Evaluation of the mechanisms of resistance to beta-lactams among Burkholderia cenocepacia clinical isolates recovered from bloodstream infections

Abstract

Cystic fibrosis patients usually become colonized by Burkholderia cepacia complex species (Bcc) species. Part of these patients will become infected along their lifetime what has lead to higher mortality rates. The beta-lactams and trimethoprim/sulfamethoxazole are antimicrobials commonly prescribed for treatment of infections caused by Bcc. However, beta-lactam resistance has already emerged among Bcc isolates. This scenario gets more complicated because resistant bacteria usually carry additional resistant determinants. Among the mechanisms of beta-lactam resistance, beta-lactamase production is the most clinically important and studied mechanism. The contribution of other mechanism of resistance to beta-lactams like target site mutations is still unknown. The penicillin-binding-proteins (PBPs) exert a fundament role in the bacterial survival. For this reason, they constitute the target for many antimicrobials, including all beta-lactams. Beta-lactam antibiotics are steriochemical analogues of immature petideoglycan subunits, and covalently bind to the PBPs active serine site. Many studies performed with Pseudomonas aeruginosa have shown that hyperexpression of chromosomal AmpC is co-regulated by PBP-4 showing that mechanisms of beta-lactam resistance are more complex than it was initially thought. Based on this fact, would the production of PenA coupled with the PBP alteration be responsible for the ceftazidime resistance found among Bcc clinical isolates? The aim of this study is to elucidate the contribution of production of penicillinase Pen, the most important beta-lactamase in Burkholderia spp., and the PBPs alteration in conferring beta-lactam resistance among Bcc clinical isolates recovered from bloodstream infections of patients admitted to a Brazilian Teaching Hospital in the last ten years. (AU)