Quinolones A Systematic Quest

Transcription

1 Quinolones A Systematic Quest David C. Hooper, M.D. Division of Infectious Diseases Infection Control Unit Massachusetts General Hospital Harvard Medical School

2 Timeline of Quinolone Development orris S, Mandell GL in Andriole V (ed). The Quinolones 1988

3 George Y. Lesher, Ph.D

4 Surprise Beginnings H 3 C O C 2 H 5 alidixic Acid COOH

5 Quinolones The irst Decade (Childhood) 1962 Discovery of alidixic Acid as antibacterial byproduct of chloroquine synthesis (Lesher) Mechanisms of Action Defined (Goss, Dietz, Cook)» Inhibition of DA synthesis » Conditional bactericidal activity alidixic Acid released for clinical use for treatment of urinary tract infections caused by enteric bacteria Resistance to alidixic Acid in E. coli mapped to chromosomal mutations (nala,b) (Hane)

6 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 DA gyrase, the 1st type 2 topoisomerase (Gellert) 1976 Development of lumequine, the 1st fluoroquinolone and tricyclic quinolone 1977 alidixic Acid resistance loci identified as encoding mutant subunits of DA gyrase of E. coli (Gellert, Cozzarelli)

7 Piromidic Acid lumequine Pipemidic Acid

8 Quinolones - The Third Decade (Adolescent Growth Spurt) 1986 orfloxacin released for clinical use in US (GU infections) 1986 Development of leroxacin, 1st 6, 8- difluoroquinolone (recognition of photosensitivity associated with 8-) 1987 Ciprofloxacin released for clinical use in US (broad indications) Identification of drug resistance by altered permeation for hydrophilic quinolones - active efflux and altered porins

9 H orfloxacin H 3 C O C 2 H 5 leroxacin COOH O H CH 2 CH 2 COOH O COOH Ciprofloxacin

10 Quinolone Phototoxicity UVA ( nm) interactions Generation of reactive oxygen species Drug concentrations in skin SARs Position 8: C-halogen > -H > C-H > C-O-R Position 7: Alkylated rings increase t½ Position 5: CH 3 > H > H 2

11 Quinolones - The ourth Decade (Problems of Adolescence) Ofloxacin PO/IV released for clinical use in US (broad indications) Discovery of Topoisomerase IV (Kato) Enoxacin PO released in US (GU indications) 1992 Temafloxacin released and withdrawn due to unexpected rare but severe toxicities (Hemolytic-Uremic Syndrome) 1992 Lomefloxacin PO released in US, 1st oncedaily fluoroquinolone Identification of quinolone inhibition of topoisomerase IV of E. coli

12 H O H CH 3 Enoxacin O Temafloxacin C 2 H 5 O COOH COOH H 3 C COOH HCl H H 3 C C 2 H 5 Lomefloxacin O COOH * Ofloxacin O CH 3

13 Quinolones - The ourth Decade (Adulthood) Identification of topoisomerase IV as principal quinolone target in S. aureus and secondary target in E. coli Levofloxacin PO/IV and sparfloxacin PO released in US (expanded Gram+ respiratory indications) Grepafloxacin PO (Respiratory/GU Indications) and Trovafloxacin PO/IV (broadest indications, 1st anti-anaerobic quinolone) released in US

14 H 3 C CH 3 O O H Levofloxacin CH 3 O CH 3 COOH CO 2 H H 3 C H 3 C H Grepafloxacin Trovafloxacin H H 2 Sparfloxacin H H 2 O O COOH CO 2 H

15 Quinolones - The ourth Decade (Adults Have Their Ups & Downs) Plasmid transferable quinolone resistance identified Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temafloxacin) Grepafloxacin withdrawn because of cardiac events. Sparfloxacin also associated with arrhythmias Gatifloxacin PO/IV and Moxifloxacin PO released with a focus on respiratory tract indications

16 Rare, Serious Idiosyncratic Reactions Temafloxacin (1992) Hemolytic uremic syndrome Coagulopathy (35%) Hepatic dysfunction (51%) Reporting incidence ~1:6000 Trovafloxacin (1999) Symptomatic hepatitis Life-threatening in ~10% Reporting incidence ~1:18,000 Blum MD et al Clin Infect Dis 18:946 Ball P et al Drug Safety 21:407

17 Quinolones - The ourth Decade (Adults Have Their Ups & Downs) Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temfloxacin) Grepafloxacin withdrawn because of cardiac events. Sparfloxacin also associated with arrhythmias Gatifloxacin PO/IV and Moxifloxacin PO released with a focus on respiratory tract indications

18 Effects of Drugs on Cardiac Conduction Drug QT C Prolongation I a kr herg IC b 30 (msec) (µm) (µm) Sparfloxacin Grepafloxacin Moxifloxacin Gatifloxacin Terfenidine 46 Erythromycin 8-15 Clarithromycin 2-6 a Anderson et al. 3rd ECC b Chen et al. ICAAC 2000 abstr 765

19 Quinolones - The ourth Decade (Adults Have Their Ups & Downs) Trovafloxacin use restricted due to rare but severe hepatotoxicity (? Legacy of temfloxacin) Grepafloxacin withdrawn because of cardiac events. Sparfloxacin also associated with arrhythmias Gatifloxacin PO/IV and Moxifloxacin PO released with a focus on respiratory tract indications

20 Quinolone Structure-Activity Relationships Domagala JM J Antimicrob Chemother 33:685

21 Quinolone Structure-Adverse Effects Relationships Domagala JM J Antimicrob Chemother 33:685

22 Quinolones - The ifth Decade (Adults Have Their Ups & Downs) Plasmid-encoded Qnr protein identified as protecting gyrase from quinolones Gemifloxacin approved for communityacquired pneumonia with 5-day regimen Plasmid-encoded quinolone-modifying enzyme identified as mutant AAC(6 )-Ib Plasmid-encoded QepA efflux pump identified Gatifloxacin withdrawn because of dysglycemia events

23 2009 irst topoisomerase IV-DA crystal structures with quinolone bound Laponogov I et al. ature Struct Mol Biol. 2009; 16:667

24 The luoroquinolone amily American Branch The Sixth Decade 12 Approvals over 17 Years orfloxacin (oroxin) 1986 Ciprofloxacin (Cipro) 1987 PO, 1990 IV Ofloxacin (loxin) 1990 PO, 1992 IV XXX Enoxacin (Penetrex) 1991 XXX Lomefloxacin (Maxaquin) 1992 Levofloxacin (Levaquin) 1996 XXX Sparfloxacin (Zagam) 1996 Grepafloxacin XXX (Raxar) 1997 Trovafloxacin XXX (Trovan) 1997 Gatifloxacin XXX (Tequin) 1999 Moxifloxacin (Avelox) 1999 Gemifloxacin (active) 2003

25 Adverse Effects of luoroquinolones Gastrointestinal ausea, vomiting, diarrhea Central ervous System Dizziness (trovafloxacin), insomnia, seizures Cardiovascular QT C prolongation (sparfloxacin, grepafloxacin > moxifloxacin) Hepatic Idiosyncratic hepatitis (trovafloxacin) Metabolic Skin Dysglycemia (gatifloxacin > levofloxacin) Photosensitivity (sparfloxacin, lomefloxacin) Other skin reactions (gemifloxacin) Musculoskeletal Tendinopathy

26 Quinolones The Sixth Decade Senescence or ew Generations to ollow The Search Goes On Keys to success: Dealing with established resistance Low potential for new resistance High tolerability (no surprises better preclinical screening tools)

27 Problems With Development of Bacterial Resistance to luoroquinolones Staphylococci (MRSA, MRSE) 60-95% Pseudomonas aeruginosa 5-30% Campylobacter jejuni 3-50% Escherichia coli 8-26% eisseria gonorrheae 6-70% Streptococcus pneumoniae 3%

28 Predicting Resistance Potential: (Which Quinolone Will Live the Longest?) Determinants of bacterial resistance Activity against both target enzymes, DA gyrase and DA topoisomerase IV Effects of native bacterial efflux systems Potency that keeps drug concentrations above the MIC of first-step resistant mutants (mutant prevention concentration)

29 Activity: (Relative to Ciprofloxacin) Sitafloxacin H 2 Pharmacokinetics: Cl O CO 2 H S. pneumoniae Other streptococci Enterococci S. aureus B. fragilis P. aeruginosa (16x) (16-32x) (16x) (>2-32x) (64x) (1-6x) 500mg PO C max 4.6 µg/ml t 1/2 = 4.5-5h; renal (70%) V d = 1.8 liters Anderson DL. Drugs of Today 2008; 44:489.

30 Prulifloxacin/Ulifloxacin Activity: (Relative to Levofloxacin) S. pneumoniae S. pyogenes Enterococci S. aureus Klebsiella spp. Enterobacter spp. P. aeruginosa (1x) (1x) (1x) (1x) (4x) (4x) (0.5-2x) Montanari MP et al. Antimicrob Agents Chemother. 2001; 45:3616

31 inafloxacin Organism MIC (median, μg/ml) ph 5.0 ph 7.3 in Cip in Cip E. coli CipS CipS K. pneumoniae CipS CipS S. aureus CipS CipS th ICAAC, IDSA Abstract

32 Zabofloxacin (DW-224a) MeO H Activity: (Relative to Moxifloxacin) O O OH S. aureus S. pneumoniae a Enterococci K. pneumoniae E. cloacae P. aeruginosa (2-4x) (16x) (4-16x) (1x) (0.5x) (~1x) [ a Advantage maintained vs parc gyra double mutants of S. pneumoniae Serial passage selection: 4-16 x MIC to max of 2 μg/ml] Park H-S et al. Antimicrob Agents Chemother. 2006; 50:2261 Kosowska-Shick K et al. Antimicrob Agents Chemother. 2006; 50:2064

33 Delafloxacin (RX-3341, ABT492) Activity: (Relative to Levofloxacin) S. aureus MRSA S. aureus MSSA Enterococci S. pyogenes S.epidermidis S. pneumoniae H. influenzae L. pneumophila Chlamydia spp. K. pneumoniae M. pneumoniae P. aeruginosa >64x >64x 16x >64x 32x 128x 16-32x 8x 2-32x 4x 2x 0.5-1x

34 WCK-771 (S-nadifloxacin) Activity: (Relative to Levofloxacin) Pharmacokinetics: S. pneumoniae S. pyogenes S. aureus a S. epidermidis ( 2x) (2x) (16-32x) (16-32x) 600mg IV C max 4.0 µg/ml t 1/2 = 6 h [ a irst-step selection: S. aureus mutations in gyra with 2x MIC] Jacobs MR et al. Antimicrob Agents Chemother 2004; 48:3338 Al-Laham A et al. J Antimicrob Chemother 2005; 56:1130 Bhagwat SS et al. Antimicrob Agents Chemother. 2006; 50:3568

35 H 2 Activity: (Relative to Levofloxacin) Pharmacokinetics: DX-619 OMe O O OH S. pneumoniae ( 128x) Other streptococci (32-64x) Enterococci (64x) S. aureus a (16-128x) Klebsiella spp. (1x) P. aeruginosa (2x) Lung:serum ratio 5.3 (3x > cipro) in mice ujikawa K et al. Antimicrob Agents Chemother. 2005; 49:3040 Wickman PA et al. Antimicrob Agents Chemother. 2006; 50:2255 ukuda Y et al. Antimicrob Agents Chemother. 2006; 50:121

36 Activity: (Relative to Levofloxacin) DC-159a S. pneumoniae Enterococci S. aureus H. influenzae Peptostreptococcus B. fragilis K. pneumoniae P. aeruginosa (8-32x) (8x) (4-16x) (1x) (32x) (16x) (1x) (0.5x) Hoshino K et al. Antimicrob Agents Chemother. 2008; 52:65

37 PD and PD Activity: (Relative to Levofloxacin) S. aureus S. pneumoniae a Enterococci S. pyogenes K. pneumoniae E. cloacae (2-32x) (16-32x) (128x) (64x) (0.12x) (0.25x) [ a irst-step mutants in gyrb (2x MIC) or gyrb pare (4x MIC)] Efficacy > levofloxacin in murine pneumococcal pneumonia model Huband MD et al. Antimicrob Agents Chemother. 2007; 51:1191

38 Activity: (Relative to Levofloxacin) ACH-702 S. aureus a (>32->64x) S. pneumoniae (16x) Enterococci (>8->32x) S. pyogenes (16x) K. pneumoniae (2x) Enterobacter spp. (0.25-1x) P. aeruginosa (0.5x) [MIC 90 : B. fragilis 0.25 μg/ml, Peptostreptococcus 0.06 μg/ml] [ a Single-step gyra mutants with 4x MIC] 48 th ICAAC, IDSA Abstract ,

39 Long Life Sometimes eeds Help from the Doctor(s) Monitoring resistance Good Infection Control to Limit Spread ocused Use to Limit Selective Pressures Adequate Dosing to Limit Mutant Selection Possible Use of Combination Regimens: With Other Antibiotics Specific Inhibitors of Resistance Mechanisms