effects:
- Lower threshold to seizure with chances of convulsion at high dose
- Crystalluria in dogs
- Hypersensitivity
- Cartilage deformities, chondro-destruction and joint growth disorders.
- Blindness in cats
- Hemolytic anemia
- Nausea, vomiting, diarrhoea
- Foetal toxicity
Contraindications and precautions:
- In patients hypersensitive to quinolones
- In growing dogs under 12-18 months
- In pregnant animals
- In patients with seizure disorders
- Patients with renal insufficiency require dosage adjustment to prevent drug accumulation
Drug interactions:
- They are potent chelators of Mg++, Ca++, Zn++, Fe++ and Al++. So quinolones interfere absorption of non-systemic antacids, nutritional supplements, multivitamins
- Probenecid block tubular secretion of quinolones and increase their half-lives
- Combination of fluoroquinolones with NSAID increase potency of fluoroquinolones to lower seizure threshold.
Clinical uses:
- Nalidixic acid are used as urinary antiseptics
- In treatment of intracellular and deep-seated infections
- Respiratory tract, urinary tract, intestine, skin and prostrate are treated by fluoroquinolones
- Meningoencephalitis, osteomyelitis and arthritis.
First-generation quinolones:
- These are non-fluorinated synthetic antibacterial drugs.
- These were first introduced in clinical practice in 1960s and 1970s.
- Narrow spectrum of antibacterial activity with efficacy against mainly gram -ve bacteria.
- Occasionally used for uncomplicated urinary tract infections.
Nalidixic acid:
- Non-fluorinated first-generation quinolone
- Primarily used as urinary antiseptic
- Active against gram -ve bacteria especially coli, Proteus, Klebsiella, Enterobacter and Shigella
- Bacteriostatic in low concentration and bactericidal in higher concentration
- Well absorbed orally (>90%) and highly plasma protein bound (>95%)
- Partly metabolized in liver by hydroxylation to potent bactericidal compound 7-hydroxynalidixic acid, which is excreted in urine along with parent drug.
- Side effects of nalidixic acid include nausea, vomiting and abdominal pain
- Primarily used as urinary antiseptic for urinary tract infections.
Dose:
For urinary tract infections
Dogs & cats: 3mg/kg, PO, 4 times daily
Second generation quinolones:
- These were developed as fluorinated quinolones with several advantages over older non-fluorinated quinolones
- They have extended spectrum of activity; active against both gram -ve and gram +ve organism and mycoplasma
- They have high potency, rapid bactericidal action, systemic effects, lower incidence of adverse effects and administration via variety of routes
- Drugs used in veterinary medicine of this class includes enrofloxacin, difloxacin, orbifloxacin, danofloxacin and marbofloxacin.
- Drugs used in human medicine include ciprofloxacin, norfloxacin, ofloxacin, sarafloxacin, enoxacin and lomefloxacin.
Enrofloxacin:
- It is prototype veterinary fluorinated quinolones developed for use in animals only
Antimicrobial spectrum:
- It has good activity against some gram +ve and many gram -ve bacilli and cocci including most strains and species of Pseudomonas, Klebsiella, E.coli, Enterobacter, Shigella, Camplyobacter, Salmonella, Haemophilus, Proteus, Serratia, Citrobacter, Yersinia and
- Brucella, Chlamydia, Staphylococcus and Mycobacterium species are also susceptible to enrofloxacin.
- Bactericidal action is concentration dependent.
- It has also long concentration dependent post-antibiotic effect of 5-15 hrs for both gram +ve and gram -ve organism.
- Active in both stationary and growth phases of bacterial replication.
Pharmacokinetics:
- It is well absorbed after oral administration with bioavailability of about 80% in dogs, 60% in adult horses and 40% in foals
- Peak plasma concentration is attained within 1 hrs of oral dosing.
- Absorption is nearly complete from IM or SC injection site.
- Distributed throughout the body including bone, synovial fluid, prostrate, aqueous humor and pleural fluid.
- Eliminated unchanged in urine
- Elimination half-lives in dogs is approximately 4-5 hours and 6 hours in cats.
Side effects/Adverse effects:
- Cartilage deformities and joint growth disorders in young dogs
- GI disorders
- Crystalluria
- CNS disorders (dizziness, stimulation)
- Acute blindness in cats in high doses
Contraindications and precautions:
- In patients hypersensitive to enrofloxacin
- In growing dogs under 12-18 months
- In pregnant animals
- In patients with seizure disorders
- Patients with renal insufficiency require dosage adjustment to prevent drug accumulation.
Indications:
- Skin infection
- Urinary tract infection
- Soft tissues infection in dogs and cats
- Enzootic pneumonia in pigs
Dose:
Dogs & cats: 2.5-5 mg/kg, PO, 1-2 times daily
5 mg/kg, IM or SC, 1-2 times daily
Cattle: 2.5 mg/kg, SC, once daily for 3 days
Calves: 2.5-5 mg/kg, PO or IM once daily
Sheep and goats: 2.5-5 mg/kg, IM, SC or IV, once daily
Third generation quinolones:
- These drugs have expanded gram -ve and improved gram +ve coverage
- Drugs of this class include pradofloxacin, ibafloxacin, levofloxacin, sparfloxacin, balofloxacin, fleroxacin, grepafloxacin, pazufloxacin, temafloxacin and tosufloxacin.
- Grepafloxacin and temafloxacin have been discontinued in human medicine due to their adverse effects like abnormal cardiac rhythm, hemolytic anemia.
Pradofloxacin:
- It is developed extensively for use in veterinary medicine.
- It is structurally different from enrofloxacin by having S,S- pyrrolidinopiperidine replacing ethyl piperazine at C-7 of enrofloxacin and cyano group is attached to C-8.
- It has enhanced activity against gram +ve bacteria relative to 1st and 2nd generation
- It is used in dogs and cats for treatment of infections including respiratory tract, urinary tract, wound, abscesses superficial and deep pyoderma.
- It is also used as adjunctive treatment to mechanical or surgical periodontal therapy in treatment of infection of gingiva and periodontal tissues.
4th generation quinolones:
- These drugs have dual mechanism of action i.e. they act at both DNA gyrase topoisomerase IV.
Moxifloxacin:
- It is 4th generation fluoroquinolones having increasing usage in clinical practice
- It has good activity against Streptococcus pneumonia, other gram +ve, gram -ve bacteria and some anaerobes.
- It is potent fluoroquinolones against Mycobacterium tuberculosis.
- It is mostly used in human medicine at last when all antibiotics fail
- It is used in respiratory tract infection, cellulitis, anthrax, intra-abdominal infections, endocarditis, meningitis and tuberculosis.
- Side effects are similar to other quinolones
Dose:
Horses: 5mg/kg, Once daily