Surveillance of in Vitro Activity of Ceftolozane-tazobactam Against Contemporary Nosocomial Gram-negative Pathogens Isolated in Russia

Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. Among nosocomial infections, the most major threat represent infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative pathogens. The most problematic are the ESKAPE microorganisms, an acronym of the most frequently isolated MDR bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp).

Extended-spectrum β-lactamases (ESBLs) have emerged as a major source of antimicrobial resistance in gram-negative pathogens. Generally encoded by plasmid-borne genes, these enzymes confer resistance to penicillins, cephalosporins, and aztreonam. In addition, their presence in bacteria has been associated with resistance to other classes of nonpenicillin antibiotics, including fluoroquinolones, aminoglycosides, trimethoprim-sulfamethoxazole, and β-lactam/β-lactamase inhibitor combinations. Thus, ESBL-producing organisms often possess a multidrug resistance phenotype. Furthermore ESBL production has been associated with severe adverse clinical and economic outcomes, including increased mortality, increased length of stay, delay in the institution of effective therapy, decreased functional status on discharge, and increased cost of care.

The recent emergence and spread of infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are concerning because carbapenems have represented a last line of defense against resistant strains of gram-negative pathogens [6]. The most clinically relevant carbapenemases in Enterobacteriaceae are the class D enzymes of the OXA-48 group, class A enzymes of the KPC type and the zinc-dependent class B metallo-β-lactamases (MβLs), represented mainly by the VIM, IMP, and NDM type.

Carbapenemase-producing Enterobacteria cause serious infections in debilitated and immunocompromised patients, in association with prolonged hospital stays and increased mortality rates, ranging from 24% to as high as 70%, depending on the study population [8,9]. Given the critical condition of these patients, treatment should be timely and rapidly efficacious. However, therapeutic options are obviously limited.

The environmental bacterium P. aeruginosa is one of the most important nosocomial pathogens, especially in intensive care units. Intrinsic and acquired antibiotic resistance makes P. aeruginosa one of the most difficult organisms to treat. The high intrinsic antibiotic resistance of P. aeruginosa is due to several mechanisms: a low outer membrane permeability, the production of an AmpC β-lactamase, and the presence of numerous genes coding for different multidrug resistance efflux pumps[10]. Loss of OprD is the most prevalent mechanism of resistance to carbapenems and is associated with resistance to imipenem and reduced susceptibility to meropenem [11].