**4. Global data in Spain: ENVIN study: RZ project**

The national study of nosocomial infection surveillance (ENVIN) represents the effort maintained over time (since 1994) to know and reduce the prevalence of nosocomial infection in ICUs. It describes nosocomial infections (NI) acquired in ICUs associated with invasive instrumentation. The data are collected mainly during the second quarter of the year (few units carry out the project throughout the year). The more frequent NI in the ICU are urinary infections associated with urinary catheter (31.87%), followed by ventilation-associated pneumonia (29.97%) and bacteremia (catheter-associated bacteriemia in 11.31%). In recent years, there has been a relative increase in the former ones and a decrease in the latter. The most frequently isolated germs in ICU infections (excluding bacteremia from other foci) are: *E. coli* (14.1%), *P. aeruginosa* (12.9%), *K. pneumoniae* (9.8%), *S. epidermidis* (8.2%), *S. aureus* (4.9%), *C. albicans* (4.8%), *E. cloacae* (3.5%), *S. marcescens* (2.7%), and so on. The type of reported patients is variable: medical (44%), 19.5% of surgeries scheduled, 10.3% of urgent surgeries and 19.8% of coronary patients. The extrinsic risk factors for nosocomial infections are: antibiotics before admission (21.1%), antibiotic treatment in ICU (64%), surgery in 30 days before (32.8%), urgent surgery during their stay in ICU (10.2%), central venous catheter (63.9%), mechanical ventilation (42.4%), bladder catheter (76.4%), parenteral nutrition (8.3%), and so on.

The implementation of the RZ project is more complex than the previous programs. It involves the collaboration of more staff and services, so the number of participating ICUs has been lower (of>190 in the first two projects, compared to 103 in RZ). In the following graphs, the evolution of the different indicators collected in the project is reviewed.

The evolution by quarters of the frequency of colonization/infection of patients with MRB, per 100 patients admitted, throughout the development of the RZ project is observed in **Figure 3**, with an ascending tendency with peaks coinciding with the collection periods of data from the ENVIN project (second quarter of each year). The average value throughout the project is 6.23 patients per 100 admissions. The colonization/infection plot for 1000 stays is similar.

Throughout the RZ project, there is an increase in the isolation of germs at the admission (acquisition prior to admission to the ICU) versus isolation during their stay (discrete decrease),

**Figure 3.** Temporal variation of the rate of MRB colonization/infection in ICU.

**Figure 2.** North-south and west-east gradient of % resistance of *K. pneumoniae* to third generation cephalosporins.

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with a tendency to stabilize the percentage of *K. pneumoniae* resistances (**Figure 2**).

The national study of nosocomial infection surveillance (ENVIN) represents the effort maintained over time (since 1994) to know and reduce the prevalence of nosocomial infection

**4. Global data in Spain: ENVIN study: RZ project**

48 h develop at least one infection (pneumonia, bacteremia or urinary tract infection). The most frequent causal germs are *P. aeruginosa* (pneumonia), *Staphylococcus* spp. coagulasenegative (bacteremia) and *Escherichia coli* (urinary tract infections). On average, 23.1% of *S. aureus* are MRSA; 3.4% of Enterococci are VRE. Resistance to third generation penicillin is described in variable percentages in E coli (20%), Klebsiella (43%) and Enterobacter (42%); resistance to carbapenems is also noticeable in Klebsiella (11%), *Pseudomonas aeruginosa* (24%) and *Acinetobacter baumannii* (69% of averages). In a report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) of 2016 [2], the main surveillance system in the European Union on bacteria that can cause serious infections, broad variations are described in relation to bacterial species, antimicrobial group and geographical region. For many combinations of bacterial species (*E. coli*, *K. pneumoniae*, *P. aeruginosa*, *Acinetobacter*, *S. aureus*, *Enterococcus*)—resistance to antimicrobial groups, there is a growing gradient from north to south, and from west to east, perhaps in relation to variations in the use of antimicrobials, infection prevention and control practices, and differences in diagnosis and healthcare utilization patterns between countries [18]. Overall, there seems to be a slowly increasing resistance over time (in the 2013–2016 interval) of E coli resistant to one of the three key antimicrobial groups (fluoroquinolones, third generation cephalosporins and aminoglycosides), taking into account colonizations and infections (**Figure 4**). The average value during the project is 3.84 patients% (previous) and 2.60% (during), with an increase of the previous ones of 26% and a decrease of those acquired during the ICU admission of 16.7%.

In relation to the germs acquired in the ICU, there was a slight increase in colonization (5%) and a significant decrease in MRB infections (45%) (**Figure 5**), with average values of 1.75% patients colonized and 1.09% of infected.

**Figure 1** (see above) and the following ones (**Figures 6**–**8**) show the tendencies initiated with the BZ and NZ projects of descent of patients admitted to the ICU with an infection (up to 8.7%, **Figure 1**), of reducing the use of antibiotics (up to 19.5% of patients, **Figure 6**), of reducing the days of antibiotic treatment (DOT, up to 109.7 per 1000 stays, **Figure 7**) and increasing days without antibiotic treatment (up to 40%, **Figure 8**). A rate of 2.15 antibiotics per patient with antibiotic treatment is described in 2016.

MRB colonization-infection rates change in successive years (**Figure 9**), with significant increases in enterobacteria carrying ESBL and carbapenemases and decrease in *A. baumannii*, *P. aeruginosa* and MRSA.

**Figure 5.** Evolution of colonized and infected patients during their stay in the ICU.

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**Figure 7.** Reduction in the use of days of antibiotic treatment (DOT) for 100 stays in the recent years.

**Figure 6.** Reduction in the use of antibiotics over time.

We can distinguish between the isolation of germs upon admission and during their stay, which can allow us to distinguish the predominant MRB germs that the patient "brings" to the ICU with those that he/she "acquires" during his stay. **Figure 10** shows that Acinetobacter infections appear mostly during their stay, against infections by ESBL-producing germs that are mostly present at admission.

**Figures 11** and **12** show an important variability in the different autonomous communities, both in the MRB isolation rate (global of 6.23 per 100 patients) and in the isolated MRB types, for a total of 3195 isolated MRBs.

**Figure 4.** Evolution of BMR isolates prior to admission to the ICU and during admission.

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**Figure 5.** Evolution of colonized and infected patients during their stay in the ICU.

**Figure 6.** Reduction in the use of antibiotics over time.

**Figure 4.** Evolution of BMR isolates prior to admission to the ICU and during admission.

taking into account colonizations and infections (**Figure 4**). The average value during the project is 3.84 patients% (previous) and 2.60% (during), with an increase of the previous ones of

In relation to the germs acquired in the ICU, there was a slight increase in colonization (5%) and a significant decrease in MRB infections (45%) (**Figure 5**), with average values of 1.75%

**Figure 1** (see above) and the following ones (**Figures 6**–**8**) show the tendencies initiated with the BZ and NZ projects of descent of patients admitted to the ICU with an infection (up to 8.7%, **Figure 1**), of reducing the use of antibiotics (up to 19.5% of patients, **Figure 6**), of reducing the days of antibiotic treatment (DOT, up to 109.7 per 1000 stays, **Figure 7**) and increasing days without antibiotic treatment (up to 40%, **Figure 8**). A rate of 2.15 antibiotics per patient

MRB colonization-infection rates change in successive years (**Figure 9**), with significant increases in enterobacteria carrying ESBL and carbapenemases and decrease in *A. baumannii*, *P. aeruginosa*

We can distinguish between the isolation of germs upon admission and during their stay, which can allow us to distinguish the predominant MRB germs that the patient "brings" to the ICU with those that he/she "acquires" during his stay. **Figure 10** shows that Acinetobacter infections appear mostly during their stay, against infections by ESBL-producing germs that

**Figures 11** and **12** show an important variability in the different autonomous communities, both in the MRB isolation rate (global of 6.23 per 100 patients) and in the isolated MRB types,

26% and a decrease of those acquired during the ICU admission of 16.7%.

patients colonized and 1.09% of infected.

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with antibiotic treatment is described in 2016.

are mostly present at admission.

for a total of 3195 isolated MRBs.

and MRSA.

**Figure 7.** Reduction in the use of days of antibiotic treatment (DOT) for 100 stays in the recent years.

**Figure 10.** Isolation of MR germs in the RZ period globally, upon admission and during their stay in the ICU.

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**Figure 11.** Isolation rate in the different autonomous communities. AND Andalucia, ARAG Aragón, ASTUR Asturias, BALEAR Balearic Islands, CANAR Canary Islands, CAST-L Castilla-León, CAST-M Castilla-La Mancha, CAT Catalonia, EXTR Extremadura, RIOJA La RIOJA, GALIC Galicia, MADR Madrid, MURC Murcia,NAV Navarra, VAL Valencian

community, EUSK Euskadi, C/M Ceuta/Melilla.

**Figure 8.** Increase in the number of days in the ICU without antibiotic treatment over the years.

**Figure 9.** Infection/colonization by MRB. ENVIN study in the interval 2006–2016.

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**Figure 10.** Isolation of MR germs in the RZ period globally, upon admission and during their stay in the ICU.

**Figure 8.** Increase in the number of days in the ICU without antibiotic treatment over the years.

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**Figure 9.** Infection/colonization by MRB. ENVIN study in the interval 2006–2016.

**Figure 11.** Isolation rate in the different autonomous communities. AND Andalucia, ARAG Aragón, ASTUR Asturias, BALEAR Balearic Islands, CANAR Canary Islands, CAST-L Castilla-León, CAST-M Castilla-La Mancha, CAT Catalonia, EXTR Extremadura, RIOJA La RIOJA, GALIC Galicia, MADR Madrid, MURC Murcia,NAV Navarra, VAL Valencian community, EUSK Euskadi, C/M Ceuta/Melilla.

**5. Data of the ICU of the hospital of Sagunto**

patients with MRB/100 admissions (**Figure 13**).

Our unit starts the data collection in the ENVIN project the same year of its beginning (1994). We started the RZ project in April 2014, and until now (January 2018) have followed the guidelines of the RZ project in the prevention and management of patients with MRB. We reported 195 isolates in 179 patients for 46 months, with 1966 admissions and a rate of 9.1

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In our unit, a high prevalence of *A. baumannii* was initially observed, without a clear seasonal profile. Over time, there is a decrease in *A. baumannii* and an increase in the ESBL carrier

**Figure 13.** Occurrence of MRB in our ICU Fromm the beginning of RZ project until February 2018. Acinetobacter

supposes globally a 25% of isolates, with a rate of 50% of ESBL producer germs.

**Figure 12.** Heterogeneity of MRB isolates, counting colonizations and infections, during the period of RZ study. In most autonomous communities, the most frequent type of MRB is ESBL producing GNB. The presence of *A. baumannii* has become much less frequent, except in Extremadura and Asturias. In the Canary Islands, there are 0 VRE isolates; in Extremadura, there are zero isolates of VRE, one isolation of carbapenemase producing germ and three isolates of *P. aeruginosa*; there are few isolates of *A. baumannii* in Aragón [9], Canary Islands [8], Galicia [3] and Navarra [5]; and finally there is no isolation (0) of *A. baumannii* in Euskadi.
