Fluoroquinolones: Parenteral use Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Université catholique de Louvain Brussels, Belgium Middle East Anti-Infectives Forum Yas Island, Abu Dhabi, U.A.E 10-11 November 2017 With approval of the Belgian Common Ethical Health Platform – visa no. 17/V1/10411/093945 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 1 Disclosures and slides availability • Research grants – Theravance, Astellas, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica – Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), and Walloon and Brussels Regions • Speaking fees – Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma • Decision-making and consultation bodies – General Assembly and steering committee of EUCAST – European Medicines Agency (external expert) – US National Institutes of Health (grant reviewing) Slides: http://www.facm.ucl.ac.be Lectures 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 2 What do we do ? • Teaching of Pharmacology and • Toxicity, medicinal chemistry, and Pharmacotherapy improved schedules of aminoglycosides • Post-graduate training on Drug Development • novel antibiotics (and last studied) • Launching of Clinical Pharmacy in Europe • beta-lactams (ceftaroline…) • Web-based courses on anti-infective • fluoroquinolones (finafloxacine…) Pharmacology • kétolides (solithromycin…) • 30 graduating students, doctoral fellows and • oxazolidinones (tedizolid …) post-graduate fellows working on anti- infective therapy (laboratory and clinical applications) www.facm.ucl.ac.be • Editorial board of AAC and IJAA • Member of the General Committee of EUCAST (for ISC) and of its Steering committee (2008-10) • Member of the Belgian Antibiotic Policy Coordination Committee • Founder and Past President of the International Society of Antiinfective Pharmacology (ISAP) A partial view of our University Clinic (900 beds) and the Education and Research buildings (5,000 students), in the outskirts of Brussels, Belgium www.isap.org 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 3 Why do I have an interest in fluoroquinolones ? Because, like Obélix, I fell into when I was young … 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 4 Why do I have an interest in fluoroquinolones ? Because, like Obélix, I fell into when I was young … 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 5 Why do I have an interest in fluoroquinolones ? Because, like Obélix, I fell into when I was young … 1990 2005 2012 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 6 What shall we discuss ? • The basics: are quinolones different by design ? • When should they be given IV ? • Indications and experience of moxifloxacin IV • The fights against resistance: the saga of the MPC • Are they toxicity issues ? • What you can do with an MIC ? 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 7 Mechanism of action of fluoroquinolones: the basics... PORIN DNA Topo DNA gyrase isomerase Gram (-) Gram (+) 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 8 2 key enzymes in DNA replication: DNA gyrase topoisomerase IV bacterial DNA is supercoiled 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 9 Ternary complex DNA - enzyme - fluoroquinolone "GyraseCiproTop" by Fdardel - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:GyraseCiproTop.png#mediaviewer/File:GyraseCiproTop.png Last accessed: 8/2/2015 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 10 Fluoroquinolones are the first entirely man-made antibiotics: do we understand our molecule ? R5 O R COOH 6 R7 X8 N R1 Don’t panic, we will travel together…. 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 11 From chloroquine to nalidixic acid... nalidixic acid N CH3 O O HN CH 3 C - O chloroquine CH N N Cl N 3 C2H5 1939 O O C O- Cl N 1962 1958 C2H5 7-chloroquinoline (synthesis intermediate found to display antibacterial activity) 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 12 From nalidixic acid to the 1st fluoroquinolone norfloxacin * make 3 key O O nalidixic acid 2 C modifications *... F - O O O C - N O N HN 1 CH3 H3C N N C2H5 1978 3 broader Gram(-) activity less protein binding (50%) longer half-life (3-4h) * Belgian patent 863,429, 1978 to Kyorin * 6-fluoro-7-pyrimidino-quinoleine 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 13 From norfloxacin to ofloxacin via pefloxacin norfloxacin O O tricyclic compound C F - (as in flumequine but O morpholine ring) N N HN CH3 O O O O C - F O- F C - O- N N N N N O H3C N CH3 H3C CH3 pefloxacin ofloxacin* * Eur. pat. Appl. 47,005 to Daiichi, 1982 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 14 From norfloxacin to ciprofloxacin norfloxacin ciprofloxacin * O O C cyclopropyl to O O F - O increase potency C - F O N N HN N N CH3 HN * Ger. pat. 3,142,854 to Bayer AG, 1983 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 15 "1st generation" fluoroquinolones ofloxacin ciprofloxacin O O O O C F -- O C - F O N N N N N O H3C HN methyl CH3 piperazine cyclo morpholine piperazine propyl 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 16 From ofloxacin to levofloxacin... Ofloxacin is a racemic mixture O O C F -- N O H Levofloxacin is the pure (-) S isomer * N N O N O H3C CH3 CH 3 The active form of ofloxacin is the (-) S isomer * Eur. pat. 206,283 to Daiichi, 1987 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 17 Activity against S. pneumoniae I II III / IV O O O O F C F C - O- O N N N N HN HN H CO 3 ciprofloxacin moxifloxacin 0.5 - 2 0.01 - 0.5 O O C - F O- N N N O H3C CH3 levofloxacin 0.5 -2 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 18 Activity against B. fragilis (anaerobe) I II III / IV O O O O F C F C - O- O N N N N HN HN H CO 3 ciprofloxacin 2 - 128 moxifloxacin 0.25 - 8 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 19 At this point … Gram (-) Gram (+) anaerobes O O O O F C F C O- O- N N N N HN HN H CO O O 3 C F -- ciprofloxacin O moxifloxacin N N N O H3C CH3 levofloxacin This is by design ! 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 20 A unbiased estimation of antibiotic activity (in the absence of resistance) MIC distributions and epidemiologic al cut-off 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 21 Gram negative: E. coli ciprofloxacin 60 10- 11 Nov 2017 levofloxacin 50 40 E. coli 30 percent of isolates 20 10 Middle East Anti http://mic.eucast.org/Eucast2/regShow.jsp?Id=1022 http:// 0 Last accessed: 8/2/2015 mic.eucast.org/Eucast2/regShow.jsp?Id=1072 -04 9.8 × 10 ciprofloxacin -Infectives Forum, Abu Dhabi, U.A.E. 2.0 × 10 -03 levofloxacin 3.9 × 10 -03 7.8 × 10 -03 0.015625 0.03125 0.0625 0.125 0.25 M IC (m g/L) 0.5 1 2 4 8 1 6 32 64 22 Gram positive: S. pneumoniae S. pneumoniae moxifloxacin 80 70 60 m oxifloxacin levofloxacin 50 40 30 percent of isolates of percent 20 levofloxacin 10 0 -04 -03 -03 -03 1 2 4 8 0.5 1 6 32 64 10 10 10 10 0.25 × × × × 0.125 0.0625 0.03125 9.8 2.0 3.9 7.8 0.015625 M IC (m g/L) http://mic.eucast.org/Eucast2/regShow.jsp?Id=1099 http://mic.eucast.org/Eucast2/regShow.jsp?Id=1310 Last accessed: 8/2/2015 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 23 Anaerobes: B. fragilis moxifloxacin 40 10- 11 Nov 2017 30 levofloxacin levofloxacin (not recommended) B . fragilis 20 percent of isolates 10 Middle East Anti 0 9.8 × 10 -04 http://mic.eucast.org/Eucast2/regShow.jsp?Id=1454-03 m oxifloxacin http:// 2.0 × 10 Last accessed: 8/2/2015 -03 - × levofloxacin Infectives Forum,mic.eucast.org/Eucast2/regShow.jsp?Id=1066 Abu Dhabi, U.A.E. 3.9 10 7.8 × 10 -03 0.015625 0.03125 0.0625 0.125 0.25 M IC (m g/L) 0.5 1 2 4 8 1 6 32 64 24 What shall we discuss ? • The basics: are quinolones different by design ? • When should they be given IV ? • Indications and experience of moxifloxacin IV • The fights against resistance: the saga of the MPC • Are they toxicity issues ? • What you can do with an MIC ? 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 25 When should a fluoroquinolone be given IV ? • Firsts, they should not in many cases because mots have a good oral bioavailability (70 to 90%) • BUT the patient may require an IV treatment: – difficulties to swallow (consciousness, …) – vomiting – GIT disease – hemodynamic instability – risk of poor compliance (!) • and the doctor may be more comfortable: – more reliable peak levels and AUC – better organ penetration … 10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E.