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Quinolones

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A Systematic Quest

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David C. Hooper, M.D.

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by e
Division of Infectious Diseases
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Infection Control Unit
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Massachusetts General Hospital

ID
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Harvard Medical School

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ES
 y
Timeline of Quinolone Development

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Norris S, Mandell GL in Andriole V (ed). The Quinolones

1988
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1926-1990
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George Y. Lesher, Ph.D. or re
Li
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 Surprise Beginnings

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COOH

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N N

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H3C © lin
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Nalidixic Acid
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 Quinolones

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The First Decade (Childhood)

br
Li
• 1962 Discovery of Nalidixic Acid as anti-

or re
bacterial byproduct of chloroquine

th tu
synthesis (Lesher)

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• 1964-66 Mechanisms of Action Defined

L
(Goss, Dietz,

by e
Cook) © lin
» Inhibition of DNA synthesis
n
• 1967
O

» Conditional bactericidal activity

Nalidixic Acid released for clinical
ID

use for
M

• 1969 treatment of urinary tract infections caused

C
ES

by enteric bacteria
Resistance to Nalidixic Acid in E. coli
 Quinolones

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The Second Decade (Adolescence)

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Li
• 1970 Development of Piromidic Acid, the 1st

or re
pyrrolindinyl quinolone

th tu
au ec
• 1975 Development of Pipemidic Acid, the 1st
piperazinyl quinolone

L
by e
• 1976 Discovery of DNA gyrase, the 1st type 2
© lin
topoisomerase (Gellert)
n
O

• 1976 Development of Flumequine, the 1st

ID

fluoroquinolone and tricyclic quinolone

M

• 1977 Nalidixic Acid resistance loci identified as

C

encoding mutant subunits of DNA gyrase

ES

of E. coli (Gellert, Cozzarelli)

 ES

Acid
C
M
Piromidic
ID
O
n
© lin
by e
L
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Flumequine
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Acid

or re
Li
Pipemidic

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y
Quinolones - The Third Decade

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ar
(Adolescent Growth Spurt)

br
Li
or re
• 1986 Norfloxacin released for clinical use in US

th tu
(GU infections)

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• 1986 Development of Fleroxacin, 1st 6, 8-

L
by e
difluoroquinolone (recognition of
© lin
photosensitivity associated with 8-F)
n
O

• 1987 Ciprofloxacin released for clinical use in

ID

US (broad indications)
M

• 1988-89 Identification of drug resistance by altered

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ES

permeation for hydrophilic quinolones - active

efflux and altered porins
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F COOH

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HN N N
HN N N

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C2H5

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Norfloxacin
O

L
Ciprofloxacin

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F COOH
© lin
n
O

H3C N N
ID

N F CH2
M
C

CH
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Fleroxacin 2F
 y
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Quinolone Phototoxicity

br
Li
or re
• UVA (320-420 nm) interactions

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au ec
• Generation of reactive oxygen

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species

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• Drug concentrations in skin
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O

• SARs
– Position 8: C-halogen > N-H > C-H > C-O-R
ID

– Position 7: Alkylated rings increase t½

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– Position 5: CH3 > H > NH2

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ES
Quinolones - The Fourth Decade

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(Problems of Adolescence)

br
Li
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• 1990 Ofloxacin PO/IV released for clinical use

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in US (broad indications)

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• 1990 Discovery of Topoisomerase IV (Kato)

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• 1991 Enoxacin PO released in US (GU

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• 1992
© lin
indications)
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Temafloxacin released and withdrawn due
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to unexpected rare but severe toxicities

ID

• 1992 (Hemolytic-Uremic Syndrome)

M

Lomefloxacin PO released in US, 1st once-

C
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• 1993-94 daily fluoroquinolone

Identification of quinolone inhibition of
 y
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F COOH

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HN N N

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F

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C2H5 C2H5
Enoxacin H3C

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O Lomefloxacin

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F COOH
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F COOH
n
O

N HCl
N
ID

HN F H3C N N N
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O *
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CH3 CH3
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Ofloxacin
Temafloxaci F
Quinolones - The Fourth Decade

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(Adulthood)

br
Li
or re
• 1994-96 Identification of topoisomerase IV as

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principal quinolone target in S. aureus

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and secondary target in E. coli

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by e
• 1996 Levofloxacin PO/IV and sparfloxacin PO
© lin
released in US (expanded Gram+ respiratory
n
O

indications)
ID

• 1997 Grepafloxacin PO (Respiratory/GU

M

Indications) and Trovafloxacin PO/IV

C

(broadest indications, 1st anti-anaerobic

ES

quinolone) released in US
 y
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F F COOH
COOH H C

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Li
H 3C N N N HN N N

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O F

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CH3 H 3C

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Sparfloxacin
Levofloxacin

L
O

by e
F CO2H
CH3
© lin
O
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F CO2H
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N N N
H
F
ID

CH3
N N H 2N
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HN H
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Grepafloxacin Trovafloxacin F
 Quinolones - The Fourth Decade

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(Adults Have Their Ups &

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Li
Downs)

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• 1998 Plasmid transferable quinolone resistance

th tu
identified

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• 1999 Trovafloxacin use restricted due to rare

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but severe hepatotoxicity (? Legacy of

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temafloxacin)
© lin
n
• 1999 Grepafloxacin withdrawn because of cardiac
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events. Sparfloxacin also associated with

ID

arrhythmias
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C

• 1999 Gatifloxacin PO/IV and Moxifloxacin PO

ES

released with a focus on respiratory tract

indications
 y
Rare, Serious Idiosyncratic Reactions

ar
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• Temafloxacin (1992)

Li
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– Hemolytic uremic syndrome

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– Coagulopathy (35%)

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– Hepatic dysfunction (51%)

L
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– Reporting incidence ~1:6000
© lin
• Trovafloxacin (1999)
n
O

– Symptomatic hepatitis
ID

– Life-threatening in ~10%
M
C

– Reporting incidence ~1:18,000

ES

Blum MD et al. 1994. Clin Infect Dis 18:946

Ball P et al. 1999. Drug Safety 21:407
 Quinolones - The Fourth Decade

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(Adults Have Their Ups &

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Li
Downs)

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• 1999 Trovafloxacin use restricted due to rare

th tu
but severe hepatotoxicity (? Legacy of

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temfloxacin)

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• 1999 © lin
Grepafloxacin withdrawn because of cardiac
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events. Sparfloxacin also associated with
O

arrhythmias
ID

• 1999 Gatifloxacin PO/IV and Moxifloxacin PO

M
C

released with a focus on respiratory tract

ES

indications
 Effects of Drugs on Cardiac

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Conduction a

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hERG IC30

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Drug QTC Prolongation Ikr

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(msec) (M) (M)

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Sparfloxacin 13-15 0.23 10

au ec
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Grepafloxacin 10 27.2 39

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Moxifloxacin © lin
n
7 -- 92
Gatifloxacin 5-6 26.5 104
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ID

Terfenidine 46
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Erythromycin 8-
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15 aAnderson et al. 3rd ECC

bChen et al. ICAAC 2000 abstr 765
 Quinolones - The Fourth Decade

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(Adults Have Their Ups &

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Li
Downs)

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• 1999 Trovafloxacin use restricted due to rare

th tu
but severe hepatotoxicity (? Legacy of

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temfloxacin)

L
by e
• 1999 © lin
Grepafloxacin withdrawn because of cardiac
n
events. Sparfloxacin also associated with
O

arrhythmias
ID

• 1999 Gatifloxacin PO/IV and Moxifloxacin PO

M
C

released with a focus on respiratory tract

ES

indications
 Quinolone Structure-Activity

y
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Relationships

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Li
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th tu
au ec
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C
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Domagala JM. 1994. J Antimicrob Chemother

 Quinolone Structure-Adverse

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Effects Relationships

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Li
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Domagala JM. 1994. J Antimicrob Chemother

 Quinolones - The Fifth Decade

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(Adults Have Their Ups &

br
Li
Downs)

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• 2002 Plasmid-encoded Qnr protein identified

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as protecting gyrase from quinolones

au ec
• 2003 Gemifloxacin approved for community-

L
by e
acquired pneumonia with 5-day regimen
© lin
• 2006 Plasmid-encoded quinolone-modifying
n
O

enzyme identified as mutant AAC(6’)-Ib

ID

• 2007 Plasmid-encoded QepA efflux pump

M

identified
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• 2008 Gatifloxacin withdrawn because of

ES

dysglycemia events
 y
• 2009 First topoisomerase IV-DNA crystal structures

ar
with quinolone bound

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Li
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© lin
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ID
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Laponogov I et al.
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Nature Struct Mol Biol.

ES

2009; 16:667
 The Fluoroquinolone Family

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American Branch – The Sixth Decade

br
12 Approvals over 17 Years

Li
or re
• Sparf lo xa cin
• Norfloxacin (Noroxin) X X X

th tu
1986 (Zagam) 1996

au ec
• Ciprofloxacin (Cipro) • GrepXaflXoxXacin

L
1987 PO, 1990 IV (Raxar) 1997

by e
• Trova fl ox acin
• Ofloxacin (Floxin) © lin X X X
(Trovan) 1997
n
1990 PO, 1992 IV
O

• • GatiflXoxXacXin
EnoxaXciXnX(Penetrex)
ID

(Tequin) 1999
1991
M

• Moxifloxacin (Avelox)
• Lome flo x acin
X X X
C

1999
ES

(Maxaquin) 1992 • Gemifloxacin (Factive)

• Levofloxacin (Levaquin) 2003
 Adverse Effects of Fluoroquinolones

y
ar
• Gastrointestinal

br
– Nausea, vomiting, diarrhea

Li
• Central Nervous System

or re
– Dizziness (trovafloxacin), insomnia, seizures

th tu
• Cardiovascular

au ec
– QTC prolongation (sparfloxacin, grepafloxacin > moxifloxacin)

L
• Hepatic

by e
– Idiosyncratic hepatitis (trovafloxacin)
• Metabolic
© lin
n
O

– Dysglycemia (gatifloxacin > levofloxacin)

ID

• Skin
– Photosensitivity (sparfloxacin, lomefloxacin)
M
C

– Other skin reactions (gemifloxacin)

ES

• Musculoskeletal
– Tendinopathy
 Quinolones – The Sixth Decade

y
ar
Senescence or

br
Li
New Generations to Follow

or re
The Search Goes On

th tu
au ec
L
• Keys to success:
by e
© lin
– Dealing with established resistance
n
O

– Low potential for new resistance

ID

– High tolerability (no surprises – better

M

preclinical screening tools)

C
ES
Problems With Development of Bacterial

y
ar
Resistance to Fluoroquinolones

br
Li
or re
Staphylococci (MRSA, MRSE) 60-95%

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au ec
Pseudomonas aeruginosa 5-30%

L
by e
Campylobacter jejuni
© lin
n 3-50%

Escherichia coli 8-26%

O
ID

Neisseria gonorrheae 6-70%

M
C

Streptococcus 3%
ES

pneumoniae
Predicting Resistance Potential:

y
ar
(Which Quinolone Will Live the

br
Li
Longest?)

or re
th tu
• Determinants of bacterial resistance

au ec
– Activity against both target enzymes,

L
DNA gyrase and DNA topoisomerase IV
by e
© lin
– Effects of native bacterial efflux systems
n
O

– Potency that keeps drug

ID

concentrations above the MIC of first-

M

step resistant mutants (mutant

C
ES

prevention concentration)
 Sitafloxacin

y
ar
O

br
F
CO2H

Li
N N

or re
Cl F
H2N

th tu
Activity: S. pneumoniae (16x)

au ec
Other streptococci (16-32x)
(Relative to

L
Enterococci (16x)
Ciprofloxacin)
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© lin S. aureus (>2-32x)
B. fragilis (64x)
n
O

P. aeruginosa (1-6x)
ID

Pharmacokinetics: 500mg PO  Cmax 4.6 g/ml

M

t 1/2 = 4.5-5h; renal (70%)

C
ES

Vd = 1.8 liters
Anderson DL. Drugs of Today 2008;
 Prulifloxacin/Ulifloxacin

y
ar
br
Li
or re
th tu
au ec
Activity: S. pneumoniae (1x)

L
S. pyogenes (1x)
(Relative to
by e
© lin
Levofloxacin)
n Enterococci (1x)
S. aureus (1x)
O

Klebsiella spp. (4x)

ID

Enterobacter spp. (4x)

M

P. aeruginosa
C
ES

(0.5-2x)
 y
Finafloxacin

ar
br
Li
Organism MIC (median, μg/ml)

or re
pH 5.0 pH 7.3

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au ec
Fin Cip Fin Cip

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E. coli

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CipS 0.031 0.5 0.125 0.016
CipNS © lin
8
n
≥16 ≥32 ≥16
K. pneumoniae
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CipS 0.063 1.0 0.125 0.031

ID

CipNS 2 ≥16 6.0 3.0

M

S. aureus
C

CipS 0.125 2.0 0.25 0.5

ES

CipNS 8.0 ≥16 8.0 ≥16

48th ICAAC, IDSA Abstract F1-2037
 Zabofloxacin (DW-224a)

y
ar
O O

br
F
OH

Li
MeO
N N N N

or re
th tu
HN

au ec
Activity: S. aureus (2-4x)

L
S. pneumoniaea (16x)
(Relative to
by e
© lin Enterococci (4-16x)
Moxifloxacin) K. pneumoniae (1x)
n
O

E. cloacae (0.5x)
ID

P. aeruginosa (~1x)
M

[aAdvantage maintained vs parC gyrA double mutants of S. pneumoniae

C

Serial passage selection: 4-16 x ↑ MIC to max of 2 μg/ml]

ES

Park H-S et al. Antimicrob Agents Chemother. 2006;

50:2261 Kosowska-Shick K et al. Antimicrob Agents Chemother.
Delafloxacin (RX-3341, ABT492)

y
ar
br
S. aureus MRSA >64x

Li
S. aureus MSSA >64x

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Enterococci 16x

th tu
S. pyogenes >64x

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S.epidermidis 32x

L
S.

by e
Activity: 128x
© lin pneumoniae 16-
(Relative to
n
H. influenzae 32x
O

Levofloxacin) L. pneumophila 8x
ID

Chlamydia 2-
M

spp. 32x
C
ES

K. pneumoniae 4x
M. pneumoniae
 WCK-771 (S-nadifloxacin)

y
ar
br
Li
or re
th tu
au ec
Activity: S. pneumoniae (2x)

L
S. pyogenes (2x)

by e
(Relative to © lin S. aureusa (16-32x)
Levofloxacin)
n
S. epidermidis (16-32x)
O

Pharmacokinetics:
ID

600mg IV  Cmax 4.0 g/ml

t 1/2 = 6 h
M
C

[aFirst-step selection: S. aureus mutations in gyrA with 2x ↑ MIC]

ES

Jacobs MR et al. Antimicrob Agents Chemother 2004;

48:3338 Al-Laham A et al. J Antimicrob Chemother 2005;
56:1130 Bhagwat SS et al. Antimicrob Agents Chemother.
 y
DX-619

ar
br
O O
OH

Li
N N

or re
H2N OMe

th tu
F

Activity: S. pneumoniae (128x)

au ec
Other streptococci (32-64x)

L
(Relative to

by e
Enterococci (64x)
Levofloxacin)© lin S. aureusa (16-128x)
n
Klebsiella spp. (1x)
O

P. aeruginosa (2x)
ID

Pharmacokinetics: Lung:serum ratio 5.3 (3x > cipro)

M

in mice
C
ES

Fujikawa K et al. Antimicrob Agents Chemother. 2005;

49:3040 Wickman PA et al. Antimicrob Agents Chemother.
2006; 50:2255 Fukuda Y et al. Antimicrob Agents Chemother.
 DC-159a

y
ar
br
Li
or re
th tu
au ec
Activity: S. pneumoniae (8-32x)

L
Enterococci (8x)
(Relative to
by e
© lin S. aureus (4-16x)
Levofloxacin) H. influenzae (1x)
n
O

Peptostreptococcus (32x)
ID

B. fragilis (16x)
M

K. pneumoniae (1x)
C

P. aeruginosa (0.5x)
ES

Hoshino K et al. Antimicrob Agents Chemother. 2008;

52:65
 PD 0305970 and PD 0326448

y
ar
br
Li
or re
th tu
au ec
Activity: S. aureus (2-32x)

L
S. pneumoniaea (16-32x)
(Relative to
by e
Levofloxacin)
© lin
n Enterococci (128x)
S. pyogenes (64x)
O

K. pneumoniae (0.12x)
ID

E. cloacae (0.25x)
M

[aFirst-step mutants in gyrB (2x ↑ MIC) or gyrB parE (4x ↑ MIC)]

C

Efficacy > levofloxacin in murine pneumococcal pneumonia model

ES

Huband MD et al. Antimicrob Agents Chemother. 2007; 51:1191

 ACH-702

y
ar
br
Li
or re
th tu
Activity: S. aureusa (>32->64x)

au ec
S. pneumoniae (16x)
(Relative to

L
Enterococci (>8->32x)

by e
Levofloxacin) © lin S. pyogenes (16x)
n
K. pneumoniae (2x)
O

Enterobacter spp. (0.25-1x)

ID

P. aeruginosa (0.5x)
M

[MIC90: B. fragilis 0.25 μg/ml, Peptostreptococcus 0.06 μg/ml]

C
ES

[aSingle-step gyrA mutants with 4x ↑ MIC]

48th
 y
Long Life Sometimes Needs

ar
br
Help from the Doctor(s)

Li
or re
th tu
• Monitoring resistance

au ec
• Good Infection Control to Limit Spread

L
by e
• Focused Use to Limit Selective Pressures
© lin
n
• Adequate Dosing to Limit Mutant Selection
O

• Possible Use of Combination Regimens:

ID
M

– With Other Antibiotics

C

– Specific Inhibitors of Resistance Mechanisms

ES