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Investigations were carried out to determine the antibiotic resistance patterns of Salmonella spp isolated from clinical and water samples in Akure metropolis. Isolation of Salmonella spp was carried out using standard procedures and isolates were identified by various biochemical tests. Antibiotic sensitivity test was carried out on all the isolates of Salmonella identified against six antibiotics of standard concentrations (gentamycin, amoxicillin, ofloxacillin, tetracycline, ciprofloxacin and pefloxacin) using Kirby-Bauer test. A total of 61 strains of Salmonella from water samples and 79 strains of Salmonella from clinical samples were identified. Furthermore, a total of 20 multiple antibiotic resistant isolates (MDRIs) of Salmonella spp were screened from the water samples while 30 MDRIs of Salmonella spp were screened out from clinical samples respectively. A total of 30 MDRIs of Salmonella spp were identified from clinical samples while 20 MDRIs of Salmonella spp were screened from water samples. High levels of antibiotic resistance were observed in MDRIs of Salmonella spp obtained. The results gave insights into the rising incidence of relapsing salmonellos is caused by MDRIs of Salmonella which was prevalent in the metropolis between July and October 2014 during which this research was conducted. Better antibiotic drug use control policies and public health education are encouraged for environmental health bio saftey of Metropolis.