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 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 antiinfective 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

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

E. coli

60 ciprofloxacin

ciprofloxacin levofloxacin 30

percent of isolates of percent 20

10 levofloxacin

-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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 22 Gram positive: S. pneumoniae

S. pneumoniae

moxifloxacin 80

60 m oxifloxacin levofloxacin 50

30 percent of isolates of percent

levofloxacin 10

-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

B . fragilis

moxifloxacin 40

30 m oxifloxacin levofloxacin

20 percent of isolates of percent

levofloxacin levofloxacin (not recommended) 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=1454 http://mic.eucast.org/Eucast2/regShow.jsp?Id=1066 Last accessed: 8/2/2015

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 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. 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 Nov 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 Nov 2017

10-11 Nov 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 29 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 30 Tissue penetration: abdominal abscesses

Rink et al. Clin Drug Investig. 2008;28:71-9. PMID: 18211115

10-11 Nov 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 Nov 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 33 Fluid penetration: CSF

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

The ratio of the AUC24h in cerebrospinal fluid to the AUC24h in serum was 0.7

10-11 Nov 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 Nov 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 Nov 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 Oflo: -- --

10-11 Nov 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 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.

10-11 Nov 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 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 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.

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 40 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 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 41 "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 Concentration needed to prevent -10 10 MPC 10 = 9 the selection of resistant organisms (about 10 x the MIC) 0.01 0.10 1.00 10.00 concentration

Dong et al; AAC 43:1756-1758

10-11 Nov 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

MPC MSW concentration MIC

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

10-11 Nov 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 Nov 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 45 The saga of the AUC / MIC vs Cmax / MIC ratio for fluoroquinolones ...

AUC / MIC 1 is predictor of activity for Gram (-) ...

1 The impact of the Cmax could not b tested in this study

Forrest et al., AAC, 1993

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 46 Is 125 good for all ??

The saga of S. pneumoniae ...

100 100

80 80

60 Emax at 60 Emax at 30 ... 125 ... 40 40 Mortality (%) Mortality

20 mortality Percent 20

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 Nov 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 PMNs So, an AUC/MIC = 125 PrimaryCyclic neutropenia may be good SecondaryDrug-induced neutropenia even for S. pneumoniae Aplastic anemia Poorly functioning PMNs Alcoholism Cirrhosis of the liver

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 48 AUC/MIC: modelling the clinical use

Odenholt & Cars J Antimicrob Chemother. 2006;58:960-5 - PMID: 16936293.

10-11 Nov 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)

Odenholt & Cars J Antimicrob Chemother. 2006;58:960-5 - PMID: 16936293.

10-11 Nov 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 …

 AUC24h / MIC: 125

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 51 Pharmacokinetics 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

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

10-11 Nov 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 Nov 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 N-1-cyclopropyl-f luoroquinolone"

O O O O F C O- C - F O- N N HN N N H CO N O 3 H3C CH3

levofloxacin moxifloxacin

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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 54 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 55 We all agree about efficacy, but what about side effects…

therapy ?

side effects ?

10-11 Nov 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 • 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 10-11 Nov 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 58 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 59 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 60 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 61 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 62 Hepatotoxicity 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

10-11 Nov 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 Nov 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.*

erythromycin: 30 moxifloxacin: 6-10 sparfloxacin: 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)

10-11 Nov 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 Nov 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 67 QTc prolongation

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

10-11 Nov 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 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) gatifloxacin 8 3 27 (12-53) erythromycin 11 –17 151 0.7 -1.1

clarithromycin 16 –31 90 1.8 -3.4 FDA warning March 12,2013 azithromycin 7 –10 124 0.6–1 cefuroxime 1 -1 42 0.2 –1

Van Bambeke & Tulkens, Drug Safety (2009) 32:359-78

10-11 Nov 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 Nov 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 Nov 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 PO= oral IV = intravenous MXF: moxifloxacin COMP = comparator

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

10-11 Nov 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 Nov 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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 74 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 75 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 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 76 Check the EUCAST breakpoints…

Enterobacteriaceae

All EUCAST data are freely available at http://www.eucast.org

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 77 Check the EUCAST breakpoints…

Enterobacteriaceae

Now, if you have an organism with an MIC of • 0.05  easy success for any fluoroquinolone (even oral) ! • 1  borderline for cipro/ moxi / norflo / oflo  ensure correct dosage ! • 2  levo BUT with a high dose ! • 4  likely to fail no matter which fluoroqunolone…

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 78 Check the EUCAST breakpoints…

Enterobacteriaceae

Maximal Interest for the Clinician

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 79 Thank you for your attention!

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 80 The "first generation" of fluoroquinolones

1960 1970 1980

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

• Rufloxacin

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 81 An interesting paper…

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

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

100

90%

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

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)

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 98 A very recent paper…

100

90%

MXF 400 mg q24h (MIC = 0.25 mg/L)

50 LVX 500 mg q12h (MIC = 1 mg/L) LVX 500 mg q24h (M IC = 1 m g/L) 25

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

10-11 Nov 2017 Middle East Anti-Infectives Forum, Abu Dhabi, U.A.E. 99