sign in sign up
<<
Home , Auguste Beernaert, Corneille Heymans, Finafloxacin

Fluoroquinolones: are they all the same (or not) ?

Paul M. Tulkens, MD, PhD

Cellular and Molecular Pharmacology Louvain Drug Research Institute Université catholique de Louvain Brussels,

Singapore

With approval of the Belgian Common Ethical Health Platform – visa no. 16/V1/7383/078554

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 1 Disclosures and slides availability • Research grants – Theravance, Astellas, Cempra, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Debiopharm, Eumedica – Fund for Sientific Research (F.R.S.-FNRS), Federal Public Service "Public Health", Walloon and Brussels Regions, (FP7 and JPIAMR)

• Speaker's honoraria – Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma, Vifor – Flemish Education Program on (Opleidingsprogramma Antibioticabeleid Vlaanderen)

• Advisory Committees and Decision-making Bodies – US National Institutes of Health (grant reviewing) – General Assembly and former member of the Steering committee of EUCAST – External expert for the European Medicines Agency (EMA) – Former member Belgian Drug Reimbursement Committee (CRM / CTG) – Member of the Belgian Policy Coordination Committee (BAPCOC) – Governance of the EU program "DRIVE AB" (new economical framework for antibiotics)

Slides: http://www.facm.ucl.ac.be  Lectures

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 2 Belgium 10 millions inhabitants … 10 Nobel prizes (10/850)

• Peace - Institute of International Law, (1904) - Auguste Beernaert (1909) - Henri Lafontaine (1913) - Father (1958) • Literature - Maurice Maeterlinck, Ghent (1911) • Medicine - , Brussels (1919) - Corneille Heymans, Ghent (1938) - , Louvain (1974) - , Brussels (1974) • Chemistry - Ilya Prigogyne, Brussels (1977) - Physics - François Englert, Brussels (2013)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 3 The Catholic University of Louvain in brief (1 of 4)

• originally founded in 1425 in the city of Louvain (in French and English; known as in Flemish)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 4 The Catholic University of Louvain in brief (2 of 4)

• It was one of the major University of the so-called "Low Countries" in the 1500 – 1800 period, with famous scholars and discoverers (Vesalius for anatomy, Erasmus for philosophy, …). Teaching was in Latin, Greek, and Hebrew (College of the 3 languages…)

The University in the 1500's Erasmus Vesalius

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 5 The Catholic University of Louvain in brief (3 of 4)

• In the 19th century, teaching was in French but in the early 1900's, a Flemish- speaking section was opened. Courses were given in both languages, attracting many students and celebrities…

Professor C. de Duve, Professor of Biochemistry, obtained the ( and Medicine) in 1974 for his work on Prof. G. Lemaitre, professor of Physics intracellular organelles and Mathematics at the University who, (lysosomes, peroxisomes…) in the 1930's, made the first suggestion of the continuous expansion of the (here in front of a centrifuge) Universe (“big bang”) (here in conversation with A. Einstein)

• in 1968, the University was divided into – a French-speaking Université catholique de Louvain – a Flemish-speaking Katholieke Universiteit Leuven…

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 6 The Catholic University of Louvain in brief (4 of 4)

• The Flemish-speaking Katholieke Universiteit Leuven has remained in Louvain (Leuven) and is named in English "Catholic Universiteit Leuven". • The French-speaking Université catholique de Louvain has moved about 25 km South in a place called "Louvain-la-Neuve, with the "Health Sciences Sector" located in Brussels (Woluwé)

Université catholique Katholieke de Louvain Universiteit http://www.uclouvain.be Leuven http://www.kuleuven.be 10 km

• Together, the two Universities have about 55,000 students

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 7 What do we do ?

• Teaching of Pharmacology and • Toxicity, medicinal chemistry, and improved schedules of aminoglycosides Pharmacotherapy • one-line monitoring of β-lactams • Post-graduate training on Drug Development • novel antibiotics (and last studied) • Launching of Clinical Pharmacy in Europe • lipoglycopeptides (oritavancin…) • Web-based courses on anti-infective • beta-lactams (ceftaroline…) Pharmacology • fluoroquinolones (finafloxacin…) • 30 graduating students, doctoral fellows and • ketolides (solithromycin…) post-graduate fellows working on anti- • oxazolidinones (tedizolid …) 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 8 Why do I have an interest in fluoroquinolones ?

Because, like Obélix, I fell into when I was young …

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 9 Why do I have an interest in fluoroquinolones ?

Because, like Obélix, I fell into when I was young …

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 10 Why do I have an interest in fluoroquinolones ?

Because, like Obélix, I fell into when I was young … 1990

2005

2012

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 11 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?)

• The real life in the lab: microbiological properties and risk of resistance… (or how to really differentiate them …)

• The real life in the doctor’s office: efficacy and tolerance… (is there a difference) ?

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 12 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?)

• The real life in the lab: microbiological properties and risk of resistance… (or how to really differentiate them …)

• The real life in the doctor’s office: efficacy and tolerance… (is there a difference) ?

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 13 Mechanism of action of fluoroquinolones: the basics...

PORIN

DNA

Topo DNA gyrase isomerase

Gram (-) Gram (+)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 14 2 key enzymes in DNA replication:

DNA gyrase

topoisomerase IV

bacterial DNA is supercoiled

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 15 A bit of history: from chloroquine to ...

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)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 16 From nalidixic acid to the 1st fluoroquinolone

*

3 key O O nalidixic acid 1 C modifications *... F - O O O

C - N O N HN 2 CH3 H3C N N C2H5 1978 3 1. broader Gram(-) activity 2. less protein binding (50%) 3. longer half-life (3-4h)

* Belgian patent 863,429, 1978 to Kyorin * 6-fluoro-7-pyrimidino-quinoleine

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 17 From norfloxacin to and

Ciprofloxacin *

O O

C F - norfloxacin O

O O N N HN C F - O ↗ activity (cyclopropyl) N N HN CH3 Ofloxacin ** O O

C - F O-

N N

N O H3C CH3 * Ger. pat. 3,142,854 to Bayer AG, 1983 ↗ half-life ** Eur. pat. Appl. 47,005 to Daiichi, 1982 (methyl) check this… (morpholine)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 18 is the active isomer of ofloxacin

Ofloxacin is a racemic mixture 50/50

O O

C - N F O- H Levofloxacin is the N N O pure (-) S isomer of N O H C 3 CH ofloxacin * 3 CH 3

The active form of ofloxacin is the (-) S isomer The (+) R isomer is inactive but toxic

* Eur. pat. 206,283 to Daiichi, 1987

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 19 The present "first generation" of fluoroquinolones ...

1960 1970 1980

t1/2 activity • Nalidixic acid • Norfloxacin 3-4 h ++ • Mainly • Ofloxacin anti Gram (-) 6 h ++ • activity • • Ciprofloxacin 3-4 h +++

• Levofloxacin 6 h ++/++

2 x more active than ofloxacin per g

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 20 How to improve the chemotherapeutic usefulness of the "first generation" fluoroquinolones

1. Maintain broad Gram(-) activity ? “2d generation”

2. Further Improve Gram(+) activity ?

3. Acquire activity against anaerobes ?

“3d generation”

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 21 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 MIC = 0.5 - 2 MIC = 0.01 - 0.5 O O

C - F O-

N N Hint: N lower MICs = a more potent antibiotic ! O H3C CH3

levofloxacin MIC = 0.5 -2

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 22 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 moxifloxacin MIC = 2-128 MIC= 0.125-8

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 23 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 !

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 24 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?)

• The real life in the lab: microbiological properties and risk of resistance… (or how to really differentiate them …)

• The real life in the doctor’s office: efficacy and tolerance… (is there a difference) ?

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 25 A unbiased estimation of antibiotic activity (in the absence of resistance)

http://www.eucast.org

MIC distributions and epidemiological cut-off

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 26 MIC for Gram-negative bacteria : E. coli as an example

E. coli

60 ciprofloxacin

50

40

ciprofloxacin levofloxacin 30

percent of isolates of percent 20

10 levofloxacin

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=1022 http://mic.eucast.org/Eucast2/regShow.jsp?Id=1072 Last accessed: 8/2/2015

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 27 MIC for Gram-positive bacteria: S. pneumoniae as an example

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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 28 Anaerobes: B. fragilis

B. fragilis

moxifloxacin 40

30 moxifloxacin s e

t levofloxacin a l o s i

f

o 20

t n e c r e p

10 levofloxacin levofloxacin (not recommended)

0 4 3 3 3 -0 -0 -0 -0 5 5 5 5 5 .5 1 2 4 8 6 2 4 2 2 2 2 .2 0 1 3 6 0 0 0 0 6 1 6 .1 0 1 1 1 1 5 3 .0 0 × × × × 1 .0 0 .8 .0 .9 .8 .0 0 9 2 3 7 0 MIC (mg/L) http://mic.eucast.org/Eucast2/regShow.jsp?Id=1454 http://mic.eucast.org/Eucast2/regShow.jsp?Id=1066 Last accessed: 8/2/2015

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 29 Killing abilities of fluoroquinolones: Are they all equal against susceptible strains ? in vitro kill curves: observations with S. pneumoniae

Same effect but at different concentrations…

Schafer et al. Diag Microb Infect Dis 2008; 60:155–161

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 30 Killing abilities of fluoroquinolones: Are they all equal against less susceptible strains ? Animal survival experiments (S. pneumonia i.p. inoculations)

Levofloxacin (LVX)

strain MIC (mg/L) MXF LVX

AR33118 (■) 0.12 1

FL2812 (●) 0.25 2

Moxifloxacin FL5629 () 4 32 (MXF)

Hint: lower dose (more to the left)  more potent antibiotic !

Huelves et al. Int J Antimicrob Agents 2006; 27:294–299

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 31 The risk for resistance to fluoroquinolones is to be “within the mutation selection window” …

Mutation selection window

MPC MSW concentration MIC

Time after administration concept from Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 32 Cmax and "Mutant Prevention Concentration" (MPC) …

1 MIC 99 = 0.8 mg/L (in this example)

10-2 "Classic" bactericidal effect 10-4 poorly sensitive organisms… 10-6

10-8 Surviving bacteria Surviving Elimination of resistant 10-10 MPC10 = 9 organisms

0.01 0.10 1.00 10.00 concentration

Dong et al: AAC 1999; 43:1756-1758

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 33 "Mutant Prevention Concentration …"

Concentration that 1 MIC 99 = 0.8 inhibits the majority of the organisms 10-2

10-4

10-6

10-8 Surviving bacteria Surviving A concentration of about 10 x the MIC is -10 10 MPC 10 = 9 needed to prevent selecting resistant subpopulations ! 0.01 0.10 1.00 10.00 concentration

Dong et al; AAC 43:1756-1758

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 34 MPC: moxifloxacin vs levofloxacin

∼10 x the median MIC (0.125 mg/L) ∼10 x the median MIC (1 mg/L)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 35 and “resistance” breakpoint vs. MIC

Maximal MIC to avoid selection % of strains resistance breakpoint of resistance  AUC/MIC = 100 100  peak/MIC = 10

Levofloxacin 500 mg 1X / day 80 moxi • AUC [(mg/l)xh] 47 • peak [mg/l] 5

 MICmax ∼ 0.5 60 Moxifloxacin 400 mg 1X / day levo • AUC [(mg/l)xh] 48 40 • peak [mg/l] 4.5

 MICmax ∼ 0.5

20

0 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 MIC data: EUCAST MIC distributions (wild type) PK data: US and EU labelling (typical values) MIC

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 36 Hs resistance to moxifloxacin materialized: evidence for S. pneumoniae in Belgium from 1999 to 2014 *

* Moxifloxacin was introduced in Belgiumin S. pneumoniae susceptibility to 2001 and became the almost only moxifloxacin in Belgium fluoroquinolone used for RTI since 2004 100

From data of a national collection

75 MXF 1999 • Non invasive respiratory tract infections MXF 2014 • similar results in 2008 for a collection of S.pneumoniae from clinically-confirmed CAP (n=132) Similar • Surveys from the Belgian Scientific Institute for 50 curves for 2001 Public Health for S. pneumoniae from through community isolates 2014 (n=156 in 1999 and 312 in 2014) cumulative percentage 25 • Data available yearly for 1999 through 2014 at http://www.iph.fgov.be

0 1 2 4 0.5 0.25 0.125 0.0625 MIC 0.03125 0.015625 0.0078125 EUCAST Vanhoof et al. 19th ECCMID, Helsinki, 2009 th breakpoint Ceyssens et al. 35 RICAI, Paris, 2015 Ceyssens et al. submitted

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 37 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?)

• The real life in the lab: microbiological properties and risk of resistance… (or how to really differentiate them …)

• The real life in the doctor’s office: efficacy and tolerance… (is there a difference) ?

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 38 Head to head comparison…

Clinical Infectious Diseases 2006;42:73-81.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 39 Head to head comparison…

Clinical Infectious Diseases 2006;42:73-81.

72-h Holter Randomisation monitor

12-lead ECG 12-lead ECG

Moxifloxacin 400mg q.d. Hospitalised CAP IV PO Levofloxacin 500mg q.d.

Visit 1 Visit 2 Test of cure Day 1 (Day 3–5) + 5–21days

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 40 and results in a snapshot…

123 /14 0

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 41 and results in a snapshot…

moxifloxacin 400 mg daily was numerically 123 superior to levofloxacin 500 mg daily /14 0

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 42 Efficacy over combination: moxifloxacin alone against levofloxacin PLUS ceftriaxone in CAP !

Clinical Infectious Diseases 2008; 46:1499-509.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 43 Efficacy: moxifloxacin alone against levofloxacin PLUS ceftriaxone in CAP !

Clinical Infectious Diseases 2008; 46:1499-509.

Background to the study • Designed to further demonstrate the efficacy and safety of moxifloxacin in CAP • According to European (EMA; CPMP) guidelines – Potent comparator (ceftriaxone/levofloxacin b.i.d.) – Review of the data by independent committees (clinical response, chest X-ray, cardiac events) – Non-inferiority trial: can do as well as this combination ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 44 What was done in MOTIV ?

C and ECG x3 Randomisation max 15 min post-dose, Day 1, Day 3

Stratification PSI III (<50%) Moxifloxacin alone *

Levofloxacin/ceftriaxone** Patients with CAP & PSI score >II Moxifloxacin alone *

PSI IV & V (≥50%) Levofloxacin/ceftriaxone **

Clinical Days Test of cure Late FU Pre-therapy evaluation 3–5 Days 4–14 Days 21–28

* moxifloxacin: 400 mg/day ** levofloxacin: 500 mg twice a day /ceftriaxone: 2g/day

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 45 Which patients ?

Moxifloxacin Ceftriaxone + Characteristic (N=291) levofloxacin (N=278)

Age (years; mean ± SD) 66.0 ± 16.2 64.8 ± 16.7 Male sex, n (%) 191 (65.6) 164 (59.0)

Cardiac comorbidity, n (%) 89 (30.6) 90 (32.4) Duration of CAP symptoms prior to 5.0 ± 3.5 4.6 ± 2.8 enrolment, mean days ± SD Failure on previous systemic 39 (13.4) 40 (14.4) antimicrobials, n (%) Intensive care admission, n (%) 25 (8.6) 30 (10.8)

PSI distribution Class III, n (%) 122 (41.9) 111 (39.9)

Class IV, n (%) 138 (47.4) 134 (48.2)

Class V, n (%) 31 (10.7) 33 (11.9)

All differences were non-significant

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 46 And what did you get ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 47 And what did you get ?

moxifloxacin 400 mg daily was not inferior to a combination of levofloxacin 2 x 500 mg daily plus ceftriaxone 2 g daily

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 48 We all agree about efficacy, but what about side effects…

therapy ?

side effects ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 49 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 • 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 * based on an analysis of the current respective labelling (European SmPC) - common: 1/10 to 1/100 - rare: 1/1000-1/10000

Note: the current EU SmPCs of levofloxacin (TAVANIC®) and of moxifloxacin state: • For [community-acquired pneumonia], TAVANICc 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 22/03/2016 Are all fluoroquinolones equal ? -- Singapore 50 A reasonable equilibrium for moxifloxacin ?

• rapid bactericidal activity • toxicity ? • ad hoc spectrum • S. pneumoniae • H. influenzae • M. catarrhalis • intracellular (atypical pneumonia, tuberculosis) • easy iv/po switch • excellent oral

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 51 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 52 Side effects of moxifloxacin (clinical trials database)

PO= oral IV = intravenous MXF: moxifloxacin COMP = comparator (see left column) Tulkens et al., Drugs R D (2012) 12: 71-100

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 53 Side effects of moxifloxacin (clinical trials database)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 54 Side effects of moxifloxacin (clinical trials database)

• AE, ADR and SADR were mainly gastrointestinal disorders and "changes observed during investigations" such as asymptomatic QT prolongation. • Incidence rates of hepatic disorders, tendon disorders, surrogates of QT prolongation, serious cutaneous reactions and Clostridium difficile-associated diarrhoea were similar with moxifloxacin and comparators.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 55 Side effects of moxifloxacin (clinical trials database)

Patients at risk ? PO sequential IV

age (> 65 y) n = 2551 vs. 2403 n = 1373 vs. 1334 n = 170 vs. 191

AE 1050 / 1021 929 / 900 83 / 81

AD R 440 / 448 348 / 307 27 / 31

SAE 207 / 184 298 / 290 32 / 24

SAD R 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

AD R 158 - 126 196 / 174 13 - 14

SAE 78 - 56 198 / 182 16 - 11

SAD R 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 56 Side effects of moxifloxacin (clinical trials database)

Patients at risk ?

PO sequential IV renal impairment n = 1283 vs. 1229 n = 889 vs. 863 n = 203 vs. 218

AE 1283 - 1229 572 - 549 102 - 92

AD R 259 - 229 196 - 181 31 - 32

SAE 94 - 80 202 - 180 26 - 22

SAD R 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

AD R 37 - 32 43 - 43 7 - 6 SAE 5 - 7 60 - 53 7 - 7

SAD R 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 57 Side effects of moxifloxacin (clinical trials database)

Patients at risk ?

PO sequential IV cardiac disorders n = 1476 vs. 1404 n = 1476 vs. 1136 n = 106 vs. 104

AE 707 - 655 804 - 804 63 - 57

AD R 340 - 297 315 - 293 16 - 25

SAE 132 - 110 251 - 246 23 - 11

SAD R 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

AD R 70 - 96 26 - 27 5 - 3

SAE 11 - 28 36 - 30 3 - 3

SAD R 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 58 Side effects of moxifloxacin (clinical trials database)

Comparison with other drugs ? A. oral therapy

1. moxifloxacin vs β-lactams

risk factor: age > 65 y diabetes renal impairment hepatic impairment cardiac disorders BMI < 18 (n= 909 vs 788) (n = 282 vs 217) (n = 347vs 380) (n = 47 vs 53) (n = 526 vs 444) (n = 70 vs 76)

AE ADR 71 - 50 SAE SADR discont. AE discont. ADR 3 - 0 death AE death ADR

0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3

relative risk estimate (moxifloxacin / comparator) 2. moxifloxacin vs macrolides

risk factor: age > 65 y diabetes renal impairment hepatic impairment cardiac disorders BMI < 18 (n = 1252 vs 942) (n = 329 vs 255) (n = 484 vs 427) (n = 44 vs 64) (n = 794 vs 623) (n = 110 vs 114)

AE ADR SAE SADR discont. AE discont. ADR death AE death ADR

0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3

relative risk estimate (moxifloxacin / comparator) Tulkens et al., Drugs R D (2012) 12: 71-100

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 59 Hepatotoxicity in large populations Crude incidence rates of acute liver injury caused by antibiotics

Incidence rate (CI) Antibiotic population per 100,000 per 100,000 endpoint Ref. users prescriptions fluoroquinolones Outpatient clinic, 0.7 (0.5-1.1) International [1] (w/o moxifloxacin) Sweden consensus (1995-2005) moxifloxacin Outpatient clinic, 0.08 (0.0-0.5) International [1] Sweden consensus (1995-2005) cotrimoxazole Saskatchewan 1.0 (0.2-5.7) 4.9 (0.9-27.6) International [2] Health Plan, Canada consensus, (1982-1986) hospitalisation erythromycin Saskatchewan 2.0 (0.7-5.9) 14.0 (4.8-41.2) International [2] Health Plan, Canada consensus, (1982-1986) hospitalisation amoxicillin- General practice 22.5 (14.7-34.4) 17.4 (11.4-26.5) International [3] clavulanic acid research database, consensus United Kingdom (1991-1992)

1. De Valle et al. Aliment Pharmacol Ther 2006 Oct 15; 24(8): 1187-95 2. Perez et al. Epidemiology 1993 Nov; 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 60 Hepatotoxicity from literature surveys

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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 61 QTc prolongation

Owens & Ambrose CID (2005) 41:S144-157

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 62 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.*

erythromycin: 30 moxifloxacin: 6-10 : 15

clarithromycin: 11-22 terfenadine: 46 fluoxetine: 2

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)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 63 Torsade de pointe: comparison of risk reporting rate of Torsades de pointe induced by antibiotics

drug No. of U.S. Cases No. of Estimated No. of Cases Reported to the Total U.S. /10 Millions FDA Prescriptions Prescriptions (millions) (95% CI) used as negative moxifloxacin 0 1.4 0 (0-26) control in RCT ciprofloxacin 2 66 0.3 (0.0-1.1) ofloxacin 2 9.5 2.1 (0.3-7.6) levofloxacin 13 24 5.4 (2.9-9.3) 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 64 Tendinopathies: main features and incidence…

in 2010

Kim & Del Rosso, J Clin Aesthet Dermatol. 2010; 3:49–54.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 65 Tendinopathies…

• In 2005, all fluoroquinolones marketed in the US have received a black box label about tendinopathies

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 66 Tendinopathies…

• But this is what we found for moxifloxacin in our survey of the whole datbase

very rare and no difference no case PO= oral IV = intravenous MXF: moxifloxacin COMP = comparator

Tulkens et al., Drugs R D (2012) 12: 71-100

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 67 Tendinopathies: incidences (revisited)…

in 2011

http://www.ismp.org/quarterwatch/2010Q2.pdf Last accessed: 20/02/2015

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 68 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 69 Moxifloxacin safety: a conclusion…

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 70 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?)

• The real life in the lab: microbiological properties and risk of resistance… (or how to really differentiate them …)

• The real life in the doctor’s office: efficacy and tolerance… (is there a difference) ?

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 71 What shall we discuss ?

• The basics: how were quinolones invented ? (are they different by design ?) Why not leaving this to the discussion ? • The real life in the lab: microbiologicalbut remembering: properties and risk of resistance… • 400 mg once daily (or how to really differentiate them …) or

• The real life in the doctor’s •office:2 x 500 efficacy mg daily and tolerance… (is there a difference) ? or … (have your pick !)

• Should we use the “best in class” ?

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 72 Thank you for your attention!

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 73 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 74 Resistance to fluoroquinolones: the basics

Gram (-) Gram (+) decreased efflux pump permeability

DNA

DNA gyrase Topo isomerase

mutation of the enzymes and/or DNA protection

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 75 Chemistry and Activity

This is where it all began..

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 76 From norfloxacin to ciprofloxacin and ofloxacin

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 ofloxacin* * Eur. pat. Appl. 47,005 to Daiichi, 1982

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 77 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 78 The "first generation" of fluoroquinolones

1960 1970 1980

t1/2 activity • Nalidixic acid • Norfloxacin 3-4 h ++ • Oxolinic acid • Pefloxacin 11 h + • • Ofloxacin improved 6 h ++ • Pipemidic acid • Ciprofloxacin anti Gram (-) 3-4 h +++ activity •

•

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 79 Ternary complex DNA - enzyme - fluoroquinolone

DNA GYRASE catalytic subunits COVALENTLY CLOSED CIRCULAR DNA

FLUOROQUINOLONES: DNA GYRASE ATP binding subunits 4 stacked molecules

(Shen, in Quinolone Antimicrobial Agents, 1993)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 80 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….

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 81 The pharmacophore common to all fluoroquinolones

BINDING TO DNA

R5 O O R C 6 - BINDING TO O BINDING TO THE ENZYME THE ENZYME

R7 X8 N

R1

AUTO-ASSEMBLING DOMAIN (for stacking)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 82 Nalidixic acid *

a • typical chemical features of O O fluoroquinolones (a, b, c) BUT a naphthyridone C - O- b (N at position 8: )

H C N N 3 • limited usefulness as drug C H 2 5 • narrow antibacterial spectrum c (Enterobacteriaceae only) • short half-life (1.5h) • high protein binding (90%)

* Belg. pat. 612,258 to Sterling Drugs, 1962

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 83 The “second generation” fluoroquinolones

1960 1970 1980 1990 2000

a • • Gram (-); • Sparfloxacin b • c • improved Gram (+) • Gatifloxacin d

anti-anaerobe

a: Toyama, 1988 (?) ; b: Dainippon, 1985-1987; c: Otskuda, 1989; d: Kyorin, 1988

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 84 The “third / fourth generation” fluoroquinolones

1960 1970 1980 1990 2000

• a • b anti-Gram (-) anti-Gram (+) • Moxifloxacin c anti-anaerobe • d

a:Kyorin, 1987; b: Pfizer, 1993; c: Bayer, 1994; d: LG Chemical Ltd., S. Korea, 1994-98

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 85 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

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 86 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 60

50 50

40 40 %(cumulative)

30 30

20 20

10 10

0 0

1 2 4 8 1 2 4 8 0.5 16 32 0.5 16 32 0.25 0.25 0.125 0.125 0.0625 0.0625 C M I (m g/L) C M I (m g/L)

MIC distributions of S. pneumonia in Belgium for CAP (n=249) Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 87 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 levofloxacin m oxifloxacin 80

70 70 % (cumulative)%

60 60 Notice how close 50 levofloxacin 50

40 MICs are to the 40 %(cumulative) breakpoint 30 30

20 20

10 10

0 0

1 2 4 8 1 2 4 8 0.5 16 32 0.5 16 32 0.25 0.25 0.125 0.125 0.0625 0.0625 M IC (m g/L) M IC (m g/L)

MIC distributions of S. pneumonia in Belgium for CAP (n=249) Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16.

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 88 A recent paper…

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 89 A very recent paper…

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 90 A very recent paper…

100

90%

75 S. pneumoniae S. MXF 400 mg q24h (MIC = 0.25 mg/L)

50

LVX 500 mg q12h (M IC = 1 m g/L) 25

Target attainment rate for rate attainment Target 0 0 6 12 18 24 30 delay (h)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 91 A very recent paper…

100

90%

75

MXF 400 mg q24h (MIC = 0.25 mg/L) to be as protective, you 50 LVX 500 mg q12h need a (MIC = 1 mg/L) twice daily LVX 500 mg q24h dosing with (M IC = 1 m g/L) 25 levofloxacin

Target attainment rate for S. pneumoniae S. for rate attainment Target 0 0 6 12 18 24 30 delay (h)

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 92 What differentiates fluoroquinolones ? Results with S. pneumoniae This why me may have less emergence of resistance …

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 93 Is there a molecular basis for a lesser emergence of resistance with moxifloxacin ?

A C8-methoxy group lowers the MPC for an N-1-cyclopropyl-f luoroquinolone"

O O O O

F C F C - O- O

N N N N HN HN H CO 3

ciprofloxacin moxifloxacin

https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdf Last accessed: 8/2/2015

22/03/2016 Are all fluoroquinolones equal ? -- Singapore 94