Fluoroquinolones: Parenteral use

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 ovember 2017 With approval of the Belgian Common Ethical Health Platform visa no. 17/V1/10411/093945 10-11 ov 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.-FRS), Ministry of Health (SPF), and Walloon and Brussels Regions Speaking fees Bayer, GSK, Sanofi, Johnson & Johnson, M-Pharma Decision-making and consultation bodies General Assembly and steering committee of EUCAST European Medicines Agency (external expert) US ational Institutes of Health (grant reviewing) Slides: http://www.facm.ucl.ac.be Lectures 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 2

What do we do? Teaching of Pharmacology and Pharmacotherapy Post-graduate training on Drug Development Launching of Clinical Pharmacy in Europe Web-based courses on anti-infective Pharmacology 30 graduating students, doctoral fellows and post-graduate fellows working on antiinfective therapy (laboratory and clinical applications) Toxicity, medicinal chemistry, and improved schedules of aminoglycosides novel antibiotics (and last studied) beta-lactams (ceftaroline ) fluoroquinolones (finafloxacine ) kétolides (solithromycin ) oxazolidinones (tedizolid ) 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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 3

Why do I have an interest in fluoroquinolones? Because, like bélix, I fell into when I was young 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 4

Why do I have an interest in fluoroquinolones? Because, like bélix, I fell into when I was young 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 5

Why do I have an interest in fluoroquinolones? Because, like bélix, I fell into when I was young 1990 2005 2012 10-11 ov 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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 7

Mechanism of action of fluoroquinolones: the basics... PRI DA DA gyrase Topo isomerase Gram (-) Gram (+) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 8

2 key enzymes in DA replication: DA gyrase topoisomerase IV bacterial DA is supercoiled 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 9

Ternary complex DA - enzyme - fluoroquinolone "GyraseCiproTop" by Fdardel - wn 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 ov 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? R 5 R 6 CH R 7 X 8 R 1 Don t panic, we will travel together. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 11

From chloroquine to nalidixic acid... nalidixic acid H CH 3 CH 3 C - Cl chloroquine CH 3 1939 1958 Cl C 2 H 5 C - C 2 H 5 1962 7-chloroquinoline (synthesis intermediate found to display antibacterial activity) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 12

From nalidixic acid to the 1st fluoroquinolone norfloxacin * nalidixic acid make 3 key modifications *... 2 F C - H 3 C C - H 1 CH 3 C 2 H 5 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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 13

From norfloxacin to ofloxacin via pefloxacin norfloxacin F C - tricyclic compound (as in flumequine but morpholine ring) H CH 3 F C - F C - H 3 C CH 3 H 3 C CH 3 * Eur. pat. Appl. 47,005 to Daiichi, 1982 pefloxacin ofloxacin* 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 14

From norfloxacin to ciprofloxacin norfloxacin ciprofloxacin * F C - cyclopropyl to increase potency F C - H CH 3 H * Ger. pat. 3,142,854 to Bayer AG, 1983 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 15

"1st generation" fluoroquinolones ofloxacin ciprofloxacin F C - F C - methyl H 3 C piperazine CH 3 morpholine H piperazine cyclo propyl 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 16

From ofloxacin to levofloxacin... floxacin is a racemic mixture H 3 C F CH 3 C - H CH 3 Levofloxacin is the pure (-) S isomer * The active form of ofloxacin is the (-) S isomer * Eur. pat. 206,283 to Daiichi, 1987 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 17

Activity against S. pneumoniae I II III / IV F C - F C - H H H C 3 ciprofloxacin 0.5-2 moxifloxacin 0.01-0.5 F C - H 3 C CH 3 levofloxacin 0.5-2 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 18

Activity against B. fragilis (anaerobe) I II III / IV F C - F C - H H H C 3 ciprofloxacin 2-128 moxifloxacin 0.25-8 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 19

At this point Gram (-) Gram (+) anaerobes F C - F C - H H H C 3 ciprofloxacin F C - moxifloxacin H 3 C CH 3 levofloxacin This is by design! 10-11 ov 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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 21

Gram negative: E. coli E. co li ciprofloxacin 60 50 percent of isolates 40 30 20 ciprofloxacin levofloxacin levofloxacin 10 0 9.8 10-04 2.0 10-03 3.9 10-03 7.8 10-03 http://mic.eucast.org/eucast2/regshow.jsp?id=1022 http://mic.eucast.org/eucast2/regshow.jsp?id=1072 Last accessed: 8/2/2015 0.015625 0.03125 0.0625 0.125 0.25 0.5 M IC (m g/l) 1 2 4 8 1 6 32 64 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 22

Gram positive: S. pneumoniae S. pneumoniae moxifloxacin 80 70 percent of isolates 60 50 40 30 m oxifloxacin levofloxacin 20 levofloxacin 10 0 9.8 10-04 2.0 10-03 3.9 10-03 7.8 10-03 0.015625 0.03125 0.0625 0.125 0.25 http://mic.eucast.org/eucast2/regshow.jsp?id=1099 http://mic.eucast.org/eucast2/regshow.jsp?id=1310 Last accessed: 8/2/2015 0.5 M IC (m g/l) 1 2 4 8 1 6 32 64 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 23

Anaerobes: B. fragilis B. fragilis moxifloxacin 40 percent of isolates 30 20 m oxifloxacin levofloxacin 10 levofloxacin levofloxacin (not recommended) 0 9.8 10-04 2.0 10-03 3.9 10-03 7.8 10-03 0.015625 0.03125 0.0625 0.125 0.25 http://mic.eucast.org/eucast2/regshow.jsp?id=1454 http://mic.eucast.org/eucast2/regshow.jsp?id=1066 Last accessed: 8/2/2015 0.5 M IC (m g/l) 1 2 4 8 1 6 32 64 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 24

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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 26

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 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 27

Moxifloxacin IV indications https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdf Last visited: 11 ov 2017 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 28

A comprehensive meta-analysis of moxifloxacin IV in skin and skin structures infections Chu et al. Drug Res (Stuttg). 2015;65:650-7 - PMID: 26070015. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 29

Tissue penetration: abdominal abscesses Rink et al. Clin Drug Investig. 2008;28:71-9. PMID: 18211115 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 31

Tissue penetration: abdominal abscesses Rink et al. Clin Drug Investig. 2008;28:71-9. PMID: 18211115 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 32

Tissue penetration: abdominal abscesses Rink et al. Clin Drug Investig. 2008;28:71-9. PMID: 18211115 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 33

Fluid penetration: CSF 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 34

Fluid penetration: CSF The ratio of the AUC 24h in cerebrospinal fluid to the AUC 24h in serum was 0.7 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 35

Penetration in other tissues and effectiveness cancellous and cortical bone: 53.86 and 41.59% of the plasma concentration 1 much above the MIC90s for common susceptible pathogens suitable for treatment of osteomyelitis. body and manubrium of the sternal bone after IV administration: 1.65 g/g and 1.64 g/g at 2 h and 1.4 g/g and 1.45 g/g at 5 h 2 considered for the treatment of osteomyelitis. prophylactic treatment of post-endoscopic retrograde cholangiopancreatography cholangitis and cholangitis-associated morbidity 3 moxifloxacin IV not inferior to ceftriaxone. 1 Metallidis et al. J Chemother. 2007;19:682-7 - PMID: 18230551 2 Metallidis et al. Int J Antimicrob Agents. 2006;28:428-32 - PMID: 17034992. 3 Kim e al. Hepatobiliary Pancreat Dis Int. 2017;16:512-518 - PMID: 28992884. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 36

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 and the saga of the MPC Are they toxicity issues? What you can do with an MIC? 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 37

Resistance must first be assessed by MIC distributions Resistance of Gram-negative (ciprofloxacin/levofloxacin) is widespread and must be assessed locally (often ward by ward) MIC distributions of fluoroquinolones against P. aeruginosa in the Academic Hospital of the University of Leuven, Belgium EUCAST breakpoints: Cipro: S 0.5 R > 0.5 Levo: S 1.0 R > 1.0 flo: -- -- 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 38

Resistance must first be assessed by MIC distributions Conversely, resistance of Gram-positive is variable High for MRSA (co-resistance frequent) Low for S. pneumonia (especially for moxifloxacin; close to breakpoint for levofloxacin) wild type population (EUCAST) clinical breakpoint: EUCAST CLSI 100 100 90 90 80 lévofloxacine moxifloxacine 80 70 70 % (cumulative) 60 50 40 60 50 40 % (cumulative) 30 30 20 20 10 10 0 0 0.0625 0.125 0.25 0.5 1 2 C M I (m g/l) 4 8 16 32 0.0625 0.125 0.25 0.5 1 2 C M I (m g/l) 4 8 16 32 MIC distributions of S. pneumonia in Belgium for CAP (n=249) Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 39

Resistance must first be assessed by MIC distributions Conversely, resistance of Gram-positive is variable High for MRSA (co-resistance frequent) Low for S. pneumonia (especially for moxifloxacin; close to breakpoint for levofloxacin) wild type population (EUCAST) clinical breakpoint: EUCAST CLSI 100 100 90 90 80 lévofloxacine moxifloxacine 80 70 70 % (cumulative) 60 50 40 otice how close levofloxacin MICs are to the breakpoint 60 50 40 % (cumulative) 30 30 20 20 10 10 0 0 0.0625 0.125 0.25 0.5 1 2 C M I (m g/l) 4 8 16 32 0.0625 0.125 0.25 0.5 1 2 C M I (m g/l) 4 8 16 32 MIC distributions of S. pneumonia in Belgium for CAP (n=249) Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 40

C max and "Mutant Prevention Concentration" (MPC) 1 MIC 99 = 0.8 mg/l (in this example) Surviving bacteria 10-2 10-4 10-6 10-8 "Classic" bactericidal effect poorly sensitive organisms Elimination 10-10 of resistant organisms MPC 10 = 9 0.01 0.10 1.00 10.00 concentration Dong et al: AAC 1999; 43:1756-1758 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 41

"Mutant Prevention Concentration " Surviving bacteria 1 10-2 10-4 10-6 10-8 MIC 99 = 0.8 10-10 MPC 10 = 9 0.01 0.10 1.00 10.00 concentration Concentration that inhibits the majority of the organisms Concentration needed to prevent the selection of resistant organisms (about 10 x the MIC) Dong et al; AAC 43:1756-1758 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 42

The risk for resistance to fluoroquinolones is to be within the mutation selection window Mutation selection window concentration MSW MPC MIC Time after administration concept from Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 43

So, what should you do with a fluoroquinolone to avoid emergence of resistance If you wish to get a faster eradication and reduce mergence of resistant peak / MIC > 10 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 44

MPC: moxifloxacin vs levofloxacin 10 x the median MIC (0.125 mg/l) 10 x the median MIC (1 mg/l) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 45

The saga of the AUC / MIC vs C max / MIC ratio for fluoroquinolones... AUC / MIC 1 is predictor of activity for Gram (-)... 1 The impact of the C max could not b tested in this study Forrest et al., AAC, 1993 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 46

Is 125 good for all?? The saga of S. pneumoniae... 100 100 Mortality (%) 80 60 40 20 Emax at 30... Percent mortality 80 60 40 20 Emax at 125... 0 0 1 2.5 5 10 25 50 100 3 10 30 100 300 1000 24 Hr AUC/MIC 24 hr AUC/MIC non-neutropenic mice neutropenic mice 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 47

Conditions That Predispose to Pneumococcal Infection Defective antibody formation PrimaryCongenital agammaglobulinemia Common variable (acquired) hypogammaglobulinemia Selective IgG subclass deficiency SecondaryMultiple myeloma Chronic lymphocytic leukemialymphoma HIV infection Defective complement (primary or secondary) Decreased or absent C1, C2, C3, C4 Insufficient numbers of PMs PrimaryCyclic neutropenia SecondaryDrug-induced neutropenia Aplastic anemia Poorly functioning PMs Alcoholism Cirrhosis of the liver So, an AUC/MIC = 125 may be good even for S. pneumoniae 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 48

AUC/MIC: modelling the clinical use denholt & Cars J Antimicrob Chemother. 2006;58:960-5 - PMID: 16936293. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 49

AUC/MIC: modelling the clinical use AUBKC: area under bacterial killing curve ( log CFU) denholt & Cars J Antimicrob Chemother. 2006;58:960-5 - PMID: 16936293. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 50

So, what should you do with a fluoroquinolone to avoid emergence of resistance and be optimal for activity If you wish to get a faster eradication and reduce mergence of resistant peak / MIC > 10 If you are interested in global effect AUC 24h / MIC: 125 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 51

Pharmacokinetics and resistance breakpoint vs. MIC % of strains 100 80 60 40 moxi Maximal MIC to avoid selection of resistance levo resistance breakpoint AUC/MIC = 100 peak/mic = 10 Levofloxacin 500 mg 1X / day AUC [(mg/l)xh] 47 peak [mg/l] 5 MIC max 0.5 Moxifloxacin 400 mg 1X / day AUC [(mg/l)xh] 48 peak [mg/l] 4.5 MIC max 0.5 20 0 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 MIC MIC data: EUCAST MIC distributions (wild type) PK data: US and EU labelling (typical values) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 52

What differentiates fluoroquinolones? Results with S. pneumoniae Would this cause less emergence of resistance? 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 53

Is there a molecular basis for a lesser emergence of resistance with moxifloxacin? A C8-methoxy group lowers the MPC for an -1-cyclopropyl-f luoroquinolone" H 3 C F C CH 3 - H F H C 3 C - levofloxacin moxifloxacin https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdf Last accessed: 8/2/2015 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 54

We all agree about efficacy, but what about side effects therapy? side effects? 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 56

All antimicrobials have associated risks * Class Drugs Frequent or serious side effects fluoroquinolones levofloxacin Anaphylactic reactions and allergic skin reactions Clostridium difficile-associated colitis Hematologic toxicity Hepatotoxicity (ALT-AST elevation [common]) Central nervous system effects: headache, insomnia, dizziness, convulsions Musculoskeletal: tendinopathies Peripheral neuropathy Prolongation of the QTc interval (cardiac disorders [rare]) Hypoglycaemia (rare) Digestive tract: nausea, diarrhoea moxifloxacin * based on an analysis of the current respective labelling (European SmPC) - common: 1/10 to 1/100 - rare: 1/1000-1/10000 Anaphylactic reactions and allergic skin reactions Clostridium difficile-associated colitis Hepatotoxicity (ALT-AST elevation [common]) Musculoskeletal: Tendinopathies Peripheral neuropathy Prolongation of the QT interval (cardiac disorders [rare]) Central nervous system effects: headache, insomnia, dizziness, convulsions Digestive tract: nausea, diarrhoea ote: the current EU SmPCs of levofloxacin (TAVAIC ) and of moxifloxacin state: For [community-acquired pneumonia], TAVAICc should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections. Moxifloxacin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections. Carbonelle et al., in preparation 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 57

Side effects of moxifloxacin (clinical trials database) Based on the analysis of 14,681 patients treated with moxifloxacin vs. 15,023 patients treated with comparators 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 58

Side effects of moxifloxacin (clinical trials database) P= oral IV = intravenous MXF: moxifloxacin CMP = comparator (see left column) Tulkens et al., Drugs R D (2012) 12: 71-100 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 59

Side effects of moxifloxacin (clinical trials database) Patients at risk? P sequential IV age (> 65 y) n = 2551 vs. 2403 n = 1373 vs. 1334 n = 170 vs. 191 AE 1050 / 1021 929 / 900 83 / 81 ADR 440 / 448 348 / 307 27 / 31 SAE 207 / 184 298 / 290 32 / 24 SADR 16 / 18 49 / 30 4 / 6 discont. AE 116 / 109 131 / 104 10 / 10 discont. ADR 78 / 74 62 / 42 4 / 6 death AE 29 / 32 100 / 98 13 / 10 death ADR. 3 / 1 2 / 3 0 / 1 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) diabetes n = 777 vs. 717 n = 926 vs. 917 n = 80 vs. 72 AE 355-310 587 / 565 42-35 ADR 158-126 196 / 174 13-14 SAE 78-56 198 / 182 16-11 SADR 11-3 22 / 11 2-2 discont. AE 34-26 78 / 64 6-6 discont. ADR 22-14 38 / 20 1-4 death AE 10-6 46 / 23 9-4 death ADR. 0-0 2 / 2 0-0 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) Tulkens et al., Drugs R D (2012) 12: 71-100 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 60

Side effects of moxifloxacin (clinical trials database) Patients at risk? renal impairment P sequential IV n = 1283 vs. 1229 n = 889 vs. 863 n = 203 vs. 218 AE 1283-1229 572-549 102-92 ADR 259-229 196-181 31-32 SAE 94-80 202-180 26-22 SADR 9-9 30-23 2-1 discont. AE 49-53 75-78 11-7 discont. ADR 27-33 28-25 2-3 death AE 12-14 58-67 10-7 death ADR. 0-3 3-3 0-0 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) hepatic impairment n = 146 vs. 163 n = 183 vs. 196 n = 46 vs. 46 AE 69-70 183-196 23-18 ADR 37-32 43-43 7-6 SAE 5-7 60-53 7-7 SADR 1-1 10-7 1-0 discont. AE 6-7 24-24 1-1 discont. ADR 6-3 11-7 1-0 death AE 2-4 14-24 2-0 death ADR. 0-1 1-2 0-0 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) Tulkens et al., Drugs R D (2012) 12: 71-100 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 61

Side effects of moxifloxacin (clinical trials database) Patients at risk? cardiac disorders P sequential IV n = 1476 vs. 1404 n = 1476 vs. 1136 n = 106 vs. 104 AE 707-655 804-804 63-57 ADR 340-297 315-293 16-25 SAE 132-110 251-246 23-11 SADR 14-8 43-35 3-2 discont. AE 70-64 119-96 7-3 discont. ADR 43-45 59-43 1-1 death AE 11-25 69-75 11-8 death ADR. 0-2 3-4 0-1 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) BMI < 18 n = 318 vs. 365 n = 116 vs. 115 n = 45 vs. 53 AE 113-171 89-83 17-10 ADR 70-96 26-27 5-3 SAE 11-28 36-30 3-3 SADR 0-5 5-4 0-0 discont. AE 14-27 10-11 1-0 discont. ADR 12-20 6-9 1-0 death AE 3-5 15-15 1-0 death ADR. 0-0 0-0 0-0 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10 relative risk estimate (moxifloxacin / comparator) Tulkens et al., Drugs R D (2012) 12: 71-100 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 62

Hepatotoxicity Crude incidence rates of acute liver injury caused by antibiotics Antibiotic population per 100,000 users fluoroquinolones (w/o moxifloxacin) moxifloxacin cotrimoxazole erythromycin amoxicillinclavulanic acid utpatient clinic, Sweden (1995-2005) utpatient clinic, Sweden (1995-2005) Saskatchewan Health Plan, Canada (1982-1986) Saskatchewan Health Plan, Canada (1982-1986) General practice research database, United Kingdom (1991-1992) Incidence rate (CI) per 100,000 prescriptions endpoint 0.7 (0.5-1.1) International consensus 0.08 (0.0-0.5) International consensus 1.0 (0.2-5.7) 4.9 (0.9-27.6) International consensus, hospitalisation 2.0 (0.7-5.9) 14.0 (4.8-41.2) International consensus, hospitalisation 22.5 (14.7-34.4) 17.4 (11.4-26.5) International consensus Ref. [1] [1] [2] [2] [3] 1. De Valle et al. Aliment Pharmacol Ther 2006 ct 15; 24(8): 1187-95 2. Perez et al. Epidemiology 1993 ov; 4(6): 496-501 3. Garcia-Rodriguez et al. Arch Intern Med 1996 Jun 24; 156(12): 1327-32 Van Bambeke & Tulkens, Drug Safety (2009) 32:359-78 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 63

Hepatotoxicity Hepatotoxicity risk of antibiotics (percentage of prescriptions for antibiotics with main indications for use in the community setting) Andrade & Tulkens, JAC (2011) 66: 1431 46 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 64

EMA position the risk of arrhythmias appears to increase with the extent of QT/QTc prolongation. Drugs [with] QT/QTc interval by around 5 ms or less do not appear to cause TdP. data on drugs [with] QT/QTc interval by 5 to < 20 ms are inconclusive, but some of these compounds have been associated with proarrhythmic risk.* moxifloxacin: 6-10 sparfloxacin: 15 erythromycin: 30 fluoxetine: 2 clarithromycin: 11-22 terfenadine: 46 0 10 20 30 40 msec 50 decisions about [drug] development and approval will depend upon the morbidity and mortality associated with the untreated disease or disorder and the demonstrated clinical benefits of the drug, especially as they compare with available therapeutic modalities. * this includes erythromycin and clarithromycin (Balardinelli et al, TIPS (2003) 24:619-625) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 65

QTcB prolongation after IV use Haverkamp et al. Curr Drug Saf. 2012;7:149-63. PMID 22873499 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 66

QTcB prolongation after IV use QTcB: QT interval corrected for heart rate and calculated according to Bazett s formula Haverkamp et al. Curr Drug Saf. 2012;7:149-63. PMID 22873499 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 67

QTc prolongation wens & Ambrose CID (2005) 41:S144-157 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 68

Torsade de pointe: comparison of risk reporting rate of Torsades de pointe induced by antibiotics drug o. of U.S. Cases Reported to the FDA o. of Estimated Total U.S. Prescriptions (millions) o. of Cases /10 Millions Prescriptions (95% CI) moxifloxacin 0 1.4 0 (0-26) ciprofloxacin 2 66 0.3 (0.0-1.1) used as negative control in RCT ofloxacin 2 9.5 2.1 (0.3-7.6) levofloxacin 13 24 5.4 (2.9-9.3) gatifloxacin 8 3 27 (12-53) erythromycin 11 17 151 0.7-1.1 clarithromycin 16 31 90 1.8-3.4 azithromycin 7 10 124 0.6 1 FDA warning March 12,2013 cefuroxime 1-1 42 0.2 1 Van Bambeke & Tulkens, Drug Safety (2009) 32:359-78 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 69

Tendinopathies: main features and incidence in 2010 Kim & Del Rosso, J Clin Aesthet Dermatol. 2010; 3:49 54. 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 70

Tendinopathies In 2005, all fluoroquinolones marketed in the US have received a black box label about tendinopathies 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 71

Tendinopathies But this is what we found for moxifloxacin in our survey of the whole clinical trial database very rare and no difference no case P= oral IV = intravenous MXF: moxifloxacin CMP = comparator Tulkens et al., Drugs R D (2012) 12: 71-100 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 72

Tendinopathies: incidences (revisited) in 2011 http://www.ismp.org/quarterwatch/2010q2.pdf Last accessed: 20/02/2015 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 73

Tendinopathies: incidences (revisited) in 2011 http://www.ismp.org/quarterwatch/2010q2.pdf Last accessed: 20/02/2015 http://www.ismp.org/quarterwatch/2010q2.pdf Last accessed: 20/02/2015 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 74

Calculation of the "attainable MIC" Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect. 2005 Apr;11(4):256-80. PMID: 15760423 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 76

Enterobacteriaceae Check the EUCAST breakpoints All EUCAST data are freely available at http://www.eucast.org 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 77

Enterobacteriaceae Check the EUCAST breakpoints ow, if you have an organism with an MIC of 0.05 easy success for any fluoroquinolone (even oral)! 1 2 4 borderline for cipro/ moxi / norflo / oflo ensure correct dosage! levo BUT with a high dose! likely to fail no matter which fluoroqunolone 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 78

Enterobacteriaceae Check the EUCAST breakpoints Maximal Interest for the Clinician ow, if you have an organism with an MIC of 0.05 easy success for any fluoroquinolone (even oral)! 1 2 4 borderline for cipro/ moxi / norflo / oflo ensure correct dosage! levo BUT with a high dose! likely to fail no matter which fluoroqunolone 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 79

Thank you for your attention! 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 80

The "first generation" of fluoroquinolones 1960 1970 1980 t 1/2 activity alidixic acid orfloxacin 3-4 h ++ xolinic acid Pefloxacin 11 h + Cinoxacin Pipemidic acid floxacin Ciprofloxacin Fleroxacin improved anti Gram (-) activity 6 h ++ 3-4 h +++ Rufloxacin 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 81

An interesting paper 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 96

An interesting paper 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 97

An interesting paper Target attainment rate for S. pneumoniae 100 75 50 25 0 90% MXF 400 mg q24h (MIC = 0.25 mg/l) LVX 500 mg q12h (M IC = 1 m g/l) 0 6 12 18 24 30 delay (h) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 98

A very recent paper Target attainment rate for S. pneumoniae 100 75 50 25 0 90% MXF 400 mg q24h (MIC = 0.25 mg/l) LVX 500 mg q12h (MIC = 1 mg/l) LVX 500 mg q24h (M IC = 1 m g/l) 0 6 12 18 24 30 delay (h) 10-11 ov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 99