, Volume 63, Issue 24, pp 2769-2802

Levofloxacin

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Summary

Abstract

Levofloxacin (Levaquin®) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. It is active against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to levofloxacin is <1% overall in the US.

A number of randomised comparative trials in the US have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. Sequential intravenous to oral levofloxacin 750mg once daily for 7–14 days was as effective in the treatment of nosocomial pneumonia as intravenous imipenem/cilastatin 500–1000mg every 6–8 hours followed by oral ciprofloxacin 750mg twice daily in one study. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once daily for 7–14 days achieved clinical and bacteriological response rates similar to those with comparator agents, including amoxicillin/clavulanic acid, clarithromycin, azithromycin, ceftriaxone and/or cefuroxime axetil and gatifloxacin. A recent study indicates that intravenous or oral levofloxacin 750mg once daily for 5 days is as effective as 500mg once daily for 10 days, in the treatment of mild to severe CAP. Exacerbations of chronic bronchitis and acute maxillary sinusitis respond well to treatment with oral levofloxacin 500mg once daily for 7 and 10–14 days, respectively.

Oral levofloxacin was as effective as ofloxacin in uncomplicated urinary tract infections and ciprofloxacin or lomefloxacin in complicated urinary tract infections. In men with chronic bacterial prostatitis treated for 28 days, oral levofloxacin 500mg once daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500mg twice daily. Uncomplicated skin infections responded well to oral levofloxacin 500mg once daily for 7–10 days, while in complicated skin infections intravenous and/or oral levofloxacin 750mg for 7–14 days was at least as effective as intravenous ticarcillin/clavulanic acid (± switch to oral amoxicillin/clavulanic acid) administered for the same duration.

Levofloxacin is generally well tolerated, with the most frequently reported adverse events being nausea and diarrhoea; in comparison with some other quinolones it has a low photosensitising potential and clinically significant cardiac and hepatic adverse events are rare.

Conclusion: Levofloxacin is a broad-spectrum antibacterial agent with activity against a range of Gram-positive and Gram-negative bacteria and atypical organisms. It provides clinical and bacteriological efficacy in a range of infections, including those caused by both penicillin-susceptible and -resistant strains of S. pneumoniae. Levofloxacin is well tolerated, and is associated with few of the phototoxic, cardiac or hepatic adverse events seen with some other quinolones. It also has a pharmacokinetic profile that is compatible with once-daily administration and allows for sequential intravenous to oral therapy. The recent approvals in the US for use in the treatment of nosocomial pneumonia and chronic bacterial prostatitis, and the introduction of a short-course, high-dose regimen for use in CAP, further extend the role of levofloxacin in treating bacterial infections.

Pharmacodynamic Properties

Levofloxacin is the L-isomer of the racemate ofloxacin. It inhibits bacterial DNA gyrase and topoisomerase IV. Levofloxacin has a broad spectrum of activity against Gram-positive and Gram-negative aerobic bacteria and atypical bacteria, but limited activity against most anaerobic bacteria.

Levofloxacin is active against Streptococcus pneumoniae (including penicillin-resistant strains [MIC value for penicillin ≥2 mg/L]) and methicillin-susceptible Staphylococcus aureus, with minimum concentrations required to inhibit the growth of 90% of strains (MIC90) in the range 1.0–2.0 mg/L and 0.25–0.5 mg/ L, respectively. The percentages of Gram-positive clinical isolates that were susceptible to levofloxacin and gatifloxacin were similar, but were higher with levofloxacin than ciprofloxacin. Levofloxacin has only limited in vitro activity against enterococci; however, it is indicated in infections caused by susceptible strains of E. faecalis.

Levofloxacin is highly active against Haemophilus influenzae (MIC90 0.008–0.12 mg/L), Moraxella catarrhalis (MIC90 ≤0.03–0.06 mg/L) and also shows activity against the Enterobacteriaceae (MIC90 ≤2.0 mg/L for most isolates). The susceptibility rates of Pseudomonas aeruginosa to levofloxacin were 62–74% compared with 63–80% for ciprofloxacin, in studies performed in North America. Levofloxacin also shows good activity against the atypical respiratory pathogens Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella spp. (MIC90 ≤0.5, 1.0 and 0.03 mg/L, respectively).

Surveillance programmes in the US have found that resistance to levofloxacin among respiratory pathogens, including S. pneumoniae, remains low overall (≤1%). The activity of levofloxacin is concentration-dependent, and area under the plasma concentration-time curve (AUC)/MIC ratios of >100–125 and >30 are predictors of clinical and bacteriological efficacy against Gram-negative bacteria and S. pneumoniae, respectively. In patients receiving a once-daily dosage of oral levofloxacin 500mg, an AUC/MIC ratio >30 for S. pneumoniae is achieved 99% of the time. Levofloxacin shows a postantibiotic effect against a range of bacteria.

Pharmacokinetic Properties

Levofloxacin is rapidly absorbed after oral administration. The absolute bioavailability is approximately 99% and its pharmacokinetics are linear over the dosage range 500–1000mg once daily for multiple-dose administration. The oral and intravenous routes are considered interchangeable. It has low plasma protein binding (24–38%) and a volume of distribution of 76–102L. Tissue distribution is extensive, with concentrations in most tissues (including the lung, prostate gland and skin) exceeding those in plasma and being many times higher than the MICs of common pathogenic bacteria at these sites. The concentrations of levofloxacin in lung tissue homogenate, epithelial lining fluid and alveolar macrophages are up to 5-, 3- and 23-fold greater than those in plasma, and the prostate/plasma penetration ratio is up to 4.

Levofloxacin undergoes only limited metabolism and the main route of excretion is through the kidneys, with 64–102% of a dose being recovered unchanged in the urine. The mean terminal elimination half-life is approximately 6–9 hours. Clearance of levofloxacin is reduced in renal impairment and dosage modifications are necessary for patients with creatinine clearance <50 mL/min.

The pharmacokinetics of levofloxacin are not significantly altered by age, sex or in patients with HIV infection. Compared with those in healthy volunteers, levofloxacin peak plasma concentration and AUC values increased by approximately 10–30% in patients with community-acquired bacterial infections. The absorption of levofloxacin is reduced by concurrent administration of magnesium-or aluminium-containing antacids, sucralfate, iron or zinc preparations. No significant interactions between levofloxacin and theophylline or warfarin were observed in healthy volunteers; however, several case reports have suggested levofloxacin may reduce the metabolism and/or clearance of these agents in certain patients. No clinically significant interactions have been reported with cimetidine, ranitidine, probenecid, cyclosporin, digoxin, zidovudine or nelfinavir.

Therapeutic Efficacy

Randomised, comparative trials have confirmed the efficacy of oral and/or intravenous levofloxacin in the treatment of adults with infections of the respiratory tract, genitourinary tract, skin and skin structures using once-daily dosages of 250, 500 or 750mg depending on the indication. Treatment duration varied for different indications. Sequential intravenous to oral therapy has been used successfully in patients with pneumonia or complicated skin infections.

Respiratory tract infections: In a study in patients with nosocomial pneumonia, 7–15 days of therapy with sequential intravenous and oral levofloxacin 750mg once daily was as effective as intravenous imipenem/cilastatin 500–1000mg every 6–8 hours followed by oral ciprofloxacin 750mg twice daily. Clinical and bacteriological response rates were 58% and 67% in levofloxacin recipients and were both 61% in patients receiving the comparator. Most patients with P. aeruginosa infection received adjunctive therapy with ceftazidime or piperacillin/tazobactam (levofloxacin group) or an aminoglycoside (comparator regimen); clinical and bacteriological response rates were 65% and 59% with the levofloxacin regimen and 41% and 29% with the comparator.

Several well-designed comparative trials of the treatment of mild to severe community-acquired pneumonia (CAP) with intravenous and/or oral levofloxacin 500mg once daily for 7–14 days have been performed. In these studies clinical and bacteriological response rates were similar in recipients of levofloxacin (86–96% and 85–98%) and the comparator (83–96% and 75–98%). Comparators included amoxicillin/clavulanic acid, clarithromycin, gatifloxacin, ceftriaxone and/or cefuroxime axetil, azithromycin (plus ceftriaxone) or a sequential regimen of ceftriaxone plus erythromycin followed by amoxicillin/clavulanic acid plus clarithromycin. Levofloxacin was effective against CAP caused by common respiratory pathogens such as S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae and Legionella spp.

Data from a recent study indicate that levofloxacin 750mg once daily for 5 days is as effective as levofloxacin 500mg once daily for 10 days in the treatment of patients with mild to severe CAP (oral or intravenous administration permissible with both regimens).

Seven days’ treatment with oral levofloxacin 500mg once daily achieved clinical response rates of 83–94% in patients with acute exacerbations of chronic bronchitis (AECB) compared with 80–93% of patients receiving comparators (cefuroxime axetil, clarithromycin, azithromycin or moxifloxacin). Bacteriological response rates were 68–96% for levofloxacin and 48–96% for the comparator groups.

In patients with acute maxillary sinusitis treatment for 10–14 days with oral levofloxacin 500mg once daily was as effective as oral amoxicillin/clavulanic acid 500mg three times daily or oral clarithromycin 500mg twice daily. Clinical response rates were 88–96% for levofloxacin and 87–94% for the comparator regimens. Bacteriological efficacy was not assessed in these trials.

Genitourinary tract infections: In urinary tract infections clinical and bacteriological response rates for oral levofloxacin ranged from 93–98% and 94–96% and those for comparator regimens from 89–97% and 92–94%. A 3-day course of levofloxacin 250mg once daily was as effective as ofloxacin 200mg twice daily in patients with uncomplicated urinary tract infections. Levofloxacin 250mg once daily for 7–10 days was as effective as ciprofloxacin 500mg twice daily for 10 days or lomefloxacin 400mg once daily for 7–10 days in patients with acute pyelonephritis and as effective as lomefloxacin 400mg once daily for 14 days in patients with complicated urinary tract infections.

In men with chronic bacterial prostatitis a 28-day course of oral levofloxacin 500mg once daily provided similar efficacy to oral ciprofloxacin 500mg twice daily administered for the same duration. Clinical response rates were 75% and 73% and bacteriological response rates 75% and 77% in levofloxacin and ciprofloxacin recipients. In patients infected with Escherichia coli bacteriological response rates were 93% with levofloxacin and 82% with ciprofloxacin.

Skin and skin structure infections: In three randomised, comparative studies of levofloxacin in uncomplicated skin and skin structure infections, oral levofloxacin 500mg was as effective as ciprofloxacin 500mg twice daily or gatifloxacin 400mg once daily (all administered for 7–10 days). In a trial involving patients with complicated infections, clinical response rates were similar with levofloxacin 750mg once daily (oral or intravenous administration for 7–14 days) and intravenous ticarcillin/clavulanic acid (3.1g every 4–6 hours with the option to switch to oral amoxicillin/clavulanic acid 875mg twice daily). The bacteriological response rate was higher with levofloxacin than the comparator regimen (84% vs 71% [95% CI for between-group difference; −24.3, −0.2]).

Tolerability

Levofloxacin is generally well tolerated. The majority of adverse events are transient and of mild to moderate severity. During phase III clinical trials in North America involving oral and/or intravenous dosages up to 750mg once daily, the incidence of adverse events considered related to levofloxacin was 6.3%, with the most frequently reported events being nausea (1.3%), diarrhoea, vaginitis, abdominal pain and insomnia (all ≤1%). Treatment was discontinued in 4.0% of patients because of adverse events. The type of adverse events seen with 750mg daily is similar to that with lower dosages.

Levofloxacin was as well tolerated as ciprofloxacin, ofloxacin, gatifloxacin, lomefloxacin and moxifloxacin in comparative clinical trials. It was also at least as well tolerated as a range of agents from other antibacterial classes used as comparators. In patients with sinusitis oral levofloxacin was associated with a significantly lower incidence of adverse events than oral amoxicillin/clavulanic acid or clarithromycin.

Levofloxacin has a low potential for causing phototoxic reactions (incidence 0.03%). Tendon disorders, severe liver toxicity and symptomatic hypoglycaemia or hyperglycaemia are rare with levofloxacin, as are clinically significant cardiac adverse events. Although prolongation of the QTC interval has been reported, few cases of torsade de pointes have occurred (<1 report per million prescriptions in the US).

Dosage and Administration

Levofloxacin is available as intravenous and oral preparations and patients may be switched between formulations without altering the dosage. In the US all dosage regimens are based on once-daily administration.

Levofloxacin 500mg once daily is the current recommended dosage for patients with AECB (administered for 7 days), acute maxillary sinusitis (10–14 days) and uncomplicated skin and skin structure infections (7–10 days). In patients with CAP, dosages of either 500mg once daily for 7–14 days or 750mg once daily for 5 days are recommended. For complicated and uncomplicated urinary tract infections 250mg once daily for 10 days or 3 days, respectively, should be used. A dosage of 750mg once daily for 7–14 days is recommended for patients with nosocomial pneumonia or complicated skin and skin structure infections. In patients with chronic bacterial prostatitis the recommended dosage is 500mg once daily for 28 days. Levofloxacin is approved for the treatment of infections caused by susceptible strains of common pathogens associated with each condition. In the case of nosocomial pneumonia involving P. aeruginosa, combination therapy with an antipseudomonal β-lactam is advised.

Modification of the dosage is required in patients with renal impairment (creatinine clearance <50 mL/min). Levofloxacin is contraindicated in patients aged under 18 years and women who are pregnant or breastfeeding. Caution should be used in those patients with risk factors for QTC prolongation or disorders that predispose them to seizures, and in diabetic patients receiving concomitant antihyperglycaemic agents. Caution is also required when administering levofloxacin concurrently with theophylline, warfarin and nonsteroidal anti-inflammatory drugs. Antacids and sucralfate should not be taken within 2 hours of levofloxacin adminstration.

Various sections of the manuscript reviewed by: J.M. Blondeau, Department of Clinical Microbiology, Royal University Hospital, Saskatoon, Saskatchewan, Canada; D.N. Fish, Department of Pharmacy Practice, Colorado Health Sciences Center, Denver, Colorado, USA; D.R.P. Guay, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA; M.P. Habib, Pulmonary Section, Veterans Affairs Medical Center, Tucson, Arizona, USA; P.B. Iannini, Department of Medicine, Danbury Hospital, Danbury, Connecticut, USA; S.L. Preston, Clinical Pharmacology Studies Unit, Albany Medical College, Albany, New York, USA; J.A. Ramirez, Department of Medicine, University of Louisville, Louisville, Kentucky, USA; K.A. Rodvold, Department of Pharmacy Practice, University of Illinois, Chicago, Illinois, USA.

Data Selection

Sources: Medical literature published in any language since 1998 on levofloxacin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘levofloxacin’. EMBASE search terms were ‘levofloxacin’ or ‘DR 3355’. AdisBase search terms were ‘levofloxacin’ or ‘DR-3355’. Searches were last updated 10 November 2003.
Selection: Studies in patients with bacterial infections who received levofloxacin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Acute exacerbations of chronic bronchitis, acute sinusitis, antibacterials, chronic bacterial prostatitis, community-acquired pneumonia, genitourinary tract infections, levofloxacin, nosocomial pneumonia, pharmacodynamics, pharmacokinetics, respiratory tract infections, skin and skin structure infections, therapeutic use, urinary tract infections.