Table of Contents
LEVAQUIN® (levofloxacin) Presentation to AIDAC October 20, 1999
FDA Approval: December 20, 1996
Community Acquired Pneumonia
Following FDA Approval 1996
Regulatory History
Rationale for the sNDA Clinical Program
Organization of Presentation
Summary - Dr. Bush
Organization of Presentation
Summary - Dr. Corrado
Organization of Presentation
Other Advisors Present
New Labeling Claim Sought (See Highlighted Text Below)
Levofloxacin Microbiological Activity Against Penicillin-Resistant Streptococcus pneumoniae
Activity of Levofloxacin Against Penicillin-Resistant Streptococcus pneumoniae
Overview
Microbiological Attributes of Levofloxacin Against Streptococcus pneumoniae
Diversity of Killing Mechanisms for ?-lactams and Quinolones in Streptococcus pneumoniae
Preferential Inhibition of E. coli DNA Gyrase
Preferential Inhibition of S. pneumoniae Topoisomerase IV by Quinolones
NCCLS Interpretive Standards for Streptococcus pneumoniae
Unrelated Resistance Mechanisms of Clinical Importance in S. pneumoniae
Lower Frequency of Selection of S. pneumoniae Quinolone Resistance by Levofloxacin
Simulated in vitro Model of Streptococcus pneumoniae Infection
No in vitro Selection of Levofloxacin-Resistant Pneumococci at Low Peak:MIC and AUC:MIC Ratios
Less Rapid Selection of Quinolone-Resistant S. pneumoniae by Levofloxacin
Minimal Effect of Single Mutations on Levofloxacin MICs in Isogenic Strains of S. pneumoniae
Effect of Multiple Mutations in Topo IV and DNA Gyrase on Levofloxacin MICs in Pneumococcal Isolates
Levofloxacin MICs in S. pneumoniae Strains With Efflux Mechanisms Selected in vitro by Ciprofloxacin
Increasing Resistance of S. pneumoniae to Penicillin and Erythromycin in the US
Multi-Drug Resistance in Penicillin-Resistant Streptococcus pneumoniae
The TRUST Studies (Tracking Resistance in the United States Today)
In Vitro Activity of Levofloxacin Against United States S. pneumoniae Clinical Isolates
Levofloxacin Activity Against United States S. pneumoniae Clinical Isolates (TRUST Studies)
Low Levofloxacin Resistance Across Sites in the TRUST Studies in 1997-99
In Vitro Activity of Levofloxacin Against Canadian S. pneumoniae Clinical Isolates
Susceptibility of S. pneumoniae in Asia and Europe 1997-1998
Number of Quinolone Prescriptions in Japan From 1993-1998
Efficacy of Levofloxacin in Murine Models of Infection With S. pneumoniae
Representative Dose-effect Relationship for Levofloxacin Administered Every 6 H Against S. pneumoniae HIP 1293 in the Murine Thigh Model of Infection
Relationship Between 24-h AUC/MIC Ratio and the Number of S. pneumoniae (7 Strains) in the Thighs of Neutropenic Mice After 24-h Therapy With Levofloxacin
Levofloxacin AUC/MIC ᡌ Predicts Efficacy Against PRSP in Murine Thigh Model
Conclusions
Levofloxacin
Levofloxacin
Penicillin Resistant S. pneumoniae
Why Consider Levofloxacin?
Characteristics to Be Considered in Choosing an Antibacterial
Levofloxacin
Levofloxacin Achieves High Plasma Levels ?g/ml
Levofloxacin 500 mg P.O. (Lung Biopsy of Lobectomy)
Pharmacokinetics: Levofloxacin Is Highly Bioavailable After Oral Administration
Levofloxacin Is Highly Distributed Into Pulmonary Tissue/fluid Levels: ELF
Levofloxacin Is Highly Distributed Into Pulmonary Tissue/fluid Levels: Alveolar Macrophage
Levofloxacin Clinical Trials
Pharmacodynamic Ratios
Levofloxacin Has Optimal Pharmacodynamic Properties
Pharmacokinetic Summary
Levofloxacin
Scope of Clinical Trials
Risk Factors for PRSP Infection
Levofloxacin Intent-to-treat Community Acquired Pneumonia Trials
Levofloxacin Clinical Trials
Levofloxacin Clinical Trials
Levofloxacin Clinical Trials
Levofloxacin
Levofloxacin Clinical Trials
Cross-Resistance of Clinical PRSP Isolates
In Vitro Summary
Levofloxacin
Levofloxacin Clinical Trials
Levofloxacin Clinical Trials
Levofloxacin Clinical Trials
Cumulative Experience for Severely Ill Evaluable Subjects with Pneumococcal Pneumonia
Levofloxacin Clinical Trials
Levofloxacin Clinical Trials
Posttherapy Clinical Success by Levofloxacin MIC - Evaluable Levofloxacin Subjects
Clinical Summary
Clinical Data Summary
Levofloxacin
Levofloxacin Clinical Trials
Phase III Studies: Other AEs of Interest
Worldwide Postmarketing Experience
U.S. Postmarketing Experience (12/96-8/99): Reports of Interest
Safety Summary
Conclusion
The Clinician’s Perspective
The Challenge of the Clinician
Present Options
Conclusion
Conclusion
Conclusion
New Labeling Claim Sought (See Highlighted Text Below)
|