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 7 th 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 activity

Characterestic features

Examples

Gram+ve

Gram-ve

Anaerobes

First(Quinolones)

__ + __ Antibacterial activity restricted to enterobacteriaceae.Narrow spectrum of activity,highly toxic and rapid emergence of resistance

nalidixic acid, flumequine, oxalinic acid cinoxacin, pipemidic acid, rosoxacin

Second (FQs)

+ + +/ - Extended antibacterial spectrum against mycoplasma and chlamydia.,

enrofloxacin, ciprofloxacin enoxacin fleroxacin lomefloxacin nadifloxacin norfloxacin ofloxacin pefloxacin rufloxacin amifloxacin danofloxacinmarbofloxacin sarafloxacinorbifloxacin ibafloxacinpradofloxacin difloxacin

Third(FQs)

+ + + + + Increased antibacterial spectrum against gram positive cocci and strict anaerobes

balofloxacin gatifloxacin grepafloxacin levofloxacin, moxifloxacin pazufloxacin 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

SpeciesDrug Dose

(mg/kg)Route Interva

l(hrs)

Major indications

Dogs cats

NorfloxacinEnrofloxacin

CiprofloxacinOrbifloxacinDifloxacinMarbofloxacinMoxifloxacin

222.5

11-232.5-7.55-10

2.75-5.5

10

POPO, IM,

IVPOPOPOPO

PO

1212

12242412

24

Skins and soft tissue infections ,bone and joint infections, CNS infections urinary tract infections,respiratory infections

Cattlesheep goats

Enrofloxacin Danofloxacin (calves)

Flumequine (calves)

2.5-56

1.25

8-15

PO, IM, SCIM

PO

244824

24

Respiratory tract, enteric infections, genito urinary infections

Swine Enrofloxacin 2.5-5 IM, PO 24 Respiratory,enteric infections

mastitis/metritis

Horse Orbifloxacin

Moxifloxacin

Marbofloxacin

5

5.8

2

PO

PO

PO

24

24

24

Skin, soft tissue infectionsSkininfections,pneumoniaGram negative infections

Poultry Enrofloxacin

Sarafloxacin

50 ppm0.5 mg/bird

20-40µg/ml in water

PO, IM

PO

WaterSID

24

Respiratory, enteric infections

Camel Enrofloxacin 2.5-5 SC 24 Bacterial infections.

Python Enrofloxacin 10

5

IM

IM

Loading dose After 48 hrs

Rabbit Enrofloxacin 5 SC 12Duck Enrofloxacin 10 IM 24Emu Enrofloxacin 2.2 IM 12Parrot Enrofloxacin 7.5-30 IM 12

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