A No-Carb Diet: An Overview of Non–Carbapenemase-Producing Carbapenem-Resistant Enterobacterales

Epidemiology

Carbapenem-resistant Enterobacterales (CRE) can generally be classified as carbapenemase-producing CRE and non–carbapenemase-producing (non-CP) CRE. The first report of non-CP CRE was published in 1989 in Nottingham, United Kingdom, and described a Klebsiella aerogenes bacterium that exhibited imipenem resistance due to outer membrane protein (OMP) alterations and β-lactamase production.¹ Nearly 40 years later, non-CP CRE spp are the most common mechanism of CRE in the US but the optimal antimicrobial treatment remains to be elucidated.^2,3 In the modern antimicrobial era, more than 97% of CRE isolates that are resistant to ertapenem but susceptible to other carbapenems are classified as non-CP CRE in the US.³ Therefore, ertapenem-monoresistant CRE may be used as a surrogate for non-CP CRE. Surveillance data from the Centers for Disease Control and Prevention found that ertapenem-monoresistant CRE spp were responsible for 62% of CRE in the US from 2016-2017.³ In the US, approximately 50% of non-CP CRE are found in Enterobacter cloacae complex.^3-5 Non-CP CRE spp are seen in Escherichia coli and Klebsiella pneumoniae less frequently in the US, but geographic variability exists.^3-5 Although non-CP CRE spp are the most frequent cause of CRE in the US, widespread differences in CRE epidemiology exist, and non-CP CRE are estimated to represent 26%, 30%, and 70% of all CRE in Korea, Thailand, and Japan, respectively.^6-8

Resistance Mechanisms

Resistance mechanisms in non-CP CRE are heterogeneous, depending on the pathogen, with variable phenotypic expression. Non-CP CRE in K pneumoniae is typically due to production of extended-spectrum β-lactamases (ESBLs) such as SHV, TEM, and CTX-M, whereas E cloacae and K aerogenes typically harbor chromosomal ampC genes.⁹ However, it is unlikely that these β-lactamases alone are responsible for carbapenem resistance in non-CP CRE, and often, the addition of mutations or deletions in the OMP is observed.¹⁰ The absence or reduced expression of ompC and ompF is commonly seen in E cloacae, whereas alterations in ompK35/K36 are more commonly seen in K pneumoniae.^9,11 Non-CP CRE should be suspected with enhanced loss of susceptibility to ertapenem relative to meropenem or imipenem. A plausible mechanism to explain this phenotype may be due to ertapenem’s larger molecular size and negative charge, reflecting delayed penetration through minor porins when major porins are mutated or deleted.¹¹ This may also explain why higher ertapenem minimum inhibitory concentrations (MICs) are observed when both major porins are deleted.⁹ Phenotypically, non-CP CRE spp often exhibit lower carbapenem MICs than carbapenemase producers.¹²

Guideline Recommendations

Although there are limited clinical data comparing antimicrobial agents, current guidance from the Infectious Diseases Society of America (IDSA) recommends the use of extended-infusion meropenem for isolates with a meropenem MIC of less than 1 μg/mL.² For meropenem-nonsusceptible isolates, the IDSA guidance document recommends ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam (TABLE 1).²

Although fluoroquinolones and trimethoprim-sulfamethoxazole are not mentioned as treatment options for non-CP CRE in the IDSA guidance document, they are highly bioavailable antimicrobials that can often remain susceptible to non-CP CRE with in vitro activity that is not compromised by β-lactamase production or OMP alteration.⁴ Meropenem In Vitro Activity Data from CRACKLE-2, a multicenter study of 49 hospitals in the US, report that approximately 25% (213 of 856) of CRE spp that are ertapenem resistant retain meropenem susceptibility.⁵ Meropenem, like other β-lactams, is recommended to have concentrations maintained at 4 times MIC or more to suppress resistance selection, and toxicity typically does not occur until meropenem trough concentrations exceed 50 μg/mL.^13,14 Therefore, therapeutic drug monitoring (TDM) of extended infusion meropenem may be a reasonable alternative to novel agents.¹⁵ Although current guidelines recommend consideration of meropenem for isolates with an MIC of less than 1 μg/mL, further research is warranted to identify the role of meropenem with TDM in non-CP CRE with elevated meropenem MICs.²

Newer β-Lactam/β-Lactamase Inhibitor In Vitro Activity

Castanheira et al performed an in vitro study of 45 non-CP CRE isolates collected from 45 US hospitals.⁴ Consistent with US data, E cloacae and K aerogenes were most common and represented 49% (22 of 45) of isolates. When applying US Food and Drug Administration (FDA) break points, ceftazidime-avibactam inhibited 100% of isolates whereas imipenem-relebactam and meropenem- vaborbactam inhibited 93% of isolates. Notably, MICs were not reported in this study, and it is noted that FDA break points are more lenient for meropenem-vaborbactam at 4 μg/mL or less compared with meropenem at 1 μg/mL or less, which makes susceptibility rates difficult to compare (TABLE 2).

Shortridge et al performed an in vitro antimicrobial susceptibility study of 125 non-CP CRE isolates from Europe, in which 78% (97 of 125) of isolates were K pneumoniae.¹⁰ The most common β-lactamase was bla_CTX-M-15 in 74% (92 of 125) of isolates, and OMP disruptions or alterations were noted among 67% (84 of 125) of isolates. The MIC required to inhibit the growth of 50% of isolates (MIC50) for imipenem, meropenem, and meropenem-vaborbactam was 4 mg/L, 8 mg/L, and 1 mg/L, respectively, which would support meropenem-vaborbactam as a therapeutic option in non-CP CRE due to bla_CTX-M-15 and OMP mutations. Whole-genome sequencing of 3 isolates (2 K pneumoniae and 1 K aerogenes) with meropenem- vaborbactam MICs up to 16 mg/L identified the presence of several β-lactamases and OMP, suggesting multiple β-lactamases are required for the development of resistance.

Finally, Bonnin et al performed an in vitro study of 248 non-CP CRE isolates from France that also consisted predominantly of K pneumoniae (n = 145) followed by E cloacae complex (n = 52).¹⁶ The overall MIC50 for meropenem and meropenem-vaborbactam was 8 mg/L and 4 mg/L, respectively.

Overall, vaborbactam enhanced meropenem activity in 17.9% of the ESBL producers and 14.2% of the ampC producers. The overall MIC50 for imipenem and imipenem-relebactam was 4 mg/L and 1 mg/L, respectively. Relebactam restored imipenem susceptibility in 26.0% of the ESBL producers and 53.0% of the ampC producers. Therefore, imipenem- relebactam may be more likely to be active against non-CP CRE in E cloacae complex and K aerogenes. When applying European Committee on Antimicrobial Susceptibility Testing (EUCAST) break points, ceftazidime-avibactam was still found to be most likely to be susceptible and the overall susceptibility rate of meropenem-vaborbactam, imipenem- relebactam, and ceftazidime-avibactam was 80.6%, 81% and 88%, respectively.

Cefiderocol In Vitro Activity

In a study of 442 CRE isolates from Europe and the US between 2020 and 2021, 110 were found to be non-CP CRE.¹⁷ When applying EUCAST break points, cefiderocol was susceptible to 85% of the 110 isolates whereas ceftazidime-avibactam was susceptible to 98% of isolates. Although this would suggest that ceftazidime- avibactam may be more reliable against non-CP CRE, cross-resistance may occur. A prior case report has demonstrated that following cefepime exposure, resistance of ceftazidime-avibactam and cefiderocol occurred in a non-CP CRE E cloacae complex, which harbored ampC β-lactamase in addition to OMP mutations.¹⁸

Clinical Outcomes

Clinical studies comparing treatment options for the management of non-CP CRE do not exist. However, several studies have compared clinical outcomes between patients infected with CP CRE and non-CP CRE and have reported conflicting results. In an observational study, Tamma et al compared 46 patients with non-CP CRE bacteremia to 37 patients with CP CRE bacteremia.¹⁹ Of the 37 patients with CP CRE, 92% had infection due to K pneumoniae carbapenemase (KPC). After adjusting for baseline confounders, 14-day mortality was higher for CP CRE compared with non-CP CRE bacteremia. However, no patients received treatment with a novel agent, given that this study was performed between March 2013 and April 2016. It is therefore unclear whether these data are as applicable to the current antimicrobial era.

Conversely, Hovan et al performed a retrospective study between 2010 and 2019 of 146 patients. Results found non-CP CRE bacteremia to be associated with a 2.4-times higher hazard of death at 30 days after bacteremia onset compared with CP-CRE.²⁰ This is despite patients with CP CRE bacteremia being less likely to receive active empiric or targeted antibiotic therapy. Furthermore, it is noted that 92% of CP CRE infections were due to KPC and only 14% of patients with CP CRE were managed with ceftazidime-avibactam or meropenem-vaborbactam.

Baek et al performed a multicenter study from South Korea between 2018 and 2022 that assessed 318 patients with CRE bacteremia. After propensity score matching, the HR for mortality in the CP CRE group was not statistically higher compared with the non-CP CRE group.⁶ Notably, KPCs represented 75% of the CP CRE and novel agents were not used in this study. In a study of 88 patients from Japan from 2016-2018, those with imipenem-like carbapenemase isolation did not have higher mortality compared with those with non-CP CRE. However, this study included patients who had colonization and did not have active infection.⁸

Finally, patients from CRACKLE-2, a multicenter study of 49 hospitals in the USA, were subsequently included in an analysis comparing 213 patients with CRE infection that was only resistant to ertapenem and 643 patients with CRE infection that was resistant to multiple carbapenems between 2016 and 2019.⁵ Of the included patients, 37% had bacteremia. Patients with CRE infections that were only resistant to ertapenem were most commonly managed with meropenem, whereas patients with CRE infections that were resistant to multiple carbapenems were most commonly managed with ceftazidime-avibactam. There was no significant difference in the adjusted probability of a more desirable outcome for a randomly selected patient between those that were infected with isolates that were only resistant to ertapenem and those infected with isolates that were resistant to multiple carbapenems.

Conclusion

Overall, clinical studies remain limited given that the antimicrobial agents used for management of non-CP CRE are highly variable. Without a direct comparison of agents, optimal antimicrobial management of non-CP CRE will remain controversial. Furthermore, none of the studies to date have assessed the subsequent development of resistance to each antimicrobial regimen following the management of non-CP CRE. The development of subsequent resistance in non-CP CRE also remains an area of further study, as cross-resistance between novel agents can occur. Finally, if carbapenems are used in accordance with IDSA recommendations, TDM should be considered.

References

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