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Drugs

, Volume 56, Issue 3, pp 487–515 | Cite as

Levofloxacin

Its Use in Infections of the Respiratory Tract, Skin, Soft Tissues and Urinary Tract
  • Heather D. Langtry
  • Harriet M. Lamb
Adis Drug Evaluation

Summary

Abstract

Levofloxacin, the optically pure levorotatory isomer of ofloxacin, is a fluoro-quinolone antibacterial agent. Like other fluoroquinolones, it acts on bacterial topoisomerase and has activity against a broad range of Gram-positive and Gram-negative organisms. Levofloxacin also appears to have improved activity against Streptococcus pneumoniae compared with ciprofloxacin or ofloxacin. Levofloxacin distributes well and achieves high levels in excess of plasma concentrations in many tissues (e.g. lung, skin, prostate). High oral bioavailability allows switching from intravenous to oral therapy without dosage adjustment.

In patients with mild to severe community-acquired pneumonia receiving treatment for 7 to 14 days, oral levofloxacin was similar in efficacy to amoxicillin/clavulanic acid, and intravenous and/or oral levofloxacin was superior to intravenous ceftriaxone and/or oral cefuroxime axetil. With levofloxacin use, clinical success (clinical cure or improvement) rates were 87 to 96% and bacteriological eradication rates were 87 to 100%. In the 5-to 10-day treatment of acute exacerbations of chronic bronchitis, oral levofloxacin was similar in efficacy to oral cefuroxime axetil or cefaclor. Levofloxacin resulted in clinical success in 78 to 94.6% of patients and bacteriological eradication in 77 to 97%. Oral levofloxacin was also similar in efficacy to amoxicillin/clavulanic acid or oral clarithromycin in patients with acute maxillary sinusitis treated for 7 to 14 days.

Equivalence between 7-to 10-day therapy with oral levofloxacin and ciprofloxacin was seen in patients with uncomplicated skin and soft tissue infections. Clinical success was seen in 97.8 and 96.1% of levofloxacin recipients and bacteriological eradication in 97.5 and 93.2%. Complicated urinary tract infections, including pyelonephritis, responded similarly well to oral levofloxacin or ciprofloxacin for 10 days or lomefloxacin for 14 days. Clinical success and bacteriological eradication rates with levofloxacin occurred in 92 to 93.3% and 93.6 to 94.7% of patients.

Conclusions: Levofloxacin can be administered in a once-daily regimen as an alternative to other fluoroquinolones in the treatment of infections of the urinary tract, skin and soft tissues. Its more interesting use is as an alternative to established treatments of respiratory tract infections. S. pneumoniae appears to be more susceptible to levofloxacin than to ciprofloxacin or ofloxacin. Other newer fluoroquinolone agents that also have enhanced in vitro antipneumococcal activity may not share the well established tolerability profile of levofloxacin, which also appears to improve on that of some older fluoroquinolones.

Pharmacology

Levofloxacin has a broad range of activity against Gram-positive and Gram-negative, atypical and intracellular bacteria and is moderately active against anaerobes.

Methicillin-or oxacillin-susceptible staphylococci (including Staphylococcus aureus, S. saprophyticus and S. epidermidis) are also susceptible to levofloxacin. Levofloxacin is similar in activity against methicillin-or oxacillin-susceptible S. epidermidis to ofloxacin or ciprofloxacin, but less active against these strains than sparfloxacin or trovafloxacin. However, staphylococci that were resistant to methicillin or oxacillin were also resistant to levofloxacin, ciprofloxacin, ofloxacin and sparfloxacin.

Streptococcus pneumoniae that were susceptible, intermediately susceptible or resistant to penicillin and S. pyogenes were all susceptible to levofloxacin. When evaluated on the basis of a 2-dilution difference between agents, the inhibitory activity of levofloxacin against S. pneumoniae appeared to be similar to that of ofloxacin, ciprofloxacin and sparfloxacin, but less than that of trovafloxacin. However, at optimum bactericidal concentrations, levofloxacin is more active against S. pneumoniae than ofloxacin, ciprofloxacin or sparfloxacin. Further, S. pneumoniae strains had minimum inhibitory concentrations below National Committee for Clinical Laboratory Standards recommended susceptibility breakpoints for levofloxacin but not for ofloxacin.

Most enterococci and Enterobacteriaceae were susceptible to levofloxacin, including Enterococcus faecalis, Citrobacter freundii, C. diversus, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Morganella morganii, Proteus mirabilis and P. vulgaris. However, Providencia stuartii and P. rettgeri were resistant or had intermediate susceptibility; most Serratia spp. were only intermediately susceptible. E.coli and K. pneumoniae with cephalosporin resistance were also resistant to levofloxacin. Resistance of these organisms to other fluoroquinolones tested was also evident.

P. aeruginosa is only moderately susceptible to levofloxacin or other fluoroquinolones, and nonpseudomonas nonfermenters also do not appear to be susceptible to levofloxacin. Anaerobes vary in susceptibility to levofloxacin, with Bacteroides fragilis strains ranging from susceptible to resistant, although Clos-tridium perfringens is susceptible. In contrast, Gram-negative bacteria, such as Haemophilus influenzae, Moraxella catarrhalis and Legionella pneumophila, and ‘atypical’ pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, are susceptible to levofloxacin and other fluoroquinolones.

Oral levofloxacin is 100% systemically available and its bioavailability is not affected by meals. Intravenous or oral routes of administration may be used interchangeably. The drug has linear pharmacokinetics over 50 to 1000mg doses. Steady state is reached after ≈3 days; the elimination half-life is 6.8 to 8.9 hours. ≈80% of a dose is found in the urine as unchanged drug and ≤5% as inactive N-oxide and demethyl metabolites within 24 hours. The active drug distributes well to target body tissues and fluids in the respiratory tract, skin, urine and prostate and its uptake by cells makes it suitable for use against intracellular pathogens. Dosages should be reduced in patients with renal failure, in whom levofloxacin elimination is decreased. Old age and gender do not affect levofloxacin pharmacokinetics.

Clinical Use

Published and unpublished studies support the use of levofloxacin in patients with community-acquired pneumonia (CAP), acute maxillary sinusitis, acute exacerbations of chronic bronchitis (AECB), uncomplicated skin and soft tissue infections (SSTIs) or complicated urinary tract infections (UTIs, including acute pyelonephritis). Its efficacy has been demonstrated in a small number of comparative studies in each of these indications, supplemented by noncomparative trials in some indications. A total of >5600 patients in these trials were evaluated on at least 1 of the major outcome indicators: clinical cure rate, clinical success rate (clinical cure or improvement) and bacteriological eradication rate.

In patients with mild to severe CAP, oral levofloxacin 500 mg/day produced a similar clinical success rate (95.2%) to that seen with amoxicillin/clavulanic acid 1500/375 mg/day (95.3%) when these regimens were administered for 7 to 10 days in a double-blind study. In contrast, intravenous or oral levofloxacin 500 mg/day resulted in a statistically superior clinical success rate (96%) to that seen with the combined results of intravenous ceftriaxone 1 or 2 g/day or oral cefur-oxime axetil 1000 mg/day (90%) after 7 to 14 days' treatment of patients with mild to severe CAP in a single-blind study. Patients with moderate to severe CAP achieved clinical cure and success rates of 65 and 87% after levofloxacin 500mg twice daily orally or intravenously and 55 and 86% after intravenous ceftriaxone 4000mg once daily. Bacteriological eradication was seen in 87 to 100% of patients receiving levofloxacin and in similar proportions of those receiving comparator agents (amoxicillin/clavulanic acid 97.5%; ceftriaxone and/or cefuroxime axetil 87%).

In AECB, oral levofloxacin 250 or 500mg once daily for 7 to 10 days was similar in efficacy to oral cefuroxime axetil 250mg twice daily for the same duration. Levofloxacin 500mg once daily was also equivalent in efficacy to cefuroxime axetil 250mg twice daily or cefaclor 250mg 3 times daily when given in shorter courses than its comparators (5 to 7 days vs 10 or 7 to 10 days). Clinical success and bacteriological eradication rates were similar between patients receiving levofloxacin (78 to 94.6% and 77 to 97%, respectively) and those receiving cefuroxime axetil (66 and 92.6%, and 68 and 95%, respectively) or cefaclor (92 and 87%, respectively).

When used for 10 to 14 days to treat radiologically confirmed acute maxillary sinusitis, oral levofloxacin 500mg once daily was similar in efficacy to oral amoxicillin/clavulanic acid 500mg/125mg 3 times daily or oral clarithromycin 500mg twice daily. Clinical cure rates with levofloxacin ranged from 58.3 to 63.2% (and were similar to that for amoxicillin/clavulanic acid, 58.6%). Bacteriological eradication rates in 2 noncomparative trials were 88.6 and 92%. Levofloxacin clinical success rates of 88.3 to 96% were also similar to those of amoxicillin/clavulanic acid (87.3%) and clarithromycin (93.3%).

When per-pathogen eradication rates were examined for respiratory pathogens detected in clinical trials, eradication rates with levofloxacin against S. aureus, M. catarrhalis, E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, C. pneumoniae, M. pneumoniae and L. pneumophila were very good to excellent and ranged from 89.1 to 100%. A lower eradication rate was seen for levofloxacin against P. aeruginosa (63%).

In patients with uncomplicated skin and soft tissue infections, oral levofloxaein 500mg once daily for 7 to 10 days was similar in efficacy to oral ciprofloxacin 500mg twice daily. Clinical success occurred in 96.1 and 97.8% of levofloxacin recipients and 93.5 and 94.3% of ciprofloxacin recipients, whereas bacteriological eradication rates were 93.2 and 97.5% for levofloxacin and 88.8 and 91.7% for ciprofloxacin. Comparisons between levofloxacin and either ciprofloxacin or lomefloxacin in patients with complicated urinary tract infections also resulted in similar efficacy between these groups. Levofloxacin 250 mg/day for 10 days produced clinical success in 92 and 92.9% of patients and bacteriological eradications in 93.6 and 95.3%. The clinical success rates were 88% after ciprofloxacin 250mg twice daily for 10 days and 88.5% after lomefloxacin 400mg once daily for 14 days; bacteriological eradication rates were 97.5 and 92.1%, respectively.

Tolerability

Adverse events associated with levofloxacin are usually transient, mild to moderate in severity and generally similar to that of other fluoroquinolone agents. Nausea (1.1 to 3%) and diarrhoea (1.1. to 2.89%), are among the more common events seen after oral or intravenous use of the drug in clinical trials. Phlebitis and reddening at the infusion site may also occur with intravenous levofloxacin. According to an overview, the overall incidence of drug-related adverse events appears to be lower with levofloxacin (3.3%) than with the other fluoroquinolones ofloxacin (4.3%), ciprofloxacin (5.5 to 10.2%) or pefloxacin (8%).

Serious adverse events include rare cases of pseudomembranous colitis and haemolytic anaemia. The safety and efficacy of levofloxacin in children and adolescents below the age of 18 years have not been established. Fluoroquinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. Photosensitisation with levofloxacin is similar in incidence to that seen with ofloxacin and ciprofloxacin. CNS events such as seizures may be related to concurrent use of theophylline or nonsteroidal anti-inflammatory drugs and may occur less frequently with levofloxacin than ofloxacin.

Sucralfate and antacids that contain di-or trivalent cations may chelate with levofloxacin and thus limit its absorption. Cimetidine and probenecid may compete with levofloxacin for renal tubular secretion and thus prolong the half-life of levofloxacin. Both hyper-and hypoglycaemia have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent.

Dosage and Administration

Levofloxacin may be used to treat acute maxillary sinusitis, AECB, CAP, SSTIs or complicated UTIs (including pyelonephritis). The drug is available in both oral and intravenous dosage forms. European and US dosage guidelines for levofloxacin differ.

In the US, levofloxacin may be administered orally or intravenously for all indications. The usual dose of 500mg once daily may be used for acute sinusitis (administered for 10 to 14 days), AECB (7 days), CAP (7 to 14 days) and uncomplicated SSTIs (7 to 10 days). Levofloxacin 250mg once daily should be administered for 10 days to treat complicated UTIs or pyelonephritis.

In Europe, oral levofloxacin 500mg once daily is used to treat sinusitis (duration 10 to 14 days) and 250 to 500mg once daily is used for AECB (7 to 10 days). In patients with CAP, intravenous or oral levofloxacin 500mg once or twice daily is administered for 7 to 14 days. Levofloxacin 250mg once daily orally or intravenously may be used for 7 to 10 days in patients with complicated UTIs or pyelonephritis, but higher intravenous dosages may be considered for patients with severe disease. A 250mg once-daily or 500mg once-or twice-daily dosage of oral levofloxacin may be administered for 7 to 14 days for SSTIs; if intravenous levofloxacin is used, 500mg twice daily is recommended.

Use of levofloxacin is contraindicated in children, adolescents, pregnant or breastfeeding women, and patients with epilepsy or a history of tendon disorders related to fluoroquinolones. Caution is warranted when patients with renal impairment receive levofloxacin concomitantly with probenecid or cimetidine; levofloxacin dosages should be adjusted according to creatinine clearance. Administration of sucralfate, iron salts or antacids containing magnesium or aluminium should be separated from levofloxacin administration by 2 hours.

Keywords

Ofloxacin Levofloxacin Antimicrob Agent Eradication Rate Sparfloxacin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, North Shore, Auckland 10New Zealand

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