The -lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. The in vitro antibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel of Pseudomonas aeruginosa isolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 g/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment.
Pseudomonas aeruginosa is a major opportunistic pathogen frequently involved in hospital-acquired infections that may be resistant to many classes of antimicrobial agents. The expression of the naturally occurring chromosomal AmpC -lactamase, as well as acquired extended-spectrum -lactamases (ESBLs), strongly limits the susceptibility of P. aeruginosa isolates to penicillins, such as piperacillin, and cephalosporins, such as ceftazidime. In addition, most of these enzymes are only poorly inhibited by the -lactamase inhibitors clavulanic acid and tazobactam. Resistance to imipenem is also common and is frequently associated with the loss of functional OprD outer membrane protein and, less frequently, with production of metallo--lactamases or specific carbapenemase class A enzymes, such as GES or KPC variants (3). Infections caused by P. aeruginosa represent a serious therapeutic challenge, with significant morbidity and mortality (8) and high rates of resistance to -lactams, aminoglycosides, and fluoroquinolones. Due to its ability to acquire and coregulate multiple resistance mechanisms, multidrug resistance is relatively common in P. aeruginosa. While carbapenems are considered the treatment of choice for severe P. aeruginosa infections, colistin is currently the only antibacterial agent active in vitro against the most highly resistant strains (6).Avibactam is a novel non--lactam inhibitor of -lactamases that is currently in clinical development with both ceftazidime and ceftaroline. It displays a broad-spectrum inhibitory profile against clinically relevant enzymes belonging to Ambler classes A and C (1, 7). Avibactam has virtually no intrinsic antibacterial activity, but it efficiently protects -lactams from hydrolysis in a variety of class A-and class C-producing strains, including ESBL and KPC producers, as well as AmpC-overexpressing strains, many of which are poorly inhibited by clavulanic acid and tazobactam. Avibactam was shown to restore ceftazidime activity against a series of selected P. aeruginosa strains with identified -lactamases (4). The aim of this study was to evaluate the in vitro antibacterial activity of the combination ceftazidime-avibactam compared with those of ceftazidime, imipenem, aztreonam, and piperacillin, alone or in combination with the commercially available inhibitors clavulanate, sulbactam, and tazobactam, against a panel of unselected, clinically isolated P. aeruginosa strains, in order...