Our New Armamentarium for Treating KPC-Producing Infections

Key Takeaways

• Klebsiella pneumoniae carbapenemase (KPC) is the most common carbapenemase in many countries, including the United States.
• Previous treatments targeting KPC-producing bacteria were toxic and pharmacokinetically suboptimal therapeutic options, but we now have newer therapies that are associated with less toxicity and improved patient outcomes.

Infections due to carbapenemase-producing Enterobacterales are associated with poor clinical outcomes and increased healthcare costs. Klebsiella pneumoniae carbapenemase (KPC) is the most common carbapenemase in many countries, including the United States, and is detectable by multiple rapid molecular diagnostic platforms. Resistance can be seen across multiple other antibiotic classes outside of carbapenems and with our traditional broad spectrum β-lactams, making treatment difficult. Fortunately, this has changed with the advent of newer and broader β-lactam therapies in the past few years. Here, we discuss a patient case and key factors to consider when selecting among current treatment options. 

Case Details
A 56-year-old man with a history of paraplegia from transverse myelitis presents to the emergency department complaining of several days of fever, anorexia, and pain in his left lower extremity. His past medical history is significant for recurrent urinary tract infections (most recent 1 month ago; treated with levofloxacin), type 2 diabetes mellitus, hypertension, and coronary artery disease with recent ST elevation myocardial infarction, with stents placed in May 2020.

On imaging, there is concern about air and soft tissue thickening in the subcutaneous fat surrounding his left lower extremity, extending up to the retroperitoneal and presacral space. He is taken emergently to the operating room for extensive debridement of the lower left extremity down to the knee.

Blood cultures that were obtained on the day of admission return positive for gram-negative rods, with K. pneumoniae and the KPC gene detected by rapid molecular diagnostics.

You realize that the piperacillin/tazobactam the patient was empirically started on will not cover this organism. What antibiotic therapy would you recommend?

Past vs Present Armamentarium
Before late 2015, to treat these infections, I would be considering toxic and pharmacokinetically suboptimal therapeutic options such as polymyxin B, tigecycline, and/or aminoglycosides in combination with high-dose, extended-infusion meropenem. Luckily, in our armamentarium, we now have more options with activity against KPC-producing Enterobacterales: 3 newer β-lactam–β-lactamase inhibitor (BL-BLI) combinations (ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam) and a siderophore cephalosporin (cefiderocol).

The newer BL-BLIs have been associated with lower rates of mortality and adverse events, particularly nephrotoxicity, compared with the previous polymyxin- or aminoglycoside-based regimens.

Selecting Among Agents
So, how do you choose among these agents empirically before susceptibilities are known? At this time, there are limited comparative studies on the effectiveness of these agents in targeting multidrug-resistant organisms and no clinical trials that directly compare these novel agents.

Ceftazidime/Avibactam
Ceftazidime/avibactam was the first novel antibiotic to hit the market for KPC-producing bacteria, and it offers activity against OXA-48–producing bacteria. Although this is still an effective treatment option for these organisms, there are issues pertaining to the emergence of resistance during therapy with this agent that are concerning.

Meropenem/Vaborbactam
Meropenem/vaborbactam has potent in vitro activity against KPC-producing bacteria due to its carbapenem backbone and kinetically favorable dosing of vaborbactam. In addition, data suggest that the emergence of resistance is less likely to occur, which has made meropenem/vaborbactam my personal preferred agent for the treatment of KPC-producing Enterobacterales, although it is not yet known if these advantages will translate to improved clinical outcomes.

Imipenem/Cilastatin/Relebactam
Imipenem/cilastatin/relebactam is the newest of the BL-BLIs and therefore has less clinical data available compared with the other agents. Imipenem/cilastatin/relebactam shares many of the same positive characteristics as meropenem/vaborbactam and is likely a very viable option, but the availability of in-house microbiologic testing and less available data limit its use compared with the other BL-BLIs.

Cefiderocol
The other alternative treatment option is cefiderocol, which has activity against numerous carbapenemases, including KPC, but also metallo-β-lactamases such as New Delhi Metallo-β-lactamase (NDM), Verona integron-mediated metallo-β-lactamase (VIM), and imipenem-resistant Pseudomonas-type carbapenemase (IMP). There are limited data evaluating the use of cefiderocol for KPC-producing Enterobacterales and no comparative data vs the newer BL-BLIs.

Although cefiderocol is a reasonable alternative agent for KPC-producing Enterobacterales, I personally prefer to reserve it for the metallo-β-lactamases, where we have even fewer treatment options available.

Other Factors to Consider
Now that we have multiple agents with activity against carbapenemase-producing Enterobacterales, careful consideration should be made when deciding which agents should be included on hospital formularies. All 3 of the BL-BLIs are recommended by the 2022 Infectious Diseases Society of America guidance for the treatment of antimicrobial-resistant gram-negative infections, specifically carbapenem-resistant Enterobacterales, and cefiderocol is recommended as an alternative.

When evaluating these novel agents for formulary status, understanding local susceptibilities and epidemiology is essential. Local microbiological testing capabilities also should be considered when selecting formulary agents to ensure the timely reporting of susceptibility data and to facilitate earlier time to effective therapy.

BL-BLIs with a carbapenem (eg, meropenem, imipenem) also can be appealing for this patient’s infection based on the source of infection, where continuing polymicrobial coverage of other possible pathogens, such as anaerobes, may be needed. Ceftazidime/avibactam does not have adequate anaerobic coverage and would need a separate agent, such as metronidazole, added. This is the case for cefiderocol, too.

We are lucky to have multiple options compared with the suboptimal treatment strategies of the past, and whether a single option will emerge as the “best” remains to be seen as we continue to gather real-world clinical data.

Your Thoughts?
How would you have managed this patient? What factors, in your experience, contribute to selecting one of these agents for infections due to KPC-producing Enterobacterales? Join the discussion by leaving a comment.