Future Considerations Although ceftaroline has limited activity against resistant Gram-negative pathogens, time–kill experiments suggest PX-478 molecular weight extended coverage against resistant Enterobacteriaceae when combined with a β-lactamase inhibitor [76]. In vitro and GSK3326595 nmr Animal studies demonstrated that avibactam, a non-β-lactam β-lactamase inhibitor, has potent synergistic
activity with ceftaroline [29, 77–80]. Avibactam appears to inhibit ESBLs, including cephalosporinases and carbapenemases, and so may potentially enhance ceftaroline’s spectrum of activity against Gram-negative bacteria. The development of a combination that offers such broad coverage is an exciting option for single-agent treatment of empiric or polymicrobial infections caused by multidrug-resistant Enterobacteriaceae and MRSA [81]. selleck compound Ceftobiprole, another new generation cephalosporin approved for use in some countries for the treatment
of complicated skin and soft tissue infections (however, rejected by the FDA in 2009 and the European Medicines Agency in 2010) has extended Gram-positive activity similar to that of ceftaroline, and Gram-negative coverage similar to that of ceftazidime, but unlike ceftaroline–avibactam, ceftobiprole remains susceptible to hydrolysis by several ESBLs [82, 83]. Ceftaroline–avibactam was well tolerated in a phase 1 trial without demonstrating significant PK
interaction when administered concomitantly [84]. A phase 2 trial selleck inhibitor for the treatment of complicated urinary tract infections (NCT01281462) has been completed. Animal models have been established to evaluate the in vivo efficacy of ceftaroline in the treatment of endocarditis, osteomyelitis and meningitis [8, 9, 24, 85, 86]. Following a 4-day course of ceftaroline fosamil in a rabbit endocarditis model, ceftaroline demonstrated superior bactericidal activity against MRSA and heterogeneous VISA when compared to vancomycin and linezolid [9]. Similarly, ceftaroline fosamil demonstrated significant bactericidal activity against MRSA and VISA, with a greater than 5 log10 colony-forming unit/g reduction of vegetation, which was comparable to that of daptomycin and superior to that of tigecycline [24]. When compared to vancomycin and linezolid, ceftaroline demonstrated improved bacterial killing of vancomycin-sensitive and vancomycin-resistant E. faecalis in both time–kill experiments and a rabbit endocarditis model [8].