Journal of Antimicrobial Chemotherapy (2000) 46, Topic T1, 1724

Introduction
Since the discovery, in 1962, of the progenitor 1,8-naph-
thyridine, nalidixic acid,
1
the utility of which was largely
limited to the treatment of Gram-negative urinary tract
infections, the quinolones have evolved to become impor-
tant and effective agents in the treatment of bacterial infec-
tion.
2
The molecular structures of the quinolones have been
adapted over time in association with clinical need. The
naphthyridone nucleus of nalidixic acid became the basis of
a series of more active compounds; piperazine substitution
at the 7-position led to compounds with signicant activity
against Pseudomonas aeruginosa, e.g. pipemidic acid, and,
uorination at the 6-position (giving the uoroquinolones)
and modication of other side chains led to enhanced
anti-Gram-positive activity, including improved potency
against the pneumococcus, improved pharmacokinetic
proles and longer serum half-lives.
3,4
These compounds,
which are suitable for once-daily administration and are
clinically effective in pneumococcal respiratory and other
Gram-positive infections, have differing adverse drug
reaction proles. In some cases, there are relationships
between structure and adverse reaction, notably in terms of
phototoxicity, which is more commonly associated with
additional uorine (lomeoxacin, sparoxacin) or chlorine
(clinaoxacin and sitaoxacin) substitution at the 8-
position, and central nervous system (CNS) effects, which
are more commonly associated with unsubstituted 7-piper-
azine derivatives.
5,6
However, more serious reactions, such
as the temaoxacin-associated haemolyticuraemic syn-
drome
7
and the recent serious, unpredictable hepatic reac-
tions associated with trovaoxacin
5
do not seem to have
any specic structural relationship. There are also no
obvious structural associations, either nuclear or sub-
stituent, with QT interval prolongation, a recently recog-
nized class effect.
8
Nevertheless, the known adverse
reaction proles and improving broad-spectrum activity
have led to the evolution of safer, more clinically efca-
cious molecules by a process akin to the Darwinian princi-
ples of tness of the surviving molecular mutations and
attrition of the defective ones.
46,9
Thus today, newer com-
pounds can be designed that maintain or enhance activity
whilst minimizing the risk of use-limiting adverse effects.
There are, thus, two aspects to the evolution and develop-
ment of the quinolones. Firstly, there is the natural
history, characterized by the development of novel struc-
tures with better activity, pharmacokinetics and tolerability
than previous members of the class. Secondly, there is
natural selection by prescribers and registration/licensing
authorities of those agents and molecular congurations
that remain useful and deselection of those that do not.
17
Quinolone generations: natural history or natural selection?
Peter Ball*
University of St Andrews, Fife, Scotland, UK
The quinolones have evolved from antibacterial agents with a limited spectrum of predomin-
antly anti-Gram-negative antimicrobial activity and a restricted number of indications to a class
of widely used oral (and, in some cases, intravenous) antibiotics with extensive indications for
infections caused by many bacterial pathogens in most body tissues and uids. This evolu-
tionary pattern has arisen through the development of new core and side-chain structures, with
associated improvements in activity, pharmacokinetics and tolerability, and through the selec-
tion of molecules that remain useful and well tolerated. This review describes the progress of
the quinolones from the rst to the third (IIIa and IIIb) generations. Special attention is given to
gemioxacin, currently the most developmentally advanced third-generation quinolone, which
has enhanced in vitro Gram-positive antimicrobial activity and no troublesome adverse drug
reactions. Preliminary data indicate that gemioxacin should prove to be an important addition
to the uoroquinolone class. Further clinical trial data are awaited with interest.
*Correspondence address. 6 Gilchrist Row, Fife KY16 8XU, UK. Tel: 44-1334-476-049; Fax: 44-1334-476-6371;
E-mail: peterball1@aol.com
2000 The British Society for Antimicrobial Chemotherapy
JAC
P. Ball
This article reviews the progress of the quinolones
from the rst-generation through to the more recently de-
veloped third-generation agents. Special attention is given
to gemioxacin, a novel advanced third-generation quino-
lone with superior Gram-positive antimicrobial activity
and retained Gram-negative activity.
The uoroquinolones and naphthyridones
The structures of the quinolones have developed along two
parallel pathways (Table I): the naphthyridones (with the
original naphthyridine core of nalidixic acid) and the
uoroquinolones, in which a carbon atom is substituted for
nitrogen at position 8 of the naphthyridine nucleus. All
have a uorine substitution at the 6-position.
The rst uoroquinolone, umequine,
10
was used transi-
ently until ocular toxicity was reported. Shortly afterwards,
second-generation agents were developed, epitomized by
ciprooxacin (Figure 1). This agent has a wider spectrum of
in vitro antibacterial activity, in particular against Gram-
negative bacteria, and is effective in the treatment of many
types of infection.
3,1113
Despite excellent results in many
respiratory infections,
14
reports of failure in pneumococcal
infection
15
have limited its use in this area.
Subsequently, newer agents were developed that had
increased antimicrobial activity against Gram-positive
pathogens; these included sparoxacin
16,17
and grepa-
oxacin.
18,19
However, sparoxacin has now largely been
abandoned because of signicant phototoxicity and poten-
tial for serious cardiac dysrhythmias, secondary to its
effects on the QT interval.
8,12
The 8-chloro compounds, such
as Bay y 3118,
20,21
clinaoxacin
22,23
and sitaoxacin,
24
were
even more active, but also photoreactive. Only sitaoxacin
remains in limited development. Moxioxacin
2527
and
gatioxacin,
28,29
both 8-methoxyquinolones, are the most
recent and most potent uoroquinolones.
Naphthyridone derivatives emerged in parallel with the
moxioxacin lineage. Enoxacin and tosuoxacin (available
in Japan) were the rst naphthyridones; they were followed
by trovaoxacin
30
and, more recently, gemioxacin
31,32
(Figure 2).
The quinolone generations
The characteristics of the quinolone generations are
summarized in Table II. The antimicrobial activity of the
uoroquinolones and naphthyridones has increased dra-
matically as each generation of quinolones has been de-
veloped. The rst-generation agents had anti-pseudomonal
activity as a result of the addition of a piperazine sub-
stituent at position 7 of the naphthyridine core. These com-
pounds were replaced by the second-generation agents, for
example ciprooxacin,
33
which had predominantly Gram-
negative activity. Improved Gram-positive activity, includ-
ing that against Streptococcus pneumoniae (MICs c.
0.250.5 mg/L
4
), was the next signicant step, seen with the
generation IIb agents such as grepaoxacin and spar-
oxacin. Generation IIIa agents (e.g. moxioxacin,
gatioxacin, sitaoxacin, clinaoxacin and trovaoxacin)
have enhanced activity against S. pneumoniae (MICs
18
Table I. The quinolones
Core structure
Generation uoroquinolone naphthyridone
I umequine nalidixic acid
IIa ciprooxacin, ooxacin, (levooxacin) enoxacin
IIb grepaoxacin, sparoxacin tosuoxacin
IIIa moxioxacin, gatioxacin, sitaoxacin, clinaoxacin trovaoxacin
IIIb none yet developed gemioxacin
Figure 1. The chemical structure of ciprooxacin. Figure 2. The chemical structure of gemioxacin.
Quinolone generations
generally c. 0.12 mg/L
4
), at the partial expense of slightly
reduced activity against P. aeruginosa. The most recent
advance in in vitro activity is represented by gemioxacin,
currently the only IIIb quinolone. Gemioxacin has a
balanced spectrum of activity with Gram-negative activity
similar to that of ciprooxacin but superior Gram-positive
activity (MIC for S. pneumoniae 0.03 mg/L).
31,32
Second generation
Generation IIa. The generation IIa quinolones have been
available since the mid-1980s and were responsible for an
enormous change in the clinical treatment of important
infections. With the advent of ciprooxacin, for almost
the rst time, serious, potentially bacteraemic Gram-nega-
19
Table II. Summary of the characteristics of the quinolone generations
Generation Characteristics
I predominantly used for the treatment of urinary tract infections
IIa enhanced activity, mainly against Gram-negative pathogens; limited potency against Gram-positive
pathogens (pneumococcus (MIC 14 mg/L) and methicillin-resistant Staphylococcus aureus);
ciprooxacin most active against P. aeruginosa
indications: urinary tract infections, pyelonephritis, gonorrhoea, chlamydial infections, prostatitis, skin
and soft tissue infections/osteomyelitis, enteric fevers, cholera and salmonellosis, infections caused by
P. aeruginosa, acute exacerbations of chronic bronchitis, nosocomial pneumonia, Legionnaires disease
class adverse drug reactions (CNS effects, gastrointestinal, skin rashes and allergic reactions, photo-
toxicity (usually 2%), cartilage damage in juvenile animals, tendinitis, usually minor renal and
hepatic syndromes); cytochrome P450 interaction (theophylline, caffeine)
emergence of resistance (P. aeruginosa, staphylococci, pneumococci, Gram-negative bacilli) in
pathogenic species with initially higher MICs, e.g. 0.5 mg/L
IIb balanced broad spectrum of activity; increased potency against pneumococci (MIC 0.250.5 mg/L); less
potent for P. aeruginosa
mode of action: frequently have two sites of action, against gyrase and topoisomerase IV
indicated for respiratory tract infections (plus IIa indications where licensed)
pharmacokinetic prole (half-life) permits once-daily dosing
class adverse drug reactions plus unexpected adverse drug reactions with individual agents
(haemolyticuraemic syndrome, QTc* prolongation, phototoxicity); variable cytochrome P450
interaction with theophyllines
IIIa enhanced activity against Gram-positive pathogens (pneumococcal MIC 0.120.25 mg/L)
favourable pharmacokinetics permitting once-daily dosing; trovaoxacin is almost entirely eliminated
by hepato-biliary excretion; for others there is balanced renal and hepato-biliary elimination
indicated for respiratory tract infections (trovaoxacin indicated for surgical and gynaecological
indications)
class adverse reaction prole; no cytochrome P450 interaction; specic adverse drug reactions with
trovaoxacin, e.g. higher incidence of CNS effects, hepatic, allergic reactions and pancreatitis; specic
effects with clinaoxacin include hypoglycaemia and increased incidence and severity of phototoxicity
IIIb markedly enhanced activity against Gram-positive bacteria (pneumococcal MIC 0.012 mg/L); retained
activity against ciprooxacin-resistant pneumococci; highly active against atypical respiratory tract
infection pathogens; retained activity versus Gram-negative pathogens
favourable pharmacokinetics permitting once-daily dosing; high V
d
and tissue penetration; balanced
elimination (30% renal)
pharmacodynamics predict high efcacy in respiratory tract infections
favourable adverse drug reaction prole: low CNS adverse drug reaction rate, no phototoxicity
*QTc, electrocardiographic QT interval corrected for heart rate.
P. Ball
tive infections, such as pyelonephritis, prostatitis and
osteomyelitis, could be treated highly effectively in the
outpatient setting with an oral antibiotic. Similarly,
P. aeruginosa respiratory infections in children with cystic
brosis could be treated orally. Enteric fever and salmonel-
losis could be treated with short-course oral therapy with
minimal relapse and low carriage rates. These exceptional
advances in antimicrobial chemotherapy were reected in
the approved indications for these agents.
4
The main disadvantage of the IIa quinolones was their
limited activity against Gram-positive pathogens, including
S. pneumoniae (because of their intrinsically low activity
against these species) and methicillin-resistant Staphylo-
coccus aureus (MRSA) (because of the development of
resistance).
34
In addition, certain class adverse events, such
as CNS effects (headache, dizziness), phototoxicity and
tendinitis, became apparent, although the more serious
events were rare.
5
Study of this group led to a greater
understanding of the metabolism of quinolones, for exam-
ple their inhibition of the cytochrome P450 1A2-mediated
metabolism of drugs, such as theophylline.
5,35
Generation IIb. The development of the generation IIb
compounds, with a more balanced spectrum of activity
encompassing the pneumococcus, resulted in the applica-
tion of uoroquinolones to respiratory tract infections. The
longer half-life of these agents also permitted once-daily
dosing.
The generation IIb quinolones were also associated with
the class adverse drug reactions described above, but other
adverse reactions were observed with individual agents.
For example, haemolyticuraemic syndrome was reported
with temaoxacin and resulted in its withdrawal,
7
and
prolongation of the electrocardiographic QT interval cor-
rected for heart rate (QTc interval), possibly predisposing
to ventricular arrhythmias, was seen with sparoxacin.
36,37
The oral tolerance of grepaoxacin is not optimal; it
interacts signicantly with theophylline (via cytochrome
P450 1A2) and QTc prolongation may occur.
38
The
occurrence of seven cardiac deaths, possibly related to
grepaoxacin, led to the withdrawal of this drug by the
manufacturer in October 1999. Other quinolones now
have data-sheet labelling warning of possible effects on
the QTc interval and associated clinical consequences,
including ventricular arrhythmias and torsade de pointes.
8
No clinically signicant effects have been observed with
gemioxacin.
Third-generation
Generation IIIa. Of the IIIa compounds, moxioxacin and
trovaoxacin both have 7-azabicyclo modications, whereas
gatioxacin retains the original 7-piperazinyl group. All
are active against penicillin-resistant S. pneumoniae and
have proven highly effective in the treatment of lower res-
piratory tract infections.
4,12,39
Moxioxacin was licensed in
Germany in 1999 and both moxioxacin and gatioxacin
are now licensed and available in the USA.
Before its withdrawal/suspension, trovaoxacin, which
had excellent activity against anaerobes, had proven effec-
tive in post-surgical intra-abdominal and gynaecological
infections.
12
The efcacy of the other IIIa/b compounds
may now be evaluated in these indications.
Members of this group share the class adverse drug reac-
tion prole, but do not interact with cytochrome P450 1A2.
Recently, however, rare but serious adverse reactions
(liver failure, hepatic dysfunction and pancreatitis) have
led to trovaoxacin being either restricted for use in
inpatients with life- or limb-threatening infections for
which no suitable safe and effective alternatives are avail-
able (in the USA) or suspended from use (in Europe).
Clinaoxacin was voluntarily withdrawn by the manufac-
turer during the registration process, at least in part
because of the excess phototoxicity and reports of hypo-
glycaemia. Fortunately, both of the 8-methoxyquinolones,
gatioxacin and moxioxacin, have satisfactory adverse
drug reaction proles and appear free of signicant clinical
problems.
12,40
Generation IIIb: gemioxacin. Gemioxacin is currently
the only generation IIIb quinolone in phase III develop-
ment. Against S. pneumoniae, gemioxacin has markedly
better activity than its predecessors, including the IIIa
quinolones.
41,42
Its side-chain structure (Figure 2) includes
the 1-cyclopropanyl group that is characteristic of most of
the uoroquinolones with good safety proles, including
ciprooxacin (Figure 1), in contrast to the 1-diuorophenyl
substituent of temaoxacin and trovaoxacin. In addition,
gemioxacin has a large side chain at position 7, thought
to be associated with reduced CNS effects,
6
and a meth-
oxyamino group, which may account for the dramatic
improvement in anti-pneumococal activity seen with this
compound.
MICs for the pneumococci show a marked increase in
activity compared with earlier compounds (Table III).
Gemioxacin also retains activity against penicillin-resis-
tant and ciprooxacin-resistant strains of S. pneumoniae.
42
Its activity against quinolone-resistant S. pneumoniae
43
may prove important in the light of the increasing problem
of resistance to penicillins, macrolides and earlier uoro-
quinolones. The small, but increasing, prevalence of quino-
lone resistance is discussed in more detail elsewhere.
4446
Gemioxacin is also highly active against clinically
signicant atypical respiratory tract pathogens such as
Chlamydia pneumoniae, Legionella pneumophila and
Mycoplasma pneumoniae (Table IV).
47,48
The safety of gemioxacin has been studied in a continu-
ing clinical trial programme; preliminary data indicate that
it has a satisfactory adverse drug reaction prole. Gemi-
oxacin has been used in single doses of 800 mg and in
multiple dosing regimens in both healthy volunteers (640
mg/day) and elderly patients (320 mg/day) and was well
20
Quinolone generations
tolerated.
4951
The CNS effects observed with gemioxacin
are similar to those seen with placebo and, to date, no
signicant/serious adverse drug reactions have been
observed.
During randomized, double-blind phase II clinical trials
of gemioxacin, the incidence of CNS, gastrointestinal and
dermatological class adverse drug reactions was, in general,
the same or better than that of the generation IIa quino-
lone, ooxacin (Figure 3).
52
The incidence of nausea seen
with gemioxacin (3.8%) appears to be lower than that
observed with grepaoxacin (15%; 2.6% discontinuation
rate) or moxioxacin (7.8%; 1% discontinuation rate).
5
The high incidence of dizziness reported with trovaoxacin
(11% with 200 mg dosage)
5
has not been seen with gemi-
oxacin (1.5%) in these early trials. To date, no cardio-
vascular effects have been recorded in patients treated with
gemioxacin.
The phototoxic potential of gemioxacin (320 mg od)
compared with ciprooxacin (500 mg bid) in healthy volun-
teers (n 30) was shown to be low and similar to that of
ciprooxacin.
53
In contrast, lomeoxacin is associated with
a signicant phototoxic potential.
54
The interaction prole of gemioxacin has been studied
in healthy volunteers. No signicant interactions were
observed after absorption with digoxin,
51
theophylline
55
or
warfarin.
56
The interaction of uoroquinolones with co-
administered antacids is well known and gemioxacin
absorption is similarly reduced by the co-administration of
Maalox.
57
Manipulation of dosing regimens (administration
either 23 h before or after antacid therapy)a simple mat-
ter with the once-daily dosing regimen of gemioxacin
can eliminate any such problems. The effect of omeprazole
on gemioxacin pharmacokinetics is not considered to be
clinically signicant; dose adjustment is unnecessary when
these agents are administered together.
58
In summary, gemioxacin is the most active quinolone
against S. pneumoniae and has a satisfactory adverse drug
reaction prole. It has a favourable pharmacokinetic
prole that allows once-daily dosing
50
and its pharmaco-
kinetic/pharmacodynamic prole suggests that it will be
21
Table III. The in vitro activities (MICs, mg/L) of gemioxacin and other quinolones against clinical
isolates of Streptococcus pneumoniae
42
Penicillin-susceptible
a
Penicillin-resistant
b
Ciprooxacin-resistant
c
(n 64) (n 75) (n 29)
MIC
50
MIC
90
MIC
50
MIC
90
MIC
50
MIC
90
Ciprooxacin 1 2 1 4 16 >32
Levooxacin 1 2 1 2 16 >32
Sparoxacin 0.5 1 0.5 0.5 8 16
Grepaoxacin 0.125 0.5 0.25 0.5 4 8
Trovaoxacin 0.125 0.5 0.125 0.25 1 4
Gemioxacin 0.03 0.03 0.03 0.06 0.25 0.5
a
Penicillin MICs 0.06 mg/L.
b
Penicillin MICs 216 mg/L.
c
Ciprooxacin MIC 8 mg/L for all strains.
Table IV. The in vitro activities (MIC range, mg/L) of gemioxacin and other quinolones against
atypical respiratory tract pathogens (data taken from reference 4 unless otherwise indicated)
Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniae
Levooxacin 0.5 0.050.1
Sparoxacin 0.090.25 0.06 0.120.25
Grepaoxacin 0.5 0.016 0.25
Trovaoxacin 0.12 0.004 0.25
Moxioxacin 0.060.1 0.015 0.060.12
Gemioxacin 0.060.12
a
0.0020.03
a
0.050.11
b
a
Data taken from reference 47.
b
Data taken from reference 48.
P. Ball
clinically effective in the treatment of respiratory tract
infections.
59
Conclusions
The quinolones have evolved from agents used solely for
the treatment of urinary tract infections to molecules with
potent activity against a wide spectrum of signicant bac-
terial pathogens and clinical utility in many indications
throughout body tissues and uids. Progressive modica-
tions in molecular conguration have resulted in improved
breadth and potency of in vitro activity and pharmaco-
kinetics, which have identied those agents t to survive in
todays therapeutic environment. Concomitantly, exces-
sive incidences of class adverse drug reactions and specic
unexpected reactions with individual agents have deter-
mined the deselection of agents such as temaoxacin,
sparoxacin, Bay y 3118 and, most recently, trovaoxacin,
clinaoxacin and grepaoxacin.
Gemioxacin is an advanced third-generation quinolone
with a broad spectrum of antimicrobial activity that
includes potent activity against S. pneumoniae. At present,
it appears to be the most potent quinolone against this
important pathogen. It also has a favourable pharmaco-
kinetic prole, characterized by a large volume of distribu-
tion and an elimination rate that suggests it to be suitable
for once-daily dosing. Preliminary data indicate that it has
a low incidence of adverse drug reactions and a low photo-
toxic potential. Further data from clinical trials of this
newly developed quinolone are awaited with interest.
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24