||Special Feature Article|
A DRUG FOR ALL SEASONS Reviewing
the Last 15 Years of Continuous Levofloxacin Use
Fluoroquinolones have been regarded as a major antimicrobial class
for a long period of time, and among these agents, levofloxacin
continues to stand out as one of the most important fluoroquinolone.
Our annual periodical, Penetration, featured a special article to
look back on a 15 year of scientific history of levofloxacin, and
its parent compound ofloxacin.
- How the Fluoroquinolones developed into a Major Class of Antibiotics
Fluoroquinolones have become one of the mainstays of antibacterial
therapy, regarded as a major antimicrobial class, with efficacy
against a wide range of important pathogens. And among the fluoroquinolones,
levofloxacin continues to stand out as one, if not the, most important
fluoroquinolone. While the history of these agents first started
in 1962 with the development of nalidixic acid, it was not until
the late 1970s that the first fluoroquinolone, norfloxacin, was
produced. Ofloxacin, a racemic compound composed of two stereo isomers,
was then introduced to the market in 1985, rapidly carving out a
role for itself, particularly in the treatment of urinary tract
disease and lower respiratory tract infections. The excellent oral
absorption of ofloxacin with its broad spectrum of activity provided
clinicians with an effective antibacterial that could safely be
prescribed on an outpatient basis. When first introduced fluoroquinolones
were primarily recommended for Gram-negative bacilli, especially
those causing urinary tract infections. They were also recommended
for enteric infections, selective decontamination in patients with
neutropenia, sexually transmitted diseases including Chlamydia spp.,
skin and soft tissue infections (SSSI) including osteomyelitis.
While they were also seen as useful in respiratory tract infections
(RTI) this was not the main therapeutic focus of the early fluoroquinolones.
- Leading the Fluoroquinolone Field
However this changed with the introduction of newer fluoroquinolones
that had enhanced activity. This was seen immediately with the development
of levofloxacin in 1986 and its introduction onto the Japanese market
in 1993. Levofloxacin was prepared by purifying and isolating the
racemic ofloxacin to produce the levo isomeric form. With twice
the potency of its parent compound, coupled with great safety, levofloxacin
proved to be a major antibacterial agent, and was subsequently approved
by the FDA in 1996 for the treatment of communityacquired pneumonia
(CAP), acute bacterial exacerbations of chronic bronchitis (ABECB),
acute maxillary sinusitis, uncomplicated SSSI, acute pyelonephritis
and complicated urinary tract infections (UTI).
Safety Issues Thinned the Ranks of the Fluoroquinolones
While in depth post-marketing surveillance data has continued to
support the safety of levofloxacin, this has not been the case for
many other fluoroquinolones. In the late 1980s there was an influx
of other second and third generation agents, which due to chemical
engineering developed increased activity against selected pathogens.
However not all of these were successful with temafloxacin withdrawn
in June 1992 due to patient's developing hemolytic uremic syndrome.
This was followed by a spate of withdrawals in 1999 due to unacceptable
adverse events: In June 1999 trovafloxacin was withdrawn or limited
in its use due to the development of serious hepatic events; grepafloxacin
was withdrawn in October 1999 following reports of cardiovascular
effects, clinafloxacin was withdrawn due to phototoxicity and hypoglycaemic
effects and sparfloxacin required labelling changes due to cardiovascular
effects. Recently there have also been concerns over the glycemic
effects associated with gatifloxacin. In contrast, throughout the
past 15 years levofloxacin has been used continuously with its safety
confirmed in over 300 million prescriptions.
to from Here?
One of the major issues concerning fluoroquinolones since the later
1990s was the need to maintain their efficacy by judicious prescribing
in order to reduce the development of resistance. The potential
to develop resistance is not the same for all fluoroquinolones,
and in this regard levofloxacin has an advantage over other agents.
In order for pathogens to become fully resistant to levofloxacin
they need to undergo two mutations, thereby drastically reducing
the likelihood of this occurring. The low rate of levofloxacin resistance
has been confirmed in a number of ongoing global surveillance studies
which continue to monitor the sensitivity of major pathogens. Resistance
rates to levofloxacin have been stable over the past five years,
averaging at less than 1% of high level resistance. Since the introduction
of levofloxacin it has carved out a significant niche for itself
as a "respiratory" fluoroquinolone, effective in both upper and
lower respiratory tract infections. In addition to its use in a
wide range of infections, levofloxacin therapeutic regimens have
changed in recent times with the advent of a high dose strategy
that has been shown to be safe and effective, allowing shorter durations
of therapy to be administered. This reduces cost as well as helping
in the fight against development of resistance. The 750 mg dosing
strategy is particularly advocated in US and European patients,
providing an effective once daily outpatient therapy for severe
infections that would have previously required hospital admission.
During the past 15 years Penetration has provided an in-depth exploration
of the best scientific literature regarding this important agent.
The following reviews summarise the most important scientific articles
that have been published regarding levofloxacin over its history
confirming it to be an agent of inestimable value. Based upon this
in-depth scientific data it is possible to look to the future with
confidence, assured that levofloxacin will remain a potent and safe
antibiotic, used around the world to treat many infections.