Carbapenemase producing Enterobacteriaceae (CPE) has emerged as a significant global public health challenge and placing infected patients at risk of potentially untreatable infections. When resistance to carbapenems occurs, there are often few alternative treatments available. Numerous international guidelines have performed systematic and evidence review to identify new strategies to prevent the entry and spread of CPE in healthcare settings. Several key strategies have been shown to be highly effective. Firstly a new strategy that is proven to be effective is the early identification of the CPE carrier patients through active surveillance cultures. While waiting for the screening results, suspected CPE carriers will be put on preemptive isolation in single room and healthcare worker will at the same time practice contact precautions. The active surveillance culture and prompt preemptive isolation will limit the entry and spread of CPE from getting into hospital. Secondly, it is of utmost importance to incorporate enforcement of the basic infection prevention and control best practices in the hospital including, full compliance to hand hygiene, appropriate use of personal protective equipment, execute antibiotic stewardship program to control abuse of antibiotics, effective environmental cleaning and decontamination, staff education and feedback, as well as surveillance of healthcare-associated infections. Such a holistic approach has been shown to be effective in inhibiting CPE from gaining foothold in the hospital.
Carbapenemase producing Enterobacteriaceae (CPE) infections and outbreaks are reported globally from different healthcare settings including the acute care and long-term care. These infections are often associated with high patient morbidity and mortality and also imposing a high cost to hospitals for controlling related outbreaks. Learning from the evidence review on the control of CPE outbreaks,[1-8] as well as the review of the international guideline on the prevention and control of CPE, a brief update on the latest recommendations and strategies is outlined for hospitals’ reference.
1 What is CPE and the challenge to healthcare?
Enterobacteriaceae are Gram-negative bacteria colonizing the normal human gastrointestinal tract and that include common pathogens such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus species. The Enterobacteriaceae can be vehicles for the dissemination of antimicrobial resistance and they are the most frequent Gram-negative bacteria to cause human infections in the community and in healthcare settings. CPE are members of the Enterobacteriaceae genus that are resistant to carbapenems, a class of last available antibiotics for treating serious infections. The most common way that CPE becomes resistant to carbapenems is by producing an enzyme called a carbapenemase that is commonly identified in clinical isolates including IMP, NDM, VIM, KPC, and OXA-48-like. Each carbapenemase has a slightly different spectrum of activity against different antibiotics such as other beta-lactams, beta-lactamase inhibitor combinations, fluoroquinolones, and aminoglycosides. Treatment of these infections is increasingly difficult as these organisms are often resistant to many and sometimes all available antibiotics. Especially vulnerable patients with comorbidities are at increased risk of developing CPE infection and dying as a consequence. CPE are highly transmissible and have a high potential to cause outbreaks in healthcare settings. Following the worldwide dissemination of CPE, a range of outbreaks have occurred across different global regions in acute care settings, as well as in long-term care facilities (LTCFs). Outbreaks of CPE have been found to be highly costly. A cost evaluation of a CPE outbreak occurring across five hospitals in the United Kingdom estimated a cost of approximately 1.1 million Euros over 10 months. Therefore the development of infection prevention and control guidelines for controlling CPE is an urgent priority.
2 Early identification
2.1 The importance of early identification of unrecognized CPE carriers with epidemiological link
Colonization with CPE usually precedes or is co-existent with CPE infection. Patients who are carriers or have clinical infections with CPE can be reservoirs for transmission to other patients, resulting in carriage, infection, or outbreaks. Identification of colonized patients on entry to the health facility is important, because transfer of colonized patients has been identified as a major risk factor for the introduction and spread of CPE. This has been clearly documented at a global level. Cross-border transfer of patients from countries with high rates of CPE has resulted in the introduction of CPE into countries that previously had detected few or no CPE isolates. Thus, early recognition of CPE colonization helps to identify patients most at-risk of subsequent CPE infection, as well as allowing the earlier initiation of infection prevention and control (IPC) measures.
2.2 “At-risk” CPE carriers with epidemiological link
Various studies are showing that some patients are at high risk as carriers of CPE, such as: 1) patients transfer between healthcare settings within the same countries; 2) patients transfer between healthcare settings across borders; 3) prior admission to an acute care facilities; 4) prior admission to a LTCF; 5) household transmission from patients discharged from healthcare settings; 6) foreign travel (e.g. recreational and medical tourism). Such patients may have had epidemiological exposures to situations and environments that can place them “at-risk” for CPE carriage. So it is important to obtain a careful medical and travel history. Patients on admission should be asked for relevant questions during the medical interview such as: 1) Whether the patient had an overnight stay in a healthcare setting in the last 12 months? 2) Has the patient been either dialysis-dependent or received cancer chemotherapy in the last 12 months? 3) Does the patient have a known history of previous carriage of CPE in the last 12 months? 4) Is the patient previously linked to a known CPE carrier?
Healthcare facilities in areas with high incidence or outbreaks of CPE are reservoirs of CPE. Patients with a history of an overnight stay in such setting in the last 12 months and patients who are re-admitted, or transferred between healthcare settings, are by definition “at-risk” and should be screened for CPE on admission. This is because admission of even one patient who is a carrier, if undetected, can result in spread of CPE. Presently many countries would actively screen patients who have had hospitalization in the past 12 months in the overseas for carriage of CPE. Certain procedures performed in the ambulatory setting can place a patient “at-risk” for carriage of CPE including patients who have been haemodialysis or peritoneal dialysis-dependent in the last 12 months and cancer (haematology and solid-tumour) patients with long-term intravenous catheters who have received cancer chemotherapy in hospital or an outpatient setting in the last 12 months.
Known CPE carriers should be carefully evaluated. Persistent carriers can be a source of transmission. High-risk populations include discharges from, or readmissions to, acute care facilities and LTCFs, and returning travelers. The period of 12 months is considered because in one study of CPE clearance in patients post-acute care discharge, the median time to negative culture was 387 days and about 40% of patients were still carriers at 12 months. Same for residents of LTCFs, they are at increased risk for persistent carriage because of frequent admissions and re-admissions to acute care facilities, residents’ known co-morbidities, a high prevalence of antimicrobial use, and frequent dependency on nursing care in LTCFs. Furthermore, adherence to isolation and IPC measures are often difficult in LTCF due to lack of resources and manpower constraint. Therefore, LTCF residents are also considered a reservoir of CPE within all types of healthcare settings.
2.3 Additional patient groups to be considered in a CPE screening strategy
A health facility may consider screening patients who have had less than 24 hours contact with a confirmed case of CPE but where there may be increased risk of transmission or acquisition of CPE. Examples of this group are patients with intellectual or cognitive impairment, participation in group activities, or immunosuppression; and patients in haematology/oncology, transplant and intensive care units. 
2.4 Screening of contacts at clustering or outbreak situations
A known CPE carrier, with whom the patient has been in contact in a healthcare setting should be regarded as a close contact. It is of utmost importance to do contact tracing when CPE clustering or outbreak situation occurs. One Israeli case-control study reported an exposure to a newly diagnosed CPE patient of ≥3 days, as a risk factor for CPE carriage in a hospital setting. However the duration of exposure is difficult to determine, though the Australia guideline recommended more than 24 hours. All contacts exposure to CPE colonized or infected patients should be screened for CPE for blocking of the transmission that may possibly cause subsequent outbreak.
2.5 Microbiological capacity
Healthcare settings should have access to microbiology laboratories with competence and the capacity to detect CPE in both clinical and screening samples. Microbiological analyses should be performed in accordance with internationally recognized standards, i.e. European Committee on Antimicrobial Susceptibility Testing or The Clinical and Laboratory Standards Institute,[13-14] including procedures for quality control. Specific algorithms for microbiological screening and processing of clinical samples may need to be adapted to local epidemiology of antimicrobial resistance, therapeutic traditions, and IPC protocols. Results from microbiological analyses should be communicated to the clinical staff in a timely manner, and clinically or epidemiologically significant findings should prompt immediate and direct contact with the clinical staff and IPC team to ensure proper follow-up. All microbiological laboratories should be linked to reference laboratories and participate in external quality assurance schemes for antimicrobial resistance.
3 Immediate IPC measures for patients with “at-risk” factors of CPE carriers
When patients are “possible carriers” with “at-risk” factors, preliminary IPC measures should be applied immediately on admission. These are: 1) Actively screen for CPE by obtaining rectal swabs and any other site that is either actively infected or considered to be colonized. 2) Put on preemptive isolation in a single room while waiting for the screening results. The single room should preferably be with en-suite bathroom in order to reduce the risk of cross transmission. If single room is unavailable, cohort in rooms with patients who carry or are infected with same CPE. 3) Implement contact precautions for all persons entering the room. Patients with one or combinations of risks should be actively screened for CPE colonization or infection upon hospital admission. The best samples to actively screen for CPE are specimens of faecal material such as rectal swabs or stool as well as specimens from active infection sites, e.g. draining wounds or catheterized urine. It is important to work closely with the microbiology. Laboratory should use the most optimal and sensitive microbiological methods for detection of CPE. The results should also be provided in a timely manner to facilitate prompt implementation of IPC measures. If the screening test result is negative for CRE, consideration may be given to discontinuing patient isolation and contact precautions, unless there is an indication for their continuation, e.g. colonization with a different multidrug-resistant organism (MDRO) or transmissible infection. Basic infection control measures must be maintained for all patients at all times.
4 Reinforcing basic IPC measure for controlling of CPE infections and colonization
IPC Team is responsible for formulating and facilitating the execution of IPC guideline. For the success of CPE prevention, it is of ultimate importance that basic IPC measures should be enforced and monitored throughout the healthcare institutions for all patients. This is the holistic trilogy approach from on admission screening of “at-risk” CPE carriers to preemptive isolation and the enforcement of basic infection control measures.
The basic IPC measures should include: 1) Initiate an effective Antibiotic Stewardship Program assuring appropriate antimicrobial use and have facility-specific treatment and prophylaxis recommendations that are based on national guidelines and local microbial susceptibility, to assist with empiric antimicrobial selection. 2) Implement an effective hand hygiene program following the World Health Organization 5 moments to prevent the transmission of CPE and other MDROs. 3) Healthcare settings should enhance microbiological capacity to detect CRE from both clinical and screening specimens and have systems in place to ensure that potentially significant results are communicated by the microbiology laboratory in a timely manner to the relevant staff in the healthcare setting along with IPC and antimicrobial stewardship. 4) When patient is suspected positive or confirmed positive of CPE or MDRO, contact precautions should be continued in single room with en-suite toilet of designated commodes; gloves and gowns should be used on entering isolation room. 5) Communication on patient/resident transfer should be done within a healthcare setting, e.g. between the laboratory and ward staff and communication on patient/resident transfer between healthcare settings within regions, country and across borders needs to be enforced by healthcare record flagging and use of patient administration IT alert system; ensure communication of local current or recent clusters or outbreaks to the receiving institution when patients/residents are transferred. 6) Enhanced environmental cleaning should be performed, especially for areas in close proximity to CPE/MDRO carriers also terminal disinfection of rooms should be performed upon transfer or discharge of patients. 7) Bathing in antiseptic can be considered for use in difficult-to-control outbreak situations. 8) Staff education should include on-going education and training be provided to all staff with patient contact, with specific reference to CPE / MDRO; regular compliance audit should be done and feedback to the frontline staff for quality improvement. 9) Staffing in ward setting should take into consideration of appropriate skill level and workload of frontline healthcare workers as well as patients acuity of care. 10) Routine surveillance of healthcare-associated infections is conducted in the healthcare institution to look for cluster and outbreak.
The hospital IPC team should execute the IPC guideline both the basic and the CPE specific measures in the hospital and that is of paramount importance. The team should conduct education and training, compliance check, audit and feedback to the front line staff. Healthcare-associated infection surveillance and outbreak detection are also the responsibilities of the IPC team.
It is evident that CPE is spreading globally. For institutions and countries where CPE is still low, immediate action should be taken to impede the entry and the spread of CPE. Admission screening of “at-risk” patients for CPE carriage is already proven to be effective in the prevention of CPE outbreaks. This new strategy emphasizes the early identification of patients infected or carriers of CPE, followed by prompt implementation of preemptive isolation. The basic IPC measures should also be reinforced to complement the effort of CPE and MDRO control. The trilogy approaches of screening, preemptive isolation and continuing good infection control measures are recommended by international guidelines. The success in controlling the spread of CRE is a multidisciplinary team effort. Health authorities, healthcare worker, and the IPC professionals should work together to adopt the new recommendations according to local needs to halt the striking spread of these deadly pathogens.