Académique Documents
Professionnel Documents
Culture Documents
Veterinary Journal
The Veterinary Journal 172 (2006) 1028
www.elsevier.com/locate/tvjl
Review
b,*
US Food and Drug Administration, Center for Veterinary Medicine, Oce of New Animal Drug Evaluation, Rockville, MD 20855, USA
b
US Food and Drug Administration, Center for Veterinary Medicine, Division of Animal and Food Microbiology,
Oce of Research, Laurel, MD 20708, USA
Abstract
The uoroquinolones are a class of compounds that comprise a large and expanding group of synthetic antimicrobial agents.
Structurally, all uoroquinolones contain a uorine molecule at the 6-position of the basic quinolone nucleus. Despite the basic similarity in the core structure of these molecules, their physicochemical properties, pharmacokinetic characteristics and microbial
activities can vary markedly across compounds. The rst of the uoroquinolones approved for use in animals, enrooxacin, was
approved in the late 1980s. Since then, ve other uoroquinolones have been marketed for use in animals in the United States, with
others currently under investigation.
This review focuses on the use of uoroquinolones within veterinary medicine, providing an overview of the structureactivity
relationship of the various members of the group, the clinical uses of uoroquinolones in veterinary medicine, their pharmacokinetics and potential interspecies dierences, an overview of the current understanding of the pharmacokinetic/pharmacodynamic relationships associated with uoroquinolones, a summary of toxicities that have been associated with this class of compounds, their use
in both in human and veterinary species, mechanisms associated with the development of microbial resistance to the uoroquinolones, and a discussion of uoroquinolone dose optimization. Although the review contains a large body of basic research information, it is intended that the contents of this review have relevance to both the research scientist and the veterinary medical
practitioner.
Published by Elsevier Ltd.
Keywords: Fluoroquinolones; Veterinary; Pharmacokinetics; Pharmacodynamics; Resistance
1. Introduction
Quinolones, also referred to as 4-quinolones, quinolone carboxylic acids and uoroquinolones, comprise a
large and expanding group of synthetic antimicrobial
agents. The rst drug of this class, nalidixic acid, was discovered in 1962 and was a modication of a compound
isolated during the production of the anti-malaria drug,
chloroquine. Nalidixic acid was rst discovered as a by*
11
2. Mechanism of action
In multiple species of bacteria, early biochemical evidence indicated that uoroquinolones damage bacterial
DNA and lead to defects in negative supercoiling (Gellert et al., 1977). This eect was linked to inhibition of
DNA gyrase activity, an enzyme found in all bacteria.
In concert with other proteins, gyrase catalyzes changes
in the degree of double-stranded DNA supercoiling. In
this capacity, it plays a vital role in DNA packing, replication and transcription.
The active holoenzyme is a heterotetramer composed
of two subunits each of gyrA and gyrB (A2B2). GyrA
binds to DNA and mediates strand breakage and rejoining activity, whereas gyrB contains the ATP binding
site. GyrA activity involves cleavage of both DNA
strands, (mediated by an enzyme-DNA covalent intermediate), passage of DNA through the break and religation of the strand. In vivo, this process results in
two negative supercoils and the hydrolysis of ATP.
The topoisomerase IV enzyme, encoded by parC/parE,
is a secondary uoroquinolone target. This enzyme is
also a multimeric protein composed of two parC subunits and two parE subunits, which exhibit sequence
homology to gyrA and gyrB, respectively. This enzyme
mediates relaxation of duplex DNA and the unlinking
of daughter chromosomes following replication (Zechiedrich and Cozzarelli, 1995).
When susceptible DNA gyrase is exposed to a
quinolone, the drug interacts at the surface of an alpha-helical domain of the enzyme involved in DNA
cleavage and re-ligation, termed the quinolone resistance determining region (see below). The toxic eects
result from the irreversible formation of a trapped
intermediate consisting of quinolone, gyrase and
cleaved DNA (Gellert et al., 1977). This prevents
progression of replication forks and transcription
12
complexes (Willmott et al., 1994), leading to fragmentation of the chromosome and cell death. Because quinolones mediate DNA damage by binding to susceptible
enzymes, uoroquinolone-resistance mutations are
recessive. The result of this is that for topoisomerasemediated uoroquinolone resistance to be transferred
horizontally, an acquired mutated gene would have to
supplant the wild-type gene.
The eect of uoroquinolones on bacterial proliferation suggests three mechanisms of cell killing (Guthrie
et al., 2004; Maxwell and Critchlow, 1998):
1. Mechanism A: common to all quinolones. This
requires RNA and protein synthesis and is only eective against dividing bacteria. Mechanism A appears
to involve the blocking of replication by the gyrase
quinolone complex on DNA.
2. Mechanism B: does not require RNA and protein
synthesis and can act on bacteria that are unable to
multiply. Mechanism B (chloramphenicol insensitive)
can be correlated with dislocation of the gyrase subunits that constrain the ternary complex.
3. Mechanism C: requires RNA and protein synthesis
but does not require cell division. Mechanism C
may correlate with trapping of topo IV complexes
on DNA.
The uoroquinolones, as with the penicillins, exhibit a paradoxical eect. Survival curves show that
when the uoroquinolone concentration is near the
minimal inhibitory concentrations (MIC) of the bacterium, the drug has a static eect on bacterial growth
(bacteriostatic). As the drug concentration increases
relative to the MIC of the bacterium, bacterial killing
increases up to a certain drug concentration (termed
the optimum bactericidal concentration). As concentrations exceed the optimum bactericidal concentration, further increases in drug concentration can lead
to a decrease in bacterial killing. Initially, these concentration-related dierences in drug eect may be
associated with the dierence between concentrations
needed to inhibit DNA supercoiling versus those
needed to inhibit bacterial growth. In general, it appears that the supercoiling reaction of gyrase is less
sensitive to the drugs than is bacterial growth by
one or two orders of magnitude (Guthrie et al.,
2004; Maxwell and Critchlow, 1998).
It is believed that the inhibition of RNA and protein
synthesis may account for this third phase of bacterial
eect (decreased killing). This implies that protein synthesis may be required for quinolone-mediated cell
death. In this regard, protein synthesis and inhibitors
such as chloramphenicol, and RNA synthesis inhibitors
(such as rifampin) reduce uoroquinolone eectiveness
in bacterial killing (Guthrie et al., 2004; Maxwell and
Critchlow, 1998).
3. Structureactivity relationship
Nalidixic acid lacks several characteristics associated
with modern 4-quinolones. For example, nalidixic acid
contains two nitrogen atoms in the basic nucleus, making it a naphthyridine rather than a quinolone, and nalidixic acid is not halogenated like other quinolones such
as chloroquine (Fig. 1). In addition, nalidixic acid exhibits modest serum and tissue concentrations, and susceptible bacteria have relatively high MIC values.
Following the discovery of the therapeutic eects of
nalidixic acid, chemists began to probe every position
within the quinolone nucleus in an attempt to improve
potency, broaden the spectrum of antibacterial activity, and reduce recognized side eects. To date, several
thousand related compounds have been synthesized.
Studies have shown that there are four components
of the 4-quinolone nucleus that, when manipulated,
can enhance the antibacterial activity of the quinolone
nucleus. These include an ethyl group at the N-1
position, a carboxylic group at C-3, an oxygen atom
at C-4 and a uorine atom at C-6. Of these, it was
the addition of a uorine atom to the 4-quinolone ring
at the 6-position that has substantially widened the
antibacterial activity spectrum of the quinolones
(Wright et al., 2000). This modication also enhanced
the quinolones oral bioavailability and tissue penetration. As a result of this discovery, all of the 4-quinolones marketed for clinical use today are halogenated
at the 6-position. Some are also halogenated at the
8-position.
The rst compound with a uoro group at position 6
was umequine which was patented in 1973 (Appelbaum and Hunter, 2000). Dioxacin has two uorine
atoms. While dual substitution does not signicantly increase its potency relative to products containing a single uorine atom, the addition of a second uorine
molecule at C-8 enhances dioxacins oral bioavailability and increases its terminal elimination half-life. How-
ever, this change also increases the potential for phototoxicity. The addition of a piperazinyl side chain at position 7 improves the ability of the drug to penetrate the
bacterial cell wall, thereby improving its activity against
Gram-negative organisms and providing some degree of
Gram-positive activity (Appelbaum and Hunter, 2000).
Noroxacin (patented in 1978) was the rst compound
to combine a piperazinyl side chain in position 7 and a
uoro group in position 6. Although the addition of a
piperazinyl ring at the 7-position resulted in increased
activity against bacteria such as P. aeruginosa and
Gram-positive cocci, noroxacin continued to suer
from poor bioavailability.
Subsequent modications resulted in signicant
improvements in oral bioavailability, as well as an increase in the spectrum of antimicrobial activity. Various
other substitutions, such as the inclusion of the ethyl
group at N-1, have enhanced both Gram-positive and
Gram-negative antimicrobial activity. Other examples
of modications at the N-1 position include the cyclopropyl group found with ciprooxacin and enrooxacin
and the phenyl ring of dioxacin (Appelbaum and Hunter, 2000).
The pharmaceutical industry has produced a large
number of derivatives and analogues of the 4-quinolone
structure. With these products, there seems to be an inverse relationship between a compounds Gram-positive
and Gram-negative activity such that enhanced activity
against one often accompanies reduced activity against
the other. Another drawback to increased activity is
the potential for increased host toxicity. For example,
several broad-spectrum uoroquinolones approved for
use in human medicine, such as temaoxacin (Federal
Register, 2004) and grepaoxacin (Glaxo Wellcome,
2004), have been voluntarily withdrawn from clinical
use as a result of emerging safety concerns.
Structural modications in quinolone compounds
over time have led to changes in pharmacokinetic properties, tolerability and antibacterial potency (Appelbaum and Hunter, 2000; Peterson, 2001). There is no
evidence to date, however, suggesting a relationship between potency and the likelihood of selecting for resistant isolates.
Varying the substitutions placed on the quinolone nucleus does aect the likelihood of drugdrug interactions
(Mizuki et al., 1996). For example, those uoroquinolones containing a bulky substituent at position 8, or
with a 4 0 -nitrogen atom in the 7-piperazinyl group, are
less prone to interact with theophylline than are those
without an 8-substituent. These substitutions tend to
make the molecule less planar, and therefore less likely
to be associated with drugdrug interactions involving
the CYP 450 system of enzymes. Examples of two compounds with bulky substituents that are approved for
human use are levooxacin and sparoxacin. With regard to veterinary examples, the bulky nature of the po-
13
pKa1
pKa2
pKa1a
pKa2a
Ciprooxacin
Danooxacin
Dioxacin
Enoxacin
Enrooxacin
Fleroxacin
Lomeoxacin
Marbooxacin
Noroxacin
Ooxacin
Peoxacin
Saraoxacin
Sparoxacin
Temaoxacin
6.0
8.8
6.1
6.0
6.0
5.7
5.8
7.6
8.5
8.7
8.0
9.3
5.86
6.07
5.66
8.24
8.56
7.24
5.88
7.74
6.4
6.1
6.3
8.7
8.2
7.6
5.69
5.94
8.02
8.22
5.62
8.18
6.2
5.6
8.6
8.8
a
Based upon a liquid chromatographic procedure using a 0% (w/w
methanol) in aqueous potassium hydrogenphthalate buer.
14
Fig. 2. Chemical structures of the uoroquinolones that have been used for the treatment of veterinary bacterial infections within the U.S.
15
Table 2
Compounds approved within the US for use in veterinary species as of November 2003
Drug 21 CFR
citation
Dosage form
Route
Species
Dose
(mg/kg)
Instructions
Withdrawal information
Enrooxacin
(520.812)
Tablet
PO
Dog, cat
520
NA
Enrooxacin
(520.812)
Enrooxacin
(520.812)
Danooxacin
(522.522)
Dioxacin
(520.645)
Injectable solution
SC
Dog
2.5
Injectable solution
SC
Cattle
Injectable solution
SC
Cattle
2.55
7.512.5
6.0
Tablet
PO
Dog
510
Tablet
PO
Dog, cat
2.755.0
Tablet
PO
Dog, cat
2.5 to 7.5
Marbooxacin
(520.13)
Orbioxacin
(520.1616)
NA
28 days
4 days
NA
NA
NA
5. Pharmacokinetics
It may be particularly important to factor a compounds pharmacokinetic and physicochemical properties into the drug and dose selection process when:
1. The animal has modied renal or hepatic function. In
this case, clearance can be compromised, leading to
higher systemic drug concentrations that may aect
product safety.
16
In cases where there are active metabolites (e.g., enrooxacin (Tyczkowska et al., 1989) and ibaoxacin
(Coulet et al., 2005)), when there is stereospecic pharmacokinetics and antimicrobial activity (e.g., ibaoxacin [Coulet et al., 2005]), or when there is high protein
binding (discussed later in this review), the analysis of
plasma and urine samples via microbiological assays
versus high-performance liquid chromatography
(HPLC) methods may lead to dierent pharmacokinetic
results. Therefore, although the merits of the respective
methods can be debated, for the purpose of this review,
all pharmacokinetic information is based upon data collected using HPLC methods.
5.1. Bioavailability
Although there is considerable individual variation
among the dierent compounds and in the dierent animal species, as a rule, the uoroquinolones are rapidly
absorbed following oral administration in monogastric
species. With ruminants, systemic concentrations of orally administered uoroquinolones are below therapeutic levels. For example, the oral bioavailability of
enrooxacin is only 10% in adult ruminants as compared to greater than 80% oral bioavailability in monogastric species (Greene and Budsberg, 1993; Vancutsem
et al., 1990).
Generally, unless administered with foods containing
a high concentration of divalent cations, the postprandial oral administration of uoroquinolones does not result in clinically signicant decreases in bioavailability
(F). A slight delay in time to peak and a decrease in peak
plasma concentrations may occur as a consequence of
the delay in gastric emptying (Blondeau, 1999). Accordingly, these drugs can generally be administered without
concern for prandial state (Allen et al., 2000; Efthymiopoulos et al., 1997; Gajjar et al., 2002; Johnson et al.,
1999). However, for lipophilic compounds, food can signicantly enhance oral bioavailability and therefore increase systemic drug concentrations. For example, food
signicantly increases the AUC and Cmax of ibaoxacin
when administered to cats (Coulet et al., 2005). With
the advent of various taste-masking techniques such as
ion exchange resins (Agarwal et al., 2000), lm coatings
(Chopra et al., 2002), and micro-encapsulation (Al Omran et al., 2002), food could potentially inuence the rate
and/or extent of drug release. Therefore, the FDA often
asks that food-eect study results be submitted to support the approval of products employing novel formulations for veterinary use.
While the lipophilicity of these molecules promotes
absorption by passive diusion, non-passive mechanisms for intestinal uptake also may exist (Dautrey
et al., 1999; Rabbaa et al., 1997). Carrier-mediated
transport across the apical membrane, as is seen with
sparoxacin, levooxacin, ciprooxacin, and noroxa-
F (%)
% Renal
% Protein binding
62
30
20
32
20
70
>95
8590
97
4060
44
50
8990
3040
6087
20
>90
88
75
10
6
5080
31
50
20
2030
45
76
17
considering free interstitial drug concentrations, investigators conrmed (based upon the use of microdialysis
methods) that unbound concentrations of uoroquinolones in interstitial uids are comparable to the free
drug concentrations in venous plasma (Araki et al.,
1997). Therefore, excluding those situations associated
with ion trapping, since equilibrium is established between blood and tissue free drug concentrations (Muller et al., 1999), tissue free drug concentrations can be
predicted on the basis of free drug concentrations in
the plasma, even in cases where there is nonlinear protein binding (Kovar et al., 1997).
5.3. Clearance and elimination
Fluoroquinolones are frequently categorized by their
primary pathway of elimination. These include elimination via renal mechanisms (e.g., enrooxacin, orbioxacin, ooxacin, temaoxacin and lometoxacin), hepatic
metabolism (e.g., dioxacin and peroxacin) or both renal and hepatic mechanisms (marbooxacin, danooxacin noroxacin, ciprooxacin and enoxacin (Karablut
and Drusano, 1993)). The extent to which the uoroquinolones undergo hepatic metabolism varies greatly
between molecules and animal species, with a corresponding wide range in terminal elimination half-life
(Greene and Budsberg, 1993; Nix and Schentag, 1988;
Vancutsem et al., 1990). Fluoroquinolone metabolic
pathways
include
glucuronidation
(cinaoxain,
grepaoxacin, sparoxacin and moxioxacin) and
N-oxidation and desmethylation (levooxacin and sparoxacin). Generally, metabolism involves the CYP 450
system (Bergogne-Berezin, 2002).
As previously stated, one mechanism of uoroquinolone elimination is via active drug secretion across the
intestinal membrane. Intestinal concentrations can also
be a function of biliary secretion. The presence of enterohepatic recirculation can increase the residence time of
a compound. For example, in beagle dogs, 80% of an
intravenous dose of dioxacin is eliminated in the feces
(Federal Register, 1998). This was largely attributable to
biliary secretion. Approximately 7280% of the drug in
the bile was the ester glucuronide, with only 69% being
the parent compound. The glucuronide appears to be
hydrolyzed in the gut, thereby restoring the parent compound which was subsequently available for re-absorption. The terminal elimination half-life of dioxacin
following oral administration to dogs is approximately
9.4 h.
The extent of renal elimination varies across the uoroquinolones. Levooxacin and gatioxacin are eliminated primarily by the kidney, with the renal clearance
of levooxacin exceeding creatinine clearance by
approximately 60%. This suggests the involvement of
both glomerular ltration and tubular section (Okazaki
et al., 1991). The latter was conrmed by a 2435%
18
decrease in renal clearance following doses of probenecid or cimetidine (Aminimanizani et al., 2001). Probenecid can also prolong the terminal elimination half-life
of gatioxacin and ciprooxacin. A summary of the
metabolism and elimination of uoroquinolones used
in veterinary species is provided in Table 4.
5.4. Interspecies dierences
There can be marked interspecies dierences in uoroquinolone pharmacokinetics. For example, the systemic clearance (CL) of dioxacin is substantially
lower in pigs (0.16 L/kg/h) as compared to chickens
(0.72 L/kg/h). However, chickens have a substantially
larger steady-state volume of distribution (Vss =
3.06 L/kg) as compared to pigs (1.7 L/kg) (Inui et al.,
1998). Nevertheless, owing to its more rapid CL, the terminal elimination half-life following an intravenous
dose in chickens (4.1 h) is more rapid than that associated with swine (T1/2 = 7.92 h). After oral administration, dioxacin bioavailability was similar across the
two species: 93.7% and 86.9% for swine and chickens,
respectively 6.
Moxioxacin pharmacokinetics was compared across
six mammalian species: dog, mini-pig, mouse, monkey,
human and rat (Siefert et al., 1999). Vss values were
found to be highly correlated to body weight (BW).
When using all ve species, the resulting allometric
equations were:
CL 1.185 L=h BW0.529 r 0.96;
V ss 3.73 L BW
0.918
r 0.99.
F (%)
T1/2
% fu
Mouse (male)
Rate (male)
Monkey (female)
Dog (female)
Minipig (female)
Human (male)
78
78
52
91
54
82
0.93
1.2
6.9
8.6
5.7
13
69
63
62
71
63
55
Table 4
Summary of pathways involved in the elimination of uoroquinolones in veterinary species
Drug
Species
References
Elimination pathway
Danooxacin
Cattle
Heitzman (1998)
Equal amounts of drug-related material in urine and feces, with 90% and 57%
being parent compound in urine and feces, respectively.
Dioxacin
Dog
80% of dose eliminated in the feces. Approximately 20% of the dose is eliminated as
two major metabolites: the glucuronide and the desmethyl derivative.
Enrooxacin
Dog
Cat
Cattle
Marbooxacin
Dog
Cat
EMEA (2004)
Orbioxacin
Dog
Cat
Ratio of label found after 72 h in urine versus feces as 28%/15% (dog) and 45%/18%
(cat). In cat, 4% of the drug in urine appeared as the N-hydroxylated compound. In
dog, 13% appeared as the glucuronidated compound.
Measured dierences in the terminal elimination halflives and bioavailability of the uoroquinolones approved for use in veterinary species within the US are
provided in Table 6.
5.5. Pharmacokinetic/pharmacodynamic relationships
The relationship between the pharmacokinetics and
microbiological activity (pharmacodynamics) of the uoroquinolones may be used to help determine the dose
needed to achieve a desired clinical outcome. From a
pharmacokinetic/pharmacodynamic (PK/PD) perspective, uoroquinolones are associated with concentration-dependent killing (Zhanel, 2001).
Parameters attributed to this include the area under
the 24-h serum (or plasma) concentration versus time
curve (AUC024 h) divided by MIC of the clinical isolate
or, if the MIC of the clinical isolate is unknown, then the
MIC90 of bacteria of the same genus and species as the
clinical isolate, (AUC/MIC) and the peak serum or plasma concentrations (Cmax) divided by the MIC, or
MIC90, (Cmax/MIC). These parameters are closely related and both are important for ensuring ecacy.
Examples of variables that can inuence the PK/PD
relationship associated with a successful clinical outcome are provided in Table 7.
Recently, Mouton et al. (2005) published a manuscript to standardize the PK/PD terminology used in
the literature. Some of the important points noted in
their review are:
1. AUC should be expressed in terms of unbound drug.
If multiple dosing regimens are applied, AUC should
be measured over a 24-h dosing interval at steady
state.
2. AUC/MIC is often expressed in terms of the dimension of time. However, since it is measured over a
set period of incubation (generally 1824 h), this ratio
can be expressed as a dimensionless value.
3. T > MIC represents the cumulative percentage of a
24-h period that the drug concentration exceeds the
MIC at steady-state pharmacokinetic conditions.
19
Inoculum eect
Pathogen growth rate (generation time)
Growth phase of the invading organism (active versus dormant)
Microbial biolm
Host response to the pathogen
a. Integrity of the immune system
b. Diusivity of drug through host exudates
c. Change in pH at site of the infection
Site of the infection
a. Natural barriers (e.g., bloodbrain barrier)
b. Tissue perfusion
c. Nature of the exudate
Table 6
Interspecies comparison of oral bioavailability and terminal elimination half-life for uoroquinolones used in veterinary species
Enrooxacin
Chicken
Turkey
Cattle
Pig
Sheep
Dog
Horse
Goat
Danooxacin
F (PO)
101
61
8
15.6
3.9
15.4
91
60
4.9
5.6
Marbooxacin
F (IM)
F (IM)
78
76
95.7
2.9
6.8
3.35
100
4.2
88
100
8.6
4.7
7.2
Based upon information from AliAbadi and Lees (2002), Carretero et al. (2002), Greene and Budsberg (1993), Mann and Frame (1992), McKellar
et al. (1998), Siefert et al. (1999) and Waxman et al. (2001).
20
21
6. Toxicities
Fluoroquinolone toxicities are, for the most part,
dose and animal species dependent (Bertino and Fish,
2000). Most reactions are considered to be minor and
reversible upon discontinuing treatment. In human
medicine, there have been reports of photosensitivity,
drugdrug interactions, central nervous system eects
(including seizures, ataxia, dizziness, insomnia, restlessness, somnolence and tremors), and crystalluria (leading
to obstructive uropathy). Many of these toxicities have
also been reported in dogs and cats. In addition, in veterinary species, reported toxicities include gastrointestinal disturbances (such as nausea, vomiting and
diarrhoea), arthropathies in young animals, especially
dogs, and ocular toxicities (including retinal degeneration in cats and subcapsular cataracts for certain
uoroquinolones).
Some uoroquinolones have been known to induce
QT prolongation in sensitive people (Cubeddu, 2003).
In a high risk patient, this could lead to Torsades de
Pointe (Owens and Ambrose, 2002a,b). Similarly, QTc
prolongation following high doses of some uoroquinolones, such as sparoxacin, has been reported in dogs
(Satoh et al., 2000). Other uoroquinolones not approved for veterinary use, but which have been associated with prolongation of cardiac repolarisation
(canine model), include gatioxacin and moxioxacin.
Conversely, sitaoxacin, a dierent third generation uoroquinolone, has no eect on canine cardiac repolarisation (Chiba et al., 2004).
Tendonitis and spontaneous tendon rupture have
been reported in people during or following therapy
with uoroquinolones. Consequently, the eect of enrooxacin on tendon cell cultures of mature and juvenile
horses has been investigated (Yoon et al., 2004). Enrooxacin was found to inhibit cell proliferation, induce
morphological changes, decrease total monosaccharide
content, and alter small proteoglycan synthesis at the
glycosylation level in equine tendon cell cultures. These
eects are more pronounced in juvenile tendon cells than
in adult equine tendon cells.
Other reported adverse events have been associated
with drugdrug interactions. The following interactions
have been reported to occur in humans via mechanisms
that may be relevant to veterinary species. Therefore, it
may be prudent to approach, with caution, the concomitant use of uoroquinolones and the following
entities:
1. Ciprooxacin and theophylline (Radandt et al.,
1992): These interactions result from uoroquinolone metabolism by the P450 CYP 1A2 isoenzyme.
Fluoroquinolone-mediated inhibition of this enzyme
prevents the metabolism/inactivation of methylxanthines such as caeine and theophylline causing
22
8. Dose optimization
Dose optimization reects the results of a multidimensional evaluation that includes such factors as (Polk,
1999):
1.
2.
3.
4.
5.
23
Ecacy
Risk of adverse events
Contraindications
Cost of therapy
Patient compliance
24
2.
3.
4.
5.
References
Agarwal, R., Mittal, R., Singh, A., 2000. Studies of ion-exchange resin
complex of chloroquine phosphate. Drug Development and
Industrial Pharmacy 26, 773776.
Albarellos, G.A., Kreil, V.E., Landoni, M.F., 2004. Pharmacokinetics
of ciprooxacin after single intravenous and repeated oral administration to cats. Journal of Veterinary Pharmacology and Therapeutics 27, 155162.
Al Omran, M.F., Al Suwayeh, S.A., El Helw, A.M., Saleh, S.I., 2002.
Taste masking of diclofenac sodium using microencapsulation.
Journal of Microencapsulation 19, 4552.
25
26
27
Rodvold, K.A., Neuhauser, M., 2001. Pharmacokinetics and pharmacodynamics of uoroquinolones. Pharmacotherapy 21, 233S252S.
Sanz-Nebot, V., Toro, I., Barbosa, J., 2001. Prediction of retention
behaviour and evaluation of pKa values of peptides and quinolones
in liquid chromatography. Journal of Chromatography A 933, 45
56.
Satoh, Y., Sugiyama, A., Chiba, K., Tamura, K., Hashimoto, K.,
2000. QT-prolonging eects of sparoxacin, a uoroquinolone
antibiotic, assessed in the in vivo canine model with monophasic
action potential monitoring. Journal of Cardiovascular Pharmacology 36, 510515.
Seguin, M.A., Papich, M.G., Sigle, K.J., Gibson, N.M., Levy, J.K.,
2004. Pharmacokinetics of enrooxacin in neonatal kittens. American Journal of Veterinary Research 65, 350356.
Siefert, H.M., Domdey-Bette, A., Henninger, K., Hucke, F., Kohlsdorfer, C., Stass, H.H., 1999. Pharmacokinetics of the 8-methoxyquinolone, moxioxacin: a comparison in humans and other
mammalian species. Journal of Antimicrobial Chemotherapy 43
(Suppl B), 6976.
Taki, H.E., Salazar, L., Guerrero, C., Philipp, W., Huang, W.M.,
Kreiswirth, B., Cole, S.T., Jacobs Jr., W.R., Telenti, A., 1994.
Cloning and nucleotide sequence of Mycobacterium tuberculosis
gyrA and gyrB genes and detection of quinolone resistance
mutations. Antimicrobial Agents and Chemotherapy 38, 773780.
Taylor, D.E., Chau, A.S., 1997. Cloning and nucleotide sequence of
the gyrA gene from Campylobacter fetus subsp. fetus ATCC 27374
and characterization of ciprooxacin-resistant laboratory and
clinical isolates. Antimicrobial Agents and Chemotherapy 41,
665671.
Tyczkowska, K., Hedeen, K.M., Aucoin, D.P., Aronson, A.L., 1989.
High-performance liquid chromatographic method for the simultaneous determination of enrooxacin and its primary metabolite
ciprooxacin in canine serum and prostatic tissue. Journal of
Chromatography 493, 337346.
Thomas, J.K., Forrest, A., Bhavnani, S.M., Hyatt, J.M., Cheng, A.,
Ballow, C.H., Schentag, J.J., 1998. Pharmacodynamic evaluation
of factors associated with the development of bacterial resistance in
acutely ill patients during therapy. Antimicrobial Agents and
Chemotherapy 42, 521527.
Toutain, P.L., 2002. Pharmacokinetic/pharmacodynamic integration
in drug development and dosage-regimen optimization for veterinary medicine. AAPS Pharmaceutical Science 4 (4), article 38.
Toutain, P.L., del Castillo, J.R., Bousquet-Melou, A., 2002. The
pharmacokineticpharmacodynamic approach to a rational dosage
regimen for antibiotics. Research in Veterinary Science 73, 105
114.
Tran, J.H., Jacoby, G.A., 2002. Mechanism of plasmid-mediated
quinolone resistance. Proceedings of the National Academy of
Sciences of United States of the America 99, 56385642.
Van Bambeke, F., Michot, J., Van Eldere, J., Tulkens, P., 2005.
Quinolonesin 2005: an update. Clinical Microbiology and Infectious Diseases 11, 256280.
Van Boven, M., Veldman, K.T., de Jong, M.C., Mevius, D.J., 2003.
Rapid selection of quinolone resistance in Campylobacter jejuni but
not in Escherichia coli in individually housed broilers. Journal of
Antimicrobial Chemotherapy 52, 719723.
Vancutsem, P.M., Babish, J.G., Schwark, W.S., 1990. The uoroquinolone antimicrobials: structure, antimicrobial activity, pharmacokinetics, clinical use in domestic animals and toxicity. Cornell
Veterinarian 80, 173186.
Vesga, O., Conklin, R., Stamstad, T., Craig, W.A., 1996. Pharmacodynamic activity of Bay 12-0839 in animal infection models. In:
Abstracts of the 36th Interscience Conference on Antimicrobial
Agents and Chemotherapy, New Orleans, LA. American Society
for Microbiology, Washington, DC, p. 123. Abstract F22.
Vila, J., Ruiz, J., Goni, P., De Anta, M.T., 1996. Detection of
mutations in parC in quinolone-resistant clinical isolates of
28