|Systematic (IUPAC) name|
|Trade names||Levaquin, Tavanic,
Quixin (eye drops)
|Licence data||US FDA:|
|Oral, IV, ophthalmic|
|Protein binding||24 to 38%|
|Metabolism||<5% desmethyl and N-oxide metabolites|
|Biological half-life||6 to 8 hours|
|Excretion||Urinary, mainly unchanged|
|CAS Registry Number|
|ATC code||J01 S01|
|Molecular mass||361.368 g/mol|
|(what is this?)|
Levofloxacin (trade names Levaquin (US), Tavanic (EU), and others) is a broad-spectrum antibiotic of the fluoroquinolone drug class, and the levo isomer of its predecessor ofloxacin. Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram negative (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), Gram positive (methicillin-sensitive but not methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes), and atypical bacterial pathogens (Chlamydophila pneumoniae and Mycoplasma pneumoniae). Compared to earlier antibiotics of the fluoroquinoline class such as ciprofloxacin, levofloxacin exhibits greater activity towards Gram-positive bacteria but lesser activity toward Gram-negative bacteria, especially Pseudomonas aeruginosa. Levofloxacin and later generation fluoroquinolones are collectively referred to as "respiratory quinolones" to distinguish them from earlier fluoroquinolones which exhibited modest activity toward the important respiratory pathogen Streptococcus pneumoniae.
Levofloxacin and other fluoroquinolones are valued for their broad spectrum of activity, excellent tissue penetration, and for their availability in both oral and intravenous formulations. Levofloxacin is used alone or in combination with other antibacterial drugs to treat certain bacterial infections including pneumonia, urinary tract infections, and abdominal infections.
Levofloxacin and other fluoroquinolones are generally well tolerated, but in rare instances have produced serious adverse reactions such as spontaneous tendon ruptures and irreversible peripheral neuropathy. Tendon damage may manifest months after therapy had been completed. Levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Overdose
- 5 Interactions
- 6 Mechanism of action
- 7 Chemical properties
- 8 Pharmacokinetics
- 9 History
- 10 Society and culture
- 11 Research
- 12 References
- 13 External links
Levofloxacin is used to treat infections including: respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, endocarditis, meningitis, pelvic inflammatory disease, traveler's diarrhea, tuberculosis and plague.
The drug exhibits enhanced activity against the important respiratory pathogen Streptococcus pneumoniae relative to earlier fluoroquinolone derivatives like ciprofloxacin. For this reason, it is considered a "respiratory fluoroquinolone" along with more recently developed fluoroquinolones such as moxifloxacin and gemifloxacin. It is less active than ciprofloxacin against Gram-negative bacteria, especially Pseudomonas aeruginosa, and lacks the anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of moxifloxacin and gemifloxacin. Levofloxacin has shown moderate activity against anaerobes, and is about twice as potent as ofloxacin against Mycobacterium tuberculosis and other mycobacteria, including Mycobacterium avium complex.
Levofloxacin plays an important role in professional medical society guidelines for the treatment of pneumonia, urinary tract infections, and abdominal infections. The Infectious Disease Society of America (IDSA) and the American Thoracic Society recommend levofloxacin and other respiratory fluoroquinolines as first line treatment for community acquired pneumonia when co-morbidities such as heart, lung, or liver disease are present or when in-patient treatment is required. Levofloxacin also plays an important role in recommended treatment regimens for ventilator-associated and healthcare-associated pneumonia.
It is recommended by the IDSA as a first-line treatment option for catheter-associated urinary tract infections in adults. In combination with metronidazole it is recommended as one of several first-line treatment options for adult patients with community-acquired intra-abdominal infections of mild-to-moderate severity. The IDSA also recommends it in combination with rifampicin as a first-line treatment for prosthetic joint infections. The American Urological Association recommends levofloxacin as a first-line treatment for bacterial prostatitis.
Levofloxacin and other fluoroquinolones have also been widely used for the outpatient treatment of uncomplicated community-acquired respiratory and urinary tract infections, indications for which major medical societies generally recommend the use of older, narrower spectrum drugs to avoid fluoroquinolone resistance development. The U.S. Food and Drug Administration (FDA) estimates that over 23 million outpatient prescriptions for fluoroquinolones were filled in the United States in 2011. Due to its widespread use, common pathogens such as Escherichia coli and Klebsiella pneumoniae have developed resistance. In many countries, resistance rates among healthcare-associated infections with these pathogens now exceeds 20%.
Levofloxacin is available in tablet form, injection, oral solution, as well as used in prescription eye and ear drops.
Use in specific populations
According to the FDA approved prescribing information, levofloxacin is pregnancy category C. This designation indicates that animal reproduction studies have shown adverse effects on the fetus and there are no adequate and well-controlled studies in humans, but the potential benefit to the mother may in some cases outweigh the risk to the fetus. Other fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.
Levofloxacin is not approved in most countries for the treatment of children except in unique and life-threatening infections because it is associated with an elevated risk of musculoskeletal injury in this population, a property it shares with other fluoroquinolones.
In the United States levofloxacin is approved for the treatment of anthrax and plague in children over six months of age.
Levofloxacin is recommended by the Pediatric Infectious Disease Society and the Infectious Disease Society of America as a first-line treatment for pediatric pneumonia caused by penicillin-resistant Streptococcus pneumoniae, and as a second-line agent for the treatment of penicillin-sensitive cases.
In one study, 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months post-treatment. At 12 months follow-up the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In the levafloxacin-treated group, approximately two-thirds of these musculoskeletal adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.
In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or the ceftriaxone in 712 children with community-acquired pneumonia, adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these adverse events were thought to be unrelated or doubtfully related to the levofloxacin. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including 5 cases of tendon rupture) and central nervous system events (19, including 5 cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.
Package inserts mention that levofloxacin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolone drugs, and that caution should be exercised in prescribing to patients with liver disease.
Most adverse reactions are mild to moderate; however, sometimes serious adverse effects occur. There is some disagreement in the medical literature regarding whether and to what extent levofloxacin and other fluoroquinolones produce serious adverse effects more frequently than other broad spectrum antibacterial drugs.
In pooled results from 7537 patients exposed to levofloxcacin in 29 clinical trials, 4.3% discontinued treatment due to adverse drug reactions. The most common adverse reactions leading to discontinuation were gastrointestinal, including nausea, vomiting, and constipation. Overall, 7% of patients experienced nausea, 6% headache, 5% diarrhea, 4% insomnia, along with other adverse reactions experienced at lower rates.
Other less common but serious adverse effects have been observed both in clinical trials as well as in reviews of post-approval spontaneous adverse event reports. Prominent among these is the potential for tendon damage, including rupture of the Achilles tendon, which is the subject of a black box warning in the official prescribing informations for all fluoroquinolones in the United States. Injury, including tendon rupture, has been observed up to 6 months after cessation of treatment; the elderly, transplant patients, and those with a current or historical corticosteroid use are at elevated risk. A population-based study in the Netherlands estimated that between 1 and 15 fluoroquinolone-attributable tendon ruptures resulted from 318,000 fluoroquinoline prescriptions in 1996. A detailed overview of risk factors for fluoroquinolone-associated tendon rupture has been published; advanced age, concurrent treatment with corticosteroids, and higher doses of fluoroquinolone appear to be the most important risk factors. The U.S. label for levofloxacin also contains a black box warning for the exacerbation of the symptoms of the neurological disease myasthenia gravis.
A wide variety of other uncommon but serious adverse events have been associated with fluoroquinolone use, with varying degrees of evidence supporting causation. These include irreversible peripheral neuropathy, anaphylaxis, hepatotoxicity, central nervous system effects including seizures and psychiatric effects, prolongation of the QT interval, blood glucose disturbances, and photosensitivity, among others. Levofloxacin may produce fewer of these rare serious adverse effects than other fluoroquinolones.
Administration of levofloxacin or other broad spectrum antibiotics is associated with Clostridium difficile associated diarrhea which may range in severity from mild diarrhea to fatal colitis. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.
Overdosing experiments in animals showed central effects such as dizziness, confusion and seizures, as well as prolongation of the QT interval and gastrointestinal disorders.
In the event of an acute overdosage, authorities recommend unspecific standard procedures such as emptying the stomach, observing the patient and maintaining appropriate hydration. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
Levofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.
When levofloxacin is taken with anti-acids containing magnesium hydroxide or aluminum hydroxide, the two combine to form insoluble salts that are difficult to absorb from the intestines. Peak serum concentrations of levofloxacin may be reduced by 90% or more, which can prevent the levofloxacin from working. Similar results have been reported when levofloxacin is taken with iron supplements and multi-vitamins containing zinc.
Unlike ciprofloxacin, levofloxacin does not appear to deactivate the drug metabolizing enzyme CYP1A2. Therefore, drugs that use that enzyme, like theophylline, do not interact with levofloxacin. It is a weak inhibitor of CYP2C9, suggesting potential to block the breakdown of warfarin and phenprocoumon. This can result in more action of drugs like warfarin, leading to more potential side effects, such as bleeding.
Mechanism of action
Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. Like all quinolones, it functions by inhibiting the two type II topoisomerase enzymes, namely DNA gyrase and topoisomerase IV. Topoisomerase IV is necessary to separate DNA that has been replicated (doubled) prior to bacterial cell division. With the DNA not being separated, the process is stopped, and the bacterium cannot divide. DNA gyrase, on the other hand, is responsible for supercoiling the DNA, so that it will fit in the newly formed cells. Both mechanisms amount to killing the bacterium, that is, levofloxacin acts as a bactericide.
Levofloxacin is the levo isomer of the racemate ofloxacin, another quinolone antimicrobial agent. In layman terms, this means that levofloxacin is the 50% of ofloxacin that have been found to be effective against bacteria, while the other 50% have been removed. As a consequence, levofloxacin dosing is half that of ofloxacin. In chemical terms, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (−)-(S)-enantiomer of the racemic ofloxacin.
The substance is used as the hemihydrate, which has the empirical formula C18H20FN3O4 · ½ H2O and a molecular mass of 370.38 g/mol. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder.
Levofloxacin is rapidly and essentially completely absorbed after oral administration, with a plasma concentration profile over time that is essentially identical to that obtained from intravenous administration of the same amount over 60 minutes. As such, the intravenous and oral formulations of levofloxacin are considered interchangeable.
The drug undergoes widespread distribution into body tissues. Peak levels in skin are achieved 3 hours after administration and exceed those in plasma by a factor of 2. Similarly, lung tissue concentrations range from two-fold to five-fold higher than plasma concentrations in the 24 hours after a single dose.
The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. Elimination occurs mainly via excretion of unmetabolized drug in the urine. Following oral administration, 87% of an administered dose was recovered in the urine as unchanged drug within 2 days. Less than 5% was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans.
Levofloxacin is marketed by Sanofi-Aventis under the trade name "Tavanic" in Europe, Africa, the Middle East and South America, and by the Ortho-McNeil Pharmaceuticals subsidiary of Johnson and Johnson in the United States.
Levofloxacin was first patented in 1987 (Levofloxacin European patent by Daiichi Pharmaceutical Co., Ltd.) and was approved by the United States Food and Drug Administration on 20 December 1996 for use in the United States to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.
The term of the levofloxacin United States patent was extended by the U.S. Patent and Trademark Office under the provisions of the Hatch Waxman Amendment. Under the terms of Hatch-Waxman, the patent terms of pharmaceutical products that contain a novel active ingredient are extended by up to five years to compensate the developer for the patent life lost while performing clinical trials and other activities required to fulfill regulatory requirements. This extension was challenged by generic drug manufacturer Lupin Pharmaceuticals who argued that since levofloxacin is a single isomer of the previously approved antibacterial ofloxacin, it is not a "novel active ingredient" and thus ineligible for patent term extension. The federal patent court ruled in favor of Ortho McNeil, and generic versions of levofloxacin did not enter the U.S. market until 2009.
Society and culture
As of 2012, Johnson and Johnson was facing around 3400 state and federal lawsuits filed by people who claimed tendon damage from levofloxacin; about 1900 pending in a class action at the United States District Court in Minnesota and about 1500 pending at a district court in New Jersey.
In October 2012, J&J settled 845 cases in the Minnesota action, after Johnson and Johnson prevailed in three of the first four cases to go to trial. By May 2014, all but 363 cases had been settled.
Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers. It can fulfill the criteria for a positive comparator, meaning in studies that require the target to have a long QT interval, it can be given to create such an interval in normally healthy individuals. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. Studies have shown that levofloxacin causes a QT lengthening that is above this threshold, indicating its potential use in QT/QTc studies.
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