Levofloxacin for community acquired pneumonia

Background Information of the Condition

Pneumonia is the leading cause of death from infection, particularly among elderly and hospitalized patients. ¹ Diagnosis is based on history, co-morbidities, physical findings, and chest x-ray. S. pneumoniae accounts for up to 50% of community-acquired pneumonia caused by bacteria.²

Drug (Product Monograph)^{3, 4}

Category: Levofloxacin, the L-isomer of the racemate ofloxacin, is a member of the fluoroquinolone class of antibiotics.

Mechanism of Action: Levofloxacin exerts its action by inhibiting the bacterial topoisomerases II (DNA gyrase) and topoisomerases IV which interferes with bacterial DNA replication, transcription, repair, and recombination.

Indications: Levofloxacin is indicated for the treatment of adults with upper and lower respiratory tract, skin/skin structure, and urinary tract infections.

Dose & Duration: the recommended dose is 500mg i.v./oral once daily for 7-14 days (normal course of therapy) or 750mg i.v./oral once daily for 5 days (short-course therapy).

Methodology of Systematic Review

Research Question:

In double blind randomized controlled trials (DB RCTs), does levofloxacin (normal and short-course therapy) provide a significant therapeutic advantage in terms of mortality or morbidity when compared to other fluoroquinolones or other classes of antibacterial agents in the treatment of adult patients with community acquired pneumonia?

Assessment principles: Double blind randomized controlled trials comparing levofloxacin to other fluoroquinolones or other classes of antibacterial agents in adult patients with community-acquired pneumonia were critically appraised. Therapeutic impact was assessed according to the following hierarchy of health outcomes – mortality, non fatal serious adverse events, quality of life, withdrawals due to adverse events, clinical response (defined as clinical resolution of signs and symptoms of infection), microbiological response (defined as bacteriological eradication of causative pathogen), and other adverse events (e.g. allergic reactions).

Search strategy: Databases searched: Medline, EMBASE and Cochrane Library (from 1966 to February 2008); the manufacturer’s submission, and references of review articles. Key search words included: “levofloxacin,” or “Levaquin,” “randomized controlled trial,” and “pneumonia.”

Search Findings: Four DB RCTs met the inclusion criteria, comparing levofloxacin to moxifloxacin, azithromycin, clarithromycin, or amoxicillin/clavulanic acid (Anzueto et al 2006, D’Ignazio et al 2005, Gotfried et al 2002 and Carbon et al 1999).^5-8

Summary of Results:

Levofloxacin compared to other fluoroquinolone antibiotics

In one DBRCT in 401 patients (65 years of age or older) with community-acquired pneumonia (Anzueto et al 2006) ⁵, IV levofloxacin 500mg daily for ≥ 2 days then oral levofloxacin 250-500mg daily after improvement for 7-14 days was not significantly different from IV moxifloxacin 400mg, daily for ≥ 2 days then oral moxifloxacin 400mg daily, after improvement for 7-14 days in terms of mortality, non-fatal serious adverse events, clinical or bacteriological response, total withdrawals and withdrawals due to adverse events. There was a significant improvement in the rate of “clinical recovery” (defined as the resolution of or reduction in acute signs and symptoms of infection) in patients receiving moxifloxacin 3 to 5 days into therapy (moxifloxacin group an ARR = 8%, NNT = 13), but not at test of cure (5-21 days post therapy). Total adverse events, reported as treatment-emergent adverse events, were significantly higher with moxifloxacin (moxifloxacin group an ARI = 11%, NNT = 9).⁵

Levofloxacin compared to other classes of antibiotic drugs

Based on three DBRCTs in 1067 randomized adult patients with mild to moderate community-acquired pneumonia in which oral levofloxacin 500mg daily for 7-10 days was compared to either a single 2000mg dose of oral azithromycin microspheres (D’Ignazio et al 2005)⁶, oral clarithromycin, extended release 1000mg daily for 7 days (Gotfried et al 2002)⁷, or oral amoxicillin/clavulanic acid 625mg t.i.d. daily for 7-10 days (Carbon et al 1999)⁸, there were no significant differences between treatment groups in terms of clinical or bacteriological response, and total number of people withdrawing from the studies. In addition, D’Ignazio et al and Carbon et al did not show significant differences in terms of mortality, non-fatal serious adverse events, and total adverse events, whereas Carbon et al and Gotfried et al did not show significant differences in withdrawals due to adverse events. D’Ignazio et al did not report withdrawals due to adverse events, while the Gotfried et al trial did not report mortality, non-fatal serious adverse events or total adverse events.

Conclusion

In double blind randomized controlled trials, levofloxacin (normal and short course of therapy) does not differ significantly compared to other fluoroquinolones or other classes of antibiotics in clinically relevant outcomes for the treatment of adult patients with community acquired pneumonia.

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References

1. Mandell, L., Bartlet, J., Dowell, S. et al. Update of practice guidelines for the management of community acquired pneumonia in immunocompetent adults. Clinical Infectious Diseases, 37: 1405-1433, 2003.
2. Guideline for the Diagnosis and Management of: Community Acquired pneumonia: adult (2008 update). Toward Optimized Practice (TOP) Program, formerly the Alberta Clinical Practice Guidelines by the Alberta Medical Association.
3. Product Monograph: Levofloxacin (Levaquin™). Antibacterial Agent. Janssen-Ortho Inc., July 16, 2007.
4. eCPS (electronic Compendium of Pharmaceuticals and Specialties), Mar. 2008
5. Anzueto, A., Niederman, M.S., Pearle, J., Restrepo, M.I. et al. Community-acquired pneumonia recovery in the elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Clinical Infectious Diseases, 42: 73-81, 2006.
6. D’Ignazio, J., Camere, M.A., Lewis, D.E., Jorgensen, D. et al. Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults. Antimicrobial Agents and Chemotherapy, 49(10): 4035-4041, 2005.
7. Gotfried, M.H., Dattani, D., Riffer, E., Devcich, K.J. et al. A controlled, double-blind, multicenter study comparing clarithromycin extended-release tablets and levofloxacin tablets in the treatment of community-acquired pneumonia. Clinical Therapeutics, 24(5): 736-751, 2002.
8. Carbon, C., Ariza, H., Rabie, W.J., Salvarezza, C.R. et al. Comparative study of levofloxacin and amoxycillin/clavulanic acid in adults with mild-to-moderate community-acquired pneumonia. Clinical Microbiology and Infection, 5(12): 724-732, 1999.