PART
II:
QUINOLONE AND
FLUOROQUINOLONE
ANTIBIOTICS
The main quinolone and
fluoroquinolone antibiotics and their full pharmaceutical names are as follows:
|
TABLE 2. MAIN
QUINOLONES MARKETED (with their |
||||
|
GROUP |
Generation |
Generic
name |
Brand
name (manufacturer) |
Year
of FDA |
|
QUINOLONES |
First |
Cinoxacin
Nalidixic
acid |
NegGram (Sanofi) |
|
|
FLUORO QUINOLONES |
Second |
Norfloxacin Ciprofloxacin Ofloxacin Enoxacin Lomefloxacin |
Noroxin (MSD) Cipro (Bayer) Floxin (Ortho) Penetrex (Aventis) Maxaquin (Searle) |
1986 1987 1990 1991 1992 |
|
Third |
Levofloxacin
|
Levaquin
(Ortho)
|
1996 1996 1999 |
|
|
Fourth |
Moxifloxacin Gemifloxacin |
Avelox
(Bayer) Factive |
1997 1999 |
|
|
UNDERGOING
CLINICAL INVESTIGATION |
many
more quinolones are expected to become available
in the years to come |
|||
The antimicrobials quinolones and
fluoroquinolones are bactericidal and inhibit the activity of DNA gyrase, so
the bacteria cannot replicate properly. Most likely they also injure the human
cells on the light of the devastating secondary effects they have. The older
quinolones, nalidixic acid and cinoxacin, are active only against
Enterobacteriaceae with no activity against gram-positive organisms, Pseudomonas aeruginosa, or anaerobes.
Furthermore, bacteria tend to become rapidly resistant to these older drugs;
they are used only for UTIs.
The
fluoroquinolones have much greater activity against Enterobacteriaceae and are
also active against staphylococci, P.
aeruginosa, Mycoplasma, Chlamydia, and some streptococci, but with the
exception of trovafloxacin, are not reliably active against anaerobes.
Ofloxacin, levofloxacin, grepafloxacin, trovafloxacin, and sparfloxacin have
the best activity against gram-positive cocci. Resistance has been noted,
particularly with P. aeruginosa and
methicillin-resistant Staphylococcus
aureus. Resistance to one fluoroquinolone generally means resistance to
all. Norfloxacin is poorly absorbed orally; the other fluoroquinolones are
better absorbed orally, resulting in blood levels adequate for treating
systemic infection.
Tequin is being pulled out of the
market (year 2006) because a class effect of quinolones like hyperglycemia and
hypoglycemia has been linked to this particular fluoroquinolone with very
serious and fatal results. It seems that this side effect is more evident in
tequin than in the rest of quinolones, but in fact, it is of the same order of
magnitude in all fluoroquinolones.
Other banned or withdrawn
quinolone antibiotics are temafloxacin (OMNIFLOX), which caused low blood
sugar, kidney failure, and a certain rare form of anemia;
grepafloxacin (RAXAR) and sparfloxacin (ZAGAM), which caused QT-interval
prolongation and increased risk of heart arrhythmias. Trovafloxacin (TROVAN)
causes liver toxicity and is no longer prescribed although has not been banned
in order to have it in reserve for very special and critical cases.
In other European countries, the
number and names of quinolones marketed is very different. Check the best and
most updated list that applies in your country, just looking in the databases
of your local health authorities.
The market of quinolones is
growing. There are many reasons for that. Doctors have become increasingly wary
of the adverse reactions of other well-known antibiotics (deafness, kidney
injuries, others) and are deprived of some of the old arsenal (penicillins) due
to the increasing resistance to antibiotics.
Therefore doctors do welcome
fluoroquinolones for every use because their toxicity is well hidden and they
do not cause the classic damage that has been concerning the medical class
during the last years, like the severe pathologies mentioned.
LEADDISCOVERY LTD IS ON THE
The quinolones are the fastest growing antibacterial
class in terms of global revenue, increasingly being used in both the hospital
and community sectors to treat a broad range of infections. However, the
forthcoming
Fluoroquinolone sales are expected to remain
relatively constant to 2011 despite the expiry of US patents for Cipro and
Levaquin in 2003 and 2010, respectively. Growth during this period will be
driven by increased use of quinolones in
the treatment of less severe respiratory tract infections in the community
sector and aggressive life-cycle management of Levaquin and Avelox.
Despite the large number and variety of products
available, the fluoroquinolone market is heavily dominated by ciprofloxacin and
levofloxacin, which together command 65% ($3.3 billion) of global sales.
Although ciprofloxacin’s key strengths lie in the
treatment of urinary tract infections (UTIs), the majority (>60%) of its
sales are derived from the treatment of infections of the respiratory tract
(RTIs), primarily because these are the most common bacterial diseases treated
across the US and EU.
As a consequence, in the years to
come, if the practice of prescribing fluoroquinolones is not adjusted to the real
toxicity of the anti-microbials, we are going to suffer a very big increase in
people affected. All floxed persons start to ask their relatives and co-workers
about their experiences with quinolones, and each one discover a handful of
close people that has been hit by the antibiotic, without linking it with the
cause.
For us is very paradoxical that
many of us know of one or more doctors that have suffered a reaction to a
fluoroquinolone (crutches for ankle pains, tendon ruptures, strong heart
abnormalities, and others) and those doctors do not engage in active
acknowledgement of the problem.
The fluoroquinolones are a class
of synthetic anti-microbial agents that were modelled after nalidixic acid, a
non-fluorinated quinolone antibiotic. The Food and Drug Administration (FDA)
approved nalidixic acid in 1963 for the treatment of urinary tract infections.
It is rapidly absorbed after oral administration and is excreted into the urine
in bactericidal concentrations. This compound has several limitations, which
prevents its use in other types of infections. Specifically, nalidixic acid has
a narrow spectrum of activity and microorganisms easily developed resistance to
this drug.
During the 1980s, modifications
of this drug were made. It had been discovered that a fluorine atom on the
number 6 carbon and a piperazine ring at the number 7 carbon greatly enhance
the spectrum of activity. These revisions to nalidixic acid's structure were
responsible for improving the activity of these agents for Gram-positive
organisms and expanding the Gram-negative spectrum to Pseudomonas aeruginosa,
Haemophilus influenzae, and Neisseria gonorrhoea.
Much like other antibiotics, the
6-fluoroquinolones work to inhibit bacterial DNA synthesis and exhibit
concentration-dependent killing of micro organisms. However, their mechanism of
action is somewhat unique in that they inhibit the bacterial DNA gyrase (the
enzyme responsible for DNA replication) in such a way that irreversible
breakages occur in the DNA strand.
Overall, with the exception of
sparfloxacin, the fluoroquinolone antibiotics are rapidly absorbed after oral
administration and reach their maximum concentrations in one to two hours. Food
may decrease the rate, but not the extent of absorption.
All fluoroquinolones are
eliminated by a combination of the kidney and the liver. Good renal function is
important in the elimination of all of these antibiotics, even when only small
amounts of unchanged drug are detectable in the urine.
Quinolones belong to the current
arsenal of antibiotics developed to treat various infections and are useful to
fight bacteria resistant to other antibiotics and for people allergic to more
benign anti-microbial organisms. They are also preferred for urinary tract infections
because some of the antibiotics used in the past were so toxic to the kidneys
or the auditory system, for instance, thus creating thousands of dialysis
patients and tens of thousands of deaf people.
After the development of the core
quinolones, -the ones on which all the rest are based- all pharmaceutical
companies want to have one or several of them in their portfolio. For that
purpose, they manipulate the original molecule, shifting positions of atoms and
links around. The new chemical thus made has slightly different properties,
many times impossible to discern, and they try to patent it and mass produce
the stuff and sell it at high prices.
Some of these new quinolones
frequently have extreme toxicity, that manufacturers make their best to conceal
or to not disclose during the pre-marketing trials, and they finally enter the
market, causing many deaths and fulminant damage until they are withdrawn, as
we have seen above.
Other quinolones are equally toxic
as the parent ones, or have modified toxicities but still bear the delayed
toxicity properties that are so convenient for not blaming the quinolones on
the damages and injuries that they cause.
Up to now, all the quinolones
marketed or in advanced stages of development possess as a class effect the
wide range toxicity reported in this paper: central and peripheral nervous
system damage, heart, liver, kidney and other systems, vision, cartilage and
tendons and all the rest that you can consult hereafter.