Levofloxacin

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Levofloxacin, sold under the brand name Levaquin among others, is a broad-spectrum antibiotic of the fluoroquinolone drug class. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), urinary tract infections, Legionnaires' disease, chronic bacterial prostatitis, and some types of gastroenteritis.

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Common side effects include nausea, diarrhea, and trouble sleeping. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

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 Levofloxacin also plays an important role in recommended treatment regimens for ventilator-associated and healthcare-associated pneumonia.

As of 2010 it was 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 to prevent bacterial prostatitis when the prostate is biopsied. and as of 2004 it was recommended to treat bacterial prostatitis by the NIH research network studying the condition.

Levofloxacin and other fluoroquinolones have also been widely used for the 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. Due to its widespread use, common pathogens such as Escherichia coli and Klebsiella pneumoniae have developed resistance. In many countries as of 2013, resistance rates among healthcare-associated infections with these pathogens exceeded 20%.

Levofloxacin is also used as antibiotic eye drops to prevent bacterial infection. Usage of levofloxacin eye drops, along with an antibiotic injection of cefuroxime or penicillin during cataract surgery, has been found to lower the chance of developing endophthalmitis, compared to eye drops or injections alone.

Pregnancy and breastfeeding

According to the FDA approved prescribing information, levofloxacin is pregnancy category C.

Levofloxacin does penetrate into breastmilk, though the concentration of levofloxacin in the breastfeeding infant is expected to be low. Due to potential risks to the baby, the manufacturer does not recommend that nursing mothers take levofloxacin.

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.

Spectrum of activity

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.

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.

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.

Resistance

Resistance to fluoroquinolones is common in staphylococcus and pseudomonas. Resistance occurs in multiple ways. One mechanism is by an alteration in topoisomerase IV enzyme. A double mutant form of S. pneumoniae Gyr A + Par C bearing Ser-81-->Phe and Ser-79-->Phe mutations were eight to sixteen times less responsive to ciprofloxacin.

Contraindications

Package inserts mention that levofloxacin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolones.

Like all fluoroquinolines, levofloxacin is contraindicated in patients with epilepsy or other seizure disorders, and in patients who have a history of quinolone-associated tendon rupture.

Adverse effects

Adverse effects are typically mild to moderate. However, severe, disabling, and potentially irreversible adverse effects sometimes occur, and for this reason it is recommended that use of fluoroquinolones be limited.

Prominent among these are adverse effects that became the subject of a black box warning by the FDA in 2016. The FDA wrote: "An FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious adverse effects that can occur together. These adverse effects can involve the tendons, muscles, joints, nerves, and central nervous system." Such injuries, including tendon rupture, has been observed up to six months after cessation of treatment; higher doses of fluoroquinolones, being elderly, transplant patients, and those with a current or historical corticosteroid use are at elevated risk. The US label for levofloxacin also contains a black box warning for the exacerbation of the symptoms of the neurological disease myasthenia gravis. Similarly, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) recommendations warn of rare but disabling and potentially irreversible adverse effects, and to recommend limiting use of these drugs. Increasing age and corticosteroid use appears to increase the risk of musculoskeletal complications.

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.

Concerning more usual adverse effects, in pooled results from 7,537 patients exposed to levofloxacin 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, and 4% insomnia, along with other adverse reactions experienced at lower rates.

Administration of levofloxacin or other broad-spectrum antibiotics is associated with Clostridioides difficile associated diarrhea which may range in severity from mild diarrhea to fatal colitis. Fluoroquinolone administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridioides strain.

More research is needed to determine the best dose and length of treatment.

Overdose

Overdosing experiments in animals showed loss of body control and drooping, difficulty breathing, tremors, and convulsions. Doses in excess of 1500&nbsp;mg/kg orally and 250&nbsp;mg/kg IV produced significant mortality in rodents. 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. However, clinical study found no significant interactions between levofloxacin and warfarin. Examples of NSAIDs include ibuprofen, naproxen, and aspirin, among others.

Probenicid and cimetidine have been found to reduce the renal clearance of levofloxacin, its main route of elimination, by 35% and 24%, respectively. 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. Levofloxacin acts as a bactericide.

Levofloxacin may act as a GABA_A receptor antagonist or negative allosteric modulator and this may be responsible for its central nervous system (CNS) adverse effects such as seizures. On the other hand, one study suggested that the convulsions induced by fluoroquinolines may be more associated with glutamate and/or GABA_B receptors than with the GABA_A receptor. As of 2011, the mechanism of action of levofloxacin's musculoskeletal complications was not clear. This enantiomer binds more effectively to the DNA gyrase enzyme and to topoisomerase IV than its (+)-(R)-counterpart. but have since been redeveloped as pure enantiomers. Distinct functional groups on this molecules include a hydroxyl group, carbonyl group, and an aromatic ring.

The substance is used as the hemihydrate, which has the empirical formula C₁₈H₂₀FN₃O₄·½H₂O and a molecular mass of 370.38&nbsp;g/mol. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder.

History

Levofloxacin is a third-generation fluoroquinolone, being one of the isomers of ofloxacin, which was a broader-spectrum conformationally locked analog of norfloxacin; both ofloxacin and levofloxaxin were synthesized and developed by scientists at Daiichi Seiyaku. The Daiichi scientists knew that ofloxacin was racemic, but tried unsuccessfully to separate the two isomers; in 1985 they succeeded in separately synthesizing the pure levo form and showed that it was less toxic and more potent than the other form. Daiichi, working with Johnson & Johnson as it had with ofloxacin, obtained FDA approval in 1996 under the brand name Levaquin

Availability

thumb|Levofloxacin and [[NaCl injection, specification is 100mL / 750mg]]

Levofloxacin is available in tablet form, injection, patches, and oral solution.

Litigation

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 or adjudicated.

Brand names

Levofloxacin is marketed by Sanofi-Aventis under a license agreement signed with Daiichi in 1993, under the brand name Tavanic.