Levofloxacin

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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 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. 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 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]). 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 (P. aeruginosa, combination therapy with an antipseudomonal β-lactam is advised. Modification of the dosage is required in patients with renal impairment (creatinine clearance C 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.