Introduction
Health care-associated infections (HAI) are one of the most common adverse events in care delivery and both the endemic burden and the occurrence of epidemics of HAI are a major public health problem. HAI have a significant impact on morbidity, mortality and quality of life and present an economic burden at the societal level. However, a large proportion of these infections is preventable by effective infection prevention and control (IPC) measures (8–10).
Carbapenem-resistant gram-negative bacteria, namely, carbapenem-resistant Enterobacteriaceae (CRE) (for example, Klebsiella pneumoniae, Escherichia coli), Acinetobacter baumannii (CRAB) and Pseudomonas aeruginosa (CRPsA), are a matter of national and international concern as they are an emerging cause of HAI that pose a significant threat to public health (1). These bacteria are difficult to treat due to high levels of antimicrobial resistance (AMR) and are associated with high mortality. Importantly, they have the potential for widespread transmission of resistance via mobile genetic elements (11).
Rationale for the development of CRE-CRAB-CRPsA guidelines
Since the publication of an expert consensus document on the core components for infection prevention and control by the World Health Organization (WHO) in 2009 (12), threats posed by epidemics, pandemics and AMR have become increasingly evident as ongoing universal challenges and they are now recognized as top priorities for action on the global health agenda. Effective IPC is the cornerstone of such action to control AMR and the spread of multidrug-resistant pathogens, such as CRE-CRAB-CRPsA. This is emphasized by the International Health Regulations (IHR), which identify effective IPC as a key strategy for dealing with public health threats of international concern. More recently, the United Nations Sustainable Development Goals (SDGs) highlighted the importance of IPC as a contributor to safe, effective high-quality health service delivery, particularly those related to water, sanitation and hygiene (WASH) and quality and universal health coverage. In 2016, WHO released the updated Guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13). These new guidelines form a key part of WHO strategies to prevent current and future threats, strengthen health service resilience and help combat AMR. During the guideline development process and the many detailed discussions by the Guideline Development Group (GDG) members, it became clear that the specific threat posed by infections due to CRE-CRAB-CRPsA required specific attention, including having clear, practical IPC guidelines on how best to manage this rapidly emerging problem. CRE-CRAB-CRPsA infections are particularly notable because they are associated with high morbidity and mortality, as well as the potential to cause outbreaks and contribute to the spread of resistance. Furthermore, it was recognized that colonization with CRE-CRAB-CRPsA precedes or is co-existent with CRE-CRAB-CRPsA infection almost universally. Thus, early recognition of CRE-CRAB-CRPsA colonization is likely to help identify patients most at risk of subsequent CRE-CRAB-CRPsA infection. This will also allow the earlier introduction of IPC measures in health care settings to prevent pathogen transmission to other patients and the hospital environment. For this reason, it was agreed that a key priority should be the development of WHO IPC guidelines specifically targeting the prevention and control of colonization and infection with CRE-CRAB-CRPsA in health care settings.
Objectives
The objectives of the guidelines are to provide:
evidence-based recommendations on the early recognition and specific required IPC practices and procedures to effectively prevent the occurrence and control the spread of CRE-CRAB-CRPsA colonization and/or infection in acute health care facilities;
an evidence-based framework to help inform the development and/or strengthening of national and facility IPC policies and programmes to control the transmission of CRE-CRAB-CRPsA in a variety of health care settings.
The recommendations included in these guidelines build upon the overarching IPC standards set by the WHO publication Guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13) and, in this context, they are meant to align with fundamental IPC principles and to strengthen their uptake.
Target audience
The CRE-CRAB-CRPsA guidelines are intended to support IPC improvement at the health care facility and national level, both in the public services and private sector. At the facility level, the main target audience is local IPC teams and/or professionals in charge of planning, developing and implementing local IPC programmes. This includes senior managers (for example, chief executive officers) and, ultimately, all health care workers providing patient care. At the national level, this document provides guidance primarily to policy-makers responsible for the establishment and monitoring of national IPC programmes and the delivery of AMR national action plans within ministries of health.
The guidelines are also relevant for national and facility safety and quality leads and managers, regulatory bodies and allied organizations, including academia, national IPC professional bodies, non-governmental organizations involved in IPC activity and civil society groups.
The guidelines focus primarily on acute health care facilities. However, the core principles and practices of IPC to be applied as a control measure against the emergence and spread of CRE-CRAB-CRPsA are common to any facility where health care is delivered. Therefore, these guidelines should also be implemented with some adaptations by primary and long-term care facilities (LTCFs) as they develop and review their IPC programmes.
Although legal, policy and regulatory contexts may vary, these guidelines are relevant to both high- and low-resource settings.
Methods
The guidelines were developed following the methods outlined in the 2014 WHO handbook for guideline development (14). The development process included six main stages: (1) identification of the PICO (Population/Participants, Intervention, Comparator, Outcome/s) question (an approach commonly used to formulate research questions); (2) performing a systematic review for the retrieval of the evidence; (3) developing an inventory of national and regional IPC action plans and strategic documents; (4) assessment and synthesis of the evidence; (5) formulation of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach; and (6) writing of the guidelines and planning for the dissemination and implementation strategies.
The development of the guidelines involved the formation of four main groups to guide the process: the WHO Guideline Steering Group, the GDG, the Systematic Reviews Expert Group and the External Peer Review Group. The WHO Steering Group identified the primary critical outcomes and topics, formulated the research questions and identified the systematic review teams, the guideline methodologist and members of the GDG. The GDG included international experts in IPC and infectious diseases, public health, researchers and patient representatives, as well as country delegates and stakeholders from the six WHO regions.
The systematic review assessed the following research question: What is an effective approach to preventing and controlling the acquisition of and infection with CR and/or CRAB and/or CRPsA among inpatients in health care facilities? Studies with no time limit applied and conference abstracts from the last five years (2012–2016) were included. Search terms included three concepts: (1) carbapenemase/carbapenem resistance; (2) core IPC measures; and (3) CRE and/or CRAB and/or CRPsA (that is, CRE-CRAB-CRPsA) colonization and/or infection rates.
The CRE-CRAB-CRPsA literature review used the risk of bias criteria developed for the Cochrane Effective Practice and Organization of Care (EPOC) reviews. Based on the systematic reviews, the GDG formulated recommendations using the GRADE approach. Finally, the GDG identified research gaps and implications for research. Additionally, a review of the guidelines was conducted by the WHO Public Health Ethics Consultation Group and feedback was incorporated accordingly.
Recommendations
The 2016 WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13) provided an initial foundation for the development of the recommendations for the prevention and control of CRE-CRAB-CRPsA. The GDG evaluated the relevance of the core components, together with the evidence emerging from the new systematic review specifically on CRE-CRAB-CRPsA. It identified eight key recommendations that apply to the facility level and which can be used to improve the development of national policy on the prevention and control of CRE-CRAB-CRPsA transmission and infection across health sectors.
The eight recommendations are summarized in , including the strength of each recommendation and the quality of the supporting evidence. Of note, the numbered list of IPC recommendations included in the guidelines is not intended to be a ranking order of the importance of each recommendation. As countries and facilities implement the recommendations (or undertake actions to review and strengthen their existing IPC programmes), they may decide to prioritize specific components depending on the context, previous achievements and identified gaps, with the long-term aim to build a comprehensive approach as detailed across all eight recommendations.
Guideline implementation
The successful implementation of these guidelines is dependent on a robust implementation strategy and a defined and appropriate process of adaptation and integration into relevant regional, national and facility-level policies and strategies. These CRE-CRAB-CRPsA guidelines should be integrated with the WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13) and the national action plans for AMR. Such IPC implementation is crucial for the achievement of strategic objective 3 of the AMR Global Action Plan adopted by all Member States at the World Health Assembly in 2015. Support by national decision-makers, key stakeholders, partner agencies and organizations is also critical to enable effective implementation and to address research gaps (as outlined in the guidelines), particularly in limited resource settings.
Tables
Table 1Summary of recommendations for the prevention and control of CRE, CRAB and CRPsA
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| Formal recommendation | Key remarks from the GDG* | Strength of recommendation and quality of evidence** |
|---|
| Recommendation 1: Implementation of multimodal IPC strategies |
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| The panel recommends that multimodal IPC strategies should be implemented to prevent and control CRECRAB-CRPsA infection or colonization and that these should consist of at least the following:
|
The evidence supporting this recommendation showed that multimodal strategies comprised of several elements implemented in an integrated way were used as the intervention in most studies. The use of multimodal strategies is also strongly recommended as the most effective approach to successfully implement IPC interventions in the 2016 WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level. Most studies were from settings with a high prevalence of CRECRAB-CRPsA. Nevertheless, the GDG considered that the IPC principles outlined in this recommendation were equally valid in all prevalence settings. While the control of large outbreaks was recognized to be very costly, these studies were all conducted in high-to-middle-income countries. Thus, there are concerns regarding the cost implications and the affordability of outbreak control in settings with limited resources. Although the scope of the evidence review and this recommendation address acute care facilities, it is equally critical that all types of health care facilities apply similar IPC principles for the control of CRE-CRAB-CRPsA. Implementing this recommendation may be complex in some health systems as it requires a multidisciplinary approach, including executive leadership, stakeholder commitment, coordination and possible modifications to workforce structure and process in some cases. Facility leadership should clearly support the IPC programme aimed at preventing the spread of CRE-CRAB-CRPsA by providing materials and organizational and administrative support through the allocation of a protected and dedicated budget, according to the IPC activity plan. Such an approach was considered to be consistent with Core component 1 in the WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level. Good quality microbiological laboratory support is a very critical factor for an effective IPC programme and implementation of this recommendation. Education/training and monitoring, auditing and feedback are critical to the success of a multimodal strategy. Emphasis should be placed on these when implementing multimodal interventions and their specific components, particularly in the context of an IPC programme. Each component of the multimodal strategy included in this recommendation is also the focus of additional stand-alone recommendations. Remarks and details of each component are provided in the dedicated sections of the guidelines.
| Strong recommendation, very low to low quality of evidence |
| Recommendation 2: Importance of hand hygiene compliance for the control of CRE-CRAB-CRPsA |
|---|
| The panel recommends that hand hygiene best practices according to the WHO guidelines on hand hygiene in health care should be implemented. |
The evidence for the high beneficial impact of good hand hygiene compliance has been reviewed previously in sufficient detail and therefore the WHO recommendations on hand hygiene in health care should be followed (see WHO guidelines on hand hygiene in health care). Effective implementation strategies have been developed, tested and are now used worldwide. Practical approaches to implement these strategies at the facility level are described in the WHO guide to implementation and associated toolkit ( http://www.who.int/infection-prevention/tools/handhygiene/). It is important to use these approaches and resources and adapt them to the local context. Hand hygiene compliance and the appropriate use of alcohol-based handrub are very dependent on appropriate product placement and availability. Adequate resources are therefore necessary to ensure these features are met. It is important to monitor hand hygiene practices through the measurement of compliance according to the approach recommended by WHO
| Strong recommendation, very low quality of evidence. |
| Recommendation 3: Surveillance of CRE-CRAB-CRPsA infection and surveillance cultures for asymptomatic CRE colonization |
|---|
The panel recommends that:
surveillance of CRE-CRAB-CRPsA infection(s) should be performed; and surveillance cultures for asymptomatic CRE colonization should also be performed, guided by local epidemiology and risk assessment. Populations to be considered for such surveillance include patients with previous CRE colonization, patient contacts of CRE colonized or infected patients and patients with a history of recent hospitalization in endemic CRE settings.
| Surveillance for CRE-CRAB-CRPsA infection/s
Surveillance of CRE-CRAB-CRPsA infection is essential (that is, clinical monitoring of signs and symptoms of infection, as well as laboratory testing and identification of carbapenem resistance among potential CRE-CRAB-CRPsA isolates from clinical samples). Laboratory testing and identification of carbapenem resistance among potential CRE-CRAB-CRPsA isolates may not be available or routine in some settings (for example, LMICs), but should now be considered as routine in all microbiology laboratories to ensure the accurate and timely recognition of CRE-CRAB-CRPsA. Surveillance of CRE-CRAB-CRPsA infection allows a facility to define the local epidemiology of CRE-CRAB-CRPsA, identify patterns and better allocate resources to areas of need.
Surveillance cultures for asymptomatic CRE colonization
Information regarding a patient’s CRE colonization status does not (yet) constitute routine standard of care provided by health systems. However, in an outbreak or situations where there is a high risk of CRE acquisition (for example, possible contact with a CRE colonized/infected patient or endemic CRE prevalence), CRE colonization status should be known. Information regarding CRE colonization status could potentially have important beneficial effects on the empiric antibiotic treatment plan for screened patients who subsequently develop potential CRE infection. This recommendation should always apply in an outbreak situation and also, ideally in endemic settings. However, the GDG extensively discussed the best approach to surveillance cultures of asymptomatic CRE colonization in a high CRE prevalence (endemic) setting, particularly in low-income settings where resources and facilities are limited and the actual appropriate improvement of IPC infrastructures and best practices may deserve prioritization over surveillance. The GDG agreed that there is no one single best approach, but instead the decision should be guided by the local epidemiology, resource availability and the likely clinical impact of a CRE outbreak. Surveillance screening should be based on patient risk assessment (that is, patients who are at a higher risk of CRE acquisition and the potential risk that these patients pose to others in their environment). The following patient risk categories should be considered: - –
patients with a previously documented history of CRE colonization or infection; - –
epidemiologically-linked contacts of newly-identified patients with CRE colonization or infection (this could include patients in the same room, unit or ward); - –
patients with a history of recent hospitalization in regions where the local epidemiology of CRE suggests an increased risk of CRE acquisition (for example, hospitalization in a facility with known or suspected CRE); - –
based on the epidemiology of their admission unit, patients who may be at increased risk of CRE acquisition and infection (for example, immunosuppressed patients and those admitted to intensive care units (ICUs), transplantation services or haematology units, etc.).
Surveillance culture of feces or rectal swabs or perianal swabs (in rare clinical situations, for example neutropenic patients) were considered the best methods in descending order of accuracy. However, it was recognized that rectal swabs were often considered to be the most suitable clinical specimen in many health care situations for practical reasons. A minimum of one culture was considered necessary, although additional cultures may increase the detection rate. Surveillance cultures should be performed as soon as possible after hospital admission or risk exposure, processed and reported promptly to avoid delays in the identification of CRE colonization. It was not possible to identify the optimal frequency of testing after admission due to limited and heterogeneous evidence; however, several studies included a regular screening timetable (for example, weekly or twice-weekly) following the initial on-admission screening.
Additional remarks
Recommended surveillance activities could involve potential harms or unintended consequences for the patient with ethical implications (for example, a sense of cultural offensiveness or stigma associated with obtaining a rectal swab or providing a stool (fecal) specimen or discrimination of colonized or infected patients). Mitigation measures were included in the “values and preferences” section, as well as important references in this field. The evidence available on surveillance cultures for CRAB and CRPsA colonization concluded that it was not sufficiently relevant to extend the recommendation to these two microorganisms. In particular, the value of active surveillance for CRAB and CRPsA colonization, while sometimes beneficial, depends on the clinical setting, epidemiological stage (for example, outbreak) and body sites. Optimal microbiological methods for CRAB and CRPsA surveillance cultures for colonization require further research.
| Strong recommendation, very low quality of evidence. |
| Recommendation 4: Contact precautions |
|---|
| The panel recommends that contact precautions should be implemented when providing care for patients colonized or infected with CRE-CRAB-CRPsA. |
“Contact precautions” include: (1) appropriate patient placement; (2) use of personal protective equipment, including gloves and gowns; (3) limiting transport and movement of patients; (4) use of disposable or dedicated patient-care equipment; and (5) prioritizing cleaning and disinfection of patient rooms (see Glossary). The use of patient isolation is addressed in Recommendation 5. Contact precautions should be considered as a standard of care for patients colonized or infected with CRE-CRAB-CRPsA in the vast majority of health systems. Health care worker education regarding the principles of IPC and monitoring of contact precautions is crucial. In some circumstances, depending on the individual risk assessment of some patients, pre-emptive isolation/cohorting and the use of contact precautions may be necessary until the results of surveillance cultures for CRE-CRAB-CRPsA are available. This was considered to be an important consideration for patients with a history of recent hospitalization in regions where the local epidemiology of CRE suggests an increased risk of CRE acquisition (see Recommendation 3: patient risk categories). Clear communication regarding a patient’s colonization/infection status is important, that is, flagging the medical chart. Applying contact precautions could involve potential unintended consequences for the patient (for example, patient frustration or discomfort during treatment with contact precautions). Mitigation measures were included in the “values and preferences” section, as well as important references in this field. Furthermore, it was recognized that occupational health issues associated with the use of some personal protective equipment (for example, latex gloves) should also be taken into consideration for health care workers.
| Strong recommendation, very low to low quality of evidence |
| Recommendation 5: Patient isolation |
|---|
| The panel recommends that patients colonized or infected with CRE-CRAB-CRPsA should be physically separated from non-colonized or non-infected patients using (a) single room isolation or (b) by cohorting patients with the same resistant pathogen. |
It was noted that there is an inconsistency in the use of the terms “isolation” and “cohorting” in some settings. For the purposes of these guidelines, the following standard definitions were used: - –
Isolation: patients should be placed in single-patient rooms (preferably with their own toilet facilities) when available. When single-patient rooms are in short supply, patients should be cohorted. - –
Cohorting: the practice of grouping together patients who are colonized or infected with the same organism to confine their care to one area and prevent contact with other patients.
The purpose of isolation is to separate colonized/infected patients from non-colonized/non-infected patients. The strongest evidence for the effectiveness of patient isolation was among patients with CRE colonization/infection. It was the panel’s view that this recommendation was also likely to be effective to prevent cross-transmission among patients colonized or infected with CRAB and/or CRPsA. Patient isolation could be associated with some potential harms and negative unintended consequences (for example, social isolation and psychological consequences, such as depression or anxiety). Mitigation measures were included in the “values and preferences” section, as well as important references in this field. The preference is for colonized/infected patients to be managed in single rooms where possible. Cohorting is reserved for situations where there are insufficient single rooms or where cohorting of patients colonized or infected with the same pathogen is a more efficient use of hospital rooms and resources. Patient isolation should always apply in an outbreak situation. Isolation in single rooms may not be possible in endemic situations, particularly in low-income settings where resources and facilities are limited. There is evidence and clinical experience to support the use of dedicated health care workers to exclusively manage isolated/cohorted patients, although there may be some feasibility issues.
| Strong recommendation, very low to low quality of evidence |
| Recommendation 6: Environmental cleaning |
|---|
| The panel recommends that compliance with environmental cleaning protocols of the immediate surrounding area (that is, the “patient zone”) of patients colonized or infected with CRE-CRAB-CRPsA should be ensured. |
The optimal cleaning agent for environmental cleaning protocols of the immediate surrounding area of patients colonized or infected with CRE-CRAB-CRPsA has not yet been defined. Three CRE-CRAB-CRPsA studies used hypochlorite (generally a concentration of 1000 parts per million [ppm]) as an agent to undertake environmental cleaning. Appropriate educational programmes for hospital cleaning staff are crucial to achieve good environmental cleaning. The use of multimodal strategies to implement environmental cleaning was considered essential. This includes institutional policies, structured education and monitoring compliance with cleaning protocols. Assessment of cleaning efficacy by performing environmental screening cultures for CRE-CRAB-CRPsA was noted to be worthwhile in some settings (Recommendation 7). In some outbreak situations, temporary ward closures were necessary to allow for enhanced cleaning.
| Strong recommendation, very low quality of evidence |
| Recommendation 7: Surveillance cultures of the environment for CRE-CRAB-CRPsA colonization/contamination |
|---|
| The panel recommends that surveillance cultures of the environment for CRE-CRAB-CRPsA may be considered when epidemiologically indicated. |
Correlation of environmental surveillance culture results to the rates of patient colonization/infection with CRE-CRAB-CRPsA should be undertaken with caution and depends on an understanding of the local clinical epidemiological data and resources. Based on expert opinion (and only limited available data), surveillance cultures of the general environment were considered most relevant to CRAB outbreaks. Outbreaks of CRPsA colonization/infection among patients appeared to be more commonly associated with environmental CRPsA contamination involving water and waste-water systems, such as sinks and taps (faucets).
| Conditional recommendation, very low quality of evidence |
| Recommendation 8: Monitoring, auditing and feedback |
|---|
| The panel recommends monitoring, auditing of the implementation of multimodal strategies and feedback of results to health care workers and decision-makers. |
Monitoring, auditing and feedback of IPC interventions are a fundamental component of any effective intervention and especially important for strategies to control CRE-CRAB-CRPsA. Appropriate training of staff who undertake monitoring and feedback of results is crucial. All components of the multimodal strategy intervention should be regularly monitored, including hand hygiene compliance. Monitoring, auditing and feedback of multimodal strategies are a key component of all IPC educational programmes. IPC monitoring should encourage improvement and promote learning from experience in a non-punitive institutional culture, thus contributing to better patient care and quality outcomes.
| Strong recommendation, very low to low quality of evidence |
CRE: carbapenem-resistant Enterobacteriaceae; CRAB: carbapenem-resistant Acinetobacter baumannii; CRPsA; carbapenem-resistant Pseudomonas aeruginosa; HAI: health care-associated infection/s; AMR: antimicrobial resistance; IPC: infection prevention and control; GDG: Guidelines Development Group.
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More detailed remarks can be found in each section dedicated to specific recommendations.
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Quality of evidence was classified as high, moderate, low, or very low according to factors that include the study methodology, consistency and precision of the results, and directness of the evidence (15).