Is There a Preferred β-Lactam/β-Lactamase Inhibitor Agent for Treatment of KPC-Producing Enterobacterales Infection?

Carbapenem-resistant Enterobacterales (CRE) are a major cause of attributable death worldwide.¹ In the United States, CRE infections are responsible for over 13,000 hospitalizations and 1100 deaths annually.² The vast majority of carbapenemase-producing CRE identified in the United States harbor Klebsiella pneumoniae carbapenemase (KPC) enzymes typically found in K pneumoniae (KPC-Kp).^3,4 Treatment of KPC-Kp infections has dramatically shifted in the past decade away from less desirable aminoglycoside-, polymyxin-, or tetracycline-based combination therapy to newer β-lactam/β-lactamase inhibitors such as ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam. Indeed, consensus guidelines⁵ and expert guidance⁶ prioritize use of β-lactam/β-lactamase inhibitor agents in updated recommendations. These recommendations are largely based on real-world evidence showing superior efficacy and/or safety compared with polymyxin-based combination therapy for KPC-Kp infections.^7-13 Although frontline use of novel β-lactam/β-lactamase inhibitors has become widely adopted, it is less clear which of the 3 commercially available agents should be preferred. Indeed, the Infectious Diseases Society of America guidance document recommends each of the 3 agents as a preferred treatment option for carbapenemase-producing CRE.⁶ Differentiating the agents may have important implications for hospital formularies and antimicrobial stewardship practices, as well as patient outcomes.

Comparative clinical data for ceftazidime-avibactam vs meropenem-vaborbactam are limited¹⁴ and have not been published for imipenem-relebactam. In fact, the data to support use of imipenem-relebactam for CRE infections are limited to 5 patients enrolled in a randomized clinical trial¹³ and 2 patients included in a retrospective patient registry.¹⁵ Moreover, in vitro activity of imipenem-relebactam is dependent upon functional outer membrane porin channels in KPC-Kp clinical isolates.^16,17 Findings from in vitro selection studies have demonstrated that imipenem-relebactam resistance may evolve through mutations in major porin genes, increased expression of KPC, and blaKPC mutations.^18-20 Although emergence of imipenem-relebactam resistance to KPC-Kp has not yet been reported following treatment, the totality of evidence is significantly less when compared with that of ceftazidime-avibactam or meropenem-vaborbactam. Thus, the European Society of Clinical Microbiology and Infectious Diseases guidelines neither recommend nor advise against the use of imipenem-relebactam for CRE infections.⁵ Until further evidence is available, clinicians are more likely to select either ceftazidime-avibactam or meropenem-vaborbactam for the treatment of invasive KPC-producing Enterobacterales infections.

Reported real-world use of ceftazidime-avibactam exceeds that of other novel CRE-active agents, given its position as the first to be approved by the FDA. Since its approval in 2015, numerous observational studies have documented the efficacy and safety of ceftazidime-avibactam for infections due to KPC-producing Enterobacterales. During this time, however, questions regarding exposures during pneumonia and the risk for the emergence of resistance have been raised.^21,22 Among patients with KPC-Kp infections, treatment-emergent resistance to ceftazidime-avibactam has been identified across data from studies and patient populations.^14,22-24 Resistance istypically mediated by mutations in blaKPC Ω-loop that result in preserved in vitro activity for meropenem-vaborbactam and imipenem-relebactam.^17,21,25, In contrast, resistance to meropenem-vaborbactam has been rarely reported.^19,23 In the only 2 published cases, meropenem-vaborbactam resistance against KPC-Kp was associated with mutations

in the ompK36 porin gene. Such mutations have been associated with attenuated virulence in murine models of infection,^26,27 which may explain the relatively low frequency with which resistance has been selected in vivo. During in vitro studies, biologically relevant concentrations of meropenem-vaborbactam suppress the emergence of resistance.²⁸ Further, meropenem-vaborbactam has been specifically designed to target KPC-producing Enterobacterales as demonstrated by the agent’s potent in vitro activity^25,29 and optimized pharmacokinetics.^30,31 Whether these characteristics translate to superior clinical efficacy over ceftazidime-avibactam is still unknown.

One multicenter, retrospective study compared the outcomes of patients with documented CRE infections who received either ceftazidime-avibactam (n = 105) or meropenem-vaborbactam (n = 26) for at least 72 hours.¹⁴ Rates of clinical success, survival, and recurrent infections within 90 days were comparable between treatment arms (Figure). Screening for the presence of carbapenemases occurred in just 45 cases, but the proportion attributed to KPC-producing Enterobacterales was similar between groups (72% vs 77%). Baseline characteristics, underlying diseases, and severity of illness were also similar between groups. Notwithstanding, some important limitations should be noted, including the potential for selection bias given the retrospective observational design of the study, inclusion of polymicrobial infections, and various sites of CRE infection. Between-group differences included a longer median time to treatment initiation for patients who received ceftazidime-avibactam (49 hours) compared with meropenem-vaborbactam (20 hours; P = .02); however, median time to first in vitro active agent was similar (25 vs 15 hours; P = .62). This may be due to more frequent use of combination therapy among patients who received ceftazidime-avibactam (61%) than those who received meropenem-vaborbactam (15%; P < .01). Treatment-emergent resistance was identified among 3 of 15 patients with recurrent infections who received ceftazidime-avibactam compared with 0 of 3 patients who received meropenem-vaborbactam.

Data from 2 sequentially published studies from a single US medical center demonstrated remarkably similar rates of clinical success and survival, which did not vary among patients receiving ceftazidime-avibactam (n = 77) or meropenem-vaborbactam (n = 20) for at least 48 hours to treat CRE infections.^22,23 Seventy-five percent of patients treated with ceftazidime-avibactam and 90% of patients treated with meropenem-vaborbactam were infected with KPC-producing Enterobacterales. Patient demographics and severity of illness were similar across both studies. The median time to treatment initiation was 72 hours for ceftazidime-avibactam and 68 hours for meropenem-vaborbactam. The majority of patients received monotherapy (69% for ceftazidime-avibactam and 80% for meropenem-vaborbactam). Rates of treatment-emergent resistance were 10.4% and 5% following receipt of ceftazidime-avibactam and meropenem-vaborbactam, respectively.

Additional comparative data can be derived from 2 multicenter, retrospective studies from Italy.^10,32 Here, patients received either ceftazidime-avibactam (n = 138) or meropenem-vaborbactam (n = 37) for compassionate use. Accordingly, median times to treatment initiation were 7 and 5 days, respectively. All patients were infected with KPC-Kp, and the vast majority had bloodstream infections. In both studies, patients were critically ill and generally received combination therapy (79% for ceftazidime-avibactam and 62% for meropenem-vaborbactam). The clinical cure rate following treatment with meropenem-vaborbactam was 76%, which is notable considering that 35% of patients had previously received ceftazidime-avibactam and 60% of KPC-Kp isolates were resistant to ceftazidime-avibactam. The clinical cure rate following treatment with ceftazidime-avibactam was not reported.¹⁰ Overall, resistance was reported in 3 patients treated with ceftazidime-avibactam and no patients treated with meropenem-vaborbactam for compassionate use.

Individually, no findings from these studies have demonstrated a difference in clinical efficacy, mortality, or development of resistance following treatment with ceftazidime-avibactam or meropenem-vaborbactam. Taken together, however, some trends have been consistently identified, including higher rates of survival and lower rates of resistance associated with meropenem-vaborbactam. These observations add to the aforementioned in vitro and pharmacokinetic advantages that have been documented. The importance of these observations ultimately depends on validation in larger, multicenter, comparative-effectiveness studies designed to control for the infecting pathogen, site of infection, and severity of illness. Until such time, these data should be interpreted cautiously given their inherent limitations. Time biases may further impact interpretation given that experience in managing CRE infections has improved over time in parallel with the availability of rapid molecular diagnostic tests, accessibility of antimicrobial susceptibility testing for newer agents, and a changing CRE epidemiology in the United States.^3,4 Even with these factors in mind, the cumulative evidence supports preference for meropenem-vaborbactam over ceftazidime-avibactam and imipenem-relebactam for treatment of KPC-producing Enterobacterales infections.⁶ Future comparative-effectiveness studies will be essential in further defining the hierarchy of these, and other newly developed agents, for treatment of infections caused by multidrug-resistant gram-negative pathogens.

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