A PNAS paper on the genomic diversity of carbapenemase producing bacteria in the US reports strong evidence of carbapenamase (an enzyme produced by bacteria that breaks down carabapenem antibiotics) activity but no sign of a carbapenemase gene. This provides a timely reminder that we are only really scratching the surface in our understanding of carbapenemases and how they work.
It is great to see PNAS publishing this detailed genomic evaluation of CPE. Isolates were collected over 16 months from 4 US hospitals: 3 in Boston (on the East coast), and one from California (in the West). A fairly random selection of isolates from earlier years was also included. They also collected carbapenem-susceptible isolates as species and time-matched ‘controls’. I was unable to find details on the selection criteria for the isolates – exactly how were they selected? Do they represent all CPE, or just some? Also, importantly, what screening was in place in the different hospitals, because this will bear heavily on one of the outcomes of the study: the number of genotypically related clusters identified.
The sample size is pretty small, with a total of 55 carbapenem-resistant Enterobacteriaceae included. KPC was the most common carbapenemase, accounting for 36 (65%) of the CPE, and K. pneumoniae was the most common species identified. A known mechanisms of carbapenem resistance (either by means of a carbapenemase or other mechanisms) could not be identified in 7 (13%) of the 55 isolates. In two of these 7, the team established that plasmid content could transform a sensitive bacterium into a resistant one, suggesting that a plasmid-mediated carbapenemase was responsible. However, despite extensive digging into the genomic material, nothing that looked like a functional carbapnemase could be found, suggesting a novel mechanism could be at play. The study also looked at the potential for horizontal gene transfer, making the case that the identification of transponons with related sequences flanking carbapenemases is evidence of recent horizontal transfer.
The study is useful in highlighting the limitations of our current level of understanding around carbapenemases, and probably argues for a pragmatic approach based on phenotypic identification of carbapenem resistance, supplemented by genotypic methods. For example, the finding of novel/unusual mechanisms of carbapenemase resistance certainly argues against using a PCR kit with primers for 4 or 5 carbapenemases without concurrent phenotypic culture.