Thorough information about Quinolones as a class of antimicrobial agent

1. Prepared by :- Ruchita V Bhavsar
1st sem M.Pharm
Guided by :- Mr. Samaresh Pal Roy
HOD of Pharmacology,
SDPC, Kim

2.  Introduction
 History
 Classification
 Mechanism of Action
 Resistance
 Pharmacokinetics
 Use
 Adverse Effects
 Interaction
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3.  The quinolones are a family of synthetic,
broad-spectrum antibiotic with bactericidal
activity.
 The term quinolone refers to potent
synthetic chemotherapeutic antibacterial
agent.
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4.  The 1st generation of the quinolones begins with
Nalidixic acid in 1962 for the treatment of
Urinary Tract Infections in humans.
 Nalidixic acid was discovered by George Lesher
and co-workers in a distillate during an attempt
at chloroquine synthesis.
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5.  Quinolones (1st generation)
 Highly protein bound
 Mostly used in UTI
 Fluoroquinolones (2nd, 3rd, 4th generation)
 Modified 1st generation quinolones
 Not highly protein bound
 Wide distribution to urine and other tissues
 Limited CSF penetration
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6. Generation Drugs Antibacterial spectrum
First
Nalidixic acid
Cinoxacin
Gram –ve bacteria
Aerobic
Second
Norfloxacin
Ciprofloxacin
Ofloxacin
Lomefloxacin
Enoxacin
Gram +ve bacteria
Aerobic
Improved activity against
Gram –ve bacteria
Third
Levofloxacin
Sparfloxacin
Gatifloxacin
Gemifloxacin
Good activity against
Anaerobic
Gram +ve bacteria
particularly pneumococci
Fourth
Trovafloxacin
Moxifloxacin
Clinafloxacin
Sitafloxacin
Anaerobic
Increased activity against
pneumococci
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7.  The first-generation agents include cinoxacin
and nalidixic acid, which are the oldest and least
often used quinolones.
 Because minimal serum levels are achieved, use
of these drugs has been restricted to the
treatment of uncomplicated urinary tract
infections.
 They are more susceptible to the development
of bacterial resistance.
 These agents are not recommended for use in
patients with poor renal function because of
significantly decreased urine concentrations.
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8.  The second-generation quinolones have increased
gram-negative activity, as well as some gram-
positive and atypical pathogen coverage.
 Compared with first-generation drugs, these agents
have broader clinical applications in the treatment
of complicated urinary tract infections and
pyelonephritis, sexually transmitted diseases,
selected pneumonias and skin infections.
 They include ciprofloxacin, lomefloxacin,
norfloxacin, ofloxacin and enoxacin.
 Ciprofloxacin and ofloxacin are the most widely
used because of their availability in oral and
intravenous formulations.
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9.  The third-generation quinolones currently include
levofloxacin, gatifloxacin, moxifloxacin and
sparfloxacin.
 These agents are separated into a third class
because of their expanded activity against gram-
positive organisms, particularly penicillin-sensitive
and penicillin-resistant S. pneumoniae, and
atypical pathogens such as Mycoplasma
pneumoniae and Chlamydia pneumoniae.
 Although the third-generation quinolones retain
broad gram-negative coverage, they are less active
than ciprofloxacin against Pseudomonas species.
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 Because of their expanded antimicrobial spectrum,
they are useful in the treatment of community-
acquired pneumonia, acute sinusitis and acute
exacerbations of chronic bronchitis.
 The FDA recommends that all of these drugs should
be avoided in patients who are taking drugs that
are known to prolong the QT interval, such as
tricyclic antidepressants, phenothiazines and class
I antiarrhythmics. In contrast, levofloxacin does
not affect the QT interval.

11.  Trovafloxacin, the current member of the fourth-
generation class, adds significant antimicrobial
activity against anaerobes while maintaining the
gram-positive and gram-negative activity of the
third-generation quinolones. It also retains activity
against Pseudomonas species comparable to that of
ciprofloxacin.
 Because of concern about hepatotoxicity,
trovafloxacin therapy should be reserved for life-
or limb-threatening infections requiring inpatient
treatment and the drug should be taken for no
longer than 14 days.
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12.  Delafloxacin (developmental code name RX-
3341) is a fluoroquinolone antibiotic being
developed.
 It is more active than other quinolones
against Gram-Positive bacteria.
 Phase II clinical trials have been completed and
Phase III trial for ACUTE BACTERIAL SKIN AND
SKIN STRUCTURE INFECTIONS (ABSSSI) is due to
begin.
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14.  The fluoroquinolones are a relatively new group
of antibiotics.
 They were first introduced in 1986, but they are
really modified quinolones, a class of antibiotics,
whose accidental discovery occured in the early
1960.
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16.  It blocks bacterial DNA synthesis by
 Inhibition of bacterial Topoisomerase II (DNA
Gyrase)
 Inhibition of Topoisomerase IV
 Inhibition of ATP dependent DNA gyrase; which
nicks doule stranded DNA, introduces negative
supercoils and then reseals the nicked ends. This
is required to prevent excessive positive
supercoiling of DNA strands when they seperate
to permit replication or transcription.
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 Inhibition of DNA gyrase also prevents the
relaxation of positively supercoiled DNA.
 Inhibition of DNA nicking–closing enzyme
responsible for DNA elongation, which leads to
break in double stranded DNA.
 Inhibition of topoisomerase IV interferes with the
separation of replicated chromosomal DNA into
respective daughter cells during cell division.

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 The critical imbalance in cellular metabolism
resulting from the inhibition of enzymes
precipitates a sequence of cellular events which
may lead to :
1. Premature cell division
2. Delayed cell division
3. Total failure of cell division leading to lysis of
the cell

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21.  Resistance appears to be the result of :
 Alteration in the quinolone enzymatic targets
(DNA gyrase), decreased outer membrane
permeability or the development of efflux
mechanisms.
 One or more point mutations in the quinolone
binding region of the target enzyme
(Topoisomerase) or from a change in the
permeability of the organism.
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25.  Absorption : Well absorbed orally with
bioavailability 80-95% Oral absorption is impaired
by divalent cations
 Distribution : Widely distributed in body fluids
and tissues but limited CSF penetration. It can
pass the placenta reaching to the foetus
 Half life : 3-8 hours in serum
 Elimination : 30-50% from urine by tubular
secretion or glomerular filtration and some
amount in bile – faeces.
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1. RTI (Respiratory Tract Infection) :
 EMPYEMA : The collection of pus in a cavity of
the body, especially in the pleural cavity (the
area between the lungs and the inner surface of
the chest wall)
 PNEUMONIA : Infection of the lungs that caused
by bacteria, viruses, fungi or parasites
 LUNG ABSCESS : Bacterial infection that occurs
in the lung tissue causing tissue to die and pus to
collect in that space
2. MENINGITIS : Inflammation of the lining of the
brain and spinal cord

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3. UTI (Urinary Tract Infection) :
 PYELONEPHRITIS : A type of urinary tract
infection (UTI) that affects one or both kidneys
caused by a bacterium mainly Escherichia coli or
virus infection. It causes the kidneys to swell
and may permanently damage them.
 EPIDIDYMITIS : Inflammation of the epididymis, a
tube near the testicles that stores and carries
sperm in men
 PROSTATITIS : Inflammation of
the prostate gland due to a
urine infection in men
 CYSTITIS : Inflammation of the
bladder usually caused by a
urine infection in women

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4. GIT (Gastro Intestinal Tract) infection :
 ENTERIC FEVER : A potentially fatal
multisystemic illness caused primarily by
Salmonella species
 BACTERIAL DIARRHOEA : Caused by
Campylobacter, salmonellae, and shigella
organisms
5. Skin & soft tissue infections :
 INFECTED ULCERS : Shallow wound that
develops on the skin
 INFECTED BURNS : Red coloured and warm to
touch due to an infection

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6. GONORRHEA : A venereal disease involving
inflammatory discharge from the urethra or
vagina.
7. CHANCROID : Bacterial infection that causes open
sores on or around the genitals of men and women
8. TUBERCULOSIS : Infectious bacterial disease
characterized by the growth of nodules (tubercles)
in the tissues, especially the lungs
9. CONJUCTIVITIS : Inflammation of the outermost
layer of the white part of the eye and the inner
surface of the eyelid

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31. CNS (Central Nervous System)
 Quinolones may displace the neuroinhibitor GABA,
resulting in CNS stimulation
 Dizziness
 Headache
 Insomnia
 Restlessness
Phototoxicity
 Skin damage after exposure to UV light due to
toxic reactions.
 These included second-degree burns, discoloration
and sometimes permanent discoloration and
scarring of the skin. 31

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Gastrointestinal
 Depletion of magnesium and disruption of cellular
enzyme function
 Disruption of mitochondrial function and energy
production
 Other common side effects are :
 Nausea
 Vomiting
 Anorexia
 Diarrhea

34. 1. NSAIDs :
 Enhance the CNS toxicity of quinolones
2. Theophylline, Caffeine or Warfirine
 Plasma concentration is increased by
Ciprofloxacin
3. Antacid or Iron salts
 Reduce the absorption of quinolones
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35.  2nd generation fluoroquinolone
 Most potent fluoroquinolone against P.
aeruginosa
 Not effective against Gram +ve and anaerobes
 Mainly effective against Gram –ve bacteria :
Enterobacteriacae H. Influenzae
Campylobacter M. Catarrhalis
Pseudomonas N. Gonorrhea
 Intracellular Pathogen :
M. Tuberculosis Mycoplasma
Chlamydia Legionella
Brucella
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CLINICAL USE :
 Urinary Tract Infections
 Travellers’ diarrhoea
 Anthrax
 Diabetic foot infections
UNIQUE QUALITIES :
 It binds to divalent cations which decreases
absorption.
 Because of its good penetration into bone, orally
administered ciprofloxacin is a useful alternative to
parenterally administered antibiotics for the
treatment of osteomyelitis caused by susceptible
organisms.

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MARKETED PREPARATIONS :
 Ciplox eye drop / Ciloxan eye drop or
ointment : Used in conjuctivitis, corneal ulcer
and before opthalmic surgery

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 Neocip 500 mg :
Cipla
 C-flox 250 mg :
Intas
 Ciprodac 500 mg :
Cadila

39.  3rd generation fluoroquinolone
 Levo-isomer
 100% oral bioavailability
 Effective against Gram +ve and Gram –ve
bacteria
 Also effective against Pathogen :
Legionella pneumophila
Atypical respiratory pathogens
Mycobacterium tuberculosis
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CLINICAL USE :
 Urinary tract infections
 Chronic bronchitis
 Nosocomial pneumonia
 Intra-abdominal infections
UNIQUE QUALITY :
 It binds to divalent cations which decreases
absorption

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MARKETED
PREPARATIONS :
 Levoslog tablet
 Levotec tablet
 Wecure ablet

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