Fluoroquinolones and Uroseptics
Mechanism of Action in General
Classification

1. Quinolone
a. Nalidixic Acid
2. Fluoroquinolones
a. 2nd Generation
i. Ciprofloxacin
b. 3rd Generation
i. Levofloxacin
th
c. 4 Generation
i. Moxifloxacin
Differences
Quinolones
Fluoroquinolone
Isnt Fluorinated
No activity against Gram
Positive
Fluorinated
Have both activity against
Gram Positive and Gram
Negative
General Characteristic
1. Both Quinolone and Fluoroquinolones are BACTERIOCIDAL
2. Fluroquinolones have the capability to enter the infected
host cell
a. Enable it to kill intracellular organism such as
i. Legionella spp.
ii. Mycoplasma spp.
iii. Chlamydia spp.


Generally, bacteria has circular DNA. During replication, this
circular DNA needs few enzymes for it to be replicated.
They are
o Helicase
 Use in unwinding the double helix DNA to form
the repilcation fork
 It also stabilizes the unwinded DNA strands so
that it wont stick back together
o DNA Gyrase/ Topoisomerase II
 During unwinding of DNA double helix, the in
front of the DNA replication fork will be
introduced with POSITIVE SUPERCOILING
 If the positive supercoiling is too extensive,
replication fork can be futher made; hence
replication process may stop
 DNA Gyrase is responsible in introducing
NEGATIVE SUPERCOILING so that the DNA
strands are not too streesful and coiled
o Topoisomerase IV
 When the replication forks meet at the end of
the circular DNA, the strand tends to stick
together
 In order to unlink the strands, Topoisomerase IV
takes part
Thus, Quinolones and Fluoroquinolones act by by acting on
both DNA Gyrase/ Topoisomerase II and Topoisomerase IV
This inhibition will lead to BACTERIOCIDAL effect


Selectivity
o Gram Positive
 DNA Gyrase/ Topoisomerase II
 Topoisomerase IV
o Gram Negative
 DNA Gyrase/ Topoisomerase II
Selective toxicity
o Due to its selective activity towards DNAGyrase and
Topoisomerase IV, in the normal dose use in
antimicrobial
therapy
Quinolones
and
Fluoroquinolone wont have any activity against
human DNA replication
o Due to the fact humans possess only Topoisomerase
III, Quinolones and Fluoroquinolones won’t be able to
exert its activity against it unless the dose is super high
Adverse Effects of Quinolones and Fluoroquinolones





Abnormal growth of cartilage and bone
o Should be avoided in
 Pregnant women (Category C)
 Children under the age of 18
Photodermatitis
o Avoid sun and UV light during treatment
Tendonitis/ Tendon rupture
CNS effects
o Confusion
o Insomnia
o Exacerbation of pshychosis
o Depression
o Somnolence
o Seizures
CVS effects
o QT prolongation
o Therefore should not be prescribed with
arrhythmic agent which cause QT prolongation
 Class 1A
 Quinidine
 Procainamide
 Class 3
 Amiodarone
 Ibutilide
anti-
Group
Quinolone
Drug
Nalidixic Acid
Ciprofloxacin
**the most
potent for P.
aeruginosa
Fluoroquinolone
Levofloxacin
Moxifloxacin
Pharmacokinetic
Spectrum of Actitivy
Therapeutic Uses
Absorption

Well-absorbed through GIT
Distribution

Poos tissue penetration

Less being distributed into body compartments

Due to its less tissue penetration, it’s not being used in systemic
infection

Low plasma level due to metabolism and extensive excretion
Metabolism

Partly metabolize in the liver
Excretion

Urine

Nalidixic Acid were found in the urine in high concentration
Absorption

Well absorbed orally

Can be administered through
o
Oral
o
IV
Distribution

Well distributed across body compartments

Therefore, it has a long post-antibiotic effect
Metabolism

Metabolized in the liver

Found to be a POTENT CYP450 INHIBITOR
o
Therefore may inhibit various drugs if prescribed together
Excretion

Excreted via urine

Gram Negative
o E. coli
o Klebsiella spp.
o Proteus spp.
o Shigella spp.
o NOT
Pseudomonas
aeruginosa
 NO activity against GRAM
POSITIVE
and
ATYPICAL
BACTERIA

Gram Negative
o Including
Pseudomonas
aeruginosa
 Gram Positive
o Only Staphylococcus spp.
o NO
activity
against
Streptococcus
pneumoniae



Absorption

Very well absorbed in GIT
Distribution

Very well distributed across body compartments

Has a long post-antibiotic effect

Long acting drug, therefore only need a single daily dose
Metabolism

So far, found to be not metabolized by liver or other part of
the body
Excretion

Excreted via urine unchanged
Absorption

Very well absorbed orally
Distribution

Distributed across body compartment

Has a long post-antibiotic effect
Metabolism

Hepatic metabolism
Excretion

Excreted via liver



Gram Negative
Gram Positive
o Improved activity against
Strep. pneumniae
 Atypical bacteria
o Improved activity against
 Mycobacterium spp.
 Chlamydia spp.
Gram Negative
Gram Positive
o The best to fight against
Strep. pneumoniae
 Atypical bacteria


Non-complicated
lower UTI’s
 Bacterial
Gastroenteritis
caused by
o E. coli
o Proteus spp.
o Klebsiella spp.
o Shigella spp.







UTIs
Peritonitis
Bacterial
Gastroenteritis
Sepsis
Skin/soft
tissue
infection
Typhoid fever
o Used as 1st line
treatment
Tuberculosis
Gonnorhea
Conjunctivitis
Respiratory
tract
infections
o Pneumonia
o Exacerbated
COPD
Mostly used in the
respiratory
tract
infections
o Pneumonia
o Exacerbated
COPD
o Tuberculosis
 Sepsis
 Peritonitis



Urinary Antiseptics/ Uroleptics
Agents that exert antibacterial action not in the blood but in the URINE
o Less effective for treatment of systemic infection
They used only in the treatment of LOWER UTI
o They must never be used to treat pyelonephritis, renal abscess, and pyeloempyema because of extremely poor tissue penetration and low blood levels
o Obstruction in the urine outflow may interfere it effective in combating organism, therefore it should not be given in patients having complicated UTI
Drugs
Nitrofurantoin
**Bateriocidal agent
Spectrum of Antimicrobial Activity

High antibacterial activity
o E.coli
o Staph saprophyticus

Low antibacterial activity
o Staph aureus
o Strep. spp
o Klebsiella spp
Clinical Uses

Prophylaxis and treatment of lower UTIs
o Simple cystitis
Fosphomycin
**Bacteriostatic agent
Spectrum of Antimicrobial Activity

Gram Negative Bacteria
o Effective against

E.coli

Salmonella spp.

Shigella spp.

Proteus spp.
o Not effective against

Pseudomonas aeruginosa

Klebsiella spp.

Gram Positive Bacteria
o Mostly resistant including

Staphylococci

Streptococci

Resistant to all Anaerobic bacteria
Pharmacokinetic
Absorption

Well absorbed in the GIT

Weak acid in nature
Distribution

Extremely
poor
tissue
penetration

Very low Vd
Metabolism

Does
not
undergo
any
metabolism
Excretion

Excreted immediately via urine
o Leads to very low plasma
concentration

Compete with Probenecid for
excretion
o Probenecid may reduce
Nitrofurantoin
urine
concentration

Activity best in acidic urine
Absorption

Well absorbed in the GIT

Administered orally
Distribution

Extremely
poor
tissue
penetration

Very low Vd
Metabolism

Does
not
undergo
any
metabolism
Excretion

Excreted immediately via urine
o Leads to very low plasma
concentration
Mechanism of Action




Adverse Effects
Nitrofurantoin is a prodrug, once
eliminated in the urine, it will be
enter the bacterial cell and
converted into a highly reactive
electrophilic intermediates
This electrophilic intermediate will
non-specifically attack
o Bacterial ribosomal protein
o DNA
o Respiration
o Pyruvate metabolism
o Other macromolecules
o Inhibition of protein synthesis

The first stage of cell wall
synthesis takes place in the
bacterial cytoplasm
o This stage is where the lowmolecular-weight precursor of
murein is synthesized
Fosphomycin
is
an
antimetabolite
of
Phosphoenolpyruvate
in
the
enzymatic
process
of
NAcetylmuramic Acid




Allergic reactions
o Rash
o Urticaria
Pulmonitis and Pulmonary Fibrosis
o Happens when it is given for
too long
Heamolysis
o Contraindicated
in
G6PDdeficiecny patient
Urine discoloration (harmless)
o Orange-brown urine color
Contraindication

G6PD deficiecny

Pregnant women


Allergic reactions
o Rash
o Urticaria
CNS effects
o Headache
o Dizziness
GIT disturbances
o Diarhhea
o Nausea