Selection and formulation of antibiotics mixed in fortified eye drops for the treatment of bacterial keratitis

D. Goulley1 , D. Hocquet2, C. Fagnoni-Legat1, Y. Pellequer 3
1 Pharmaceutical department, 3 boulevard A. Flemming, University Hospital Besançon
2 Bacteriological department, 3 boulevard A. Flemming, University Hospital Besançon
3 PEPITE EA4267, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
Contact : damien.goulley@hotmail.fr

Aims
Bacterial Keratitis (BK) are corneal infections that can lead to blindness. This pathology affects almost 500 000 cases per year around the world (1). To treat BK, Ceftazidim (C), Gentamicin (G) and Vancomycin (V) Fortified Antibiotic Eye-drops (FAEs) are prepared by hospital pharmacy. FAEs increase drug concentration in infection site comparatively to commercial eye-drops. Linked to the difficulty of drug administration plan and to medication adherence, the main aim of this work is to mix C, G and V to reduce number of administrations considering that C and V in solution form pH linked precipitate (2). In a second time, polymers solutions like artificial tears (AT) will be used to increase residence time of FAEs.

Materials and methods
FAEs were prepared with pharmaceutical specialities for intravenous administration ± AT. C-G-V precipitate identification was conducted by H-NMR. Physical stability of FAEs: pH, osmolarity, visual aspect were tested during 14 days as well as antibacterial activity on 3 bacterial strains which are sensitive to one antibiotic per strain.

Results
C-G-V FAEs precipitate was formed instantaneously and was composed of C and V. Afteracidification (pH < 3), no precipitate was formed contrary to alkalinization (8 < pH ≤ 9) where precipitate was delayed at day 1 for mixed C-V ± AT and at day 3 for C-G-V ± AT FAEs respectively. Antibacterial activities evaluation indicated that inhibition diameters were different from C, G and V references at day 4 for C-V-NaOH ± AT and immediately for C-G-V-NaOH ± AT.

Discussion and conclusion
pH adjustment < 3 is not compatible with ocular administration (pH < 3.5) contrary to FAEs with pH ≤ 9. Precipitate was formed at day 1 and 3 in mixed C-V-NaOH and C-G-V- NaOH ± AT respectively and did not permit to use them. However, mixed C-G and G-V could be good FAEs candidates to be mixed for clinical use due to pH, osmolarity values and antibacterial activities which are maintained over time. Their stabilities must be investigated in deeper by chromatographic method, tolerance and penetrating tests with in vitro models must be performed.

1 Chiquet C et al. Prescrire les collyres fortifiés. J Fr Ophtalmol. 2007;30(4):423–30
2 Fiscella RG. Physical Incompatibility of Vancomycin and Ceftazidime for Intravitreal Injection. Arch Ophthalmol. 1993;111(6):730

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