Aqueous and Vitreous Penetration of Oral Cefixime and ...

Eye Penetrance to Oral Cefixime & Cipro ? Attarzadeh et al Iranian Journal of Ophthalmology ? Volume 20 ? Number 3 ? 2008

Aqueous and Vitreous Penetration of Oral Cefixime and

Ciprofloxacin in Rabbit Eye

Abbas Attarzadeh, MD1 ? Mohsen Afroozifar, MD2 ? Nader Tanideh, MD3 Jamshid Kohanteb4 ? Vahid Ghasemifar, MD5 ? Asadollah Katbab, MD5

Abstract

Purpose: To investigate the penetration of cefixime and ciprofloxacin to the rabbit eye on the basis of microbial inhibition of aqueous and vitreous humour after oral administration. Methods: In this experimental study, 36 rabbits (72 eyes) were randomly divided into two groups; group A consisted of 20 rabbits and group B 16 rabbits. Each group was divided into four equal subgroups. The rabbits in each subgroup of group A received 4, 8, 12, and 20 mg/kg of syrup of cefixime every 12 hr respectively and the rabbits in each subgroup of group B received 20, 40, 60, and 80 mg/kg tablet of ciprofloxacin respectively every 12 hr. Immediately after the first dose of the drugs, the anterior chamber of one eye was irrigated randomly by 30-40 cc of ringer lactate solution alongside with mild traumatization of iris. Then by 4, 8, 12, 24 and 72 hr intervals after the 3rd dose, 0.1 cc of aqueous, 0.2-0.5 cc of vitreous, 3 cc of blood and one standard disk of the used antibiotic was placed on culture media of a known bacteria which was completely sensitive to the respective antibiotic. Forty eight hours later, the microbial inhibition zone of each sample and the standard disk of antibiotic were compared. Results: No microbial inhibition was seen by sample of aqueous and vitreous, although very large zone of inhibition was seen by blood sample and standard disk of antibiotic. Conclusion: It seems that oral cefixime and ciprofloxacin do not produce an effective dose for microbial inhibition in rabbit eye.

Keywords: Rabbit, Cefixime, Ciprofloxacin, Aqueous, Vitreous

Iranian Journal of Ophthalmology 2008;20(3):15-18

1. Professor of Ophthalmology, Poostchi Ophthalmology Research Center, Khalili Hospital, Shiraz University of Medical Sciences

2. Ophthalmologist, Poostchi Ophthalmology Research Center, Khalili Hospital, Shiraz University of Medical Sciences

3. Resident in Veterinary Surgery, Instructor of Pharmacology Department, Shiraz University of Medical Sciences

4. Assistant Professor of Microbiology, Microbiology Department, Shiraz University of Medical Sciences

5. Associate Professor of Ophthalmology, Poostchi Ophthalmology Research Center, Khalili Hospital, Shiraz University of Medical Sciences

Received: December 23, 2005 Accepted: August 17, 2006

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Correspondence to: Abbas Attarzadeh, MD Poostchi Ophthalmology

Research Center Khalili Hospital, Shiraz

Tel:+98 711 2302830 Email: attarza@

Eye Penetrance to Oral Cefixime & Cipro ? Attarzadeh et al Iranian Journal of Ophthalmology ? Volume 20 ? Number 3 ? 2008

Introduction

Endophthalmitis is a serious and dangerous complication of penetrating eye trauma or ophthalmic interventions. The most common bacteria responsible for endophthalmitis are Staph epidermidis, Bacillus cereous, Strep pneumonia and Staph aureus.1-3 Broad spectrum antibiotics injected intravitreally are most commonly used for the treatment of endophthalmitis, but intravenous antibiotics are introduced as a preventing measure for intraocular infection after penetrating trauma of the eye.4-6 On the other hand medications such as fluoroquinolones (ciprofloxacin) are used as additive agents after intravitreal injections or sometimes for prophylaxis alone.7 This study tries to find out oral medications which will have a good penetration into the vitreous and aqueous without any age restriction as is concerned with fluoroquiolones. This study was done in the animal lab and microbiology ward of Shiraz University of Medical Sciences.

Methods

In this double blind study 36 rabbits (albino Dutch type) weighting between 2-2.5 kg, aged between 10-12 month, which were kept with available water and food ad libitum with photoperiod of 12 hrs, were divided into two groups.

Group A consisted of 20 rabbits, which were divided into four smaller subgroups. Each subgroup consisted of five rabbits that received 4, 8, 12, and 20 mg/kg cefixime syrup (Padtan-Teb Co., Iran) respectively every 12 hrs through gavage tube. Immediately after the first dose the rabbits were anesthetized in sterile condition in operating room by injecting ketamine 44 mg/kg and xylazine 8 mg/kg intramuscularly. One of the eyes were selected randomly and was cleaned by 10% povidone iodine and after placing the lid speculum the eye was rinsed by ringer lactate solution. Using operation microscope we approached the anterior chamber (with knife no. 15?) from the limbus and irrigated the anterior chamber with 30-50 cc ringer lactate solution. At the same time we scratched the surface of the iris (with

needle) to cause bleeding and disruption of the blood-ocular barriers. The second and third doses of cefixime were given 12 hrs apart after the operation. Four hrs after the third dose (28 hrs after the first dose) again with the same condition and under general anesthesia, and with the aid of an operating microscope, 0.1 cc of aqueous and 0.2-0.5 cc of vitreous were withdrawn separately from both eyes of each rabbit (both the operated and untouched eye). At the same time 3 cc blood was withdrawn from the rabbits and all the samples were carried out to the microbial culture media, on which proteus vulgaris was cultured. The culture media was blood agar and the proteus was proven to be sensitive to cefixime and ciprofloxacin. We had 4 discs. The first disc was smeary with 0.1 cc aqueous, the second disc was smeary with 0.2 cc of vitreous, the third disc was smeary with plasma and the forth disc was standard disc on antibiotic which have had 5 micrograms of the considered antibiotic (discs were made of whatman paper No 1 with a diameter of 6 mm). After 48 hrs samples were compared according to the zone of microbial inhibition. Then in 4, 12, 24 and 72 hrs intervals after the first sampling, it was repeated again in the same manner and 48 hrs after each sampling, the samples were checked for inhibition zone on microbial media and were compared with the standard disc.

Group B consisted of 16 rabbits that were divided into 4 equal subgroups. To each group 20, 40, 60 and 80 mg of ciprofloxacin (dissolved tablets in water) were given respectively through the gavage tube every 12 hrs. Immediately after the first dose, anterior chamber irrigation of one eye of each rabbit was done to disturb the blood-ocular barrier. After 4, 12, 24 and 72 hrs following the first dose, blood and ocular samples in the same manner as mentioned above were obtained and the results of inhibition zones were compared with each other. It is important to note that in the last step of sampling of 24 and 72 hrs (specially from the vitreous samples) more than 0.5 cc of vitreous and 0.2 cc of aqueous were withdrawn and put on the culture media.

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Eye Penetrance to Oral Cefixime & Cipro ? Attarzadeh et al Iranian Journal of Ophthalmology ? Volume 20 ? Number 3 ? 2008

Results

In all culture media after 48 hrs, large inhibition zone (25-27 mm) was recorded with blood samples and in 70% of cases the inhibition zone was greater than the inhibition zone of standard disc of antibiotics. But in all of the samples drawn from the vitreous and aqueous, for both eyes, which underwent irrigation of anterior chamber, and the intact eyes, no inhibition zone was detected even after higher doses than normal (Figure 1).

Figure 1. Culture media after 48 hrs. No inhibition zones are seen around aqueous vitreous disc.

Discussion

In this study the penetration of oral cefixime and ciprofloxacin into rabbit eye and the influence of the disturbance of blood-ocular barrier on penetration of these medications into rabbit eye was investigated by measuring the inhibition zone produced by the samples of aqueous and vitreous of the rabbit eyes after the medications were given to the rabbits. In fact we wanted to know how effective the ciprofloxacin and cefixime are in the aqueous and vitreous if they penetrate to the globe (bioactivity).

In one study which was done by Ozt?rk et al8 , after producing inflammation in the eye of 16 rabbits via injecting Staphylococcus aureus in the rabbit eye, the rabbits were divided into two groups. To one group topical ciprofloxacin one drop q4h was given, and to the other group oral ciprofloxacin 40 mg/kg q12h with topical ciprofloxacin q4h was given and 1.5 hr after the third dose of oral ciprofloxacin, the drug concentration in the

aqueous and vitreous was measured. The result showed that the inflammation increased the drug penetration into the eye. They also proved that the oral form combined with the topical form of drug produced higher concentration in the vitreous than the topical form alone.

In another study preformed by Ozt?rk et al9, the effective inflammation and also the effect of long time use of topical ciprofloxacin was studied in the rabbit eye. They concluded that both the inflammation and the long term use of the drug in the topical form caused the increased concentration of the drug in the rabbit eye.

In other study performed by Cekic et al,10 oral and topical ciprofloxacin was given to one group of patients and topical ciprofloxacin alone to the other group of patients before vitrectomy operation and measured drug concentration in the vitreous and aqueous. The study showed that concentration of ciprofloxacin was higher in the first group rather than topical ciprofloxacin alone.

In another study performed by Madu et al11, after the use of intravenous ciprofloxacin in 14 rabbits it was found that the concentration of this drug in the vitreous after the systemic use was much lower than the needed concentration for inhibition of most Staph epidermidis (which are the most common cause of postoperative endophthalmitis). The noticeable point is that in the mentioned studies only the concentration of the drug was measured directly in the vitreous and aqueous but in our study the ability of microbial inhibition of aqueous and vitreous (bioactivity) was measured after oral usage of these drugs. However, although good microbial inhibition was seen by the standard antibiotic discs and blood sample, no inhibition was seen by the vitreous and aqueous samples.

Conclusion

It seems that the use of cefixime and ciprofloxacin alone in the oral form would not cause an effective concentration in the aqueous and vitreous of the rabbit eye.

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Eye Penetrance to Oral Cefixime & Cipro ? Attarzadeh et al Iranian Journal of Ophthalmology ? Volume 20 ? Number 3 ? 2008

References

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2. Rao NA, Cousing S, Forster D. Intraocular inflammation and uveitis. In: Basic and Clinical Science Course. American Academy of Ophthalmology 2003;197-210.

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4. Meredith TA. Posttraumatic endophthalmitis. Arch Ophthalmol 1999;117(4):520-1. 5. Forster RK. Endophthalmitis. In: Tasman W, Jaeger EA, eds. Duane's Clinical Ophthalmology.

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aqueous and vitreous humor in inflamed eyes. Retina 1999;19(3):218-22. 9. Ozt?rk F, Kurt E, Inan UU, et al. The effects of prolonged acute use and inflammation on the

ocular penetration of topical ciprofloxacin. Int J Pharm 2000;204(1-2):97-100. 10. Ceki? O, Batman C, Yasar U, et al. Human aqueous and vitreous humour levels of

ciprofloxacin following oral and topical administration. Eye 1999;13 (Pt 4):555-8. 11. Madu AA, Mayers M, Perkins R, et al. Aqueous and vitreous penetration of ciprofloxacin

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