Quinolones & fluoroquinolones

Some details about Quinolones and fluoroquinolones , it's classification, MOA , ADRs and therapeutic uses.

1. QUINOLONES & FLUOROQUINOLONES







Ameena kadar k a
GRACE COLLEGE OF PHARMACY
Palakkad

2.  QUINOLONES & FLUOROQUINOLONES :
 These are synthetic antimicrobials having a quinolone structure
and are active primarily against gram-negative bacteria, though
the newer fluorinated compounds also inhibit gram positive
ones.
 The first member Nalidixic acid introduced in mid- 1960s had
usefulness limited to urinary and G.I tract infections because of
low potency, modest blood and tissue levels, restricted spectrum
and high frequency of bacterial resistance.
 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 (FQs) with high potency, expanded
spectrum, slow development of resistance, better tissue penetration
and good tolerability.
 Unfortunately, overuse resulted in rising rates of resistance in
gram-negative and gram-positive organisms, increased frequency
of Clostridium difficile infections, and identification of numerous
untoward adverse effects.
 Consequently, these agents have been relegated to second-line
options for various indications.

 CLASSIFICATION :

3.  Nalidixic acid :
 First member of Quinolones.
 It is active against gram-negative bacteria, especially
coliforrns: £. coli, Proleus, K/ebsiella, Emerobacter, 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 t½ -8 hrs.

4.  Concentration of the free drug in plasma and most tissues
attained with the usual doses is nontherapeutic for systemic
infections.
 However, high concentration attained in urine (20-50 times
that in plasma) and gut lumen is lethal to the common urinary
pathogens and diarrhoea causing coliforms.
 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).
 Individuals with G-6-PD deficiency may develop haemolysis.
 Nalidixic acid is contraindicated in infants.
 Dose: 0.5- 1 g TDS or QID.
 It has been largely superseedcd by FQs, but may occasionally
be used for urinary tract infection and in diarrhoea.

 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 bacteria and anaerobes, and/or confering
metabolic stability (longer t½).
 These are referred to as 'second generation ' FQs.
 Some of the newer ones have high activity against gram positive
cocci.

5.  MOA :
 The FQs inhibit the enzyme bacterial DNA gyrase (primarily
active in gram negative bacteria), which nicks double-stranded
DNA, introduces negative supercoils and then reseals the nicked
ends.
 This is necessary to prevent excessive positive supercoiling 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.
 The FQs bind to A subunit with high affinity and interfere with its
strand cutting and resealing function.
 In gram-positive bacteria the major target of FQ action is a similar
enzyme topoisomerase 1V which nicks and separates daughter
DNA strands after DNA replication.
 Greater affinity of a FQ for topoisomerase IV may confer higher
potency against gram-positive bacteria.
 The bactericidal action probably results from digestion of the DNA
by exonucleases whose production is signalled by the damaged
DNA.
 In place of DNA gyrase or topoisomerase IV, the mammalian
cells possess an enzyme topoisomerase lI (that also removes
positive supercoils) which has very low affinity for FQs- hence the
low toxicity to host cells.

6. Action Type 11 DNA Topoisomerase

7.  Mechanism of resistance :
 When the fluoroquinolones were first introduced, there was
optimism that resistance would not develop.
 Although no plasmid-mediated resistance has been reported,
resistant MRSA, pseudomonas, coagulase-negative staphylococci,
and enterococci have unfortunately emerged due to chromosomal
mutations.
 Cross-resistance exists among the quinolones.
 The mechanisms responsible for this resistance include the
following.
1. Altered target:
 Mutations in the bacterial DNA gyrase have been associated
with a decreased affinity for fluoroquinolones. Topoisomerase
IV also undergoes mutations.
 Resistance is frequently associated with mutations in both
DNA gyrase and topoisomerase IV.

8. 2. Decreased accumulation:
 Reduced intracellular concentration of the drugs in the
bacterial cell is linked to two mechanisms.
 One involves a decreased number of porin proteins in the
outer membrane of the resistant cell, thereby impairing access
of the drugs to the intracellular topoisomerases.
 The other mechanism is associated with an energy-dependent
efflux system in the cell membrane.

 Antimicrobial spectrum :
 FQs are bactericidal and exhibit AUC/MIC dependent killing.
 Bactericidal activity becomes more pronounced as the serum drug
concentration increases to approximately 30-fold the minimum
inhibitory concentration.
 In general, they are effective against gram-negative organisms
such as the Enterobacteriaceae, Pseudomonas species, Haemophilus
influenzae, Moraxella catarrhalis, Legionellaceae, chlamydia,
mycoplasma and some mycobacteria.
 They are effective in the treatment of gonorrhea but not
syphilis.
 The newer agents (for example, levofloxacin and moxifloxacin)
also have good activity against some gram-positive organisms,
such as Streptococcus pneumoniae.
 Moxifloxacin has activity against many anaerobes.
 If used prophylactically before transurethral surgery, FQs lower the
incidence of postsurgical urinary tract infections (UTIs).
 It has become common practice to classify the fluoroquinolones
into “generations,” based on their antimicrobial targets.

9.  Ciprofloxacin and norfloxacin are assigned to the second
generation because of their activity against aerobic gram-
negative and atypical bacteria.
 In addition, these fluoroquinolones exhibit significant
intracellular penetration, allowing therapy for infections in which
a bacterium spends part or all of its life cycle inside a host cell (for
example, chlamydia, mycoplasma, and legionella).
 Levofloxacin is classified as third generation because of its
increased activity against gram-positive bacteria.
 The fourth generation includes only moxifloxacin because of its
activity against anaerobic, as well as, gram-positive organisms.


1. 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.

10.  The MlC of ciprofloxacin against these bacteria is usually < 0.1
µg/ml, while gram-positive bacteria are inhibited at relatively
higher concentrations.
occur in - 10% patients, but are generally mild: withdrawal is
needed only in 1.5%
 The distinctive microbiological features of ciprofloxacin (also
other FQs) are:
• Bactericidal activity and high potency: MBCs are close to MICs.
• Relatively long post-antibiotic effect on Enterobactcriaceae,
Pseudomonas and Staph.
• Low frequency of mutational resistance.
• Low propensity to select plasmid type resistant mutants.
• Protective intestinal streptococci and anaerobes are spared.
• Less active in acidic pH.
 Pharmacokinetics :
 Rapidly absorbed orally, but food delays absorption, and first
pass metabolism occurs.
 Ciprofloxacin (and other FQs except norfloxacin) attain bactericidal
levels in blood and have good tissue penetrability.
 Concentration in lung, sputum, muscle, prostate and phagocytes
exceeds that in plasma, but CSF and aqueous levels are lower.
 It is excreted primarily in urine, both by glomerular filtration and
tubular secretion.
 Adverse effects :
 Ciprofioxacin has good safety record: side effects occur in - 10%
patients, but are generally mild: withdrawal is needed only in 1.5%.
• Gastrointestinal: nausea, vomiting, bad taste, anorexia.
Because gut anaerobes are not affected- diarrhoea is infrequent.
• CNS: dizziness, headache, restlessness, anxiety, insomnia,
impairment of concentration and dexterity (caution while driving).

11. Tremor and seizures are rare, occur only at high doses or when
predisposing factors are present.
• Skin/hypersensitivity: rash, pruritus, photosensitivity, urticaria,
swelling of lips, etc.
Serious cutaneous reactions are rare.
• Tendonitis and tendon rupture: a few cases have occurred. Risk
of tendon damage is higher in patients above 60 years of age and in
those receiving corticosteroids. Due to reports of cartilage
damage, FQs should be used cautiously in children.
Ciprofloxacin and other FQs are contraindicated during
pregnancy.


 Interactions :
• Plasma concentration of theophylline, caffeine and warfarin is
increased by ciprofloxacin due to inhibition of metabolism: CNS
toxicity can occur by concurrent use of theophylline and a FQ.
•NSAIDs may enhance the CNS toxicity of FQs: seizures are
reported.
• Antacids, sucralfate and iron salts given together reduce absorption
of FQs.
 Uses :
 Effective in a broad range of infections.
 Extensively employed for empirical 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 (UTI):

12.  High cure rates, even in complicatcd cases or those with
indwelling catheters/prostatitis, have been achieved.
 Chronic Pseudomonas infections respond less completely, but
among all FQs ciprofloxacin is the most active against
Pseudomonas.
2. Gonorrhoea:
 Initially ciprofloxacin was nearly I00% curative in non-PPNG
as well as PPNG (Pencillinase Producing N. gonorrhoeae)
infections, but has become nondependable now; therefore not
used.
3. Chancroid:
 Ciprofloxacin 500 mg BD for 3 days is a second line alternative
drug to ceftriaxone/azithromycin.

4. Bacterial gastroenteritis:
 Currently, ciprofloxacin is the most commonly used drug for
empirical therapy of diarrhoea.
5. Typhoid:
 Ciprofloxacin (750 mg BD) is mostly used FQs.
 Ofloxacin, levofloxacin are nearly equally efficacious
alternatives.
6. Bone, soft /issue, gynaecological and wound infections:
 caused by resistant staph. and gram-negative bacteria mostly
respond to ciprofloxacin.
 High cure rates have been obtained in osteomyelitis and joint
infections but prolonged treatment (6-8 weeks) with high doses
(750 mg BD) is required.
 Used along with clindamycin/ metronidazole (to cover
anaerobes) it is a good drug for diabetic foot.
7. Respiratory infections:

13.  It should not be used as the primary drug because pneumococci
and streptococci have low and variable susceptibility.
 However, it can treat atypical pneumonia due to Mycoplasma,
Legionella, H. influenzae, Branh. catarrhalis, and Chlamydiae.
 Several 2nd generation FQs (levofloxacin, gemifloxacin,
moxifloxacin) have now become available for the treatment of
pneumonias and chronic bronchitis.
8. Anthrax:
 The US-FDA has approved its use for post exposure treatment of
inhalational anthrax which may occur due to bioterrorism.
9. Tuberculosis :
 Moxifloxacin and levofloxacin are second line drugs which can be
used as a component of combination chemotherapy against
multidrug resistant tuberculosis.
 Ciprofloxacin is less active against M. tuberculosis, but is the most
active FQ against Mycobact. avium complex (MAC).
10. Gram-negative septicaemias:
 Parenteral ciprofloxacin may be combined with a third generation
cephalosporin or an aminoglycoside.
11. Meningitis:
 Though penetration in CSF is not very good, ciprofloxacin has
been successfully used in gram-negative bacterial meningitis,
especially that occurring in immunocompromised patients or those
with CSF shunts.
 It can cure meningococcal carrier state.
12. Prophylaxis: of infections in neutropenic/cancer and other
susceptible patients.
13. Conjunctivitis: by gram-negative bacteria: topical therapy is
effective.

14.  Typical therapeutic applications of Fluoroquinolones

2. Norfloxacin :
 It is the least potent FQ: MIC values for most gram-negative
bacteria are 2- 8 times higher than that of ciprofloxacin.
 Many Pseudomonas and gram-positive organisms are not
inhibited.
 Moreover, it attains lower concentration in tissues which are non-
therapeutic.
 It is primarily used for urinary tract infections.
 Given for 8- 12 weeks, it can treat chronic UTI.
 It is also good for bacterial diarrhoeas, because high concentrations
are present in the gut, and anaerobic flora of the gut is not
disturbed.


3. Pefloxacin :
 It is the methyl derivative of norfloxacin which is more lipid
soluble, completely absorbed orally, penetrates tissues better and
attains higher plasma concentrations.

15.  Passage into CSF is greater than other FQs-can be used for
meningeal infections.
 It is highly metabolized- partly to norfloxacin which contributes to
its activity.
 It has longer t½: cumulates on repeated dosing achieving plasma
concentrations twice as high as after a single dose.
 Because of this it is effective in some systemic infections as well.
 Dose of pefloxacin needs to be reduced in liver disease, but not in
renal insufficiency.
4. Ofloxacin :
 Less active than ciprofloxacin against gram-negative bacteria,
but equally or more potent against Strep. Pyogenes and other
gram-positive cocci and certain anaerobes.
 Good activity against Chlamydia and Mycoplasma has been noted.
 It is an alternative drug for nonspecific urethritis, cervicitis and
atypical pneumonia caused by Chlamydia trachomatis.
 lt also inhibits M. tuberculosis; can be used in resist alll cases of
TB.
 High activity is exhibited against M. leprae, and it is being used in
alternative multidrug therapy regimens.
 Relatively lipid soluble
 Oral bioavailability is high , and higher plasma concentrations
are attained.
 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.

16.  It is suitable for chronic bronchitis and other respiratory or
ENT infections as well as for chlamydia urethritis as an
alternative drug.
 Inhibition of theophylline metabolism is less marked.
5. Levofloxacin:
 lt is the active levo(S) isomer of ofloxacin having improved
activity against Strep. pneumoniae, M. ruberculosis and some
other gram-positive and gram-negative bacteria.
 Anaerobes are moderately susceptible.
 Oral bioavailability of levofloxacin is nearly 100%; oral and I.V.
doses are similar.
 It is mainly excreted unchanged, and a single daily dose is
sufficient because of slower elimination and higher potency.
 Theophylline, warfarin, cyclosporine and zidovudine
pharmacokinetics has been found to remain unchanged during
levofloxacin treatment.
 The primary indication of levofloxacin is community acquired
pneumonia and exacerbations of chronic bronchitis in which upto
90% cure rate has been obtained.
 High cure rates have been noted in sinusitis, pyelonephritis,
prostatitis and other UTI, as well as skin/soft tissue infections.
 It is an alternative drug for chlamydia urethritis.
 It is the second most active FQ for TB, and in India it is a
component of the standardized regimen for MDR-TB.


6. Lomefloxacin :
 IL is a second generntion difluorinated quinolone, more active
against some gram-negative bacteria and chlamydia.

17.  However, due to higher incidence of phototoxicity and Q-T
prolongation, it has been withdrawn in USA and some other
countries, but is available in India though infrequently used.
7. Sparfloxacin :
 Another second generation difluorinated quinolone which has
enhanced activity against gram-positive bacteria, Bacteroides
fragilis, other anaerobes and mycobacteria.
 Its major indications include pneumonia, exacerbations of chronic
bronchitis, sinusitis and other ENT infections.
 However, it has frequently caused phototoxic reactions: recipients
should be cautioned not to go out in the sun.
 Prolongation of QTc interval has been noted in 3% recipients; fatal
arrhythmias have occurred.
8. Moxifloxacin :
 A long-acting 2nd generation FQ having high activity against
Str.pneumoniae, other gram-positive bacteria including β-lactam/
macrolide resistant ones and some anaerobes.
 It is the most potent FQ against M. tuberculosis, and is extensively
used in MDR-TB.
 Bacterial topoisomerase IV is the major target of action.
 It is primarily used for pneumonias, bronchitis, sinusitis, otitis
media, in which efficacy is comparable to β-lactam antibiotics.
 Because urinary concentrations are low, it is not used for urinary
tract infections.
 It is primarily metabolized in liver; should not be given to liver
disease patients.
 No dose modification is needed in renal disease.
 Side effects are similar to other FQs.

18.  It should not be given to patients predisposed to seizures and to
those receiving proarrhythmic drugs, because it can prolong Q-T:
interval, and the combination may precipitate serious arrhythmias.
 Phototoxicity occurs rarely.
9. Gemifloxacin :
 Another broad spectrum FQ, active mainly against aerobic gram
positive bacteria, especially Strep. pneumoniae, H. influenzae,
Moraxella, Mycoplasma pneumoniae, Chlamydia pneumophila,
Klebsiella including some multidrug resistant strains.
 Some anaerobes are also inhibited.
 It is rapidly absorbed, undergoes limited metabolism, and is
excreted in urine as well as faeces, both as unchanged drug and as
metabolites.
 Dose needs to be halved if creatinine clearance is <40 ml/min.
 Side effects are diarrhea, nausea, headache, dizziness and rise in
serum amino-transferases.
 Skin rashes are more common.
 It can enhance warfarin effect, and carries the risk of additive Q-T
prolongation with other drugs.
 It is indicated in community acquired pneumonia and for acute
exacerbations of chronic bronchitis.
10. Prulifloxacin :
 This newer 2nd generation FQ is a prodrug of Ulifloxacin, a broad
spectrum antibacterial active against both gram positive as well as
gram negative bacteria, including many resistant strains.
 It is rapidly absorbed and converted to ulifoxacin during first pass
metabolism.
 Ulifloxacin is then excreted primarily unchanged in urine.

19.  It has shown good efficacy in acute exacerbations of chronic
bronchitis, as well as in uncomplicated or complicated UTI.
 Its side effect profile is similar to that of ciprofloxacin.
 Gastrointestinal and CNS disturbances, urticaria and
photosensitivity are reported.
 It is claimed not to prolong Q-T interval.
11. Pazufloxacin :
 It is an atypical quinolone antimicrobial with a fused tricyclic
ring, developed in Japan in the 1990s.
 Only an injectable formulation as 'mesylate' is marketed for
I.V. infusion.
 Antimicrobial spectrum of Pazufloxacin is wide covering both
gram +ve and -ve bacteria, including several resistant strains and
some anaerobes.
 It inhibits both bacterial DNA gyrase and topoisomerase IV
confering gram -ve and gram +ve activity as well as low potential
to select resistam mutans.
 Most enterobaeteriaceae are highly susceptible while good
activity has been noted against resistant Pseudomonas, MRSA,
ampicillin resistant H. influenzae and K.pneumoniae.
 After I.V infusion pazufloxacin penetrates most body fluids
including CSF, and is mainly excreted unchanged in urine with a
t½ of 1.5-2 hours.
 Clinical indications; pneumonia, lung abscesses, upper and lower
UTI, peritonitis, intraabdominal abscesses, endometritis,
secondary infections after burns, injuries and empirical therapy of
nosocomial infections.
 Adverse effects are nausea, diarrhoea, rashes, rarely seizures.
Risk of seizures may limit dosage.

20. 12. Balofloxacin :
 It is shown to be batericidal against many gram +ve and gram -ve
bacteria, including Strep. pneumoniae and MRSA, by inhibiting
bacterial DNA gyrase.
 Absorbed orally
 Metabolized and excreted in urine with a t½ of 7- 8 hrs.
 Adverse effects are nausea, dizziness, loss of appetite, skin
rashes, photosensitivity reactions, peripheral neuropathy.
 Indications of balofloxacin include sinusitis, exacerbations of
chronic bronchitis, community acquired pneumonia and UTI.

21.  REFERENCES ;
 Essentials of Medical Pharmacology by K D Tripathi, 8
th
edition,
Page No.759-765.
 Lippincott Illustrated Reviews Pharmacology by Karen Whalen, 5
th

edition, Page No.409-413.
 Rang & Dale’s Pharmacology, 9
th
edition, Page No.672.