Quinolones A Systematic Quest David C. Hooper, M.D. Division of Infectious Diseases Infection Control Unit Massachusetts© by General author Hospital Harvard Medical School ESCMID Online Lecture Library Timeline of Quinolone Development © by author ESCMIDNorris S, Mandell Online GL in Andriole Lecture V (ed). The Library Quinolones 1988 © by author George Y. Lesher, Ph.D. ESCMID Online1926- Lecture1990 Library Surprise Beginnings O COOH N N H3C C2H5 © by author Nalidixic Acid ESCMID Online Lecture Library Quinolones The First Decade (Childhood) • 1962 Discovery of Nalidixic Acid as anti- bacterial byproduct of chloroquine synthesis (Lesher) • 1964-66 Mechanisms of Action Defined (Goss, Dietz, Cook) » Inhibition of DNA synthesis » Conditional bactericidal activity • 1967 Nalidixic Acid released for clinical use for treatment of© urinary by author tract infections caused by enteric bacteria • 1969 Resistance to Nalidixic Acid in E. coli ESCMID mapped Online to chromosomal Lecture mutations Library (nalA,B) (Hane) Quinolones The Second Decade (Adolescence) • 1970 Development of Piromidic Acid, the 1st pyrrolindinyl quinolone • 1975 Development of Pipemidic Acid, the 1st piperazinyl quinolone • 1976 Discovery of DNA gyrase, the 1st type 2 topoisomerase (Gellert) • 1976 Development of Flumequine, the 1st fluoroquinolone© andby tricyclicauthor quinolone • 1977 Nalidixic Acid resistance loci identified as encoding mutant subunits of DNA gyrase ESCMIDof E. coli Online (Gellert, LectureCozzarelli) Library Piromidic Acid Pipemidic Acid © by author ESCMID OnlineFlumequine Lecture Library Quinolones - The Third Decade (Adolescent Growth Spurt) • 1986 Norfloxacin released for clinical use in US (GU infections) • 1986 Development of Fleroxacin, 1st 6, 8- difluoroquinolone (recognition of photosensitivity associated with 8-F) • 1987 Ciprofloxacin released for clinical use in US (broad ©indications) by author • 1988-89 Identification of drug resistance by altered permeation for hydrophilic quinolones - active ESCMID efflux andOnline altered Lecture porins Library O O F COOH F COOH HN N N HN N N C H Norfloxacin 2 5 O F COOH Ciprofloxacin H3C N N N © by author F CH2 CH2 ESCMIDFleroxacin OnlineF Lecture Library Quinolone Phototoxicity • UVA (320-420 nm) interactions • Generation of reactive oxygen species • Drug concentrations in skin • SARs – Position 8: C-halogen > N-H > C-H > C-O-R – Position 7: Alkylated© by authorrings increase t½ – Position 5: CH3 > H > NH2 ESCMID Online Lecture Library Quinolones - The Fourth Decade (Problems of Adolescence) • 1990 Ofloxacin PO/IV released for clinical use in US (broad indications) • 1990 Discovery of Topoisomerase IV (Kato) • 1991 Enoxacin PO released in US (GU indications) • 1992 Temafloxacin released and withdrawn due to unexpected rare but severe toxicities (Hemolytic©-Uremic by author Syndrome) • 1992 Lomefloxacin PO released in US, 1st once- daily fluoroquinolone • 1993ESCMID-94 Identification Online of Lecture quinolone Libraryinhibition of topoisomerase IV of E. coli O O F COOH F COOH HN N N N HN N N C2H5 Enoxacin F C2H5 H3C O Lomefloxacin F COOH O F COOH HCl N N F © by author HN H3C N N N O * CH3 CH3 ESCMID Online LectureOfloxacin Library Temafloxacin F Quinolones - The Fourth Decade (Adulthood) • 1994-96 Identification of topoisomerase IV as principal quinolone target in S. aureus and secondary target in E. coli • 1996 Levofloxacin PO/IV and sparfloxacin PO released in US (expanded Gram+ respiratory indications) • 1997 Grepafloxacin© by PO author (Respiratory/GU Indications) and Trovafloxacin PO/IV (broadest indications, 1st anti-anaerobic ESCMID quinolone) Online released Lecture in US Library O NH2 O F COOH F COOH H3C H3C N N N HN N N O F CH3 H3C Sparfloxacin Levofloxacin O F CO2H CH3 O F CO H 2 N H N N F CH3 © by author N N H2N HN H GrepafloxacinESCMID Online LectureTrovafloxacin Library F Quinolones - The Fourth Decade (Adults Have Their Ups & Downs) • 1998 Plasmid transferable quinolone resistance identified • 1999 Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temafloxacin) • 1999 Grepafloxacin withdrawn because of cardiac events. Sparfloxacin© by author also associated with arrhythmias • 1999 Gatifloxacin PO/IV and Moxifloxacin PO ESCMID released Online with a focus Lecture on respiratory Library tract indications Rare, Serious Idiosyncratic Reactions • Temafloxacin (1992) – Hemolytic uremic syndrome – Coagulopathy (35%) – Hepatic dysfunction (51%) – Reporting incidence ~1:6000 • Trovafloxacin (1999) – Symptomatic hepatitis© by author – Life-threatening in ~10% – Reporting incidence ~1:18,000 ESCMID OnlineBlum MD Lectureet al. 1994. ClinLibrary Infect Dis 18:946 Ball P et al. 1999. Drug Safety 21:407 Quinolones - The Fourth Decade (Adults Have Their Ups & Downs) • 1999 Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temfloxacin) • 1999 Grepafloxacin withdrawn because of cardiac events. Sparfloxacin also associated with arrhythmias © by author • 1999 Gatifloxacin PO/IV and Moxifloxacin PO released with a focus on respiratory tract ESCMID indications Online Lecture Library Effects of Drugs on Cardiac Conduction a b Drug QTC Prolongation Ikr hERG IC30 (msec) (µM) (µM) Sparfloxacin 13-15 0.23 10 Grepafloxacin 10 27.2 39 Moxifloxacin 7 -- 92 Gatifloxacin 5-6 26.5 104 Terfenidine 46 © by author Erythromycin 8-15 aAnderson et al. 3rd ECC ClarithromycinESCMID Online2-6 bChen Lecture et al. ICAAC Library 2000 abstr 765 Quinolones - The Fourth Decade (Adults Have Their Ups & Downs) • 1999 Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temfloxacin) • 1999 Grepafloxacin withdrawn because of cardiac events. Sparfloxacin also associated with arrhythmias © by author • 1999 Gatifloxacin PO/IV and Moxifloxacin PO released with a focus on respiratory tract ESCMID indications Online Lecture Library Quinolone Structure-Activity Relationships © by author ESCMID Online Lecture Library Domagala JM. 1994. J Antimicrob Chemother 33:685 Quinolone Structure-Adverse Effects Relationships © by author ESCMIDDomagala JM. Online 1994. J Antimicrob Lecture Chemother Library 33:685 Quinolones - The Fifth Decade (Adults Have Their Ups & Downs) • 2002 Plasmid-encoded Qnr protein identified as protecting gyrase from quinolones • 2003 Gemifloxacin approved for community- acquired pneumonia with 5-day regimen • 2006 Plasmid-encoded quinolone-modifying enzyme identified as mutant AAC(6’)-Ib • 2007 Plasmid-encoded© by QepAauthor efflux pump identified • 2008 Gatifloxacin withdrawn because of ESCMID dysglycemia Online events Lecture Library • 2009 First topoisomerase IV-DNA crystal structures with quinolone bound © by author Laponogov I et al. Nature Struct Mol Biol. ESCMID Online Lecture2009; 16:667Library The Fluoroquinolone Family American Branch – The Sixth Decade 12 Approvals over 17 Years • Norfloxacin (Noroxin) • SparfloxacinXXX (Zagam) 1986 1996 • Ciprofloxacin (Cipro) • GrepafloxacinXXX (Raxar) 1987 PO, 1990 IV 1997 • Ofloxacin (Floxin) • TrovafloxacinXXX (Trovan) 1990 PO, 1992 IV 1997 • EnoxacinXXX (Penetrex) • GatifloxacinXXX (Tequin) 1991 © by author1999 • LomefloxacinXXX (Maxaquin) • Moxifloxacin (Avelox) 1992 1999 • LevofloxacinESCMID (Levaquin) Online Lecture• Gemifloxacin Library (Factive) 1996 2003 Adverse Effects of Fluoroquinolones • Gastrointestinal – Nausea, vomiting, diarrhea • Central Nervous System – Dizziness (trovafloxacin), insomnia, seizures • Cardiovascular – QTC prolongation (sparfloxacin, grepafloxacin > moxifloxacin) • Hepatic – Idiosyncratic hepatitis (trovafloxacin) • Metabolic – Dysglycemia (gatifloxacin > levofloxacin) • Skin © by author – Photosensitivity (sparfloxacin, lomefloxacin) – Other skin reactions (gemifloxacin) • Musculoskeletal – ESCMIDTendinopathy Online Lecture Library Quinolones – The Sixth Decade Senescence or New Generations to Follow The Search Goes On • Keys to success: – Dealing with established resistance – Low potential for new resistance © by author – High tolerability (no surprises – better preclinical screening tools) ESCMID Online Lecture Library Problems With Development of Bacterial Resistance to Fluoroquinolones Staphylococci (MRSA, MRSE) 60-95% Pseudomonas aeruginosa 5-30% Campylobacter jejuni 3-50% Escherichia coli 8-26% Neisseria gonorrheae© by author 6-70% Streptococcus pneumoniae 3% ESCMID Online Lecture Library Predicting Resistance Potential: (Which Quinolone Will Live the Longest?) • Determinants of bacterial resistance – Activity against both target enzymes, DNA gyrase and DNA topoisomerase IV – Effects of native bacterial efflux systems – Potency that keeps© by drug author concentrations above the MIC of first-step resistant mutants (mutant prevention ESCMIDconcentration) Online Lecture Library Sitafloxacin O F CO2H N N Cl F H2N Activity: S. pneumoniae (16x) Other streptococci (16-32x) (Relative to Enterococci (16x) Ciprofloxacin) S. aureus (>2-32x) B. fragilis (64x) P. aeruginosa (1-6x) © by author→ µ Pharmacokinetics: 500mg PO Cmax 4.6 g/ml t 1/2 = 4.5-5h; renal (70%) Vd = 1.8 liters ESCMID OnlineAnderson Lecture DL. Drugs Library of Today 2008; 44:489. Prulifloxacin/Ulifloxacin Activity: S. pneumoniae (1x) S. pyogenes (1x) (Relative to Enterococci (1x) Levofloxacin) S. aureus (1x) Klebsiella spp. (4x) © byEnterobacter author spp. (4x) P. aeruginosa (0.5-2x) ESCMIDMontanari MP Online et al. Antimicrob Lecture Agents Chemother. Library 2001; 45:3616 Finafloxacin Organism MIC (median, μg/ml) pH 5.0 pH 7.3 Fin Cip Fin Cip E. coli CipS 0.031 0.5 0.125 0.016