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We used the transcutaneous route to perform trepanning with a biopsy needle followed by injection of a suspension of S. [31] who developed an experimental model of acute osteomyelitis in rabbits and had a high bacterial load in the bone marrow, allowing the infection to persist for at least 14 days. After inoculation of the animals, the bacterial loads reached range from 10 7 to 10 8 CFU/g in bone marrow. This confirms that this experimental model is useful to evaluate the in vivo activity of antibacterial agents in bone infection. For the treatment pathways of animals, we chose the intramuscular route rather than intravenous route. Our choice can be explained by the fact that intravenous drug administration in rabbits is extremely challenging due to the lack of available veins, and it is not possible to maintain an intravenous catheter for a long time in a vigilant rabbit. Moreover, intramuscular administration of antibiotics can result in peak serum concentrations within minutes at levels comparable to those observed after intravenous injections [52]. During the experiment, we monitored not only the bacterial load in the bone marrow but also body temperature and body weight. The results obtained showed that after inoculation, there is an increase in temperature and a loss of weight for the infected rabbits. Weight loss can be caused by a lack of appetite resulting from stress during the establishment of the model. However, the treatment of rabbits, especially with AMC associated with 1,8-cineole, is followed by a return of body temperature to its normal value and a weight similar to that of uninfected animals by the end of the 14th day. These results showed that these parameters could be useful for monitoring osteomyelitis. In the development of an MRSA animal model of osteomyelitis, Helbig et al. [54] monitored infection by measuring body temperature and body weight in combination with other parameters. After four days of treatment, the bacterial loads in bone marrow showed that AMC in combination with either 1,8-cineole or gentamicin had the same efficacy with a percentage reduction of 99.99% and 99.98%, respectively, by the end of the experiment. This efficiency is significantly superior to that obtained with the AMC alone (99.81% of reduction) or gentamicin alone (99.49% of reduction). The treatment with 1,8-cineole alone showed the lowest percentage of reduction (89.91%). [45] have reported that among the possible strategies for treating S. aureus -related diseases, the simultaneous administration of at least two antibiotics is often used. This simultaneous use of antibiotics is effective in extending their spectrum. However, it leads to the emergence of several multiresistant strains [55, 56], especially in hospitals where there is a great amount of pressure to select resistant strains by commonly used antibiotics [57]. Hence, there is an interest in substituting one of the two antibiotics by a natural antimicrobial agent such as 1,8-cineole. This substitution can lead to a reduction of the minimum effective dose of drugs, thus minimizing their possible toxic side effects and combating the resistance phenomenon with a lower treatment cost [58]. In this study, the enhancement of the activity of AMC was observed when it is associated with 1,8-cineole. Remmal and Akhmouch reported that cineole makes it possible to increase the efficacy of amoxicillin [28]. Specifically, they have demonstrated that the combination of amoxicillin and cineole makes it possible to obtain a synergistic effect which considerably reinforces the antibacterial activity of amoxicillin. Remmal and Akhmouch explained this by the fact that, in the presence of 1,8-cineole, stable amoxicillin complexes comprising at least three amoxicillin molecules form and protect the antibiotic against the action of ? -lactamases in resistant bacteria. Additionally, 1,8-cineole has the capacity to destabilize the cell membrane or to affect cell respiration [49]. Therefore, its association with antibiotics can simultaneously act on different target sites, therefore, improving the observed results when compared to the antibiotic effect alone. To our knowledge, this is the first in-depth study of the combination of AMC and gentamicin antibiotics with 1,8-cineole against S. Our results show that boosting the antimicrobial effect of antibiotics using 1,8-cineole appears to be a promising approach to investigate new pathways in the development of new antimicrobial drugs. The data amoxicillin for conjunctivitis used to support the findings of this study are available from the corresponding author upon request. The authors declare that they have no conflicts of interest. This work is a partial fulfillment of Soukayna Hriouech’s Ph.D. thesis; it was supported by a grant from the University Sidi Mohamed Ben Abdallah for the Laboratory of Biotechnology. Helene Mock for their assistance in checking the English of the manuscript. Bettencourt, “Osteomyelitis: an overview of antimicrobial therapy,” Brazilian Journal of Pharmaceutical Sciences , vol. Karmazyn, “Osteomyelitis of the ribs in children: a rare and potentially challenging diagnosis,” Pediatric Radiology , vol. Paakkonen, “Acute osteomyelitis in children,” New England Journal of Medicine , vol. El hamdi, Le Profil Epidemiologique des Infections Osteo-Articulaires Chez l’enfant (A Propos de 264 Cas) , Universite Sidi Mohammed Ben Abdellah, Faculte de medecine et de pharmacie, Fes, Morocco, 2016. Salcido, “Osteomyelitis,” Advances in Skin & Wound Care , vol. Fowler, “ Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management,” Clinical Microbiology Reviews , vol. Mortazavi, “A comparative study on the effects of vancomycin, enrofloxacin, and trimethoprim/sulfamethoxazole on methicillin-resistant Staphylococcus aureus osteomyelitis in an animal model,” Comparative Clinical Pathology , vol. Albrecht et al., “Vancomycin-resistant Staphylococcus aureus - Delaware, 2015,” MMWR. Remmal, “Oregano and clove essential oils induce surface alteration of Saccharomyces mixing amoxicillin with tamiflu cerevisiae,” Phytotherapy Research , vol. Remmal, “Evaluation of carvacrol and eugenol as prophylaxis and treatment of vaginal candidiasis in an immunosuppressed rat model,” Journal of Antimicrobial Chemotherapy , vol. Chami, “In vitro destruction of Eimeria oocysts by essential oils,” Veterinary Parasitology , vol. Remmal, “The mechanism of bactericidal action of oregano and clove essential oils and of their phenolic major components on Escherichia coli and Bacillus subtilis ,” Journal of Essential Oil Research , vol. Essential oil and its majority compound 1,8-cineole at sublethal amounts induce No direct and cross protection in Staphylococcus aureus ATCC 6538,” Foodborne Pathogens and amoxicillin for dental abscess Disease , vol. Yamaoka et al., “Antimicrobial activity of essential oils against Helicobacter pylori ,” Helicobacter , vol. Kowalczyk et al., “The ability of selected plant essential oils to enhance the action of recommended antibiotics against pathogenic wound bacteria,” Burns , vol. Juergens, “New perspectives for mucolytic, anti-inflammatory and adjunctive therapy with 1, 8-cineole in COPD and asthma: review on the new therapeutic approach,” Advances in Therapy , vol. Komiya, “Specific induction of apoptosis by 1, 8-cineole in two human leukemia cell lines, but not a in human stomach cancer cell line,” Oncology Reports , vol. Falconer et al., “Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy,” Nature Chemical Biology , vol. Burt, “Synergy between essential oil components and antibiotics: a review,” Critical buy amoxicillin online without a prescription Reviews in Microbiology , vol. Silva, “Antibacterial activity of plant extracts and phytochemicals on antibiotic-resistant bacteria,” Brazilian Journal of Microbiology , vol. Tantaoui-Elaraki, “Improved method for the determination of antimicrobial activity of essential oils in agar medium,” Journal of Essential Oil Research , vol. View at: Publisher Site | Google Scholar Clinical and Laboratory Standards Institute, Performance Standards for Antimicrobial Susceptibility Testing; buy amoxicillin for human online Twentieth Informational Supplement. M100 , Clinical and Laboratory Standards Institute, Wayne, PA, USA, 2019. Timinouni et al., “Staphylococcus aureus nasal carriage in a Moroccan dialysis center and isolates characterization,” Hemodialysis International , vol. Lakusic, “Antioxidant and antimicrobial activity of different extracts from leaves and roots of Jovibarba heuffelii (Schott.) A. Weinstein, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. M100 , Clinical and Laboratory Standards Institute, Wayne, PA, USA, 2018. Wink, “Synergistic properties of the terpenoids aromadendrene and 1,8-cineole from the essential oil of Eucalyptus globulus against antibiotic-susceptible and antibiotic-resistant pathogens,” Phytomedicine , vol. Abrini, “Study of synergy between Mentha pulegium essential oil, honey and bacteriocin-like inhibitory substance E204 against Listeria monocytogenes CECT 4032 and Escherichia coli K12,” International Journal of Current Research in Biosciences and Plant Biology , vol. Akhmouch, “Pharmaceutical formulation comprising cineole and amoxicillin,” 2019, U.S. Olukowade, “Effect of amoxycillin/clavulanic acid (Augmentin 625®) on antioxidant indices and markers of renal and hepatic damage in rats,” Journal of Toxicology. Elsharawy et al., “Optimizing gentamicin dosing in pediatrics using Monte Carlo simulations,” The Pediatric Infectious Disease Journal , vol. Hamel et al., “A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit,” Letters in Applied Microbiology , vol. Le Mabecque et al., “ In vivo assessment of the antimicrobial activity of a calcium-deficient apatite vancomycin drug delivery system in a methicillin-resistant Staphylococcus aureus rabbit osteomyelitis experimental model,” Antimicrobial Agents and Chemotherapy , vol. Jacqueline et al., “Intermittent active motion versus immobilization in the treatment of Staphylococcus aureus -induced arthritis in a rabbit model,” Journal of Children’s Orthopaedics , vol. Wang, “Osteomyelitis: recent advances in pathophysiology and therapeutic strategies,” Journal of Orthopaedics , vol. Robineau, “Treatment options for diabetic foot osteomyelitis,” Expert Opinion on Pharmacotherapy , vol. Moreillon, “ In vitro prevention of the emergence of daptomycin resistance in Staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin,” International Journal of Antimicrobial Agents , vol. Goldstein, Bactericidie: Aspects Theoriques et Therapeutiques , Maloine, Paris, France, 1990. European Committee on Antimicrobial Susceptibility Testing, Breakpoint Tables for Interpretation of MICs and Zone Diameters , European Committee on Antimicrobial Susceptibility Testing, Vaxjo, Sweden, 2018. Barry, “Antistaphylococcal activity of amoxicillin and ticarcillin when combined with clavulanic acid evaluation of oxacillin-resistant and oxacillin-susceptible isolates,” Diagnostic Microbiology and Infectious Disease , vol. Kali, “Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus : a brief review,” Pharmacognosy Reviews , vol. Johler, “ Staphylococcus aureus related to bovine mastitis in Switzerland: clonal diversity, virulence gene profiles, and antimicrobial resistance of isolates collected throughout 2017,” Journal of Dairy Science , vol.
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