Control of Carbapenemase-producing Enterobacteriaceae: Beyond the Hospital

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most worrying multidrug-resistant Gram-negative organisms that emerge as an increasingly serious public health threat. The presence of plasmid-mediated carbapenemase genes in the environment, companion and food animals enables them to act as potential reservoirs leading to community acquisition of carbapenemase-producing Enterobacteriaceae (CPE) [1]. A person may start as an asymptomatic CPE carrier with low bacterial load in the gastrointestinal tract, but the bacterial load increases with the use of broad-spectrum antimicrobial agents, especially during hospitalization [2]. Consequently, healthcare facilities are notorious epidemic centers for CPE transmissions, particularly in settings where hand hygiene and environmental hygiene are suboptimal due to low staff to patient ratio. Nosocomial outbreaks of CPE are frequently reported in clinical units and even at hospital level, posing a great challenge to infection control professionals [3].

Recognizing the need for controlling the spread of CPE in both community and healthcare settings, Shen Z et al. conducted a cross-sectional observational study to understand the prevalence of fecal carriage of CRE and CPE, with a particular focus on E. coli, among healthy volunteers in 19 provinces across China [4]. They found that the prevalence of CRE and CPE was 2.4% (92/non-duplicated 3859 stool specimens) and 1.1% (43/3859) respectively. The prevalence of CRE in the community was comparable to the corresponding figures in the hospitals, where the rate of CRE isolated in clinical specimens of E. coli was around 0.6–3.6%, as illustrated in the China Antimicrobial Resistance Surveillance Report, which is a nationwide survey with specimens collected from hospitals located in 25 provinces and municipalities in China [5]. In fact, the burden of asymptomatic gastrointestinal colonization of CRE and CPE might have been underestimated as the recruited subjects had not received antimicrobial agents 3 months prior to the collection of fecal specimens.

Rapid dissemination of plasmid IncX3 carrying the carbapenemase gene, bla_NDM-5, among E. coli isolates in healthy volunteers, along with the identification of bla_NDM-5 in poultry opens a new horizon for the investigation of transmission dynamics of antimicrobial resistance. The extensive spread of bla_NDM in China is strongly linked to this epidemic plasmid which we first described in 2012 [6], [7]. We believe that the global dissemination of CTX-M type extended-spectrum beta-lactamase (ESBL) foretells the future of bla_NDM in the next 5 to 10 years, which will most likely spread across the globe and render treatment by carbapenem futile.

In this study, co-existence of bla_NDM-5 and mcr-1 (plasmid-mediated colistin resistance) in 0.36% (14/3859) of healthy volunteers is a new but not unexpected finding. In fact, mcr-1 carriage in E. coli isolates has been shown in 14.9% (78/523 samples) of raw meat and 21% (166/804) food animals, as well as 1% (16/1322 samples) from hospitalized patients with infection in China [8]. These carbapenem- and colistin-resistant E. coli will become nightmares for patients and doctors. Epidemiological analysis to understand risk factors for community acquisition of CPE and plasmid-mediated colistin-resistant Enterobacteriaceae is urgently warranted. Without the understanding of risk factors among silent CPE carriers in the community, universal admission screening or admission screening in high-risk clinical units such as transplant, oncology centers, or intensive care units, may be a potential option. These patients with newly diagnosed CPE upon admission should be placed in a single room with strict contact precautions, with particular emphasis on directly observed hand hygiene [9]. Otherwise, the risk of nosocomial transmission of CPE may not be minimized.

Dissemination of CPE as well as plasmid-mediated colistin-resistant Enterobacteriaceae has evidently spread beyond hospitals. An antimicrobial stewardship program in the healthcare setting alone is grossly insufficient in the grand scheme of things. Antimicrobial use must be tightly regulated to eliminate such selective pressure, including the illegalization of antimicrobials as growth promoters in animal feeds, and the regulation of antimicrobial use in veterinary practice in addition to human medicine [10].

Key factors that contribute to community transmission are inadequate hygiene (farms, food processing, kitchen, toilet, hand washing), waste disposal and antibiotic overuse. In terms of treatment, while New Delhi metallo-beta-lactamase (NDM) was first identified 10 years ago, little progress has been made in the antibiotic pipeline. All the new beta-lactamase inhibitors (relebactam, avibactam, vaborbactam) are ineffective against NDM leaving us few or no effective options to tackle infections caused by these organisms. This is why a worldwide orchestrated effort is desperately needed for the control of CPE, and understanding the prevalence of CPE in the community is definitely a start.