LevofloxacinEric Scholar University of Nebraska Medical Center, Omaha, USA

ã 2007 Elsevier Inc. All rights reserved.

Introduction

Levofloxacin is a third-generation fluoroquinolone that displays several advantages overearlier quinolones. It has enhanced antibacterial activity especially versus streptococci. Italso has a longer half-life in comparison to earlier quinolones, and has a lesser potentialfor central nervous system side effects and a lesser number of drug interactions. It isapproved for the treatment of urinary tract infections, chronic bronchitis, community-acquired pneumonia, skin and skin structure infections, and sinusitis.

NomenclatureName of the Clinical

Form

Levofloxacin

Related Names

Source: EMTREE

Levofloxacin; cravit; dr 3355; elequine; floxacin; hr355;

levaquin; rwj 25213; tavanic; dr3355; hr 355; quixin;

rwj25213

Chemical Names Levofloxacin is the S-(-) isomer of ofloxacin. It is(-)-(S)-9-fluoro-

2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-

7H-pyridol[1,2,3-de][1,4]benzoxazine-6-carboxylic

CAS Number 138199-71-0

Basic ChemistryChemical Structure

Structure

Comments While levofloxacin is a racemic mixture, the antibacterial activity

of the S-isomer is several fold higher than the R-isomer. Hence,

most of the antibacterial activity is due to the S-isomer.

Levofloxacin is a third-generation fluoroquinolone having

structural modifications that improve it properties as compared

to earlier quinolones. The enhanced streptococcal activity

results from modifications in the piperazine group at C-7 of the

quinolone nucleus. The addition of sterically bulky methyl

groups on this substituent improves gram-positive activity and

diminishes the potential for adverse central nervous system

effects and drug interactions Owens and Ambrose (2000).

Chemical Formula C18 H20 F N3 O4

Properties

Physical Properties Levofloxacin is composed of white to light yellow needles melting

at 226� C with decomposition. Levofloxacin forms stable

coordination complexes with metal ions.

1

Molecular Weight 361.371

Solubility The solubility of levofloxacin in water is essentially constant from

pH 0.6 to 5.8 (100 mg/ml). Above pH 5.8 solubility increases

rapidly, reaching a maximum of 272 mg/ml at pH 6.7. Above

this pH, its solubility decreases to aminimum of 50mg/ml at pH

6.9 Nichols (2000).

Ionization Constant

Value Salt Conditions Reference Comments

pKa 5.7 Dahloff (1998)

pKa 8.0 Dahloff (1998)

Human Pharmacokinetics

Levofloxacin is absorbed almost completely after oral administration. The oral and i.v.routes are considered interchangeable. It is excreted primarily unchanged in urine.Levofloxacin is fairly well distributed throughout the body Drugdex (2002).

Pharmacokinetic Properties

Value Units

Prep. andRoute ofAdmin. Reference Comments

Absorption Levofloxacin is very well-absorbed following oral administration.

Bioavailability 99 % p.o. Dahloff (

1998)

p.o. and i.v. routes are

considered

interchangeable.Distribution Levofloxacin is well-distributed throughout the body. Distribution to the lungs is

very good, while distribution to the central nervous system is only fair.

Volume ofDistribution

1.25 l/kg p.o. Product InformationLevaquin

(2002)

Plasma Protein

Binding

24–38 % p.o. Dahloff

(1998)Metabolism The metabolism of levofloxacin is minimal, with two inactive metabolites being

identified (desmethyllevofloxacin and an N-oxide).

Plasma Half-Life 4–8 hrs p.o. Dahloff

(1998)

Plasma half-life of

levofloxacin isincreased with

decreased renal

function, necessitating

a change of dose.Bio Half-Life

Clearance 96–142ml/min/

kg

p.o. Product Information

Levaquin(2002)

Routes ofElimination

Most of an administered dose is excreted through the kidney (61–87%) as the

parent compound.

Targets-Pharmacodynamics

Like other quinolones, levofloxacin is a bactericidal agent that acts by preventing DNAreplication. This occurs by inhibiting the enzyme DNA gyrase (topoisomerase II), which

Levofloxacin2

plays a vital role in uncoiling the DNA molecule when the two DNA strands need toseparate during mitosis. Quinolones bind simultaneously to the A subunit of topoisomer-ase II and to DN A. Norfloxacin also inhibits a related enzyme, topoisomerase IV, whichmay underlie its activity against gram-positive bacteria. With the newer quinolones likelevofloxacin there is a more balanced inhibition of the gyrase and topoisomerase IVenzymes Hooper (2000), Hooper (2001), Scholar and Pratt (2000).

Target Name(s):

DNA gyrase (bacterial topoisomerase II)Bacterial topoisomerase IV

Therapeutics

Levofloxacin is used for the treatment of a range of infections, including those in whichStreptococcus pneumonia is a potential pathogen. One of its most important attributes is itsefficacy against community-acquired pneumonia, which is similar to that of gatifloxacinand at least as good as the third-generation cephalosporins. Levofloxacin has also beenapproved for the treatment of both complicated and uncomplicated urinary tract infec-tions, skin and skin structure infections, and maxillary sinusitis. An ophthalmic solution isindicated for the treatment of bacterial conjunctivitis. Levofloxacin therapy can be startedwith, or changed to, the oral dosage form at the same dose and duration as soon asclinically appropriate Langtry and Lamb (1998), Hurst et al (2002), Medical Letter (1997),Product Information Levaquin (2002).

Indications

Value Units

Prep. andRoute ofAdmin. Reference Comments

Chronic BronchitisDosage 500 mg p.o. or i.v. every 24

hrs for 7 days

Product

Information

Levaquin (2002)Community-Acquired pneumoniaDosage 500 mg p.o. or i.v. every

24 hrs for 7–14days

Product

InformationLevaquin (2002)

PyelonephritisDosage 250 mg p.o. or i.v., every

24 hrs for 10days

Product

InformationLevaquin (2002)

SinusitisDosage 500 mg p.o. or i.v., every

24 hrs for 10–14days

Product

InformationLevaquin (2002)

Skin and Skin Structure Infections (uncomplicated)Dosage 500 mg p.o. or i.v., every

24 hrs for 7–10

days

ProductInformation

Levaquin (2002)

Includes abscesses,cellulitis, furuncles,

impetigo, pyoderma,

and wound infections.

Skin and Skin Structure Infections (complicated)Dosage 750 mg p.o. or i.v., every

24 hrs for 7–14

days

Product

Information

Levaquin (2002)

Includes surgical

incisions, bites, and

lacerations that have

Levofloxacin 3

become infected,

major abscesses, andinfected ulcers.

Urinary Tract Infections (complicated and uncomplicated)Dosage 250 mg p.o. or i.v., every

24 hrs for 3 days

(10 days for

complicated

infections)

ProductInformation

Levaquin (2002)

Uncomplicatedinfections include

those caused by E.coli,

Kebsiella pneumoniae,

and Staphlococcussaprophyticus.

Complicated infections

include those caused

by Enterococcusfaecalis, Enterobacter

cloacae, E.coli, K.

pneumoniae, Proteusmirabilis and

Pseudomonas

aeruginioa.

ConjunctivitisDosage 1–2 drops 0.5% ophthalmic

solution. Days

1and 2, every

2 hrs while awake(up to 8 times a

day); days 3–7,

1–2

drops every 4hrs while awake

(up to 4 times/

day)

Product

Information

Quixin (2000)

Infectious Diarrhea (prophylaxis)Dosage 500 mg p.o. every 24 hrs

for a maximum

of 3 weeks(traveler’s

diarrhea).

Drugdex (2002)

Infectious Diarrhea (treatment)Dosage 500 mg p.o., one time

dose for

traveler’s

diarrhea andevery 24 hrs

for 3 days for

severe diarrhea

Drugdex (2002)

Contraindications

Levofloxacin is contraindicated for individuals with a history of hypersensitivity to anyquinolone antibiotic. Its efficacy and safety have not been established in pregnant andlactating women. It should not be used in children or adolescents under eighteen years ofage because of the risk of cartilage damage and consequent growth impairment. Doseadjustments are required for those with impaired renal function due to decreased clear-ance of the drug. As a result of the central nervous system stimulant effects of fluoroqui-nolones, levofloxacin should be used with caution in patients with a history of epilepsy.

Levofloxacin4

Adverse Effects

Most adverse effects associated with the use of levofloxacin transient and mild tomoderate in severity. The most common are nausea (1.3%), diarrhea (1.1%), vaginitis(0.7%), pruritus (0.5%), abdominal pain, dizziness, flatulence, and rash. The overallincidence of adverse events is 6.2%, with less than 4% having to stop treatment. The i.v. administration of levofloxacin is associated with some local irritation. Levofloxacin,ofloxacin, and moxifloxacin have the lowest potential of the fluoroquinolones for inducingcentral nervous system adverse effects. Levofloxacin also has a low potential for photo-toxic reactions, and levofloxacin-associated tendonitis and/or tendon rupture is alsouncommon as are adverse cardiac and hepatic effects Hurst et al (2002), Carbon (2001).

Agent-Agent Interactions

Agent name Mode of Interaction

Antacids Antacids impair the absorption of levofloxacin. Antacids containing

magnesium, aluminum or sucralfate should not be taken within 2 hours

of levofloxacin administration Shiba et al (1992).

Multivitamins Products containing iron or zinc may impair absorption of levofloxacinand should not be taken within 2 hours of its administration.

Live typhoid vaccine Antibiotics that display activity against Salmonella typhi organisms may

interfere with the immunological response to the live typhoid vaccineProduct Information Vivotif (1997).

Didanosine Didanosine may reduce levofloxacin absorption by chelation Product

Information Levaquin (2002).

Nonsteroidalantiinflammatory agents

When levofloxacin is administered concurrently with nonsteroidal anti-inflammatory agents there is an Increased risk of seizures.

Bretylium When taken with levofloxacin, this agent has an additive effect on QT

prolongation Product Information Levaquin (2002).

Moricizine When taken with levofloxacin, this agent has an additive effect on QTprolongation Product Information Levaquin (2002).

Phenothiazines When taken with levofloxacin, this agent has an additive effect on QT

prolongation Product Information Levaquin (2002).Pirmenol When taken with levofloxacin, this agent has an additive effect on QT

prolongation Product Information Levaquin (2002).

Procainamide When taken with levofloxacin, this agent has an additive effect on QT

prolongation Product Information Levaquin (2002).Sotalol When taken with levofloxacin, this agent has an additive effect on QT

prolongation Product Information Levaquin (2002).

Lithium Concomitant administration of levofloxacin and lithium may cause acute

renal failure Takahashi et al (2000).

Pre-Clinical Research

Levofloxacin, like most quinolones, is very effective against gram-negative organisms. It ismore active than ofloxacin and less active than ciprofloxacin against most Enterobacter-iaceae and Pseudomonas aeruginosa. While levofloxacin is slightly more active againstBacteroides fragilis than ciprofloxacin, it has low activity against anaerobes. Levofloxacinis about twice as active as ciprofloxacin against penicillin-susceptible and-resistant Strep-tococcus pneumoniae, and 2–4 fold more active against methicillin-susceptible Staphlococcusaureus. It has variable activity against gram-positive anaerobes. Levofloxacin activity iscomparable to ofloxacin against M. tuberculosis. Langtry and Lamb (1998), Hurst et al(2002), Kucers et al (1997), Jacobs (1999).

Levofloxacin 5

Other Information – Web Sites

Micromedex general drug information: http://www.micromedex.com/General drug information: http://medscape.com/drugdb/search.aspFDA site, general drug information: http://www.fda.gov/cder/drug/default.htm

Journal Citations

Hurst, M., Lamb, H.M., Scott, L.J., Figgitt, D.P., 2002. Levofloxacin. An updated review of its use in thetreatment of bacterial infections. Drugs, 62, 2127–2167.

Langtry, H.D., Lamb, H.M., 1998. Levofloxacin. Its use in infections of the respiratory tract, skin, soft tissuesand urinary tract. Drugs, 56, 487–515.

Carbon, C., 2001. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy,47(Supp 3), 9–14.

Hooper, D.C., 2001. Mechanisms of action of antimicrobials: Focus on fluoroquinolones. Clin. InfectiousDiseases, 32(Supp 1), S9–S15.

Shiba, K., Sakai, O., Shimada, J., Okazaki, O., Aoki, H., Hakusui, H., 1992. Effects of antacids, ferroussulphate, and ranitidine on absorption of DR-3355 in humans. Antimicrob. Agents Chemother, 36,2270–2274.

Takahashi, H., Higuchi, H., Shimizu, T., 2000. Severe lithium toxicity induced by combined levofloxacinadministration. J. Clin. Psych., 61, 949–950.

Jacobs, M.R., 1999. Activity of quinolones against mycobacteria. Drugs, 58(Supp 2), 19–22.Owens, R.C., Ambrose, P.G., 2000. Clinical use of the fluoroquinolones. Med. Clin. N.A., 84, 1447–1469.Hooper, D.C., 2000. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin.

Infectious Diseases, 31(Suppl 2), S24–S28.

Book Citations

Scholar, E.M., Pratt, W., 2000. The Fluoroquinolones. The Antimicrobial Drugs, Edition 2, pp. 257–279,Oxford Univ. Press, NY, NY.

Dahloff, A., 1998. Quinolones. Schonfeld, H. (Ed.), Pharmacokinetics of Selected Antibacterial Agents, pp.85–108, Karger, N.Y., NY.

Drugdex, 2002. Micromedex (Online Version). Micromedex Inc., Englewood, CO.Kucers, A., Crowe, S.M., Grayson, M.L., Hoy, J.F., 1997. Levofloxacin. The Use of Antibiotics. A Clinical

Review of Antibacterial, Antifungal and Antiviral Drugs, Edition 5, pp. 1158–1163, ButterworthHeinemann, Oxford, England.

Medical Letter, 1997. Sparfloxacin and Levofloxacin, Edition 39(Issue), pp. 41–43, Medical Letter.Product Information Levaquin 2002 Product Info LevaquinW, levofloxacin. Ortho-McNeil Pharmaceutical,

Inc., Raritan, NJ.Product Information Quixin 2000 Product Info Quixin, levofloxacin 0.5% ophthalmic solution. Santen Inc.,

Napa, CA.Product Information Vivotif 1997 Product Information: VivtifW Berna vaccine, typhoid vaccine live oral ty21a.

Berna Products Corp. (Eon Labs), Coral Gables, FL.Nichols, W.K., 2000. Anti-infectives. Gennaro, A.R. (Ed.), Remington: The science and practice of

pharmacy, Edition 20, pp. 1507–1561, Lippincott Williams and Wilkins, Philadelphia, PA.

Further Reading

The Antimicrobial Drugs, In E. C. Scholar and W. Pratt, Edition 2, Oxford Univ. Press, 2000Goodman and Gilman, The Pharmacological Basis of Therapeutics, In J. G. Hardman and L. E. Limbird

(eds.), Edition 10, McGraw-Hill, 2001Kucers, A., Crowe, S.M., Grayson, M. L. and Hoy, J.F., The Use of Antibiotics, Butterworth-Heineman,

1997

Levofloxacin6