Pharmacology of The Fluoroquinolonas

The
Veterinary Journal
The Veterinary Journal 172 (2006) 1028
www.elsevier.com/locate/tvjl
Review
Pharmacology of the uoroquinolones:

A perspective for the use in domestic animals
Marilyn Martinez a, Patrick McDermott b, Robert Walker
a
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*
Corresponding author. Tel.: +1 301 210 4187; fax: +1 301 210

4685.
E-mail address: rwalker@cvm.fda.gov (R. Walker).
1090-0233/$ - see front matter. Published by Elsevier Ltd.
doi:10.1016/j.tvjl.2005.07.010
product of anti-malarial research in 1962 (Lesher et al.,

1962) and was approved for clinical use in 1965. However, its antibacterial spectrum of activity was restricted
to the Enterobacteriaceae and, because of limitations in
absorption and distribution, the drug was eective solely
for the treatment of urinary tract infections. In the 1980s,
the addition both of a uorine molecule at the 6-position
of the basic quinolone structure and a piperazine substitution at the 7-position was found to enhance quinolone
antibacterial activity, gaining eectiveness against such
organisms as Pseudomonas aeruginosa and Gram-positive cocci, and to increase the extent of oral drug absorption and tissue distribution (Ball, 2000).
M. Martinez et al. / The Veterinary Journal 172 (2006) 1028
Products possessing this uorine molecule are known

as the uoroquinolones. The rst uoroquinolone
approved for use in clinical medicine was noroxacin,
followed shortly thereafter by ciprooxacin in the mid
1980s. 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 USA, with others currently under investigation.
Generally speaking, quinolones may be classied into
one of three generations (although some authors have
suggested that these compounds can be divided into four
generations, e.g., Van Bambeke et al., 2005). The distinctions between these generations are not clearly delineated, especially for those drugs that may be classied as
second and third generation compounds. The rst generation comprises the original quinolone compounds
such as nalidixic acid, oxolinic acid, pipemidic acid
and cinoxacin. These molecules were associated with
poor oral bioavailability, limited distribution into systemic tissues, and a spectrum of activity limited to Escherichia coli and several other Gram-negative organisms.
The second generation drugs, the rst of the uoroquinolones, were developed in the 1980s, exhibited increased
antibacterial activity against the Enterobacteriaceae and
other Gram-negative bacteria (such as P. aeruginosa),
and had some activity against certain Gram-positive
cocci. Structural changes associated with the second
generation increased their oral bioavailability and systemic distribution. Quinolones tting into this category
include entities such as noroxacin, ciprooxacin, enrooxacin, danooxacin, dioxacin and marbooxacin.
The third generation drugs maintained the favorable
characteristics of the second generation drugs while
exhibiting increased activity against Gram-positive bacteria, anaerobes and mycobacteria. These compounds
also exhibited excellent oral bioavailability and were
associated with a prolonged terminal elimination halflife. The third generation uoroquinolones have lower
central nervous system toxicities and exhibit fewer interactions with the cytochrome P450 (CYP 450) system
(Ball, 2000).
With regard to quinolones, specic compounds associated with the four generations (some not approved for
use within the USA) are provided below (Owens and
Ambrose, 2002a):
1. First generation: nalidixic acid, oxolinic acid and
cinoxacin.
2. Second generation: ciprooxacin, enrooxacin, marbooxacin, danooxacin, dioxacin, noroxacin
and enoxacin.
3. Third generation: orbioxacin, levooxacin, sparoxacin and grepaoxacin.
4. Fourth generation: trovaoxacin, gatioxacin, moxioxacin, gemioxacin and sitaoxacin.
11
An update on the perspective relating to the clinical

use of uoroquinolones in human patients has been
recently published elsewhere (Van Bambeke et al.,
2005).
While in some cases, principles concerning the physicochemical properties of the uoroquinolones as a drug
class will be based upon information generated with
compounds approved for human use, the purpose of this
review is to focus primarily on the uoroquinolones that
have been marketed for use in animals. Discussions include the dierences in chemical structure relative to
antibacterial activity, pharmacokinetic and pharmacodynamic parameters, the application of these parameters
in dose determination, the clinical use of the molecules,
their potential toxicities, and a synopsis of mechanisms
associated with the development of bacteria resistant
to these compounds.
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-
Fig. 1. Nalidixic acid.
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
sition 7 substituent for danooxacin results in its

negligible interaction with the CYP 450 enzymes (refer
to the pharmacokinetic section for further discussion
of veterinary elimination pathways).
Structural modication may also aect the interaction of the uoroquinolone with divalent cations. When
there are fewer substitutions on the quinolone nucleus or
on the piperazinyl group (e.g., noroxacin, ciprooxacin
and enoxacin), there is a greater reduction in uoroquinolone bioavailability in the presence of divalent cations. In particular, substitution at the 5-position
diminishes the interaction with divalent cations, suggesting that the 5-substituent may aect the formation and/
or stability of non-absorbable chelated complexes
(Appelbaum and Hunter, 2000; Peterson, 2001). It
should be noted that sucralfate has an eect similar to
that of divalent cations on the bioavailability of these
compounds (Polk, 1989; Radandt et al., 1992).
Structureactivity relationships have been identied
for certain adverse eects. For example, phototoxicity
is more commonly associated with a uorine or chlorine
substitution at the 8-position. Central nervous system
eects are more commonly associated with the unsubstituted 7-piperazine derivatives. However, in other cases,
such as QTc prolongation, no clear cut structureactivity relationship is observed (Ball, 2000).
Because of their chemical structure, uoroquinolones
are zwitterions, containing two ionizable moieties. The
lowest pKa value is associated with the acidic carboxylic
acid moiety while the second is attributable to the basic
tertiary amine. Examples of pKa values (using varied
methods) are provided in Table 1 (Barbosa et al.,
1999; Barron et al., 2001; Dalho, 1989; Escribano
et al., 1997; Mitscher et al., 1993). It should be noted
that pKa estimates can vary, depending upon the buer
system used and the experimental conditions (Barbosa
et al., 1999, 2001; Barron et al., 2001; Sanz-Nebot
et al., 2001).
Table 1
pKa values associated with various uoroquinolones
Compound
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
When pH values are lower than the pKa1, quinolones

have a net positive charge. These lower pKa values determine the pH range within which the drug is soluble in
aqueous uids. This is particularly important for dissolution of suspensions and tablets. However, in concentrated acidic urine, such as may be found in dogs and
cats, some quinolones form needle-shaped crystals
(Merck Veterinary Manual, 1998).
With few exceptions, uoroquinolones exhibit poor
water solubility between pH 6 and 8. At pH values between the pKa1 and pKa2, these zwitterions have a net
neutral charge. Accordingly, they can freely diuse
across biological membranes, but exhibit very poor solubility in aqueous uids. For this reason, liquid formulations of various quinolones for oral or parenteral
administration usually contain freely soluble salts in stable aqueous solutions. Solid formulations (e.g., tablets,
capsules or boluses) contain the active ingredient either
in its betaine form or, occasionally, as the hydrochloride
salt (Merck Veterinary Manual, 1998). At pH values
exceeding pKa2, the quinolones have a net negative
charge.
Passive diusion across biological membranes is a
function of uoroquinolone lipophilicity relative to
the pKa values of the two ionizable moieties. Two uoroquinolones, enrooxacin and ooxacin, can be used
as examples of the impact of pKa on product bioavailability. With enrooxacin, maximum aqueous solubility occurs at pH 5.02, with low aqueous solubility
occurring within the pH range of pH 6.08.0. However,
it is also within this pH range that enrooxacin has its
greatest lipid solubility. This lipophilicity facilitates its
diusion into biological tissues, including bacterial
cells. Maximal transfer of drug from the aqueous to
the lipid phase (octanol/water partitioning) occurs at
pH 7.0 (Lizondo et al., 1997). Similarly, maximal

absorption of ooxacin occurs at neutral pH, which
corresponds to the pH value when ooxacin liposolubility is at its maximum. Above and below pH 7.0,
ooxacin absorption declines, with pH having a greater
eect on the R(+) as compared to S() enantiomer
(Rabbaa et al., 1997).
The importance of understanding the relationship between pKa, pH and drug diusion is exemplied by the
relationship between antimicrobial activity and prostatitis (Wagenlehner and Naber, 2003). Depending upon the
pKa of the compound, the presence of a pH gradient between the infected tissue and blood can result in ion
trapping. In these situations, ionized drug is trapped at
the site of the infection, resulting in higher tissue drug
concentrations as compared to the blood. Interspecies
dierences in the pH of prostatic uid (acidic in dog,
alkaline in humans) can lead to interspecies dierences
in the extent of ion trapping. However, the higher concentrations in dogs may not result in higher antimicrobial activity as the ionized form of the drug may
poorly penetrate the bacterial wall.
4. Clinical use of uoroquinolones in veterinary medicine

There are currently six uoroquinolones that have
been approved for use in animals within the US. The
structures are shown in Fig. 2. These include enrooxacin, dioxacin, danooxacin, marbooxacin, orbioxacin and saraoxacin. However, eective April 30, 2001,
the US Food and Drug Administrations Center for Veterinary Medicine (CVM) proposed withdrawing the
approvals of two new animal drug applications (NADAs) sponsored by Abbott Laboratories (Federal
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
To be given as single or divided

(b.i.d.) daily doses. Administer
for 23 days beyond cessation of
clinical signs, for a maximum of
30 days
As an initial dose, followed by
tablets
Q 24 h for 35 days
Administered once
Repeat 48 h after rst injection
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)
Administer once daily for 23

days beyond cessation of clinical
signs
Q 24 h
Administer for 23 days after
cessation of clinical signs, for a
maximum of 30 days
NA
28 days
4 days
NA
NA
NA
Summary is based upon information contained within 21 CFR, April 2003.
Register, 2001). The NADAs provide for use of

saraoxacin formulations to treat colibacillosis in poultry. One is NADA 141-017 for SaraFlox (saraoxacin
hydrochloride) WSP, a water-soluble powder used in
the drinking water for control of mortality associated
with E. coli in broiler chickens and E. coli and Pasteurella multocida in turkeys. The other is NADA 141-018
for SaraFlox (saraoxacin hydrochloride) injectable
solution used in 18-day embryonated broiler eggs and
day-old broiler chickens for control of early chick mortality associated with E. coli. Concerns focused on the
potential selection of uoroquinolone-resistant foodborne zoonotic pathogens when these products are
administered to poultry. For similar reasons, the withdrawal of the US approval of enrooxacin for administration to poultry has been proposed and is still in
litigation (Federal Register, 2000).
Products approved for marketing within the US,
summary information, along with the corresponding
Code of Federal Regulations (CFR) citation, are provided in Table 2.
2. The infection is associated with a purulent discharge

(which can aect protein binding and drug diusion
at the site of infection) or is in a region that may
not be highly accessible to the compound.
3. The susceptibility of the pathogen is unknown or the
pathogen susceptibility is classied as Intermediate
based upon Clinical Laboratory Standards Institute,
CLSI, criteria, (CLSI is the new name of the former
National Committee for Clinical Laboratory Standards, NCCLS).
4. Dosing conditions (e.g., food eects) can aect drug
bioavailability and therefore, the level of systemic
drug exposure.
5. There is concomitant drug use, resulting in potential
drugdrug interactions.
6. The animal is infected with a highly virulent bacterial
strain or the host presents with compromised immune
function (e.g., geriatric animals or animals on corticosteroid therapy), rendering dose optimization very
important.
7. When developing prudent use practices to limit the
likelihood of resistance development.
5. Pharmacokinetics
Although this section on pharmacokinetics is intended to be applicable to veterinary drug products,

very little information on basic principles has been generated using compounds approved for veterinary use.
Consequently, much of the following discussion is taken
from studies employing compounds used in humans.
Nevertheless, the ndings from these studies reect generalizations that are relevant to the entire uoroquinolone class of drugs, and can be applied to understand
the veterinary-specic compounds.
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-
cin, has been reported (Griths et al., 1994; Rabbaa

et al., 1997). Whenever carrier-mediated transport is involved in intestinal absorption, it is critical that the
product is fully dissolved by the time that the dosage
form reaches the absorbing segment of the small intestine. If this is not the case, poor oral bioavailability
and lower than expected systemic drug concentrations
may occur. In addition, transporter saturation and competitive transporter binding (by other molecules) may
occur (Griths et al., 1994).
Intestinal transporters may also be an important
mechanism of drug elimination, resulting in the active
secretion of drug from the blood back into the intestine.
Such transporter mechanisms have been described for a
variety of compounds, including ciprooxacin, noroxacin and peroxacin (Dautrey et al., 1999; Griths
et al., 1994). Interestingly, this intestinal secretion may
involve dierent transporters for dierent uoroquinolones. For example, while sparoxacin is a P-glycoprotein substrate, ciprooxacin transport may be
mediated by organic anion and/or cation transporters
(Dautrey et al., 1999). Given concerns regarding the potential for changes in the susceptibility of the intestinal
microora when these compounds are administered to
food producing animals, this secretion process may also
have consequences that aect human food safety (Food
& Drug Administration, 2004).
5.2. Protein binding and tissue distribution
Protein binding is a function of the number of binding sites on the protein (n), the protein concentration (P)
and the anity constant dening the strength of binding
(KA) (Bergogne-Berezin, 2002). The in vivo activity of
an antimicrobial agent, as well as the drugs ability to
transfer from blood to tissue, is dependent on the free
concentration of the drug. Therefore, when using pharmacokinetic and pharmacodynamic principles to evaluate an appropriate uoroquinolone dose, it is critical
that assessments be made on the basis of free rather than
total drug concentrations (Bergogne-Berezin, 2002;
Craig and Ebert, 1989; Derendorf, 2003; Drusano,
2002). In this regard, it is also important to note that
in vitro MIC values are determined on the basis of free
(unbound) drug concentrations. Unfortunately, within
the veterinary literature, there is little consideration given to free drug concentrations, and most pharmacokinetic studies report exposure metrics (e.g., area under
the curve, AUC, and maximum observed concentration,
Cmax) for total drug concentrations. Toutain et al.
(2002) provides an excellent overview of why free rather
than total drug concentrations should be considered. A
summary of protein binding (based upon human data) is
provided in Table 3.
Equilibrium exists between the free drug concentrations in blood and the free drug concentrations in

Table 3
Fluoroquinolone elimination mechanism, bioavailability and protein
binding characteristics
Compound
Cinoxacin
Ciprooxacin
Enoxacin
Fleroxacin
Gatioxacin
Gemioxacin
Levooxacin
Moxioxacin
Noroxacin
Ooxacin
Sparoxacin
Trovooxacin
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
For consistency, all data reect information derived from human

subjects. Similar properties can be anticipated for veterinary species.
Based upon information from Aminimanizani et al. (2001), BergogneBerezin (2002) and Wright et al. (2000).
tissues. Therefore, free uoroquinolone concentrations

in serum generally reect concentrations within the
extracellular uids, where the majority of infections occur. However, potential barriers may inuence diusion
of the drug to the site of infection, leading to discrepancies between free serum concentrations and bacterial
drug exposure. Examples of such barriers include
formed abscesses, the bloodbrain barrier, bacterial biolm and inammation debris (Costerton et al., 1999;
Toutain et al., 2002). For this reason, understanding
the host response to a particular type of infectious agent
will greatly facilitate eorts to develop and use pharmacokinetic/pharmacodynamic relationships for dose optimization. Similarly, understanding the binding
characteristics of the drug and its ability to diuse across
biological barriers (e.g., as aected by charge, pKa values and its partitioning behaviour) will help clinicians
dene an appropriate therapeutic moiety.
Fluoroquinolones are characteristically associated
with volumes of distribution well in excess of 1.0
L/kg (Aminimanizani et al., 2001; Lode et al., 1998;
Rodvold and Neuhauser, 2001). When considering
these values, it is important to recognize that compartmental uid volumes are actually 0.05 L/kg for
plasma, 0.2 L/kg for extracellular uids and 0.7 L/kg
for total body water (Wamberg et al., 2002). Volumes
in excess of 0.7 L/kg indicate that a drug is binding
preferentially to tissues, may or may not be available
for activity, and may have been sequestered into cells.
For example, when testing the ability of human polymorphonuclear leucocytes to concentrate various uoroquinolones (in vitro test), ratios of intracellular
versus extracellular concentrations ranged from 3.5 (eroxacin) to about 7.0 for ooxacin (R and S forms)
and lomeoxacin (Butts, 1994). These high concentrations reect active transport of drug into the neutrophils (Walters et al., 1999). Nevertheless, when
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.
The largest back-calculated prediction error for CL was

associated with dogs (65% error) and swine (47% error).
The back-calculated prediction error for Vss was 13%
(dog) and 21% (swine). The relationship between terminal elimination half-life, fraction unbound in plasma (fu)
for all six species included in this study, as well as the

bioavailability of an oral dose, is provided in Table 5.
Similarly, Cox et al. (2004) examined the allometric
relationship for CL and Vss following ciprooxacin
across a variety of mammalian species (including cow,
pig, sheep, dog, rat, monkey, goat, bualo and humans),
and reports the following estimated relationships:
CL 20.6 mL= min BW0.815 r 0.95;
V ss 3.5 L BW0.947 r 0.93.
In that same study, Cox and colleagues examined the
allometric relationship for enrooxacin. The resulting
plot of log weight versus log CL or log Vss showed substantial scatter (resulting equations were CL = 15.9
(mL/min) BW0.764r = 0.77; Vss = 6.0 (L) BW0.724
r = 0.81). However, even when there are very high values for r, allometric scaling may not accurately extrapolate CL or Vss to an unknown animal species. In
particular, large extrapolation errors can occur when
trying to predict pharmacokinetic parameter values for
large species such as horses and cattle (Mahmood, Martinez, Hunter, personal communication). On the other
hand, there have been numerous cases, when equations
with low values of r provided highly accurate extrapolations to the unknown animal species (Mahmood, 2001).
Table 5
Interspecies dierences in absorption, protein binding and terminal
elimination half-life of moxioxacin across animal species
Species
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
From Siefert et al. (1999).
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
Federal Register (1998)

Seguin et al. (2004)
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
Boothe et al. (2002)

McKellar et al. (1998)
Albarellos et al. (2004)
Enrooxacin is extensively metabolized by the liver, being transformed into

ciprooxacin, as well as several other minor metabolites. Somewhat lower
ciprooxacin levels are observed in cats (20% of total compound appears as
ciprooxacin in blood) as compared to dogs and cattle (50% of total compound
appears as ciprooxacin in blood).
Marbooxacin
Dog
Cat
EMEA (2004)
Excreted primarily in urine with limited biotransformation. Small amounts of

desmethyl and N-oxide metabolites present in dogs, pigs, rats and cattle.
Orbioxacin
Dog
Cat
Matsumoto et al. (1997)

Matsumoto et al. (1998)
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
4. In vitro PAE is the period of suppression of bacterial

growth after a brief exposure of an organism to an
antimicrobial compound (unit = time). In this case,
drug has been removed.
5. In vivo PAE represents the dierence in time for the
number of bacteria in a tissue of treated versus control animals to increase 1 log 10 over values observed
when drug concentrations in serum or at the infection
site fall below the MIC (unit = time). The in vivo
PAE includes any eects associated with sub-MIC
concentrations.
6. Sub-MIC eect is any eect of an antimicrobial on a
micro-organism at concentrations below the MIC
(unit = time).
7. Post-antibiotic sub-MIC eect is the eect of subMIC drug concentrations on bacterial growth following serial exposure to drug concentrations exceeding
the MIC (unit = time).
Regarding the duration of a post-antibiotic eect
(PAE), mathematical models have recently been developed to help predict the duration of the PAE based
upon variables such as the terminal elimination half-life
(T1/2), the rate of bacterial killing (e), the slope of the
curve relating the magnitude of bacterial kill versus drug
concentration (c = the Hill Coecient), the estimated
number of viable bacteria at the infection site, the
Table 7
Factors inuencing the accuracy of ecacy predictions based upon
PK/PD relationships
1
2
3
4
5
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)
Terminal T1/2 (h)
101
61
8
15.6
3.9
15.4
91
60
4.9
5.6
Marbooxacin
F (IM)
Terminal T1/2 (h)
F (IM)
Terminal T1/2 (h)
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
maximum number of bacteria (or attainable bacterial

density), the concentration associated with 50% of the
maximal eect (EC50), and the MIC of the targeted
pathogen (Mouton and Vinks, 2005a, b). Considerations associated with the development of a concentration versus eect model, from which terms such as
Emax, EC50 and c can be derive, has been extensively reviewed elsewhere (Toutain, 2002; Toutain et al., 2002).
Within any given bacterial population, there is the
possibility of bacterial subpopulations that are less susceptible to the antimicrobial agent. As demonstrated by
Blaser et al. (1987) and Drusano (2004), unless these less
susceptible pathogens are killed, succeeding microbial
generations will re-populate the infection site with
pathogens whose MIC values are higher than those
found within the initial infection. Accordingly, ensuring
adequate exposure following an initial dose of a uoroquinolone is as important as insuring that high drug
concentrations occur after repeated administration.
Drug concentrations need to be adequate to either destroy the existing bacterial population at the site of the
infection or (at least) to reduce its size to the point where
the hosts defence mechanisms can successfully control
and eliminate the remaining pathogens.
Cmax/MIC ratios may be particularly important in
the presence of bacteria with higher MIC values or in
the presences of rapidly proliferating bacteria (Craig
and Dalho, 1998). With the latter, rapidly proliferating
bacteria have a greater likelihood of undergoing a mutational event that could lead to the genesis of a less susceptible population. In infectious disease processes
where there is a high bacterial burden (inoculum eect),
the risk of a mutational event is increased due simply to
the laws of probability (Craig and Dalho, 1998; Drusano et al., 1993). In these cases, to ensure maximum
killing, the targeted Cmax/MIC ratios are approximately
10 12 (Drusano et al., 1993; Preston et al., 1998). Such
ratios ensure increased killing of susceptible organisms,
an increased killing or inhibition of organisms with
higher MICs and thus, fewer surviving organisms for
the host defences to scavenge during the troughs of systemic drug concentrations. High drug concentrations,
relative to the MIC, may also contribute to increased
PAE. For those bacteriadrug combinations that exhibit
a PAE, in vivo PAEs have been shown to be longer than
in vitro PAEs for most organisms. b-Haemolytic streptococci are notable exceptions. Thus, optimizing the
Cmax to MIC ratio will delay the re-growth of the pathogen, sometimes by several hours. The result of using
this type of dosing regimen is that there are fewer organisms remaining that can reproduce into a resistant
subpopulation.
Despite the large body of information suggesting that
uoroquinolones are highly eective in the presence of
high Cmax/MIC values, exceptions to this rule have been
observed. For example, in the case of Bacillus anthracis,
hollow bre studies suggest that AUC/MIC was more

predictive of success as compared to Cmax/MIC (Deziel
et al., 2001). This result relates to the ndings described
by MacGowan et al. (2000, 2001), where time to kill 99%
of the inoculum depends on Cmax/MIC, but the ability
to maintain this decrease in microbial counts (termed
area under the bacterial killing curve, or AUBKC) is related to AUC/MIC (in vitro test conditions). If the
duration of time between doses is extended beyond
24 h (as was tested for gemioxacin), eectiveness may
also depend upon the duration of time that drug concentrations exceed the MIC (T > MIC) (MacGowan et al.,
2001).
When a Cmax/MIC ratio of 10 is not possible, the
contribution of time of exposure becomes increasingly
important and the target for ecacy defaults to the
AUC/MIC ratio (Owens and Ambrose, 2002a). AUC/
MIC also serves as the pivotal PK/PD index when the
infection is caused by relatively slow growing bacteria,
when there is little or no PAE that will contribute to
bacterial killing, or when the MIC for the pathogen is
relatively low. A variety of animal model studies (based
on infections caused by Gram-negative organisms) have
shown that AUC/MIC values of 100 or greater have
been needed to insure host survival (Craig, 1998; Craig
and Dalho, 1998; Thomas et al., 1998). This value of
100 translates to drug concentrations equalling approximately four times the MIC throughout the 24-h dosing
interval, corresponding to the ndings by Walker, 2000
(in vitro dioxacin concentrations needed to ensure a
bactericidal eect against the clinical isolates of dogs
presenting with recurrent urinary tract infections). The
importance of AUC/MIC is consistent with clinical outcomes observed with moxioxacin (Vesga et al., 1996),
ciprooxacin (Forrest et al., 1993) and grepaoxacin
(Forrest et al., 1997).
Studies report that the AUC/MIC values needed to
ensure a successful therapeutic outcome may be dierent
for infections caused by Gram-negative and Gram-positive bacteria. For Gram-negative organisms, the estimated AUC/MIC ratios needed to ensure bacterial
cure and prevent the selection of resistant strains is estimated to be approximately 125 (Forrest et al., 1993). In
contrast, the AUC/MIC ratio for Gram-positive bacteria is considerably lower, approximately 3050 for a
number of drugmicrobe combinations (Ibrahim et al.,
2002; Preston et al., 1998; Wright et al., 2000). Studies
involving the third and fourth generation uoroquinolones suggest that for Gram-positive organisms AUC/
MIC values are substantially lower when Cmax/MIC values are P10 (Nightingale et al., 2000). For example,
Forrest et al. (1997) noted that in 73 patients with
chronic acute bacterial exacerbations of chronic bronchitis, ratios of P175 were needed when grepaoxacin
was used to treat infections associated with Gram-negative organisms while ratios of P92 were adequate to
treat Gram-positive infections. An excellent overview of

in vitro, animal model and human clinical pharmacodynamic trials conducted with various uoroquinolones
and across a variety of bacterial species is provided by
Wright et al. (2000).
Pharmacokineticpharmacodynamic
relationships
can serve as a valuable guide for obtaining initial estimates of doses that may be needed to achieve a desired
clinical response, to modify a dosing regimen in patients
presenting with altered clearance, or to scale a dose
based upon susceptibility information on the invading
pathogen. However, it is incorrect to use these relationships as a mechanism for either assessing product eectiveness (in lieu of clinical data) or for comparing
products. There are numerous factors that pharmacokinetics and pharmacodynamics alone cannot accurately
predict. For example, in vitro MIC values do not provide information on time to kill, time to maximum kill,
log change within a xed time or the maximum reduction in viable bacterial counts (MacGowan and Bowker,
2002). Furthermore, serum drug concentrations do not
necessarily reect a compounds ability to diuse into
the site of infection and into the bacterial cell.
Along with concerns about microbial susceptibility
patterns, a drugs bactericidal activities can vary with
the intracellular pH versus drug pKa, oxygen content,
and intracellular enzymatic activity (Butts, 1994). Moreover, drug potency is often considered in terms of MIC,
which is a static eect on microbial growth. The MIC
may not be the same as a compounds minimum bactericidal concentration (MBC). Since both the MIC and
MBC values are in vitro estimates, they do not reect
a drugs rate of killing, the eect of serum on antimicrobial activity, PAE, or post antimicrobial sub-MIC eects
(Craig and Dalho, 1998). Moreover, while some uoroquinolones demonstrate in vivo and in vitro activity
against stationary phase bacteria (e.g., ooxacin and
ciprooxacin), others (noroxacin) do not (Lode et al.,
1998). In addition, once a certain AUC/MIC or
Cmax/MIC ratio is achieved for a particular compound,
further increases in these ratios may not improve clinical
ecacy. As indicated earlier, at high FQ concentrations,
both RNA synthesis and protein synthesis can be inhibited, thereby causing a decrease in bactericidal activity
(Lode et al., 1998). Ultimately, it is the integrity of the
host immune response that will determine the eectiveness of the targeted pharmacokineticpharmacodynamic relationship (Andes and Craig, 2002; Toutain
et al., 2002).
The establishment of pharmacokineticpharmacodynamic relationships within the human pharmaceutical
community is generally determined for a particular
drugbacterium combination, requiring that tens of
thousands of subjects be evaluated. It is only through
the collection of huge amounts of data that specic criteria can be developed.
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
excess CNS and cardiac stimulation. This potential

interaction may have veterinary relevance in that
ciprooxacin is a metabolite of enrooxacin.
2. Probenecid and renal elimination: probenecid may
decrease the renal clearance of uoroquinolones
(Aminimanizani et al., 2001). Multiple drug eects on
cardiac repolarisation: to minimise risk of Q-T
prolongation and subsequent Torsades de Pointe, uoroquinolones should not be co-administered with
other Q-T prolonging drugs such as erythromycin,
disopyramide, or antidepressants such as amitriptyline
(Curtis et al., 2003; Owens and Ambrose, 2002a,b).
7. Fluoroquinolones and resistance

The development of uoroquinolone resistance via
mutations in topoisomerases has been studied extensively. For detailed discussion, a number of excellent reviews are in the literature (Drlica and Malik, 2003;
Hawkey, 2003; Hooper, 2002). Resistance is mediated
primarily by target mutations in DNA gyrase (topoisomerase II) (Nakamura et al., 1989; Yoshida et al.,
1990), with secondary mutations in topoisomerase IV
contributing to higher levels of resistance (Vila et al.,
1996). Amino acid substitutions that can result in
bacterial resistance have been localized to a specic
topoisomerase subdomain termed the quinolone resistance-determining region (QRDR) within gyrA (Yoshida et al., 1988, 1990) and parC (Khodursky et al.,
1995). In E. coli, most mutations associated with quinolone resistance occur in the QRDR at serine 83 (Ser83)
and aspartate 87 of gyrA, and at serine 79 and aspartate
83 of parC and at analogous sites in other species (Bebear et al., 2003; Taki et al., 1994; Taylor and Chau,
1997). DNA sequence analysis of Staphylococcus aureus
and Streptococcus genes shows that the situation can be
reversed in Gram-positive bacteria, where topoisomerase IV (encoded by grlA and grlB) is the primary uoroquinolone target (Munoz and De La Campa, 1996; Ng
et al., 1996). In both cases, mutations decrease the
quinolone anity for the enzyme/DNA complex (Maxwell and Critchlow, 1998), and allow DNA replication
to continue in the presence of uoroquinolone concentrations that are inhibitory to wild-type cell growth.
Among Gram-negative organisms, quinolone resistance typically develops in a stepwise manner. A single
QRDR mutation, usually at Ser83, confers resistance
to nalidixic acid and decreases susceptibility to uoroquinolones (ciprooxacin MICs 0.1251 lg/mL from a
wild-type baseline of 0.0150.03 lg/mL). Secondary
mutations in the gyrA QRDR lead to overt uoroquinolone resistance (ciprooxacin MICs P4 lg/mL). However, this does not hold true for all Gram-negative
bacteria. In Campylobacter, which lacks topoisomerase
IV, a single mutation in gyrA is sucient to impart

high-level ciprooxacin MICs (32 lg/mL) (Wang et al.,
1993). This feature helps explain the higher prevalence
of resistance in Campylobacter, compared with E. coli,
from food animals exposed to uoroquinolones (Van
Boven et al., 2003).
In addition to structural mutations in the topoisomerase genes, uoroquinolone resistance is mediated
by decreased permeability of the bacterial cell wall and
by the activity of energy-dependent eux pumps. Fluoroquinolone resistance due to target mutations typically
results in decreased susceptibility or resistance to other
members of the class for both veterinary and human
drugs (Everett et al., 1996; Piddock et al., 1998). Resistance due to decreased permeability and active eux often are less specic, generating cross-resistance to
multiple classes of antimicrobials (Poole, 2000).
It appears that most uoroquinolones cross the
Gram-negative outer membrane through protein channels called porins (Nikaido and Vaara, 1985), although
some may diuse directly across the lipid bilayer. Thus,
the number and size of the porins can contribute to the
intrinsic susceptibility of bacteria to quinolone agents.
Resistance due to decreased quinolone inux is generally
reected in low-level changes in susceptibility and may
help to contribute to dierences in potency among dierent uoroquinolone derivatives. Porin deciency has
been associated with quinolone resistance in E. coli
and Pseudomonas. For example, mutations of the
E. coli porin OmpF produced about a 2-fold increase
in quinolone MICs (Alekshun and Levy, 1999).
It is dicult to experimentally assess the role of porins without also accounting for eects due to eux. Permeability changes mediated by altered porins are often
part of a coordinated cellular response to the presence
of numerous toxic agents, which includes simultaneous
upregulation of eux. In E. coli, de-repression in regulatory loci such as marA or soxS leads to decreased
uoroquinolone susceptibility via simultaneous upregulation of the AcrAB-TolC eux pump (Okusu et al.,
1996) and downregulation of the OmpF porin (Cohen
et al., 1988). This mechanism confers decreased susceptibility to a large number of other antimicrobial agents
in addition to uoroquinolones. Analogous regulatory
loci exist among other species of bacteria (Cohen
et al., 1993).
In antimicrobial eux systems, membrane-localized
proteins actively pump drug from the cell before it can
diuse to its primary target within the active site of
DNA gyrase. Because they are driven by the proton motive force, energy uncouplers can be used to study their
role in resistance. The E. coli genome carries as many as
30 potential eux pumps, many of which mediate antimicrobial eux. Some are eective for specic agents,
whereas others protect against a variety of structurally
diverse compounds. In addition, a single bacterium
may contain multiple eux pumps (e.g., AcrAB and

cmlA) that are capable of extruding the same antimicrobial agent. Constitutive and inducible eux is a known
mechanism of uoroquinolone resistance in both Gramnegative and Gram-positive bacteria, and may be more
important than secondary mutations in topoisomerase
IV genes. For example, it has been shown that deletion
of the gene encoding the inducible AcrAB eux pump
reduces ciprooxacin MICs to near wild-type levels in
cells carrying topoisomerase mutations (Oethinger
et al., 2000). In Campylobacter, where eux mediated
by CmeAB is constitutive, uoroquinolone MICs in
wild-type cells are 34-fold higher than those typical of
E. coli. Insertional inactivation of CmeAB in C. jejuni
reduces ciprooxacin MICs to levels near that of wildtype E. coli (0.003 lg/mL) (Luo et al., 2003). These ndings have led some drug developers to examine bacterial
eux systems as potential targets for compounded antimicrobial therapeutics.
It has long been thought that bacterial uoroquinolone resistance disseminates exclusively via clonal
expansion under selective pressure. Recently, a plasmid-mediated quinolone resistance gene (qnr) was described, rst in clinical isolates of Klebsiella
pneumoniae (Martinez-Martinez et al., 1998) and later
in E. coli (Jacoby et al., 2003; Wang et al., 2003). The
gene is located near sequences (qacEA1, sulI) typically
associated with class I integrons: the qnr gene encodes
a 218 amino acid protein belonging to the pentapeptide
repeat family (Tran and Jacoby, 2002). In a concentration-dependent manner, qnr functions by protecting
E. coli DNA gyrase, but not topoisomerase IV, from
inhibition by ciprooxacin (Tran and Jacoby, 2002).
The qnr gene confers a small decrease in quinolone susceptibility such that qnr+ strains are still considered
clinically susceptible. It has been suggested that the impact on clinical resistance results from the ability of qnr
to permit selection of topoisomerase mutants at concentrations that normally would be toxic to the bacterium
(Martinez-Martinez et al., 1998).
Each of the uoroquinolone resistance mechanisms
(target modication, decreased permeability, eux and
target protection) can occur simultaneously within the
same cell, thereby leading to very high resistance levels.
To date, no mechanisms based on enzymatic inactivation/modication of quinolones have been discovered.
Because quinolones are synthetic antimicrobials with
no known natural analogues, it is less likely that this
type of mechanism will emerge.
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
Theoretically, this objective appears straightforward.

However, there are numerous challenges to face when
striving to optimize a dose under clinical conditions.
Firstly, we must dene our therapeutic objective. Is it
a cessation of clinical signs of disease or microbial
cure? If microbial cure is not obtained, how does that
impact the potential for relapse or for the spread of
resistant microbial strains to other hosts? In this regard, it is of interest to note that based upon isolates
from the canine urinary tract at the University of Missouri-Columbia Veterinary Medical Diagnostic Lab,
there has been an increase in the number of resistant
organisms isolated between 1992 and 2001. The clinical
relevance of these nding has not been determined
(Cohn et al., 2003). Secondly, when selecting a drug,
dose and dosing regimen, it is relatively uncommon
to have identied, via culture, the pathogenic organism
and its susceptibility pattern. Consequently, practice
experience plus publicly available information on the
various choices of antimicrobial agent is often the primary consideration in drug selection and dose determination. Finally, when treating food animal species,
where numerous animals may be involved, there is
the concern of cost, ease of use, stress (animal and handler), residues and microbial safety (Food & Drug
Administration, 2004).
The goal of any prescribing clinician is to identify a
therapeutic regimen that will have a reasonable chance
for success. At least in part, the availability of interpretive criteria and susceptibility breakpoints can provide
an invaluable guide to the selection of an appropriate
therapeutic intervention (Mouton, 2003). However, even
if breakpoints are available, there remains an enormous
number of variables for the attending clinician to consider. These include:
1. What are the pharmacokinetic characteristics of that
drug in my patient and what blood levels am I likely
to achieve with any particular dosing regimen? In this
regard, the use of Monte Carlo simulation and the
concept of selecting a dose on the basis of its probability of therapeutic success is extremely attractive
(Ambrose and Grasela, 2000; Dudley and Ambrose,
2000). However, these methods are only as good as
the users estimates of the pharmacokinetic parameters, the population distribution of these parameters,
and the MIC distribution of the pathogen (assuming
that the pathogen has been identied). Moreover,
there are very few clinical situations in which the
attending veterinarian will have access to (or the time
24
2.
3.
4.
5.
to run) these kinds of simulations. Therefore, these

technologies are currently limited to use as research
tools.
If the drug is intended for use in food producing animals, how can the drug intake be optimized? This is a
particularly challenging question when dosing poultry, aquatic species or large pens of animals.
What level of drug exposure is needed to insure that
pathogen load is reduced to where the host immune
system can eectively eliminate the remaining
pathogens?
How will the pathogen respond to this drug in vivo?
This question needs to be addressed in relation to the
potential presence of biological barriers (host or bacterial) as well as potential dierences in bacterial
in vivo versus in vitro growth rate.
Finally, for food producing animals, there is always
the need to consider drug, dose, duration of dosing
and the withdrawal time needed to minimize the risk
of violative residues. This can be particularly challenging in aquatic species where residue depletion
may vary markedly as a function of species of sh
or water temperature (Lucchetti et al., 2004). In addition, environmental consequences of uoroquinolone
use for treating aquatic species needs also to be considered (Robinson et al., 2005).
Ultimately, as aptly stated by Ron Polk in a 1999

article regarding optimal use of antibiotics,
Far more is known about the basic chemistry of antibiotics, their pharmacokinetics, and their mechanisms of
action and of resistance than is known about the practical
problem of what dose to give.
Hopefully, the magnitude of this uncertainty will
diminish over time as more sponsors of veterinary antimicrobial agents work with organizations such as the
CLSI to establish susceptible, intermediate and resistant
breakpoints (interpretive criteria) and as tools such as
the Veterinary Antimicrobial Decision System (http://
www.vetmed.iastate.edu/departments/vdpam/pam/vads.
asp) become available to assist veterinarians in judging
therapeutic options.
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.
Alekshun, M.N., Levy, S.B., 1999. The mar regulon: multiple

resistance to antibiotics and other toxic chemicals. Trends in
Microbiology 7, 410413.
AliAbadi, F.S., Lees, P., 2002. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbooxacin in calf
serum, exudate and transudate. Journal of Veterinary Pharmacological Therapy 25, 161174.
Allen, A., Bygate, E., Clark, D., Lewis, A., Pay, V., 2000. The eect of
food on the bioavailability of oral gemioxacin in healthy
volunteers. International Journal of Antimicrobial Agents 16, 45
50.
Ambrose, P.G., Grasela, D.M., 2000. The use of Monte Carlo
simulation to examine pharmacodynamic variance of drugs:
uoroquinolone pharmacodynamics against Streptococcus pneumoniae. Diagnostic Microbiology and Infectious Disease 38,
151.
Aminimanizani, A., Beringer, P., Jellie, R., 2001. Comparative
pharmacokinetics and pharmacodynamics of the newer uoroquinolone antibacterials. Clinical Pharmacokinetics 40, 169187.
Andes, D., Craig, W.A., 2002. Pharmacodynamics of the new
uoroquinolone gatioxacin in murine thigh and lung infection
models. Antimicrobial Agents and Chemotherapy 46, 16651670.
Appelbaum, P.C., Hunter, P.A., 2000. The uoroquinolone antibacterials: past, present and future perspectives. International Journal
of Antimicrobial Agents 16, 515.
Araki, H., Ogake, N., Minami, S., Watanabe, Y., Narita, H., Tamai,
I., Tsuji, A., 1997. Application of muscle microdialysis to evaluate
the concentrations of the uoroquinolones pazuoxacin and
ooxacin in the tissue interstitial uids of rats. Journal of
Pharmacy and Pharmacology 49, 11411144.
Ball, P., 2000. Quinolone generations: natural history or natural
selection. Journal of Antimicrobial Chemotherapy 46 (Suppl T1),
1724.
Barbosa, J., Barron, D., Cano, J., Jimenez-Lozano, E., Sanz-Nebot,
V., Toro, I., 2001. Evaluation of electrophoretic method versus
chromatographic, potentiometric and absorptiometric methodologies for determining pKa values of quinolones in hydroorganic
mixtures. Journal of Pharmaceutical and Biomedical Analysis 24,
10871098.
Barbosa, J., Barron, D., Jimenez-Lozano, E., 1999. Electrophoretic
behaviour of quinolones in capillary electrophoresis. Eect of pH
and evaluation of ionization constants. Journal of Chromatography A 839, 183192.
Barron, D., Jimenez-Lozano, E., Barbosa, J., 2001. Prediction of
electrophoretic behaviour of a series of quinolones in aqueous
methanol. Journal of Chromatography A 919, 395406.
Bebear, C.M., Renaudin, H., Charron, A., Clerc, M., Pereyre, S.,
Bebear, C., 2003. DNA gyrase and topoisomerase IV mutations in
clinical isolates of Ureaplasma spp. and Mycoplasma hominis
resistant to uoroquinolones. Antimicrobial Agents and Chemotherapy 47, 33233325.
Bergogne-Berezin, E., 2002. Clinical role of protein binding of
quinolones. Clinical Pharmacokinetics 41, 741750.
Bertino Jr., J., Fish, D., 2000. The safety prole of the uoroquinolones. Clinical Therapeutics 22, 798817.
Blaser, J., Stone, B.B., Groner, M.C., Zinner, S.H., 1987. Comparative
study with enoxacin and netilmicin in a pharmacodynamic model
to determine importance of ratio of antibiotic peak concentration
to MIC for bactericidal activity and emergence of resistance.
Antimicrobial Agents and Chemotherapy 31, 10541060.
Blondeau, J.M., 1999. Expanded activity and utility of the new
uoroquinolones: a review. Clinical Therapeutics 21, 340.
Boothe, D.M., Boeckh, A., Boothe, H.W., Wilkie, S., Jones, S., 2002.
Plasma concentrations of enrooxacin and its active metabolite
ciprooxacin in dogs following single oral administration of
enrooxacin at 7.5, 10, or 20 mg/kg. Veterinary Therapeutics 3,
409419.

Butts, J.D., 1994. Intracellular concentrations of antibacterial agents
and related clinical implications. Clinical Pharmacokinetics 27, 63
84.
Carretero, M., Rodriguez, C., San Andres, M.I., Fores, P., de Lucas,
J.J., Nieto, J., San Andres, M.D., Gonzalez, F., 2002. Pharmacokinetics of marbooxacin in mature horses after single intravenous
and intramuscular administration. Equine Veterinary Journal 34,
360365.
Chiba, K., Sugiyama, A., Hagiwara, T., Takahashi, S., Takasuna, K.,
Hashimoto, K., 2004. In vivo experimental approach for the risk
assessment of uoroquinolone antibacterial agents-induced long
QT syndrome. European Journal of Pharmacology 486, 189200.
Chopra, R., Alderborn, G., Newton, J.M., Podczeck, F., 2002. The
inuence of lm coating on pellet properties. Pharmaceutical
Development and Technology 7, 5968.
Cohn, L.A., Gary, A.T., Fales, W.H., Madsen, R.W., 2003. Trends in
uoroquinolone resistance of bacteria isolated from canine urinary
tracts. Journal of Veterinary Diagnostic Investigation 15, 338343.
Cohen, S.P., McMurray, L.M., Levy, S.B., 1988. marA locus causes
decreased expression of OmpF porin in multiple-antibiotic-resistant (Mar) mutants of Escherichia coli. Journal of Bacteriology
170, 54165422.
Cohen, S.P., Yan, W., Levy, S.B., 1993. A multidrug resistance
regulatory chromosomal locus is widespread among enteric bacteria. Journal of Infectious Diseases 168, 484488.
Costerton, J.W., Stewart, P.S., Greenberg, E.P., 1999. Bacterial
biolms: a common cause of persistent infections. Science 284,
13181322.
Coulet, M., Morello, C., Cox, P., Lohuis, J., 2005. Pharmacokinetics
of ibaoxacin in healthy cats. Journal of Veterinary Pharmacology
and Therapeutics 28, 3744.
Cox, S.K., Cottrell, M.B., Smith, L., Papich, M.G., Frazier, D.L.,
Bartges, J., 2004. Allometric analysis of ciprooxacin and enrooxacin pharmacokinetics across species. Journal of Veterinary
Pharmacological and Therapeutics 27, 139146.
Craig, W.A., 1998. Pharmacokinetic/pharmacodynamic parameters:
rationale for antibacterial dosing of mice and men. Clinical
Infectious Diseases 26, 110.
Craig, W.A., Dalho, A., 1998. Pharmacodynamics of uoroquinolones in experimental animals. In: Born, G.V.R., Cuatrecas, P.,
Ganten, D., Herken, H., Melmon, K.L., Starke, K. (Eds.),
Handbook of Experimental Pharmacology. Springer, Berlin, pp.
208232.
Craig, W.A., Ebert, S.C., 1989. Protein binding and its signicance in
antibacterial therapy. Infectious Disease Clinics of North America
3, 407414.
Cubeddu, L.X., 2003. QT prolongation and fatal arrhythmias: a review
of clinical implications and eects of drugs. American Journal
Therapeutics 10, 452457.
Curtis, L.H., Ostbye, T., Sendersky, V., Hutchison, S., Allen LaPointe,
N.M., Al Khatib, S.M., Usdin, Y.S., Dans, P.E., Wright, A., Cali,
R.M., Woosley, R.L., Schulman, K.A., 2003. Prescription of QTprolonging drugs in a cohort of about 5 million outpatients.
American Journal of Medicine 114, 135141.
Dalho, A., 1989. A review of quinolones. In: Proceedings of an
International Telesymposium. J. R. Prous Science, Barcelona,
Spain, pp. 277312.
Dautrey, S., Felice, K., Petiet, A., Lacour, B., Carbon, C., Farinotti,
R., 1999. Active intestinal elimination of ciprooxacin in rats:
modulation by dierent substrates. British Journal of Pharmacology 127, 17281734.
Derendorf, H. 2003. Microdialysis-based PK/PD approaches in antimicrobial drug development. Available from: <http://www.aapspharmaceutica.com/inside/focus_groups/microdial/derendorf.pdf>,
2003 (9-17-2004. Ref Type: Electronic Citation).
Deziel, M.R., Louis, A., Heine, H., Bush, K., Kao, M., Kelley, M.,
Drusano, G.L., 2001. Evaluation of levooxacin in a hollow ber
25
infection model against Bacillus anthracis utilizing both human and

Rhesus Monkey pharmacokinetic proles. Abstracts of the 41st
Annual Meeting of the Interscience Conference on Antimicrobial
Agents and Chemotherapy. Abstract # A-1157, Chicago, IL.
Drlica, K., Malik, M., 2003. Fluoroquinolones: action and resistance:
Current Topics in Medical Chemistry 3, 249282.
Drusano, G.L. 2002. Pharmacodynamics of uoroquinolones. In:
Proceedings of the 10th ISAP Symposium: Pharmacokinetics and
Pharmacodynamics (PK/PD): Towards Denitive Criteria. Milan,
Italy, April 2728.
Drusano, G.L., 2004. Antimicrobial pharmacodynamics: critical
interactions of bug and drug. Nature Reviews Microbiology 2,
289300.
Drusano, G.L., Johnson, D.E., Rosen, M., Standiford, H.C., 1993.
Pharmacodynamics of a uoroquinolone antimicrobial agent in a
neutropenic rat model of Pseudomonas sepsis. Antimicrobial
Agents and Chemotherapy 37, 483490.
Dudley, M.N., Ambrose, P.G., 2000. Pharmacodynamics in the study
of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime time. Current Opinions in Microbiology 3,
515521.
Efthymiopoulos, C., Bramer, S.L., Maroli, A., 1997. Eect of food and
gastric pH on the bioavailability of grepaoxacin. Clinical Pharmacokinetics 33 (Suppl. 1), 1824.
EMEA. European Agency for the Evaluation of Medicinal Products,
Veterinary Medicines and Information Technology Unit. Marbooxacin summary report, 3/96. Available from: <http://www.
emea.eu.int/pdfs/vet/mrls/007996en.pdf> (Accessed June 4, 2004).
Escribano, E., Calpena, A.C., Garrigues, T.M., Freixas, J., Domenech,
J., Moreno, J., 1997. Structureabsorption relationships of a series
of 6-uoroquinolones. Antimicrobial Agents and Chemotherapy
41, 19962000.
Everett, M.J., Jin, Y.F., Ricci, V., Piddock, L.J., 1996. Contributions
of individual mechanisms to uoroquinolone resistance in 36
Escherichia coli strains isolated from humans and animals. Antimicrobial Agents and Chemotherapy 40, 23802386.
Federal Register. 63 Fed. Reg. 8122 (Feb 18 1998). 1998.
Federal Register. 65 Fed. Reg. 64954 (Oct 31, 2000). 2000.
Federal Register. 66 Fed. Reg. 21400 (April 30, 2001). [Docket No.
00N-1571]. 2001.
Federal Register. 62 Fed. Reg. 50387 (Sept 25, 1997). 2004.
Food & Drug Administration 2004. Center for Veterinary Medicine
Guidance for Industry #152: Assessment of the Eects of antimicrobial Drug Residues from Food of Animal Origin on the Human
Intestinal Flora. Available from: <http://www.fda.gov/cvm/guidance/guideline159.doc> (Accessed Sept 17, 2004).
Forrest, A., Chodosh, S., Amantea, M.A., Collins, D.A., Schentag,
J.J., 1997. Pharmacokinetics and pharmacodynamics of oral
grepaoxacin in patients with acute bacterial exacerbations of
chronic bronchitis. Journal of Antimicrobial Chemotherapy 40
(Suppl A), 4557.
Forrest, A., Nix, D.E., Ballow, C.H., Goss, T.F., Birmingham, M.C.,
Schentag, J.J., 1993. Pharmacodynamics of intravenous ciprooxacin in seriously ill patients. Antimicrobial Agents and Chemotherapy 37, 10731081.
Gajjar, D.A., Sukoneck, S.C., Bello, A., Ge, Z., Christopher, L.,
Grasela, D.M., 2002. Eect of a high-fat meal on the pharmacokinetics of the des-F(6)-quinolone BMS-284756. Pharmacotherapy
22, 160165.
Gellert, M., Mizuuchi, K., ODea, M.H., Itoh, T., Tomizawa, J.I.,
1977. Nalidixic acid resistance: a second genetic character
involved in DNA gyrase activity. Proceedings of the National
Academy of Sciences United States of the America 74, 4772
4776.
Glaxo Wellcome. 2004. Glaxo Wellcome voluntarily withdraws Raxar
(Grepaoxacin). Available from: <http://www.fda.gov/medwatch/
safety/1999/raxar.html> (Accessed Sept 21, 2004).
26
Greene, C.E., Budsberg, S.C., 1993. Veterinary use of quinolones. In:

Hooper, D.C., Wolfson, J.S. (Eds.), Quinolone Antimicrobial
Agents. American Society for Microbiology, Washington, DC, pp.
473488.
Griths, N.M., Hirst, B.H., Simmons, N.L., 1994. Active intestinal
secretion of the uoroquinolone antibacterials ciprooxacin, noroxacin and peoxacin; a common secretory pathway? Journal of
Pharmacology and Experimental Therapeutics 269, 496502.
Guthrie, R.M., Jacobs, M., Low, D.E., Mandell, L., Slama, T., 2004.
Treating resistant respiratory infections in the primary care setting:
the role of the new quinolones. University of Cincinnati College of
Medicine Continuing Medical Education.
Hawkey, P.M., 2003. Mechanisms of quinolone action and microbial
response. Journal of Antimicrobial Chemotherapy 51 (Suppl 1),
2935.
Heitzman, R.J., 1998. Residues of some veterinary drugs in animals
and foods. In: 48th Meeting of the Joint FAO/WHO Expert
Committee on Food Additives. FAO Food and Nutrition Paper
41/10. Geneva, Switzerland, 1827 February 1997. Available from:
http://www.fao.org/docrep/W8338E/w8338e07.htm> (Accessed 9/
20/2004).
Hooper, D.C., 2002. Fluoroquinolone resistance among Grampositive cocci. Lancet Infectious Diseases 2, 530538.
Ibrahim, K.H., Hovde, L.B., Ross, G., Gunderson, B., Wright, D.H.,
Rotschafer, J.C., 2002. Microbiologic eectiveness of time- or
concentration-based dosing strategies in Streptococcus pneumoniae.
Diagnostic Microbiology Infectious Diseases 44, 265271.
Inui, T., Taira, T., Matsushita, T., Endo, T., 1998. Pharmacokinetic
properties and oral bioavailabilities of dioxacin in pig and
chicken. Xenobiotica 28, 887893.
Jacoby, G.A., Chow, N., Waites, K.B., 2003. Prevalence of plasmidmediated quinolone resistance. Antimicrobial Agents and Chemotherapy 47, 559562.
Johnson, R.D., Door, M.B., Hunt, T.L., Jensen, B.K., Talbot, G.H.,
1999. Eects of food on the pharmacokinetics of sparoxacin.
Clinical Therapeutics 21, 982991.
Karablut, N., Drusano, G.L., 1993. Pharmacokinetics of the quinolone antimicrobial agents. In: Hooper, D.C., Wolfson, J.S. (Eds.),
Quinolone Antimicrobial Agents. American Society for Microbiology, Washington, DC, pp. 195223.
Khodursky, A.B., Zechiedrich, E.L., Cozzarelli, N.R., 1995. Topoisomerase IV is a target of quinolones in Escherichia coli. Proceedings
for the National Academy of Sciences United States of the America
92, 1180111805.
Kovar, A., Dalla, C.T., Derendorf, H., 1997. Comparison of plasma
and free tissue levels of ceftriaxone in rats by microdialysis. Journal
of Pharmaceutical Sciences 86, 5256.
Lesher, G.Y., Foelich, E.J., Gruett, M.D., Baily, J.H., Brundage, P.R.,
1962. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. Journal of Medical Pharmacy and Chemistry 91,
10631065.
Lizondo, M., Pons, M., Gallardo, M., Estelrich, J., 1997. Physicochemical properties of enrooxacin. Journal of Pharmaceutical and
Biomedical Analysis 15, 18451849.
Lode, H., Borner, K., Koeppe, P., 1998. Pharmacodynamics of
uoroquinolones. Clinical Infectious Diseases 27, 3339.
Lucchetti, D., Fabrizi, L., Guandalini, E., Podesta`, E., Marvasi, L.,
Zaghini, A., Coni, E., 2004. Long depletion time of enrooxacin in
rainbow trout (Oncorhnchus mykiss). Antimicrobial Agents and
Chemotherapy 48, 39123917.
Luo, N., Sahin, O., Lin, J., Michel, L.O., Zhang, Q., 2003. In vivo
selection of Campylobacter isolates with high levels of uoroquinolone resistance associated with gyrA mutations and the function
of the CmeABC eux pump. Antimicrobial Agents and Chemotherapy 47, 390394.
MacGowan, A., Bowker, K., 2002. Developments in PK/PD: optimising ecacy and prevention of resistance. A critical review of
PK/PD in in vitro models. International Journal of Antimicrobial

Agents 19, 291298.
MacGowan, A., Rogers, C., Holt, H.A., Wootton, M., Bowker, K.,
2000. Assessment of dierent antibacterial eect measures used in
in vitro models of infection and subsequent use in pharmacodynamic correlations for moxioxacin. Journal of Antimicrobial
MacGowan, A.P., Rogers, C.A., Holt, H.A., Wooton, M., Bowker,
K.E., 2001. Pharmacodynamics of gemioxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model of
infection. Antimicrobial Agents and Chemotherapy 45, 29162921.
Mahmood, I., 2001. Application of preclinical data to initiate the
modied continual reassessment method for maximum tolerated
dose-nding trials. Journal of Clinical Pharmacology 41, 1924.
Mann, D.D., Frame, G.M., 1992. Pharmacokinetic study of danooxacin in cattle and swine. American Journal of Veterinary
Research 53, 10221026.
Martinez-Martinez, L., Pascual, A., Jacoby, G.A., 1998. Quinolone
resistance from a transferable plasmid. Lancet 351, 797799.
Matsumoto, S., Takahashi, M., Kitadai, N., Katae, H., 1998. A study
of metabolites isolated from the urine samples of cats and dogs
administered orbioxacin. Journal of Veterinary Medical Science
60, 12591261.
Matsumoto, S., Takahashi, M., Yoshida, M., Komatsu, T., Kitadai,
N., Horii, Y., Katae, H., 1997. Absorption, distribution and
excretion of orbioxacin in dogs and cats. Journal of Japanese
Veterinary Medical Association 50, 470474.
Maxwell, A., Critchlow, S.E., 1998. Mode of action. In: Kuhlman, J.,
Zeiler, H.J. (Eds.), Quinolone Antibacterials. Springer, Berlin, pp.
119166.
McKellar, Q.A., Gibson, I.F., McCormack, R.Z., 1998. Pharmacokinetics and tissue disposition of danooxacin in sheep. Biopharmaceutics and Drug Disposition 19, 123129.
Merck Veterinary Manual, 1998. Quinolones. In: Aiello, S., Mays, A.
(Eds.), Title. Merck & Co., Whitehouse Station, NJ, pp. 1761
1765.
Mitscher, L.A., Devasthale, P., Zavod, R., 1993. Structureactivity
relationships. In: Hooper, D.C., Wolfson, J.S. (Eds.), Quinolone
Antimicrobial Agents. The American Society for Microbiology,
Washington, DC, pp. 351.
Mizuki, Y., Fujiwara, I., Yamaguchi, T., Sekine, Y., 1996. Structurerelated inhibitory eect of antimicrobial enoxacin and derivatives
on theophylline metabolism by rat liver microsomes. Antimicrobial
Mouton, J.W., 2003. Impact of pharmacodynamics on breakpoint
selection for susceptibility testing. Infectious Disease Clinics of
North America 17, 579598.
Mouton, J.W., Dudley, M.N., Cars, O., Derendorf, H., Drusano,
G.L., 2005. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update.
Journal of Antimicrobial Chemotherapy 55, 601607.
Mouton, J.W., Vinks, A.A., 2005a. Pharmacokinetic/pharmacodynamic modelling of antibacterials in vitro and in vivo using
bacterial growth and kill kinetics: the minimum inhibitory
concentration versus stationary concentration. Clinical Pharmacokinetics 44, 201210.
Mouton, J.W., Vinks, A.A., 2005b. Relationship between minimum
inhibitory concentration and stationary concentration revisited:
growth rates and minimum bactericidal concentrations. Clinical
Pharmacokinetics 44, 767780.
Muller, M., Stab, H., Brunner, M., Moller, JG., Lackner, E., Eichler,
H.G., 1999. Penetration of moxioxacin into peripheral compartments in humans. Antimicrobial Agents and Chemotherapy 43,
23452349.
Munoz, R., De La Campa, A.G., 1996. ParC subunit of DNA
topoisomerase IV of Streptococcus pneumoniae is a primary target
of uoroquinolones and cooperates with DNA gyrase A subunit in

forming resistance phenotype. Antimicrobial Agents and Chemotherapy 40, 22522257.
Nakamura, S., Nakamura, M., Kojima, T., Yoshida, H., 1989. gyrA
and gyrB mutations in quinolone-resistant strains of Escherichia
coli. Antimicrobial Agents and Chemotherapy 33, 254255.
Ng, E.Y., Trucksis, M., Hooper, D.C., 1996. Quinolone resistance
mutations in topoisomerase IV: relationship to the qA locus and
genetic evidence that topoisomerase IV is the primary target and
DNA gyrase is the secondary target of uoroquinolones in
Staphylococcus aureus. Antimicrobial Agents and Chemotherapy
40, 18811888.
Nightingale, C.H., Grant, E.M., Quintiliani, R., 2000. Pharmacodynamics and pharmacokinetics of levooxacin. Chemotherapy 46
(Suppl 1), 614.
Nikaido, H., Vaara, M., 1985. Molecular basis of bacterial outer
membrane permeability. Microbiological Reviews 49, 132.
Nix, D.E., Schentag, J.J., 1988. The quinolones: an overview and
comparative appraisal of their pharmacokinetics and pharmacodynamics. Journal of Clinical Pharmacology 28, 169178.
Oethinger, M., Kern, W.V., Jellen-Ritter, A.S., McMurry, L.M., Levy,
S.B., 2000. Ineectiveness of topoisomerase mutations in mediating
clinically signicant uoroquinolone resistance in Escherichia coli
in the absence of the AcrAB eux pump. Antimicrobial Agents
and Chemotherapy 44, 1013.
Okazaki, O., Kojima, C., Hakusui, H., Nakashima, M., 1991.
Enantioselective disposition of ooxacin in humans. Antimicrobial
Okusu, H., Ma, D., Nikaido, H., 1996. AcrAB eux pump plays a
major role in the antibiotic resistance phenotype of Escherichia coli
multiple-antibiotic-resistance (Mar) mutants. Journal of Bacteriology 178, 306308.
Owens Jr., R.C., Ambrose, P.G., 2002a. Pharmacodynamics of
quinolones. In: Nightingale, C.H., Murakawa, T., Owens Jr.,
R.C. (Eds.), Antimicrobial Pharmacodynamics in Theory and
Clinical Practice. Marcel Dekker, Inc.,, New York, NY, pp. 155
176.
Owens Jr., R.C., Ambrose, P.G., 2002b. Torsades de pointes associated with uoroquinolones. Pharmacotherapy 22, 663668.
Peterson, L.R., 2001. Quinolone molecular structureactivity relationships: what we have learned about improving antimicrobial
activity. Clinical Infectious Diseases 33 (Suppl 3), S180S186.
Piddock, L.J., Ricci, V., McLaren, I., Griggs, D.J., 1998. Role of
mutation in the gyrA and parC genes of nalidixic-acid-resistant
salmonella serotypes isolated from animals in the United Kingdom.
Journal of Antimicrobial Chemotherapy 41, 635641.
Polk, R., 1999. Optimal use of modern antibiotics: emerging trends.
Clinical Infectious Diseases 29, 264274.
Polk, R.E., 1989. Drugdrug interactions with ciprooxacin and other
uoroquinolones. American Journal of Medicine 87, 76S81S.
Poole, K., 2000. Eux-mediated resistance to uoroquinolones in
gram-negative bacteria. Antimicrobial Agents and Chemotherapy
44, 22332241.
Preston, S.L., Drusano, G.L., Berman, A.L., Fowler, C.L., Chow,
A.T., Dornseif, B., Reichl, V., Natarajan, J., Corrado, M., 1998.
Pharmacodynamics of levooxacin: a new paradigm for early
clinical trials. Journal of the American Medical Association 279,
125129.
Rabbaa, L., Dautrey, S., Colas-Linhart, N., Carbon, C., Farinotti, R.,
1997. Absorption of ooxacin isomers in the rat small intestine.
Antimicrobial Agents and Chemotherapy 41, 22742277.
Radandt, J.M., Marchbanks, C.R., Dudley, M.N., 1992. Interactions
of uoroquinolones with other drugs: mechanisms, variability,
clinical signicance, and management. Clinical Infectious Diseases
14, 272284.
Robinson, A., Belden, J.B., Lydy, M.J., 2005. Toxicity of uoroquinolone antibiotics to aquatic organisms. Environmental Toxicology and Chemistry 24, 423430.
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
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
Escherichia coli. Antimicrobial Agents and Chemotherapy 40, 491

493.
Wagenlehner, F.M., Naber, K.G., 2003. Antimicrobial treatment
of prostatitis. Expert Review of Anti-Infective Therapy 1, 275
282.
Walker, R.D., 2000. The use of uoroquinolones for companion
animal antimicrobial therapy. Australian Veterinary Journal 78,
8490.
Walters, J.D., Zhang, F., Nakkula, R.J., 1999. Mechanisms of
uoroquinolone transport by human neutrophils. Antimicrobial
Wamberg, S., Sandgaard, N.C.F., Bie, P., 2002. Simultaneous determination of total body water and plasma volume in conscious dogs
by the indicator dilution principle. Journal of Nutrition 132,
1711S1713S.
Wang, M., Tran, J.H., Jacoby, G.A., Zhang, Y., Wang, F., Hooper,
D.C., 2003. Plasmid-mediated quinolone resistance in clinical
isolates of Escherichia coli from Shanghai, China. Antimicrobial
Wang, Y., Huang, W.M., Taylor, D.E., 1993. Cloning and nucleotide
sequence of the Campylobacter jejuni gyrA gene and characterization of quinolone resistance mutations. Antimicrobial Agents and
Waxman, S., Rodriguez, C., Gonzalez, F., De Vicente, M.L., San
Andres, M.I., San Andres, M.D., 2001. Pharmacokinetic behavior
of marbooxacin after intravenous and intramuscular administra-
tions in adult goats. Journal of Veterinary Pharmacological

Therapy 24, 375378.
Willmott, C.J., Critchlow, S.E., Eperon, I.C., Maxwell, A., 1994. The
complex of DNA gyrase and quinolone drugs with DNA forms a
barrier to transcription by RNA polymerase. Journal of Molecular
Biology 242, 351363.
Wright, D.H., Brown, G.H., Peterson, M.L., Rotschafer, J.C., 2000.
Application of uoroquinolone pharmacodynamics. Journal of
Antimicrobial Chemotherapy 46, 669683.
Yoon, J.H., Brooks Jr., R.L., Khan, A., Pan, H., Bryan, J., Zhang, J.,
Budsberg, S.C., Mueller, P.O., Halper, J., 2004. The eect of
enrooxacin on cell proliferation and proteoglycans in horse
tendon cells. Cell Biology Toxicology 20, 4154.
Yoshida, H., Bogaki, M., Nakamura, M., Nakamura, S., 1990.
Quinolone resistance-determining region in the DNA gyrase gyrA
gene of Escherichia coli. Antimicrobial Agents and Chemotherapy
34, 12711272.
Yoshida, H., Kojima, T., Yamagishi, J., Nakamura, S., 1988.
Quinolone-resistant mutations of the gyrA gene of Escherichia
coli. Molecular and General Genetics 211, 17.
Zechiedrich, E.L., Cozzarelli, N.R., 1995. Roles of topoisomerase IV
and DNA gyrase in DNA unlinking during replication in Escherichia coli. Genes and Development 9, 28592869.
Zhanel, G.G., 2001. Inuence of Pharmacokinetic and Pharmacodynamic Principles on Antibiotic Selection. Current Infectious
Disease Report 3, 2934.

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product of anti-malarial research in 1962 (Lesher et al.,

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

Products possessing this uorine molecule are known

An update on the perspective relating to the clinical

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

Fig. 1. Nalidixic acid.

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

sition 7 substituent for danooxacin results in its

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

When pH values are lower than the pKa1, quinolones

pH 7.0 (Lizondo et al., 1997). Similarly, maximal

4. Clinical use of uoroquinolones in veterinary medicine

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

To be given as single or divided

Administer once daily for 23

Summary is based upon information contained within 21 CFR, April 2003.

Register, 2001). The NADAs provide for use of

2. The infection is associated with a purulent discharge

Although this section on pharmacokinetics is intended to be applicable to veterinary drug products,

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

cin, has been reported (Griths et al., 1994; Rabbaa

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

For consistency, all data reect information derived from human

tissues. Therefore, free uoroquinolone concentrations

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

The largest back-calculated prediction error for CL was

for all six species included in this study, as well as the

From Siefert et al. (1999).

Federal Register (1998)

Boothe et al. (2002)

Enrooxacin is extensively metabolized by the liver, being transformed into

Excreted primarily in urine with limited biotransformation. Small amounts of

Matsumoto et al. (1997)

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

4. In vitro PAE is the period of suppression of bacterial

Terminal T1/2 (h)

Terminal T1/2 (h)

Terminal T1/2 (h)

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

maximum number of bacteria (or attainable bacterial

hollow bre studies suggest that AUC/MIC was more

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

treat Gram-positive infections. An excellent overview of

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

excess CNS and cardiac stimulation. This potential

7. Fluoroquinolones and resistance

IV, a single mutation in gyrA is sucient to impart

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

may contain multiple eux pumps (e.g., AcrAB and

Theoretically, this objective appears straightforward.

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

to run) these kinds of simulations. Therefore, these

Ultimately, as aptly stated by Ron Polk in a 1999

Alekshun, M.N., Levy, S.B., 1999. The mar regulon: multiple

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

infection model against Bacillus anthracis utilizing both human and

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028

Greene, C.E., Budsberg, S.C., 1993. Veterinary use of quinolones. In:

PK/PD in in vitro models. International Journal of Antimicrobial

M. Martinez et al. / The Veterinary Journal 172 (2006) 1028