Quinolones Printout

8/3/2019 Quinolones Printout

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QUINOLONES

SUBMITTED BY

JITHIN G

PG IN ORTHODONTICS



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INTRODUCTION

These are synthetic antimicrobials having

a quinolone structure that are active primarily against

gram-negative bacteria, though newer fluorinated

compounds also inhibit gram-positive ones. The first

member Nalidixic acld introduced in mid-1960s had

usefulness limited to urinary and g.i. tract infections

because of low potency, modest blood and tissue levels,

Iimited spectrum and high frequency of bacterialresistance. A breakthrough was achieved in the early

1980s by fluorination of the quinolone structure at

position 6 and introduction of a piperazine substitution at

position 7 resulting in derivatives called fluoroquinolones

with high potency, expanded spectrum, slow

development of resistance, better tissue penetration andgood tolerability.



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Nalidixic acid

It is active against gram-negative bacteria, especially

coliforms: E. coli, Proteus, Klebsiella, Enterobacter,

shigella but not Pseudomonas. It acts by inhibiting

bacterial DNA gyrase and is bactericidal. Resistance to

nalidixic acid develops rather rapidly. Nalidixic acid is

absorbed orally, highly plasma protein bound and partly

metabolized in liver: one of the metabolites is active. It is

excreted in urine with a plasma t1/2 -8 hrs.

Concentration of the free drug in plasma and most

tissues attained with the usual doses is non-therapeuticfor systemic infections (MIC values for most susceptible

bacteria just approach the 'break-point' concentration).

However, high concentration attained in urine (20-50

times that in plasma) is lethal to the common urinary

pathogens.

Adverse effects These are relatively infrequent, consist

mostly of g.i. upset and rashes. Most important toxicity is

neurological-headache, drowsiness, vertigo, visual

disturbances, occasionally seizures (especially in

children). Phototoxicity is rare. Individuals with G-6-PD

deficiency may develop haemolysis. Nalidixic acid iscontraindicated in infants.



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Dose:0.5-1gm TID or QID;

Use

1. Nalidixic acid is primarily used as a urinary antiseptic,

generally as a second line drug in recurrent cases or on

the basis of sensitivity reports. Nitrofurantoin should not

be given concurrently- antagonism occurs.

2. It has also been employed in diarrhoea caused by

Proteus, E - coli, Shigella or Salmonella, and has aspecial place in ampicillin resistant Shigella enteritis.

FLUOROQUINOLONES

These are quinolone antimicrobials having one or more

fluorine substitutions. The 'first generation'

fluoroquinolones (FQs) introduced in 1980s have one

fluoro substitution. In the 1990s, compounds with

additional fluoro and other substitutions have been

developed-further extending antimicrobial activity to

gram-positive cocci and anaerobes, and/or confering

metabolic stability (longer t1/2). These are referred to as'second generation' FQs.

1 ST GENERATION

Norfloxacin

Ofloxacin

Ciprofloxacin

Pefloxacin



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2ND GENERATION

Lomefloxacin

Sparfloxacin

Levofloxacin

Gatifloxacin

Moxifloxacin

Mechanism of action

The FQs inhibit the enzyme bacterial DNA gyrase, which

nicks double-stranded DNA, introduces negative

supercoils and then reseals the nicked ends. Thisis necessary to prevent excessive positive super-coiling

of the strands when they separate to permit replication

or transcription. The DNA gyrase consists of two A and

two B subunits: The A subunit carries out nicking of

DNA, B subunit introduces negative supercoils and then

A subunit reseals the strands. FQs bind to A-subunitwith high affinity and interfere with its strand cutting and

resealing function. Recent evidence indicates that in

gram-positive bacteria the major target of FQ action is a

similar enzyme topoisomerase IV which nicks and

separates daughter DNA strands after DNA replication.

Greater affinity for topoisomerase IV may confer higher

potency against gram-positive bacteria. The bactericidal



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action probably results from digestion of DNA by

exonucleases whose production is signalled by the

damaged DNA. In place of DNA gyrase or

topoisometase IV, the mammalian cells possess an

enzyme topoisomerase II (that also removes positive

supercoils) which has very low affinity for FQs hence the

low toxicity to host cells. Mechanism of resistance.

Because of the unique mechanism of action plasmid

mediated transferable resistance probably does not

occur. Resistance noted so far is due to chromosomalmutation producing a DNA gyrase or topoisomerase IV

with reduced affinity for FQs, or due to reduced

permeability increased efflux of these drugs across

bacterial membranes. In contrast to nalidixic acid which

selects single step resistant mutants at high frequency,

FQ-resistant mutants are not easily selected. Therefore,resistance to FQs has been slow to develop. However,

increasing resistance has been reported among

Salmonella Pseudomonas, staphylococci, gonococo

and pneumococci.Ciprofloxacin (prototype)

It is the most potent first generation FQ active

against a broad range of bacteria, the most susceptible

ones are the aerobic gram-negative bacilli, especially

the Enterobacteriaceae and Neisseria. The MIC of

ciprofloxacin against the bacteria is usually < 0.1 μg/ml,



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while grampositive bacteria are inhibited at relatively

higher concentrations.

Pharmacokinetics

Ciprofloxacin is rapidly absorbed orally, but

food delays absorption, and first pass metabolism

occurs. The most prominent feature of ciprofloxacin (and

other FQs) is high tissue penetrability: concentration in

lung, sputum, muscle, bone, prostate and phagocytes

exceeds that in plasma, but CSF and aqueous levels are

lower. It is excreted primarily in urine,both by glomerularfiltration and tubular secretion. Urinary and biliary

concentrations are 10-50 fold higher than plasma.

Uses

Ciprofloxacin is effective in a broad range

of infections including some difficult to treat ones.Because of wide-spectrum bactericidal activity, oral

efficacy and good tolerability, it is being extensively

employed for blind therapy of any infection, but should

not be used for minor cases or where gram-positive

organisms and/or anaerobes are primarily causative. In

severe infections, therapy may be initiated by i.v.

infusion and then switched over to oral route.

1. Urinary tract infections

2. Gonorrhoea

3. Chancroid

4. Bacterial gastroenteritis

5. Typhoid



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6. Bone, soft tissue,gynaecological and wound infection

7. Respiratory infections

8. Tuberculosis

9. Gram-negative septicaemias

10.Meningitis

11. Prophylaxis of infections in neutropenic, gram-

negative bacteria

12. Conjunctivitis

Norfloxacin It is less potent than ciprofloxacin. MIC

values for most gram-negative bacteria are 2-4 times

higher. Many Pseudomonas and gram- positive

organisms are not inhibited at clinically attained

concentrations. Moreover, it attains lower concentration

in tissues. It is metabolized as well as excretedunchanged in urine. Norfloxacin is primarily used for

urinary and genital tract infections. It is also good for

bacterial diarrhoeas, because high concentrations are

present in the gut and anaerobic flora is not disturbed.

Norfloxacin is not recommended for respiratory and

other systemic infections, particularly where gram-

positive cocci are involved.

Pefloxacin

It is the methyl derivative of norfloxacin;

more lipid soluble, completely absorbed orally,

penetrates tissues better and attains higher plasma

concentrations. Passage into CSF is higher than other



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FQs-preferred for meningeal infections. It is highly

metabolized-partly to norfloxacin which contributes to its

activity. Pefloxacin has longer t1/2: cumulates on

repeated dosing achieving plasma concentrations twice

as high as after a single dose. Because of this it is

effective in many systemic infections in addition to those

of the urinary and g.i. tract, though the in vivo activity is

similar to norfloxacin. Dose of pefloxacin needs to be

reduced in liver disease, but not in renal insufficiency.

Pefloxacin is an alternative to ciprofloxacin for typhoid.However, it is less effective in gram-positive coccal and

Listeria infections

Ofloxacin

This FQ is intermediate between ciprofloxacin and

norfloxacin in activity against gram-negative bacteria,but it is comparable to more potent than ciprofloxacin for

gram-positive organisms.it is an alternative drug for

urethritis, cervicitis and atypical pneumonia. It also

inhibits M. tuberculosis;can be used in place of

ciprofloxacin. It is highly active against M. leprae: is

being used in alternative multidrug therapy regimens.

Ofloxacin is relatively lipid soluble; oral bioavailability is

high: attains higher plasma concentrations. Food does

not interfere with its absorption. It is excreted largely

unchanged in urine; dose needs to be reduced in renal

failure. Ofloxacin is comparable to ciprofloxacin in

the therapy of systemic and mixed infections. It is

particularly suitable for chronic bronchitis and other



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respiratory or ENT infections. Inhibition of theophyllinemetabolism is less marked. Gonorrhoea has beentreated with a single 200 mg dose. It is also useful in

non-gonococcal urethritis.

Levofloxacin It is the levoisomer of ofloxacin having

improved activity against Strep. Pneumonine and some

other gram-positive and gram-negative bacteria.

Anaerobes are moderately susceptible. Oral

bioavailability of levofloxacin is nearly 100%; oral andi.v. doses are similar. It is mainly excreted unchanged

and a single daily dose is sufficient because of slower

elimination. Theophylline, warfarin, cyclosporine and

zidovudine pharmacokinetics has been found to remain

unchanged during levofloxacin treatment. The primary

indication of levofloxacin is community acquiredpneumonia and exacerbations of chronic bronchitis in

which 87-96o% cure rate has been obtained. High cure

rates have been noted in sinusitis, enteric fevers,

pyelonephritis and skin/soft tissue infections as well.

LomefloxacinIt is a second generation difluorinated

quinolone, equal in activity to ciprofloxacin but more

active against some gram-negative bacteria and

chlamydia. Because of longer tl1/2 and persistence in

tissues, it is suitable for single daily administration. It is

primarily excreted unchanged in urine; dose needs to be



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reduced in renal insufficiency. Interaction with

theophylline has not been noted, but warfarin levels are

increased.

SparfloxacinThis second generation difluorinated

quinolone has enhanced activity against gram-positive

bacteria (especially Strep. pneumoniae,

Staphylococcus,Enterococcus), Bacteroides fragilis,

other anaerobes and mycobacteria. Its major indicationsinclude pneumonia, exacerbations of chronic bronchitis,

sinusitis and other ENT infections. Reports suggest

good efficacy in tuberculosis, MAC infection in AIDS

patients and in leprosy. Also used for chlamydial

infections. It does not alter the pharmacokinetics of

theophylline and warfarin. However, it has caused a

higher incidence of phototoxic reactions: recipients

should be cautioned not to go out in the sun. Slight

prolongation of QTc interval has been noted in 3%

recipients; should be avoided in patients taking

cisapride, tricyclic antidepressants, phenothiazines,

class IA and class III antiarrhythmics, etc. Because of

longer t1/2 it is suitable for single daily dosing.

Gatifloxacin

Another 2nd generation FQ that has

excellent activity against Strep. pneumoniae, many

atypical respiratory pathogens including Chlamydia

pneumoniae and certain anaerobes. M. tuberculoslsis

also inhibited. A greater affinity for topo-isomerase IV



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may be responsible for improved activity against gram-

positive cocci. The major indication of gatifloxacin is

community acquired pneumonia, exacerbation of chronic

bronchitis, and other upper/lower respiratory tract

infections

MoxiflsxacinIt is also a long-acting 2nd generation

FQ having high activity against Str-pneumoniae, other

gram-positive bacteria including B-lactam,macrolideresistant ones and some anaerobes.It is the most potent

FQ against M. Tuberculosls, Bacterial topo-isomerase IV

is the major target of action. Moxifloxacin is primarily

used for pneumonias, bronchitis, sinusitis, otitis media,

in which efficacy is comparable to B-lactam antibiotics.

However, it is not good for urinary tract infections. Sideeffects are similar to other FQs. It should not be given to

patients predisposed to seizures and to those receiving

proarrhythmic drugs, because it can prolong Q-T"

interval. Phototoxicity occurs only rarely.

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