CIPROFLOXACIN; THE FREQUENT USE IN POULTRY AND ITS CONSEQUENCES ON HUMAN HEALTH

Abstract

Fluoroquinolones are bactericidal agents that exhibit AUC/MIC dependent
killing. In general, they are effective against Gram-negative organisms and some mycobacteria.
Ciprofloxacin is the members of this group and its bactericidal action involves the impeding of
enzyme topoisomerase II and IV. In human beings, this drug is recommended for a variety of
infections including typhoid fever,chronic bacterial prostatitis, lower respiratory tract infections,
skin infections, urinary tract infections, acute exacerbations of chronic bronchitis, complicated
intra-abdominal infections, infectious diarrhea, and uncomplicated cervical as well as urethral
gonorrhea.The drug is as effective in animals as in humans, and is therefore used in animals
as well. According to European health law and National Office of Animal Health (NOAH), UK,
the statutory withdrawal period for veterinary medicinal products must not be less than 28 days
for meat from poultry. The chicken used for meat purpose usually is of the age between 6 to 8
weeks, therefore the use of the drug must be discontinued by the age of 2 weeks. Whereas the
age of chick at which it usually develops indicated diseases, is 3 weeks. In this situation, it is not
possible to attain a withdrawal period of 28 days. Based on these observations, ciprofloxacin
use may not be recommended in poultry for treatment of diseases as it may cause unnecessary
exposure to humans while utilizing poultry meat and may lead to the development of drug
resistance

Full text

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CIPROFLOXACIN
1
The Professional Medical Journal
www.theprofesional.com
CIPROFLOXACIN;
THE FREQUENT USE IN POULTRY AND ITS CONSEQUENCES ON
HUMAN HEALTH
Dr. Ghulam Jilany Khan1, Dr. Rizwan Ahmad Khan2, Dr. Imtiaz Majeed3, Dr. Faheem Ahmed Siddiqui4
Dr. Sara Khan5
REVIEW PROF-2599
ABSTRACT… Fluoroquinolones are bactericidal agents that exhibit AUC/MIC dependent
killing. In general, they are effective against Gram-negative organisms and some mycobacteria.
Ciprooxacin is the members of this group and its bactericidal action involves the impeding of
enzyme topoisomerase II and IV. In human beings, this drug is recommended for a variety of
infections including typhoid fever,chronic bacterial prostatitis, lower respiratory tract infections,
skin infections, urinary tract infections, acute exacerbations of chronic bronchitis, complicated
intra-abdominal infections, infectious diarrhea, and uncomplicated cervical as well as urethral
gonorrhea.The drug is as effective in animals as in humans, and is therefore used in animals
as well. According to European health law and National Ofce of Animal Health (NOAH), UK,
the statutory withdrawal period for veterinary medicinal products must not be less than 28 days
for meat from poultry. The chicken used for meat purpose usually is of the age between 6 to 8
weeks, therefore the use of the drug must be discontinued by the age of 2 weeks. Whereas the
age of chick at which it usually develops indicated diseases, is 3 weeks. In this situation, it is not
possible to attain a withdrawal period of 28 days. Based on these observations, ciprooxacin
use may not be recommended in poultry for treatment of diseases as it may cause unnecessary
exposure to humans while utilizing poultry meat and may lead to the development of drug
resistance.
Key words: Ciprooxacin, Withdrawal, Fluoroquinolones, Poultry, Drug
resistance
1. Dr. Ghulam Jilany Khan.
Department of Pharmacology,
Jiangsu Center for Drug Screening,
China Pharmaceutical University,
PR China.
Department of Pharmacology and
Therapeutics, Faculty of Pharmacy,
University of Central Punjab,
Lahore, Pakistan.
2. Associate Prof.
(MBBS, FRCS)
Associate Professor,
Department of Surgery,
Shalamar Hospital / Shalamar
Medical & Dental College,
Shalamar Link Road, Lahore,
Pakistan.
3,4
Faculty of Pharmacy,
University of central Punjab,
Lahore, Pakistan
5. Department of Pharmaceutical
Chemistry, University College
Of Pharmacy, University of The
Punjab, Lahore, Pakistan.
Correspondence Address:
Dr. Ghulam Jilany Khan,
Department of Pharmacology and
Therapeutics,
Faculty of Pharmacy (FOP),
University of Central Punjab,
Lahore, Pakistan.
u4574904@hotmail.com.
Article received on:
22/07/2014
Accepted for publication:
05/11/2014
Received after proof reading:
17/01/2015
Article Citation: Khan GJ, Khan RA, Majeed I, Siddiqui FA, Khan S. Ciprooxacin; the frequent
use in poultry and its consequences on human health. Professional Med J
2015;22(1):001-005.
INTRODUCTION
Ciprooxacin belongs to the group of drugs
called uoroquinolones1. Introduction of the rst
uorinated quinolone, noroxacin lead to the
development of other members of this group2,
such as ciprooxacin, which has wide clinical
applications, better safety prole and good in
vitro effectiveness against resistant pathogenic
organisms as compared to other classes of
antibiotics3. Fluoroquinolones are bactericidal
agents and exhibit AUC/MIC dependent killing.In
general, they are effective against Gram-negative
organisms and some mycobacteria4. The
molecular formula of Ciprooxacin is C17H18FN3O3
having a molar mass of of 331.4g/mol. Chemically
it is 1-cyclopropyl-6-uoro-1,4-dihydro-4-oxo-
7-(1-piperazinyl)-3-quinolinecarboxylic acid5.
Physically the drug exists in crystalline form at
room temperature with a light yellow color6. The
structural formula of ciprooxacin is7

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CIPROFLOXACIN
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Pharmacokinetic properties of ciprooxacin
Ciprooxacin is well absorbed from gastrointestinal
tract after oral administration with a serum
protein binding of about 20 to 40%. The absolute
bioavailability of the drug is almost 70% and it is
not affected by rst pass metabolism8.
The drug is distributed through out the body
after oral administration. The tissue concentration
generally exceeds serum concentration
especially in genital tissuesincluding prostate.
The drug is found in active form, in nasal and
bronchial secretions, skin blister uid, mucosa of
the sinuses, sputum, saliva, lymph, prostatic
secretions, peritoneal uid and bile9,10. A deep
analysis reveals the noticeable amounts of
ciprooxacin incartilage, and bones, fats, lungs,
skin and skeletal muscles11, while less amount of
drug has been detected in vitreous humor of the
eyes12.This feature of deep penetration makes the
use of this drug questionable in meat producing
animals.
Upon urine analysis, four metabolites
(approximately 15% of oral dose) of ciprooxacin
have been identied13. It is observed that
ciprooxacin impedes human cytochrome P450
1A2 (CYP1A2) mediated metabolism, therefore
co-administration of this drug with other drugs
which are primarily metabolized by CYP1A2
may result in increased plasma concentrations
of the later drugs and has the potential to cause
clinically signicant adverse events14.
In individuals with normal renal function,
ciprooxacin’s elimination half-life in the serum is
about 4 hours. Approximately 40 to 50% of oral dose
of the drug is excreted in the urine as unchanged15.
Concurrent use of ciprooxacin with probenecid
(a drug to treat gout and hyperuricemia)can lead
to 50% increase in concentration of ciprooxacin
in systemic circulation because of its reduced
renal clearance16,17.
Pharmacodynamic properties of ciprooxacin
Antibacterial (bactericide) action of ciprooxacin is
exhibited by deterring the enzymes topoisomerase
IV and topoisomerase II (DNA gyrase). These
enzymes are the basic requirements of bacteria
for DNA repair, transcription, recombination, and
replication18.
Antimicrobial spectrum
Antibacterial spectrum of ciprooxacin includes;
Streptococcus pneumoniae (penicillin susceptible
isolates only), Enterococcus faecalis (vancomycin-
susceptible isolates only), Staphylococcus
epidermidis (methicillin-susceptible isolates only),
Staphylococcus saprophyticus, Staphylococcus
aureus (methicillin-susceptible isolates only),
Streptococcus pyogenes, Gram-negative
bacteria, Citrobacterkoseri (diversus), Proteus mi
rabilis,Citrobacterfreundii,Enterobacter cloacae,
Escherichia coli, Neisseria gonorrhoeae,Morgan
ellamorganii,Haemophilusinuenza,Haemophilus
para inuenzae,Klebsiella pneumonia, Moraxella
catarrhalis, Campylobacter jejuni, Proteus
vulgaris, Providencia rettgeri, Providencia stuartii,
Pseudomonas aeruginosa, Salmonella typhi,
Serratia marcescens, Shigella boydii, Shigella
dysenteriae, Shigella exneri, Shigella sonnei.19
Drug Resistance
Microorganisms resistant to penicillins,
cephalosporins, aminoglycosides, macrolides,
and tetracyclines may be susceptible to
uoroquinolones, including ciprooxacin because
of different bactericidal mechanism20. Even then,
resistance to uoroquinolones is possible either
by decreased outer membrane permeability,
mutations in the DNA gyrases, or drug efux. In
vitro studies have shown that, resistance develops
slowly with the prolong exposure to low doses of
ciprooxacin by multiple step mutations21.
Clinical Uses In humans
Besides the prophylactic use, ciprooxacin
is indicated for the treatment of infections
like; typhoid fever (enteric fever), urinary tract
infections, chronic bacterial prostatitis, for the
treatment of acute exacerbations of chronic
bronchitis, skin and skin structure infections,
complicated intra-abdominal infections, acute
uncomplicated cystitis in females, lower
respiratory tract infections, acute sinusitis, bone
and joint infections, infectious diarrhea, as well as

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CIPROFLOXACIN
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uncomplicated cervical and urethral gonorrhea
caused by neisseria gonorrhoeae22-27.
Uses in Poultry
In veterinary medicines, ciprooxacin is often
recommended for respiratory tract infections,
gastrointestinal tract infections and urinary tract
infections caused by Campylobacter, E. coli,
Haemophilus, Mycoplasma, Pasteurella and
Salmonella species28. These diseases start
appearing in poultry from the age of three days to
several months, on an average the most vulnerable
age is 3 weeks for respiratory diseases29 and 4 to
6 weeks for gastrointestinal diseases30.
Dose of ciprooxacin in poultry
Different manufacturers recommend different
doses of the drug ranging from 1mg/ml to 1
mg/15ml in drinking water, on an average a young
chick consumes 250ml water per day which
means the intake of the drug is from 17mg to
250mg per day31,32,33.
Withdrawal period:
Withdrawal period is the time required after the
administration of a drug to an animal to assure
that drug residues in the marketable/saleable
product are below a determined maximum
residue limit (MRL). Withdrawal period is of
most concern during the administration of
drug to any edible product or food animal for
meat or eggs. According to European health
law and National Ofce of Animal Health, UK,
the statutory withdrawal period for Veterinary
Medicinal Products must not be less than 28 days
for meat from poultry and mammals34. However
ciprooxacin has a withdrawal period of 12-15
days in absolute conditions35.The recommended
duration of the therapy is 5-7 days and may be
prolonged upto 2 weeks depending upon the
severity and type of disease.
Administration of ciprooxacin to animals
(produced for commercial purpose) with a serious
impaired hepatic and/or renal function can alter
(increase) the protein binding of the drug leading
to an increased withdrawal time period of up to
23 days which is actually 12-15 days in normal
considerations.
CONCLUSIONS
From this study, it is clear that extensive use
of ciprooxacin in poultry is most likely to
develop complications/ resistance in pathogenic
organisms to human because of following
reasons;
Normal withdrawal period of the drug in animal
is 12-15 days from the time of last administered
dose. Administration of ciprooxacin to animals
(produced for commercial purpose) with seriously
impaired hepatic and/or renal function can alter
(increase) the protein binding of the drug leading
to an increased withdrawal time period (up to 23
days).
The usual age of the poultry chicken used for meat
purpose is 6-8 weeks (42-56 days), which means
that the therapy of ciprooxacin must be stopped
at the age of 19th day in order to complete the
withdrawal period of 23 days.
The usual age at which the respiratory diseases
affect the chicken is 21 days (at the age of 3
weeks) while the use of ciprooxacin must be
stopped before the age of 19th day, therefore its
use must be discouraged.
Furthermore its use may cause abnormal delivery
of drug to humans which may cause toxicity
in patients having probenecid therapy as co-
current use of ciprooxacin with probenecid (a
drug to treat gout and hyperuricemia) can lead
to 50% increase in concentration of ciprooxacin
in systemic circulation because of its reduced
renal clearance. It is observed that Ciprooxacin
impedes human cytochrome P450 1A2 (CYP1A2)
mediated metabolism.
Co-administration of ciprooxacin (even in a
very minute quantity) with other drugs which are
primarily metabolized by CYP1A2 particularly the
drugs which already have very narrow therapeutic
window like theophylline and tizanidine may
cause serious adverse events.
Similarly some other drugs of very common
and often long term use like,terbinane,

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CIPROFLOXACIN
4
warfarin, clopidogrel,ondansetron, propafenone,
leunomide,propranolol, verapamil, naproxen,
zileutin, olanzapine, imipramine and mexiletine
may also show an increased plasma concentration
when used with ciprooxacin and have the
potential danger to cause clinically signicant
adverse events.
Overall, it is not possible to attain the complete
withdrawl period with the use of ciprooxacin in
poultry animals used for meat purpose within
the age of 6-8 weeks.While the unnecessary
exposure of ciprooxacin with a low dose for a
long period may also has its drawbacks regarding
the development of resistance in humans.
Conict of no interest statement
All the authors of this manuscript declare no
conict of interest to any individual or manufacturer
or company or organization.
Copyright© 05 Nov, 2014.
REFERENCES
1. Emmerson, A. M., & Jones, A. M. The quinolones:
decades of development and use. Journal of
Antimicrobial Chemotherapy, 2003;51(suppl 1), 13-20.
2. Asif, M., Siddiqui, A. A., & Husain, A. Quinolone
derivatives as antitubercular drugs. Medicinal
Chemistry Research, 2013;22(3), 1029-1042.
3. Herrlin, K., Segerdahl, M., Gustafsson, L. L., &Kalso,
E. Methadone, ciprooxacin, and adverse drug
reactions. The Lancet, 2000;356(9247), 2069-2070.
4. Johnson, J. L., Hadad, D. J., Boom, W. H., Daley, C. L.,
Peloquin, C. A., Eisenach, K. D., ... &Dietze, R. Early and
extended early bactericidal activity of levooxacin,
gatioxacin and moxioxacin in pulmonary
tuberculosis. The International Journal of Tuberculosis
and Lung Disease, 2006;10(6), 605-612.
5. Si, Z., Wang, L., Hu, J., & Jiang, W. Enhanced
luminescence of terbium - 1 - cyclopropyl - 6
uoro-1, 4-dihydro - 4 - oxo - 7 - (1- piperazinyl)- 3
-quinolinecarboxylic acid with lanthanum and its
application. Microchemical journal, 2001;70(1), 19-24.
6. Hossen, S. M., Islam, M. S., Masumder, K. U., Hossain,
M. S., Chowdhury, A., Deb, A. K., &Shobuj, S. M. In-
vitro interactions of Ciprooxacin Hydrochloride
with different essential mineral salts and its inuence
on antimicrobial activity (MIC) of Ciprooxacin
Hydrochloride. International Journal of Pharmaceutical
and Life Sciences, 2012;1(3).
7. Jiménez-Garrido, N., Perello, L., Ortiz, R., Alzuet,
G., Gonzalez-Alvarez, M., Canton, E., ...& Perez-
Priede, M. Antibacterial studies, DNA oxidative
cleavage, and crystal structures of Cu (II) and Co
(II) complexes with two quinolone family members,
ciprooxacin and enoxacin. Journal of inorganic
biochemistry, 2005;99(3), 677-689.
8. Lister, P. D., & Sanders, C. C. Pharmacodynamics
of trovaoxacin, ooxacin, and ciprooxacin
against Streptococcus pneumoniae in an in vitro
pharmacokinetic model. Antimicrobial agents and
chemotherapy, 1999;43(5), 1118-1123.
9. Alan, C., Koçoglu, H., Ersay, A. R., Ertung, Y., &
Kurt, H. A. Unexpected severe hepatotoxicity of
ciprooxacine: two case reports. Drug and chemical
toxicology, 2011;34(2), 189-191.
10. Rodvold, K. A., &Piscitelli, S. C. New oral macrolide
and uoroquinolone antibiotics: an overview of
pharmacokinetics, interactions, and safety. Clinical
infectious diseases, 1993; 17(Supplement 1),
S192-S199.
11. Wallace, R. J., Brown, B. A., &Onyi, G. O. Skin, soft
tissue, and bone infections due to Mycobacterium
chelonaechelonae: importance of prior corticosteroid
therapy, frequency of disseminated infections,
and resistance to oral antimicrobials other than
clarithromycin. Journal of Infectious Diseases,
1992;166(2), 405-412.
12. Yalvac, I. S., Basci, N. E., Bozkurt, A., &Duman, S.
Penetration of topically applied ciprooxacin and
ooxacin into the aqueous humor and vitreous. Journal
of Cataract & Refractive Surgery, 2003;29(3), 487-491.
13. Navalón, A., Ballesteros, O., Blanc, R., &Vılchez,
J. L. Determination of ciprooxacin in human
urine and serum samples by solid-phase
spectrouorimetry. Talanta, 2000;52(5), 845-852.
14. Granfors, M. T., Backman, J. T., Neuvonen, M., &
Neuvonen, P. J. Ciprooxacin greatly increases
concentrations and cypotensive effect of tizanidine
by inhibiting its cytochrome P450 1A2–mediated
presystemic metabolism*. Clinical Pharmacology &
Therapeutics, 2004;76(6), 598-606.
15. Schaeffer, A. J. The expanding role of uoroquinolones.
The American journal of medicine, 2002;113(1), 45-54.
16. Matera, M. G. Pharmacologic characteristics
of prulioxacin. Pulmonary pharmacology &
therapeutics, 2006;19, 20-29.
17. Zhang, L., Reynolds, K. S., Zhao, P., & Huang, S. M.
4

Professional Med J 2015;22(1): 001-005 www.theprofessional.com
CIPROFLOXACIN
5
Drug interactions evaluation: an integrated part of
risk assessment of therapeutics. Toxicology and
applied pharmacology, 2010;243(2), 134-145.
18. Hawkey, P. M. Mechanisms of quinolone action
and microbial response. Journal of Antimicrobial
Chemotherapy, 2003;51(suppl 1), 29-35.
19. Paterson, D. L., Mulazimoglu, L., Casellas, J. M., Ko,
W. C., Goossens, H., Von Gottberg, A., ... & Victor, L.
Y. Epidemiology of ciprooxacin resistance and its
relationship to extended-spectrum β-lactamase
production in Klebsiellapneumoniae isolates causing
bacteremia. Clinical infectious diseases, 2000;30(3),
473-478.
20. Kümmerer, K. Antibiotics in the aquatic environment–a
review–part I. Chemosphere, 2009;75(4), 417-434.
21. Ruiz, J. Mechanisms of resistance to quinolones:
target alterations, decreased accumulation and
DNA gyrase protection. Journal of Antimicrobial
Chemotherapy, 2003;51(5), 1109-1117.
22. Schaeffer, A. J. The expanding role of
uoroquinolones. The American journal of
medicine, 2002;113(1), 45-54.
23. Halling-Sørensen, B., Lützhøft, H. C. H., Andersen, H.
R., &Ingerslev, F. Environmental risk assessment of
antibiotics: comparison of mecillinam, trimethoprim
and ciprooxacin. Journal of antimicrobial
chemotherapy, 2000;46(suppl 1), 53-58.
24. Petrilli, A. S., Dantas, L. S., Campos, M. C., Tanaka,
C., Ginani, V. C., &Seber, A. Oral ciprooxacin vs.
intravenous ceftriaxone administered in an outpatient
setting for fever and neutropenia in low‐risk pediatric
oncology patients: Randomized prospective
trial. Medical and pediatric oncology, 2000;34(2), 87-91.
25. Arslan, H., Azap, Ö. K., Ergönül, Ö.,&Timurkaynak,
F. Risk factors for ciprooxacin resistance among
Escherichia coli strains isolated from community-
acquired urinary tract infections in Turkey. Journal of
Antimicrobial Chemotherapy, 2005;56(5), 914-918.
26. Graffunder, E. M., &Venezia, R. A. Risk factors
associated with nosocomial methicillin-resistant
Staphylococcus aureus (MRSA) infection including
previous use of antimicrobials. Journal of Antimicrobial
Chemotherapy,2002;49(6), 999-1005.
27. Heystek, M., & Ross, J. D. C. A randomized
double-blind comparison of moxioxacin and
doxycycline/metronidazole/ciprooxacin in
the treatment of acute, uncomplicated pelvic
inammatory disease. International journal of STD &
AIDS, 2009;20(10), 690-695.
28. Mishra, S. K., &Agrawal, D. A Concise Manual of
Pathogenic Microbiology. John Wiley & Sons 2012.
29. Nili, H., &Asasi, K. Natural cases and an experimental
study of H9N2 avian inuenza in commercial broiler
chickens of Iran. Avian Pathology, 2002;31(3), 247-252.
30. Kariyawasam, S., Wilkie, B. N., & Gyles, C. L. Resistance
of broiler chickens to Escherichia coli respiratory
tract infection induced by passively transferred egg-
yolk antibodies. Veterinary microbiology, 2004;98(3),
273-284.
31. Posyniak, A., Zmudzki, J., & Niedzielska, J. Liquid
chromatography analysis of enrooxacin and
ciprooxacin in chicken blood spotted on lter-paper
disks. Journal of Chromatography B, 2002;780(2), 309-
314.
32. Posyniak, A., Zmudzki, J., &Niedzielska, J. Liquid
chromatography analysis of enrooxacin and
ciprooxacin in chicken blood spotted on lter-paper
disks. Journal of Chromatography B, 2002;780(2), 309-
314.
33. Qiao, F., & Sun, H. Simultaneous extraction of
enrooxacin and ciprooxacin from chicken tissue
by molecularly imprinted matrix solid-phase
dispersion. Journal of pharmaceutical and biomedical
analysis, 2010;53(3), 795-798.
34. Humphrey, T. J., Jørgensen, F., Frost, J. A., Wadda,
H., Domingue, G., Elviss, N. C., ...&Piddock, L.
J. Prevalence and subtypes of ciprooxacin-
resistant Campylobacter spp. in commercial
poultry ocks before, during, and after treatment
with uoroquinolones. Antimicrobial agents and
chemotherapy,2005;49(2), 690-698.
35. Farnell, M. B., Donoghue, A. M., Cole, K., ReyesHerrera,
I., Blore, P. J., & Donoghue, D. J. Campylobacter
susceptibility to ciprooxacin and corresponding
uoroquinolone concentrations within the
gastrointestinal tracts of chickens*. Journal of applied
microbiology, 2005;99(5), 1043-1050.
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