Here we will discuss the mechanisms of carbapenem resistance:
- Enterobacteriacae:
- Cephalosporinase & porin loss
- Carbapenemase
- Pseudomonas aeruginosa:
- Porin loss
- Up-regulated efflux
- Carbapenemase
- Acinetobacter spp.
- Cephalosporinase & porin loss
- Carbapenemase
Here is a diagram of Pseudomonas aeruginosa:
Carbapenemases:
- Class A: KPC, SME, IMI, NMC, GES.Seen in Enterobacteriacae & rarely in P. aeruginosa
- Class B (metallo-ß-lactamase): IMP, GIM, VIM, SPM. Seen in P. aeruginosa, Enterobacteriacae and Acinetobacter spp.
- Class D: OXA. Acinetobacter spp.
Porins:
P. aeruginosa produces several different porins, oprF being the major species present in all strains. Although mutants lacking oprF have been reported, loss of oprF has not been found to be a major cause of antibiotic resistance, presumably because such strains have restricted ability to take up hydrophilic nutrients. OprD is a specialized porin which has a specific role in the uptake of positively charged amino acids such as lysine. Loss of oprD is frequently associated with resistance to imipenem, which requires this porin to cross the outer membrane. Loss of the oprD porin increases the minimum inhibitory concentration from 1–2 to 8–32 mg/L and 17% rate of resistance has been reported during treatment. Interestingly, meropenem is not affected by loss of oprD, indicating that the carbapenems have crossed the outer membrane by different channels.
Imipenem, and to a certain degree also meropenem, enters P. aeruginosa through an outer membrane protein, OprD. Loss of this membrane protein has been shown to play a major role in the acquired resistance to imipenem, and to a lesser extent to meropenem. Furthermore, imipenem selects for OprD-deficient mutants in 15 – 20% of patients treated with this antibiotic. In such mutants, susceptibility to imipenem is affected to a greater extent than meropenem susceptibility, an effect attributed to the greater instability of imipenem to AmpC and to the greater OprD dependency of imipenem.
Resistance to carbapenems in P. aeruginosa can also arise from overexpression of the efflux pump MexAB-OprM. This efflux pump is able to export both quinolones and b-lactams, except imipenem, explaining raised MICs for meropenem but not for imipenem in hyperproducing mutants.
What causes resistance to carbapenems?
Resistance to carbapenems occurs either through bacterial production of β-lactamase enzymes that hydrolyze the antimicrobial agent or through porin changes in the bacterial cell wall that reduce the permeability of the drug into the organism. In some organisms, both mechanisms may be present. DNA coding for enzyme production can be passed from organism to organism via plasmids or can occur through mutation of an existing β-lactamase enzyme. Porin changes arise through mutation.
What causes different levels of resistance?
The level of resistance is determined by the efficiency of the enzyme for hydrolyzing the drug and by the number of resistance mechanisms present in the organism. Organisms can produce more than one hydrolyzing enzyme and may show modifications in more than one porin, producing high-level resistance to the carbapenems (minimum inhibitory concentration [MIC] >16 µg/ml). Organisms with decreased susceptibility produced by porin changes alone often have lower MICs (2-8 µg/ml).
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