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Treating P. aeruginosa With Difficult to Treat Resistance
Where Are We Now? A Decade of Using Newer β-lactams to Treat Pseudomonas aeruginosa With Difficult-to-Treat Resistance

Released: September 25, 2024

Expiration: September 24, 2025

Marguerite L. Monogue
Marguerite L. Monogue, PharmD, BCIDP
Activity Information

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Key Takeaways
  • Over the last decade, newer agents such as ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol have been approved to treat P . aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa).
  • Treatment selection for DTR P. aeruginosa depends on the source of infection, anticipated (or confirmed) antimicrobial susceptibilities, and severity of infection. 

Pseudomonas aeruginosa is a gram-negative pathogen known to cause hospital-acquired infections, including bloodstream infections and pneumonia. Because of the variety of mechanisms of resistance exhibited by P. aeruginosa, selection of appropriate antimicrobial therapy can be complicated. 

Over the past decade, new agents targeting P. aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa) have entered the scene. These newer antimicrobials possess enhanced stability against various resistance mechanisms of P. aeruginosa. But where does that leave us? 

In this commentary, I will review a patient case and discuss key considerations for optimizing therapeutic options for infections caused by DTR P. aeruginosa, including the role of these newer antimicrobials.

Case Details
A 78-year-old with a history of chronic obstructive pulmonary disease and type 2 diabetes mellitus was admitted to the hospital with acute abdominal pain, leukocytosis, nausea, and vomiting. The patient was found to have a perforated appendix.

Piperacillin/tazobactam was empirically started, and the patient underwent successful surgical intervention. Three days postoperative, their clinical status worsened: the patient developed persistent leukocytosis, fever, and severe respiratory distress requiring supplemental oxygen, which was concerning for hospital-acquired pneumonia. Respiratory and blood cultures were obtained, and antibiotics were broadened to vancomycin and meropenem. A chest x-ray revealed a right lower lobe infiltrate.

The following day, the fever continued and the patient had increasing oxygen requirements. Updated respiratory culture results showed P. aeruginosa. Based on susceptibility reporting (Table), meropenem was changed to cefepime, as a prolonged infusion, and vancomycin was discontinued.

Table. Antimicrobial Susceptibility Testing Results

 

Seven days later, the patient’s respiratory status is back to baseline, but the patient has a new fever, increasing leukocytosis, and severe abdominal pain. On imaging, a large intra-abdominal abscess near the operative site is seen, requiring drainage by interventional radiology. In response, 2 sets of blood cultures are drawn. What empiric changes would you consider at this time?

Therapeutic Considerations
It is possible that the patient has DTR P. aeruginosa bacteremia, likely precipitated from their initial presentation of perforated appendicitis and secondary postoperative infection. Following the initial surgical intervention, the patient potentially had transient bacteremia and/or an aspiration event causing hospital-acquired pneumonia. While receiving antipseudomonal treatment that targeted the respiratory isolate, an intra-abdominal abscess continued to develop, suggesting missed coverage of a preexisting isolate or on-treatment resistance against the current antimicrobial therapy (cefepime).

In terms of treatment, DTR P. aeruginosa is defined as exhibiting nonsusceptibility to all the following: aztreonam, ceftazidime, cefepime, piperacillin/tazobactam, imipenem/cilastatin, meropenem, ciprofloxacin, and levofloxacin.

Prior to 2014, only a few options to treat DTR P. aeruginosa were available. Antimicrobials were limited to polymyxins, aminoglycosides, and combination therapies that were often associated with unfavorable toxicity and limited efficacy. The past decade has replenished the antipseudomonal toolbox with 4 new β-lactam antimicrobials: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol.

Ceftolozane/tazobactam
Ceftolozane/tazobactam is made up of a newer cephalosporin, ceftolozane, with a traditional β-lactamase inhibitor, tazobactam. The large side chain of ceftolozane results in greater stability against Pseudomonas-derived cephalosporinase (PDC) type β-lactamases, which are frequently present in P. aeruginosa. Ceftolozane is also significantly less affected by changes in porin permeability compared with traditional cephalosporins.

Ceftazidime/avibactam
Ceftazidime/avibactam is a combination of a traditional cephalosporin, ceftazidime, with a novel β-lactamase inhibitor, avibactam. The avibactam component restores the activity of ceftazidime against P. aeruginosa by inhibiting various β-lactamases, such as PDC, Klebsiella pneumoniae carbapenemase (KPC), and Guiana extended-spectrum (GES).

Imipenem/cilastatin/relebactam
Imipenem/cilastatin/relebactam contains the well-known carbapenem, imipenem, and a novel β-lactamase inhibitor, relebactam. The relebactam component restores the activity of imipenem against P. aeruginosa by inhibiting various β-lactamases such as PDC and KPC.

Cefiderocol
Cefiderocol is a siderophore cephalosporin with broad activity against multidrug-resistant gram-negative organisms, including DTR P. aeruginosa. Cefiderocol uses iron to facilitate entry into the outer cell membrane, bypassing mutations within efflux pumps and porin channels. Furthermore, its side channel improves its stability against several β-lactamases, including metallo-β-lactamase (MBL).

According to the 2024 Infectious Diseases Society of America (IDSA) treatment guidance, the preferred antibiotics for DTR P. aeruginosa are dependent on the source of infection. Preferred options include:

  • Uncomplicated cystitis: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol
  • Pyelonephritis or complicated urinary tract infections: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol
  • Infections outside of the urinary tract: ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/cilastatin/relebactam
  • Infections caused by MBL-producing organisms: cefiderocol

There is a lack of head-to-head clinical efficacy data. Because of this, selecting an appropriate DTR P. aeruginosa regimen relies on understanding regional susceptibility differences due to the varying occurrence of resistance mechanisms. In the United States, DTR P. aeruginosa is often caused by the production of PDC β-lactamases, mutations in the outer membrane porin channels, and/or efflux pumps.

Ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/cilastatin/relebactam retain similar activity against DTR P. aeruginosa isolates (85%-90% susceptible), whereas cefiderocol tends to be the most reliable (99% susceptible). However, because of the broad gram-negative activity of cefiderocol, it is not considered first-line treatment for infections outside the urinary tract in the absence of MBL production or suspected resistance to the other DTR P. aeruginosa agents.

Back to the Case
As expected, blood cultures grew P. aeruginosa. Given the patient’s clinical presentation, culture results, including their initial respiratory culture result, and corresponding exposures to piperacillin/tazobactam, cefepime, and meropenem, the team was concerned about DTR P. aeruginosa.

Upon susceptibility testing, the strain showed resistance to levofloxacin, ceftazidime, cefepime, piperacillin/tazobactam, and meropenem and susceptibility to ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/cilastatin/relebactam. Based on susceptibility results, ceftolozane/tazobactam, ceftazidime/avibactam, or imipenem/cilastatin/relebactam could have been chosen owing to their reliable activity against the isolates in the absence of prior exposures, and the choice would be informed by local resistance patterns. In addition, if the infection was caused by an MBL-producing organism, cefiderocol could have been chosen.

Learn More
To learn more about IDSA guidance updates on the treatment of antimicrobial-resistant gram-negative infections, including other organisms such as carbapenem-resistant Enterobacterales and Stenotrophomonas maltophilia, join me and Dr. Michael Satlin at our live symposium at IDWeek 2024 in Los Angeles, California. You can participate in person or via live simulcast.

Your Thoughts?
How would you have managed this patient? What is your first-line agent for DTR P. aeruginosa? Join the discussion by leaving a comment.