Intrinsic Gaps in the Carbapenem Spectrum
Carbapenems, a class of $\beta$-lactam antibiotics, are known for their broad-spectrum activity against many Gram-positive, Gram-negative, and anaerobic bacteria. They work by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs). However, this mechanism of action also explains why they are naturally ineffective against certain pathogens lacking the target structure or possessing innate resistance mechanisms.
Methicillin-Resistant Staphylococcus aureus (MRSA)
One of the most significant and well-known gaps in carbapenem coverage is MRSA. The resistance in MRSA is primarily mediated by the mecA gene, which encodes a variant PBP, PBP2a, that carbapenems cannot effectively bind to,. As a result, MRSA strains are resistant to all $\beta$-lactam agents, including carbapenems, with few exceptions. For infections suspected or confirmed to be caused by MRSA, alternative antibiotic classes like glycopeptides (e.g., vancomycin) or lipopeptides (e.g., daptomycin) are necessary.
Vancomycin-Resistant Enterococci (VRE)
Carbapenems are generally not considered active against most enterococcal infections. Specifically, carbapenems have poor activity against Enterococcus faecium. While some carbapenems like imipenem show activity against E. faecalis, the overall unreliability against enterococci makes them poor choices for suspected or confirmed enterococcal infections, especially VRE,.
Stenotrophomonas maltophilia
This opportunistic pathogen is intrinsically resistant to carbapenems,. Its resistance is due to the natural production of inducible L1 metallo-$\beta$-lactamase (MBL). This enzyme can inactivate carbapenems, rendering them useless against S. maltophilia. As such, treatment for this bacterium requires non-carbapenem antibiotics, typically involving trimethoprim-sulfamethoxazole.
Atypical Bacteria
Carbapenems, like all $\beta$-lactam antibiotics, target the bacterial cell wall. Atypical bacteria, such as Mycoplasma, Chlamydia, and Legionella, lack a cell wall,. Therefore, carbapenems are completely ineffective against infections caused by these organisms.
Acquired Resistance and the Threat of CRE
Beyond intrinsic limitations, the most concerning threat to carbapenem efficacy is the rise of acquired resistance, most notably seen in Carbapenem-Resistant Enterobacterales (CRE). CRE are bacteria that have developed resistance mechanisms, often in healthcare settings, that render carbapenems ineffective,.
Mechanisms of Acquired Resistance
Carbapenem resistance is not a single phenomenon but results from various mechanisms that can work synergistically:
- Carbapenemase Production: This is the most common and clinically significant mechanism. The bacteria produce enzymes, called carbapenemases, that hydrolyze the $\beta$-lactam ring of the antibiotic, deactivating it. Examples include Klebsiella pneumoniae carbapenemases (KPCs), metallo-$\beta$-lactamases (MBLs) like NDM and VIM, and OXA-48-like carbapenemases,. The genes for these enzymes are often located on mobile plasmids, allowing rapid spread between different bacterial species,.
- Porin Channel Alterations: In Gram-negative bacteria, carbapenems must pass through outer membrane porin channels to reach their target PBPs. Mutations or downregulation of these channels, such as OprD in Pseudomonas aeruginosa, can significantly reduce the permeability of the bacterial membrane, preventing the antibiotic from entering.
- Efflux Pump Overexpression: Some bacteria can overexpress efflux pumps, which are cellular transporters that actively pump antibiotics out of the bacterial cell, reducing the drug's concentration to sub-inhibitory levels.
Differential Coverage Among Carbapenems
It is important to note that not all carbapenems have the same spectrum of activity, and some have specific limitations that should be considered. This is particularly relevant for the treatment of certain hospital-acquired infections caused by opportunistic pathogens.
| Feature | Imipenem | Meropenem | Ertapenem | Doripenem |
|---|---|---|---|---|
| Activity against Pseudomonas aeruginosa | Less potent than meropenem/doripenem | Highly potent | No activity, | Highly potent |
| Activity against Acinetobacter species | Good activity | Good activity | No activity, | Good activity |
| Activity against Enterococcus faecalis | Good activity | Ineffective | Less reliable | Good activity |
| Neurotoxicity | Highest risk for seizures | Low risk | Low risk | Low risk |
Conclusion
While carbapenems are indispensable last-line agents for severe and multidrug-resistant infections, their broad spectrum is not all-encompassing. Critical gaps exist for pathogens with intrinsic resistance, including MRSA, most Enterococci (especially VRE), Stenotrophomonas maltophilia, and atypical bacteria,,,. Moreover, the emergence of CRE, capable of neutralizing carbapenems via carbapenemases or other resistance mechanisms, is a growing public health crisis that further narrows the therapeutic window for these valuable antibiotics. Clinical decisions must be guided by susceptibility testing, local epidemiology, and an understanding of specific carbapenem limitations to ensure effective treatment and combat the spread of antimicrobial resistance.
For more information on preventing carbapenem-resistant Enterobacterales, visit the CDC on CRE.
