Development of the quinolones

Abstract

Since their discovery in the early 1960s, the quinolone group of antibacterials has generated considerable clinical and scientific interest. Nalidixic acid, the first quinolone to be developed, was obtained as an impurity during the manufacture of quinine. Since this time, many derivatives have been synthesized and evaluated for their antibacterial potency. Two major groups of compounds have been developed from the basic molecule: quinolones and naphthyridones. Manipulations of the basic molecule, including replacing hydrogen with fluorine at position 6, substituting a diamine residue at position 7 and adding new residues at position 1 of the quinolone ring, have led to enhanced antibacterial efficacy. In general these compounds are well tolerated. However, some of these structural changes have been found to correlate with specific adverse events: the addition of fluorine or chlorine at position 8 being associated with photo-reactivity, e.g. Bay y 3118 and sparfloxacin; and the substitution of an amine or a methyl group at position 5 having a potential role in QTc prolongation, e.g. sparfloxacin and grepafloxacin. Progressive modifications in molecular configuration have resulted in improved breadth and potency of in vitro activity and pharmacokinetics. One of the most significant developments has been the improved anti-Gram-positive activity of the newer compounds, such as moxifloxacin and garenoxacin. In the current millennium, these new agents may play an important role in the treatment of respiratory infections.

Full text

Journal of Antimicrobial Chemotherapy (2003)
51
, Suppl. S1, 1–11
DOI: 10.1093/jac/dkg212
1
...................................................................................................................................................................................................................................................................
© 2003 The British Society for Antimicrobial Chemotherapy
Development of the quinolones
Monique I. Andersson and Alasdair P. MacGowan*
Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol,
Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK
Since their discovery in the early 1960s, the quinolone group of antibacterials has generated
considerable clinical and scientific interest. Nalidixic acid, the first quinolone to be developed,
was obtained as an impurity during the manufacture of quinine. Since this time, many deriva-
tives have been synthesized and evaluated for their antibacterial potency. Two major groups of
compounds have been developed from the basic molecule: quinolones and naphthyridones.
Manipulations of the basic molecule, including replacing hydrogen with fluorine at position 6,
substituting a diamine residue at position 7 and adding new residues at position 1 of the quino-
lone ring, have led to enhanced antibacterial efficacy. In general these compounds are well toler-
ated. However, some of these structural changes have been found to correlate with specific
adverse events: the addition of fluorine or chlorine at position 8 being associated with photo-
reactivity, e.g. Bay y 3118 and sparfloxacin; and the substitution of an amine or a methyl group at
position 5 having a potential role in QTc prolongation, e.g. sparfloxacin and grepafloxacin. Pro-
gressive modifications in molecular configuration have resulted in improved breadth and
potency of
in vitro
activity and pharmacokinetics. One of the most significant developments has
been the improved anti-Gram-positive activity of the newer compounds, such as moxifloxacin
and garenoxacin. In the current millennium, these new agents may play an important role in the
treatment of respiratory infections.
Keywords: quinolones, pharmacokinetics, pharmacodynamics, drug development
Introduction
Quinolones have been the centre of considerable scientific
and clinical interest since their discovery in the early 1960s.
This is because they potentially offer many of the attributes of
an ideal antibiotic, combining high potency, a broad spectrum
of activity, good bioavailability, oral and intravenous formu-
lations, high serum levels, a large volume of distribution indi-
cating concentration in tissues and a potentially low incidence
of side-effects. Much research has attempted to make these
potential attributes real. Nalidixic acid was the first quinolone
to be developed (Table 1), but it took more than a decade
before additional compounds, such as flumequin, norfloxacin
and enoxacin became available for clinical use. The main use
for all these agents was the treatment of urinary tract infec-
tion. In the late 1980s more systemically active drugs, such as
ciprofloxacin and ofloxacin, were marketed. Recently, there
has been a considerable increase in the number of agents that
are in development, and to date over 10 000 molecules have
been patented. This review will trace the development of
quinolones from their sole use as treatment for urinary tract
infections, via systemic use, to those agents whose primary
use is for the treatment of respiratory tract infections. This
development may be described in terms of structures,
potency, pharmacokinetics and pharmacodynamics, and
finally indications and clinical use.
Structural developments
Quinolones were derived from quinine. Figure 1 shows the
basic fluoroquinolone molecule or ‘pharmacore’.
1
The addi-
tion of a fluorine molecule at position 6 was one of the earliest
changes to the structure. This single alteration provides a
more than 10-fold increase in gyrase inhibition and up to
100-fold improvement in MIC. Two major groups have been
developed from the basic structure: quinolones and naph-
thyridones.
1–5
The presence of a nitrogen at position 8 identi-
..................................................................................................................................................................................................................................................................
*Corresponding author. Tel: +44-117-959-5652; Fax: +44-117-959-3154; E-mail: alasdair.macgowan@north-bristol.swest.nhs.uk
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M. I. Andersson and A. P. MacGowan
2
fies the naphthyridones, a carbon and associated group at
position 8 identifies the quinolones.
1–5
The quinolones and napththyridones were further enhanced
by the addition of groups to the N
1
, C-5 and C-7 positions of
their respective basic molecules. The addition of piperazine to
the C-7 position (e.g. norfloxacin) improves activity against
Gram-negative organisms. There are data to suggest that a
piperazine ring may play a role in inhibiting efflux mechan-
isms, thereby improving the potency of these drugs. The
structure of norfloxacin illustrates these developments and
subsequent to this all quinolones (except garenoxacin) have a
fluorine at position 6 and many have six-membered rings at
position C-7 (Figure 2). The presence of a pyrrolodinyl group
at position C-7 (e.g. clinafloxacin) improves activity against
Gram-positive organisms. In addition to piperazine at the C-7
position, a cyclopropyl group was introduced to the N
1
posi-
tion and is best exemplified by ciprofloxacin, which was first
synthesized in 1983 (Figure 3). This increases the potency of
the drug and many subsequent quinolones have a cyclopropyl
group (e.g. grepafloxacin, moxifloxacin, gatifloxacin and
garenoxacin; Figure 4). The addition of a 2,4-difluorophenyl
group at position 1 (e.g. trovafloxacin) also improves
potency, especially in improving activity against anaerobes.
A number of other structural manipulations have been tried
to improve the anti-Gram-positive activity of fluoroquino-
lones. One of the first additions was an NH
2
group at position
Table 1.
Chronology of quinolones that reached the UK
market
Date Quinolone
1960–1969 nalidixic acid
1970–1975 cinoxacin
1975–1985 norfloxacin
1985–1990 ciprofloxacin, ofloxacin
1990–1995 temafloxacin, sparfloxacin
1995–2000 grepafloxacin, levofloxacin, trovafloxacin
2000–2005 moxifloxacin, possibly gemifloxacin and
garenoxacin in 2003 or later
Figure 1.
Structure of the quinolone and napthyridone molecule. In
molecules where X is a carbon atom, the molecule is a quinolone
(cinoxacin, norfloxacin, ofloxacin, ciprofloxacin, temafloxacin, spar-
floxacin, grepafloxacin, levofloxacin, clinafloxacin, moxifloxacin, gati-
floxacin). Where X is a nitrogen atom the molecule is a naphthyridone
(nalidixic acid, enoxacin, tosufloxacin, trovafloxacin, gemifloxacin).
Adapted from Domagala (1994).
2
Figure 2.
Modifications of quinolone structures: norfloxacin. In all
subsequent molecules, except garenoxacin, fluorine was retained at
position 6. A six-membered ring at position 7 is found in ciprofloxacin,
temafloxacin, sparfloxacin, ofloxacin and levofloxacin.
Figure 3.
Modification of quinolone structures: ciprofloxacin. A cyclo-
propyl group at position 1 is found in sparfloxacin, grepafloxacin, clina-
floxacin, gatifloxacin, moxifloxacin and garenoxacin.
Figure 4.
Modification of quinolone structures: moxifloxacin. A five-
membered ring or azabiocyclo rings at position 7 are found in clina-
floxacin and trovafloxacin (five-membered ring) or moxifloxacin and
garenoxacin (azabicyclo rings). A methoxy group at position 8 is found
in moxifloxacin and gatifloxacin. A difluoromethyl ether (OHF
2
) group
is found at position 8 in garenoxacin.
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Development of the quinolones
3
C-5, which resulted in a general increase in anti-Gram-positive
activity. This is seen with sparfloxacin which otherwise has a
very similar structure to ciprofloxacin. Sparfloxacin also has
a fluorine at position C-6, a piperazine at position C-7 and is
alkylated. Grepafloxacin is also substituted at position C-5
but by a CH
3
group and has improved anti-Gram-positive
potency compared with ciprofloxacin. The substituents at
position C-7 are associated with a number of key attributes,
such as antibacterial spectrum, bioavailability and side-effects.
The most common substituents are cyclic amino groups,
for example piperazine or pyrrolidine rings; other groups
have been less successful. Piperazine rings are particularly
common (e.g. norfloxacin, enoxacin or ciprofloxacin) and
confer potency against Gram-negative bacteria. The addition
of methyl groups can improve both oral absorption and
in vivo
activity. However, the improved activity against
Gram-positive bacteria can sometimes be at the expense of
activity against
Pseudomonas aeruginosa
.
Pyrrolidine rings (five-membered) are also common sub-
stituents at position 7, and are associated with enhanced
potency against Gram-positive bacteria. However, this group
is associated with low water solubility and low oral bioavail-
ability so
in vivo
activity may be compromised. Introduction
of methyl groups on the pyrrolidine ring helps to overcome
some of these physical properties. Gemifloxacin, a naphthyri-
done, is a good example of the advantages and disadvantages
associated with a pyrrolidine ring at position 7.
6
The addition
of azabicyclo groups onto position 7 has resulted in agents
(moxifloxacin and trovafloxacin) with significant anti-Gram-
positive activity, marked lipophilicity and half-lives of
>10 h.
7,8
Manipulation of the group at position 8 has also been
shown to play a role in altering oral pharmacokinetics, broad-
ening the spectrum of activity and reducing the selection of
mutants.
9–13
Whilst alkylation has been shown to increase
further anti-Gram-positive activity, it also improves tissue
penetration and extends the half-life by increasing lipophil-
icity, as with grepafloxacin, levofloxacin and sparfloxacin.
The structural changes to the quinolone molecule and
correlation with adverse events are now well documented.
3,14
Photo-reactivity is probably most influenced by position 8,
with fluorine or chlorine producing most phototoxic potential
(e.g. lomefloxacin, clinafloxacin, Bay y 3118 and spar-
floxacin) and methoxy groups the least (e.g. moxifloxacin or
gatifloxacin). Garenoxacin has fluorine incorporated through
a C-8 difluoromethyl ether linkage as there is no fluorine at
C-6. It has been suggested that substitution at position 5 may
have a role in QTc prolongation as those agents that have been
associated with significant problems, such as sparfloxacin
and grepafloxacin, have either a NH
2
or a CH
3
group in this
position.
15,16
Much speculation has also surrounded the likely structural
correlates of the haemolytic uraemic-like syndrome caused
by temafloxacin,
17
hepatic eosinophilia caused by trova-
floxacin,
18
pulmonary interstitial eosinophilia and other
immunological side-effects caused by tosufloxacin
19
and
gemifloxacin, and the hypoglycaemia seen with temafloxacin
and clinafloxacin.
18,20,21
Although a number of these agents
are naphthyridones (trovafloxacin, tosufloxacin and gemi-
floxacin) others are fluoroquinolones (temafloxacin), hence it
is unclear whether this difference is relevant. A more power-
ful association is that of the 2,4-difluorophenyl group at posi-
tion 1, as this is shared by trovafloxacin, temafloxacin and
tosufloxacin
1
but not by gemifloxacin.
6
A further hypothesis
is that metabolites of these agents (as yet not fully identified),
which share common structures, may be responsible for some
of the immunologically mediated adverse events seen with
these drugs.
The naphthyridones can be modified by the addition of
cyclopropyl groups in the same way as the quinolones. A five-
membered ring has been added to the molecule of gemi-
floxacin at position 7. Trovafloxacin has an azabicyclo ring,
which improves anti-Gram-positive activity, increases the
half-life and results in resistance to efflux pumps.
8
Developments in potency
The development of these agents can be described in terms
of their potency against Gram-positive, Gram-negative or
atypical bacteria. In terms of anti-Gram-negative potency,
as indicated by MIC
90
s, the activity of quinolones against
Enterobacteriaceae such as
Escherichia coli
and
Klebsiella
spp
.
has not changed significantly since the development of
norfloxacin (Table 2).
6,22–31
In terms of their MIC
90
s, the early
drugs (nalidixic acid and cinoxacin) did not have very good
anti-pseudomonal potency. In general, the newer agents have
improved activity against pathogens such as
Mycoplasma
pneumoniae
and other atypical bacteria, and some have
improved activity against Gram-negative anaerobes, such as
Bacteroides fragilis
(Tables 2 and 3). However, many of the
newer agents, such as gatifloxacin, gemifloxacin, gare-
noxacin and moxifloxacin, are not as potent as ciprofloxacin
against
P. aeruginosa
.
One of the more interesting developments in terms of
potency is the area of anti-Gram-positive activity. Although
it is unlikely any fluoroquinolone will have activity against
ciprofloxacin-resistant
Staphylococcus aureus
, a major
development has been in the activity of these drugs against
ciprofloxacin-sensitive
S. aureus, Streptococcus pneumoniae
and Group A streptococci.
10,12,32–35
This is one of the key
advances in terms of the development of these agents.
Table 4
22–31,36–39
lists the fluoroquinolones on the basis of
their MIC
90
s for five Gram-positive species. Nalidixic acid,
cinoxacin and enoxacin have no activity at all, whereas gemi-
floxacin has an MIC
90
of 0.03 mg/L for
S. pneumoniae
, and is
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M. I. Andersson and A. P. MacGowan
4
equivalent to the earlier compounds in terms of activity
against the majority of Gram-negatives (Table 2). The activ-
ity against enterococci is less clearly defined because differ-
ent species are often classified together, and the proportions
of
Enterococcus faecium
and
Enterococcus faecalis
are not
provided. This is important as
E. faecium
is more resistant
than
E. faecalis
.
Developments in pharmacodynamics and
pharmacokinetics
Pharmacokinetics (PK) refers to changes in drug concen-
tration as the drug moves through the body, whilst pharmaco-
dynamics (PD) refers to how the drug action changes with
concentration or dose.
T
a
bl
e
2
.
Deve
l
opment o
f
qu
i
no
l
one potency aga
i
nst
G
ram-negat
i
ve
b
acter
i
a
MIC
90
(mg/L)
Quinolone
E. coli
Klebsiella
spp.
Enterobacter
/
Citrobacter
spp.
Serratia
spp.
Haemophilus
influenzae P. aeruginosa B. fragilis
Nalidixic acid 8 16 >64 >64 2 >64 >64
Cinoxacin 8 8 >64 >64 2 >64 >64
Enoxacin 0.25 2 1 4 0.12 2 >64
Norfloxacin 0.12 0.5 0.25 2 0.06 2 >64
Ciprofloxacin 0.03 0.25 0.12 0.5 0.03 1 16
Ofloxacin 0.12 0.5 0.5 1 0.03 4 16
Levofloxacin 0.12 0.25 0.5 0.5 0.03 2 8
Temafloxacin 0.06 0.5 0.5 0.5 0.03 1 4
Trovafloxacin 0.06 0.25 0.06 1 0.01 1 0.25
Clinafloxacin 0.01 0.03 0.12 0.25 0.01 0.5 0.25
Sparfloxacin 0.06 0.5 0.5 4 0.03 4 4
Grepafloxacin 0.06 0.12 0.5 2 0.01 8 8
Moxifloxacin 0.06 0.12 1 2 0.06 8 1
Gatifloxacin 0.06 0.25 0.5 1 0.03 4 1
Gemifloxacin 0.03 0.25 0.5 2 0.06 4 ND
Garenoxacin 0.06 0.5 1.0 2 0.03 16 1
Table 3.
Development of quinolone potency against atypical bacteria
MIC
90
(mg/L)
Quinolone
Legionella
pneumophila
M. pneumoniae Chlamydia
spp
. Mycoplasma
hominis
Ureaplasma
urealyticum
Nalidixic acid 0.25 >64 >64 >64 >64
Enoxacin 0.12 4 8 8 16
Norfloxacin 0.06 16 16 8 16
Ciprofloxacin 0.01 2 2 1 4
Ofloxacin 0.03 2 2 0.5 1
Levofloxacin 0.01 1 1 0.25 1
Trovafloxacin 0.01 0.25 0.12 0.5 0.5
Clinafloxacin 0.008 0.03 0.12 0.03 0.12
Sparfloxacin 0.06 0.5 0.5 0.5 0.5
Grepafloxacin 0.01 0.5 0.12 0.12 0.5
Moxifloxacin 0.01 0.12 0.12 0.06 0.25
Gatifloxacin 0.01 0.12 0.25 0.12 0.25
Gemifloxacin 0.008 0.12 0.06 0.01 0.25
Garenoxacin 0.008 0.06 0.016 0.03 0.06
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Development of the quinolones
5
Nalidixic acid is a drug that is excreted in urine and has very
variable systemic absorption. Essentially it is not a systemic
drug, but a urinary agent. Over time, larger serum area under
the curve (AUC) or peak serum (
C
max
) values are consistently
seen as the quinolones have developed, and oral absorption
has markedly improved compared with that of nalidixic acid
(Table 5).
6,30,31,40,41
The half-life of these agents has also
tended to increase as structural modifications have been made
to the molecule. However, since the activity of quinolones is
concentration dependent, meaning that the extent of bacterial
killing increases as drug concentrations increase, and they
have a prolonged post-antibiotic effect (PAE),
42
a long half-
life is not an absolute prerequisite for once-daily dosing.
14,43,44
No trend in protein binding has become apparent over time
with some agents having a binding of <30% (norfloxacin,
temafloxacin and gatifloxacin) and others >70% (nalidixic
T
a
bl
e
4
.
Deve
l
opment o
f
qu
i
no
l
one potency aga
i
nst
G
ram-pos
i
t
i
ve
b
acter
i
a
MIC
90
(mg/L)
Quinolone
S. aureus
(methicillin sensitive)
S. pneumoniae
Group A
streptococci
Enterococcus
spp.
Clostridium
perfringens
Nalidixic acid >64 >64 >64 >64 >64
Cinoxacin >64 >64 >64 >64 >64
Enoxacin 2 64 64 8 >64
Ciprofloxacin 1 2 1 4 0.5
Ofloxacin 0.5 2 2 2 1
Levofloxacin 0.25 1 1 2 0.5
Temafloxacin 0.25 0.5 0.5 2 1
Sparfloxacin 0.12 0.5 1.0 2 0.25
Grepafloxacin 0.12 0.25 1.0 4 1
Gatifloxacin 0.25 0.25 0.25 1 0.5
Trovafloxacin 0.03 0.12 0.25 1 0.25
Moxifloxacin 0.06 0.12 0.25 2 0.25
Clinafloxacin 0.06 0.12 0.06 0.25 0.12
Gemifloxacin 0.06 0.03 0.06 4 ND
Garenoxacin 0.03 0.12 0.25 0.5 0.25
Tabl e 5 .
Development of quinolone pharmacokinetics
Quinolone
Dose (g)
(frequency
per day)
C
max
(mg/L) AUC (mg
⋅
h/L)
Half-life
(h)
Protein binding
(%) Elimination route
Nalidixic acid 1 (
×
4) variable variable 1.5 90 renal
Enoxacin 0.5 (
×
2) 1.5 19 2 60 renal
Enoxacin 0.6 (
×
1) 3.7 29 6 70 renal
Norfloxacin 0.4 (
×
2) 1.5 10 3 15 renal and hepatic
Ciprofloxacin 0.75 (
×
2) 3.5 30 4 40 renal and enteral
Ofloxacin 0.4 (
×
2) 4.8 64 6 40 renal
Levofloxacin 0.5 (
×
1) 5.2 48 7 40 renal
Temafloxacin 0.6 (
×
2) 7.0 134 8 25 renal
Trovafloxacin 0.3 (
×
1) 2.5 40 12 85 hepatic
Clinafloxacin 0.2 (
×
2) 1.6 18 6 40 renal
Sparfloxacin 0.4 (
×
1) 1.0 20 18 40 renal and hepatic
Grepafloxacin 0.4 (
×
1) 1.4 14 14 50 hepatic
Moxifloxacin 0.4 (
×
1) 3.1 30 13 50 hepatic
Gatifloxacin 0.4 (
×
1) 4.0 37 9 20 renal
Gemifloxacin 0.32 (
×
1) 1.0 9 7 60 renal and other
Garenoxacin 0.4 (
×
1) 5.8 59 15 87 renal and other
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M. I. Andersson and A. P. MacGowan
6
acid, enoxacin, trovafloxacin and garenoxacin). Non-renal
clearance seems to have become a feature of a number of the
newer agents (e.g. trovafloxacin, grepafloxacin, moxifloxacin
and garenoxacin), although many fluoroquinolones and
naphthyridones are eliminated primarily by metabolism and
renal clearance (glomerular filtration and active tubular
secretion). Clearly, a high free-drug
C
max
and AUCs, com-
bined with lower MIC, are a significant advance because they
will have the effect of increasing the value of
C
max
/MIC or
AUC/MIC ratios.
There is always a certain amount of debate as to whether the
C
max
/MIC or the AUC/MIC is more important in terms of
fluoroquinolone bacteriological and clinical outcomes in
man. This is probably not important because the co-variable
nature of these two pharmacokinetic parameters makes it dif-
ficult to identify which one is dominant in determining micro-
biological and clinical outcome. In general, agents with large
AUC also have high
C
max
concentrations. The other area of
considerable pharmacodynamic debate has been what break-
point or critical PK/PD ratio is required to optimize micro-
biological or clinical outcomes. For example, if there is a
range of values, the bigger numbers are more likely to be pre-
dictive of good clinical outcome in terms of the microbiology
and the emergence of resistance.
45
At present it is reasonable
to assume that almost all the drugs that have AUC/MIC ratios
>100 are likely to have useful activity against Enterobac-
teriaceae and
P. aeruginosa
, while a target of free AUC/MIC
of 30–40 is required for
S. pneumoniae.
46
For predicting efficacy against most infections, pharmaco-
dynamic variables (for example, AUC/MIC or
C
max
/MIC) are
driven by changes in potency, much more than they are driven
by changes in pharmacokinetics. The MIC changes are some-
times 100-fold between agents, whereas the pharmacokinetic
changes are probably at most five-fold between any of these
agents. For example, as ciprofloxacin has an AUC/MIC
between 25 and 50 for the therapy of
P. aeruginosa
, it can
be anticipated that levofloxacin, trovafloxacin and clina-
floxacin will have similar activity to ciprofloxacin against
P. aeruginosa
(Table 6).
47,48
In contrast, some of the newer
drugs, such as grepafloxacin, moxifloxacin, gatifloxacin,
sparfloxacin, gemifloxacin or garenoxacin, together with
some of the older urinary drugs like norfloxacin, are unlikely
to have significant clinical activity against
P. aeruginosa
at
present doses. Pharmacodynamics would predict that all but
the very early quinolones will have good clinical activity
T
a
bl
e
6
.
Deve
l
opment o
f
qu
i
no
l
one p
h
armaco
d
ynam
i
cs aga
i
nst
G
ram-negat
i
ve pat
h
ogens
AUC/MIC (total)
E. coli H. influenzae P. aeruginosa
<12.5 nalidixic acid nalidixic acid nalidixic acid, enoxacin, norfloxacin, sparfloxacin,
grepafloxacin, moxifloxacin, gatifloxacin, gemifloxacin, garenoxacin
12.5–25 enoxacin, ofloxacin
25–50 ciprofloxacin, levofloxacin, trovafloxacin, clinafloxacin
50–100 norfloxacin
>100 all others all others temafloxacin
Table 7.
Development of quinolone pharmacodynamics against Gram-positive pathogens
AUC/MIC
(total)
S. aureus S. pneumoniae
Group A streptococci
<12.5 nalidixic acid, cinoxacin,
norfloxacin
nalidixic acid, cinoxacin, enoxacin,
norfloxacin
nalidixic acid, cinoxacin,
enoxacin,
norfloxacin
12.5–25 enoxacin ciprofloxacin sparfloxacin, grepafloxacin
25–50 ciprofloxacin ofloxacin, levofloxacin, grepafloxacin ciprofloxacin, ofloxacin,
levofloxacin
50–100 sparfloxacin
>100 ofloxacin, levofloxacin, temafloxacin,
trovafloxacin, clinafloxacin,
grepafloxacin, moxifloxacin,
gatifloxacin, gemifloxacin,
garenoxacin
temafloxacin, trovafloxacin,
clinafloxacin, moxifloxacin,
gatifloxacin, gemifloxacin,
garenoxacin
temafloxacin, trovafloxacin,
clinafloxacin, moxifloxacin,
gatifloxacin, gemifloxacin,
garenoxacin
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Development of the quinolones
7
against
E. coli
and
H. influenzae
causing systemic infection
(Table 6).
With respect to the Gram-positive organisms, it is clear that
the urinary drugs are not going to have useful clinical activity
against
S. pneumoniae
,
S. aureus
or
Streptococcus pyogenes
(Table 7). Whereas with ofloxacin, levofloxacin, grepa-
floxacin and sparfloxacin, AUC/MIC ratios of >25 are begin-
ning to predict clinically useful outcomes for non-immuno-
compromised patients with mild to moderate community-
acquired disease. In the context of immunocompromised
patients (those with co-morbidity or ITU patients) or in order
to prevent the emergence of resistance, ratios should probably
be higher. The more recently developed fluoroquinolones,
such as trovafloxacin, gatifloxacin, gemifloxacin, moxi-
floxacin and garenoxacin, are likely to have useful clinical
activity against
S. pneumoniae
, a prediction now supported by
clinical trials data in community-acquired pneumonia
49
and
acute exacerbation of chronic bronchitis (AECB).
50,51
The
small amount of existing clinical data also implies that these
agents are clinically active against ciprofloxacin-susceptible
S. aureus
and Group A streptococci.
32–35,52
Toxicology
Many of the more recently developed quinolones do not have
the toxicological disadvantages of the earlier compounds, for
example the QTc prolongation that has limited the use of spar-
floxacin and grepafloxacin. Other effects include a haemo-
lytic uraemic-like syndrome with temafloxacin,
17
a metallic
taste with grepafloxacin,
53
hepatitis with trovafloxacin,
54
unexpected hypoglycaemia with clinafloxacin and tema-
floxacin,
21,55,56
a number of immunologically mediated
adverse events with tosufloxacin,
18
and an immune-mediated
rash in young women with gemifloxacin.
6
To date there are
little toxicological data on garenoxacin.
Indications and use
The pharmacokinetic and
in vitro
potency profiles of fluoro-
quinolones determine the areas of clinical use. This has
shifted from agents used predominantly for the treatment of
urinary tract infections in the 1960s/70s, to more systemic use
in the 1980s/90s, and in the current millennium, to the treat-
ment of respiratory tract infections. Sparfloxacin and grepa-
Table 8.
Proposed classification of fluoroquinolones
Agents Activity Clinical applications
Urinary agents (1960–1985)
nalidixic acid
cinoxacin
enoxacin
norfloxacin
activity against common
Enterobacteriaceae, short serum
half-lives, renal elimination
main use in UTI
Gram-negative systemic agents (1985–1995)
ciprofloxacin
ofloxacin
levofloxacin
wide activity against Gram-negatives,
including
P. aeruginosa
, marginal
activity against Gram-positives,
longer serum half-lives
widely used against
tissue-based and urinary
infections
Broad spectrum systemic agents (1990–2000)
temafloxacin
clinafloxacin
trovafloxacin
wide activity against Gram-negatives,
including
P. aeruginosa
for some
agents, and Gram-positives, for some
agents long serum half-lives, some
activity against anaerobes
widely used against a
broad range of tissue-
based infections
Respiratory agents (1995 onwards)
levofloxacin
sparfloxacin
grepafloxacin
moxifloxacin
gatifloxacin
gemifloxacin
garenoxacin
wide activity against
Enterobacteriaceae, active against
Gram-positives, especially
S.
pneumoniae
, active against atypical
bacteria, variable activity against
anaerobes, long serum half-life
main use in respiratory
tract infection
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M. I. Andersson and A. P. MacGowan
8
floxacin were the first agents to focus on the respiratory tract,
exploiting their activity against
S. pneumoniae
and atypical
organisms. More recently a further group of agents (moxi-
floxacin, gatifloxacin, gemifloxacin and garenoxacin) with
more convincing potential in the respiratory tract have been
developed. Thus development has moved from the urinary to
the respiratory tract via a miscellaneous group of systemic
indications. Levofloxacin is one example of a drug where
there is a wide range of potential uses, but in terms of market-
ing the main focus appears to be respiratory.
On this basis, quinolones can be classified into four groups
according to clinical use, potency, pharmacokinetics and
pharmacodynamics. The first group consists of urinary agents
that are, in general, the older drugs which are active against
the common Enterobacteriaceae and tend to have short half-
lives and renal elimination (Table 8). The second group
includes the anti-Gram-negative systemic agents such as
ciprofloxacin, levofloxacin and ofloxacin which, according
to their pharmacokinetics and activity, indicate that they can
be used for Gram-negative infection and as anti-pseudomonal
agents. There is, however, debate about their use in various
areas of Gram-positive infection. The third group, of which
trovafloxacin and temafloxacin are the best examples, have
sufficiently broad activity in terms of anti-Gram-negative,
Figure 5.
Development of quinolones.
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Development of the quinolones
9
anti-Gram-positive, antipseudomonal and anti-anaerobic
activity, to indicate their use for a wide range of tissue-based
infections. The fourth group includes the respiratory agents,
some of which are also in other categories. These drugs have
activity against
S. pneumoniae
and atypical organisms, but
are less active against
P. aeruginosa.
Some of these agents,
such as moxifloxacin and garenoxacin, may be as active as
trovafloxacin against anaerobes, suggesting that with time,
their clinical indications may expand beyond the respiratory
area. The nomenclature of the quinolones is complex, and
these agents have also been classified in terms of generation
57
(discussed in this supplement in the article by P. Ball). How-
ever, whichever classification is used, it is clear that these
agents are not a homogeneous group of antibiotics, and that
important differences exist between them.
Conclusions
Modifications in the basic structure of quinolones have
increased their antibacterial spectrum and potency, as well as
improving bioavailability, making quinolones useful agents
for the treatment of urinary, systemic and respiratory tract
infections. An ‘evolutionary’ tree is shown in Figure 5. How-
ever, safety concerns continue with some members of this
class and have resulted in the withdrawal of some agents after
marketing (temafloxacin, grepafloxacin, sparfloxacin, trova-
floxacin) or others in late development (clinafloxacin and
gemifloxacin). It is still unclear as to which structure–
function relationships have resulted in these problems, so
despite a good deal of progress being made in terms of
in vitro
activity and pharmacodynamics, progress in the area of toxi-
cology has been erratic.
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