Carbapenem-Resistant Enterobacterales (CREs)

Introduction

Carbapenem-Resistant Enterobacterales (CRE) represent a formidable challenge in modern medicine. These bacteria are part of the Enterobacterales order a group that includes common pathogens such as Escherichia coli and Klebsiella pneumoniae. Carbapenem-Resistant Enterobacterales (CRE) have developed resistance to carbapenems, a class of antibiotics considered the last line of defense against multidrug-resistant bacterial infections. The global spread of Carbapenem-Resistant Enterobacterales (CRE) has raised alarms in clinical and public health communities due to limited treatment options, high mortality rates, and the potential for rapid transmission in healthcare settings.

The Enterobacterales Family

Enterobacterales is an order of Gram-negative bacteria that primarily inhabit the intestines of humans and animals. Members of this group include:

• Escherichia coli (E. coli)
• Klebsiella pneumoniae
• Enterobacter cloacae
• Serratia marcescens
• Proteus mirabilis
• Citrobacter freundii

These organisms are common causes of urinary tract infections (UTIs), pneumonia, bloodstream infections, intra-abdominal infections, and wound infections. While many Enterobacterales exist as harmless commensals, certain strains have acquired virulence factors and antibiotic resistance mechanisms, making them significant clinical pathogens.

What Are Carbapenems?

Carbapenems are a class of β-lactam antibiotics known for their broad-spectrum activity. They are often reserved for severe or high-risk bacterial infections where other antibiotics have failed. Examples include:

• Imipenem
• Meropenem
• Ertapenem
• Doripenem

Their efficacy lies in their ability to inhibit bacterial cell wall synthesis and resist degradation by most β-lactamases, enzymes that many bacteria use to neutralize penicillins and cephalosporins. However, with increasing carbapenem use, resistance has emerged, primarily through the acquisition of carbapenemase enzymes.

Mechanisms of Carbapenem Resistance

CRE possess the ability to withstand carbapenem antibiotics through various mechanisms:

• Production of Carbapenemases: Enzymes such as KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi metallo-β-lactamase), VIM (Verona integron-encoded metallo-β-lactamase), and OXA-48-type carbapenemases directly break down carbapenem molecules, rendering them ineffective.
• Efflux Pumps: Increased activity of cellular pumps can expel antibiotics from bacterial cells before they can act.
• Reduced Permeability: Alterations in the bacterial outer membrane can prevent antibiotics from entering the cell.
• Combination of Mechanisms: Often, resistance is multifactorial, involving both enzyme production and structural changes.

The genes encoding carbapenemases are frequently located on plasmids—mobile genetic elements that facilitate rapid and widespread transmission of resistance between bacteria, both within and across species.

Epidemiology and Global Spread

Since their first identification in the early 2000s, Carbapenem-Resistant Enterobacterales have rapidly disseminated worldwide. Outbreaks have been reported in North America, Europe, Asia, and beyond. Hospitalized patients, particularly those in intensive care units (ICUs), are at the highest risk due to frequent antibiotic exposure, invasive procedures, and underlying illness.

Factors contributing to the spread of Carbapenem-Resistant Enterobacterales include:

• International travel and medical tourism
• Overuse and misuse of antibiotics in humans and animals
• Inefficient infection control practices
• Prolonged hospital stays and use of indwelling devices (e.g., catheters, ventilators)

The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) have classified CRE as urgent public health threats, necessitating coordinated global action.

Clinical Impact

Infections caused by CRE are associated with:

• High mortality rates, often exceeding 40% in cases of bloodstream infections
• Prolonged hospitalizations and increased healthcare costs
• Limited effective treatment options, leading to reliance on older, more toxic drugs such as colistin and tigecycline

Common clinical presentations include:

• Urinary tract infections (UTIs)
• Pneumonia (especially ventilator-associated)
• Bacteremia (bloodstream infection)
• Intra-abdominal and wound infections

Patients with weakened immune systems, the elderly, and those with chronic health conditions are particularly vulnerable.

Diagnosis

Early detection of CRE is essential for patient management and infection control. Diagnostic approaches include:

• Cultures: Isolation of Enterobacterales from clinical specimens (e.g., blood, urine, respiratory samples)
• Antibiotic Susceptibility Testing: Determines resistance to carbapenems and other antibiotics
• Polymerase Chain Reaction (PCR): Detects genes encoding carbapenemases (e.g., blaKPC, blaNDM, blaVIM, blaOXA-48)
• Phenotypic Assays: Tests such as the modified Hodge test, Carba NP test, and others confirm carbapenemase production

Hospitals routinely screen high-risk patients, particularly those transferred from other facilities or regions with high CRE prevalence.

Treatment Challenges

The therapeutic options for CRE infections are extremely limited. Many CRE isolates are resistant not only to carbapenems but also to most other antibiotic classes, including penicillins, cephalosporins, fluoroquinolones, and aminoglycosides.

Current treatment strategies involve:

• Combination Therapy: Using two or more antibiotics with different mechanisms to improve efficacy and reduce resistance emergence.
• Novel Agents: Recent approvals include ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin, which may be active against some CRE strains.
• Older Agents: Drugs such as colistin and fosfomycin are sometimes used despite their toxicity and pharmacological limitations.

Individualized therapy based on susceptibility testing and infectious diseases consultation is recommended. However, treatment failures and relapses are common.

Infection Prevention and Control

Preventing the spread of CRE in healthcare settings requires stringent infection control measures:

• Hand hygiene with alcohol-based solutions or soap and water
• Contact precautions, including gloves, gowns, and dedicated patient equipment
• Screening and isolating colonized or infected patients
• Environmental cleaning and disinfection
• Antibiotic stewardship programs to minimize unnecessary use
• Education and training of healthcare workers

Community transmission, though less common, is increasingly recognized and warrants public health attention.

Public Health Implications

CRE pose a significant threat to global health. They compromise the management of common infections and medical procedures, including surgeries, organ transplants, and cancer therapy. Without effective antibiotics, the risk of untreatable infections rises, threatening decades of medical progress.

Global surveillance, coordinated response, and investment in research for new diagnostics, therapeutics, and vaccines are critical. Education for healthcare professionals and the public about the dangers of antibiotic misuse is also crucial.

Nursing Care of Patients with Carbapenem-Resistant Enterobacterales (CRE)

Nurses play a pivotal role in the management and prevention of CRE infections. Their responsibilities extend from early identification and isolation to ongoing surveillance, patient and family education, and holistic patient care.

Assessment and Early Identification

1. Risk Factor Assessment

• Review patient history for prior infections or colonization with multidrug-resistant organisms (MDROs).
• Identify risk factors such as recent hospitalization, long-term care residency, use of invasive medical devices, immunosuppression, and history of antibiotic usage, especially carbapenems.

2. Clinical Assessment

• Monitor for signs and symptoms of infection: fever, chills, increased white blood cell count, localizing symptoms (e.g., dysuria, respiratory distress, wound drainage).
• Observe for subtle changes in vital signs or mental status, especially in older adults and immunocompromised patients.

3. Laboratory and Diagnostic Support

• Collect appropriate specimens for culture and sensitivity testing before initiating antibiotics whenever possible.
• Ensure prompt transport of specimens to the laboratory.
• Monitor laboratory results for evidence of resistance and relay findings to the healthcare team promptly.

Infection Prevention and Control

The cornerstone of CRE management is the prevention of transmission within healthcare settings.

1. Standard and Transmission-Based Precautions

• Practice meticulous hand hygiene before and after patient contact, after removing gloves, and after contact with potentially contaminated surfaces.
• Use alcohol-based hand rubs or soap and water; the latter is preferred if hands are visibly soiled.
• Apply contact precautions: wear gloves and gowns upon room entry and remove and dispose of them before leaving the patient’s environment.

2. Patient Placement and Cohorting

• Place CRE-infected or colonized patients in single rooms whenever feasible.
• If single rooms are unavailable, cohort patients with the same CRE organism together.
• Dedicate non-critical equipment (e.g., stethoscopes, thermometers) to individual patients and disinfect between uses.

3. Environmental Cleaning

• Ensure thorough and frequent cleaning of patient rooms, especially high-touch surfaces (bed rails, bedside tables, doorknobs, call bells).
• Use Environmental Protection Agency (EPA)-approved disinfectants effective against CRE.
• Monitor cleaning practices for adherence to protocols.

4. Visitor Education and Restrictions

• Educate visitors on the importance of hand hygiene and the proper use of personal protective equipment (PPE).
• Restrict visitor movement within the facility to minimize cross-contamination.

Therapeutic Management and Nursing Interventions

1. Administering Antimicrobial Therapy

• Administer antibiotics as ordered, ensuring the correct drug, dose, route, and timing.
• Monitor for adverse drug reactions, especially nephrotoxicity and ototoxicity associated with some second-line agents used to treat CRE.
• Collaborate with pharmacists and infectious disease specialists regarding medication adjustments based on renal function and culture results.

2. Monitoring and Managing Complications

• Assess for signs of worsening infection or sepsis: hypotension, tachycardia, decreased urine output, altered mental status.
• Supportive care may include intravenous fluids, vasopressors, and oxygen therapy as needed.
• Monitor laboratory markers (e.g., complete blood count, renal and liver function tests, lactate) closely.

3. Supportive and Symptom-Based Care

• Provide wound care, respiratory care, or urinary catheter care as appropriate, using aseptic technique at all times.
• Manage fever, pain, and other symptoms to maximize patient comfort and promote recovery.
• Encourage adequate hydration and nutrition, including assistance with meals or supplements for at-risk patients.

4. Psychosocial Support

• Address the anxiety and stress associated with isolation protocols and severe infection.
• Provide emotional support to patients and families, explaining the reasons for precautions and treatment plans in understandable language.
• Facilitate communication with loved ones through telephone or video calls if visitation is restricted.

Education and Discharge Planning

1. Patient and Family Education

• Teach patients and families about CRE, its transmission, treatment, and the importance of adherence to infection control measures.
• Demonstrate proper hand hygiene and, if necessary, wound or catheter care techniques.
• Explain the rationale for antibiotics, possible side effects, and the importance of completing the prescribed course.

2. Preparing for Discharge

• Assess the suitability of the home environment for continued precautions, especially if the patient remains colonized with CRE.
• Coordinate with case managers and social workers to arrange for home health services, if required.
• Provide written instructions on infection prevention for home and community settings, including safe handling of wound dressings, laundry, and waste.
• Advise follow-up appointments and whom to contact in case of worsening symptoms.

Interdisciplinary Collaboration

Managing CRE infections requires a team approach. Nurses should:

• Communicate regularly with physicians, pharmacists, infection control practitioners, and other healthcare professionals.
• Participate in antimicrobial stewardship programs to ensure judicious use of antibiotics and reduce the risk of further resistance.
• Contribute to surveillance efforts by reporting new cases and adhering to data collection protocols.

Ongoing Surveillance and Quality Improvement

1. Surveillance

• Support facility-wide surveillance activities to promptly identify and contain outbreaks.
• Track infection rates, sources, and outcomes as part of infection control committees.

2. Education and Training

• Participate in continuing education on MDROs, PPE use, and emerging therapies for CRE.
• Promote a culture of safety by modeling and reinforcing best practices in infection prevention.

Ethical and Legal Considerations

Nurses must balance infection control with respect for patient dignity, privacy, and autonomy. Always:

• Obtain informed consent for treatments and procedures.
• Safeguard confidential health information, including CRE status.
• Advocate for equitable care and resources for affected patients.

REFERENCES

1. Centers for Disease Control and Prevention (U.S.). CRE Technical Information. https://www.cdc.gov/hai/organisms/cre/technical-info.html. Last reviewed 12/22/2019.
2. Hu Q, Chen J, Sun S, Deng S. Mortality-Related Risk Factors and Novel Antimicrobial Regimens for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review https://pubmed.ncbi.nlm.nih.gov/36465807/. Infect Drug Resist. 2022 Nov 28;15:6907-6926.
3. Janda JM, Abbott SL. The Changing Face of the Family Enterobacteriaceae (Order: “Enterobacterales”): New Members, Taxonomic Issues, Geographic Expansion, and New Diseases and Disease Syndromes.. https://pubmed.ncbi.nlm.nih.gov/33627443/ Clin Microbiol Rev. 2021 Feb 24;34(2):e00174-20.
4. Mackow NA, van Duin D. Reviewing novel treatment options for carbapenem-resistant Enterobacterales. Expert Rev Anti Infect Ther. 2024 Jan-Jun;22(1-3):71-85. doi: 10.1080/14787210.2024.2303028. Epub 2024 Feb 12. PMID: 38183224; PMCID: PMC11500727.
5. Smith HZ, Hollingshead CM, Kendall B. Carbapenem-Resistant Enterobacterales. 2024 Feb 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 31869168. https://pubmed.ncbi.nlm.nih.gov/31869168/
6. Merck Manual, Professional Version. Carbapenems.. https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/carbapenems Reviewed 5/2022.
7. Tompkins K, van Duin D. Treatment for carbapenem-resistant Enterobacterales infections: recent advances and future directions. Eur J Clin Microbiol Infect Dis. 2021 Oct;40(10):2053-2068. https://pubmed.ncbi.nlm.nih.gov/37374993/
8. Sheu CC, Chang YT, Lin SY, Chen YH, Hsueh PR. Infections Caused by Carbapenem-Resistant Enterobacteriaceae: An Update on Therapeutic Options. https://pubmed.ncbi.nlm.nih.gov/30761114/. Front Microbiol. 2019 Jan 30;10:80.

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