fluoroquinolones: are they all the same (or not) · fluoroquinolones: are they all the same (or...
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Fluoroquinolones: are they all the same (or not) ?
Paul M. Tulkens, MD, PhD
Cellular and Molecular PharmacologyLouvain Drug Research Institute
Université catholique de LouvainBrussels, Belgium
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With approval of the Belgian Common Ethical Health Platform – visa no. 16/V1/7383/078554
Singapore
Disclosures and slides availability
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• 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, European Union (FP7 and JPIAMR)
• Speaker's honoraria – Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma, Vifor
– Flemish Education Program on Antibiotics (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 Antibiotic Policy Coordination Committee (BAPCOC)
– Governance of the EU program "DRIVE AB" (new economical framework for antibiotics)
Slides: http://www.facm.ucl.ac.be Lectures
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Belgium 10 millions inhabitants …
10 Nobel prizes (10/850)
• Peace- Institute of International Law, Ghent (1904)- Auguste Beernaert (1909)- Henri Lafontaine (1913)- Father Dominique Pire (1958)
• Literature- Maurice Maeterlinck, Ghent (1911)
• Medicine- Jules Bordet, Brussels (1919)- Corneille Heymans, Ghent (1938)- Christian de Duve, Louvain (1974)- Albert Claude, Brussels (1974)
• Chemistry- Ilya Prigogyne, Brussels (1977)
- Physics- François Englert, Brussels (2013)
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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 Leuven in Flemish)
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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
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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…
• in 1968, the University was divided into – a French-speaking Université catholique de Louvain– a Flemish-speaking Katholieke Universiteit Leuven…
Prof. G. Lemaitre, professor of Physics and Mathematics at the University who, in the 1930's, made the first suggestion of the continuous expansion of the Universe (“big bang”) (here in conversation with A. Einstein)
Professor C. de Duve, Professor of Biochemistry, obtained the Nobel Prize (Physiology and Medicine) in 1974 for his work on intracellular organelles (lysosomes, peroxisomes…)
(here in front of a centrifuge)
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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)
• Together, the two Universities have about 55,000 students
Universitécatholiquede Louvain
http://www.uclouvain.be
KatholiekeUniversiteit
Leuvenhttp://www.kuleuven.be
10 km
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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 anti-infective therapy (laboratory and clinical applications)
• Toxicity, medicinal chemistry, and improved schedules of aminoglycosides
• one-line monitoring of β-lactams• novel antibiotics (and last studied)
• lipoglycopeptides (oritavancin…) • beta-lactams (ceftaroline…)• fluoroquinolones (finafloxacin…)• ketolides (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)
www.isap.orgA partial view of our University Clinic (900 beds) and the Education and Research buildings (5,000 students), in the outskirts of Brussels, Belgium
Why do I have an interest in fluoroquinolones ?
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Because, like Obélix,
I fell into when I was young …
Why do I have an interest in fluoroquinolones ?
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Because, like Obélix,
I fell into when I was young …
Why do I have an interest in fluoroquinolones ?
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Because, like Obélix,
I fell into when I was young … 1990
2005
2012
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” ?
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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
Are all fluoroquinolones equal ? -- Singapore 14
Mechanism of action of fluoroquinolones:the basics...
DNA
PORIN
Gram (-) Gram (+)
TopoisomeraseDNA gyrase
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2 key enzymes in DNA replication:
bacterial DNA is supercoiled
DNA gyrase
topoisomerase IV
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A bit of history: from chloroquine to nalidixic acid...
nalidixic acid
N
HN
Cl
N CH3
CH3
chloroquine
1939
19581962
N
CO
C2H5
O-
O
Cl
NN
C
O
O -
H3C
O
C2H5
7-chloroquinoline(synthesis intermediate
found to display antibacterial activity)
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From nalidixic acid to the 1st fluoroquinolone
nalidixic acid
* Belgian patent 863,429, 1978 to Kyorin
NN
C
O
C2H5
O-
O
H3C
N
C
O
FO-
O
HNN
CH3
norfloxacin *
19782
1
3
3 keymodifications *...
1. broader Gram(-) activity2. less protein binding (50%)3. longer half-life (3-4h)
* 6-fluoro-7-pyrimidino-quinoleine
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From norfloxacin to ciprofloxacin and ofloxacin
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↗ half-life(methyl)
N
C
O
FO-
O
HN
N
CH3
norfloxacin
OCH3
-
H3C
N
C
O
O-
O
N
N
F
Ofloxacin **
↗ activity(cyclopropyl)
N
C
O
O-
O
HN
N
F
Ciprofloxacin *
check this…(morpholine)
** Eur. pat. Appl. 47,005 to Daiichi, 1982
* Ger. pat. 3,142,854 to Bayer AG, 1983
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Levofloxacin is the active isomer of ofloxacin
Ofloxacin is a racemic mixture50/50
OCH3
-
H3C
N
C
O
O-
O
N
N
F N
CH3
HO Levofloxacin is the
pure (-) S isomer of ofloxacin *
* Eur. pat. 206,283 to Daiichi, 1987
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The active form of ofloxacin is the (-) S isomerThe (+) R isomer is inactive but toxic
Are all fluoroquinolones equal ? -- Singapore 20
The present "first generation" of fluoroquinolones ...
1960 1970 1980
• Nalidixic acid• Oxolinic acid
• Flumequine
• Pipemidic acid
• Norfloxacin
• Ofloxacin
• Ciprofloxacin
Mainly anti Gram (-)
activity
t1/2 activity3-4 h ++
6 h ++
3-4 h +++
• Levofloxacin 6 h ++/++
2 x more active than
ofloxacin per g
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How to improve the chemotherapeutic usefulness ofthe "first generation" fluoroquinolones
1. Maintain broad Gram(-) activity ?
2. Further Improve Gram(+) activity ?
3. Acquire activity against anaerobes ?
“2d generation”
“3d generation”
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Activity against S. pneumoniae
N
C
O
FO-
O
HNN
ciprofloxacinMIC = 0.5 - 2
I III / IV
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N
C
O
FO-
O
H CO3
HN N
moxifloxacinMIC = 0.01 - 0.5
II
OCH3
-
H3C
N
C
O
O-
O
N
N
F
levofloxacinMIC = 0.5 -2
Hint:lower MICs = a more potent antibiotic !
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Activity against B. fragilis (anaerobe)
N
C
O
FO-
O
HNN N
C
O
FO-
O
H CO3
HN N
ciprofloxacinMIC = 2-128
moxifloxacinMIC= 0.125-8
I III / IV
22/03/2016
II
At this point …
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Gram (-) Gram (+)
N
C
O
FO-
O
HNN N
C
O
FO-
O
H CO3
HN N
OCH3
-
H3C
N
C
O
O-
O
N
N
Fciprofloxacin moxifloxacin
levofloxacin
anaerobes
This is by design !
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” ?
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A unbiased estimation of antibiotic activity (in the absence of resistance)
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MIC distributions
and epidemiological
cut-off
http://www.eucast.org
MIC for Gram-negative bacteria : E. coli as an example
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9 .8× 1 0
-04
2 .0× 1 0
-03
3 .9× 1 0
-03
7 .8× 1 0
-03
0 .01 5 6 2 5
0 .03 1 2 5
0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 2 6 4
0
1 0
2 0
3 0
4 0
5 0
6 0
E . c o li
M IC (m g /L )
pe
rce
nt
of
iso
late
s
c ip ro f lo x a c inle v o f lo x a c in
ciprofloxacin
levofloxacin
http://mic.eucast.org/Eucast2/regShow.jsp?Id=1022http://mic.eucast.org/Eucast2/regShow.jsp?Id=1072Last accessed: 8/2/2015
MIC for Gram-positive bacteria: S. pneumoniae as an example
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moxifloxacin
levofloxacin
9 .8× 1 0
-04
2 .0× 1 0
-03
3 .9× 1 0
-03
7 .8× 1 0
-03
0 .01 5 6 2 5
0 .03 1 2 5
0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 2 6 4
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
S . p n e u m o n ia e
M IC (m g /L )
pe
rce
nt
of
iso
late
s
m o x if lo x a c in
le v o f lo x a c in
http://mic.eucast.org/Eucast2/regShow.jsp?Id=1099http://mic.eucast.org/Eucast2/regShow.jsp?Id=1310Last accessed: 8/2/2015
Anaerobes: B. fragilis
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moxifloxacin
levofloxacin
9.8×1
0-04
2.0×1
0-03
3.9×1
0-03
7.8×1
0-03
0.015
625
0.031
25
0.062
50.1
25 0.25 0.5 1 2 4 8 16 32 64
0
10
20
30
40
B. fragilis
MIC (mg/L)
perc
ent o
f iso
late
s
moxifloxacinlevofloxacin
http://mic.eucast.org/Eucast2/regShow.jsp?Id=1454http://mic.eucast.org/Eucast2/regShow.jsp?Id=1066Last accessed: 8/2/2015
levofloxacin(not recommended)
Killing abilities of fluoroquinolones: Are they all equal against susceptible strains ?
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in vitro kill curves: observations with S. pneumoniae
Schafer et al. Diag Microb Infect Dis 2008; 60:155–161
Same effect but at different concentrations…
Killing abilities of fluoroquinolones: Are they all equal against less susceptible strains ?
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Animal survival experiments (S. pneumonia i.p. inoculations)
strain MIC (mg/L)
MXF LVX
AR33118 (■) 0.12 1
FL2812 (●) 0.25 2
FL5629 () 4 32
Huelves et al. Int J Antimicrob Agents 2006; 27:294–299
Levofloxacin(LVX)
Moxifloxacin(MXF)
Hint: lower dose (more to the left) more potent antibiotic !
The risk for resistance to fluoroquinolones is to be “within the mutation selection window” …
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Time after administration
MIC
MPC
conc
entra
tion
MSW
concept from Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80
Mutation selection window
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0.01 0.10 1.00 10.00
10-2
1
concentration
10-4
10-6
10-8
10-10 MPC10 = 9
Dong et al: AAC 1999; 43:1756-1758
Cmax and "Mutant Prevention Concentration" (MPC) …
"Classic" bactericidal effect
Elimination of resistant organisms
Surv
ivin
g ba
cter
ia
MIC 99 = 0.8 mg/L (in this example)
poorly sensitive organisms…
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0.01 0.10 1.00 10.00
10-2
1
concentration
10-4
10-6
10-8
10-10 MPC 10 = 9
Dong et al; AAC 43:1756-1758
"Mutant Prevention Concentration …"Su
rviv
ing
bact
eria
MIC 99 = 0.8Concentration that inhibits the majorityof the organisms
A concentration of about 10 x the MIC is needed to prevent selecting resistant subpopulations !
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MPC: moxifloxacin vs levofloxacin
∼10 x the median MIC (0.125 mg/L) ∼10 x the
median MIC (1 mg/L)
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Pharmacokinetics and “resistance” breakpoint vs. MIC
Levofloxacin 500 mg 1X / day• AUC [(mg/l)xh] 47 • peak [mg/l] 5 MICmax ∼ 0.5
Moxifloxacin 400 mg 1X / day• AUC [(mg/l)xh] 48• peak [mg/l] 4.5 MICmax ∼ 0.5
0
20
40
60
80
100
0.015 0.03 0.06 0.125 0.25 0.5 1 2 4
MIC
moxi
resistance breakpoint AUC/MIC = 100 peak/MIC = 10
MIC data: EUCAST MIC distributions (wild type)PK data: US and EU labelling (typical values)
levo
% of strains
Maximal MICto avoid selection
of resistance
S. pneumoniae susceptibility tomoxifloxacin in Belgium
0.007
8125
0.015
625
0.031
250.0
625
0.125 0.2
5 0.5 1 2 40
25
50
75
100
MXF 2014
MXF 1999
MIC
cum
ulat
ive
perc
enta
ge
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Hs resistance to moxifloxacin materialized:evidence for S. pneumoniae in Belgium from 1999 to 2014 *
EUCASTbreakpoint
* Moxifloxacin was introduced in Belgiumin2001 and became the almost only fluoroquinolone used for RTI since 2004
• Surveys from the Belgian Scientific Institute for Public Health for S. pneumoniae from community isolates (n=156 in 1999 and 312 in 2014)
• Data available yearly for 1999 through 2014 at http://www.iph.fgov.be
From data of a national collection
• Non invasive respiratory tract infections
• similar results in 2008 for a collection of S.pneumoniaefrom clinically-confirmed CAP (n=132)
Similar curves for
2001 through
2014
Vanhoof et al. 19th ECCMID, Helsinki, 2009Ceyssens et al. 35th RICAI, Paris, 2015
Ceyssens et al. submitted
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” ?
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Head to head comparison…
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Clinical Infectious Diseases 2006;42:73-81.
Head to head comparison…
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Clinical Infectious Diseases 2006;42:73-81.
HospitalisedCAP
Visit 1Day 1
Test of cure+ 5–21days
Visit 2(Day 3–5)
PO
Randomisation
12-lead ECG
Moxifloxacin 400mg q.d.IV
Levofloxacin 500mg q.d.
72-h Holter monitor
12-lead ECG
and results in a snapshot…
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123/140
and results in a snapshot…
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123/140
moxifloxacin 400 mg daily was numerically superior to levofloxacin 500 mg daily
Efficacy over combination: moxifloxacin alone against levofloxacin PLUS ceftriaxone in CAP !
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Clinical Infectious Diseases 2008; 46:1499-509.
Efficacy: moxifloxacin alone against levofloxacin PLUS ceftriaxone in CAP !
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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 ?
What was done in MOTIV ?
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Moxifloxacin alone *
Levofloxacin/ceftriaxone**
PSI IV & V (≥50%)
PSI III (<50%)
Clinical evaluation
Stratification
Pre-therapy Test of cureDays 4–14
Patients with CAP & PSI score
>II
Cmax and ECG x315 min post-dose, Day 1, Day 3Randomisation
Days 3–5
Late FU Days 21–28
Moxifloxacin alone *
Levofloxacin/ceftriaxone **
* moxifloxacin: 400 mg/day** levofloxacin: 500 mg twice a day /ceftriaxone: 2g/day
Which patients ?
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All differences were non-significant
Characteristic Moxifloxacin(N=291)
Ceftriaxone +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 enrolment, mean days ± SD 5.0 ± 3.5 4.6 ± 2.8
Failure on previous systemic antimicrobials, n (%) 39 (13.4) 40 (14.4)
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)
And what did you get ?
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And what did you get ?
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moxifloxacin 400 mg daily was not inferior to a combinationof levofloxacin 2 x 500 mg daily plus ceftriaxone 2 g daily
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We all agree about efficacy, but what about side effects…
therapy ?
side effects ?
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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
Carbonelle et al. , in preparation
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.
A reasonable equilibrium for moxifloxacin ?
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• rapid bactericidal activity• ad hoc spectrum
• S. pneumoniae• H. influenzae• M. catarrhalis• intracellular (atypical pneumonia, tuberculosis)
• easy iv/po switch • excellent oral bioavailability
• toxicity ?
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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
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Side effects of moxifloxacin(clinical trials database)
Tulkens et al., Drugs R D (2012) 12: 71-100
PO= oral IV = intravenousMXF: moxifloxacinCOMP = comparator (see left column)
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Side effects of moxifloxacin(clinical trials database)
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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.
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Side effects of moxifloxacin(clinical trials database)
0.2 0.5 2 50.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
0 - 0
10 - 6
22 - 14
34 - 26
11 - 3
78 - 56
158 - 126
355 - 310
0.2 0.5 2 5
n = 2551 vs. 2403
0.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
3 / 1
29 / 32
78 / 74
116 / 109
16 / 18
207 / 184
440 / 448
1050 / 1021
PO
2 / 3
100 / 98
62 / 42
131 / 104
49 / 30
298 / 290
348 / 307
929 / 900
0.2 0.5 2 5
n = 1373 vs. 1334
0.1 1 100.2 0.5 2 5 0.2 0.5 2 5
n = 170 vs. 191
0.1 1 100.2 0.5 2 5
0 / 1
13 / 10
4 / 6
10 / 10
4 / 6
32 / 24
27 / 31
83 / 81
0.2 0.5 2 5
n = 926 vs. 917
0.1 1 100.2 0.5 2 5
2 / 2
46 / 23
38 / 20
78 / 64
22 / 11
198 / 182
196 / 174
587 / 565
sequential IV
age (> 65 y)
0.2 0.5 2 5
n = 80 vs. 72
0.1 1 100.2 0.5 2 5
0 - 0
9 - 4
6- 6
2 - 2
16 - 11
13 - 14
42 - 35
1 - 4
diabetes n = 777 vs. 717
relative risk estimate (moxifloxacin / comparator)
relative risk estimate (moxifloxacin / comparator)
Patients at risk ?
Tulkens et al., Drugs R D (2012) 12: 71-100
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Side effects of moxifloxacin(clinical trials database)
Patients at risk ?
0.2 0.5 2 5
n = 1283 vs. 1229
0.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
0 - 3
12 - 14
27 - 33
49 - 53
9 - 9
94 - 80
259 - 229
1283 - 1229
0.2 0.5 2 5
n = 889 vs. 863
0.1 1 100.2 0.5 2 5
3 - 3
58 - 67
28 - 25
75 - 78
30 - 23
202 - 180
196 - 181
572 - 549
0.2 0.5 2 5
n = 203 vs. 218
0.1 1 100.2 0.5 2 5
0 - 0
10 - 7
2 - 3
11 - 7
2 - 1
26 - 22
31 - 32
102 - 92
0.2 0.5 2 5
n = 183 vs. 196
0.1 1 100.2 0.5 2 5
1 - 2
14 - 24
11 - 7
24 - 24
10 - 7
60 - 53
43 - 43
183 - 196
renal impairment
0.2 0.5 2 5
n = 146 vs. 163
0.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
0 - 1
2 - 4
6 - 3
6 - 7
1 - 1
5 - 7
37 - 32
69 - 70
0.2 0.5 2 5
n = 46 vs. 46
0.1 1 100.2 0.5 2 5
0 - 0
2 - 0
1 - 0
1 - 1
1 - 0
7 - 7
7 - 6
23 - 18
hepatic impairment
relative risk estimate (moxifloxacin / comparator)
relative risk estimate (moxifloxacin / comparator)
Tulkens et al., Drugs R D (2012) 12: 71-100
PO sequential IV
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Side effects of moxifloxacin(clinical trials database)
Patients at risk ?
0.2 0.5 2 5
n = 1476 vs. 1404
0.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
0 - 2
11 - 25
43 - 45
70 - 64
14 - 8
132 - 110
340 - 297
707 - 655
0.2 0.5 2 5
n = 1476 vs. 1136
0.1 1 100.2 0.5 2 5
3 - 4
69 - 75
59 - 43
119 - 96
43 - 35
251 - 246
315 - 293
804 - 804
0.2 0.5 2 5
n = 106 vs. 104
0.1 1 100.2 0.5 2 5
0 - 1
11 - 8
7 - 3
3 - 2
23 - 11
16 - 25
63 - 57
1 - 1
0.2 0.5 2 5
n = 116 vs. 115
0.1 1 100.2 0.5 2 5
0 - 0
15 - 15
6 - 9
10 - 11
5 - 4
36 - 30
26 - 27
89 - 83
cardiac disorders
0.2 0.5 2 5
n = 318 vs. 365
0.1 1 100.2 0.5 2 5
death ADR.
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
0 - 0
3 - 5
12 - 20
14 - 27
0 - 5
11 - 28
70 - 96
113 - 171
0.2 0.5 1 2 5
n = 45 vs. 53
0.1 100.2 0.5 1 2 5
0 - 0
1 - 0
1 - 0
1 - 0
0 - 0
3 - 3
5 - 3
17 - 10
BMI < 18
relative risk estimate (moxifloxacin / comparator)
relative risk estimate (moxifloxacin / comparator)
Tulkens et al., Drugs R D (2012) 12: 71-100
PO sequential IV
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Side effects of moxifloxacin(clinical trials database)
Comparison with other drugs ?
age > 65 y (n= 909 vs 788)
0 1 2 3
death ADR
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
diabetes (n = 282 vs 217)
0 1 2 3
renal impairment(n = 347vs 380)
0 1 2 3
71 - 50
hepatic impairment(n = 47 vs 53)
0 1 2 3
3 - 0
cardiac disorders(n = 526 vs 444)
0 1 2 3
BMI < 18 (n = 70 vs 76)
0 1 2 3
1. moxifloxacin vs β -lactams
A. oral therapy
age > 65 y (n = 1252 vs 942)
0 1 2 3
death ADR
death AE
discont. ADR
discont. AE
SADR
SAE
ADR
AE
diabetes(n = 329 vs 255)
0 1 2 3
renal impairment(n = 484 vs 427)
0 1 2 3
hepatic impairment(n = 44 vs 64)
0 1 2 3
cardiac disorders(n = 794 vs 623)
0 1 2 3
BMI < 18(n = 110 vs 114)
0 1 2 3
2. moxifloxacin vs macrolides
risk factor:
risk factor:
relative risk estimate (moxifloxacin / comparator)
relative risk estimate (moxifloxacin / comparator)
Tulkens et al., Drugs R D (2012) 12: 71-100
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Hepatotoxicity in large populationsCrude incidence rates of acute liver injury caused by antibiotics
Incidence rate (CI)Antibiotic population per 100,000
usersper 100,000
prescriptionsendpoint Ref.
fluoroquinolones(w/o moxifloxacin)
Outpatient clinic, Sweden(1995-2005)
0.7 (0.5-1.1) International consensus
[1]
moxifloxacin Outpatient clinic, Sweden(1995-2005)
0.08 (0.0-0.5) International consensus
[1]
cotrimoxazole Saskatchewan Health Plan, Canada (1982-1986)
1.0 (0.2-5.7) 4.9 (0.9-27.6) International consensus, hospitalisation
[2]
erythromycin Saskatchewan Health Plan, Canada (1982-1986)
2.0 (0.7-5.9) 14.0 (4.8-41.2) International consensus, hospitalisation
[2]
amoxicillin-clavulanic acid
General practice research database, United Kingdom (1991-1992)
22.5 (14.7-34.4) 17.4 (11.4-26.5) International consensus
[3]
1. De Valle et al. Aliment Pharmacol Ther 2006 Oct 15; 24(8): 1187-952. Perez et al. Epidemiology 1993 Nov; 4(6): 496-5013. Garcia-Rodriguez et al. Arch Intern Med 1996 Jun 24; 156(12): 1327-32 Van Bambeke & Tulkens, Drug Safety (2009) 32:359-78
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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
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QTc prolongation
Owens & Ambrose CID (2005) 41:S144-157
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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.*
… 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)
50
fluoxetine: 2
sparfloxacin: 15
terfenadine: 46
0 10 20 30 40 msec
erythromycin: 30
clarithromycin: 11-22
moxifloxacin: 6-10
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Torsade de pointe: comparison of risk
drug No. of U.S. Cases Reported to the FDA
No. of Estimated Total U.S. Prescriptions (millions)
No. of Cases /10 Millions Prescriptions (95% CI)
moxifloxacin 0 1.4 0 (0-26)
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
azithromycin 7 –10 124 0.6–1
cefuroxime 1 -1 42 0.2 –1
reporting rate of Torsades de pointe induced by antibiotics
Van Bambeke & Tulkens, Drug Safety (2009) 32:359-78
used as negative controlin RCT
FDA warning March 12,2013
Tendinopathies: main features and incidence…
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Kim & Del Rosso, J Clin Aesthet Dermatol. 2010; 3:49–54.
in 2010
Tendinopathies…
• In 2005, all fluoroquinolones marketed in the US have received a black box label about tendinopathies
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Tendinopathies…
• But this is what we found for moxifloxacin in our survey of the whole clinical trial datbase
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PO= oral IV = intravenousMXF: moxifloxacinCOMP = comparator
very rare and no difference no case
Tulkens et al., Drugs R D (2012) 12: 71-100
Tendinopathies: incidences (revisited)…
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in 2011
http://www.ismp.org/quarterwatch/2010Q2.pdfLast accessed: 20/02/2015
Tendinopathies: incidences (revisited)…
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in 2011
http://www.ismp.org/quarterwatch/2010Q2.pdfLast accessed: 20/02/2015
http://www.ismp.org/quarterwatch/2010Q2.pdfLast accessed: 20/02/2015
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Moxifloxacin safety: a conclusion…
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 ?)
• 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” ?
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Why not leaving this to the discussion ?
but remembering:
• 400 mg once daily
or
• 2 x 500 mg daily
or … (have your pick !)
Thank you for your attention!
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Are all fluoroquinolones equal ? -- Singapore 74
Ternary complex DNA - enzyme - fluoroquinolone
22/03/2016
"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.pngLast accessed: 8/2/2015
Are all fluoroquinolones equal ? -- Singapore 75
Resistance to fluoroquinolones: the basics
DNA
Gram (-) Gram (+)
decreasedpermeability
mutation of the enzymesand/or DNA protection
efflux pump
Topoisomerase
DNA gyrase
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Chemistry and Activity
This is where it all began..
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* Eur. pat. Appl. 47,005 to Daiichi, 1982
From norfloxacin to ciprofloxacin and ofloxacin
-
H3C
OCH3
N
C
O
O-
O
N
N
CH3
-
H3C
N
C
O
O-
O
N
N
F F
ofloxacin*pefloxacin
tricyclic compound(as in flumequine but
morpholine ring)
O O
norfloxacin
N
CFO-
HN
N
CH3
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* Ger. pat. 3,142,854 to Bayer AG, 1983
From norfloxacin to ciprofloxacin
N
C
O
FO-
O
HN
N
N
C
O
O-
O
HN
NCH3
F
norfloxacin
ciprofloxacin *cyclopropyl toincrease potency
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The "first generation" of fluoroquinolones
1960 1970 1980
• Nalidixic acid• Oxolinic acid
• Cinoxacin
• Pipemidic acid
• Norfloxacin• Pefloxacin• Ofloxacin• Ciprofloxacin• Fleroxacin
• Rufloxacin
improved anti Gram (-)activity
t1/2 activity3-4 h ++11 h +
6 h ++
3-4 h +++
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Ternary complex DNA - enzyme - fluoroquinolone
FLUOROQUINOLONES:
4 stacked molecules
DNA GYRASEcatalytic subunits
DNA GYRASEATP binding subunits
COVALENTLY CLOSED CIRCULAR DNA
(Shen, in Quinolone Antimicrobial Agents, 1993)
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Fluoroquinolones are the first entirely man-made antibiotics:
do we understand our molecule ?
NX8
COOH
OR5
R6
R7
R1
Don’t panic, we will travel together….
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The pharmacophore common to all fluoroquinolones
NX8
C
OR5
R6
R7
R1
O
O-
BINDING TO DNA
AUTO-ASSEMBLING DOMAIN(for stacking)
BINDING TOTHE ENZYME
BINDING TOTHE ENZYME
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Nalidixic acid *
* Belg. pat. 612,258 to Sterling Drugs, 1962
• typical chemical features of fluoroquinolones (a, b, c)
BUT a naphthyridone(N at position 8: )
• limited usefulness as drug• narrow antibacterial spectrum
(Enterobacteriaceae only)• short half-life (1.5h)• high protein binding (90%)
-
a
b
c
NN
CO
C2H5
O-
O
H3C
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1960 1970 1980 1990 2000
• Temafloxacin a
• Sparfloxacin b
• Grepafloxacin c
• Gatifloxacin d
The “second generation” fluoroquinolones
• Gram (-);
• improved Gram (+)
anti-anaerobe
a: Toyama, 1988 (?) ; b: Dainippon, 1985-1987; c: Otskuda, 1989; d: Kyorin, 1988
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1960 1970 1980 1990 2000
The “third / fourth generation” fluoroquinolones
• Trovafloxacin b
• Moxifloxacin c
• Clinafloxacin a
• Gemifloxacin d
anti-Gram (-)anti-Gram (+)anti-anaerobe
a:Kyorin, 1987; b: Pfizer, 1993; c: Bayer, 1994; d: LG Chemical Ltd., S. Korea, 1994-98
22/03/2016
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)
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MIC distributions of fluoroquinolonesagainst P. aeruginosain the Academic Hospital of the University of Leuven, Belgium
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)
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0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 20
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
m o x if lo x a c in e
C M I (m g /L )
% (c
um
ula
tive
)
0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 20
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
lé v o f lo x a c in e
C M I (m g /L )
% (
cu
mu
lati
ve
)
w i ld ty p e p o p u la t io n (E U C A S T ) c lin ic a l b re a k p o in t: E U C A S T C L S I
MIC distributions of S. pneumonia in Belgium for CAP (n=249)Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16.
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)
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0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 20
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
m o x if lo x a c in
M IC (m g /L )
% (c
um
ula
tive
)
0 .06 2 5
0 .12 5
0 .25
0 .5 1 2 4 8 1 6 3 20
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
le v o f lo x a c in
M IC (m g /L )
% (
cu
mu
lati
ve
)
w i ld ty p e p o p u la t io n (E U C A S T ) c lin ic a l b re a k p o in t: E U C A S T C L S I
MIC distributions of S. pneumonia in Belgium for CAP (n=249)Lismond et al. Int J Antimicrob Agents. 2012 Mar;39(3):208-16.
Notice how close levofloxacin
MICs are to the breakpoint
A recent paper…
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A very recent paper…
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A very recent paper…
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0 6 1 2 1 8 2 4 3 00
2 5
5 0
7 5
1 0 0
L V X 5 0 0 m g q 1 2 h(M IC = 1 m g /L )
M X F 4 0 0 m g q 2 4 h(M IC = 0 .2 5 m g /L )
d e la y (h )
Ta
rge
t a
tta
inm
en
t ra
te f
or
S.
pn
eu
mo
nia
e9 0 %
A very recent paper…
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0 6 1 2 1 8 2 4 3 00
2 5
5 0
7 5
1 0 0
L V X 5 0 0 m g q 2 4 h(M IC = 1 m g /L )
L V X 5 0 0 m g q 1 2 h (M IC = 1 m g /L )
M X F 4 0 0 m g q 2 4 h(M IC = 0 .2 5 m g /L )
d e la y (h )
Ta
rge
t a
tta
inm
en
t ra
te f
or
S.
pn
eu
mo
nia
e9 0 %
to be as protective, you need a twice dailydosing with levofloxacin
What differentiates fluoroquinolones ?
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Results with S. pneumoniaeThis why me may have less emergence of resistance …
Are all fluoroquinolones equal ? -- Singapore 94
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"
22/03/2016
N
C
O
FO-
O
HNN
ciprofloxacin moxifloxacin
N
C
O
FO-
O
H CO3
HN N
https://www.merck.com/product/usa/pi_circulars/a/avelox/avelox_pi.pdfLast accessed: 8/2/2015