The role of routine SARS-CoV-2 screening of healthcare-workers in acute care hospitals in 2020: a systematic review and meta-analysis.

BACKGROUND: Healthcare workers (HCW) are at increased risk of infection with SARS-CoV-2. Vulnerable patient populations in particular must be protected, and clinics should not become transmission hotspots to avoid delaying medical treatments independent of COVID. Because asymptomatic transmission has been described, routine screening of asymptomatic HCW would potentially be able to interrupt chains of infection through early detection. METHODS: A systematic search was conducted in the Cochrane COVID-19 Study Register, Web of Science and WHO COVID-19 Global literature on coronavirus with regard to non-incident related testing of healthcare workers using polymerase chain reaction on May 4th 2021. Studies since January 2020 were included. An assessment of risk of bias and representativeness was performed. RESULTS: The search identified 39 studies with heterogeneous designs. Data collection of the included studies took place from January to August 2020. The studies were conducted worldwide and the sample size of the included HCW ranged from 70 to 9449 participants. In total, 1000 of 51,700 (1.9%) asymptomatic HCW were tested positive for SARS-CoV-2 using PCR testing. The proportion of positive test results ranged between 0 and 14.3%. No study reported on HCW-screening related reductions in infected person-days. DISCUSSION AND CONCLUSIONS: The heterogeneous proportions might be explained by different regional incidences, lock-downs, and pre-analytical pitfalls that reduce the sensitivity of the nasopharyngeal swab. The very high prevalence in some studies indicates that screening HCW for SARS-CoV-2 may be important particularly in geographical regions and pandemic periods with a high-incidence. With low numbers and an increasing rate of vaccinated HCW, a strict cost-benefit consideration must be made, especially in times of low incidences. Since we found no studies that reported on HCW-screening related reductions in infected person-days, re-evaluation should be done when these are available.

Emergence of pan-resistance in KPC-2 carbapenemase-producing Klebsiella pneumoniae in Crete, Greece: a close call.

OBJECTIVES: KPC-2-producing Klebsiella pneumoniae (KPC-KP) ST258 has been rapidly expanding and is often associated with serious nosocomial infections. Last-line antibiotics such as colistin and tigecycline often remain the only treatment option. We describe here the evolving genetic background of KPC-KP isolates in Crete, Greece. METHODS: We tested the antibiotic susceptibility of 34 clinical isolates from patients hospitalized in 2010 and 2013-14. Whole-genome sequences of these isolates were analysed for acquired resistance genes and gene mutations. RESULTS: All KPC-KP isolates belonged to ST258 with the exception of one ST147 isolate. From 2014, 26% of isolates were non-susceptible to all antibiotics, compared with 0 of 11 isolates from 2010. Colistin resistance was associated with mutations in mgrB, which was present in 61% of isolates from 2014. Core-genome MLST analysis showed that pan-resistant isolates were closely related and appeared in two separate clusters. CONCLUSIONS: KPC-KP is rapidly evolving to pan-resistance in Crete. We identified molecular resistance markers for pan-resistant isolates and showed that core-genome MLST is a promising tool for molecular fingerprinting of KPC-KP ST258.

Using an index-based approach to assess the population-level appropriateness of empirical antibiotic therapy.

OBJECTIVES: The population-level appropriateness of empirical antibiotic therapy can be conventionally measured by ascertainment of treatment coverage. This method involves a complex resource-intensive case-by-case assessment of the prescribed antibiotic treatment and the resistance of the causative microorganism. We aimed to develop an alternative approach based, instead, on the use of routinely available surveillance data. METHODS: We calculated a drug effectiveness index by combining three simple aggregated metrics: relative frequency of aetiological agents, level of resistance and relative frequency of antibiotic use. To evaluate the applicability of our approach, we used this metric to estimate the population-level appropriateness of guideline-compliant and non-guideline-compliant empirical treatment regimens in the context of the Dutch national guidelines for complicated urinary tract infections. RESULTS: The drug effectiveness index agrees within 5% with results obtained with the conventional approach based on a case-by-case ascertainment of treatment coverage. Additionally, we estimated that the appropriateness of 2008 antibiotic prescribing regimens would have declined by up to 4% by year 2011 in the Netherlands due to the emergence and expansion of antibiotic resistance. CONCLUSIONS: The index-based framework can be an alternative approach to the estimation of point values and counterfactual trends in population-level empirical treatment appropriateness. In resource-constrained settings, where empirical prescribing is most prevalent and comprehensive studies to directly measure appropriateness may not be a practical proposition, an index-based approach could provide useful information to aid in the development and monitoring of antibiotic prescription guidelines.

Louse-borne relapsing fever (Borrelia recurrentis) in asylum seekers from Eritrea, the Netherlands, July 2015.

Two patients from Eritrea, recently arrived in the Netherlands, presented with fever and were investigated for malaria. Bloodfilms showed spirochetes but no blood parasites. Louse-borne relapsing fever caused by Borrelia recurrentis was diagnosed. Treatment was complicated by severe Jarisch-Herxheimer reactions in both patients. Physicians should be aware of the possibility of B. recurrentis infection in migrant populations who travel under crowded conditions, especially after passing through endemic areas such as Ethiopia and neighbouring countries.

Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy, November 2013 to April 2014.

Consecutive non-replicate clinical isolates (n=191) of carbapenem non-susceptible Enterobacteriaceae were collected from 21 hospital laboratories across Italy from November 2013 to April 2014 as part of the European Survey on Carbapenemase-producing Enterobacteriaceae (EuSCAPE) project. Klebsiella pneumonia carbapenemase-producing K. pneumoniae (KPC-KP) represented 178 (93%) isolates with 76 (43%) respectively resistant to colistin, a key drug for treating carbapenamase-producing Enterobacteriaceae. KPC-KP colistin-resistant isolates were detected in all participating laboratories. This underscores a concerning evolution of colistin resistance in a setting of high KPC-KP endemicity.

Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011.

On 31 May 2011, after notification of Klebsiella pneumoniae (KP)(OXA-48;CTX-M-15) in two patients, nosocomial transmission was suspected in a Dutch hospital. Hospital-wide infection control measures and an outbreak investigation were initiated. A total of 72,147 patients were categorised into groups based on risk of OXA-48 colonisation or infection, and 7,527 were screened for Enterobacteriaceae(OXA-48) by polymerase chain reaction (PCR). Stored KP isolates (n=408) were retrospectively tested for OXA-48 and CTX-M-1 group extended-spectrum beta-lactamases (ESBL). 285 KP isolates from retrospective and prospective patient screening were genotyped by amplified fragment length polymorphism (AFLP). 41 isolates harbouring different Enterobacteriaceae species were analysed by plasmid multilocus sequence typing (pMLST). No nosocomial transmission of Enterobacteriaceae(OXA-48) was detected after 18 July 2011. Enterobacteriaceae(OXA-48) were found in 118 patients (KP (n=99), Escherichia coli (n=56), ≥1 Enterobacteriaceae(OXA-48) species (n=52)), of whom 21 had clinical infections. 39/41 (95%) of OXA-48 containing plasmids were identical in pMLST. Minimum inhibitory concentrations (MICs) of KP(OXA-48) and E. coli(OXA-48) for imipenem and meropenem ranged from ≤1 to ≥16 mg/L, and 153/157 (97%) had MIC >0.25 mg/L for ertapenem. AFLP identified a cluster of 203 genetically linked isolates (62 KP(OXA-48;CTX-M15); 107 KP(CTX-M-15); 34 KP(OXA-48)). The 'oldest' KP(CTX-M-15) and KP(OXA-48) clonal types originated from February 2009 and September 2010, respectively. The last presumed outbreak-related KP(OXA-48) was detected in April 2012. Uncontrolled transmission of KP(CTX-M-15) evolved into a nosocomial outbreak of KP(OXA-48;CTX-M15) with large phenotypical heterogeneity. Although the outbreak was successfully controlled, the contribution of individual containment measures and of the hospital relocating into a new building just before outbreak notification was impossible to quantify.

The dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey.

Staphylococcus aureus is one of the most important human pathogens and meticillin-resistant S. aureus (MRSA) presents a major cause of healthcare- and community-acquired infections. This study investigated the spatial and temporal changes of S. aureus causing bacteraemia in Europe over a five-year interval and explored the possibility of integrating pathogen-based typing data with epidemiological and clinical information at a European level. Between January 2011 and July 2011, 350 laboratories serving 453 hospitals in 25 countries collected 3,753 isolates (meticillin-sensitive S. aureus (MSSA) and MRSA) from patients with S. aureus bloodstream infections. All isolates were sent to the national staphylococcal reference laboratories and characterised by quality-controlled spa typing. Data were uploaded to an interactive web-based mapping tool. A wide geographical distribution of spa types was found, with some prevalent in all European countries. MSSA was more diverse than MRSA. MRSA differed considerably between countries with major international clones expanding or receding when compared to a 2006 survey. We provide evidence that a network approach of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of S. aureus populations such as early signalling of emerging strains, cross-border spread and importation by travel.

From theory to practice: molecular strain typing for the clinical and public health setting.

The persistence and transmission of infectious disease is one of the most enduring and daunting concerns in healthcare. Over the years, epidemiological analysis especially of bacterial etiological agents has undergone a remarkable evolutionary metamorphosis. While initially relying on purely phenotypic characterisation, advances in molecular biology have found translational application in a number of approaches to strain typing which commonly centre either on 'epityping' (molecular epidemiology) to characterise outbreaks, perform surveillance, and trace evolutionary pathways, or 'pathotyping' to compare strains based on the presence or absence of specific virulence or resistance genes. A perspective overview of strain typing is presented here considering the issues surrounding analyses which are employed in the localised clinical setting as well as at a more regional/national public health level. The discussion especially considers the shortcomings inherent in epidemiological analysis: less than full isolate characterisation by the typing method and limitations imposed by the available data, context, and time constraints of the epidemiological investigation (i.e. the available epidemiological window). However, the promises outweigh the pitfalls as one considers the potential for advances in genomic characterisation and information technology to provide an unprecedented aggregate of epidemiological information and analysis.

Overview of molecular typing methods for outbreak detection and epidemiological surveillance.

Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage-type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages.

Latent introduction to the Netherlands of multiple antibiotic resistance including NDM-1 after hospitalisation in Egypt, August 2013.

We describe the introduction of various multi-drug resistant bacterial strains, including an NDM-1-producing Klebsiella pneumoniae, through a traveller returning from Egypt, where they had been admitted to a private hospital. All family members of the patient were colonised with one or more extended-spectrum beta-lactamase producing strains. These findings emphasise the importance of adherence to isolation precautions for returning patients and suggest the need for inclusion of Enterobacteriaceae in admission screening.

Carbapenemase-producing Enterobacteriaceae in Europe: a survey among national experts from 39 countries, February 2013.

The spread of carbapenemase-producing Enterobacteriaceae (CPE) is a threat to healthcare delivery, although its extent differs substantially from country to country. In February 2013, national experts from 39 European countries were invited to self-assess the current epidemiological situation of CPE in their country. Information about national management of CPE was also reported. The results highlight the urgent need for a coordinated European effort on early diagnosis, active surveillance, and guidance on infection control measures.

Epidemiology and outcomes of vancomycin-resistant enterococcus infections: a systematic review and meta-analysis.

Vancomycin-resistant enterococci (VRE) cause many infections in the healthcare context. Knowledge regarding the epidemiology and burden of VRE infections, however, remains fragmented. We aimed to summarize recent studies on VRE epidemiology and outcomes in hospitals, long-term-care facilities (LTCFs) and nursing homes worldwide based on current epidemiological reports. We searched MEDLINE/PubMed, the Cochrane Library, and Web of Science for observational studies, which reported on VRE faecium and faecalis infections in in-patients published between January 2014 and December 2020. Outcomes were incidence, infection rate, mortality, length of stay (LOS), and healthcare costs. We conducted a meta-analysis on mortality (PROSPERO registration number: CRD42020146389). Of 681 identified publications, 57 studies were included in the analysis. Overall quality of evidence was moderate to low. VRE incidence was rarely and heterogeneously reported. VRE infection rate differed highly (1-55%). The meta-analysis showed a higher mortality for VRE faecium bloodstream infections (BSIs) compared with VSE faecium BSIs (risk ratio, RR 1.46; 95% confidence interval (CI) 1.17-1.82). No difference was observed when comparing VRE faecium vs VRE faecalis BSI (RR 1.00, 95% CI 0.52-1.93). LOS was higher in BSIs caused by E. faecium vs E. faecalis. Only three studies reported healthcare costs. In contrast to previous findings, our meta-analysis of included studies indicates that vancomycin resistance independent of VRE species may be associated with a higher mortality. We identified a lack of standardization in reporting outcomes, information regarding healthcare costs, and state-of-the-art microbiological species identification methodology, which may inform the set-up and reporting of future studies.

Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins.

OBJECTIVES: This study determined excess mortality and length of hospital stay (LOS) attributable to bloodstream infection (BSI) caused by third-generation-cephalosporin-resistant Escherichia coli in Europe. METHODS: A prospective parallel matched cohort design was used. Cohort I consisted of patients with third-generation-cephalosporin-resistant E. coli BSI (REC) and cohort II consisted of patients with third-generation-cephalosporin-susceptible E. coli BSI (SEC). Patients in both cohorts were matched for LOS before infection with patients free of the respective BSI. Thirteen European tertiary care centres participated between July 2007 and June 2008. RESULTS: Cohort I consisted of 111 REC patients and 204 controls and cohort II consisted of 1110 SEC patients and 2084 controls. REC patients had a higher mortality at 30 days (adjusted odds ratio = 4.6) and a higher hospital mortality (adjusted hazard ratio = 5.7) than their controls. LOS was increased by 8 days. For SEC patients, these figures were adjusted odds ratio = 1.9, adjusted hazard ratio = 2.0 and excess LOS = 3 days. A 2.5 times [95% confidence interval (95% CI) 0.9-6.8] increase in all-cause mortality at 30 days and a 2.9 times (95% CI 1.2-6.9) increase in mortality during entire hospital stay as well as an excess LOS of 5 days (95% CI 0.4-10.2) could be attributed to resistance to third-generation cephalosporins in E. coli BSI. CONCLUSIONS: Morbidity and mortality attributable to third-generation-cephalosporin-resistant E. coli BSI is significant. If prevailing resistance trends continue, high societal and economic costs can be expected. Better management of infections caused by resistant E. coli is becoming essential.

Escherichia coli and Staphylococcus aureus: bad news and good news from the European Antimicrobial Resistance Surveillance Network (EARS-Net, formerly EARSS), 2002 to 2009.

Based on data collected by the European Antimicrobial Resistance Surveillance Network (EARS-Net) and the former EARSS, the present study describes the trends in antimicrobial susceptibility patterns and occurrence of invasive infections caused by Escherichia coli and Staphylococcus aureus in the period from 2002 to 2009. Antimicrobial susceptibility results from 198 laboratories in 22 European countries reporting continuously on these two microorganisms during the entire study period were included in the analysis. The number of bloodstream infections caused by E. coli increased remarkably by 71% during the study period, while bloodstream infections caused by S. aureus increased by 34%. At the same time, an alarming increase of antimicrobial resistance in E. coli was observed, whereas for S. aureus the proportion of meticillin resistant isolates decreased. The observed trend suggests an increasing burden of disease caused by E. coli. The reduction in the proportion of meticillin-resistant S. aureus and the lesser increase in S. aureus infections, compared with E. coli, may reflect the success of infection control measures at hospital level in several European countries.

Vancomycin-heteroresistant phenotype in invasive methicillin-resistant Staphylococcus aureus isolates belonging to spa type 041.

The aim of this study was to characterise invasive methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains from Italy and to investigate the presence of heteroresistant vancomycin-intermediate S. aureus (h-VISA). Eighty-two MSSA and 66 MRSA strains obtained from 19 laboratories were submitted to in vitro susceptibility testing; MRSA strains were also analysed by the macro Etest (MET) and vancomycin population analysis profiles (PAP) to detect the presence of h-VISA. Genotyping included the detection of agr locus, SCCmec typing, spa typing and multilocus sequence typing (MLST). By Etest, 66% of all isolates showed a minimum inhibitory concentration (MIC) >or=1.5 microg/ml and two MRSA strains were categorised as VISA (MIC = 3 microg/ml). Twelve MRSA strains were positive by MET; of these, 9 (14% of all MRSA) were confirmed as h-VISA by PAP. MRSA strains were assigned to 14 spa types, with t001, t008 and t041 including 77% of the isolates. The most common spa type, t041, characterised as ST228/273-MRSA-I (CC5) and comprising 24 isolates, included one VISA and eight h-VISA. This is the first description of a close association between h-VISA and t041, a spa type common in Italy and in other European countries, that highlights the importance of molecular typing to identify clones of special clinical relevance.

Carbapenem-non-susceptible Enterobacteriaceae in Europe: conclusions from a meeting of national experts.

The emergence and global spread of carbapenemase-producing Enterobacteriaceae is of great concern to health services worldwide. These bacteria are often resistant to all beta-lactam antibiotics and frequently co-resistant to most other antibiotics, leaving very few treatment options. The epidemiology is compounded by the diversity of carbapenem-hydrolysing enzymes and the ability of their genes to spread between different bacterial species. Difficulties are also encountered by laboratories when trying to detect carbapenemase production during routine diagnostic procedures due to an often heterogeneous expression of resistance. Some of the resistance genes are associated with successful clonal lineages which have a selective advantage in those hospitals where antimicrobial use is high and opportunities for transmission exist; others are more often associated with transmissible plasmids. A genetically distinct strain of Klebsiella pneumoniae sequence type (ST) 258 harbouring the K. pneumoniae carbapenemases (KPC) has been causing epidemics of national and international proportions. It follows the pathways of patient referrals, causing hospital outbreaks along the way. Simultaneously, diverse strains harbouring New Delhi metallo-beta-lactamase (NDM-1) are repeatedly being imported into Europe, commonly via patients with prior medical exposure in the Indian subcontinent. Since the nature and scale of carbapenem-non-susceptible Entrobacteriaceae as a threat to hospital patients in Europe remains unclear, a consultation of experts from 31 countries set out to identify the gaps in diagnostic and response capacity, to index the magnitude of carbapenem-non-susceptibility across Europe using a novel five-level staging system, and to provide elements of a strategy to combat this public health issue in a concerted manner

Replacement of methicillin-resistant Staphylococcus aureus clones in Hungary over time: a 10-year surveillance study.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Hungary has been increasing and is now close to 20% among invasive isolates of S. aureus. In order to understand the evolution of MRSA in Hungary, two collections of isolates were studied: 22 representatives of a collection of 238 MRSA isolates recovered between 1994 and 1998, and a collection of 299 MRSA isolates recovered between 2001 and 2004. The isolates were first characterised by pulsed-field gel electrophoresis (PFGE) and were distributed into 19 different PFGE patterns. Representatives of each pattern were further characterised by spa typing, multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec (SCCmec) typing. The Hungarian clone that was predominant in 1994-1998 (PFGE E, ST239-III) had almost disappeared in 2003-2004, being replaced by the Southern German clone (PFGE B, ST228-I) and the New York/Japan epidemic clone (PFGE A, ST5-II), which represented c. 85% of the 2001-2004 isolates. Thus, this study describes, for the first time, the co-dominance and extensive spread of the New York/Japan clone in a European country.

Cost-sharing strategies combining targeted public subsidies with private-sector delivery achieve high bednet coverage and reduced malaria transmission in Kilombero Valley, southern Tanzania.

BACKGROUND: Cost-sharing schemes incorporating modest targeted subsidies have promoted insecticide-treated nets (ITNs) for malaria prevention in the Kilombero Valley, southern Tanzania, since 1996. Here we evaluate resulting changes in bednet coverage and malaria transmission. METHODS: Bednets were sold through local agents at fixed prices representing a 34% subsidy relative to full delivery cost. A further targeted subsidy of 15% was provided to vulnerable groups through discount vouchers delivered through antenatal clinics and regular immunizations. Continuous entomological surveys (2,376 trap nights) were conducted from October 2001 to September 2003 in 25 randomly-selected population clusters of a demographic surveillance system which monitored net coverage. RESULTS: Mean net usage of 75% (11,982/16,086) across all age groups was achieved but now-obsolete technologies available at the time resulted in low insecticide treatment rates. Malaria transmission remained intense but was substantially reduced: Compared with an exceptionally high historical mean EIR of 1481, even non-users of nets were protected (EIR [fold reduction] = 349 infectious bites per person per year [x4]), while the average resident (244 [x6]), users of typical nets (210 [x7]) and users of insecticidal nets (105 [x14]) enjoyed increasing benefits. CONCLUSION: Despite low net treatment levels, community-level protection was equivalent to the personal protection of an ITN. Greater gains for net users and non-users are predicted if more expensive long-lasting ITN technologies can be similarly promoted with correspondingly augmented subsidies. Cost sharing strategies represent an important option for national programmes lacking adequate financing to fully subsidize comprehensive ITN coverage.

Mathematical modelling: a tool for hospital infection control.

Health-care-associated infections caused by antibiotic-resistant pathogens have become a menace in hospitals worldwide and infection control measures have lead to vastly different outcomes in different countries. During the past 6 years, a theoretical framework based on mathematical models has emerged that provides solid and testable hypotheses and opens the road to a quantitative assessment of the main obstructions that undermine current efforts to control the spread of health-care-associated infections in hospitals and communities. We aim to explain to a broader audience of professionals in health care, infection control, and health systems administration some of these models that can improve the understanding of the hidden dynamics of health-care-associated infections. We also appraise their usefulness and limitations as an innovative research and decision tool for control purposes.