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 are a major public health problem. HAI have a significant impact on morbidity, mortality and quality of life and represent an economic burden at the societal level. However, a large proportion of HAI are preventable and there is a growing body of evidence to help raise awareness of the global burden of harm caused by these infections (8, 9), including strategies to reduce their spread (10).
Infection prevention and control (IPC) is a universally relevant component of all health systems and affects the health and safety of both people who use services and those who provide them. Driven by a number of emerging factors in the field of global public health, there is a need to support Member States in the development and strengthening of IPC capacity to achieve resilient health systems, both at the national and facility levels. These factors are closely related to the aftermath of recent global public health emergencies of international concern, such as the 2013–2015 Ebola virus disease outbreak and the current review of the International Health Regulations (IHR), together with the World Health Organization (WHO) action agenda for antimicrobial resistance (AMR) and its lead role in implementing the associated Global Action Plan.
There is a worldwide consensus that urgent action is needed by all Member States to prevent and control the spread of antimicrobial-resistant microorganisms. Following the endorsement of the Global Action Plan to Combat AMR, all Member States committed to develop their national action plans by the World Health Assembly 2017, with the inclusion of IPC as one of the five objectives. International experts, including the AMR Strategic and Technical Advisory Group highlighted the urgent need for WHO to have a strong leadership role, including the development of guidelines and implementation packages on targeted procedures to contain the spread of specific microorganisms.
In a recent formal WHO meeting for the development of guidelines on core components of IPC programmes, experts recommended that priority should be given to carbapenem-resistant gram-negative bacteria, a problem of emerging concern, which poses a significant public health threat in both high- and low-to-middle-income countries. No specific international evidence-based guidelines are currently available on IPC best practices and procedures to prevent and control carbapenem-resistant gram-negative bacteria and the experts considered that there is an urgent need for such guidance.
1.1. Epidemiology and burden of disease of carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRAB) and Pseudomonas aeruginosa (CRPsA)
Carbapenem-resistant gram-negative bacteria, namely, CRE (for example, Klebsiella pneumoniae, Escherichia coli), CRAB and CRPsA, 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 AMR and are associated with high mortality. Importantly, they have the potential for widespread transmission of resistance via mobile genetic elements (11). While some strains are innately resistant to carbapenems, others contain mobile genetic elements (for example, plasmids, transposons) that result in the production of carbapenemase enzymes (carbapenemases), which break down most beta-lactam antibiotics, including carbapenems. Frequently, these carbapenemase-producing (CP) genes are co-located on the same mobile element with other resistance genes, which can result in co-resistance to many other antibiotic drug classes (1–3). Notably, these carbapenemase-encoding mobile genetic elements can be readily transmitted between intestinal bacteria (11). Thus, while carbapenem-resistant strains of these pathogens are frequently CP (CP-Enterobacteriaceae [CPE], CP-A. baumannii and CP-P. aeruginosa), they may have other carbapenem resistance mechanisms that make them equally difficult to treat and manage clinically. For this reason, IPC actions should focus on all strains of CRE, CRAB and CRPsA, regardless of their resistance mechanism. Adequate IPC measures are essential in both outbreak and endemic settings (4).
During the last decade, there has been an alarming global increase in the incidence and prevalence of carbapenem-resistant gram-negative bacteria. In Europe, the population-weighted mean percentage of invasive isolates resistant to carbapenems in 2015 was 17.8% for P. aeruginosa, 8.1% for K. pneumoniae and 0.1% for E. coli (16). Increasing trends of invasive isolates of carbapenem-resistant K. pneumoniae were observed from 2012–2015, particularly in Croatia, Portugal, Romania and Spain. Countries with the highest rates of carbapenem-resistant K. pneumoniae included Greece, Italy and Romania (16). Among 27 countries reporting resistance results for more than 10 A. baumannii isolates, 12 had percentage rates of carbapenem resistance of 50% or higher (17). According to a point prevalence survey of HAI and antimicrobial use in Europe, 18 of 28 countries reported CRE and three countries reported HAI with more than 20% of resistant isolates, with the highest percentage (39.9%) in Greece (18). In the United States of America (USA), 49.5% of A. baumannii, 19.2% of P. aeruginosa, 7.9% of K. pneumoniae and 0.6% of E. coli invasive isolates submitted to the National Healthcare Safety Network were resistant to carbapenems in 2014 (19).
According to the 2014 global report on AMR, carbapenem-resistant K. pneumoniae were reported from all WHO regions, although only 37% of Member States could provide data (20). This included two regions with some countries reporting up to 50% of K. pneumoniae resistant to carbapenems. There was some variation in the reported geographical spread of CRE and carbapenemase genes. Identified high-prevalence areas and countries included Greece, Israel, Italy, North Africa, Turkey, the USA and the Indian subcontinent (20). In particular, a rapid international spread of K. pneumoniae CPE due to the clonal expansion of certain strains (that is, clonal complex 258) has been observed since its discovery in the USA in 1996 (21). Of notable concern, human isolates harbouring the MCR-1 gene, which infers resistance to colistin, a powerful antimicrobial considered as the last line of defense against CRE, have been reported recently across hospitals in the Asia/Pacific region, Europe, Latin America and North America (22).
Carbapenem-resistant gram-negative bacteria are highly transmissible and have a high potential to cause outbreaks in health care settings. Following the worldwide dissemination of CRE, a range of outbreaks have occurred across different global regions in acute care settings, as well as in long-term care (23–29). In Europe, several large hospital outbreaks have occurred in the Czech Republic, France, Germany, Greece, Italy, Spain and the United Kingdom, particularly of carbapenem-resistant K. pneumoniae (30). A comparison of the epidemiological stages (that is, sporadic cases, hospital outbreaks, regional spread, endemicity) of CPE and CRAB in Europe in 2013 suggested that CRAB had a broader dissemination (31). Outbreaks of CRAB have been found to be mainly transmitted via the hands of health care workers, contaminated equipment and the health care environment (32, 33). Similar outbreaks of CRPsA have also been reported, including an association with contaminated medical devices (3, 34, 35).
Outbreaks of carbapenem-resistant gram-negative bacteria have been found to be highly costly. For example, 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 (36).
Mortality and clinical outcomes associated with carbapenem-resistant gram-negative bacteria can be severe. A meta-analysis evaluating the number of deaths attributable to CRE infections found that 26–44% of deaths across seven studies were attributable to carbapenem resistance. Among these, the number of deaths among CRE-infected patients was two-fold higher than those attributed to carbapenem-susceptible Enterobacteriaceae (37). An observational study in seven Latin American countries found that the attributable mortality was significantly higher in patients with CPE bloodstream infections than those where the pathogens were carbapenem-susceptible (38). The European Centre for Disease Control and Prevention also reported mortality ranging from 30–70% and above 50% in patients with CRE bloodstream infections (30). One meta-analysis found that patients with CRPsA bacteremia had 3.07 higher odds of death compared to those with carbapenem-susceptible P. aeruginosa bacteremia (95% confidence interval [CI]: 1.60–5.89) (39). Another meta-analysis found a significant association between carbapenem resistance and mortality among A. baumannii patients (adjusted odds ratio: 2.49; 95% CI: 1.61–3.84) (40).
1.2. Rationale for developing recommendations to prevent and control colonization and/or infection with CRE-CRAB-CRPsA
The Guidelines Development Group (GDG) was particularly concerned about the burden of illness associated with infection and colonization due to CRE-CRAB-CRPsA and considered the development of IPC guidelines as an urgent priority to stop the spread of these microorganisms. The reasons for this included:
The GDG also emphasized that the focus on the prevention and control of CRE-CRAB-CRPsA should be seen in the context of the broader priority to implement effective IPC for the prevention of all HAI and the strengthening of health care service delivery. 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. This is emphasized by the IHR, which identify effective IPC as a key strategy for preparedness and response to public health threats of international concern. Furthermore, the United Nations Sustainable Development Goals (SDG) highlight the importance of IPC as a contributor to safe and effective high-quality health service delivery, particularly those related to water, sanitation and hygiene (WASH) and quality universal health coverage.
The 2016 evidence-based WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13) and key principles of standard and transmission-based precautions (5) provide a foundation for the development of an effective IPC programme and related practices. Efforts should be made to implement these core components and key principles. The recommended best practices and procedures to prevent and control CRE-CRAB-CRPsA included in this guideline strongly build upon these core component recommendations.
Although not included in the scope of these guidelines, antimicrobial stewardship or “coordinated interventions designed to improve and measure the appropriate use of [antibiotic] agents by promoting the selection of the optimal [antibiotic] drug regimen including dosing, duration of therapy, and route of administration” also play an important role in the prevention of CRE-CRAB-CRPsA and have been referenced in other CRECRAB-CRPsA guidance documents (43, 44). Antimicrobial stewardship interventions have been linked to decreased rates of antimicrobial resistance and improved patient outcomes (43).
1.3. Scope and objectives of the guidelines
The overarching question that defines the purpose of these CRE-CRAB-CRPsA guidelines is:
What is an effective approach to preventing and controlling the acquisition of and infection with CRE-CRAB-CRPsA among inpatients in health care facilities?
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 and private sectors. At the facility level, the main target audience are the IPC leads and focal persons (that is, professionals in charge of planning, developing and implementing local facility IPC programmes) and 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 countermeasure to the emergence and spread of CRE-CRAB-CRPsA, are common to any facility where health care is delivered. Therefore, the key principles of these guidelines should also be implemented by primary care and LTCFs as they develop and review their IPC programmes while taking the local setting into account.
While legal, policy and regulatory contexts may vary, these guidelines are relevant to both high-and low-resource settings.
Objectives and scope of the guidelines
The primary objective of these guidelines is to provide evidence- and expert consensus-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. They are also intended to provide an evidence-based framework to 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 settings. The recommendations can be adapted to the local context based on information collected ahead of implementation and thus influenced by available resources and public health needs.
The CRE-CRAB-CRPsA guidelines are based on the foundation provided by the 2016 WHO guidelines on core components of infection prevention and control programmes at the national and acute health care facility level (13), with the aim to specifically describe best practices and procedures to prevent and control the spread of CRE-CRAB-CRPsA in health care. The GDG evaluated the relevance of these components, together with the evidence emerging from systematic reviews, and developed the recommendations listed in this document, which are meant to align with fundamental IPC principles and to strengthen their uptake.
It is essential to note that the numbered list of IPC recommendations included in these guidelines are by no means intended to be a ranking order of the importance of each component. 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 in the guidelines.
