In vitro activities of ceftobiprole combined with amikacin or levofloxacin against Pseudomonas aeruginosa: evidence of a synergistic effect using time–kill methodology

Kresken, Michael; Körber-Irrgang, Barbara; Läuffer, Jörg; Decker-Burgard, Sabine; Davies, Todd

In vitro activities of ceftobiprole combined with amikacin or levofloxacin against Pseudomonas aeruginosa: evidence of a synergistic effect using time–kill methodology

2011

Kresken, Michael | Körber-Irrgang, Barbara | Läuffer, Jörg | Decker-Burgard, Sabine | Davies, Todd

Ceftobiprole is an investigational intravenous broad-spectrum cephalosporin with in vitro activity against Gram-positive and Gram-negative pathogens, including meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Pseudomonas aeruginosa is a frequent nosocomial pathogen, increasingly associated with complicated skin and skin-structure infections. Combination antimicrobial therapy is recommended as empirical therapy for serious infections where P. aeruginosa is suspected. Therefore, in this study the interaction of ceftobiprole with two other antipseudomonal agents (amikacin and levofloxacin) was investigated. Time–kill studies were performed for each single agent and for the combination of ceftobiprole 4mg/L with either amikacin or levofloxacin at 0.5×, 1× and 2× the minimum inhibitory concentration. Five clinical isolates of P. aeruginosa as well as the P. aeruginosa ATCC 27853 reference strain were tested at initial inocula of 5×10⁵colony-forming units (CFU)/mL (low inoculum) or 5×10⁷CFU/mL (high inoculum). Synergy was defined as a decrease of ≥2log₁₀CFU/mL with the combination compared with the most active single drug at 6h and 24h. At low inoculum with ceftobiprole as a single agent, viable counts were decreased by 1.5–2log₁₀ at 6h. Addition of either amikacin or levofloxacin resulted in synergistic bactericidal activity at 24h. At high inoculum the combination of ceftobiprole with amikacin or levofloxacin demonstrated synergism in one of three and three of five strains, respectively. This study demonstrated that the combination of ceftobiprole at a clinically achievable concentration of 4mg/L with amikacin or levofloxacin exhibited synergistic activity against P. aeruginosa. There was no evidence of antagonism for either combination.

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