|Systematic (IUPAC) name|
|Trade names||Levaquin, Tavanic, Iquix, others|
|By mouth, IV, eye drops|
|Metabolism||<5% desmethyl and N-oxide metabolites|
|Biological half-life||6.9 hours|
|Excretion||Renal, mostly unchanged (83%)|
|ATC code||J01MA12 (WHO) S01AE05 (WHO)|
|Molar mass||361.368 g/mol|
|(what is this?)|
Levofloxacin, sold under the trade names Levaquin among others, is an antibiotic. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, urinary tract infections, chronic prostatitis, and some types of gastroenteritis. Along with other antibiotics it may be used to treat tuberculosis, meningitis, or pelvic inflammatory disease. It is available by mouth or intravenously.
Common side effects include nausea, diarrhea, and trouble sleeping. Serious side effects may include tendon rupture, tendon inflammation, seizures, psychosis, and potentially permanent peripheral nerve damage. Tendon damage may appear months after treatment is completed. People may also sunburn more easily. In people with myasthenia gravis muscle weakness and breathing problems may worsen. The risk of use during pregnancy is low and it is probably okay during breastfeeding. Levofloxacin is a broad-spectrum antibiotic of the fluoroquinolone drug class. It usually results in death of the bacteria. It is the left sided isomer of the medication ofloxacin.
Levofloxacin was approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. It is available as a generic medication. The wholesale cost in the developing world is about 0.44 to 0.95 USD per week of treatment. In the United States a week of treatment cost about 50 to 100 USD.
- 1 Medical uses
- 2 Contraindications and drug interactions
- 3 Adverse effects
- 4 Overdose
- 5 Mechanism of action
- 6 Chemical properties
- 7 Pharmacokinetics
- 8 History
- 9 Society and culture
- 10 References
- 11 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.
As of 2016, the US Food and Drug Administration (FDA) recommended that "serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options. For patients with these conditions, fluoroquinolones should be reserved for those who do not have alternative treatment options."
Levofloxacin is used for the treatment of pneumonia, urinary tract infections, and abdominal infections. As of 2007 the Infectious Disease Society of America (IDSA) and the American Thoracic Society recommended 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.
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 20054 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%.
Pregnancy and breastfeeding
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.
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.
Levofloxacin is available in tablet form, injection, and oral solution.
Contraindications and drug interactions
Levofloxacin may prolong the QT interval in some people, especially older ones, and levofloxacin should not be used for people with a family history of Long QT syndrome, or who have long QT, chronic low potassium,it should not be prescribed with other drugs that prolong the QT interval.
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.
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.
A 2011 review examining musculoskeletal complications of fluoroquinolones proposed guidelines with respect to administration to athletes, that called for avoiding all use of fluoroquinolone antibiotics if possible, and if they are used: ensure there is informed consent about the musculoskeletal risks, and inform coaching staff; do not use any corticosteroids if fluoroquinolones are used; consider dietary supplements of magnesium and antioxidants during treatment; reduce training until the course of antibiotic is finished and then carefully increase back to normal; and monitor for six months after the course is finished, and stop all athletic activity if symptoms emerge.
While typical drug side effects reactions are mild to moderate; sometimes serious adverse effects occur.
Prominent among these are side 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 side effects that can occur together. These side effects can involve the tendons, muscles, joints, nerves, and central nervous system." Such injuries, 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 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.
Increasing age and concomitant corticosteroid use appears to increase the risk of musculoskeletal complications.
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 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.
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.
With regard to more usual side effects, 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.
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 loss of body control and drooping, difficulty breathing, tremors, and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.
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.
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. In this way, levofloxacin acts as a bactericide.
As of 2011 the mechanism of action for the drug's musculoskeletal complications were not clear.
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. 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 a second-generation fluoroquinolone, being one of the isomers of ofloxacin, which was a broader-spectrum 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.
It was first approved for marketing in Japan in 1993 for oral administration, and Daiichi marketed it there under the brand name Cravit. Daiichi, working with Johnson & Johnson as it with ofloxacin, obtained FDA approval in 1996 under the brand name Levaquin to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.
Levofloxacin had reached blockbuster status by this time; worldwide sales for J&J alone were US$1.6 billion in 2009.
The term of the levofloxacin United States patent was extended by the U.S. Patent and Trademark Office 810 days under the provisions of the Hatch Waxman Amendment so that the patent would expire in 2010 instead of 2008. This extension was challenged by generic drug manufacturer Lupin Pharmaceuticals, which did not challenge the validity of the patent, but only the validity of the patent extension, arguing that the patent did not cover a "product" and so Hatch-Waxman was not available for extensions. The federal patent court ruled in favor of J&J and Daiichi, and generic versions of levofloxacin did not enter the U.S. market until 2009.
Society and culture
The FDA estimated that in 2011 over 23 million outpatient prescriptions for fluoroquinolones, of which levofloxacin made up 28%, were filled in the United States.
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.
- Zhanel GG, Fontaine S, Adam H, Schurek K, Mayer M, Noreddin AM, Gin AS, Rubinstein E, Hoban DJ (2006). "A Review of New Fluoroquinolones : Focus on their Use in Respiratory Tract Infections". Treat Respir Med. 5 (6): 437–65. PMID 17154673.
- "Levofloxacin". The American Society of Health-System Pharmacists. Retrieved August 25, 2016.
- Yaffe, Gerald G. Briggs, Roger K. Freeman, Sumner J. (2011). Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 828. ISBN 9781608317080.
- "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- "Levofloxacin". International Drug Price Indicator Guide. Retrieved August 25, 2016.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 102. ISBN 9781284057560.
- "US Label" (PDF). 2016.
- "FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur". US Department of Health and Human Services. US Food and Drug Administration. 25 August 2016.
- Mandell LA, Wunderink RG, Anzueto A, et al. (March 2007). "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID 17278083.
- File TM (August 2010). "Recommendations for treatment of hospital-acquired and ventilator-associated pneumonia: review of recent international guidelines". Clin. Infect. Dis. 51 Suppl 1: S42–7. doi:10.1086/653048. PMID 20597671.
- Hooton TM, Bradley SF, Cardenas DD, et al. (March 2010). "Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America". Clin. Infect. Dis. 50 (5): 625–63. doi:10.1086/650482. PMID 20175247.
- Solomkin JS, Mazuski JE, Bradley JS, et al. (January 2010). "Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America". Clin. Infect. Dis. 50 (2): 133–64. doi:10.1086/649554. PMID 20034345.
- Osmon DR, Berbari EF, Berendt AR, et al. (January 2013). "Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America". Clin. Infect. Dis. 56 (1): 1–10. doi:10.1093/cid/cis966. PMID 23230301.
- American Urological Association. 2016 The Prevention and Treatment of the More Common Complications Related to Prostate Biopsy Update
- Schaeffer AJ (September 2004). "NIDDK-sponsored chronic prostatitis collaborative research network (CPCRN) 5-year data and treatment guidelines for bacterial prostatitis". Int. J. Antimicrob. Agents. 24 Suppl 1: S49–52. doi:10.1016/j.ijantimicag.2004.02.009. PMID 15364307.
- ECDC (2014). "Antimicrobial resistance surveillance in Europe 2014" (PDF).
- CDC. "Antibiotic Resistance Threats in the United States, 2013" (PDF).
- Shin HC, Kim JC, Chung MK (September 2003). "Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats". Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136 (1): 95–102. doi:10.1016/j.cca.2003.08.004. PMID 14522602.
- Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H (February 1993). "Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women". Antimicrob. Agents Chemother. 37 (2): 293–6. doi:10.1128/AAC.37.2.293. PMC . PMID 8452360.
- Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, Kaplan SL, Mace SE, McCracken GH, Moore MR, St Peter SD, Stockwell JA, Swanson JT (2011). "The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America". Clin. Infect. Dis. 53 (7): e25–76. doi:10.1093/cid/cir531. PMID 21880587.
- Noel GJ, Bradley JS, Kauffman RE (October 2007). "Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders". Pediatr. Infect. Dis. J. 26 (10): 879–91. doi:10.1097/INF.0b013e3180cbd382. PMID 17901792.
- Wispelwey B, Schafer KR (November 2010). "Fluoroquinolones in the management of community-acquired pneumonia in primary care". Expert Rev Anti Infect Ther. 8 (11): 1259–71. doi:10.1586/eri.10.110. PMID 21073291.
- Lafredo SC, Foleno BD, Fu KP (1993). "Induction of resistance of Streptococcus pneumoniae to quinolones in vitro". Chemotherapy. 39 (1): 36–9. doi:10.1159/000238971. PMID 8383031.
- Fu KP, Lafredo SC, Foleno B, et al. (April 1992). "In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin". Antimicrob. Agents Chemother. 36 (4): 860–6. doi:10.1128/aac.36.4.860. PMC . PMID 1503449.
- Blondeau JM (May 1999). "A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new respiratory quinolones'". J. Antimicrob. Chemother. 43 Suppl B (90002): 1–11. doi:10.1093/jac/43.suppl_2.1. PMID 10382869.
- Cormican MG, Jones RN (January 1997). "Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone". Antimicrob. Agents Chemother. 41 (1): 204–11. PMC . PMID 8980783.
- John A. Bosso (1998). "New and Emerging Quinolone Antibiotics". Journal of Infectious Disease Pharmacotherapy. 2 (4): 61–76. doi:10.1300/J100v02n04_06. ISSN 1068-7777.
- Yamane N, Jones RN, Frei R, Hoban DJ, Pignatari AC, Marco F (April 1994). "Levofloxacin in vitro activity: results from an international comparative study with ofloxacin and ciprofloxacin". J Chemother. 6 (2): 83–91. PMID 8077990.
- UK electronic Medicines Compendium (eMC) Levofloxacin 250mg and 500mg Tablets. Last revised in July 2013
- Zhang L, Wei MJ, Zhao CY, Qi HM (December 2008). "Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes". Acta Pharmacol. Sin. 29 (12): 1507–14. doi:10.1111/j.1745-7254.2008.00908.x. PMID 19026171.
- Schelleman H, Bilker WB, Brensinger CM, Han X, Kimmel SE, Hennessy S (November 2008). "Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding". Clin. Pharmacol. Ther. 84 (5): 581–8. doi:10.1038/clpt.2008.150. PMC . PMID 18685566.
- Domagala JM (April 1994). "Structure-activity and structure-side-effect relationships for the quinolone antibacterials". J. Antimicrob. Chemother. 33 (4): 685–706. doi:10.1093/jac/33.4.685. PMID 8056688.
- Rodvold KA, Piscitelli SC (August 1993). "New oral macrolide and fluoroquinolone antibiotics: an overview of pharmacokinetics, interactions, and safety". Clin. Infect. Dis. 17 Suppl 1: S192–9. doi:10.1093/clinids/17.supplement_1.s192. PMID 8399914.
- Tanaka M, Kurata T, Fujisawa C, et al. (October 1993). "Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide". Antimicrob. Agents Chemother. 37 (10): 2173–8. doi:10.1128/aac.37.10.2173. PMC . PMID 8257141.
- Hall, MM; Finnoff, JT; Smith, J (February 2011). "Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population.". PM & R : the journal of injury, function, and rehabilitation. 3 (2): 132–42. PMID 21333952.
- Khaliq Y, Zhanel GG (June 2003). "Fluoroquinolone-associated tendinopathy: a critical review of the literature". Clin. Infect. Dis. 36 (11): 1404–10. doi:10.1086/375078. PMID 12766835.
- Kim GK (April 2010). "The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know?". J Clin Aesthet Dermatol. 3 (4): 49–54. PMC . PMID 20725547.
- Jones SC, Sorbello A, Boucher RM (October 2011). "Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review". Drug Saf. 34 (10): 839–47. doi:10.2165/11593110-000000000-00000. PMID 21879778.
- Carbon C (2001). "Comparison of side effects of levofloxacin versus other fluoroquinolones". Chemotherapy. 47 Suppl 3 (3): 9–14; discussion 44–8. doi:10.1159/000057839. PMID 11549784.
- Liu HH (May 2010). "Safety profile of the fluoroquinolones: focus on levofloxacin". Drug Saf. 33 (5): 353–69. doi:10.2165/11536360-000000000-00000. PMID 20397737.
- Karageorgopoulos DE, Giannopoulou KP, Grammatikos AP, Dimopoulos G, Falagas ME (March 2008). "Fluoroquinolones compared with beta-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials". CMAJ. 178 (7): 845–54. doi:10.1503/cmaj.071157. PMC . PMID 18362380.
- Lipsky BA, Baker CA (February 1999). "Fluoroquinolone toxicity profiles: a review focusing on newer agents". Clin. Infect. Dis. 28 (2): 352–64. doi:10.1086/515104. PMID 10064255.
- Stahlmann R, Lode HM (July 2013). "Risks associated with the therapeutic use of fluoroquinolones". Expert Opin Drug Saf. 12 (4): 497–505. doi:10.1517/14740338.2013.796362. PMID 23651367.
- Vardakas KZ, Konstantelias AA, Loizidis G, Rafailidis PI, Falagas ME (November 2012). "Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis". Int. J. Infect. Dis. 16 (11): e768–73. doi:10.1016/j.ijid.2012.07.010. PMID 22921930.
- Drlica K, Zhao X (1 September 1997). "DNA gyrase, topoisomerase IV, and the 4-quinolones". Microbiol Mol Biol Rev. 61 (3): 377–92. PMC . PMID 9293187.
- Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 814f. ISBN 3-8047-1763-2.
- "STATISTICAL REVIEW AND EVALUATION" (PDF). USA: FDA. 21 November 1996.
- Morrissey, I.; Hoshino, K.; Sato, K.; Yoshida, A.; Hayakawa, I.; Bures, MG.; Shen, LL. (August 1996). "Mechanism of differential activities of ofloxacin enantiomers" (PDF). Antimicrob Agents Chemother. 40 (8): 1775–84. PMC . PMID 8843280.
- Kannappan, Valliappan; Mannemala, Sai Sandeep (7 June 2014). "Multiple Response Optimization of a HPLC Method for the Determination of Enantiomeric Purity of S-Ofloxacin". Chromatographia. 77 (17–18): 1203–1211. doi:10.1007/s10337-014-2699-4.
- Walter Sneader (31 October 2005). Drug Discovery: A History. John Wiley & Sons. p. 295. ISBN 978-0-470-01552-0.
- Staff, Fish and Richardson. memorANDA, Q2, 2009 p. VIII. Cites US Patent 5,053,407
- S Atarashi from Daiichi. Research and Development of Quinolones in Daiichi Sankyo Co., Ltd. Page accessed August 25, 2016
- Katie Taylor (October 2010). "Drug In Focus: Levofloxacin". GenericsWeb.
- "FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection". US Department of Health and Human Services. US Food and Drug Administration. 16 January 2016.
- Judge John R. Tunheim. "Levaquin MDL". USA: US Courts. Retrieved 7 September 2009.
- Charles Toutant (6 July 2009). "Litigation Over Johnson & Johnson Antibiotic Levaquin Designated N.J. Mass Tort". New Jersey Law Journal.
- Margaret Cronin Fisk and Beth Hawkins for Bloomberg News. Nov 1, 2012 Johnson & Johnson Settles 845 Levaquin Lawsuits
- "Johnson & Johnson Settles 845 Levaquin Lawsuits - Businessweek".
- "Levaquin MDL | United States District Court - District of Minnesota, United States District Court - District of Minnesota".