Navigating Antibiotic Choices in the Face of Diverse Carbapenemase-Producing Enterobacteriaceae

The landscape of antibiotic resistance among Gram-negative bacteria, particularly Carbapenemase-Producing Enterobacteriaceae (CPE), presents significant clinical challenges that require nuanced understanding of both the molecular mechanisms of resistance and the regional epidemiology influencing these mechanisms.

Ceftazidime-avibactam is the preferred choice for infections caused by Enterobacteriaceae harboring OXA-48-like enzymes. The efficacy of this combination is attributed to avibactam’s robust inhibition of OXA-48-like carbapenemases, which enhances the bactericidal activity of ceftazidime.

For NDM-producing Enterobacteriaceae, which often produce class B metallo-β-lactamases (MBLs), recommended treatments include ceftazidime-avibactam plus aztreonam or cefiderocol monotherapy. Notably, aztreonam is resistant to hydrolysis by NDM and other MBLs, but its effectiveness is compromised by co-produced β-lactamases like ESBLs, AmpC, KPCs, or OXA-48-like enzymes. Here, avibactam’s inhibition of these additional β-lactamases restores aztreonam’s activity, making this combination especially valuable in regions with a high prevalence of MBLs.

In the treatment of KPC-producing infections, meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred, leveraging their potent activity against class A carbapenemases. Among these, meropenem-vaborbactam is slightly favored based on clinical outcomes and the relative emergence of resistance, as evidenced by available data.

Aztreonam, specifically, is stable against hydrolysis by class B MBLs like NDM, which positions it as a crucial agent against MBL producers. However, its utility is limited when these pathogens co-produce other β-lactamases that can degrade aztreonam. Avibactam, a broad-spectrum β-lactamase inhibitor, counters this by inhibiting serine β-lactamases such as ESBLs, AmpC, KPC, and OXA-48-like enzymes. This dual inhibition mechanism not only targets robust MBLs but also other co-produced β-lactamases, thus broadening the therapeutic efficacy of aztreonam against resistant strains.

It’s important to consider the global distribution of carbapenemases: β-lactam–β-lactamase inhibitor (βL-βLI) combinations like ceftazidime-avibactam and meropenem-vaborbactam are effective against class A carbapenemases such as KPC but are generally ineffective against class B MBLs, including NDMs. The Asian continent, with an estimated 60% of global NDM producers, exemplifies a region where these βL-βLI combinations would be less useful, highlighting the need for alternative therapies in such settings.

The investigational aztreonam-avibactam combination promises efficacy in treating infections that involve both MBLs and other β-lactamases. The dual inhibition mechanism not only targets the robust MBLs but also counters the resistance posed by co-produced β-lactamases, offering a potential therapeutic advantage in regions heavily impacted by these resistance factors.

Understanding the epidemiology of specific carbapenemase genes is critical. Dual carbapenemase carriage, typically NDM co-occurring with KPC or OXA-48-like carbapenemases, is not uncommon and requires astute clinical insight into local resistance patterns for effective treatment planning.

This deep dive into the molecular and epidemiological aspects of carbapenemase production underscores the necessity for tailored antibiotic strategies that align with regional resistance profiles. Effective management of CPE infections depends on the continued advancement of diagnostic capabilities, therapeutic interventions, and an acute awareness of the geographic distribution of carbapenemase genes.

Antimicrobial stewardship is crucial for managing the use of novel antibiotics, particularly in the context of complex infections caused by carbapenemase-producing Enterobacteriaceae (CPE). Stewardship efforts aim to ensure judicious use of these potent drugs to avoid treating patients who are merely colonized rather than infected. This distinction is vital, as inappropriate use of broad-spectrum antibiotics can lead to unnecessary treatment, increased healthcare costs, and the acceleration of antibiotic resistance.

Effective stewardship involves tailoring antibiotic therapy based on precise microbial identification and susceptibility testing, optimizing dosing regimens to maximize efficacy while minimizing toxicity, and shortening the duration of therapy to the necessary minimum. By adhering to these principles, healthcare providers can preserve the effectiveness of current treatment options, safeguard patient outcomes, and reduce the overall burden of antibiotic resistance.