Carbapenem Resistant EnterobacteriaceaeEdit

Carbapenem resistant Enterobacteriaceae (CRE) are a group of Gram-negative bacteria within the family Enterobacteriaceae that have acquired resistance to carbapenems, a class of antibiotics that are often reserved for severe, life-threatening infections. CRE most commonly involve species such as Klebsiella pneumoniae and Escherichia coli, but other members of the family—including Enterobacter spp., Serratia spp., and Citrobacter spp.—can also harbor carbapenem resistance. Resistance can arise from production of carbapenemase enzymes that directly break down carbapenems, or from non-enzymatic mechanisms such as porin loss in combination with upregulated beta-lactamases. CRE infections are challenging to treat, and their spread within hospitals and communities is a major concern for patient safety, antimicrobial stewardship, and public health planning. The rise of CRE has driven the development of rapid diagnostics, new antimicrobial agents, and intensified infection control measures in healthcare settings.

This topic sits at the intersection of microbiology, medicine, and policy, because the biology of resistance interacts with antibiotic use, infection prevention, and surveillance systems. Understanding CRE requires attention to the biology of resistance genes, the clinical contexts in which infections occur, and the health systems needed to prevent transmission and ensure access to effective therapies. While individual stewardship decisions matter at the bedside, the broader challenge is coordinated action across laboratories, hospitals, and public health authorities to limit the spread of these organisms and preserve the effectiveness of available treatments.

Definition and taxonomy

Carbapenem resistant Enterobacteriaceae are defined by their resistance to carbapenems, typically assessed through clinical microbiology testing. CRE can be broadly divided into those that produce carbapenemases (carbapenemase-producing Enterobacteriaceae, or CPE) and those that resist carbapenems through non-carbapenemase mechanisms. The major carbapenemase families include the metallo-beta-lactamases and serine carbapenemases, notably KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi metallo-beta-lactamase), VIM (Verona integron-encoded metalloproteinase), IMP (imipenemase), and OXA-48-like enzymes. Resistance genes often reside on plasmids, transposons, and other mobile elements, enabling rapid horizontal transfer between species and within bacterial communities.

Species most frequently implicated in CRE infections include Klebsiella pneumoniae and Escherichia coli, but other enteric bacteria in the Enterobacteriaceae family—such as Enterobacter, Serratia, and Citrobacter—can harbor carbapenem resistance. The term CRE can thus refer to a broad spectrum of organisms sharing the resistance phenotype, whereas the term CPE highlights the subset carrying carbapenemase genes.

Mechanisms of resistance

Carbapenem resistance in Enterobacteriaceae stems from a combination of mechanisms:

Carbapenemase production: Bacteria synthesize enzymes that hydrolyze carbapenems, directly neutralizing the antibiotic. The main families are KPC, NDM, VIM, IMP, and OXA-48-like enzymes.
Porin loss and efflux: Structural changes in outer membrane porins reduce antibiotic entry, and efflux pumps expel antimicrobial agents, sometimes in conjunction with AmpC beta-lactamases or ESBLs to diminish susceptibility.
Combination effects: In some cases, non-carbapenemase producers achieve high-level resistance when porin loss co-occurs with other beta-lactamases.

The presence and type of resistance mechanism influence both the clinical phenotype and the choice of therapeutic options. Molecular tests that detect carbapenemase genes and phenotypic assays that infer carbapenemase activity are used to classify isolates and guide treatment and infection control.

Epidemiology and transmission

CRE are a global health concern, with uneven geographic distribution and varying patterns of spread. In many settings, CRE colonization, rather than active infection, serves as a reservoir that sustains transmission within hospitals and other facilities. Transmission is facilitated by:

Dense patient populations and invasive procedures (for example, catheterization and mechanical ventilation).
Antibiotic use that selects for resistant strains.
Movement of patients between healthcare facilities, and international travel or medical tourism.
Environmental contamination and staff-to-patient transmission in high-risk units.

Surveillance data show regional differences in the prevalence of carbapenemases. For instance, certain carbapenemase genes have become endemic in some regions while being less common in others. Ongoing global surveillance, hospital screening programs, and coordinated public health responses are essential to track trends and implement targeted infection control measures.

Clinical significance and infection types

CRE infections include bloodstream infections, pneumonia (including ventilator-associated pneumonia), intra-abdominal infections, urinary tract infections, and soft-tissue infections. They are associated with higher morbidity and mortality, longer hospital stays, and increased healthcare costs compared with non-CRE infections. Outcomes depend on factors such as host comorbidity, source control, timeliness of appropriate therapy, and appropriateness of the antimicrobial regimen chosen.

The choice of empirical and definitive therapy depends on local epidemiology and the carbapenemase profile of the isolate. In some cases, CRE remain susceptible to non-carbapenem antibiotics, while in others, treatment options are severely limited. Clinicians must balance the risks of toxicity, inadequate source control, and the emergence of further resistance when designing regimens.

Diagnosis and surveillance

Diagnosis relies on a combination of phenotypic and genotypic approaches:

Phenotypic susceptibility testing identifies resistance to carbapenems and suggests the presence of a carbapenemase, often using automated systems or manual methods.
Rapid molecular tests detect specific carbapenemase genes (e.g., KPC, NDM, VIM, IMP, OXA-48) directly from clinical specimens or cultures.
Phenotypic enzyme tests and immunochromatographic assays can provide rapid information about carbapenemase activity and help guide immediate infection control decisions.
Species identification and antimicrobial susceptibility profiling remain essential for selecting effective therapies.

Public health surveillance platforms, such as Global Antimicrobial Resistance and Use Surveillance System and national programs, monitor CRE incidence, track outbreaks, and inform policy decisions. Molecular typing and epidemiological investigations help distinguish clonal spread from sporadic cases, aiding containment efforts.

Treatment and management

Treating CRE infections involves a combination of selecting agents with demonstrable activity against the isolate, optimizing pharmacokinetics and pharmacodynamics, and achieving source control when possible. Therapeutic options vary by carbapenemase type and local susceptibility patterns. Important considerations include:

Ceftazidime-avibactam is active against many KPC-producing strains and can be a first-line option in appropriate settings, but it is less effective against certain metallo-beta-lactamase producers (e.g., many NDM producers) unless combined with other agents.
Meropenem-vaborbactam and imipenem-relebactam are useful in certain carbapenemase contexts, particularly for KPC producers, and can be considered when susceptibility allows.
Aztreonam-avibactam provides activity against several metallo-beta-lactamase producers when combined with a beta-lactamase inhibitor, exploiting aztreonam’s stability to metallo-beta-lactamases.
Cefiderocol is a siderophore cephalosporin with activity against a broad range of CRE, including some metallo-beta-lactamases, but its use depends on local data and regulatory approval.
Older agents such as colistin (polymyxins), tigecycline, and fosfomycin may play roles in certain regimens, particularly when other options are limited, but they carry safety concerns and variable efficacy.
Combination therapy is common, particularly for severe infections, to maximize chances of clinical response and limit resistance selection. Decisions are guided by the organism’s susceptibility profile, site of infection, patient factors, and local resistance patterns.
Antimicrobial stewardship is essential to preserve the effectiveness of available agents, minimize toxicity, and reduce the emergence of further resistance. When possible, doctors aim for definitive therapy informed by culture results rather than prolonged empiric broad-spectrum regimens.
Source control, including drainage of abscesses or surgical management of intra-abdominal infections, remains a critical component of treatment.

The landscape of CRE treatment continues to evolve with ongoing research, and regional formularies may differ in available options. Clinicians must stay informed about local resistance trends, emerging therapies, and updated guidelines to optimize outcomes.

Infection prevention and control

Preventing CRE transmission in healthcare settings requires a combination of standard precautions, contact precautions for carriers or infected patients, and targeted screening strategies. Key elements include:

Rigorous hand hygiene and adherence to infection prevention protocols.
Isolation or cohorting of CRE-positive patients and dedicated staff when feasible.
Environmental cleaning and disinfection, with attention to high-touch surfaces and shared equipment.
Active surveillance to identify colonized patients, particularly in high-risk units such as intensive care and long-term care facilities.
Antimicrobial stewardship to minimize unnecessary antibiotic exposure and selection for resistant organisms.
Education of healthcare workers, patients, and visitors about transmission risks and prevention measures.

Public health authorities monitor outbreaks and provide guidance for containment, while hospitals collaborate with laboratories to ensure timely detection and reporting of CRE cases.

Research and future directions

Ongoing research seeks to improve every link in the CRE cycle: rapid and accurate diagnostics, effective and safe treatments, and stronger prevention strategies. Areas of focus include:

Development of rapid molecular and phenotypic tests to identify carbapenemase genes and resistance mechanisms at the point of care.
Expansion of the armamentarium with novel antibiotics and beta-lactamase inhibitors tailored to specific resistance mechanisms.
Innovative approaches to infection control, including environmental decontamination technologies and improved screening algorithms.
Alternatives and adjuncts to antibiotics, such as phage therapy, anti-virulence strategies, immunotherapies, and vaccines, to reduce colonization and infection.
Better understanding of plasmid biology and the ecology of resistance to inform strategies that disrupt gene transfer and persistence in microbial communities.