Levofloxacin (Levaquin®)

Based on "Antibiotic and Chemotherapy"
written by Roger G. Finch

History

Japanese biopharmaceutical companies have played an important role in new drug development. There are upwards of 117 useful antibiotics and related medicines of Japanese origin. More than 40 medications have been licensed out around the world. The first antibiotic developed by Japan scientists was colistin (discovered in 1950) followed by well-known agents such as mitomycin C (1955), kanamycin (1957), cefazolin (1969), amikacin (1972), piperacillin (1976), norfloxacin (1977), cefoperazone (1978), ofloxacin (1980), clarithromycin (1984), meropenem (1987), and others 3. The major group is the beta-lactam antibiotics (up to 15), followed by 7 fluoroquinolones.

Levofloxacin (the optical S-(-) isomer of ofloxacin) was developed by the Daiichi Pharmaceutical Co. Ltd. (now Daiichi Sankyo Pharmaceutical Co. Ltd - one of Japan's largest pharmaceutical companies), in Japan. Levofloxacin was developed to ensure excellent ofloxacin's antibacterial potency and minimize toxicity.

Levofloxacin was first launched in Japan in 1993 under the brand name Cravit. It is currently marketed in the U.S. by Ortho McNeil Pharmaceutical under the name Levaquin, under license from Daiichi. Sanofi-Aventis sells levofloxacin under the brand Tavanic in Europe.

FDA approved uses

• Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.
• Acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
• Nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal b-lactam is recommended.
• Community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae.
• Complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis.
• Uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes.
• Chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis.
• Complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa.
• Acute pyelonephritis (mild to moderate) caused by Escherichia coli.
• Uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae or Staphylococcus saprophyticus.
• Inhalational anthrax (post-exposure) - to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Note: Levofloxacin is NOT effective in the treatment of syphilis.

Off-label & Investigational uses

• Helicobacter Pylori eradication 23
• Pelvic inflammatory disease (PID)
• Gynecological infections 15
• Enterocolitis (Shigella spp.) 24
• Epididymitis (non-gonococcal) 16
• Gonococcal infections 17
• Legionnaires disease (Legionella pneumophila) 18
• Peritonitis 25
• Tuberculosis 9
• Community-acquired pneumonia in children 5
• Typhoid fever 7
• Endocarditis 14

Levofloxacin "pros" and "cons"

Advantages:

• Convenient once-daily dosing - this is of particular benefit in non-compliant patients
• Rapidly bactericidal with a broad spectrum of activity 1
• Better safety and tolerability 10-12 - one of the least likely fluoroquinolones to cause any cardiovascular effects 8, central nervous system disturbances and phototoxicity
• Less significant drug interactions than with other fluoroquinolones, as levofloxacin does not have a major P-450 metabolism
• Relatively low emergence of resistant organisms
• Expanded gram-positive spectrum of activity. Levofloxacin is the most active fluoroquinolone against Streptococcus pneumoniae.
• Moderate anaerobic activity (most quinolones possess weak activity against anaerobes) 13
• Excellent activity against lower respiratory tract pathogens27
• Levofloxacin is currently the only respiratory fluoroquinolone approved for the treatment of nosocomial pneumonia. It is very effective against atypical respiratory pathogens (Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae) and resistant pneumococci.
• Excellent bioavailability both orally and intravenously
• Teatment of acute exacerbations of chronic obstructive pulmonary disease with levofloxacin may reduce hospitalizations compared with standard antibiotics 6
• May be a good choice in persons with liver disease in whom other fluoroquinolones are contraindicated 19
• Does not interact with alcohol

Disadvantages:

• Not active against methicillin-resistant staphylococci, including S. aureus, S. epidermidis and S. haemolyticus 2
• Risk of tendon ruptures - the risk of tendon injury is higher in persons taking corticosteroids, especially the elderly (older than 60 years) 4. The risk is higher with higher doses and longer duration of levofloxacin therapy28.
• Risk of peripheral neuropathy (nerve damage) 20, the symptoms include pain, burning, tingling, numbness, weakness, other alterations of sensation
• Risk of prolongation of the QT interval, arrhythmia, and rare cases of torsades de pointes
• Central nervous system and psychiatric side effects, such as convulsions, confusion, anxiety, depression, and insomnia
• Expensive -- not available in generic version
• May delay the fracture healing 21. The research data suggests that use of levofloxacin during early fracture repair may compromise the clinical course of fracture-healing.
• Risk of dysglycemia in petients with diabetes 22.

Mode of action

Chemically, levofloxacin is the S-enantiomer (L-isomer) of ofloxacin, and has approximately twice the potency of ofloxacin, because the R+enantiomer (D-isomer) of ofloxacin is essentially inactive. In addition, the S-enantiomer (L-isomer) of ofloxacin, has substantially less toxicity.

Levofloxacin is a bactericidal antibiotic (kills the bacteria). It inhibits DNA-gyrase in susceptible organisms thereby inhibits relaxation of supercoiled DNA and promotes breakage of DNA strands. DNA gyrase (topoisomerase II), is an essential bacterial enzyme that maintains the superhelical structure of DNA and is required for DNA replication and transcription, DNA repair, recombination, and transposition.

Levofloxacin-induced Tendinitis and Tendon rupture

If you experience pain in any tendon while taking Levofloxacin you should stop the medication and immediately contact your doctor.

61% of fluoroquinolone-associated tendon ruptures reported to the FDA (from November 1997 through December 31, 2005) were associated with levofloxacin 4. This drug has been the most heavily prescribed fluoroquinolone, accounting for approximately 45% of all fluoroquinolone prescriptions during that time. The mean age of patients with tendinopathy was 58.9 years for the cases in the FDA database.

Tendonitis causes pain and swelling in the affected tendon and is treated by removing the offending agent, anti-inflammatory medication, rest, and physical rehabilitation.

Although the exact mechanism of injury in fiuoroquinolone-associated tendinopathy is unknown, it is widely speculated that fiuoroquinolones are directly toxic to tendon fibers possibly associated with further decreased blood supply that particularly targets tendons that generally have a limited blood supply to begin with.

Tendinitis and tendon rupture most frequently involves the Achilles tendon, the tendon that runs from the back of the heel to the calf. Rupture of the Achilles tendon may require surgical repair. Levaquin has also been linked to tendon ruptures in the rotator cuff (shoulder), the biceps, the hand, and the thumb. This reaction appears to be more common in those taking steroids, in older patients, and in kidney transplant recipients, but many cases have occurred in people without any of these risk factors. The onset of symptoms is sudden and has occurred as soon as 24 hours after starting treatment with a fiuoroquinolone.

False-positive opiate results

Levofloxacin can produce false-positive urine opiate screening results26.

Time to clear out of the system

Levofloxacin half-life is 6-8 hours.

Further reading

• Levofloxacin (Levaquin) versus other medications

References

• 1. Davis R, Bryson HM. Levofloxacin: a review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs. 1994; 47(4):677-700.
• 2. vonEiff C. Peters G. In vitro activity of ofloxacin, levofloxacin and D-ofloxacin against staphylococci. J Antimicrob Chemother, 1996;38:259-263.
• 3. Kumazawa J, Yagisawa M. The history of antibiotics: the Japanese story. J Infect Chemother. 2002 Jun;8(2):125-33. PubMed
• 4. August 29, 2006 Andrew Van Eschenbach, M.D., Acting Commissioner. U.S. Food and Drug Administration
• 5. Bradley JS, Arguedas A, Blumer JL, Saez-Llorens X, Melkote R, Noel GJ. Comparative study of levofloxacin in the treatment of children with community-acquired pneumonia. Pediatr Infect Dis J. 2007 Oct;26(10):868-78. PubMed
• 6.Ruiz-Gonzalez A, Gimenez A, Gomez-Arbones X, Soler-Gonzalez J, Sanchez V, Falguera M, Porcel JM. Open-label, randomized comparison trial of long-term outcomes of levofloxacin versus standard antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease. Respirology. 2007 Jan;12(1):117-21. PubMed
• 7. Nelwan RH, Chen K, Nafrialdi , Paramita D. Open study on efficacy and safety of levofloxacin in treatment of uncomplicated typhoid fever. Southeast Asian J Trop Med Public Health. 2006 Jan;37(1):126-30. PubMed
• 8. Makaryus AN, Byrns K, Makaryus MN, Natarajan U, Singer C, Goldner B. Effect of ciprofloxacin and levofloxacin on the QT interval: is this a significant "clinical" event? South Med J. 2006 Jan;99(1):52-6. PubMed
• 9. Richeldi L, Covi M, Ferrara G, Franco F, Vailati P, Meschiari E, Fabbri LM, Velluti G. Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis. Monaldi Arch Chest Dis. 2002 Feb;57(1):39-43. PubMed
• 10. Yagawa K. Latest industry information on the safety profile of levofloxacin in Japan. Chemotherapy. 2001;47 Suppl 3:38-43; PubMed
• 11. Kahn JB. Latest industry information on the safety profile of levofloxacin in the US. Chemotherapy. 2001;47 Suppl 3:32-7; PubMed
• 12. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47 Suppl 3:9-14; PubMed
• 13. Pendland SL, Diaz-Linares M, Garey KW, Woodward JG, Ryu S, Danziger LH. Bactericidal activity and postantibiotic effect of levofloxacin against anaerobes. Antimicrob Agents Chemother. 1999 Oct;43(10):2547-9. PubMed
• 14. Entenza JM, Vouillamoz J, Glauser MP, Moreillon P. Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1997 Aug;41(8):1662-7. PubMed
• 15. Matsuda S, Oh K, Hirayama H. Pharmacokinetic and clinical evaluation of levofloxacin in obstetrical and gynecological field. Jpn J Antibiot. 1992 Mar;45(3):285-92. PubMed
• 16. Saito I, Suzuki A, Saiko Y, Yokozawa M, Ono K, Miyata K, Miyamura R, Hamaya O, Kaneko K, Yamamoto T. Acute nongonococcal epididymitis--pharmacological and therapeutic aspects of levofloxacin. Hinyokika Kiyo. 1992 May;38(5):623-8. PubMed
• 17. Saito I, Suzuki A, Saiko Y, Yokozawa M, Ono K. Bacteriological and clinical studies on levofloxacin in male gonococcal urethritis. Hinyokika Kiyo. 1992 May;38(5):629-32. PubMed
• 18. Blazquez Garrido RM, Espinosa Parra FJ, Alemany Frances L, Ramos Guevara RM, Sanchez-Nieto JM, Segovia Hernandez M, Serrano Martinez JA, Huerta FH. Antimicrobial chemotherapy for Legionnaires disease. Clin Infect Dis. 2005 Mar 15;40(6):800-6. PubMed
• 19. Esposito S, Noviello S, Leone S, Ianniello F, Ascione T, Gaeta GB. Clinical efficacy and tolerability of levofloxacin in patients with liver disease: a prospective, non comparative, observational study. J Chemother. 2006 Feb;18(1):33-7. PubMed
• 20. Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother. 2001 Dec;35(12):1540-7. PubMed
• 21. Perry AC, Prpa B, Rouse MS, Piper KE, Hanssen AD, Steckelberg JM, Patel R. Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clin Orthop Relat Res. 2003 Sep;(414):95-100. PubMed
• 22. Lodise T, Graves J, Miller C, Mohr JF, Lomaestro B, Smith RP. Pharmacotherapy. 2007 Nov;27(11):1498-505.
• 23. Gisbert JP, Pérez-Aisa A, Bermejo F, et al. Second-line therapy with levofloxacin after failure of treatment to eradicate helicobacter pylori infection: time trends in a Spanish Multicenter Study of 1000 patients. J Clin Gastroenterol. 2013 Feb;47(2):130-5. PubMed
• 24. Hamamoto A, Kinosita K, Suyama N, Ishii Y, Kohno S. Shigella sonnei outbreak in Nagasaki. Kansenshogaku Zasshi. 2000 Dec;74(12):1004-11. PubMed
• 25. Eagye KJ, Kuti JL, Dowzicky M, Nicolau DP. Empiric therapy for secondary peritonitis. Clin Ther. 2007 May;29(5):889-99. PubMed
• 26. Shafiq Q, Mutgi A. Urine opiate screening: false-positive result with levofloxacin. CMAJ. 2010 Oct 19;182(15):1644-5 PubMed
• 27. Sarkar S, Chakraborty A, Sengupta M, et al. In vitro activity of levofloxacin against lower respiratory tract pathogens. J Basic Clin Pharm. 2015 Jun;6(3):89-93.
• 28. Bidell MR, Lodise TP. Fluoroquinolone-Associated Tendinopathy: Does Levofloxacin Pose the Greatest Risk? Pharmacotherapy. 2016 Jun;36(6):679-93. PubMed

Published: March 31, 2008
Last updated: February 01, 2017