Qambar Abbas

QUINOLONES & FLUOQUINOLONES

Keyword : FQ = Fluoroquinolones

 The original drug “Nalidixic acid” contains quinolone ring.

 Activity of nalidixic acid was moderate spectrum, only suscepted to Gram negative bacteria 
Very low tissue distribution.
 Pharmacologists added fluorine group with nalidixic acid ( Quinolone) and synthesized a new
drug group called “Fluoroquinolones” ( Fluorinated Quinolones)

Superiority over other antibiotics:

1. Significant oral bioavailability
2. 3rd and 4th generation FQ (Fluoroquinolones) have very deep penetration / distribution
into tissues and even cells  kills intracellular bacteria ( Chlamydia, Mycobacterium TB,
brucella, Legionella)
3. New FQ are very broad spectrum
4. High potency
5. Excellent safety profile

MECHANISM OF ACTION
They are Bactericidal. How they kill the bacteria?
 THEME : FQ induces positive supercoiling in bacteria during replication process by
blocking the ligase site/ domain of the DNA topoisomerase II ( DNA gyrase) in Gram
negative and DNA topoisomerase IV in gram positive bacteria No replicationNo RNA
and protein  No bacterial growth cell death
 ( NOTE: (i) DNA topoisomerase II is also called DNA gyrase – FQ targets this enzyme in
Gram negative bacteria. Structure and Function  Contains 2 domains/sites (a)
Endonuclease site by which it cuts the strand fragment without mutation and promotes
negative Supercoiling by unwinding the strand. (b) Ligase domain by which it
rejoined/reconnected/reconstructed/rebuild the unwinded strand )

 ( FQ targets DNA topoisomerase II in gram negative bacteria  NO relaxation of two

strands )

 (FQ targets DNA topoisomerase IV in gram positive bacteria  NO separation of

multiple strands)

EXPLANATION: Normal biochemistry of DNA replication should be understand before

going into detail

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 For bacterial growth, they need protein synthesized from RNA, RNA is synthesized from
DNA by DNA replication.
 Bacterial DNA  Chromosomes Normally double helix strand should be untwisted /
unwinded separated Unwinding is necessary for replication
 When DNA helicase separates double strands from the center  twist moves towards
the periphery  become over twisted / over super coiled
 This over supercoiling (positive supercoiling) should be prevented for replication  This
over super coiling is prevented by DNA topoisonerase II ( gyrase) and IV
 DNA topoisomerase contains two domains (i) Endonuclease domain which helps in
cutting the fragment of DNA and The positive (more) super coiling becomes Negative
(less) supercoiled. (ii) Ligase domain which acts like a glue and helps the unwinded
strand Rejoin together be adding the previously removed fragment without mutation.
 As a result the strands are becomes negative (less ) supercoiled.

How Fluoroquinolones interferes with this normal DNA replication process and inhibits DNA
synthesis? / MECHANISM OF ACTION.
 FQ enters inside bacteria by passive diffusion  Binds with the ligase point  prevents
the process of Re-joining of the cuted DNA fragment  The cutter ( endonuclease)
domains continues to cut the fragment again and again but there is no enzyme present
to ligase ( add/re-join) it.  Replication is inhibited  No proteins formation for normal
cellular activities Ultimate bacterial cell death .

FQ classification by Generations and its susceptibility features.

1st Generation 2nd Generation 3rd Generation 4th generation

Nalidixic acid Ciprofloxacin* ( Ciproxin 250, 500 Levofloxacin* (Leflox 250,500 Moxifloxacin* (avelox
( Nalasid mg ) mg -- OD) 400mg -OD)
400mg ) Ofloxacin ( Oflobid 100,200,400 mg Sparfloxacin (Sparaxin 100mg) Gatifloxacin ( Gatcin
Norflixacin ( Uriflox 400mg) 200, 400mg)
Lomefloxacin ( Maxaquin 200,400 mg)
Moderate (i) Broad (i) Broad

(ii) Moderate (ii) Broad

(iii) Atypical
(iii) Atypical

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 Gram negative bacilli

 Gram positive Cocci
 Atypical organisms
 Anaerobic organisms
 Gram positive bacilli

I’ll review on what’s the difference among drugs of different generations

1st generation :
 Moderate activity against Gram negative bacilli
 Not widely used due to poor body distribution

2nd Generation : Ciprofloxacin

 Very good activity against many gram negative bacilli
 Additionally, moderate Activity against some Gram positive Cocci but notably it is not
active against S. Pneumonia (Respiratory infections)
 Highly effective against enterbactercea ( sallmonella, shigella, E. Coli and caphylobactor)
 Also active against Atypical “intracellular organisms” like clamydia and Mycobacterium
TB

3rd Generation : Levofloxacin

 Active against many Gram negative Bacilli, many gram positive cocci, additionaly it is
also active against Streptococcus pneumonia notable. That’s why it is called respiratory
Fluoroquinolone

4th Generation : Moxifloxacin

 Active against many Gram negative bacilli, many gram positive cocci, additionally many
gram positive bacilli and anaerobes

( 2nd, 3rd and 4th gen are active against atypical organisms like clamydia and Mycobacterium TB… …
Moxifloxacin is preferred over all which mixed infection is susceptible caused by anerobes )

Clincal uses :
1st Generation : Nalidixic acid
 UTI only : because they are poorly distribute in the body and only concenrates in Urine

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 Uncommonly used now

2nd Generation : Ciprofloxacin

 GIT infections : caused by Enterobacilli ( not enterococci) i-e Dysentery
 Travelers diarrhea : Caused by Toxigenic E. Coli.
 Cystic fibrosis : caused by pseudomonas aeroginusa  Child dies often due to cystic
fibrosis  life threatening condition
 Resistant TB : caused by Mycobacterium TB. They can easiky kill intracellular organisms
like M. TB
 Anthrax : caused by Bacillus anthracis, spread from infected animal and soil, effects
mainly skin but can also lungs.
 Osteomyelitis : Infection of bone and bone marrow
 Typhoid fever : Caused by Salmonella typhi
 Alternative : Choice instead aminogylcosides ( toxic)
 Synergisticaly : with cephalosporins
 (NOTE : NORFLOXACIN Only concerates in urine  treats UTI and prostratitis in males
for longer duration of about 3,4 weeks. NORFLOXACIN cannot well distributed in the
body  not used for systemic infections)
MISUSE:
o Cipro is most commonly misused antibiotic in Pakistan for wrong dieases, which
cipro can’t perfectly eradicate  Resistant strains are developing sharply. 
Should be unused for that conditions.
o It is unfortunately used against MRSA  many, including Cipro antibiotics fails
on it, should be avoided.
o Lobar pneumonia caused by S. Pneumonae, cipro can not eradicate, should be
avoided
o Enterococci : Cipro can’t kill Enterococci but , can kill enterobacilli.

3rd Generation :Levofloxacin

 Same as Ciprofloxacin but additionally, it can also kill S. Pneumonae
 Prostatis : in males, regimens lasts longer than usual (4,5days ) for about 3,4 weeks
 Pneumonia : both Hospital + community acquired, caused by S. pneumonia
 STDs : only Gonorrhea , not syphilis
 Skin infections
 Acute bacterial sinusitis
 Acute exacerbation of chronic bronchitis

4th Generation : Moxifloxacin

 Same as Cipro and levo but additionaly, it is also active against:-
 Mixed infections caused by anerobes

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 Alternative choice in renal impaired patients because only Moxi is cleared by billiary
system while others are cleared by kidneys.

Mechanisms of resistance :
i. Bacteria prevents FQ from entering : Some gram negative bacteria decrease the
number of porins or to mske them narrow FQ cannt enters inside the bacterial cell.
ii. Efflux pump : after bacteria passes porins successfully , the accumulated bacteria
pumped back by the soecial efflux pump.
iii. Modification in Drug: bacteria mutates to encodes some proteins with modify the drug
chemistry to make ineffective
iv. Altered target: Bacterial DNA mutates and changes the size of ligase domain so that the
drug is unable to fit into it or make them dysfunctional.
v. Plasmid associated resistance : newly discovered mechanism by which the bacteria
becomes resistant is : Bacterial plasmid mutates which encodes DNA  synthesize
proteins which destroys FQ.

Pharmacokinetics :
 Taken orally
 Better bioavailability ( newer generstions have 80-90% )
 The absorbed drugs shows entero hepato-billiary circulation
( GITliverhepatocytesbile re-back to GIT Recycle)
 But most of reaches to systemic circulation where they distributed widely into tissues
even inside the cell.
 With the exception of Ofloxacin , none of them can cross BBB.
 Except Moxifloxacin, all are cleared by renal tubular secretion ( active transport) 
passed into urine unchanged ( that’s why they have excellent activity against
UTIbinfections.
 Levo and moxi have post antibiotics effect as well as long half life so they are given OD.

Adverse effects :
Though they have good safty profile but in rare cases, it may produce some adverse
effects.
I. Clostridium C. difficile associated Diarrhea and Colitis :
 Many normal flora residing in the intestine have competition for nutrients for nutrients,
so they don’t allow each other to cause infection, one of them is C. difficile.

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 Ciprofloxacin ( notable including other broad spectrum antibiotics such as clindamycin ,

amoxicilin and 4th generation cephalosporin ) kills many GI normal flora unfortunately
except C.difficile  C. Dificile have no competition for nutrients starts replication
Fighting starts B/W WBCs anf C.dificile started damages colon membrane fibrin
comes out of this damaged membrane and makes a new membrane over colon lining 
This membrane is called psudomembranous and this inflamed colon is called colitis 
this condition is called pseudomembranous colitis
II. Megacolon : Due to this pseudomembranous colitis, Mynteric and Orbic nervous system
of PSNS innervated in GIT is damaged  PSNS control is lost  Colon becomes relaxed
 Colon filled with full of gas  This is called megacolon, a fetal condition.
 Metronidazol is the first line and vancomycin is the second line drugs of choices in C.
difficile associated diarhea, colitis and megacolon.
III. Seizures : (1) FQ inhibits GABA-A receptors  High abnormal firing of current
Seizures. (2) Subgroups of cytochrome P-450 catabolizes some drugs like caffeine
theophylline and warfarin..  FQ blocks the cyp-p 450 enzymes ⬆️concentration of
theophylline, caffeine and warfarin  ⬆️Theophylline and caffeine triggers seizures by
over stimulating nervous system and ⬆️warfarin leads to bleeding.
IV. Phototoxicity : FQ makes skin very sensitive to sunlightFlushed skin/red skin 
should be discontinued
V. Arthropathy : FQ stopd the formation of newly cartilages
VI. Tendinitis : FQ increases the chances of tendinitis especially in elderly people >60 or
children < 18
VII. CVS : Increases QTc prolongation ( also called Torsas de points arrhythmia )

Interactions :
 FQ should not be taken with diavalent or trivalent cations containg drugs or food
because they form chelate ( Antacids : magnesium oxide containing mg++, aluminum
hydroxide containing Al+++ ,,, iron supplements containing fe++ ,,,,, milk containing Ca+
+ ,,,,, cheese etc)

Contraindication :
 Pregnancy : causes catilage damage kn baby
 Nursing mothers : FQ can pass through milk
 Cvs patients.
 Children < 18

Some important notes Not discussed above / points to remember :

 Cipro and levo is also effective against meningitis caused by Neisseria meningitidis
(Gram negative cocci) but it doesn’t cross BBB so clinically it is not used for meningitis)

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 Moxifloxacin lacks susceptibility against Pseudomonas aeroginusa making ineefective to

treatCyctic fibrosis.
 Moxifloxacin, the only FQ is excreted via bile route than Feace instead kidneys than
urine, making moxi uneffective in UTI
 FQ is widely used in UTIs but, Levo and moxi is not used for gonorrhea (UTI) due to
increased prevalence of resistance. ( Recommended : gemifloxacin+azithromycin in
combination, or gemifloxacin + ceftriaxone,,, or doxycycline,,, or if pregnancy, cefixime
+azithromycin but please consult the recommended guidelines to treat UTIs)
 Levo and moxi is effective for Lower respiratory tract infection (others are not used)
because these can kill most of lower respiratory tract infection causes bacteria including
notably S. Pneumonae (the most common respiratory pathogen).
 Unique feature about FQ are designed for Gram negative bacteria as noted , other
antibiotics are mostly active against Gram positive bacteria.
 Ciprofloxacin is the most active among all FQs against Gram positive baccili.
 Side effects : The popularity of FQs are due to its excellent safty profile but in rare
ocassions, they cause side effects include arrythimias, colitis, megacolon, arthropathy,
tendonitis
 These are avoided in pregnancy in breast feedings because they may cause catilage
formation in neonates.

Contraindication :
 arrhythmias,
 under 18,
 60> aged people,
 Pregnancy and nursing mothers.

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