Carbapenems were the reserve agents: broad, stable against most beta-lactamases, and kept back for the cases where nothing else worked. Losing them is the single biggest reason carbapenem resistant organisms sit at the top of every priority pathogen list.
Two routes to a carbapenem resistant isolate
Route one: a carbapenemase
An enzyme that hydrolyses the carbapenem directly. Four families do most of the clinical work:
| Family | Ambler class | Notes |
|---|---|---|
| KPC | A, serine | Common in K. pneumoniae, inhibited by avibactam and vaborbactam |
| NDM | B, metallo | Zinc dependent, not inhibited by the current serine inhibitors |
| VIM and IMP | B, metallo | Same problem as NDM, frequent in P. aeruginosa |
| OXA-48 like | D, serine | Weak carbapenemase activity that is enough when combined with porin loss |
The serine versus metallo split matters commercially as well as scientifically, because the newer inhibitor combinations restore activity against the serine enzymes and not against the metallo ones.
Route two: porin loss with a lesser enzyme
An isolate with an extended spectrum beta-lactamase or a derepressed AmpC, plus loss or mutation of the OmpK35 and OmpK36 porins in K. pneumoniae, can be carbapenem resistant without carrying a carbapenemase at all. Less enzyme gets less drug, because much less drug arrives. It is the clearest example of the interaction described on the Gram-negative bacteria page: transport and catalysis multiplying rather than adding.
The organisms
- Carbapenem resistant Enterobacterales, principally K. pneumoniae and E. coli. Usually plasmid mediated, so it spreads between species.
- Acinetobacter baumannii, typically through OXA type enzymes on a background of low permeability and strong efflux. Also unusually persistent in the hospital environment.
- Pseudomonas aeruginosa, where intrinsic mechanisms, porin OprD loss and metallo enzymes combine.
What is left
- Ceftazidime-avibactam, active against KPC and OXA-48 like producers, not against metallo enzymes.
- Meropenem-vaborbactam and imipenem-relebactam, aimed principally at KPC.
- Cefiderocol, a siderophore cephalosporin that hitches a ride on iron uptake and retains activity against several metallo producers.
- Colistin, still used where nothing else remains, with real toxicity and with plasmid borne mcr resistance now circulating.
- Combination approaches, including aztreonam with avibactam for metallo producers, since aztreonam is stable to metallo enzymes but vulnerable to the serine ones the same isolate usually carries.
Screening implications
If your series is a beta-lactam, the carbapenemase question is the program. Three things are worth establishing early:
- Which enzyme classes hydrolyse it. Stability against a metallo enzyme is a different molecule level property from stability against KPC.
- Whether an inhibitor partner is plausible. A scaffold that is fine in combination is a different development path from one that must stand alone.
- Whether porin loss alone defeats it. A compound that only enters through a single porin is fragile even against isolates with no carbapenemase.
A screen against the Gram-negative panel with K. pneumoniae (CRE) included gives the first read on all three, with the mechanism named rather than left as a high number. The wider mechanism landscape is on the antibiotic resistance page, and the surveillance context is under antimicrobial resistance.