Churchward, Colin Peter (2016) Fatty acids and monoglycerides as novel prophylaxis against gonococcal ophthalmia neonatorum. (PhD thesis), Kingston University, .
Abstract
Neonates born to mothers with an active gonorrhoea infection can develop serious sight threatening eye infections. The causative agent, Neisseria gonorrhoeae, is passed to the neonate during birth, and infects the eyes of the neonate. The condition, ophthalmia neonatorum, develops 0-14 days after birth and initially presents as a painful inflammation of the eye with yellowish purulent discharge from one or both eyes. One preventative action used by some countries is the use of an ophthalmic prophylaxis which is usually an ophthalmic ointment which contains an antibiotic. This its self can cause chemical conjunctivitis. This study evaluates the potential to use a fatty acid or fatty acid derivative as the active antimicrobial agent in an ophthalmic prophylaxis. A panel of thirty-seven initial candidates were screened for anti-gonococcal properties. Seven of this panel were selected and tested against for ocular irritation potential using in vitro models and anti-gonococcal properties tested further in simulated tear fluid. Finally a single candidate, monocaprin, was selected as the main drug candidate. Ophthalmic formulations of liquid and semi-solid dosage forms were made and evaluated. Liquid dosage forms performed the best in in vitro tested and were further evaluated in cell culture and explanted models. The cell culture model suggested that monocaprin could be used to prevent infection 90 minutes after the cell were inoculated with the bacteria. An explanted corneal infection model was used to assess the potential formulations. It was shown that the anti-gonococcal properties of the drug candidate were inhibited on the ocular surface but this this could be countered by increasing the amount of monocaprin in the formulation. The formulations containing 0.188 % and 0.25 % (w/w) monocaprin were in some cases able to totally clear inoculations of higher cell numbers on the surface of the eye. Passage on agar plates containing monocaprin showed that increasing resistance due to genomic mutation is not likely and that existing mechanisms of fatty acid resistance did not give cross-resistance to monocaprin. However, duplicate samples passaged on monocaprin both acquired identical mutations in the dksA gene which may confer a small decrease in susceptibility. Also, work done on the processing of natural sources of fatty acids showed that treatment of coconut oil by use of a purified lipase or a lipase secreting yeast produced powerful anti-gonococcal substances. This could has the potential to be used in developing nations treat gonococcal and other bacterial infection. Overall, the work in thesis demonstrates that there is potential in the use a fatty acid or fatty acid derivative, most likely monocaprin, to be used as the active antimicrobial agent in an ophthalmic prophylaxis but more evaluation in terms of in vivo testing is required to demonstrate that the higher levels of monocaprin do not cause irritation to the eye.
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