Quinolones and Fluoroquinolones

Quinolones & Fluoroquinolones

 

Introduction:

Quinolones and Fluoroquinolones are a group of synthetic broad spectrum antibiotics.These antibiotics were also isolated from natural resources. One of the most important member of quinolone group of antibiotic was Nalidix Acid.The Problem with this compound was that it was narrow spectrum and it has moderate gram negative activity but it has no gram positive activity.Apart from this issue the nalidix acid was poorly distributed in the body and that is why quinolones are not effective for systemic bacterial infections.so with the passage of time scientist added flourine with mother compound i.e Nalidix acid to improve their activity  so “a group of broad spectrum antibiotics which are flourinated analogues of nalidix acid are called fluoroquinolones ”
These antibiotics are the most famous drugs these days because of their good absorption and spectrum of activity against all type of bacteria and these agents can be effectively used in systemic infections.

Why they are so important ?

A)Very Good Oral Absorption.
B)Very good distribution means deep peneteration in the tissues very effiently.because of their deep penetretion they can kill intracellular organisms.e.g chlamydia,TB,Legionella,brucella.
C)Newer agents are very broad spectrum.
D)They have high potency.
E)They are very well tolerated (Very safe drugs compare to other antibiotic drugs)

What is the mechanism of action of quinolones on bacteria?
OR
How does quinolone work?
OR

Mechanism of action of Quinolones and Fluoroquinolones :

  • These drugs are bactericidal But the question is how they kill the bacteria ?
    Quinolones And Fluoroquinolones are acting on enzymes called topoisomerases or DNA Gyrase.They inhibit bacterial replication by interfering with their DNA replication pathway. DNA is the core genetic material of the cells, and is responsible for correct functioning of the cell. During protein synthesis and DNA replication, the double-stranded DNA must unwind into one stranded structure, that allows for complementary base pairing to occur and synthesis of messenger RNA to procede. Normally This moving of DNA within the bacterium is completed by enzymes called DNA topoisomerase type 2 or DNA gyrase There are two functional Domains Of Topoisomerase 2 enzyme i.e Nuclease domain And Ligase domain.Basically this DNA gyrase (Nuclease Domain) cut the one side of two stranded DNA  and then (Ligase domain ) reseal it after unwinding.This Process continue and the bacteria keep growing but quinolones and fluoroquinolones inhibit or didn’t allow the enzyme Ligase sub doamin to refix or reseal the broken or cut edge of DNA and that is why the bacteria is unable to replicate or even synthesize proteins.First & Second Generation fluoroquinolones Work On this Enzyme .
  • There is another enzyme which is called topoisomerase type 4 which is little different from the type 2 enzyme they also have two domains but the nulcease domain has two sub domain which is responsible for cutting of untangled DNA into fragments the mechanism of fluoroquinolones is same like Topoisomerase 2 they inhibit the function of Ligase and make it dysfunctional.Nuclease domain keep on cutting the DNA into fragments but the ligase is not able to reseal it and the DNA Convert into small fragments and bacteria die.Third and Fourth generation Work Best on both type 2 and type 4 Topoisomerases.And that is the reason Third and Fourth Generation drugs are more broad spectrum in activity .
  • Initially the quinolone and fluoroquinoles first and second generation drugs were best work on gram negative bacteria.but the newer group work on both gram negative and gram positive .

 

  • Mnemonics For Mechanism:
  • Quinolones & Fluoroquinolones: Topple the Queen“: Quinolone interferes withTopoisomerase II.

Classification of quinolones and fluoroquinolones

The first generation i.e Nalidix acid is only quinolone other 3 classes are flouroquinolones.All Other compounds are the derivaties of Nalidix acid.Following are some classes of quinolones and fluoroquinolones ;

  • A)First Generation:
  • Nalidix acid
    B)Second Generation :
  • Ciprofloxacin
  • Norfloxacin
  • Ofloxacin
  • Lomefloxacin
  • Enoxacin
    Norfloxacin don’t absorb very well and they are not used most commonly While ciprofloxacin is the most commonly used drug in this class.
    C)Third Generation :
  • Levofloxacin
  • Gatifloxacin
  • Sparfloxacin
    (D)Fourth Generation :
  • Moxifloxacin
  • Trovafloxacin

Spectrum of activity 

1)First Generation Nalidix acid is moderatly effective (Not very effective) against gram negative bacteria.This drug is not used these day because of poor distribution in the body so it is use in rare uncomplicated urinary tract infections.because this drug is eliminated from the body through renal system and it concentrate into urinary system.

2)Second Generation
They become more effient against gram negative as compare to Nalidix acid.And Also have some less gram positive coverage but keep in mind it doesn’t work on streptococcus pneumoniae .
Ciprofloxacin is also effective against atypical organism like chalymdia ,mycoplasma both of these organism cause respiratory tract infections.
Means second generation has expanded its spectrum from moderate to more effective against gram negative bacteria some added benefits to gram positive bacteria and to atypical organisms.

Ciprofloxacin show more activity against pseudomonas aeruginosa than other fluoroquinolones.

Ciprofloxacin and ofloxacin are also good against Mycobacterium tuberculosis,mycobacterium Fortuitum and Mycobacterium Kansasii.but if use alone these are effective against M.avium infection.So for M.avium treatment they have to be combined with other antituberculous drugs.

Norfloxacin shows least activity against both gram postive and gram negative organisms.

Uses / Indications Of Ciprofloxacin

Where not to use this antibiotic ?
Don’t use this antibiotic more often because of the development of resistant strain and due to over usage, ciprofloxacin is failing against bacteria because of development of resistance.
Every doctor know there is one resistance type of organism i.e MRSA (Methicillin resistance staphylococcus aureus )it is resitant to many other antibiotic and the latest news is even ciprofloxacin is failing on this .
Don’t use this antibiotic in Pneumococcus and Enterococcus infections .

Where to Use Ciprofloxacin ?
A)GIT :Its very effective in traveller diarhea caused by toxic ecoli.
B)Ciprofloxacin is more effective in cystic fibrosis due to infection by pseudomonas auregenosa.
Usually flouroquinolones is contraindicated in children under the age of 18 because in animal model it is approved that flouroqinolones can damage the cartilages and they can produce arthropathy so it should not be used in pregnant women.

C)Ciprofloxacin and Ofloxacin are effective in treatment of typhoid fever .

D)Ciprofloxacin can be used to eradicate the nasopharyngeal carrier -state with meningococci.

E)Ciprofloxacin is the drug of choice in the treatment and prevention of anthranx.

3)Third Generation: Levofloxacin
Good against gram negative but has more activity against gram positive including streptococcus pnemoniea means levofloxacin can be used in pnemonia and that is why this is also called respiratory quinolones .
Levofloxacin is also effective against chlamydia ,mycoplasma and atypical pnemonia.

Levofloxacin and sparfloxacin show improved activity against streptococci and also effective against penicillin resistant pneumococci.

Levofloxacin
DON’T Use this antibiotic
if you are allergic to this drug or other drugs of this class like ciprofloxacin,norfloxacin,moxifloxacin.

Avoid taking antacids, vitamin or mineral supplements, sucralfate  or didanosine powder or chewable tablets within 2 hours before or after you take levofloxacin.

Before taking levofloxacin, tell your doctor if you have muscle weakness ,kidney or liver disease,or trouble breathing,seizures,joint problems, diabetes, myasthenia gravis, a history of head injury of brain tumor, a condition called pseudotumor cerebri, a personal or family history of Long QT syndrome,low levels of potassium in your blood,or if you have ever had an allergic reaction to an antibiotic.

Levofloxacin may cause swelling or tearing of a tendon, especially in the Achilles’ tendon of the heel. These effects may be more likely to occur if you are over 60, or if you have had a kidney,heart, or lung transplant.
if you take steroid medication, Stop taking levofloxacin and call your doctor at once if you have sudden pain, swelling, tenderness, stiffness.

Uses of levofloxacin
Levofloxacin is used to treat bacterial infections that cause bronchitis or pneumonia,means that action of this drug is more extended against pneumococci and also used to treat people who have been exposed to anthrax or plague.
Levofloxacin is also used to treat bacterial infections of the sinuses,skin,kidneys, bladder, or prostate.

4)Fourth Generation.Moxifloxacin
Levofloxacin and moxifloxacin both are called respiratory quinolones .
Its spectrum of activity further broaden against gram positive cocci and gram positive bacilli .
Moxifloxacin can kill the anaerobic organisms and that is why this can be used in mixed infections .

Moxifloxacin ,Gatifloxacin,Sparfloxacin and Gemifloxacin are effective against gram positive organism especially against pneumococci and to some extent staphylococci.

Moxifloxacin Uses
Moxifloxacin is used to treat a variety of bacterial infections. It works by stopping the growth of bacteria.

Moxifloxacin is used to treat bacterial infections, including:
community acquired pneumonia,throat, sinus, and lung infections stomach infections skin infections

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