1. Quinolones
A new four‑ generation classification of the quinolone
drugs takes into account the expanded antimicrobial
spectrum of the more recently introduced
fluoroquinolones and their clinical indications.
First‑ generation drugs (e.g., nalidixic acid) achieve
minimal serum levels.
Second‑ generation quinolones (e.g., ciprofloxacin) have
increased gram‑ negative and systemic activity.
Third‑ generation drugs (e.g., levofloxacin) have expanded
activity against gram‑ positive bacteria and atypical
pathogens.
Fourth‑ generation quinolone drugs (currently only
trovafloxacin) add significant activity against
anaerobes

2. Quinolones
The newer fluoroquinolones have broad‑ spectrum
bactericidal activity, excellent oral bioavailability, good
tissue penetration and favorable safety and tolerability
profiles
The quinolones can be differentiated within classes based
on their pharmacokinetic properties.
The new classification can help family physicians
prescribe these drugs appropriately. (Am Fam
Physician 2000;61:2741‑ 8.)

3. Quinolones
The original quinolone antibiotics included nalidixic acid
(NegGram), cinoxacin (Cinobac) and oxolinic acid (no
longer available in the United States).
The addition of fluoride to the original quinolone
antibiotic compounds yielded a new class of drugs, the
fluoroquinolones, which have a broader antimicrobial
spectrum and improved pharmacokinetic properties
Enhanced antimicrobial activity has extended the use of
the fluoroquinolones beyond the traditional indications
for quinolone antibiotics in the treatment of urinary
tract infections.

4. Quinolones
The fluoroquinolones are effective in a wider variety of
infectious diseases, including skin and respiratory
infections.
Because of their excellent safety and tolerability,
fluoroquinolones become popular alternatives to
penicillin and cephalosporin derivatives in the
treatment of various infections
The most recently released agents have significant
antimicrobial activity against gram‑ positive
streptococci, atypical pathogens and anaerobes

5. Fluoroquinolones
The fluoroquinolones are broad‑ spectrum antibiotics with
particular activity against gram‑ negative organisms,
especially Pseudomonas aeruginosa.
These agents are well absorbed when given orally.
Tissue and fluid concentrations often exceed the serum
drug concentration, making these antibiotics are
particularly useful for certain .infections, such as
pneumonia.
Fluoroquinolones are usually well tolerated, with few side
effects. However, they can have serious adverse effects

6. Fluoroquinolones
The most common adverse effects of the fluoroquinolones
are nausea, vomiting and diarrhea, which occur in 3 to
6 percent of recipients.
Other more serious but less common side effects are
central nervous system effects (headache, confusion
and dizziness), phototoxicity (more common with
lomefloxacin [Maxaquin] and sparfloxacin [Zagam]),
cardiotoxicity (sparfloxacin) and hepatotoxicity
(trovafloxacin [Trovan]).
These drugs are not recommended for use in patients
younger than 18 years or in pregnant or lactating
women

7. Fluoroquinolones
Mechanism of Action
A. Blocks bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA gyrase) and topoisomerase IV.
B. Inhibition of DNA gyrase II prevents the relaxation of
positively supercoiled DNA that is required for normal
transcription and replication
C. Inhibition of topoisomerase IV interferes with the
separation of replicated chromosomal DNA into
respective daughter cells during cell division.

8. Fluoroquinolones
DNA Gyrase belongs to the topoisomerases which are
involved in the replication, transcription,
recombination and repair of bacterial DNA
Type II topoisomerase cleaves sugar-phosphate bonds in
both DNA strands thus making possible the
supercoiling required for the transition into the lag
phase after cellular division.
This compact supercoiled order is necessary for the
chromosome to be placed in the cell coat.

9. Fluoroquinolones
Type I topoisomerase is needed to despiralize (uncoil) the
DNA in a single strand.
A stepwise decoiling takes place during the metabolic
phases (formation of m-RNA.
Type II topoisomerase is required for final coiling.
DNA gyrase is a tetramer consisting of two different
subunits ( two A and two B)

10. Fluoroquinolones
DNA gyrase causes an opening of DNA by binding of a
hydroxyl group of a tyrosine residue of subunit A to a
phosphate group
Supercoiling occurs where part of the DNA strand pulls
through the opening. This step requires energy from
subunit B, an ATPase.
The incision in the DNA molecule is sealed again by
subunit A using energy gained by hydrolysis of a
phosphate ester of tyrosine.

11. Fluoroquinolones
DNA gyrase inhibitors interfere with the sealing of DNA
strands, leading to a rapid breakdown of metabolism in
susceptible bacteria.
The effect of gyrase inhibitors is confined to bacteria
because of different chromosomal configurations of
DNA in higher organisms

12. Fluoroquinolones
The fluoroquinolones are bactericidal antibiotics that act
by specifically targeting DNA gyrase.
In contrast toaminoglycosides and beta‑ lactams, some
fluoroquinolones are active against dormant and
replicating bacteria.
Fluoroquinolones exhibit a postantibiotic effect following
bacterial exposure to inhibitory concentrations. The
antibacterial effect continues for approximately two to
three hours after bacteria are exposed to these drugs,
despite subinhibitory concentrations.
The duration of the postantibiotic effect may be increased
with longer bacterial drug exposure and higher drug
concentrations.

13. Fluoroquinolones
Antibacterial Activity
Anaerobes are generally resistant to fluoroquinolones
Norfloxacin - least active of fluoroquinolones
Ofloxacin and Ciprofloxacin - inhibit gram negative cocci and
bacilli at low concentrations however little activity against
streptococci (pneumococcus and enterococci), therefore
these are not good for respiratory tract infections.
Levofloxacin (the L isomer of ofloxacin) and Sparfloxacin more
active against staph and strep than cipro and ofloxacin.
Fluoroquinolones have activity against intracellular pathogens
such as legionella, and chlamydia
fluoroquinolones have activity against some mycobacteria
including myco. TB and MI/MA complex

14. Fluoroquinolones
Resistance
Resistance appears to be the result of: alterations in the
quinolone enzymatic targets (DNA gyrase), decreased
outer membrane permeability or the development of
efflux mechanisms.
Resistance may result from one or more point mutations
in the quinolone binding region of the target enzyme
(topoisomerase II or IV) or from a change in the
permeability of the organism (ability of the antibiotic
to penetrate the cell membrane)

15. Fluoroquinolones
E. Coli
DNA gyrase - primary target enzyme with Single step
mutants exhibiting amino acid substitution in the A
subunit of gyrase
Topoisomerase IV - secondary target that is altered in
mutants expressing higher levels of resistance
Staphylococci and Streptococci
Topoisomerase IV is primary target
DNA gyrase is secondary target

16. Fluoroquinolones
Resistance patterns in pneumococci (in Canada)
The prevalence of pneumococci with reduced susceptibility to
fluoroquinolones increased significantly from 0% in 1988 and 1993
to 1.7% in 1997 and 1998.*
Among adults, the prevalence increased from 1.5% in 1993 and 1994
combined to 2.9% in 1997 and 1998 combined.
The greatest change in reduced susceptibility was seen in adults aged
between 15 and 64 years; the prevalence of pneumococci increased
from 0.5% in 1993 and 1994 to 2% in 1997 and 1998.
* Pneumococci with reduced susceptibility to fluoroquinolones were
defined as those for which the minimum inhibitory concentration
(MIC) of ciprofloxacin was => 4 µg/ml.

17. Fluoroquinolones
The number of fluoroquinolone prescriptions increased
from 0.8 per 100 persons per year in 1988 to 5.5 per
100 persons per year in 1997.
Per capita use of fluoroquinolones was greatest among
people aged => 65 years and in Ontario.
Resistant strains of Staphylococcus aureus and
Pseudomonas aeruginosa have also appeared

18. Fluoroquinolones
Resistance to quinolones can also develop because of
alterations in bacterial permeability and the
development of efflux pumps.
This resistance mechanism is shared with antimicrobial
agents structurally unrelated to the quinolones, such as
the beta‑ lactams, tetracyclines and chloramphenicol
(Chloromycetin).
Cross‑ resistance among the quinolones is expected, but the
extent to which the minimum inhibitory concentration
is affected varies from agent to agent.

19. Fluoroquinolones
In Vitro Efficacy Study
Isolates are from cancer patients who have been previously
treated with antibiotics including beta‑ lactams,
aminoglycosides, and quinolones.
Clinical trials are needed to determine if differences from this
in vitro study correspond to differences in clinical outcomes
Trovafloxacin, ciprofloxacin, levofloxacin, and sparfloxacin
have comparable sensitivity profiles against gram‑ negative
bacteria.
Trovafloxacin appears to be the most active quinolone against
gram‑ positive bacteria.

20. Fluoroquinolones
Antibiotic Use During Pregnancy
Relatively Safe
Penicillins, Cephalosporins, Erythromycin base
Caution Advised
Trimethoprin/Sulfamethazole, Metronidazole,
Aminoglycosides, Chloramphenicol
Relatively Contraindicated
Tetracyclines, Erythromycin estolate, Fluoroquinolones

21. Fluoroquinolones
The administration of fluoroquinolone antibiotics
(ciprofloxacin, norfloxacin) is considered contraindicated
during pregnancy. The fluoroquinolones have been shown
to cause permanent lameness in immature animals. There
are no reports of fetal defects in humans, but because of the
irreversible nature of the lesion, it is prudent to completely
avoid fluoroquinolones during pregnancy.
Additionally, norfloxacin has been embryocidal and slightly
maternotoxic in cynomolgus monkeys receiving 10 times the
equivalent therapeutic dose used in humans

22. Fluoroquinolones
Six new fluoroquinolones have been introduced in the
United States during the past five years.
Levofloxacin (Levaquin) and sparfloxacin became
available in 1996.
Grepafloxacin (Rexar) and trovafloxacin were introduced
in 1997.
Gatifloxacin (Tequin) and moxifloxacin (Avelox) became
available in early 2000.
In December 1999, grepafloxacin was voluntarily
withdrawn because of the possibility of torsades de
pointes occurring with its use.

23. Fluoroquinolones
Compared with ciprofloxacin (the prototypical agent of
the original fluoroquinolones), the newest
fluoroquinolones have enhanced activity against
gram‑ positive bacteria with only a minimal decrease in
activity against gram‑ negative bacteria.
Their expanded gram‑ positive activity is especially
important because it includes significant activity
against Streptococcus pneumoniae
Levofloxacin has enhanced activity against S.
pneumoniae, S. aureus and Enterococcus species, as
well as good activity against Mycoplasma and
Chlamydia species

24. Fluoroquinolones
Sparfloxacin has a further expanded spectrum of activity
that includes some activity against anaerobes.
Sparfloxacin has even greater activity against Mycoplasma
species.
Trovafloxacin is the fluoroquinolone with the most potent
anaerobic activity, including activity against Bacteroides
species. As a result, this agent has the broadest spectrum
of activity of the currently available quinolones, as well as
a wide range of indications

25. Fluoroquinolones
Nadifloxacin (Acuatim) is a fluoroquinolone for topical
use. No FDA approval for use in USA
Adverse effects of the topical 1% cream have included
local erythema and pruritus
Data regarding systemic absorption/pharmacokinetics are
lacking
Topical nadifloxacin may be a useful alternative in acne
vulgaris and bacterial skin infections
Its structure is similar to that of ofloxacin. Like other
fluoroquinolones, antimicrobial activity is achieved by
inhibiting DNA gyrase (topoisomerase II)

26. Fluoroquinolones
The first‑ generation formulation included cinoxacin,
nalidixic acid and oxolinic acid.
These early quinolones targeted gram‑ negative organisms
including Escherichia coli, and Klebsiella and Proteus
species.
Nalidixic acid was once the most commonly used
preparation, but poor tissue and serum concentrations
now limit its
use to the treatment of simple urinary tract infections. Its
utility is also limited by its relatively short half‑ life
(requiring four doses daily), narrow spectrum of
activity and the rapid development of bacterial
resistance.

27. Fluoroquinolones
Second‑ generation quinolones have a fluorine substituent in
the main quinolone ring that significantly increases
antibacterial activity.
These fluoroquinolones (ciprofloxacin, enoxacin,
lomefloxacin, ofloxacin and norfloxacin) exhibit good
activity against gram‑ negative bacilli and
moderate‑ to‑ good activity against Staphylococcus species.
Ciprofloxacin and ofloxacin have good tissue penetration
and reach macrophages and polymorphonuclear
leukocytes, making them useful beyond the treatment of
urinary tract infections. In addition, their activity against
Legionella pneumophila is good; their activity against
Chlamydia pneumoniae and Mycoplasma pneumoniae is
more variable

28. Fluoroquinolones
Norfloxacin
Least potent fluoroquinolone
Norfloxacin is a "second‑generation" quinoline carboxylic
acid antimicrobial agent
Norfloxacin is primarily indicated in urinary tract infections
and gonorrhea.
The ophthalmic solution may be used in the treatment of
conjunctivitis.

29. Fluoroquinolones
Ciprofloxacin exhibits good activity against Pseudomonas
aeruginosa and strong gram‑ negative activity that may be
superior to that of ofloxacin.
Coverage against Streptococcus pneumoniae is inadequate,
making the use of ciprofloxacin inappropriate in patients
with community‑ acquired pneumonia.
In summary, ciprofloxacin and ofloxacin are effective in
treating (1) urinary tract infections caused by susceptible
organisms, (2) respiratory tract infections caused by
susceptible gram‑ negative organisms, (3) skin and
soft‑ tissue infections and (4) osteomyelitis (ciprofloxacin
only)

30. Fluoroquinolones
The third‑ generation fluoroquinolones (grepafloxacin,
levofloxacin and sparfloxacin) have expanded coverage
against streptococci and atypical organisms.
This attribute has improved the usefulness of fluoroquinolones
in treating patients with community‑ acquired pneumonia
acute sinusitis and acute exacerbations of chronic
bronchitis, which are their primary FDA‑ labeled
indications.
Activity against Haemophilus influenzae and Moraxella
catarrhalis is high,
Activity against other gram‑ negative bacteria, especially P.
aeruginosa, is less than that of ciprofloxacin

31. Fluoroquinolones
All third‑ generation fluoroquinolones are taken once daily.
In patients with renal disease, dose adjustment for
levofloxacin and sparfloxacin is necessary.
In summary, this generation of fluoroquinolones is useful in
treating patients with the following conditions:
(4) - community‑ acquired pneumonia and bacterial
exacerbations of acute bronchitis,
(5) - urinary tract infections and
(6) - skin or skin‑ structure infections.

32. Fluoroquinolones
Levofloxacin does not affect the QT interval.
The fluoroquinolone ofloxacin exists as 2 optically‑ active
isomers due to its asymmetric center at C3 of the oxazine
ring.
Levofloxacin is the S(‑ )‑ enantiomer of ofloxacin, and is
considered primarily responsible for the clinical
antibacterial efficacy of the racemate .
It is reportedly 8 to 128 times more potent than
R(+)‑ ofloxacin (DR‑ 3354), and twice as potent as racemic
ofloxacin.
Results of some animal studies suggest that levofloxacin may
have a lower propensity for adverse central nervous system
effects than ofloxacin

33. Fluoroquinolones
Fourth‑ generation fluoroquinolones (clinafloxacin, gatifloxacin,
moxifloxacin and trovafloxacin) add significant anaerobic
coverage.
A long half‑ life allows once‑ daily dosage, and extensive hepatic
metabolism makes dose adjustment unnecessary in patients
with renal disease.
Indications for use include nosocomial pneumonia,
intra‑ abdominal infections and serious penicillin‑ or
cephalosporin‑ resistant S. pneumoniae infections.
Gatifloxacin has FDA‑ labeled indications for urinary tract
infections and gonorrhea.

34. Fluoroquinolones
Because of reports of rare but serious liver injuries, the U.S.
Food and Drug Administration issued an advisory notice
(June 1999) that trovafloxacin should be reserved for use in
patients meeting all of the following criteria:
(1) management of a life‑ or limb‑ threatening disease,
(2) treatment should be initiated in an inpatient setting
and
(3) the physician believes that the benefit of the product
for the patient outweighs the potential risk.
Dosage duration should be no longer than 14 days, and
therapy should be discontinued if clinical symptoms of liver
dysfunction are present.

35. Fluoroquinolones
Sparfloxacin carries a significant risk of phototoxicity.
Grepafloxacin, sparfloxacin and moxifloxacin have been
reported to cause prolongation of the QT interval;
Gatifloxacin has not been reported to cause QT prolongation.
The FDA recommends that all of these drugs should be
avoided in patients who are taking drugs that are known to
prolong the QT interval, such as tricyclic antidepressants,
phenothiazines and class I antiarrhythmics.
Levofloxacin does not affect the QT interval.
Rapid bolus intravenous injection may cause hypotension;
administer over a period of not less than 60 minutes

36. Cost of Fluoroquinolone Therapy
Agent Usual Dose Cost in Dollars
Norfloxacin (Noroxin) 400 mg twice daily orally 68
Lomefloxacin (Maxaquin) 400 mg per day orally 66
Enoxacin (Penetrex) 200 to 400 mg b.i.d. orally 62 to 65
Ofloxin (Floxin) 200 to 400 mg b.i.d. orally 75 to 94
400 mg every 12 hours I.V. 158
Ciprofloxacin (Cipro) 250 to 750 mg b.i.d. orally 68 to 80
400 mg every 12 hours I.V. 69 to 81
Levofloxacin (Levaquin) 250 to 500 mg per day orally 69 to 81
500 mg every 24 hours I.V. 119

37. Cost of Fluoroquinolone Therapy
Agent Usual dose Cost in Dollars
Sparfloxacin(Zagam) 200 mg per day orally 67
Gatifloxacin (Tequin) 400 mg per day orally 70
400 mg every 24 hours I.V. 119
Moxifloxacin (Avelox) 400 mg per day orally 87
Trovafloxacin (Trovan) 100 to 200 mg per day orally 59 to 72
Alatrofloxacin (Trovan) 200 mg every 24 hours I.V. 111
‑Estimated cost to the pharmacist (rounded to the nearest dollar) for 10
days of oral therapy or three days of intravenous treatment, based on
average wholesale prices in Red book. Montvale, N.J.: Medical
Economics Data, 2000. Cost to the patient will be higher, depending on
prescription filling fee.