The Challenge of Treating CPE
Carbapenemase-producing Enterobacteriaceae (CPE) present a formidable challenge to modern medicine due to their ability to resist carbapenems, a class of last-resort antibiotics. The bacteria produce carbapenemase enzymes that deactivate these powerful drugs, often alongside other resistance mechanisms that render many first- and second-line antibiotics ineffective. The therapeutic landscape is therefore limited, and treatment decisions must be carefully tailored to the specific carbapenemase type and the patient's condition, often in consultation with an infectious disease specialist.
Novel Beta-Lactam/Beta-Lactamase Inhibitors
To overcome carbapenemase resistance, several new drug combinations have been developed. These combine a potent beta-lactam antibiotic with a novel beta-lactamase inhibitor that can protect the antibiotic from the degrading effects of the carbapenemase enzyme.
- Ceftazidime-avibactam (Avycaz): This combination is highly effective against CPE that produce Class A (KPC) and Class D (OXA-48-like) carbapenemases. However, it is not active against Class B metallo-beta-lactamases (MBLs), such as NDM, IMP, and VIM. For infections involving MBL-producing Enterobacterales, ceftazidime-avibactam can be used in combination with aztreonam as a salvage option.
- Meropenem-vaborbactam (Vabomere): Recommended for invasive infections caused by KPC-producing Enterobacterales, this combination is effective against Class A carbapenemases. Similar to ceftazidime-avibactam, it does not have activity against MBLs or OXA-48-like enzymes.
- Imipenem-cilastatin-relebactam (Recarbrio): This combination has proven effective against many imipenem-nonsusceptible Enterobacterales, including those with KPC and Class C enzymes. It is used for complicated urinary tract infections, complicated intra-abdominal infections, and hospital-acquired/ventilator-associated pneumonia. Relebactam inhibits Class A and Class C enzymes but, like other novel combinations, is not active against MBLs.
Re-emerging and Repurposed Antibiotics
In some cases, older agents are used, often in combination, to treat CPE infections. Their use is typically reserved for specific situations or when newer agents are unavailable, often due to emerging resistance and side effects.
- Polymyxins (Colistin/Polymyxin B): Once a cornerstone of CRE therapy, these drugs have significant nephrotoxicity and neurotoxicity. Emerging resistance and poor outcomes when used as monotherapy have led to their use being largely restricted to combination therapy or as a last resort.
- Tigecycline: A tetracycline antibiotic, tigecycline is active against many CPE isolates. However, it is not recommended for urinary tract infections due to low urinary concentrations and has been associated with increased mortality in certain cases, such as pneumonia. High doses and combination therapy are often required for invasive infections.
- Fosfomycin: This antibiotic, which inhibits bacterial cell wall synthesis, retains activity against many CRE isolates and can be used for uncomplicated urinary tract infections. For systemic infections, it is typically used in combination with other agents due to the risk of resistance developing rapidly during monotherapy.
- Plazomicin: A newer aminoglycoside, plazomicin was engineered to overcome common aminoglycoside-modifying enzymes produced by some CRE. It shows activity against CPE but, like other aminoglycosides, is ineffective against MBL-producing CRE due to the presence of 16S ribosomal methyltransferases.
Siderophore Cephalosporin: Cefiderocol
Cefiderocol (Fetroja) is a unique siderophore cephalosporin that employs a "Trojan horse" mechanism to gain entry into Gram-negative bacteria. It is active against a broad spectrum of carbapenemases, including Class A (KPC), Class B (MBLs), and Class D (OXA-48). However, a clinical trial (CREDIBLE-CR) revealed a higher all-cause mortality rate in cefiderocol-treated patients compared to those on best available therapy for severe infections. The FDA has since issued a warning, and its use is typically reserved for patients with limited or no alternative options.
Combination Therapy: The Standard of Care
For severe CPE infections, especially those outside the urinary tract or involving bacteremia, combination therapy with two or more active agents is often the standard of care. This approach can improve clinical outcomes and potentially slow the development of resistance. The specific combination is determined by the isolate's susceptibility profile and the type of carbapenemase identified.
Choosing the Right Antibiotic for CPE: A Comparison
| Antibiotic/Combination | Carbapenemase Activity (Primary) | Common Uses | Key Considerations |
|---|---|---|---|
| Ceftazidime-avibactam | KPC (Class A), OXA-48 (Class D) | Complicated UTIs, intra-abdominal infections, pneumonia | Ineffective against MBLs; can be combined with aztreonam for MBLs |
| Meropenem-vaborbactam | KPC (Class A) | Complicated UTIs, intra-abdominal infections, pneumonia | Not active against MBLs or OXA-48 |
| Imipenem-relebactam | KPC (Class A), AmpC (Class C) | Complicated UTIs, intra-abdominal infections, pneumonia | Not active against MBLs |
| Cefiderocol | KPC (A), MBLs (B), OXA-48 (D) | Severe infections with limited alternatives, complicated UTIs, pneumonia | Caution due to mortality concerns in some patient groups; potential resistance development |
| Polymyxins (Colistin) | Broad (used for various CRE) | Last resort therapy, often combined | High toxicity; resistance is a growing concern |
| Tigecycline | Broad (used for various CRE) | Intra-abdominal infections, skin/soft tissue infections | Not for UTIs; high doses needed for invasive infections; mortality concerns |
The Future of CPE Treatment and Antimicrobial Stewardship
The ongoing spread of CPE, coupled with the potential for resistance to even novel agents, underscores the critical need for robust antimicrobial stewardship programs. These programs are essential for promoting appropriate antibiotic prescribing, reducing the overuse of last-resort drugs, and ensuring the long-term effectiveness of available treatments. The development of new antibiotics active against all carbapenemase classes is a global priority, but prevention through stringent infection control remains the most effective strategy. The Centers for Disease Control and Prevention (CDC) provides guidelines for infection control in healthcare settings to limit the spread of CRE.
Conclusion: A Multifaceted Approach Is Crucial
No single antibiotic is reliably used for CPE infections. Successful treatment depends on a multifaceted approach that includes rapid identification of the specific resistance mechanism, selection of appropriate agents (including newer beta-lactam/beta-lactamase inhibitor combinations), and often the use of combination therapy, particularly for severe infections. The decision-making process is highly specialized and requires collaboration with infectious disease experts, as inappropriate therapy is linked to significantly higher mortality rates. As resistance continues to evolve, effective treatment will rely on ongoing antimicrobial surveillance, research into new therapeutic options, and strict adherence to infection control protocols.
