, Volume 68, Issue 4, pp 535-565
Date: 17 Sep 2012

Levofloxacin

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Summary

Abstract

Levofloxacin (Levaquin®) is a fluoroquinolone antibacterial that is the L-isomer of ofloxacin. A high-dose (750 mg) short-course (5 days) of once-daily levofloxacin is approved for use in the US in the treatment of community-acquired pneumonia (CAP), acute bacterial sinusitis (ABS), complicated urinary tract infections (UTI) and acute pyelonephritis (AP).

The broad spectrum antibacterial profile of levofloxacin means that monotherapy is often a possibility in patients with CAP at times when other agents may require combination therapy, although levofloxacin can be used in combination therapy when necessary. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent bactericidal activity and may reduce the potential for resistance to emerge. In addition, this regimen lends itself to better compliance because of the shorter duration of treatment and the convenient once-daily administration schedule.

Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation; importantly, patients can transition between the formulations, which results in more options in regards to the treatment regimen and the potential for patients with varying degrees of illness to be treated. Levofloxacin has good tissue penetration and an adequate concentration can be maintained in the urinary tract to treat uropathogens.

Levofloxacin is generally well tolerated and has good efficacy in the treatment of patients with CAP, ABS, complicated UTI and AP. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP, ABS and UTIs is well established, and the high-dose, short-course levofloxacin regimen has been shown to be noninferior to the 10-day regimen in CAP and ABS, and to have a similar tolerability profile. Similarly, the high-dose, short-course levofloxacin regimen is noninferior to ciprofloxacin in patients with complicated UTI or AP. Thus, levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens; however, its use should be considered carefully so that the potential for resistance selection can be minimized and its usefulness in severe infections and against a range of penicillin- and macrolide-resistant pathogens can be maintained.

Pharmacodynamic Properties

Levofloxacin is the synthetic L-isomer of the racemic quinolone ofloxacin. It interferes with critical processes in the bacterial cell, such as DNA replication, transcription, repair and recombination, by inhibiting type II topoisomerases. Levofloxacin is active against a broad range of Gram-positive, Gram-negative and atypical bacteria that may be causative pathogens in community-acquired and nosocomial infections.

In general, levofloxacin shows good in vitro activity against clinically-relevant Gram-positive, -negative and atypical organisms. Levofloxacin is active against the Gram-positive penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, the Gram-negative species Enterobacter cloacae and Proteus mirabilis, and the atypical organisms Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae, with minimum concentrations required to inhibit the growth of 90% of strains (MIC90) of ≤2 mg/L. Levofloxacin is highly active against the Gram-negative species Haemophilus influenzae, H. parainfluenzae and Moraxella catarrhalis (MIC90 of ≤0.06 mg/L), including β-lactamase positive strains of H. influenzae and M. catarrhalis. The activity of levofloxacin against Gram-positive meticillin/oxacillin-susceptible Staphylococcus aureus is slightly reduced, with the MIC90 (≤4 mg/L) in the susceptible to intermediate range, and the activity of levofloxacin against the Gram-negative Escherichia coli (MIC90 ≤0.06 to >8 mg/L) and Pseudomonas aeruginosa (MIC90 0.5–64 mg/L) is variable.

Rates of S. pneumoniae resistance to levofloxacin have remained ≤1% in surveillance programmes undertaken in the US, Canada and worldwide; in penicillin-resistant isolates of S. pneumoniae, the rate of resistance to levofloxacin was ≤2.7%. Recent data suggest that the rate of levofloxacin resistance in S. pneumoniae in the US has decreased between 2004 and 2006. Levofloxacin resistance has not been identified in H. influenzae or M. catarrhalis in surveillance studies conducted up to 2005, but it has been identified in E. coli, P. aeruginosa and S. aureus.

As the activity of levofloxacin is concentration dependent, the most common predictor of microbiological and clinical efficacy is the area under the plasma concentration-time curve (AUC): MIC ratio. A ratio of >30 was used in some studies to predict in vivo activity, particularly against S. pneumoniae, but a higher ratio (>100) is suggested as being predictive of a bactericidal effect and thus reducing the potential of first-step mutations occurring. In simulated pharmacodynamic analyses of levofloxacin 750 mg, the probability of an AUC: MIC target of ≥30 being attained in the plasma was ≥97%.

Pharmacokinetic Properties

Following oral administration, levofloxacin is rapidly absorbed and maximum plasma concentrations are attained in 1–2 hours. The absolute bioavailability of levofloxacin is ≈99% and the oral solution or tablet formulations and intravenous formulation are bioequivalent. Plasma protein binding is low (≤38%). Levofloxacin is distributed throughout the body and the concentration in other tissues (e.g. epithelial lining fluid, alveolar cells or macrophages, paranasal sinuses mucosa and urine) can exceed that in the plasma 2–4 hours after administration.

The pharmacokinetics of levofloxacin are not affected by age, gender, race, HIV status or the presence of a serious community-acquired bacterial infection. However, gastrointestinal absorption of the drug can be reduced by magnesium- or aluminium-containing antacids, metal cations, such as iron and vitamin preparations with zinc, as well as sucralfate. The concomitant use of levofloxacin with a range of other drugs has not resulted in any clinically significant effects in a small number of formal drug interaction studies. Clinically significant effects, such as symptomatic hyperglycaemia and hypoglycaemia, have been reported with levofloxacin, usually in patients with diabetes mellitus receiving concomitant hypoglycaemic agents/insulin. Postmarketing experience includes reports that levofloxacin enhances the effects of warfarin.

Therapeutic Efficacy

The efficacy of oral and/or intravenous levofloxacin 750 mg once daily for 5 days has been established in randomized, well designed trials in adults with CAP, ABS, complicated UTI or AP. Levofloxacin 750 mg once daily for 5 days was noninferior to levofloxacin 500 mg once daily for 10 days in the treatment of adults with CAP and ABS infections according to the primary endpoint of clinical response rate 7–14 days after the end of treatment. Clinical and microbiological response rates in the clinically evaluable population of patients with CAP were 92.4% versus 91.1% and 93.2% versus 92.4% in those receiving the 750 mg dosage regimen versus the 500 mg dosage regimen. In patients with ABS, the corresponding response rates were 91.4% versus 88.6% and 91.5% versus 89.4%, respectively.

Levofloxacin 750 mg once daily for 5 days was noninferior to ciprofloxacin 400 mg or 500 mg twice daily for 10 days in the treatment of adults with complicated UTI or AP infections according to the primary endpoint of microbiological response (eradication) rate on day 15–22 of the study. The microbiological response rate in levofloxacin or ciprofloxacin recipients (all patients with complicated UTI or AP) in the co-primary endpoint populations was 79.8% versus 79.8% (modified intent-to-treat population) and 86% versus 89.2% (microbiologically evaluable population). Clinical response rates in the corresponding groups were 81.1% versus 80.1% and 86.4% versus 88.4%, respectively.

Tolerability

Levofloxacin is generally well tolerated in patients with respiratory or UTIs. In a pooled analysis of patients with respiratory infections, the most commonly reported treatment-emergent adverse events included nausea, headache, diarrhoea, insomnia, constipation, abdominal pain, dizziness, dyspepsia and vomiting; the incidence of drug-related adverse events was not significantly different between those receiving the levofloxacin 750 mg or 500 mg regimen. No clinically important adverse events that occurred were deemed to be drug related. Discontinuation of therapy because of drug-related adverse events occurred in <2% of patients with respiratory infections. The most common treatment-emergent adverse events in patients with complicated UTI or AP were similar to those observed in patients with respiratory infections.