Carbapenem-resistant Enterobacteria (CRE) Treatments

Current effective antibiotics for the treatment of infections caused by carbapenem-resistant enterobacteria (CRE) and the likelihood that these antibiotics will still be effective 10 years from now.

Treatment options for CRE infections are very limited and resistance to antibiotics currently in use is rising. Polymyxins such as colistin and polymyxin B have been widely used as the drug of choice to treat infections caused by CRE.  Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act on gram-negative bacteria. They act by disrupting their outer membrane permeability and damaging their cytoplasmic membrane. Polymyxin resistance is rapidly increasing. This resistance has been shown to be mediated by the phosphoethanolamine (PEA) modification of lipid A. Both chromosome-encoded and plasmid encoded PEA transferase has been reported in gram-negative bacteria.

Tigecycline has also been a drug of choice for treatment of infections caused by CRE. Tigecycline is a glycylcycline antimicrobial agent which is active against a variety of gram-positive and gram-negative organisms in vitro. Tigecycline binds to the bacterial 30S ribosome which blocks entry of transfer RNA which prevents protein synthesis. This halts the incorporation of amino acids into the growing peptide chains and limits bacterial growth. High-dosage use of Tigecycline has been studied due to tigecyclines non-nephrotoxic nature in comparison to other active antimicrobial agents for CRE. Tigecycline resistance is on the rise and has been demonstrated across a wide range of bacterial species.

Carbapenems still play a part in the treatment of CRE infections and are considered a last resort drug for the treatment of infections caused by multi-drug resistance gram-negative bacteria. Carbapenem is a -lactam antibiotic which acts by inhibiting transpeptidases and prevents peptidoglycan synthesis. This leads to lytic cell death. Carbapenems are used in the treatment of CRE with lower minimal inhibitory concentrations (MICs). Carbapenems are used in higher doses, in combination with other active anti-CRE agents or through double-carbapenem therapy (DCT). The resistance of CRE to carbapenems is based on two mechanisms, carbapenemase production or the combination of structural mutations with the production of other -lactamases.

Antibiotics currently in development for the treatment of infections caused by CRE

Cefiderocol is the first siderophore antibiotic to advance into late-stage development. Cefiderocol is a novel siderophore cephalosporin which exhibits activity both in vitro and in vivo against a wide range of gram-negative bacteria including CRE. Cefiderocol has a unique antibacterial mechanism in which it attaches its catechol side chain to ferric acid. This complex is then actively transported into the bacteria via bacterial ion transporters. Cefiderocol is also highly effective against carbapenemase hydrolysis. Cefiderocol has been shown to be active in vitro against CRE isolates with 97% of isolates showing a minimal inhibitory concentration of 4mg/L or lower. Cefiderocol is currently undergoing trials to access its efficacy for severe infections caused by CRE gram-negative pathogens.

Vabomere is a drug which was recently approved by the FDA. Vabomere is a combination of meropenem-vaborbactum, a carbapenem antibiotic and novel boronic acid-based beta inhibitor.  Vaborbactam inhibits certain types of resistance mechanisms used by bacteria. Vaborbactam potentiates the activity of meropenem.  Vaborbactum is a cyclic boronate ester which acts configures the compound into the correct conformation. Meropenem is a carbapenem antibiotic that inhibits cell wall synthesis of most gram positive and gram negative bacteria. Meropenem does this by binding to penicillin-binding proteins and as a result inhibiting the cross-linking of peptidoglycan chains leading to cell lysis. Vabomere has shown effective in vitro antibacterial activity against CRE isolates. The susceptibility rates ranging from 66.2 to 100%.

LYS228 is a new monobactam that strongly binds to PBP-3 and inhibits bacterial peptidoglycan synthesis. LYS228 has retained potency against CRE as it is stable against NDM-1, KPCs and most ESBLs. LYS228 is active against both wild-type and -lactamase-producing  Enterobacteriaceae and has a potency similar to tigecycline. LYS228 is currently in phase II trials testing its clinical response and safety and tolerability in patients with cUTIs.

Ways of reducing/preventing further carbapenem resistance in enterobacteria

Combination therapy is method to reduce carbapenem resistance. Combination therapy can help reduce the resistance by eliminating a sub-population of bacteria resistant to the second antibiotic used in the treatment.  Antimicrobial activity can be enhanced by combination therapy use by potentially targeting two different cellular pathways which is made possible by the use of two different antibacterials. Combination therapy can be used to promote entry by use of polymyxins which disrupt the outer membrane of gram negative bacteria and therefore promote the entry of the other antibiotic used. Carbapenems have been successfully used in combination therapies with other anti-CRE agents. Double carbapenem is a combination therapy. The most studied double carbapenem therapy is ertapenem which is given prior to prolonged high-dose treatment with meropenem. Ertapenem is hypothesized to play a sacrificial role due to its increased affinity to KPC. This permits the sustenance of a high concentration of carbapenem.

Antimicrobial stewardship can help prevent and reduce carbapenem resistance. Antimicrobial stewardship is defined as an organisational or healthcare system wide approach to promote and monitor judicious use of antimicrobials to preserve their future effectiveness. Avoidance of unnecessary use of drugs will help prevent emergence of resistance and allow appropriate use to have positive clinical outcomes. Rapid diagnosis is critical to antimicrobial stewardship as identification of the pathogen is preferred before the beginning of therapy. Rapid diagnostic tests allows for de-escalation, the modification of empiric therapy when it is appropriate, and minimization of duration of therapy. Automation is a big factor to rapid diagnostic identification.  Automation can be partial, one or two phases of testing of pathogen identification is automated, or total, all aspects of pathogen identification are automated. Automation allows for faster identification, treatment options and for a high level of quality control.

Prevention of transmission is a way to reduce carbapenem resistance. Prevention in hospital settings is achievable. Prevention in the community has many different difficulties to overcome and may be seen as unachievable. A prevention bundle can be used in hospital settings for example. This includes hand hygiene, use of gloves and gowns, dedicated medical equipment e.g. stethoscopes, patients in private rooms, designated health care workers to care for a patient, active surveillance screening and bathing patients in chlorohexidine. Chlorohexidine is a disinfectant and antiseptic. All of these steps are in place to limit spread of pathogens including those that are resistant to antibiotics.

References

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