Appropriate Use of Quinolones Quinolones in the in the Appropriate Use of Hospital: Is Microbiology Telling You All? Hospital: Is Microbiology Telling You All? 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 Lesson to Students – Leuven, March 27 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 Fluoroquinolones Mechanisms of Action Mechanisms of Action • Inhibit DNA synthesis Inhibit DNA synthesis • • Stabilize DNA strand breaks created by Stabilize DNA strand breaks created by • actions of DNA gyrase gyrase and and topoisomerase topoisomerase actions of DNA IV by binding enzyme- -DNA complexes DNA complexes IV by binding enzyme • Bactericidal Bactericidal - - requires additional events requires additional events • after initial interaction with enzyme- -DNA DNA after initial interaction with enzyme complexes complexes
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
Properties of Newer Quinolones Properties of Newer Quinolones • Broad spectrum activity • Broad spectrum activity – Gram-negative bacteria – Gram-negative bacteria – Improved against Gram-positive bacteria – Improved against Gram-positive bacteria – Improved against Anaerobes – Improved against Anaerobes • Once or twice daily dosing • Once or twice daily dosing • Some with apparent reduced risk of • Some with apparent reduced risk of selection of resistance selection of resistance
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
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
Pharmacokinetic Properties of Pharmacokinetic Properties of IV Fluoroquinolones Fluoroquinolones IV Drug Dose C C max t ½ Renal Drug Dose t Renal max ½ μ g/ml) (h) ( μ Clearance Clearance (mg - - g/ml) (h) (mg ( frequency) (% of total) frequency) (% of total) Ciprofloxacin 400 BID 4.3 3.3 50 Ciprofloxacin 400 BID 4.3 3.3 50 Levofloxacin 500 QD 6.4 6- -8 65 8 65 Levofloxacin 500 QD 6.4 6 750 QD 12.1 750 QD 12.1 Gatifloxacin 400 QD 4.6 7- -8 80 8 80 Gatifloxacin 400 QD 4.6 7 Moxifloxacin 400 QD 4.2 13 22 Moxifloxacin 400 QD 4.2 13 22
Specific Uses of Fluoroquinolones Fluoroquinolones Specific Uses of • Typhoid and enteric fever Typhoid and enteric fever • • Prostatitis Prostatitis ( (vs vs trimethoprim trimethoprim- -sulfa) sulfa) • • Complicated urinary tract infections Complicated urinary tract infections • • Community Community- -acquired pneumonia acquired pneumonia • – hospitalized patients ( hospitalized patients (vs vs ceftriaxone ceftriaxone + + macrolide macrolide) ) – • Prosthetic joint infection Prosthetic joint infection • – for salvage when prosthesis cannot be removed for salvage when prosthesis cannot be removed – – with with rifampin rifampin –
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 •
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 •
Fluoroquinolone Drug Interactions • Antacids, Antacids, sucralfate sucralfate, multivalent , multivalent cations cations • impair oral absorption impair oral absorption • Increase Increase theophylline theophylline and caffeine and caffeine • (Enoxacin Enoxacin > Ciprofloxacin) > Ciprofloxacin) ( • NSAIDs NSAIDs possibly possibly potentiate potentiate neurotoxicity neurotoxicity • (Enoxacin Enoxacin) ) ( A sporadic A • Potentiation Potentiation of of warfarin warfarin effect is effect is sporadic • • High doses may increase High doses may increase cyclosporin cyclosporin levels levels • (Ciprofloxacin) (Ciprofloxacin) A Seen in some elderly patients on multiple drugs
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