Antibiotic Quinolone history,classification,mechanism of action and adverse effect

Antibiotic Quinolone history,classification,mechanism of action and adverse effect

1. AMIR SOHAIL

2. The Quinolones
•The Quinolones
•The quinolones are really not antibiotics. By definition,
an antibiotic means something that's produced by
another living substance. That's the real definition. We
have a lot of chemotherapeutic antimicrobials that have
activity against organisms for which we loosely use the
term antibiotic, but they're really chemicals.

3. History
•A group of synthetic antibacterial agents
mainly effective against G-ve
•Nalidixic acid first member introduced in
1962 for urinary and GIT infections
•Nalidixic acid is derived from chloroquine.
•Its congeners Oxolinic acid and rosoxacin
with more potency in 1970s
•Second generation called fluoroquinolones
with extended spectrum and systemic
effects in 1980s

4. Nalidixic acid is considered to be the predecessor of all members of the
quinolone family, including the second, third and fourth generations
commonly known as fluoroquinolones.
This first generation also included other quinolone drugs, such as
pipemidic acid, oxolinic acid, and cinoxacin, which were
introduced in the 1970s. They proved to be only marginal
improvements over nalidixic acid. Though it is generally accepted
nalidixic acid is to be considered the first quinolone drug, this has
been disputed over the years by a few researchers who believe
chloroquine, from which nalidixic acid is derived, is to be
considered the first quinolone drug, rather than nalidixic acid.

5. •Since the introduction of nalidixic acid in 1962,
more than 10,000 analogshave been
synthesized, but only a handful have found their
way into clinical practice.

6. Chemistry of Quinolones
They are
synthetic
fluorinated
analogs of
nalidixic acid.

7. Basic Structure of 4-quinolones
(Short for 4-oxo-1, 4-hydroquinoline)

8. •The carboxyl group at position 3 and
ketone group at position 4 are essential for
antimicrobial activity.
•Substitution at position 6 with a fluorine
moiety markedly increase antibacterial
activity against G+ve, G-ve , Mycoplasma
and chlamydia. All fluorinated 4-
quinolones are called Fluoroquinolones.

9. •Addition of a piperazine ring at position 7
on fluoroquinolones increases tissue and
bacterial penetration and improves
spectrum of activity to include
Pseudomonas ( e.g. Ciprofloxacin,
Enrofloxacin )

10. •Substitution with an oxygen atom at
position 8 improves activity against G+ve
and anaerobic organisms without affecting
bactericidal profile.
•Change to a carbon from nitrogen at
position 8 decreases some adverse CNS
effects and increases activity against
Staphylococci.

11. Generations
•Researchers divide the quinolones into generations based on their
antibacterial spectrum.The earlier-generation agents are, in general,
more narrow-spectrum than the later ones, but no standard is
employed to determine which drug belongs to which generation. The
only universal standard applied is the grouping of the nonfluorinated
drugs found within this class (quinolones) within the 'first-generation'
heading. As such, a wide variation exists within the literature
dependent upon the methods employed by the authors.
•Some researchers group these drugs by patent dates.
•Some by a specific decade (i.e., '60s, '70s, '80s, etc.).
•Others by the various structural changes
.

12. Classification of Quinolones
1.First-generation of quinolones
Nalidixic acid, oxolinc acid, cinoxacin,
Useful only for treatment of lower urinary tract
infections.
Pipemidic acid, its activity against G
-
bacilli is more
powerful. The resistance to these drugs is less.

13. Classification of Quinolones
2. Fluoroquinolones, they were originally
developed because of their excellent activity
against G
-
aerobic bacteria; they had limited
activity against G
+
organisms.

14. Chemistry of Quinolones

15. Chemistry ofQuinolones

16. Chemistry ofQuinolones

17. Classification of Quinolones
3. The newer fluoroquinolones
Moxifloxacin and trovafloxacin,
they have enhanced G
+
activity, also have
good activity against anaerobic bacteria, which
other fluoroquinolones lack.

18. Classification of Quinolones
4. Fluoroquinolones also are active against
agents of atypical pneumonia, such as
mycoplasmas and chlamydiae, and intracellular
pathogens, e.g. legionella species and some
mycobacteria, including Mycobacterium
tuberculosis and M avium complex.

19. •First-generation
•cinoxacin (Cinobac) (Removed from clinical use)
.
•flumequine (Flubactin) (genotoxic carcinogen)(veterinary use).
•nalidixic acid (NegGam, Wintomylon) (genotoxic carcinogen).
•oxolinic acid (Uroxin) (currently unavailable in the United States).
•piromidic acid (Panacid) (currently unavailable in the United States).
•pipemidic acid (Dolcol) (currently unavailable in the United States).
•rosoxacin (Eradacil) (restricted use, currently unavailable in the
United. States)

20. •Second-generation
•ciprofloxacin (Zoxan, Ciprobay, Cipro, Ciproxin)
•enoxacin (Enroxil, Penetrex) (removed from clinical use)
•fleroxacin (Megalone, Roquinol) (removed from clinical use)
•lomefloxacin (Maxaquin)(discontinued in the United States)
•nadifloxacin (Acuatim, Nadoxin, Nadixa) (currently unavailable in the United
States)
•norfloxacin (Lexinor, Noroxin, Quinabic, Janacin)(restricted use)
.
•ofloxacin (Floxin, Oxaldin, Tarivid)(only as ophthalmic in the United States)
•pefloxacin (Peflacine) (currently unavailable in the United States)
•rufloxacin (Uroflox) (currently unavailable in the United States)

21. •Third-generation
•Unlike the first-and second-generations, the third-generation is active
against streptococci.
•balofloxacin(Baloxin) (currently unavailable in the United States)
•grepafloxacin (Raxar) (removed from clinical use)
•levofloxacin(Cravit, Levaquin) Currently involved in MDL litigation in the
United States due to unacceptable safety profile.
•pazufloxacin(Pasil, Pazucross) (currently unavailable in the United States)
•sparfloxacin (Zagam)(currently unavailable in the United States).
•temafloxacin (Omniflox) (removed from clinical use
•tosufloxacin (Ozex, Tosacin) (currently unavailable in the United States).

22. •Fourth-generation
•Fourth generation fluoroquinolones act at DNA gyrase and topoisomerase
IV. This dual action slows development of resistance.
•Clinafloxacin(currently unavailable in the United States)
•gatifloxacin (Zigat, Tequin) (Zymar -opth.) (Tequin removed from clinical
use)
.
•gemifloxacin (Factive).
•moxifloxacin(Avelox,Vigamox)(restricted use).
•sitafloxacin (Gracevit) (currently unavailable in the United States)
•trovafloxacin (Trovan) (removed from clinical use)
.
•prulifloxacin (Quisnon) (currently unavailable in the United States)
•In development
•garenoxacin (Geninax)(application withdrawn due to toxicity)
•delafloxacin

23. •Veterinary use
•The quinolones have been widely used in agriculture, and several
agents having veterinary, but not human, use exist.
•danofloxacin(Advocin, Advocid) (for veterinary use)
•difloxacin(Dicural, Vetequinon) (for veterinary use)
•enrofloxacin (Baytril) (for veterinary use)
•ibafloxacin(Ibaflin) (for veterinary use)
•marbofloxacin(Marbocyl, Zenequin) (for veterinary use)
•orbifloxacin(Orbax, Victas) (for veterinary use)
•sarafloxacin(Floxasol, Saraflox, Sarafin) (for veterinary use)

24. Chemistry ofQuinolones

25. Antimicrobial effects ofQuinolones
①Broad spectrum
a.First-generation, G
-
aerobic bacteria;
b.Second-generation, more activity
against G
-
aerobic bacteria;
c.Third-generation, fluoroquinolones,
possess excellent G
-
activity & moderate to
good activity against G
+
bacteria, anaerobes,

26. Antimicrobial effects ofQuinolones
②Bactericidal
Ciprofloxacin is the most active agent against
G
-
bacteria, particularly Ps. aeruginosa.
Levofloxacin has superior activity against G
+
organisms, including St. pneumoniae.
Clinafloxacin has the best activity of them
against G
+
cocci.

27. Summary of antimicrobial spectrum of quinolones

28. Typical therapeutic applications of ciprofloxacin.

29. •Ciprofloxacin is the prototype drug.

30. Mechanism of action
1.They block bacterial DNA synthesis by inhibiting
bacterial topoisomerase Ⅱ(DNA gyrase) and
topoisomerase Ⅳ.
DNA gyrase is responsible for supercoiling of
DNA,hence prevent supercoiling of DNA resulting in
the inhibition of DNA synthesis which is responsible
mainly for their activity against gram negative
bacteria.
They also inhibit topoisomerase Ⅳwhich contributes
towards their activity against gram positive bacteria

31. •Supercoiling is the process of coiling of double stranded
DNA molecule on itself so that a DNA upto 1.3mm length
can be tightly and compactly packed inside bacterial cell.
The supercoiling requires first nicking of double
stranded DNA molecule and then resealing it after the
super twist(passage of double stranded DNA through
nick).This is carried out by DNA gyrase in an energy
dependent reaction.

33. 2. Inhibition of DNA gyrase prevents the relaxation of
positively supercoiled DNA that is required for normal
transcription and replication.
3.Inhibiton of topoisomerase Ⅳprobably interferes with
separation of replicated chromosomal DNA into the
respective daughter cells during cell division.

34. Mechanism of action
4.The gyrase is composed of two A subunits and
two B subunits. The A subunits can cut one of
double strands of the DNA to permit passage of
the other segment of DNA through the break and
negative supercoil is formed; the break is then
resealed. This is an ATP-dependent reaction.
The energy is provided by B units.

35. Mechanism of action
5.Quinolones is an inhibitor of A subunits.
Therefore, the action of gyrase is inhibited and
DNA replication or transcription is blocked as
result of the death of bacteria.
6. Novobiocinis an inhibitor of the B subunit of
DNA gyrase and is active mainly against G
+
bacteria.

36. Action of Type II DNA topoisomerase

38. •Initiation of DNA synthesis requires replication
of the strands.
•This replication inserts a positive supercoil,
which is relaxed by Topoisomereas II by a
nicking ,pass through & resealing process----
the configuration or topology is changed,
without any change in DNA’ s primary sequence

39. Inhibition of Topoisomerase IV:
Topoisomerase IVis required for cell division .
They inhibit Topoisomerase IVspeciallyin
G+ve bacteria.
It interferes with separation of replicated
chromosomal DNA into daughter cells during
cell division.
So they kill the micro-organisms

40. Mechanism of action (Selective toxicity).
•Quinolones and fluoroquinolones are chemotherapeutic bactericidal
drugs, eradicating bacteria by interfering with DNA replication.
•The other protein synthesis inhibitor antibiotics used today (e.g.,
tetracyclines, lincomycin, erythromycin, and chloramphenicol)
do not interact with components of eukaryotic ribosomal particles
and, thus, have not been shown to be toxic to eukaryotes,as
opposed to the fluoroquinolone class of drugs. (Selective toxicity).
•Other drugs used to treat bacterial infections, such aspenicillins
and cephalosporins, inhibit cell wall biosynthesis, thereby causing
bacterial cell death, as opposed to the interference with DNA
replication as seen within the fluoroquinolone class of drugs.

41. •Quinolones inhibit the bacterial DNA
gyrase or the topoisomerase II enzyme,
thereby inhibiting DNA replication and
transcription.
•Recent evidence has shown eukaryotic
topoisomerase II is also a target for a
variety of quinolone-based drugs.
•Thus far, most of the compounds that
show high activity against the eukaryotic
type II enzyme contain aromatic
substituents at their C-7 positions.

42. •Quinolones can enter cells easily via porinsand,
therefore, are often used to treat intracellular
pathogens such as Legionella pneumophilaand
Mycoplasma pneumoniae.
•For many Gram-negative bacteria, DNA gyrase is the
target, where as topoisomerase IV is the target for many
Gram-positive bacteria.
•However, there is debate concerning whether the
quinolones still have such an adverse effect on the DNA
of healthy cells, in the manner described above, hence
contributing to their adverse safety profile. This class has
been shown to damage mitochondrial DNA.

43. •Bacterial DNA gyrase is structurally different
from the mammalian enzyme. Some anti cancer
drugs (Doxorubicin) act on mammalian DNA
gyrase

45. Bactericidal Effect
•A proposed common mechanism of killing by bactericidal
antibiotics. Antibiotics with diverse targets (ribosome for
aminoglycosides, DNA gyrase for quinolone and
penicillin-binding proteins for -lactam) trigger NADH
depletion and superoxide (O
2
-
) formation by
hyperactivation of the electron transport chain. Free-
radical damage of iron-sulfur clusters releases
ferrous ion, inducing the generation of highly
destructive hydroxyl radicals 1(OH) and cell death.
(Figure courtesy of James J Collins).

47. Resistance to Quinolones
1. Due to
①One or more point mutations in the quinolone
binding region of the target enzyme
②A change in the permeability of the organism
2. DNA gyrase is the primary target in E coli, with single-
step mutants exhibiting amino acid substitution in the A
subunit of gyrase.
3. Topoisomerase Ⅳis a secondary target in E coli that is
altered in mutants expressing higher levels of
resistance.

48. Resistance to Quinolones
4. In staphylococci and streptococci, the situation
is reversed, topoisomerase Ⅳis the primary
target, and gyrase is the secondary target.
5. Resistance to one fluoroquinolone, particularly if
of high level, generally confers cross-resistance
to all other members of this class.

49. Pharmacokinetics of Quinolones
①Oral given, well absorbed
②Distributed widely in body fluids and
tissues, pass placenta reach to the fetus,
③Biotransformation of the drugs in the liver
④Most eliminated by renal, either tubular
secretion or glomerular filtration.

50. Quinolones
Alatrovafloxacin is the inactive, prodrug form of
trovafloxacin for parenteral administration. It is
rapidly converted to the active compound.
Concentrations in prostate, kidney, neutrophils,
and macrophages exceed serum concentrations.

52. Administration and fate of the fluoroquinolones.

53. Effect of dietary calcium on the absorption of
ciprofloxaxin

56. Clinical uses ofQuinolones
1.Nalidixic acid is only second-line drug
treating urinary infection with gram-
negative bacilli (Bacillus coli, Bacillus
proteus , etc).
2.Pipemidic acid is not only used treating
infection of urinary tract but also treating
intestinal and biliary tract infection with
sensitive bacteria.

57. Clinical uses ofQuinolones
3.Fluoroquinolones are extensively used
treating general infection.
①urinary tract infections, even when
caused by multidrug-resistant bacteria,
②Intestinal and biliary tract infections
③Soft tissue infections
④Bone, joint and in intra-abdominal
⑤Respiratory tract infections

58. Clinical uses ofQuinolones
Ciprofloxacin and ofloxacin are effective for
gonococcal infection, including disseminated
disease. They are occasionally used for
treatment of tuberculosis and atypical
mycobacterial infections. They are suitable
for eradication of meningococci from carriers.

59. Clinical uses ofQuinolones
Ofloxacin is effective for chlamydial
urethritis or cervicitis.
Ciprofloxacin is a second-line agent for
legionellosis.
Levofloxacin, sparfloxacin are used for
treatment of upper and lower
respiratory tract infections.

60. Drug interactions with fluoroquinolones

61. Adverse effects of Quinolones
①The most common effects are nausea,
vomiting, and diarrhea.
②Headache, dizziness, insomnia, skin
rash, occasionally.
③Liver toxicity is rarely for trovafloxacin.
④Photosensitivity occurs with lomefloxacin
and pefloxacin.

62. Adverse effects of Quinolones
⑤Fluoroquinolones may damage growing
cartilage and cause an arthropathy.They
are not used in patients under 18 years
of age. The arthropathy is reversible.
Since fluoroquinolones are excreted in
breast milk, they are contraindicated for
nursing mothers, also for gravida.

63. •Mechanism of toxicity
•The mechanisms of the toxicity of fluoroquinolones has
been attributed to their interactions with different
receptor complexes, such as blockade of the GABAa
receptor complex within the central nervous system,
leading to excitotoxic type effects and oxidative stress.
The severity of oxidative stress generated by
fluoroquinolones has been described as 'enormous' by
the authors of one research study and they suggested
co-administration of anti-oxidantswhen using
fluoroquinolones to minimise the potential for oxidative
related cellular damage.

64. Interactions
•Theophylline, nonsteroidal anti-inflammatory drugs and
corticosteroids enhance the toxicity of fluoroquinolones.
•Products containing multivalent,cationssuch as aluminium-or
magnesium-containing antacids and products containing calcium, iron, or
zinc, invariably result in marked reduction of oral absorption of
fluoroquinolones.
•Other drugs that interact with fluoroquinolones include antacids,
sucralfate, probenecid, cimetidine, warfarin, antiviral agents,
phenytoin, cyclosporine, rifampin, pyrazinamide, andcycloserine.
•Many fluoroquinolones, especially ciprofloxacin, inhibit the cytochrme
P450 isoform CYP1A2. This inhibition causes an increased level of, for
example, antidepressants such as amitriptylineand imipramine,
clozapine (an atypical antipsychotic), caffeine, olanzapine (an atypical
antipsychotic), ropivacaine(a local anaesthetic), theophylline (a
xanthine), and zolmitriptan(a serotonin receptor agonist).

65. Some adverse reactions to fluoroquinolones.

66. Nitrofurans
•A group of synthetic antibacterial
compounds containing 5-nitrofuran ring.
•The ring is essential for antibacterial
activity
•Important members are
Furazolidone
Nitrofurantoin
Furaltadone
Nitrofurazone
Nifuroxime

68. Mechanism of action
•Prodrug converted to reactive substance
in susceptible bacteria
•Reactive substances inhibit carbohydrate
metabolism by blocking oxidative
decarboxylation of pyruvate to acetyl
coenzyme A
•This deprives essential energy
•May also inhibit mRNA translation
•Bacteria reduces nitrofurans more readily
than host cells so selective toxicity.

69. Antibacteria spectrum
•Broad spectrum Effective against some G+, G-
bacteria
•May also be active against coccidia,
trichomonias, amoebae, giardia, but low
potency.
•Bacteriostatic but may become cidal at high
doses.
•Bacteria resistance is limited and develops
slowly.

70. Pharmacokinetics
•Not absorbed orally or rapidly eliminated
from the body so not enough
concentration except urine
•Not used for systemic action
•Acidic urine promotes passive
reabsorption

71. Adverse Effects
•GI disturbances: Nausea, Vomiting,
Diarrhoea
•CNS signs: Excitement, Tremors,
Convulsions, peripheral neuritis.
•Depression of spermatogenesis, ocular
disturbances and poor weight gain.
•Hypersensitivity reactions
•Some are carcinogenic in laboratory
animals.

72. Contraindications
•Inhibit MAO so not used with such drugs
•Not used systemically due to toxicity
•Applied topically for cutaneous infections
or wound dressing

73. Nitrofurans
1.Nitrofurantoin
2.Furazolidone
It is not absorbed from GI tract after
oral administration, used to treat
GI tract infections. Antibiotic
activity and adverses are same
as nitrofurantoin.

74. Nitrofurans
It is bacteriostatic and bactericidal for
many G
+
and G
-
bacteria.
Resistance emerges slowly, there is
no cross-resistance between
nitrofurantoin and other
antimicrobial agents.
The mechanism of action is not
clearly defined.

75. Nitrofurantoin
Activity of nitrofurantoin is greatly
enhanced at pH 5.5 or below.
It is well absorbed after ingestion. It is
excreted into the urine by both
glomerular filtration and tubular
secretion.
It is used to treat urinary tract infection.
*Nitrofurantoin antagonizes the action
of nalidixic acid.

76. Nitrofurantoin
Anorexia, nausea, and vomiting are the
principal side effects.
Neuropathies and hemolytic anemia
occur in glucose-6-phosphate
dehydrogenase dificiency.
Rashes, pulmonary infiltration and
other hypersensitivity reactions may
occur.

77. Nitroimidazoles
•Agroup of synthetic drugs which have
both antiprotozoal and antibacterial
activities
•Important members
•1. Metronidazole
•2. Dimetridazole

78. Metronidazole

79. Metronidazole
It is a nitroimidazole antiprotozoal and antibacterial
drug.
Activity against anaerobes, including bacteroides
and clostridium species.
Well absorbed after oral administration, widely
distributed in tissues, also be given by IV, or by
rectal suppository.

80. Metronidazole
It penetrates well into the cerebrospinal fluid,
reaching levels similar to those in serum.
It is metabolized in the liver and may accumulate in
hepatic failure.
It is used to treat
Anaerobic or mixed intra-abdominal infections,
Vaginitis (trichomonas, bacterial vaginosis),
Antibiotic-associated enterocolitis, and
Brain abscess.

81. Metronidazole
The mechanism of action
The nitro group of metronidazole is chemically
reduced in anaerobic bacteria and sensitive
protozoans.
Reactive reduction products appear to be
responsible for antimicrobial activity.
For disrupting DNA synthesis, it first reduces to a
cytotoxic metabolite

82. Metronidazole
Adverse effects include
Nausea
Diarrhea
Stomatitis and
Peripheral neuropathy with prolonged use.
It has a disulfiram-like effect, and patients should
be instructed to avoid alcohol.

83. Urinary Tract
Antiseptics/Antimicrobials
•Methenamine
•Nitrofurantoin
•Nalidixic acid

84. Formation of formaldehyde from methenamine at acid
pH.