Infection prevention and control strategies against carbapenem resistant Enterobacteriaceae – a systematic review

Abstract

Background

Antimicrobial resistance is exponentially worsening, and the spread of prevalent carbapenem resistant Enterobacteriaceae (CRE) is a major contributor to this global concern. Infection prevention and control strategies are increasingly consolidated key tools to control this worldwide problem.

Aim

To identify, collect and analyse available evidence regarding the impact of infection prevention and control strategies on prevalent CRE dissemination.

Methods

Pubmed®, Scopus® and Web of Science® were searched systematically for articles published between 1th January 2017 and 30th June 2020, guided by the research question ‘What are the most effective and efficient strategies to prevent and control infection/colonisation caused by Carbapenem resistant Escherichia coli and Carbapenem resistant Klebsiella pneumoniae?’.

Findings

Eleven thousand six hundred and thirty-five publications were found, but after applying the inclusion and exclusion criteria, only 30 were selected. The majority of reviewed studies (n = 24) were performed in outbreak situations, 26 studies occurred in acute care units and of those, 17 in intensive care units . From the set of implemented infection prevention and control measures, in 29 studies surveillance cultures were applied, in 23 studies patients were isolated or cohorted and, in general, all described the implementation of standard and contact precaution measures.

Conclusion

This systematic review underlines the importance of infection prevention and control strategies in CRE dissemination, standing out the need of further studies outside outbreak and intensive care units contexts. Investment increments and training and educating of all involved are also important contributors to shift this problem, but still with relevant gaps in their implementation, in all types of care units, that need to be addressed.

Background and skin and soft

Antimicrobial resistance (AMR) is a growing global challenge (World Health Organization (WHO), 2019), estimating to cause 2.4 million deaths by 2050, a number higher than the predicted mortality due to cancer (Organisation for Economic Co-operation and Development (OECD), 2018). Multidrug resistance (MDR) is a worrisome problem, since it greatly reduces therapeutic options and its prevalence is also exponentially rising in several pathogens (Holmes et al., 2016; O’Neill, 2014).

Antimicrobials are among the most prescribed drugs in medicine, yet up to 50% are prescribed unnecessarily, increasing the selective pressure for pathogens, one of the main factors for MDR emergence (Holmes et al., 2016). AMR control is attained not by adding new antimicrobials to the treatment options but, more importantly, by improving antimicrobials usage, currently known as antimicrobial stewardship (AS). Parallel to AS, infection prevention is certainly one of the first practical milestones for AMR control, by its inherent goal of preventing the infection to occur, and thus preventing the use of antimicrobials, being an essential set of actions for AMR control, acknowledged as more effective in the short term (O’Neill, 2014), Infection Prevention and Control (IPC) is a tried-and-true, cost-effective approach, with the capacity to sustain or even potentiate antimicrobial usage successes (Zingg et al., 2019).

IPC measures are practical, evidence-based approaches to prevent the risk of pathogens transmission (National Health and Medical Council (NHMC), 2010). Universally considered essential for all healthcare systems, IPC translate into improved health and biosafety gains to all stakeholders: patients, visitors, healthcare workers (HCW) and overall society (WHO, 2016a). The major goal of an IPC program is to decrease the incidence of healthcare associated infections (HAI) ideally to zero. Globally, on average, one in every ten inpatients develops an HAI. WHO data shows that effective IPC programmes can reduce HAI rates by at least 30%, and surveillance activities can further reduce HAI by 25–57% (WHO, 2016b).

IPC guidelines include standard precautions and transmission-based precautions. Standard precautions, underpin routine best practices including hand hygiene, respiratory hygiene and cough etiquette, principles of asepsis, personal protective equipment (PPE) usage, patient placement, sterilisation and medical devices decontamination, environmental cleaning, safe handling of linen and laundry, waste management, prevention of injuries from sharp instruments and post-exposure prophylaxis (NHMC, 2010; WHO, 2016a). Transmission-based precautions are designed according to pathogens transmission route with the goal of adequately breaking their chain of infection (NHMC, 2010). In healthcare settings, transmission routes occur mainly through direct contact (including bloodborne), droplet and airborne, varying according to the type of microorganism and, in some cases, transmission can occur by more than one route (Public Health Agency of Canada (PHAC), 2012). Transmission-based precautions involve a combination of measures: continued implementation of standard precautions like the appropriate use of PPE (gloves, apron or gowns, surgical masks or respirators and protective eyewear), patient-dedicated equipment, allocation of single rooms or patients cohorting, appropriate air handling requirements, enhanced cleaning and disinfection of the patient environment and restricted transfer of patients within and between facilities (NHMC, 2010). If successfully implemented, standard and transmission-based precautions can prevent any type of infectious agent from being transmitted to susceptible hosts, including MDR pathogens. IPC practices should be tailored to the level of care that is being provided in the different types of healthcare settings, the inherent risk to individuals and the population, if infection occurs (PHAC, 2012), but also regarding the different pathogens and their MDR.

Transmission of MDR pathogens between patients, including those who are either infected or asymptomatically colonised, greatly accounts for AMR increase. The purpose of screening patients by active surveillance cultures (ASC) is to prevent patient-to-patient transmission by identifying colonised and infected patients, to allow early implementation of transmission-based precautions. Execute ASC involves the collection of specimens for culture whether or not the patient is exhibiting signs or symptoms of infection, and in addition to specimens collected at hospital admission, ASC may also be performed periodically during hospitalisation (Weber et al., 2007).

AS is defined as the optimal selection, dosage and duration of an antimicrobial treatment, translated in the best clinical outcome during an infection treatment, minimal toxicity to the patient and impact on subsequent AMR development (Doron and Davidson, 2011) in the pathogen to debleat and the microbial commensals that inhabit the patient, that act as AMR reservoirs (Wang et al., 2019). Antimicrobial misuse, or overuse, facilitates AMR and MDR development, making AS an important synergistic aid to any IPC strategy. With IPC and AS sharing the common goal of incrementing patients’ biosafety and improving health outcomes, these programs cannot be conducted independently and require interdependent and coordinated actions (Manning et al., 2018).

Carbapenem resistant Enterobacteriaceae, including Escherichia coli and Klebsiella pneumoniae, are a matter of national and international concern as they are an emerging cause of HAI, with very limited treatment options (WHO, 2019). The European Centre for Disease Control (ECDC) report on AMR Surveillance in Europe, published in the end of 2019, shows that more than a third (37.2%) of all reported K. pneumoniae were resistant to at least one of the antimicrobial groups under regular surveillance (aminopenicillins, fluoroquinolones, third-generation cephalosporins, aminoglycosides and carbapenems) and 7.5% were carbapenem resistant K. pneumoniae (CRKP). E. coli were also prevalent, with 58.3% being resistant to at least one of the reported antimicrobial groups. However, carbapenem resistant E. coli (CREC) rates were low, with less than 0.1% prevalence (European Centre for Disease Prevention and Control, 2019).

Despite efforts to control carbapenem resistance and its prevalence in Enterobacteriaceae and other bacterial groups, a definitive solution to this problem is still far from being achieved (Durante-Mangoni et al., 2019). Understanding which are the most adequate IPC strategies to fight CRE spread is paramount to help control these prevalent MDR agents (Magiorakos et al., 2017; Tomczyk et al., 2019). Several systematic reviews addressing CRE pharmacological solutions and genetic innovations are available; however, systematic information on IPC strategies to fight CRE is not common. This systematic review intends to identify, collect and evaluate the available evidence regarding the impact of IPC strategies on CREC and CRKP management.

Methods

A systematic review of literature was carried out following a protocol performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA–P) guidelines (Shamseer et al., 2015). The review question was ‘What are the most effective and efficient strategies to prevent and control infection/colonisation caused by CREC and CRKP?

Literature search was conducted in July 2020, using PubMed Central®, Scopus® and Web of Science®. All databases were searched using a combination of keywords in titles, abstracts and keywords (Table 1). The applied criteria to include studies in the analysis were the following: description of IPC strategies in CREC and CRKP infection and/or colonisation; original research studies published in English between 1st January 2017 and 30th June 2020. The authors considered three years and a half of publication, between 2017 and 2020, as the adequate time to guarantee the up-to-datedness of the revised publications. Two of the three authors of this review were responsible for the selection of articles. The exclusion criteria were the following: articles published in journals not related to health sciences, studies including animals, non-research articles such as opinion articles, conference abstracts, textiles and disinfectants development, studies approaching genetic technologies and pharmacological development to manage CREC and CRKP.

Table 1.

Search terms for database searches.

Database	Search Terms
Scopus®	(Carbapenem resistant OR Carbapenemase producing) AND (Escherichia coli OR Klebsiella pneumoniae) AND (Infection Prevention and Control OR Healthcare associated infection OR Healthcare worker OR Occupational Health OR Safety OR Antimicrobial Stewardship)
PubMed®	(Carbapenem resistant Escherichia coli OR Carbapenemase producing Escherichia coli) OR (Carbapenem resistant Klebsiella pneumoniae OR Carbapenemase producing Klebsiella pneumoniae) AND (Infection Prevention and Control OR Healthcare associated infection OR Healthcare worker OR Occupational Health OR Safety OR Antimicrobial Stewardship)
Web of Science®	(Carbapenem resistant Escherichia coli OR Carbapenemase producing Escherichia coli) OR (Carbapenem resistant Klebsiella pneumoniae OR Carbapenemase producing Klebsiella pneumoniae) AND (Infection Prevention and Control OR Healthcare associated infection OR Healthcare worker OR Occupational Health OR Safety OR Antimicrobial Stewardship)

For selected randomised studies, risk of bias was assessed by the following criteria: random sequence generation; allocation concealment; blinding of participants, personnel and outcomes; incomplete outcome data; selective outcome reporting; and other sources of bias in accordance with the methods recommended by the Cochrane Collaboration Tool (Higgins et al., 2011). The following three judgements were used: low risk, high risk or unclear, either lack of information or uncertainty over the potentiality for bias. However, the developed search could also find outbreaks reports, and these studies were assessed through the ORION (Outbreak Reports and Intervention studies of Nosocomial infection) Statement (Stone et al., 2007), case reports using the CARE (CAse REport) Checklist (Riley et al., 2017), before–after studies with no group control, observational cohort and cross-sectional studies, assessed by the National Heart, Lung and Blood Institute (NHLBI) Study Quality Assessment Tools (NHLBI,(National Heart et al., 2014), as being of ‘good’, ‘fair’ or “poor” quality.

Results

Overall, 11,635 records were identified through database search as potentially relevant articles. According to PRISMA-P guidelines (Shamseer et al., 2015), 4044 were screened by title and abstract, and for not addressing the inclusion criteria, 3892 articles were excluded. A total of 152 studies were assessed according to the eligibility criteria, of which 109 were excluded for being duplicates from the selected databases. Thirteen articles were excluded because they did not present any IPC strategy for CREC or CRKP infection or had methodological pitfalls. Thirty studies met the inclusion criteria and were thus included in this systematic review (Figure 1). Quality assessment, performed by one of the authors, using ORION, CARE and NHLBI tools, showed that all included studies were of good quality (Appendix). Acknowledging this as an infrequent result, the analysis was repeated, returning the same results.

Figure 1.

PRISMA-P flow diagram of search strategy and study selection.

Analysing the type of studies (Table 2), one was a retrospective and prospective case–control, three were prospective studies and all others (87%) were retrospective. Of these, one was cross-sectional, one quasi-experimental before and after, one survey, one epidemiological and two cohort studies. Twenty-four studies (80%) were conducted in the context of an outbreak. Studies duration ranged from 1 month to 8 years, with a mean duration of 18 months. Number of patients ranged from five to 1446, with a mean number of 129 participants. Only four studies included children and neonates, with all others (n = 26) considering only adult patients. Regarding the setting where studies were conducted, the majority were on acute care with only three involving patients in rehabilitation units and one in a residential care home. From the 26 studies conducted in hospitals, more than half (n = 17) were carried out in intensive care units (ICU). Others were carried out in a diverse set of departments in acute care units (Gorgulho et al., 2020; Trepanier et al., 2017), as cardiology wards (Decraene et al., 2018) or a liver unit (Martin et al., 2017).

Table 2.

Characterization of included studies.

Study	Design and duration	Population/ Wards/Situation	Pathogen and AMR feature	Samples and detection methods	Outcomes	Limitations
Ahn (2019)Korea	- Retrospective - 3 months (July to Sep, 2017) - Outbreak	• 20 patients • ICU Medicine	CREC • NDM • OXA	- Blood, urine and stool - ID: blood agar, chromogenic culture media and MacConkey agar plates - AST: Modified Hodge test, Carba NP test - CRE: XpertCarba-R assay	Rapid detection is one of the most important factors to prevent CRE dissemination. In acute settings, if IPC team fails to ensure early control of CRE transmission, patients who can opt for homecare are advised an early discharge	—
Barratt (2017) New Zealand	- Retrospective - 4 months (Sep to Dec 2015) - Outbreak	• 4 patients • Haematology, Gastroenterology, Nephrology	KPC • NDM	- Urine, stool, rectal - ID: MALDI-TOF - AST: Modified Hodge test - CRE: Carba NP test	A multi-disciplinary and multifaceted approach successfully curtailed the outbreak CRE may be under-detected in New Zealand IPC and screening policies should include CRE Contaminated shared equipment or patient environment may have been a source of transmission of CRE during the outbreak	—
Battikh (2017) Tunisia	- Retrospective - 1 year (Jan to Dec 2014) - Outbreak	• 21 patients • Neonatal and adult ICUs	KPC • VIM • KPC	- Blood, catheters, pus and tracheal aspirate - ID: VITEK®2 - AST: DD in Mueller-Hinton agar plates - CRE: Modified Hodge test	Copresence of 2 carbapenemases associated with colistin resistance is worrisome due to the possibility of dissemination and limitations on therapeutic options. It is essential to streamline the use of antimicrobials and apply IPC measures to prevent the emergence of colistin resistance	—
Bocanegra-Ibarias (2019) Mexico	- Retrospective - 1 month (Sep 2017) - Outbreak	• 67 patients • 65 HCWs • ICU Neurology	KPC • NDM	- Rectal - ID: MALDI-TOF - AST: not reported - CRE: CarbaNP test	A hospital outbreak caused by KPC was contained though active epidemiological and microbiological surveillance. With the methodology used, the detection of the NDM gene in faecal samples was obtained in approximately 15 hours after sampling	• Do not have the complete genome sequence of NDM KPC strains, which would have allowed to infer interpatient transmission.
Borgmann (2017) Germany	- Retrospective cohort - 4 months (Oct 2014 to Jan 2015) - Outbreak	• 23 patients • Acute rehabilitation	KPC and CREC • OXA-48	- Rectal - ID: VITEK®2 - AST: VITEK®2 - CRE: E-test®, Modified Hodge test and XpertCarba-R assay	Antimicrobial treatment seemed to be a risk factor for transmission of OXA positive KPC Patients´ age, gender, Barthel index at admission, and residence with a KPC colonised roommate were not a risk	• Single-centre study • Small sample size • Not clear the patient index, when colonisation happened, as well as transmissions routes.
Brkic (2017) Croatia	- Retrospective - 1 year (May 2015 to May 2016) - Outbreak	• 12 patients • ICU, Surgery, Medicine, Neurology	KPC • KPC	- Stool, rectal, nasal, oropharyngeal and axillary skin - ID: VITEK®2 - AST: DD and E-test® - CRE: PCR test	Rapid detection of KPC and vigorous implementation of IPC measures were essential to control the outbreak	—
Bruins (2020) Netherlands	- Retrospective - 13 months (Feb 2017 to Mar 2018) - Outbreak	• 8 patients • Residential care home	CREC • VIM	- Urine, rectal - ID: agar plates - AST: not reported - CRE: PCR test	VIM carbapenemase-producing Enterobacteriaceae (CPE) spread was associated with the use of shared toilets in communal areas. 7months after IPC measures implementation, all carriers were found to be VIM-negative, and after 1 year, VIM CPE was no longer detectable in the environment A customised bundled approach was vital to control the outbreak successfully. Current guidelines should be adapted to all different types of residential care homes in order to effectively fight the spread of MDR pathogens	—
Castagnola (2019) Italia	- Retrospective, epidemiologic - 5 years (Jan 2013 to Dec 2017)	• 53 patients • Paediatric hospital	CREC and KPC • VIM • KPC • NDM • OXA-48	- Blood, CSF samples and rectal - ID: MacConkey agar plates - AST: agar plates - CRE: XpertCarba-R assay	Metallo-β-lactamases were the most frequently identified carbapenemases in Enterobacteriaceae. E. coli and K. pneumoniae the most frequently isolated pathogens carrying them. Proactive IPC strategy was effective in containing in-hospital spreading	—
Chen (2019) China	- Retrospective - 5 months (Dec 2016 to Apr 2017) - Outbreak	• 8 patients • Infectiology, ICU	KPC • KPC	- Blood, sputum, urine, and venous exudate - ID: not re ported - AST: DD- CRE: PCR test	Two groups of KPC were responsible for a nosocomial outbreak and demonstrated the transmission route from 2 index patients. Plasmid carriage and phylogeny are useful tools for identifying clades involved in KPC transmission Real-time surveillance of nosocomial outbreaks can help identify the origin of infection and detailed transmission route, which will facilitate the ir timely control	HCW and environmental implication not fully demonstrated • Single-centre and short duration study • Small sample size
Cienfuegos-Gallet (2019) Colombia	- Prospective case–control and cohort - 2 years (Feb to Mar, 2014 and Oct 2014 to Sep 2015)	• 338 patients • ICU, Medicine	KPC • KPC	- Urine, blood, tracheal aspirate, skin and soft tissue samples, wounds and abscesses drainage - ID: VITEK®2 - AST: VITEK®2 - CRE: PCR test	Short antimicrobial courses had the potential to reduce the selection and transmission of KPC High mortaility burden occurred in patients infected with KPC in an endemic setting and lead to increased mortality via inappropriate antimicrobial treatment and inappropriate use of urinary catheters Dissemination of hypervirulent clones could add to the list of challenges for AMR control	• Lack of implementation of active surveillance cultures • Information about antimicrobial exposure was limited to hospital registries • Results were from an institution in an endemic region of carbapenem resistance.
Decraene (2018) England	- Retrospective - 9 years (2009 to 2017) - Outbreak	• 268 patients • Cardiology	CREC and KPC • KPC • NDM • OXA-48	- Rectal - ID: MALDI-TOF - AST: ChromID CARBA - CRE: XpertCarba-R assay	Highlight the limited evidence for managing large CRE outbreaks, including environmental sampling protocols and interventions Widespread colonisation with carbapenemase-producing E. coli is a concern	• Observational study • Limited environmental sampling • Although genetic overlap between environmental and patient isolates was consistent with transmission between them, numbers were too small to infer directionality
Duman (2020) Turkey	- Retrospective and prospective case–control - 3 months (Oct to Dec 2017) - Outbreak	• 21 patients • ICU	KPC • NDM • OXA-48	- Rectal - ID: MALDI-TOF - AST: Kirby-Bauer disk diffusion - CRE: PCR test	IPC measures that successfully controlled this outbreak were hand hygiene, tight contact prevention, good clean-up of the hospital environment and medical devices. It would be beneficial to take IPC measures to prevent the spread of these strains to the community and hospital settings	—
Ece (2018) Turkey	- Retrospective - 3 months (Apr to Jun, 2013) - Outbreak	• 14 patients • UCI, Haematology, Anaesthesiology, Urology	KPC • OXA-48	- Tracheal aspirate, blood, urine and sputum - ID: VITEK®2 - AST: VITEK® 2 - CRE: Modified Hodge test	All K. pneumoniae strains had OXA-48. Clonal spreading was particularly detected in Anaesthesiology ICU Molecular epidemiological monitoring may prevent the spread of MDR pathogens	—
Ferrari (2019) Italy	- Retrospective - 10 months (Aug 2015 to May 2016) - Outbreak	• 23 patients • ICU	KPC • KPC	- Rectal swabs, blood, bronchial aspirates and wash, urine and wounds - ID: MALDI-TOF - AST: BD Phoenix 100 - CRE: E-test®	A clear correlation between AMR profiles and number of colonisations or infections is not clearly evident. Highlight on the importance of overall environmental context, possibly more than the intrinsic characteristics of a strain, in determining the spread of different KPC isolates	—
García-Arenzana (2019) Spain	- Retrospective - 1 month (Jul 2015) - Outbreak	• 18 patients • Medicine	KPC • OXA-48	- Rectal - ID: MacConkey agar plates and MALDI-TOF - AST: Wider®system and MicroScan® WalkAway - CRE: Modified Hodge test and PCR test	18 cases detected, 14 nosocomial. 4 different clones of K. pneumoniae OXA-48 were responsible for 83.3% of them Hand hygiene and training the personnel in standard precautions are two effective tools in decreasing KPC transmission. Although general cleaning and handwashing are fundamental in any outbreak control, decontamination with more aggressive methods, like vaporised hydrogen peroxide, might be the lane to eradicate persistent outbreaks Strong microbiological surveillance and a multidisciplinary control team are helpful to control transmission during outbreaks	—
Gorgulho (2020) Portugal	- Retrospective - 4 years (2015 to 2018) - Outbreak	• 113 patients • Acute care (departments not reported)	KPC • OXA-48 • KPC	- Rectal and other specimens not mentioned - ID: VITEK®2 and Brilliance CRE Agar - AST: E-test and VITEK®2 - CRE: Coris immunochromatography test	OXA-48 outbreak. Surveillance should be in place as these isolates are probably spreading. Effective communication, multidisciplinary team work and proper IPC measures are some of the best strategies during outbreaks	• Small sample size • High proportion of samples with no carbapenemase identification due to the previous centralisation of microbiologic analysis and poor communication between institutions • It is an exclusively descriptive report.Case–control studies and further statistical analysis to identify risk factors for acquiring CRE
Gu (2018) China	- Retrospective - 6 months (Mar to Aug 2016) - Outbreak	• 5 patients • ICU	KPC • KPC	- Blood, stool, sputum - ID: VITEK®2 - AST: VITEK®2 - CRE: PCR test	ST11 KPC strains pose a threat to human health because they are simultaneously hypervirulent, MDR, and highly transmissible. IPC measures should be implemented to prevent dissemination in the hospital setting and the community	• Small sample size
Hernández-García Spain 2019	- Retrospective - 6 months (Sep 2015 to Feb 2016) - Outbreak	• 9 patients • Neurosurgery	KPC • NDM • OXA-48 • VIM	- Rectal, urine , respiratory - ID: MALDI-TOF - AST: MIC gradient strips - CRE: KPC/MBL/OXA-48 Confirm Kit and the Modified Hodge test	Although further dissemination of NDM-KPC isolates was controlled following reinforcement of IPC measures, results highlight the rapid dissemination of NDM through epidemic clones with a high capacity for dispersion and persistence in the hospital environment Admission of undetectable or asymptomatic colonised patients from endemic countries should alert for the risk of introduction and establishment of these potential MDR strains in local epidemiology	—
Kong (2019) China	- Retrospective - 1 year (Sep 2015 to Sep 2016) - Outbreak	• 12 patients • Neonatalogy	KPC • NDM	- Sputum, blood and urine - ID: MALDI-TOF - AST: VITEK®2 - CRE: PCR test	First study that describes the outbreak of ST337 NDM producing K. pneumoniae from neonates in China. Their resistance profile may help paediatricians promote the prudent use of antimicrobials in child health care Worldwide surveillance and implementation of stricter IPC measures are urgently needed to prevent these MDR pathogens from further disseminating in neonatal wards	—
Legeay( 2018) France	- Prospective cohort - 6 months (Nov 2013 to Apr 2016) - Outbreak	• 74 patients • Medicine, Surgery, Obstetric, Rehabilitation	CREC and KPC • OXA-48	- Rectal - ID: ChromID Carba Smart agar - AST: not reported - CRE: GeneXpert Carba-R system	Understanding ward variables associated with CPE spread can help design suitable solutions. Colonisation pressure and antimicrobial consumption seem to be driving in-hospital transmission, along with caregiver/patient ratio. Considering the high colonisation pressure, daily dedicated healthcare workers for managing CPE patients are needed Important role of training courses, audit and education in reducing CPE in-hospital transmission. Coordination between IPC and AS teams is also crucial to prevent CPE spread	• Insufficient power to identify other risk factors for transmission and did not thoroughly investigate the individual reservoir in the variable ‘colonisation pressure’ • No assessment of adherence to the IPC instructions • Rectal swabbing without enrichment media may reduce detection sensitivity
Li (2019) China	- Retrospective, quasi-experimental, before and after - 4 years (Jan 2013 to Jun 2016)	• 629 patients • ICU	KPC • VIM • KPC • OXA-48	- Nasopharyngeal, sputum, tracheal , urine and other infection sites - ID: VITEK®2 - AST: DD - CRE: PCR test	Comprehensive IPC interventions including de-escalation and targeted bundle interventions showed a significant reduction in ICU-acquired KPC colonisations/infections, despite ongoing admission of patients colonised/infected with KPC	• Single-centre study • Small sample size • Interventions were multimodal which precludes determination of the effectiveness of any single measure
Madueno (2017) Spain	- Retrospective - 2 years (Oct 2013 to Dec 2015) - Outbreak	• 267 patients • ICU, Medicine Surgery	KPC • OXA-48	- Rectal, blood, urine, catheter tip, skin and soft tissue - ID: VITEK®2 - AST: VITEK®2 - CRE: Modified Hodge test and PCR test	OXA-48 K. pneumoniae high dissemination capacity in a hospital. Clinical infection represents a significant burden on hospitals and is associated with high mortality rates. Active surveillance programmes should focus on hospital readmissions in order to control the spread of CRE	• Single-centre study • Unknown number of patients who developed infection among patients known to be OXA-48 K. pneumoniae carriers
Martin (2017) United Kingdom	- Retrospective - 7 months (Jul 2013 to Jan 2014) - Outbreak	• 20 patients • Liver unit	KPC • KPC	- Blood, urine cultures, intra-operative, rectal - ID: MALDI-TOF - AST: DD test - CRE: Modified Hodge test, E-test® and PCR test	Considerable potential for rapid dissemination of carbapenemase genes among Klebsiella spp. and other Enterobacteriaceae, despite the implementation of extensive IPC interventions This outbreak resulted in changes to clinical care: transplant assessments were transferred to the outpatient setting and included CPE screening, strict algorithms for admission screening/isolation on the liver transplant unit, discharge CPE screening and carbapenems paring antimicrobial prescribing strategies were implemented	• Potential underestimation of infection/colonisation episodes • Few publicly available UK KPC-carrying whole-genome and plasmid sequences, limiting the ability to contextualise the local strains • Not possible to evaluate the relative impact of each IPC measure on reducing CPE transmission
Pirs (2019) Slovenia	- Retrospective - 2 years (Oct 2014 to Sep 2016) - Outbreak	• 40 patients • ICU, Medicine, Infectiology, Surgeryl	CREC and KPC • NDM • OXA-48	- Rectal, blood, urine, lower respiratory tract, abdominal and wounds/tissue - ID: MALDI-TOF - AST: DD test - CRE: LightMix modular carbapenemase kits	Initial standard IPC measures failed to prevent the outbreak. Strict infection control measures, control of patient movement and limiting patient transfers between wards, strict screening policy coupled with a comprehensive educational campaign at all levels, and strong management support contributed to the successful control of the outbreak The greatest hindrances to outbreak control were the high number of transfers between wards and the impossibility of assigning dedicated HCWs was not always possible	—
Protonotariou (2018) Greece	- Retrospective - 2 years (Jan 2013 to Jan 2015) - Outbreak	• 25 patients • ICU	KPC • VIM • KPC	- Blood, urine, venous catheters, pus, bronchial secretion - ID: VITEK®2 - AST: VITEK®2 and E-test® - CRE: Modified Hodge test and PCR test	Long-term outbreak of a KPC ST147 clonal strain co-producing KPC-2 and VIM-1 presumably cross-transmitted among patients hospitalised in ICU. Early recognition of such strains and implementation of appropriate IPC measures are crucial for containing their spread	• Lack of implementation of active surveillance cultures
Smolders (2019) Belgium	- Retrospective - 1 year (Jan 2017 to Jan 2018) - Outbreak	• 103 patients • ICU	CREC and KPC • OXA-48	- Rectal, urine and bronchial aspirates - ID: CPE culture medium and chromID Carba Smart selective - AST: MALDI-TOF - CRE: Phoenix expert system and E-test®	Epidemiological analysis demonstrated a positive and significant relationship between contaminated sinks and CPE acquisition of patients admitted to ICU rooms, demonstrating sinks as the environmental reservoir. Decontamination of sink drains with acetic acid is a valuable alternative to other methods, such as heated sinks and water-free care, especially when other options are not feasible in the short term. Acetic acid is cheap, widely available, effective and manageable from a safety and technical point of view	• Did not investigate clonal relations between CPE strains recovered from sinks and patients
Spencer (2019) USA	- Retrospective cohort - 8 years (2010 to 2017) - Outbreak	• 67 patients • Acute care, rehab and outpatient facilities	KPC • KPC	- Urine, blood, tracheal aspirate, abscess drainage, wound and rectal - ID: Blood agar plate and a MacConkey agar plate - AST: E-test® - CRE: Modified Hodge test	Related CRKP were shared between facilities, which catalysed systemwide changes to address gaps in traditional, facility-based infection prevention and control	• Using cryopreserved clinical isolates may have reduced precision in detection • Incomplete sampling of isolates limited ability to determine potentially important sources of infection
Trepanier (2017) United Kingdom	- Retrospective survey - 6 months (Nov 2013 to Apr 2014)	• 89 patients • Acute care (departments not reported)	CREC and KPC • KPC • OXA-48 • VIM • NDM	- Stool and urine, wounds, throat, lines and devices - ID: MALDITOF and VITEK®2 - AST: agar dilution and VITEK®2 - CRE: PCR test	UK prevalence and incidence of clinically significant CRE is currently low, but these MDR bacteria affect most UK regions. Recommended IPC measures were not universally followed, notably screening high-risk patients on admission, using a CRE ‘flag’ on patients’ records and alerting hospitals when transferring affected patients. Continued vigilance and improved monitoring of CPE are required throughout UK to monitor the impact of intervention measures	—
Yan (2019) China	- Prospective -7 months (Jun to Dec 2017)	• 67 patients • 52 HCWs • ICU	KPC • KPC • OXA-48	- Sputum, urine, and abscesses drainage - ID: VITEK®2 - AST: VITEK®2, E-test® - CRE: PCR test	KPC isolates can transfer between patients, ICU staff and environment Environmental contamination and KPC-positive patients were the most frequent sources of transmission to ICU staff hands, gloves or gowns. Compliance with contact precautions and more aggressive environmental cleaning and disinfection may decrease transmission of KPC isolates	• Genetic environment surrounding study and plasmid type were deficient
Yin (2020) China	- Retrospective, cross-sectional - 1 year (Jan 2017 to Jan 2018)	• 1446 patients • Paediatric and neonatal ICUs, Neonatalogy and Haematology	CREC and KPC • KPC • NDM	- Rectal and pharyngeal swabs, stool - ID: MALDI-TOF - AST: VITEK®2 - CRE: PCR test	Active screening and appropriate patient placement can effectively reduce CRE colonisation and nosocomial infection. KPC strains isolated were highly homologous and mainly hospital-acquired, showing that large-scale screening and effective IPC measures are urgently needed to prevent diverse CRE variants from causing epidemics in the future	• Minimum inhibitory concentrations of fosfomycin, polymyxin and tigecycline were lacking • Single-centre study • Data were collected for only one year

Twenty studies approached CRKP dissemination, two analysed CREC infection and/or colonisation and eight analysed both. Collected biological samples had several sources: blood, urine, catheter tips, rectal and stool samples, tracheobronchial, oropharyngeal and nasal secretions, abscess drainages and skin and soft tissue.

Considering IPC standard and transmission-based precautions (Table 3), hand hygiene was described in 19 (63%) of the 30 reviewed studies. Hand hygiene compliance was evaluated using the WHO protocol (Brkic et al., 2017), according to ‘The Five Moments for Hand Hygiene’ (Barratt et al., 2017; Li et al., 2019). In several reviewed studies, hand hygiene compliance was evaluated, using direct observation methodology, included in training sessions and promoted not only to HCW (Ece et al., 2018) but also to other stakeholders, such as the relatives who visit patients (Hernández-García et al., 2019; Protonotariou et al., 2018). Only two of those 19 articles mentioned the use of alcohol-based solutions for hand hygiene (Hernández-García et al., 2019; Li et al., 2019). No other article mentioned the use of other types of disinfectant solutions, nor the simple use of soap and water for hand hygiene.

Table 3.

Implemented Infection Prevention and Control measures in included studies.

Study	Patient active surveillance cultures	Isolation/cohort of colonised/ infected patients	Environment cleaning protocols	Antimicrobial stewardship	Hand hygiene	Surfaces surveillance	HCWs protective equipment	Equipment for single-patient use	Educational sessions, feedback results
Ahn	✓	✓	NR	NR	NR	NR	NR	NR	NR
Barratt	✓	✓	✓	✓	✓	NR	✓	NR	✓
Battikh	✓	NR	✓	✓	✓	✓	NR	NR	NR
Bocanegra-Ibarias	✓ and HCW	NR	NR	NR	✓	✓	✓	C	✓
Borgmann	✓	✓	✓	✓	C	NR	✓	C	NR
Brkic	✓ and HCW	✓	✓	NR	✓	✓	C	C	✓
Bruins	✓	✓	✓	✓	✓	✓	✓	C	✓
Castagnola	✓	✓	NR	NR	C	NR	C	C	NR
Chen	✓ and HCW	✓	✓	✓	✓	✓	C	C	NR
Cienfuegos-Gallet	✓	✓	NR	✓	C	NR	C	C	✓
Decraene	✓	✓	✓	✓	C	✓	C	C	NR
Duman	✓	✓	✓	✓	✓	✓	✓	C	✓
Ece	✓	✓	✓	✓	✓	NR	C	C	✓
Ferrari	✓	Not performed	✓	NR	C	✓	C	✓	✓
García-Arenzana	✓	✓	✓	✓	✓	✓	C	C	✓
Gorgulho	✓	✓	NR	✓	NR	NR	NR	NR	✓
Gu	✓	✓	✓	✓	NR	NR	✓	NR	NR
Hernández-García	✓	✓	✓	✓	✓	NR	C	C	NR
Kong	✓	✓	✓	✓	C	NR	C	C	NR
Legeay	✓	✓	NR	✓	✓	NR	C	C	✓
Li	✓	✓	✓	✓	✓	NR	✓	✓	✓
Madueno	✓	✓	✓	✓	C	NR	C	C	✓
Martin	✓	✓	✓	✓	✓	NR	✓	✓	✓
Pirs	✓	✓	✓	✓	✓	NR	C	C	✓
Protonotariou	Not performed	✓	✓	✓	✓	✓	NR	NR	✓
Smolders	✓	NR	✓	NR	NR	✓	NR	NR	NR
Spencer	✓	✓	✓	✓	✓	NR	C	C	✓
Trepanier	✓	✓	✓	✓	✓	NR	C	✓	✓
Yan	✓HCW and PPE	NR	✓	NR	✓	✓	✓	C	NR
Yin	✓	✓	✓	NR	✓	NR	✓	NR	✓

✓ - Executed; NR – Not Reported; C – implied measures in contact precautions; HCW – Healthcare workers; PPE – Personal Protective Equipment.

Regarding environmental cleaning, 24 (80%) studies reported the reinforcement of implemented protocols, and of those, 12 indicated the used disinfectant: hydrogen peroxide vapour, hypochlorite and chlorine solutions, quaternary ammonium compounds and ultraviolet light systems. Only one study assessed the effectiveness of the environmental cleaning, using the adenosine triphosphate bioluminescence assay (Spencer et al., 2019). Twenty-three studies (77%) proceeded to isolation or cohorting of colonised/infected patients with CREC and/or CRKP, four studies (13%) did not mention to have implemented this IPC measure and one stated that no cohort or isolation of patients was applied. In one specific study, the effect of various types of contact isolation on blocking CRE transmission was analysed. Authors compared single room (type A – one patient in one room) with same room (type B – patients infected or colonised with CRE placed in same room), same area (type C – patients infected or colonised with the same CRE placed as a cohort in the same area of a big ward, with a partition barrier) and no cohort placement (type D – patients with or without CRE or with different CRE without any cohort placement). Results indicated that both nosocomial CRE colonisation and infection incidence dramatically decreased in the wards where type A or B placements were performed (p < 0.05), while no significant changes found in wards with type C or type D placements (Yin et al., 2020)

Regarding the use of HCW protective equipment and the availability of equipment for single-patient use, these measures were rarely mentioned in reviewed studies, but were implicitly included in the contact measures mentioned as applied (n = 19; 63%). Only ten (33%) studies described protective equipment by HCW, which included the use of gloves gowns, aprons (Duman et al., 2020) and masks (Borgmann et al., 2018). In one specific study, in pre-outbreak IPC interventions gloves and aprons (no sleeves) were used for care provision to patients under contact isolation, while in post-outbreak period, those patients were managed using dedicated equipment and single-use long-sleeve gowns (Martin et al., 2017). Four (13%) reviewed studies described the use of individualised equipment for each patient colonised/infected with CRKP or CREC. Other IPC standard measures, like respiratory hygiene and cough etiquette, principles of asepsis, prevention of injuries from sharp instruments and post-exposure prophylaxis, were not mentioned in the reviewed studies.

Considering other activities allied to IPC, in all reviewed studies but one, ASC were performed. In four studies, apart from ASC on patients, surveillance cultures in HCW hands and gowns were also performed. Moreover, 12 (40%) of the 30 reviewed studies described to have performed CRKP and CREC surfaces contamination surveillance. One specific study (Yan et al., 2019) collected samples from 20 sites within 2 m from the patient’s bed such as: room – linens, bed rails, call buttons; bathroom – sinks, toilet seats; equipment – wheelchairs, ventilators, computers and endoscopes.

Eighteen studies reported to have conducted educational sessions on IPC principles, AS, contact precautions, hygiene and cleaning protocols, including also debriefings or audits (observation and feedbacks) for environmental cleaning and hand hygiene. In one of these studies, a clinical microbiologist and IPC practitioners conducted the educational sessions addressing HCW questions previously collected (Bruins et al., 2020). In Legeay et al. (2018), IPC practitioners recommended that all scheduled care (clinical rounds, nurses rounds, sampling rounds) should leave the carriers/infected rooms to the end of the round. In another reviewed study, educational sessions were conducted by a multidisciplinary team, specifically constituted for that purpose (García-Arenzana et al., 2020) Gorgulho et al. (2020) described that patients and families were also educated on IPC measures and instructed to warn the hospital staff in subsequent hospital visits of their previous infection/colonisation with CRE. Before and after quasi-experimental study, when modified IPC interventions were applied in addition to the standard IPC interventions, extensive external medical staff education, all consulting staff, rehabilitative physicians and external nurses had lectures and practical IPC education once a month (Li et al., 2019).

Finally, regarding AS, 22 studies (73%) described them, namely, the analysis of previous antimicrobials consumption and duration (over the latest year) and the selected antimicrobial therapy in current treatment.

Discussion

One of the most important strategies to fight AMR is IPC, practical and scientific sustained measures to prevent the risk of pathogens transmission, with positive impact in health and biosafety of all stakeholders: patients, visitors, HCW and ultimately the entire society (NHMC, 2010; WHO, 2016a). Regarding the impact of IPC strategies on CREC and CRKP management, it is important to discuss the fundamental role of standard and transmission-based IPC precautions.

Several reviewed studies suggest transversal standard and transmission-based IPC (Battikh et al., 2017; Brkic et al., 2017; Gu et al., 2018; Spencer et al., 2019; Yan et al., 2019) crucial to contain CRE and other pathogens dissemination (Protonotariou et al., 2018), at all moments, not only in outbreaks (Castagnola et al., 2019), and in all settings, including homecare (Ahn et al., 2019). IPC practices should be tailored to the level of care that is being provided in the different healthcare settings and combined with the inherent risk to individuals and population (PHAC, 2012).

Regarding hand hygiene, 19 of the 30 reviewed studies described it. WHO (2009) claims that healthcare facilities leaderships must ensure that all HCW are familiar with proper hand hygiene technique and its rationale. Hand hygiene policies are not enough. Adherence rates must be monitored and communicated directly to front line staff and facilities administration. Indeed, one of reviewed studies conducted a one-month observation study among HCW resulting in 36% handwashing compliance. Owing to this, handwashing training sessions for all HCW were undertaken and the compliance increased to 85% in a new observation study a month later (García-Arenzana et al., 2020). In addition, feedback should be provided to staff who miss hand hygiene, and facilities should ensure access to adequate hand hygiene stations (i.e. clean sinks and/or alcohol-based hand rubs) stocked with supplies (e.g. towels and soap) and clear of clutter (WHO, 2009).

Patients colonised/infected with CRKP and CREC were isolated in 25 (83%) reviewed studies. These results corroborate the enforcement of this IPC approach in all healthcare settings. Patients should be placed in single rooms, preferably with an en-suite bathroom (Clark et al., 2018) and care should be provided by dedicated HCW (Pirš et al., 2019). Cohorting should be used in situations of insufficient single rooms (WHO, 2019). Moreover, patients with suspected or known CRE colonisation must not be placed in a room with high-risk patients (open wounds, in-dwelling devices, immune compromise) and long-term patients (Clark et al., 2018).

CRE are frequently reported in device-associated infections, particularly catheter-associated urinary tract infections. In fact, one reviewed study reported that patients using urinary catheters had an increased 2.60 odd ratio (1.25–5.37; 95% confidence interval) of having a CRKP infection compared to patients without urinary catheters (Cienfuegos-Gallet et al., 2019). Another study, Li and colleagues (2019), emphasised the importance of strategies to prevent device-related infections, that should be implemented by targeted bundles interventions, as prevention of intravascular catheter-related infection, ventilation associated pneumonia and skin and soft tissue infections.

Regarding the use of PPE and its availability for single-patient use, these measures were rarely mentioned in the reviewed studies but implicitly included in the contact measures mentioned as applied. The studies evidenced the efficacy of the already existing WHO guidelines: contact precautions in all interactions with CRE positive patients in addition to standard precautions, as well as pre-emptive contact for all patients with suspicion of CRE carriage while waiting for the laboratory identification/confirmation results. Periodic audits of compliance to these IPC measures have also been linked to favourable outcomes (Magiorakos et al., 2017); thus IPC teams, staff and leaderships should make efforts to include them in their IPC program. Regarding the use of gloves, wearing them for all direct care and activities in the patient room or bed space; changing them when moving from a contaminated body site to a clean one or before touching the environment; removing and discarding gloves immediately after care or environment cleaning, as emphasised by WHO (2009), are mandatory, and demonstrated to be effective in CRE control in all reviewed studies. Similar evidence was obtained regarding the use of protective gowns, where long-sleeved ones should be used in all activities with skin or clothing direct contact with the patient or their environment (Ontario Agency for Health Protection, 2019).

Patients colonised or infected with CRE widely contaminate their surroundings (Smolders et al., 2019). Routine daily cleaning must be guaranteed for all patients in all situations, irrespective of their CRE (or other pathogen) colonisation/infection status, but if a colonisation or infection is known, environmental cleaning frequency must increase (more than once a day), including disinfection of highly manipulated surfaces, with isolation areas being cleaned and disinfected after non-isolation areas and cleaning solutions and equipment must be discarded/laundered immediately after use (WHO, 2019). Twenty-four of the reviewed studies reported the reinforcement of environmental cleaning protocols as successful contributors to manage CRE outbreaks. Monitoring the efficacy of facilities cleaning is crucial, with environmental ASC as key (Ferrari et al., 2019). Despite that, only 12 of the 30 reviewed studies conducted ASC to monitor CRE surfaces contamination.

The reviewed studies had some limitations that can provide clues for future research (Shamseer et al., 2015). Small sample sizes (Battikh et al., 2017; Brkic et al., 2017; Borgmann et al., 2018; Chen et al., 2019; Gorgulho et al., 2020; Gu et al., 2018; Li et al., 2019), single-centre studies (Chen et al., 2019; Kong et al., 2019; Li et al., 2019; Madueno et al., 2017), small number of environmental samples (Decraene et al., 2018; Yan et al., 2019) and information on antimicrobial consumption limited to facilities records (Cienfuegos-Gallet et al., 2019) were indicated as limitations. Unknown CREC and CRKP transmission routes (Borgmann et al., 2018; Li et al., 2019) were also highlighted as relevant limitations as well as the retrospective (Chen et al., 2019; Madueno et al., 2017; Spencer et al., 2019) and observational (Decraene et al., 2018; Gorgulho et al., 2020) nature of data collection. Absence of ASC limited the studies by reducing the availability of important information on CRE incidence and prevalence (Cienfuegos-Gallet et al., 2019; Protonotariou et al., 2018). For future studies, authors suggested the implementation of multicentric studies (Borgmann et al., 2018; Chen et al., 2019; Li et al., 2019; Madueno et al., 2017) with significant sample sizes (Battikh et al., 2017; Borgmann et al., 2018; Brkic et al., 2017; Chen et al., 2019; Gu et al., 2018; Li et al., 2019). Although retrospective data is significant to understand the background of the studied population and facilities, it is important to monitor patients progress during their stay in the healthcare facility, and thus prospective studies are important to be conducted.

Other limitation not mentioned in the analysed literature is the role of patients and their informal caregivers in IPC measures compliance and the influence of education and training. There are documents and guidelines for HCW and informal caregivers on specific measures to prevent and control CRE infection/colonisation (Clark et al., 2018; Magiorakos et al., 2017); however, literature is scarce regarding the translation to practice and its success in preventing the dissemination of these MDR agents. HCW responsible for patient, family and other informal caregivers education should empower them on their significant roles, benefiting from specific training tailored to their needs and demands, to make them more skillful in IPC practices (Wilmont et al., 2018). Regarding HCW, IPC education is essential for an effective IPC program and thus, it must be universal and regular, using team and task-based participatory strategies (WHO, 2019). Effective communication and teaching tools are essential to ensure HCW perceptions, awareness, understanding and behaviours that can effectively reduce HAI acquisition and transmission (Macdonald, 2018).

Most of the reviewed studies were performed in ICU. ICU patients are highly vulnerable to HAI-MDR infection due to several intrinsic and extrinsic factors like the use of invasive devices, patient’s low immunity and poor nutritional status. The lifesaving critical care performed in an ICU requires the contributions of many HCW and patient care devices, which poses an additional risk of transmission from personnel or fomites to the patient (Strich and Palmore, 2017). Although it is highly important to study and improve ICU-specific IPC measures, it is difficult to translate the obtained information from these units to other wards or other healthcare units. Studies outside ICU and acute care are needed, to contribute with information that is relevant for the specificities of those sites.

CRKP and CREC are shared between facilities and spreading to the community mostly due to unidentified colonised patients that act as transmission vehicles (Madueno et al., 2017). Additionally, the number of CRE infected/colonised patients in contexts closer to community is becoming more frequent, like long-term healthcare units (LTHU) or other units that accommodate patients from multiple backgrounds (Tomczyk et al., 2019). LTHU receive predominantly frail elders with an increased risk for CRE carriage, among other MDR pathogens, due to their frequent admissions and re-admissions in acute care facilities, diverse comorbidities, high prevalence of antimicrobial use and frequent dependency of care including invasive devices management (Mills et al., 2016). No reviewed study explored this problem, which can be relevant for future work in the area. Lastly, it is essential that future studies are conducted outside the context of an outbreak, during the normal course of healthcare (outbreaks are always preceded by periods of normality).

Emerging AMR is a global problem, which can only be controlled if all players collaborate, relying on four pillars that need to work in parallel: surveillance of infections, resistance and antimicrobial use; IPC measures in preventing AMR transmission; AS; and finally, research and development (Zingg et al., 2019). WHO (2019) advocates that IPC strategies implementation is most effective when using a multimodal strategy, a set of several elements implemented in an integrated way to improve outcomes and changing behaviours, as bundles and checklists. Intervention bundles are common in IPC, and the impact of each component might be estimated by a stepwise approach. However, no consensus on the adequate combination of IPC measures has yet been found due to differences in CRE prevalence, underlying resistance mechanisms, environmental settings and available resources between institutions at a national and international level (Vock and Tschudin-Sutter, 2019). These barriers are similar to all other MDR pathogens, causers of HAI and the global AMR and MDR worldwide crisis we are facing. It is unwise to forget that the spread of CRE and other MDR agents is as quick as bacterial reproduction, and thus, all moments and contexts should be viewed as IPC opportunities. IPC is the first shield of protection for patients, HCW, informal caregivers and community.

Conclusion

Current systematic review highlighted the benefits of IPC strategies to prevent and control CRE dissemination. From the conducted analysis stands out the importance of a consistent and persistent implementation, optimisation and combination of IPC measures, AS and surveillance cultures. Transversal standard and transmission-based IPC are crucial to contain CRE and other pathogens dissemination, not only in outbreaks but at all moments, and in all healthcare settings, as emphasised by the reviewed studies, mostly conducted in ICU and outbreak situations. Devaluation of HCW training and education of patients and informal caregivers is also a problem that needs to be properly addressed, as the few available evidence of its efficacy highlights huge positive results when applied.

Studying IPC measures, regardless the pathogens under analysis, is complex due to its multimodal feature, the need of longitudinal monitoring of processes and the involvement of people implying ethical procedures. However, it is not because of its complexity that IPC strategies should be left aside as a valid and useful tool to fight AMR, since they are faster, cheaper and adaptable to the contexts.

Finally, this review enhanced the importance of conducting multicentric, prospective and more structured experimental studies to allow a better evaluation of the individual impact of each IPC intervention in the control of HAI and AMR dissemination, namely, ASC, patients’ isolation/cohort, hand hygiene, environmental cleaning and surveillance. This information is paramount to improve IPC guidelines and further increment their contribution in the fight against AMR and MDR.

ORCID iD

Catarina Santos-Marques https://orcid.org/0000-0002-3460-2275