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.

Looking Back – 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.
Levofloxacin – 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).
How 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.
Where 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.

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