Selection of hyperproduction of AmpC and SME-1 in a carbapenem-resistant Serratia marcescens isolate during antibiotic therapy

• Published in: Journal of antimicrobial chemotherapy 2018-05, Vol.73 (5), p.1256-1262
• Main Authors: Hemarajata, Peera, Amick, Thomas, Yang, Shangxin, Gregson, Aric, Holzmeyer, Cameron, Bush, Karen, Humphries, Romney M
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bacteremia - drug therapy; Bacterial Proteins - metabolism; beta-Lactam Resistance; beta-Lactamases - metabolism; Ciprofloxacin - adverse effects; Ciprofloxacin - pharmacology; Ciprofloxacin - therapeutic use; Gene Expression Profiling; Humans; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination - adverse effects; Piperacillin, Tazobactam Drug Combination - pharmacology; Piperacillin, Tazobactam Drug Combination - therapeutic use; Real-Time Polymerase Chain Reaction; Selection, Genetic; Serratia Infections - drug therapy; Serratia marcescens - drug effects; Serratia marcescens - enzymology; Whole Genome Sequencing
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dky028

Antibiotic selective pressure may result in changes to antimicrobial susceptibility throughout the course of infection, especially for organisms that harbour chromosomally encoded AmpC β-lactamases, notably Enterobacter spp., in which hyperexpression of ampC may be induced following treatment with cephalosporins. In this study, we document a case of bacteraemia caused by a blaSME-1-harbouring Serratia marcescens that subsequently developed resistance to expanded-spectrum cephalosporins, piperacillin/tazobactam and fluoroquinolones, over the course of several months of treatment with piperacillin/tazobactam and ciprofloxacin. Susceptibility testing and WGS were performed on three S. marcescens isolates from the patient. β-Lactamase activity in the presence or absence of induction by imipenem was measured by nitrocefin hydrolysis assays. Expression of ampC and blaSME-1 under the same conditions was determined by real-time PCR. WGS demonstrated accumulation of missense and nonsense mutations in ampD associated with stable derepression of AmpC. Gene expression and β-lactamase activity of both AmpC and SME-1 were inducible in the initial susceptible isolate, but were constitutively high in the resistant isolate, in which total β-lactamase activity was increased by 128-fold. Although development of such in vitro resistance due to selective pressure imposed by antibiotics is reportedly low in S. marcescens, our findings highlight the need to evaluate isolates on a regular basis during long-term antibiotic therapy.