Sheema Khanam Quinolone resistance slide share

1. RESISTANCE TO
QUINOLONES Sheema Khanam
M.pharm(pharmacology)
1st
year 2nd
sem.
Enrollment no:1900100952

2. 2
INTRODUCTION
❑ Quinolones are a family of synthetic, broad- spectrum anti-biotic with
bactericidal activity.
❑ 1st
gen. of quinolones begins with Nalidixic acid in 1962 for the treatment of
UtI in humans .
❑ Nalidixic acid was discovered by George Lesher and co-workers in a
distillate during an attempt at chloroquine synthesis.
❑ Introduction of first fluorinated quinolone, norfloxacin, was rapidly
followed by development of other members of this group, such as
ciprofloxacin, which has wide clinical application.
❑ Today,over 10,000 analogs have been synthesized.

3. 3
CLASSIFICATION
❑ 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

4. 4
Some drug discussed here
Flouroquinolone 1st
generation Nalidixic acid NEGGRAM
Fluoroquinolone 2nd
feneration Ciprofloxacin CIPRO,norfloxacin NOROXIN,Ofloxacin
FLOXIN
Fluoroquinolone 3rd
generation Levofloxacin (LEVAQUIN)
Fluoroquinolone 4th
generation Moxifloxacin (AVELOX)
Inhibitor of folate synthesis Mafenide (SULFAMYLON), Silver sulfadiazine
(SILVADENE) ,Sulfasalazine(
AZULFIDINE),Sulfisoxazole GANTRISIN
Inhibitor of folate reduction Pyrimethamine (DARAPRIM)
Trimethoprim (PROLOPRIM)
Combination of inhibitors of folate synthesis and
reduction.
Cotrimoxazole(trimethoprim+sulphamethoxazole)
BACTRIM
Urinary tract antiseptics Nitrofurantoin (MACROBID)

5. 5
A. Mechanism of action
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 double stranded
DNA, introduces negative supercoils and then reseals the nicked
ends. This is required to prevent excessive positive supercoiling of
DNA strands when they separate to permit replication or
transcription.
Inhibition of DNA gyrase also prevents the relaxation of positively
supercoiled DNA.

6. 6
❑ 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.
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

7. 7

8. 8

9. 9
B. Antimicrobial spectrum
❑ In general, they are effective against gram negative organisms such as
the Enterobacteriaceae, Pseudomonas species,haemophilus
influenzae, mycoplasma and some mycobacteria.
❑ fluoroquinolones 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.
❑The nonfluorinated quinolone nalidixic acid is considered to be first
generation, with a narrow spectrum of susceptible organisms
usually confined to the urinary tract.

10. 10
❑ Ciprofloxacin and norfloxacin are assigned to the second generation
because of their activity against aerobic gram-negative and atypical
bacteria.(for example,mycoplasma, and legionella).
❑ Levofloxacin is classified as third generation because of its increased
activity against gram-positive bacteria.
❑ Lastly, the fourth generation includes only moxifloxacin because
of its activity against anaerobic, as well as, gram-positive organisms.

11. 11
Examples of clinically useful fluoroquinolones
1.Ciprofloxacin: The serum levels of ciprofloxacin that are
achieved are effective against many systemic infections with the
exception of serious infections caused by methicillin-resistant
Staphylococcus aureus (MRSA), the enterococci, and
pneumococci.
•Ciprofloxacin is particularly useful in treating infections caused
by many Enterobacteriaceae and other gram-negative bacilli.
For example, traveler’s diarrhea caused by E. coli can
be effectively treated.
•The drug is also used as an alternative to more toxic drugs, such
as the aminoglycosides.

12. 12
❑ It is the most potent of the fluoroquinolones for Pseudomonas
aeruginosa infections and therefore, is used in the treatment of
pseudomonal infections associated with cystic fibrosis.
❑The drug is also used as an alternative to more toxic drugs, such as
the aminoglycosides.
❑ It may act synergistically with β-lactams and is also of benefit in
treating resistant tuberculosis.
❑ Ciprofloxacin is also commonly used to treat typhoid fever in
third-world countries.

13. 13
2. Norfloxacin: Norfloxacin (nor-FLOX-a-sin] is effective against both
gram-negative (including P. aeruginosa) and gram-positive organisms
in treating complicated and uncomplicated UTIs, prostatitis and
traveler's diarrhea (unlabeled use).
• It is not effective in systemic iinfections.
3. Levofloxacin: Levofloxacin is an isomer of ofloxacin and has
largely replaced it clinically.
•It can be used in the treatment of prostatitis due to E. coli and of
sexully transmitted diseases, with the exception of syphilis.
•It may be used as alternative therapy in patients with gonorrhea.

14. 14
4. Moxifloxacin: Moxifloxacin is not only has enhanced activity
against gram-positive organisms (for example, S.
pneumoniae) but also has excellent activity against many
anaerobes.
•it has very poor activity against P. aeruginosa.
• Moxifloxacin does not concentrate in urine and is not
indicated for the treatment of UTIs.

15. 15
D. 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 topoiomerase IV.

16. 16
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.

17. 17
PHARMACOKINETICS
❑ 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.

18. 18
F. Adverse reactions
In general, these agents are very well tolerated. Toxicities similar to
those for nalidixic acid have been reported for the fluoroquinolones.
1.Gastrointestinal: The most common adverse effects of the
fluoroquinolones are nausea, vomiting, and diarrhea, which occur in
three to six percent of patients.
2. Central nervous system problems: The most prominent central
nervous system (CNS) effects of fluoroquinolone treatment are
headache and dizziness or light-headedness. Thus, patients with CNS
disorders, such as epilepsy, should be treated cautiously with these
drugs.

19. 19
Contraindications:
Moxifloxacin and other fluoroquinolones may prolong the QTc interval
and, thus, should not be used in patients who are predisposed to
arrhythmias or are taking antiarrhythmic medications and not being
actively monitored.
3. Phototoxicity: Patients taking fluoroquinolones are advised to
avoid excessive sunlight and to apply sunscreens. However,
the later may not protect completely. Thus, it is advisable that
the drug should be discontinued at the first sign of phototoxicity.

20. 20
INTERACTIONS
1.NSAIDs :
Enhance the CNS toxicity of
quinolones
2.Theophylline, Caffeine or Warfarine
❑ Plasma concentration is
increased by Ciprofloxacin
3.Antacid or Iron salts
Reduce the absorption of
quinolones

21. REFERENCES
• Clark M.A.;Finkel R.;lippincott’s
pharmacology,fifth edition,pg no:-409-413.
21

22. 22
THANK YOU