Fluoroquinolones in 2007: the Angels, the in 2007: the Angels, the Fluoroquinolones Devils, and What Should the Clinician Do? Devils, and What Should the Clinician Do? David C. Hooper, M.D. David C. Hooper, M.D. Division of Infectious Diseases Division of Infectious Diseases Infection Control Unit Infection Control Unit Massachusetts General Hospital Massachusetts General Hospital Harvard Medical School Harvard Medical School Boston, Massachusetts Boston, Massachusetts GSK Chair of Infectious Diseases Clinical Seminar – Mont-Godinne, March 29 th , 2007
Sites of Action of Antimicrobial Sites of Action of Antimicrobial Agents in Clinical Use Agents in Clinical Use Topoisomerase IV Daptomycin (Lipopeptide) Linezolid (Oxazolidinone) Telithromycin (Ketolide) Glycylcyclines Neu HC. Science 1992; 257:1064-73
Fluoroquinolones Available Available Fluoroquinolones in the United States in the United States • Norfloxacin Norfloxacin ( (Noroxin Noroxin) ) • Levofloxacin Levofloxacin ( (Levaquin Levaquin) ) • • 1986 (PO) 1996 (IV & PO) 1986 (PO) 1996 (IV & PO) • Ciprofloxacin ( Ciprofloxacin (Cipro Cipro) ) • Gatifloxacin Gatifloxacin ( (Tequin Tequin) ) • • 1987 (PO), 1990 (IV) 1999 (IV & PO) 1987 (PO), 1990 (IV) 1999 (IV & PO) • Moxifloxacin Moxifloxacin ( (Avelox Avelox) ) • Ofloxacin Ofloxacin ( (Floxin Floxin) ) • • 1990 (PO), 1992 (IV) 1999 (PO), 2001 (IV) 1990 (PO), 1992 (IV) 1999 (PO), 2001 (IV) • Gemifloxacin Gemifloxacin ( (Factive Factive) ) • 2003 (PO) 2003 (PO)
Fluoroquinolone Structures Gemifloxacin
Fluoroquinolone Use in Patients with Use in Patients with Fluoroquinolone Respiratory Tract Infections Respiratory Tract Infections in the United States in the United States Levofloxacin Ciprofloxacin Ofloxacin Doern GV Clin Infect Dis. 2001;23(suppl 3):S187-92
Outpatient Systemic Antibacterial Outpatient Systemic Antibacterial Use – – Europe vs. United States Europe vs. United States Use Goossens H et al. Clin Infect Dis. 2007; 44:1091
Quinolone Use – Europe vs. US Goossens H et al. Clin Infect Dis. 2007; 44:1091
Quinolone Use – Europe vs. US Goossens H et al. Clin Infect Dis. 2007; 44:1091
Fluoroquinolones Fluoroquinolones Spectrum of Activity Spectrum of Activity • Enterobacteriaceae Enterobacteriaceae • • Haemophilus Haemophilus spp spp. . Neisseria Neisseria spp spp. . • • Legionella Legionella, , Mycoplasma Mycoplasma, Chlamydia , Chlamydia • [Levofloxacin Levofloxacin, , Gatifloxacin Gatifloxacin, , [ Moxifloxacin] ] Moxifloxacin • Pseudomonas Pseudomonas aeruginosa aeruginosa [Ciprofloxacin, [Ciprofloxacin, • Levofloxacin] ] Levofloxacin
Fluoroquinolones Fluoroquinolones Spectrum of Activity Spectrum of Activity • Staphylococci (MSSA, MSSE) [ Staphylococci (MSSA, MSSE) [Levofloxacin Levofloxacin, , • Gatifloxacin, , Moxifloxacin Moxifloxacin, , Gemifloxacin Gemifloxacin] ] Gatifloxacin • Streptococci (+/ Streptococci (+/- - enterococci enterococci) [ ) [Levofloxacin Levofloxacin, , • Gatifloxacin, , Moxifloxacin Moxifloxacin, , Gemifloxacin Gemifloxacin] ] Gatifloxacin • Anaerobes [ Anaerobes [Gatifloxacin Gatifloxacin, , Moxifloxacin Moxifloxacin] ] • • Mycobacteria Mycobacteria ( ( M. tuberculosis, M. M. tuberculosis, M. kansasii kansasii, , • M. fortuitum fortuitum ) [Ciprofloxacin, ) [Ciprofloxacin, Levofloxacin Levofloxacin, , M. Gatifloxacin, , Moxifloxacin Moxifloxacin] ] Gatifloxacin
General Clinical Uses of Fluoroquinolones General • Urinary Tract Infections Urinary Tract Infections • • Prostatitis Prostatitis • • Sexually Transmitted Diseases Sexually Transmitted Diseases • • Gastroenteritis Gastroenteritis • • Intraabdominal Intraabdominal Infections Infections • • Respiratory Tract Infections Respiratory Tract Infections • • Bone & Joint Infections Bone & Joint Infections • • Skin & Soft Tissue Infections Skin & Soft Tissue Infections • • Other Broad Uses in Hospitalized Patients Other Broad Uses in Hospitalized Patients •
General Clinical Uses of Fluoroquinolones • Urinary Tract Infections Urinary Tract Infections • • Prostatitis Prostatitis • • Sexually Transmitted Diseases Sexually Transmitted Diseases • • Gastroenteritis Gastroenteritis • • Intraabdominal Intraabdominal Infections Infections • • Respiratory Tract Infections Respiratory Tract Infections • • Bone & Joint Infections Bone & Joint Infections • • Skin & Soft Tissue Infections Skin & Soft Tissue Infections • • Other Broad Uses in Hospitalized Patients Other Broad Uses in Hospitalized Patients •
Cross Resistance Among Penicillin- -Resistant Resistant Cross Resistance Among Penicillin Strains of Streptococcus Streptococcus pneumoniae pneumoniae Strains of Antimicrobial % Resistant to Other Antimicrobial Antimicrobial % Resistant to Other Antimicrobial Penicillin Penicillin Penicillin Penicillin Penicillin Penicillin Susceptible Intermediate Resistant Susceptible Intermediate Resistant (n=2636) (n=356, 10% 10%) (n=483, ) (n=483, 14% 14%) ) (n=2636) (n=356, Amoxicillin 0.0 1.8 82.2 Amoxicillin 0.0 1.8 82.2 Cefuroxime 0.1 34.8 100 Cefuroxime 0.1 34.8 100 Cefotaxime 0.0 2.8 42.4 Cefotaxime 0.0 2.8 42.4 Meropenem 0.0 0.8 52.0 Meropenem 0.0 0.8 52.0 Erythromycin 3.2 35.1 61.3 Erythromycin 3.2 35.1 61.3 TMP- -SMX SMX 6.6 49.4 92.3 TMP 6.6 49.4 92.3 Tetracycline 1.3 19.1 25.5 Tetracycline 1.3 19.1 25.5 Whitney CG et al. N. Engl. J. Med. 2000;343:1917-24
Cross Resistance Among Penicillin- -Resistant Resistant Cross Resistance Among Penicillin Strains of Streptococcus Streptococcus pneumoniae pneumoniae Strains of Antimicrobial % Resistant to Other Antimicrobial Antimicrobial % Resistant to Other Antimicrobial Penicillin Penicillin Penicillin Penicillin Penicillin Penicillin Susceptible Intermediate Resistant Susceptible Intermediate Resistant (n=2636) (n=356) (n=483) (n=2636) (n=356) (n=483) Chloramphenicol 0.4 6.7 14.7 Chloramphenicol 0.4 6.7 14.7 Clindamycin 0.5 10.7 12.2 Clindamycin 0.5 10.7 12.2 Rifampin 0.2 0.0 0.2 Rifampin 0.2 0.0 0.2 Levofloxacin 0.1 0.3 0.7 Levofloxacin 0.1 0.3 0.7 Quinupristin- - Quinupristin dalfopristin 0.0 0.6 0.2 dalfopristin 0.0 0.6 0.2 Whitney CG et al. N. Engl. J. Med. 2000;343:1917-24
Activity of Quinolones Against 75 Ciprofloxacin-Resistant Isolates of Streptococcus pneumoniae μ g/ml) Cumulative % Isolates at MIC ( μ Quinolone g/ml) Quinolone Cumulative % Isolates at MIC ( ≤ 0.06 0.12 ≤ 0.06 0.12- -0.25 0.5 0.25 0.5- -1 2 1 2- -4 8 4 8- -16 32 16 32- -64 64 Levofloxacin 16 67 95 100 Levofloxacin 16 67 95 100 Gatifloxacin 4 64 93 100 Gatifloxacin 4 64 93 100 Moxifloxacin 56 71 97 100 Moxifloxacin 56 71 97 100 Gemifloxacin 61 92 100 Gemifloxacin 61 92 100 Chen DK et al. 1999. N Engl J Med. 341:233-9
Pharmacokinetic Properties of Pharmacokinetic Properties of Oral Fluoroquinolones Fluoroquinolones Oral Drug Dose C C max t ½ Renal Drug Dose t Renal max ½ μ g/ml) (h) ( μ g/ml) (h) Clearance Clearance (mg - - (mg ( frequency) (% of total) frequency) (% of total) Ciprofloxacin 500 BID 2.2 3.3 50 Ciprofloxacin 500 BID 2.2 3.3 50 Levofloxacin 500 QD 5.7 6- -8 65 8 65 Levofloxacin 500 QD 5.7 6 750 QD 8.6 750 QD 8.6 Gatifloxacin 400 QD 4.1 7- -8 80 8 80 Gatifloxacin 400 QD 4.1 7 Moxifloxacin 400 QD 4.5 13 22 Moxifloxacin 400 QD 4.5 13 22 Gemifloxacin 320 QD 1.8 7 30 Gemifloxacin 320 QD 1.8
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