FLUOROQUINOLONE

ANTIMICROBIALS IN ANIMAL HEALTH

The quinolones are a family of broad-spectrum antibacterials. The parent of the group is
nalidixic acid., first introduced in to clinical practice in 1963. It had limited clinical
application due to its poor oral absorption, poor tolerance, and toxicity, narrow spectrum
of antibacterial activity and rapid development of resistance. (Walker RD and Dowling
PM, 2006)

Several other later approved quinolones like oxolinic acid, pipemidic acid, piromidic acid
and flumequine exhibited increased antibacterial activity, t with limited absorption and
distribution. The addition of both a fluorine molecule at the 6th position of the basic
quinolone structure and a piperazine substitution at the 7th position enhanced the
antibacterial activity, oral absorption and tissue distribution of these compounds. The
quinolone nucleus possessing the fluorine molecule gave the group the name
Fluoroquinolones (FQs), to which the majority of quinolones in clinical use presently
belong to.

The FQs, also known as 4-quinolones, pyridine beta carboxylic acids or quinolone
carboxylic acids are a large and expanding group of synthetic antimicrobial agents that
are rapidly bactericidal against a wide variety of clinically important pathogenic
organisms; are well tolerated by animals and can be administered by a variety of routes.
(Papich MG and Riviere JE, 2001)

The members of this group that are currently labeled for use in animals have the same
quinolone structure, each with modifications that account for pharmacokinetic variations
in the medications with not much significant change in the antibacterial spectrum of
activity.( Spreng M et al, 1995). Since the the first approved fluoroquinolone in
humans (norfloxacin, followed by ciprofloxacin) and animals (enrofloxacin), several
other FQs have been developed and currently being used in clinics, though FQs approved
for use in animals are limited.
 Since the development of newer quinolones and their release in the mid-1980s, there
has been extensive clinical use of these agents in both human and veterinary medicine.
Quinolones have been approved and used extensively for treatment of a broad range of
clinical infections, including genitourinary, gastrointestinal, and respiratory as well as
infections of bone, joints, and skin. In the context of increasing resistance of gram-
negative bacteria to other classes of antimicrobials, these agents have provided valuable
alternative therapies. The extra label use of these agents in food-producing animals
presents a risk to the public health as it could increase the level of drug resistant zoonotic
pathogens at the time of slaughter, which may result in transfer of pathogens resistant to
FQs from animals to human beings.
Classification
Fluoroquinolones (FQs) are classified in to three generations based primarily on
their spectrum of activity, related to the biological activity. The earlier generation FQs
exhibited good activity against wide range of aerobic gram-negative bacteria, less
activity against gram positive bacteria, especially enterococci and anaerobic bacteria, as
compared to the newer FQs which are active against strict anaerobes also. The
spectrum of activity of the older quinolones was essentially against enterobacteriaceae,
whereas the newer fluoroquinolones have a wider spectrum including activity against
many gram negative and gram positive bacilli and cocci, some intracellular organisms
(Rickettsia spp. and Mycobacterium spp.) and Mycoplasma spp. (Cambau et al., 1993;
Gautier-Bouchardon et al., 2002; Hannan et al., 1997; Rolain et al., 2002; Walker,
2000). Third generation quinolones such as moxifloxacin have enhanced activity against
gram positive bacteria relative to first and second generation compounds and good
activity against anaerobes (Hawkey, 2003). Pradofloxacin developed exclusively for use
in veterinary medicine, is a second generation FQ, exhibiting enhanced spectrum of
activity against gram positive and anaerobic organisms than the second generation
compounds such as enrofloxacin and marbofloxacin. (Papich MG and Riviere JE, 2001)
 Generation Spectrum of Characterestic Examples
activity features
Gra Gra Ana
m m e
+ve -ve rob
es
First __ + __ Antibacterial activity nalidixic acid, flumequine,
(Quinolones) restricted to oxalinic acid cinoxacin,
enterobacteriaceae. pipemidic acid, rosoxacin
Narrow spectrum of
activity,highly toxic
and rapid emergence of
resistance
Second + + +/ - Extended antibacterial enrofloxacin, ciprofloxacin
(FQs) spectrum against enoxacin fleroxacin
mycoplasma and lomefloxacin nadifloxacin
chlamydia., norfloxacin ofloxacin
pefloxacin rufloxacin
amifloxacin danofloxacin
marbofloxacin sarafloxacin
orbifloxacin ibafloxacin
pradofloxacin difloxacin
Third ++ ++ + Increased antibacterial balofloxacin gatifloxacin
(FQs) spectrum grepafloxacin
against gram levofloxacin,
positive cocci moxifloxacin
and strict pazufloxacin
anaerobes sparfloxacin
temafloxacin
tosufloxacin
ecinofloxacin
clinafloxacin
trovafloxacin

FQs currently approved for use in animals (WHO,1998):

The FQs approved for use in veterinary medicine in different species of animals includes
enrofloxacin, (cattle,swine,poultry, dog,cat),danofloxacin (cattle,swine,poultry),
norfloxacin,ofloxacin,
sarafloxacin(poultry),amifloxacin,ciprofloxacin(swine,poultry),orbifloxacin,marbofloxacin(catt
le, swine,dog,cat),ibafloxacin,pradofloxacin (dog,cat),difloxacin (swine,poultry, ,dog), oxolinic
acid and flumequine (cattle, swine, poultry).
Chemistry
All the currently available FQs possess the same quinolone structure; the carboxyl group and
the ketone groups are necessary for the antibacterial activity. The fluorine at position 6
differentiates the FQs from quinolones and accounts for the improved spectrum and potency.
Various chemical substitutions and side groups account for the different physical
characteristics of each drug, like volume of distribution, lipophilicity, oral absorption and
elimination rate, though the change in the antibacterial spectrum is only marginal.
Antimicrobial spectrum
 FQS are broad spectrum rapidly acting bactericidal antibacterials, exhibiting
concentration dependent post antibiotic effect; in which growth of pathogens remain
inhibited for varying periods (4-8hours) after fluoroquinolone concentration falls below
minimum inhibitory concentration. This makes them to be administered once daily and
the low MIC values add to the reduction in the dosage and slower development of
resistance.

They exhibit excellent activity against wide range of gram negative bacteria including
Enterobacteria, Pasteurella,, Bordetella, Brucella, and Pseudomonas aeruginosa;.
good to moderate activity against staphylococci, mycoplasma,, chlamydia,
mycobacteria and ureaplasma.and little or no activity against streptococci.

Older FQs are less active against gram positive bacteria especially enterococci, and
are poorly effective against anaerobes. Newer FQs like moxifloxacin, gatifloxacin,
trovafloxacin, clinafloxacin and sitafloxacin have increased activity against
staphylococci, streptococci, enterococci and strict anaerobes like Clostridium
perfringens, Bacteroides fragilis.

 Many gram negative bacteria that are resistant to other classes of antibacterial agents,
such as aminoglycosides, antipseudomonal penicillins and third generation
cephalosporins remain susceptible to the FQs.

 FQs have greater efficacy and broad spectrum of activity against ocular pathogens.
Better ocular tolerability with less toxicity to corneal epithelium makes FQs as good
ocular antiinfectives. Topical ciprofloxacin is effective for bacterial conjunctivitis and
keratitis. Ofloxacin achieves the highest aqueous and vitreous concentration on
topical application or topical combined with intravenous administration among the
FQs. (Yu-Speight et al,2002) Norfloxacin has less ability to penetrate the cornea; is
indicated for the treatment of bacterial conjunctivitis but not bacterial keratitis.
Moxifloxacin and gatifloxacin are the other agents with better intraocular penetrability.
(Thomas J Kern 2004)

They are active in presence of abscess in spite of unfavorable environmental

conditions due to their amphoteric nature. The lipophilic property aids in good oral
absorption, bioavailability and larger volume of distribution with low plasma protein
binding.

Fluoroquinolones such as norfloxacin, ciprofloxacin, enrofloxacin, orbifloxacin,

marbofloxacin and difloxacin are used for resistant bacterial urinary tract infections.
Difloxacin undergoes more hepatic excretion than the other fluroquinolones;
consequently less is excreted into urine. The quinolones should be reserved for
treatment when other therapeutic agents have failed unless there is compelling evidence
that the organism in question is highly resistant to other antibacterial agents.

 Orbifloxacin (5mg/kg/day) and marbofloxacin (2mg/kg,/day) are suitable for horses

with good oral absorption and favourable activity against Enterobacteriaceae
(Mark.G.Papich,2003).

Levofloxacin possesses excellent activity against gram positive, gram negative and
anaerobic bacteria (Davis and Bryson, 1994; North et al., 1998), as compared to other
fluoroquinolones, ofloxacin and ciprofloxacin; it also has more pronounced bactericidal
activity against organisms like Pseudomonas, Enterobacter and Klebsiella (Klesel et
al., 1995). The drug distributes well to target body tissues and fluids in the respiratory
tract, skin, urine and prostate and its uptake by cells makes it suitable for use against
intracellular pathogens (Langtry and Lamb, 1998).

 The newer generation FQs such as gatifloxacin and moxifloxacin have a spectrum
that includes gram positive bacteria and anaerobes not covered by older FQs like
enrofloxacin, orbifloxacin and marbofloxacin. This increased anaerobic spectrum of
 activity may cause antibiotic associated diarrhoea in horses. (Mark.G.Papich,2003).
These newer generation fluoroquinolones should not be used in horses with colic.

Moxiifloxacin has a chemical structure that is slightly different from other FQs, as a
result of which, it has greater activity against gram positive bacteria and anaerobes
than other veterinary FQs (Mark G Papich, 2007) and can be used against bacteria
resistant to other FQs.

Mechanism of action

The FQs inhibit bacterial DNA gyrase or topoisomerase IV (a type II topoisomerase),

thereby prevent DNA supercoiling and replication. Cell respiration and division end, and
membrane integrity is interrupted resulting in bactericidal effect. Mammalian cell type II
topoisomerase is not affected by FQs until drug concentrations are at least 100 times
higher than concentrations recommended to inhibit the bacteria. Bacterial resistance to
fluoroquinolones most commonly occurs by alteration of the target, DNA gyrase
(topoisomerase II), via mutation commonly occuring at the topoisomerase IV
target. (Brown SA.1996).Resistance is usually chromosomally
developed and, therefore, remains after antimicrobial therapy ends.
Cross-resistance of enrofloxacin with other fluoroquinolones can occur.
(Vancutsem PM et al, 1990)

Absorption

Oral absorption of FQs is high for most animals. In cats, dogs, and pigs, oral absorption
of FQs approaches 100%, but in ruminants, it is generally less Rapidly absorbed in
monogastric species and preruminant calves. Absorption in adult ruminants is variable
and has ranged from 10 to 50%. (Vancutsem PM et al, 1990). For example, the oral
bioavailability of enrofloxacin is good (80%) in sheep, adult horses (60%) and foals.
(42%), while being poor in neonatal kittens. (Seguin et al, 2004)).

The absorption is not affected by administration with food, although absorption may
be delayed, in some cases. (Mark G. Papich, 2001). The horse may be unique
regarding the oral bioavailability patterns in that enrofloxacin, marbofloxacin, and
orbifloxacin are considered to have clinically adequate bioavailabilities, but lower with
ciprofloxacin (Giguere S et al, 1996). Absorption from parenteral administration of
FQs is rapid and often nearly complete. Parenteral availability is
approximately complete in pre ruminant and ruminant cattle;
supravailibility from extravascular routes has been seen in
horses(Brown SA,1996), resulting from enterohepatic recycling of the
drug. In some animals, there is delayed absorption from intramuscular or subcutaneous
administration, producing longer half-lives from these routes compared to intravenous
absorption.

Divalent and trivalent cations can affect the absoprtion .Accumulation of FQs within
the bacteria is antagonized by cations by binding at the cell surface resulting from
chelation with cations.

Distribution

Higher degree of tissue penetration and systemic steady state concentration is achieved
with extended elimination half lives. FQs like
difloxacin,enrofloxacin,marbofloxacin,orbifloxacin,ofloxacin,gatifloxacin and
ciprofloxacin have been shown to reach effective concentrations in the CNS that are
within the therapeutic range for many pathogens., making them to be used in bacterial
meningitis.

Rapidly and extensively distributed to tissues tissues like kidney, lung,

prostate, genital tract, bones, phagocytes and inflammatory fluids. because of their
lipophilic nature and low protein binding. Differences in volume of distribution among
the FQs however, account for a range of maximum plasma concentrations among
the drugs. Drugs with the lower volume of distribution are diluted less in body fluid and
produce higher plasma concentrations than drugs with a higher volume of distribution.
The consequence of this difference is reflected in the dose administered, as to achieve
the same peak serum concentration, drugs with a high volume of distribution will require
a higher dose.

Enrofloxacin appears rapidly in milk after parenteral administration,

reaching a peak concentration 30 to 60 minutes after intravenous injection, followed by a
gradual decline in milk concentration similar to that occurring in serum concentration.
FQs are rapidly accumulated in macrophages and neutrophils. Unlike other antibiotics
that concentrate in subcellular sites within phagocytic cells, these are distributed into the
cytosol where they can reach intracellular pathogens.(Brucella, Mycoplasma,
Mycobacterium species) This intracellular concentration may be several times greater
than plasma concentrations ( Hawkins EC et al 1998)

Biotransformation

Metabolism occurs primarily in liver. In general, phase I metabolism occurs primarily

through hydroxylation and oxidation to oxoquinolones. Oxidized metabolites have some
antibacterial activity where as glucoronide conjugates are devoid of activity.
Enrofloxacin and pefloxacin are N-dealkylated to form ciprofloxacin and norfloxacin
respectively; both metabolites being antimicrobially active in many species. Because
minimum inhibitory concentrations for some pathogens are lower for ciprofloxacin than
for enrofloxacin therapeutic concentrations of ciprofloxacin can be reached with dosing
calculated to achieve effective enrofloxacin concentrations. Ciprofloxacin can be
considered as an important contributor to the activity of enrofloxacin. Levofloxacin is
metabolized in the liver to demethyl-levofloxacin and levofloxacin-Noxide and excreted
in urine (Langtry and Lamb, 1998). Other metabolic pathways for FQs include oxidation,
glucoronidation, sulfoxidation and acetylation. The elimination is mainly through urine,
some fraction also getting excreted through feces and milk

Adverse Effects

FQs are relatively safe antimicrobial agents; Administered at therapeutic doses, toxic
effects are mild and are limited to gastrointestinal disturbances such as nausea, vomition,
diarrhoea, decreased appetite or anorexia. Other adverse effects noticed include

1. Noninflammatory erosive arthropathies occur in growing animals treated with

FQs. A single very large dose or repeated l moderately large doses, form vesicles
in the articular cartilage, which can then progressively rupture and produce
cartilaginous erosions, particularly in weight bearing joints. This is due to an early
 phase burst in oxidative metabolism in immature chondrocytes precipitating cell
death. The mechanism for damage to cartilage is via the chelation of magnesium
by the drug; magnesium being necessary for proper development of the cartilage
matrix, especially in young, growing animals. Chelation of magnesium results in
loss of proteoglycan in the articular cartilage.(Mark G Papich and Riviere
JE,2001) The damage is characterized by erosion, cleft formation in articular
cartilage and synovial joint effusion which is clinically manifested as lameness.
For this reason, FQ should not be administered to horses less than 3 years of age,
and should be avoided during rapid growth, typically up to 8 -12 months of age in
small and medium breed dogs and up to 18months of age in giant breeds of dogs.
Kitten, calves and pigs are much more resistant to this effect.

2. Retinal degeneration especially seen in cats with high dose of therapy with any
FQ, is often manifested as temporary or permanent acute blindness with
mydriasis. Although retinal toxicity is noted to be idiosyncratic in some cats, cats
with renal or liver disease are at increased risk for toxicity, as reduced metabolism
will result in higher plasma levels of fluoroquinolones and their metabolites. Risk
factors for cat include i) high dose resulting in high plasma concentration ii) rapid
IV administration iii) chronic treatment iv) advanced age v) prolonged exposure
to UV light while on therapy vi) drug interactions. However studies with
marbofloxacin, orbifloxacin, pradofloxacin did not demonstrate any ocular
toxicity. A dose of 3 mg/kg once daily or 2.5 mg/kg twice daily is recommended
in cats with renal or liver disease. Fluoroquinolones should not be used in cats
with liver or renal disease. Use of any fluoroquinolone in cats should be reserved
for those with serious infections. Topical use of fluoroquinolones has not been
associated with retinal toxicity in cats. (Thomas .J.Kern , 2004)

3. Neurotoxic effects causing CNS disturbances (seizures, ataxia, dizziness,

restlessness, tremors, convulsions, urination defecation and emesis within 2-3
minutes) have been reported in horse, dog and cats. Rapid IV administration of
high doses of these agents cause transcient neurological signs including
excitability and seizure like activity, which subside within several minutes in the
affected dogs and can be avoided by giving slow infusion.. Enrofloxacin has been
 associated with increased frequency and intency of seizures in epileptic dogs.
The epileptogenic adverse effect of FQs is due to GABA receptor antagonism,
and is usually dose and specific FQ dependent.

4. Enrofloxacin administered intramuscularly to horses results in severe irritation,

swelling and tenderness at the site of injection, with elevated creatine kinase
activity for up to 32 hours after injection. Cattle formulations can be administered
by slow intravenous injection or formulated in to a gel for oral administration.
(Walker, RD. and Dowling PM, 2006). Oral erosions or ulcers in horses with oral
gel formulations, decreased appetite, polydipsia and polyuria in birds; transient
lameness in calves; transient local tissue reaction with injection in cattle causing
trim loss of edible tissue at slaughter are the other adverse effects noticed in
animals that have been administered with different FQ compounds.

5. Photosensitization occurs with all marked FQs, especially pefloxacin, although it

is rare for norfloxacin and ciprofloxacin.

6. Though not mutagenic, large doses of FQs have resulted in embryonic deaths in
laboratory animals, which has not been observed in other target species of
animals treated with therapeutic doses of FQs.

7. The effects like ocular cataract, achilles tendon rupture, renal toxicity showing
mild interstitial nephritis, acute renal failure and crystalluria being noticed in
humans associated with the overdosage/ prolonged use, have not been reported
in animals.

8. Temofloxacin ,causing haemolytic uraemic anaemia, and grepafloxacin and

trovafloxacin, causing serious hepatotoxicity with hepatic and renal dysfunction
have been withdrawn from use in 1992 and 1999 respectively.

9. The attributes of FQs make them likely to cross the placenta in many species;
however, adverse effects have not yet been reported with FQs administered to
pregnant animal. However administration during pregnancy and even in lactating
animals is generally not recommended, based on reports of arthropathy in
immature animals. (Mark G Papich and Riviere JE. 2001).
Interactions

• The FQs are synergestic with beta lactams, aminoglycosides, imidazoles,

and vancomycin against many bacterial pathogens, particularly against
enetrobacteriaceae, gram positive bacteria and anaerobes.

• Antagonism in streptococci and enterococci occur between the FQs and

either the macrolides or tetracyclines. FQs are completely antagonistic with
chloramphenicol.

• Concurrent oral administration of drugs that contain divalent or trivalent

cations, such as aluminum, calcium, iron, magnesium, or zinc cations will
significantly inhibit oral absorption of fluoroquinolones (e.g., enrofloxacin).
Compounds that may contain these cations are antacids, sucralfate, laxatives, iron
supplements, molasses and multivitamins. ((Mark G. Papich, 2001).) If at all
necessary, antacids and other medications are to be taken at least two to four
hours before or after oral administration of fluoroquinolones.

• The co administration of nonsteroidal anti-inflammatory drugs with FQs

may affect the pharmacokinetics of one or both drugs; the clinical significance of
which is not known. FQs are competitive inhibitors of gamma aminobutyric acid
receptor binding, and NSAIDS have been shown to enhance this effect; Thus
concurrent administration of NSAIDS with quinolone antibiotics may increase the
risk of CNS stimulation and convulsions

• Concurrent administration of FQs can reduce the elimination of drugs that

depend on hepatic metabolism for their excretion. The hepatic clearance of
methylxanthines, like theophylline and caffeine gets reduced on concurrent
administration with FQs, resulting in CNS related toxicity signs caused by them.

• Probenecid decreases the renal tubular secretion of FQs, resulting in

decreased urinary excretion of the fluoroquinolone, prolonged elimination half
life, and increased risk of toxicity; this interaction is more significant with FQs
getting excreted largely unchanged
 • Concurrent use of warfarin has been reported to increase the anticoagulant
effect of warfarin, increasing the chance of bleeding, even though FQs may not
alter the prothrombin time significantly

• FQs are incompatible with aminophylline, amoxicillin, cefepime,

clindamycin,dexamethasone, floxacillin, furosemide, heparin, and phenytoin. If
they are to be given concurrently with another medication, each medication
should be administered separately in different syrienges according to the
recommended dosage and route of administration for each medication.

Precautions

• In Central nervous system (CNS) disorders, history of seizures: FQs have

been associated with CNS stimulation that may lead to seizures in few rare
cases and should be used with caution

• In hepatic disease and severe renal failure: As FQs are primarily eliminated
by a combination of renal clearance and hepatic metabolism, sometimes with
significant biliary secretion; the predominance of one route over another
depends on the functioning status of kidney and liver

• Undue exposure to excessive sunlight to be avoided while receiving FQ

therapy as to avoid phototoxicity.

• In patients receiving drugs that affect the QTc interval such as cisapride,
erythromycin, antipsychotics, and tricyclic antidepressants and in history of
QTc prolongation or proarrhythmic conditions such as hypokalemia,
bradycardia or recent myocardial ischemia.

• Symptoms of peripheral neuropathy including pain, burning, tingling,

numbness, and/or weakness if develops, treatment should be discontinued.

• FQs are better taken at least one hour before or at least two hours after food
or ingestion of milk and/or other dairy products.
 • Intravenous dose may be administered as a single daily dose or divided into
two equal doses administered every twelve hours. To avoid adverse effects,
the drug should be diluted in saline and infused over 15 to 20 minutes.

Contraindications: Hypersensitivity to quinolones-animals with a history of

hypersensitivity to quinolones are at risk for developing reactions to them ; In young,
growing and immature cats, dogs, and horses and in patients receiving class IA (e.g.,
quinidine, procainamide) or class III (e.g., amiodarone, sotalol), antiarrhythmic
agents as FQ may cause changes in the electrocardiogram (QT interval
prolongation), the significance of which is not known.

The use of FQs in animals, even when limited to therapeutic use, may facilitate
the emergence of bacterial resistance. When this occurs in enteric pathogens, the
potential for transfer to humans exists, especially through food. Cross-resistance
occurs throughout this entire class of drugs; therefore, resistance to one
fluoroquinolone will compromise the effectiveness of all fluoroquinolone drugs
Veterinarians, as part of the public health community, have a responsibility to avoid
unnecessary or inappropriate treatment of animals with fluoroquinolones.

USUAL DOSAGES OF APPROVED FLUOROQUINOLONES IN ANIMALS

Species Drug Dose Route Interva Major indications
(mg/kg) l
(hrs)
Dogs Norfloxacin 22 PO 12 Skins and soft
cats Enrofloxacin 2.5 PO, IM, 12 tissue infections
IV ,bone and joint
Ciprofloxacin 11-23 PO 12 infections, CNS
Orbifloxacin 2.5-7.5 PO 24 infections urinary
Difloxacin 5-10 PO 24 tract infections,
Marbofloxacin 2.75-5.5 PO 12 respiratory
Moxifloxacin infections
10 PO 24

Cattle Enrofloxacin 2.5-5 PO, IM, 24 Respiratory tract,

sheep Danofloxacin 6 SC 48 enteric infections,
goats (calves) 1.25 IM 24 genito urinary
infections
Flumequine 8-15 PO 24
(calves)
Swine Enrofloxacin 2.5-5 IM, PO 24 Respiratory,
enteric infections
mastitis/metritis

Horse Orbifloxacin 5 PO 24 Skin, soft tissue

infections
Moxifloxacin 5.8 PO 24 Skininfections,pne
umonia
Marbofloxacin 2 PO 24 Gram negative
infections
Poultry Enrofloxacin 50 ppm PO, IM Water Respiratory,
0.5 mg/bird SID enteric infections

Sarafloxacin 20-40µg/ml PO 24
in water
Camel Enrofloxacin 2.5-5 SC 24 Bacterial
infections.
Python Enrofloxacin 10 IM Loadin
g dose
5 IM After
48 hrs
Rabbit Enrofloxacin 5 SC 12
Duck Enrofloxacin 10 IM 24
Emu Enrofloxacin 2.2 IM 12
Parrot Enrofloxacin 7.5-30 IM 12
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