Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

Abstract

The therapeutic activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was compared to that of vancomycin in a rat tissue cage model of chronic methicillin-resistant Staphylococcus aureus (MRSA) foreign-body infection. The MICs and MBCs of ceftobiprole and vancomycin in Mueller-Hinton broth for strain MRGR3 were 1 and 4 and 1 and 2 g/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 g/ml of ceftobiprole or vancomycin were equivalent. After 2 weeks of infection, mean ؎ standard error of the mean viable counts of strain MRGR3 were 6.83 ؎ 0.11 log CFU/ml of tissue cage fluid (n ‫؍‬ 87). High-dose regimens of ceftobiprole medocaril (equivalent to 150 mg/kg of ceftobiprole) or 50 mg/kg vancomycin produced nearly identical average peak and trough levels of ceftobiprole and vancomycin in tissue cage fluid, which exceeded the MBC of either antibiotic towards strain MRGR3 for >75% of each dosing interval. After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly (P < 0.02) by 0.68 ؎ 0.28 (n ‫؍‬ 29) and 0.88 ؎ 0.22 (n ‫؍‬ 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.Infections due to Staphylococcus aureus associated with foreign implants, such as orthopedic prostheses and permanently inserted catheters, are very difficult to manage by antimicrobial chemotherapy. Semisynthetic penicillins, imipenem, vancomycin, fluoroquinolones, and glycopeptides show limited or no significant efficacy in the clinic or experimental therapy of prosthetic infections, and treatment with these drugs for this indication often result in clinical failures (4, 45). The increasing prevalence of clinical isolates of methicillin-resistant S. aureus (MRSA), which frequently display multidrug resistance against all semisynthetic penicillins, penems, macrolides, aminoglycosides, and fluoroquinolones, is a worldwide problem (8,16,31). Multidrug-resistant S. aureus is of particular concern because of its widespread occurrence, intrinsic virulence, and high adaptability to diverse environments (8, 31). This problem has been compounded recently by the emergence of clinical isolates exhibiting intermediate (19-21, 24, 28, 29, 31, 39, 40, 46) or high (5, 11, 47) levels of resistance to glycopeptides, engendering the risk of virtually untreatable infections. Global dispersal of multidrugresistant staphylococci mandates continual development of novel bactericidal agents able to combat such dangerous pathogens.Recent development of ␤-lactams targeting penicillin-binding protein 2Ј (PBP2Ј), which is chiefly responsible for methicillin resistance in S. aureus, repr...

Efficacies of Ceftobiprole Medocaril and Comparators in a Rabbit Model of Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus

“…␤-lactam antibiotics, on the other hand, are generally considered safe, with an extensive history of use and a low incidence of reported serious adverse effects. The refractoriness of staphylococci to selection for endogenous resistance to ceftobiprole (4,27) suggests that emergence of resistance during a course of therapy with this cephalosporin would be a rare event. The pharmacokinetic and safety profiles of ceftobiprole medocaril (15), plus its broad antibacterial spectrum, including MRSA, suggest that ceftobiprole could become a candidate for parenteral treatment of osteomyelitis.…”

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

“…39 No difference was found between animals treated with ceftobiprole medocaril and those treated with vancomycin in a rat tissue cage model of chronic MRSA foreign-body infection. 40 No differences were found in the microbiological cure among 4 weeks treatment with ceftobiprole medocaril, vancomycin or linezolid in a rabbit model of MRSA tibial osteomyelitis. 41 Ceftobiprole medocaril had comparable activity to that of ampicillin against four strains of E. faecalis (including beta-lactamase producing and vancomycin resistant strains in a mouse peritonitis model).…”

Comparison of Tigecycline and Vancomycin for Treatment of Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus

“…We previously used a rat tissue cage model of S. aureus chronic foreign-body infections for evaluating a number of antimicrobial agents, namely vancomycin (17), teicoplanin (31), imipenem (30), ceftobiprole (37), daptomycin (29,35), and several fluoroquinolones (2,17,36). This study reports the activity of tigecycline compared to that of the reference anti-MRSA agent vancomycin in a tissue cage model of MRSA chronic foreign-body infection.…”

“…The animal protocol used for evaluating the in vivo activities of tigecycline and vancomycin was previously described in detail (17,37) and approved by the Ethics Committee of the Faculty of Medicine, University of Geneva, and the Veterinary Office of the State of Geneva. Three weeks after subcutaneous implantation of four tissue cages per animal in anesthetized Wistar rats (37), tissue cage fluids were checked for sterility (17).…”

“…Three weeks after subcutaneous implantation of four tissue cages per animal in anesthetized Wistar rats (37), tissue cage fluids were checked for sterility (17).…”