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Bloodstream infections in Europe. Report of ESGNI-001 and ESGNI-002 Studies.


 

AUTHORS:
 
 

E. Bouza, J.Pérez-Molina and P. Muñoz on behalf of the Cooperative Group of the European Study Group on Nosocomial Infections (ESGNI).
 
 

CORRESPONDENCE AND REPRINT REQUESTS TO:
 
 

Emilio Bouza. M.D.

Servicio de Microbiología Clínica y Enfermedades Infecciosas-VIH.

Hospital General Universitario "Gregorio Marañón".

Dr. Esquerdo 46.

28007 Madrid. Spain.

Phone: 0034-915868453

Fax: 0034-915044906

E-mail: ebouza@microb.net
 

SUMMARY
 
 

Data regarding the incidence, etiology and outcome of bloodstream infections taken on a broad European basis is scarce. We collected such information (ESGNI-001 and ESGNI-002 studies) and compared the situation in EU and non-EU European countries.

A total of 122 hospitals from 28 countries participated in one or both studies. The global rate of blood cultures per 1,000 admissions was 242.4, being significantly higher among EU countries (255.9) than in non-EU countries (192.8). Globally, 14.4% of all blood extractions grew one or more microorganisms. The rate of positivity was significantly greater in non-EU countries (19.1%) than in EU countries (13.4%) (p<0.0001). The calculated incidence of significant episodes of bacteremia/1,000 admissions was 27.2.

The five most commonly isolated microorganisms were: S. aureus, E. coli, S. epidermidis and other coagulase negative Staphylococci, S. pneumoniae, and P. aeruginosa. Overall, 11% of the episodes were polymicrobial (12.7% in EU countries vs 6% in non EU countries; p=0.13). Grampositive bacteria represented 52.9% of all isolates, whereas gramnegative bacteria were 41.2%. Fungi and anaerobes were 4.6% and 1.3% respectively.

The acquisition of bloodstream infections was nosocomial in 72.8% of cases (68.3% in EU countries vs 86.5% in non-EU countries p=0.003).

According to the severity of underlying disease, 10.5% of the patients with significant bacteremia had rapidly fatal diseases, 38% had ultimately fatal diseases and 51% had diseases considered as non-fatal according to the McCabe classification.

Regarding the severity score of sepsis, 76% were classified as plain sepsis, 14% as severe sepsis, 5.3% developed septic shock and 4.9% went on to have multiorganic failure. When EU and non-EU countries were compared there were no significant differences in the clinical data, reported between both groups.

Overall 22.6% of patients did not receive treatment or treatment was considered inadequate. The mortality rate was 19.0% with a mortality attributable to bacteremia of 7.1% (Table-8). Again there were no differences between EU and non-EU countries.

The multivariable analysis showed that the factors remaining independent predictors of mortality were: age (OR 1.02-1.09; p=0.0002), severity of underlying diseases and severity of sepsis score.
  Titan gel

INTRODUCTION

Information regarding the evolution, incidence, etiology and prognosis of bloodstream infections is usually obtained from reports of single institutions of the "so called" developed world. These reports, suggest an increasing trend in the incidence of significant bacteremia as well as a shift in the etiology of this dreaded infection in recent years. This is probably related to changes in the underlying diseases of susceptible populations, to more aggressive and invasive medical practice, and to the presence of more virulent and difficult-to-treat microorganisms1-9.

Data regarding the incidence, etiology and outcome of bloodstream infections taken on a broad European basis is scarce, as is information concerning this issue in many countries not yet belonging to the European Union (EU).
 

With these drawbacks in mind, the European Study Group on Nosocomial Infections (ESGNI) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook two complementary studies (ESGNI-001 and ESGNI-002) designed to obtain information on the microbiology workload, prevalence, etiology and outcome of significant episodes of bloodstream infections in EU and non-EU European countries.
 

MATERIAL AND METHODS

ESGNI-001 study was a questionnaire directed to the Microbiology laboratories of every European hospital with one or more ESCMID members and all those interested in participating from different European hospitals, with a first part requesting information regarding the population served by the hospital, total number of beds, total number of admissions, total number of blood samples processed, total number of sterile samples and total number of positive samples (significant or not) during 1997. The second part of the ESGNI-1 questionnaire was a point prevalence study, collecting the information generated on a single day (March 25th, 1998) and requesting the following: total number of blood samples reported positive or negative that day , total number of samples with growth of one or more microorganisms either significant or contaminant, and total number of significant episodes of bloodstream infections reported on the Study Day. For each episode of significant bacteremia we requested information regarding the microorganism or microorganisms present and the antibiotic susceptibility profile regardless of the laboratory method employed. The list of antimicrobials included: penicillin, ampicillin, ticarcillin, amoxicillin-clavulanate, methicillin, cefazolin, cefuroxime, cefotaxime, ceftazidime, imipenem, aztreonam, ciprofloxacin, cotrimoxazole, gentamicin, tobramycin, amikacin, streptomycin, rifampin, erythromycin, clindamicin, vancomycin, tetracycline and chloramphenicol.
 

ESGNI-002 was a clinical study related to ESGNI-001. We requested the following information from clinical microbiologists and clinicians regarding episodes of significant bacteremia occurring on the Study Day: age, sex, weighted index of comorbidity of the affected patient, classification of the underlying disease according to the McCabe and Jackson groups, severity of illness according to a sepsis score, and predisposing conditions for infection. Regarding antimicrobial treatment we classified it as adequate or inadequate, we registered days of antimicrobial administration and finally, patients were followed up until their death or discharge. Deaths were classified as attributable or not attributable to the bloodstream infection.
 
 

Not all hospitals enrolled in ESGNI-001 were obliged to participate in ESGNI-002. This report brings together the information on the protocols received until July 31st 1998.
 
 

Definitions used
 
 

Sample: A sample is defined as a set of all blood culture bottles (aerobic and anaerobic) filled with a single blood extraction.

Contaminant microorganism: The following microorganisms are categorised as probable contaminants: Bacillus sp, Corynebacterium sp (except C. jeikeium), Lactobacillus sp, and Propionibacterium. Coagulase-negative Staphylococcus , or viridans group Streptococcus isolates are considered to be probable pathogens only if they are recovered from ³ 2 samples, or if the significance is clinically obvious.

Polymicrobial bacteremia: polymicrobial bacteremia is defined as isolation of more than one microorganism during a single bacteremic episode.

Bloodstream infectious episode: Episodes of bacteremia, fungemia, or mycobacteremia refer only to patients. All microorganisms isolated from blood within one week are considered as a single episode.

Nosocomial bloodstream infection: a nosocomial episode is considered to be the occurrence of any bloodstream infection beginning at least 72 hours after admission. The same definition is applied to fungemia.

Severity of illness10:

* SEPSIS: Systemic response manifested by two or more of the following conditions as a result of infection: a) Temperature >38oC or <36 oC, b) Heart rate>90 beats/min, c) Respiratory rate >20 breaths/min or PaCO2 <32 mmHg, d) WBC >12,000 cells/mm3, <4,000 cells/mm3, or >10% immature (band) forms.

* SEVERE SEPSIS: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

* SEPTIC SHOCK: Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.

* MULTIORGAN FAILURE: Failure of three or more organ systems during at least a 24-hour period, as a consequence of bacteremia.

Predisposing factors to bloodstream infection: a) Bladder catheter, I.V. catheter, intubation, neutropenia and prosthetic material if they were present at the time of infection, b) Surgery if it was during hospital admittance, c) Corticosteroids if they have been taken at a dose of 20 mg of prednisone daily (or equivalent) for at least two weeks, or 30 mg of prednisone daily for at least one week, before the positive blood culture, d) Cytotoxic therapy if the patient received any kind of antineoplasic in the four weeks previous to the bloodstream infectious episode, e) Antibiotics if the patient received any oral or parenteral antibiotic in the 15 days previous to the bloodstream infectious episode, f) Upper/lower endoscopy and urological intervention if they were performed in the 72 hours previous to the bloodstream infectious episode, and g) Other invasive procedures (i.e. deep tissue biopsy, bronchoscopy, cardiac catheterization, etc) if they were performed in the 72 hours previous to the bloodstream infectious episode.

Adequacy of treatment: Treatment is considered adequate if the patient received one or more antibiotics active in vitro against the microorganisms isolated, for at least seven days.

Days of treatment: Consider only the number of days of adequate treatment.

Death attributable to bloodstream infection: Death is considered as attributable to bloodstream infection if it occurs during the phase of active infection or while the patient is undergoing antibiotic treatment.
 
 

McCabe and Jackson Groups11, and the Charlson weighted index12 were used as comorbidity indexes.
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Data analysis

We expressed continuous variables as the mean and standard deviation (SD) when normally distributed or as the median and interquartile range (IQR) if their distribution was skewed, and discrete variables as percentages. We used the Student's unpaired t-test to compare continuous variables, the Mann-Whitney U test to compare continuous variables not normally distributed, and the chi-square or Fisher exact test to compare proportions. All statistical tests were two-tailed.

To control for confounding variables in the analysis of death among patients with bacteremia, we carried out a multivariable analysis by logistic regression (LR) that gave us a mathematical model relating the death to the different risk factors. We performed the LR with the enter method and the inclusion of variables in the model was decided according to their significance in the bivariable analysis, together with the importance given to each variable regardless of whether or not it was clearly significant in this analysis. The model was adjusted using the Hosmer-Lemeshow method. We calculated the odds ratio and 95% CIs for all significant predictors of death. The final model included the following variables: severity of illness, Mc Cabe and Jackson Groups, days of treatment, age, Charlson index, adequacy of treatment and the presence of bladder catheter, intubation, treatment with corticosteroids or previous use of antibiotics. We also tested for all pairwise interactions between significant risk factors in the multivariable model.
 

RESULTS

A total of 122 hospitals from 28 countries participated in one or both studies (Table-1). Although most of those participating sent both studies, this was not so in every case. Therefore, the tables indicate on which basis (hospitals or cases) the calculations have been made.
 

Table-1. Participant hospitals.
 
Country
No of hospital participating
Austria
6
Belgium
6
Bulgaria
2
Croatia
6
Czech Republic
5
Denmark
1
Finland
1
France
9
Germany
8
Greece
10
Holland
7
Hungary
2
Iceland
1
Ireland
1
Italy
9
Latvia
1
Lithuania
1
Norway
3
Portugal
4
Russia
1
Slovak Republic
2
Slovenia
2
Spain
16
Sweden
2
Switzerland
3
Turkey
4
United Kingdom
8
Yugoslavia
1

 

Laboratory workload of bloodstream infections during 1997
 

We obtained this information from 112 hospitals of different size (26.7% had £ 500 beds, 34.2% had 501-1,000 beds, and 39.1% > 1,000 beds). Overall, the total number of admissions in those institutions during 1997 was 3,500,330 and the total number of blood samples obtained for blood culture was 848,806 (Table-2). This means a blood sample for blood culturing every 4.12 admissions. The global rate of blood cultures per 1,000 admissions was 242.4, being significantly higher among EU countries (255.9) than in non-EU countries (192.8). Globally, 14.4% of all blood extractions grew one or more microorganisms. The rate of positivity was significantly greater in non-EU countries (19.1%) than in EU countries (13.4%) (p<0.0001).
 

Table-2. Microbiology workload in 1997.
 
  EU countries

(n=84)

NEU countries

(n=28)

Total

(n=112) 

Total number of blood samples 704,843 143,963
848,806
Total number of admissions 2,753,600 746,730
3,500,330
Admissions/blood sample 3.9 5.1
4.12
Blood samples/1,000 ad. Year* 255.9 192.8
242.4
Positive blood samples 94,831 27,595
122,426
Percentage of positives* 13.4% 19.1%
14.4%

* p<0.001
 

Microbiology data on the Study Day

Data regarding microbiology workload on the Study Day is largely confirmatory of 1997 data. We recorded 3,183 blood samples taken for culture in 112 institutions, of which 496 were positive (15.5%), representing 261 episodes of significant bacteremias (Table 3).

If we take the total number of admissions in 1997 (Table 1) we can make a rough estimate of the rate of significant bacteremic episodes/1,000 admissions. The total number of significant bacteremic episodes on the Study Day was 261 (Table-3), and the daily number of admissions can be estimated as 3,500,330/365 days = 9,590 admissions/day. Therefore, the incidence of significant episodes of bacteremia/1,000 admissions would be 27.2.
 

Table-3. Data regarding the study day (25th of March, 1998).
 
  EU countries

(n=84)

Non-EU

(n=28)

Total

(n=112) 

Total number of blood samples 2,639 544
3,183
Positive blood samples 396 100
496
Significant episodes of bloodstream infection 200 61
261
Percentage of positives* 15% 18.4%
15.5%

* p=0.048

The number of microorganisms isolated from significant episodes of bacteremia was 304. The etiology of the episodes is summarized in Table-4. The five most commonly isolated microorganisms were: S. aureus, E. coli, S. epidermidis and other coagulase negative Staphylococci, S. pneumoniae, and P. aeruginosa. Overall, 11% of the episodes were polymicrobial (12.7% in EU countries vs 6% in non EU countries; p=0.13). Gram-positive bacteria represented 52.9% of all isolates, whereas gram-negative bacteria were 41.2%. Fungi and anaerobes were 4.6% and 1.3% respectively. The type of microorganism was comparable between both groups of hospitals (EU and non-EU) with the single exception of Pseudomonas aeruginosa which was isolated more frequently in non-EU countries (p=0.03).

The acquisition of bloodstream infections was nosocomial in 72.8% of the cases (68.3% in EU countries vs 86.5% in non-EU countries p=0.003).

Table-4. Most frequent isolates.
 
  EU countries

(n=233)

NEU countries

(n=71)

Total 

(n=304)

S. aureus 37 9
46 (15.1%)
E. coli 37 7
44 (14.5%)
S. epidermidis 21 12
33 (10.8%)
CNS 14 7
21 (7.0%)
S. pneumoniae 16 2
18 (5.9%)
P. aeruginosa* 7 9
16 (5.3%)
K. pneumoniae 11 5
16 (5.3%)
Candida spp

(C. albicans)

10

(4)

4

(3)

14 (4.6%)

7 (2.3%)

Enterococcus spp 11 3
14 (4.6%)
Enterobacter spp 10 2
12 (3.9%)
Acinetobacter spp 7 4
11 (3.6%)
Other 51 7
59 (19.4%)

* p=0.03

Resistance patterns of the most frequent isolates

The ESGNI-001 Study was not designed to study the prevalence of antibiotic resistance among the different organisms obtained from bloodstream infections, given the small number of isolates that can be collected in a single day and because sensitivity assays were not performed in a central laboratory. In spite of this we considered of interest the information summarised in Table 5. Overall, 43% of S. aureus were resistant to methicillin and no isolate was resistant to vancomycin. The percentage of E. coli resistant to ampicillin was 52%. Macrolide-resistant S. pneumoniae occurred in 31.5% of the isolates and imipenem- resistant P. aeruginosa occurred in 25% of the isolates.
 

Table-5.
 
Microorganism Antimicrobial
Total No of isolates tested
% of resistance
S. aureus Methicillin
42
42.8
S. aureus Ciprofloxacin
28
39.3
S. aureus Cotrimoxazole
35
8.6
S. aureus Vancomycin
45
0.0
E. coli Ampicillin
42
52.3
E. coli Amoxicillin-clavulanate
33
12.1
E. coli Ciprofloxacin
42
9.5
E. coli Cotrimoxazole
35
22.8
S. epidermidis and other CNS Methicillin
46
63.0
S. epidermidis and other CNS Vancomycin
49
0.0
S. pneumoniae Penicillin
16
0.0
S. pneumoniae Vancomycin
13
0.0
S. pneumoniae Erithromycin
16
31.5
P. aeruginosa Ceftazidime
15
26.7
P. aeruginosa Imipenem
16
25.0
P. aeruginosa Ciprofloxacin
15
13.3
P. aeruginosa Gentamicin
13
23.0
K. pneumoniae Cefotaxime
16
31.2
K. pneumoniae Imipenem
16
0.0
K. pneumoniae Ciprofloxacin
15
0.0
Enterococcus spp Ampicillin
10
10.0
Enterococcus spp Vancomycin
9
0.0

There were no statistical differences between EU and Non-EU countries according to the percentage of resistance with the exception of K. Pneumoniae (resistance to cefotaxime was observed only in non-EU countries).
 

Clinical information
 

We obtained complete clinical information of the protocol in 228 individuals with bloodstream infections active on the Study Day (Table 6). There were 113 males (52%) and 105 females (48%) whose ages ranged from less than 1 year to 96 years (mean 49 years, SD 25.7).

According to the severity of underlying disease, 10.5% of the patients had rapidly fatal diseases, 38% had ultimately fatal diseases and 51% had diseases considered as non-fatal according to the McCabe and Jackson classification. Comorbidity illness were rated according to Charlson's criteria and the mean index was 2.97 (range 0-13).

Regarding the severity score of sepsis, 76% were classified as plain sepsis, 14% as severe sepsis, 5.3% developed septic shock and 4.9% went on to have multiorganic failure.
 

Table-6. Demographic and clinical data
 
  EU countries

(n=168)

Non-EU countries

(n=60)

Total 

(n=228)

Age (SD) range. 50.9 (25.9) 0-96 45.5 (24.6) 0-79
49.0 (25.7) 0-96
Sex: Female

Male

81 (48.2%)

87 (51.8%)

24 (40%)

36 (60%)

105 (48.2%)

113 (51.8%)

Charlson index (SD) range 2.98 (2.6) 0-13 2.93 (3.0) 0-13
2.97 (2.7) 0-13
Mc Cabe and Jackson groups:

1

2

3

15 (8.9%)

64 (38.1%)

89 (53.0%)

9 (15%)

23 (38.3%)

28 (46.7%)

24 (10.5%)

87 (38.1%)

117 (51.4%)

Severity of illness*:

Sepsis

Severe sepsis

Septic shock

Multiorgan failure

126 (76.8%)

23 (14.0%)

7 (4.3%)

8 (4.9%)

45 (72.7%)

9 (14.5%)

5 (8.0%)

3 (4.8%)

171 (75.7%)

32 (14.1%)

12 (5.3%)

11 (4.9%)

* n=226
 
 

The most important predisposing factors for bacteremia are summarised in Table 7. Overall, I.V. catheter, previous antibiotic use, urinary catheter and previous surgery were the most common (Table-7). When EU and non-EU countries were compared, there were no significant differences in the clinical data between both groups.
 

Table-7. Predisposing factors to bloodstream infection
 
  EU countries

(n=168)

Non-EU countries

(60)

Total 

(228)

I.V. catheter 123 (73.2%) 39 (65.0%)
162 (71.0%)
Previous use of antibiotics 95 (56.5%) 39 (65.0%)
134 (58.8%)
Bladder catheter 64 (38.1%) 20 (33.3%)
84 (36.8%)
Previous surgery 44 (26.2%) 17 (28.3%)
61 (26.7%)
Intubation 45 (26.8%) 10 (16.6%)
55 (24.1%)
Corticosteroids 33 (19.6%) 14 (23.0%)
47 (20.6%)
Cytotoxic therapy 22 (13.1%) 14 (23.0%)
36 (15.8%)
Prosthetic material 18 (10.7%) 6 (10.0%)
24 (10.5%)
Other invasive procedures 19 (11.3%) 5 (8.3%)
24 (10.5%)
Neutropenia 14 (8.3%) 9 (15.0%)
23 (10.0%)
Upper/lower endoscopy 15 (8.9%) 5 (8.3%)
20 (8.8%)
Urological intervention 7 (4.2%) 2 (3.3%)
9 (3.9%)
HIV infection 3 (1.8%) 0 (0.0%)
3 (1.3%)

 

Overall, 92.9% of patients received antibiotic treatment, considered as adequate in 77.4% of all patients (175/226). Therefore 22.6% of patients did not receive treatment or treatment was considered inadequate. The median of days of treatment was 10 (IQR 5-14d; range 0-50). The mortality rate was 19.0% with a mortality attributable to bacteremia of 7.1% (Table-8). Again there were no differences between EU and non-EU countries.
 
 

Table-8. Antibiotic treatment and outcome
 
  EU countries

(n=167)

NEU countries

(n=59)

Total 

(n=226)

Treatment given 151 (90.4%) 58 (98.3%)
209 (92.5%)
Treatment adequate 129 (77.2%) 46 (78.0%)
175 (77.4%)
Median days of treatment (IQR), range 9 d (5-14), 0-50. 10 d (5-14), 0-35.
10 d (5-14), 0-50
Patient death 29 (17.4%) 14 (23.7%)
43 (19.0%)
Death attributable to bloodstream infection 12 (7.2%) 4 (6.8%)
16 (7.1%)

 

Clinical characteristics and predisposing factors for infection were compared in patients who died and who survived (Table 9). In the univariate analysis, overall mortality was associated with advanced age, poor status of health previous to the bacteremic episode and a higher severity of illness, a shorter number of days of treatment, the presence of indwelling catheterization, tracheal intubation and inadequacy of antimicrobial therapy
 

Table-9. Comparison between patients according to outcome.
 
  Patients who survived

(n=183)

Patient who died

(n=43)

P value
Age (SD)
45.4 (26.4)
63.8 (15.9)
< 0.001
Sex (Male)
94 (51.4%)
28 (65.1%)
NS
Charlson index (SD)
2.82 (2.7)
3.67 (2.87)
0.046
Mc Cabe and Jackson

Nonfatal

Ultimately fatal

Rapidly fatal

106 (57.9%)

68 (37.2%)

9 (4.9%)

10 (23.3%)

18 (41.9%)

15 (34.9%)

<0.001 for linear trend

 
 
Severity

Sepsis

Severe sepsis

Septic shock

Multiorgan failure

154 (84.1%)

22 (12.0%)

5 (2.7%)

2 (1.1%)

17 (39.5%)

10 (23.3%)

7 (16.3%)

9 (20.9%)

<0.001 for linear trend
Treatment days (SD)
10.03 (8.3)
6.1 (9.2)
0.008
I.V. catheter
130 (71.0%)
32 (74.4%)
NS
Previous use of antibiotics
103 (56.3%)
31 (72.1%)
0.060
Bladder catheter
57 (31.1%)
27 (62.8%)
<0.001
Previous surgery
49 (27.2%)
12 (28.6%)
NS
Intubation
36 (19.7%)
19 (44.2%)
0.001
Corticosteroids
33 (18.0%)
14 (32.6%)
0.058
Cytotoxic therapy
29 (15.8%)
6 (14.0%)
NS
Prosthetic material
20 (10.9%)
4 (9.3%)
NS
Other invasive procedures
18 (9.8%)
6 (14.0%)
NS
Neutropenia
19 (10.4%)
4 (9.3%)
NS
Upper/lower endoscopy
16 (8.7%)
4 (9.3%)
NS
Urological intervention
5 (2.7%)
4 (9.3%)
NS
HIV infection
3 (1.6%)
0 (0%)
NS
Inadequate treatment
36 (19.7%)
15 (34.9%)
0.041

 

The multivariable analysis showed that the factors remaining independent predictors of mortality were: age (OR 1.02-1.09; p=0.0002), severity of underlying diseases and severity of sepsis score (Table 10). While the severity of illness score was predictive overall and for each category, Mc Cabe and Jackson groups were good overall but only the rapidly fatal category showed significantly more risk of death.
 
 

Table-10. Risk factors for mortality among patients with bacteremia.
 
 
ODDS RATIO
OR 95% CI
P value
Severity

Sepsis

Severe sepsis

Septic shock

Multiorgan failure

1

6.50

12.02

99.43

Reference category

1.83-23.05

2.58-55.98

8.75-1129.26

<0.0001
 
 

0.0037

0.0015

0.0002

Mc Cabe and Jackson

Nonfatal

Ultimately fatal

Rapidly fatal

1

1.77

24.82

Reference category

0.57-5.47

4.91-125.31

0.0004
 
 

0.31

0.0001

Age (for each year)
1.05
1.02-1.09
0.0002

  Goji cream

DISCUSSION

There is general agreement on drawing blood for culture in febrile (³ 38ºC) or hypothermic patients, in patients with leukocytosis (³ 10,000 wbc/m L), in those with granulocytopenia (< 1,000 g/m L) and in neonates and elderly patients who may remain afebrile despite other signs of sepsis13. However, we were unable to find reliable figures regarding the number of blood cultures considered adequate or inadequate in the microbiology laboratory workload of modern institutions. In this study, the number of blood samples/1,000 admissions was 242.4 with a percentage of positive samples of 14.4%. The rate is higher in EU countries when compared with non-EU countries, although the rate of positivity is higher in the last group, in comparison with EU countries. This fact may reflect a lesser use of blood cultures which would be carried out on people with a higher suspicion of bacteremia in non-EU countries.

Our data provides a figure of 27.2 episodes of significant bacteremia/1,000 admissions with no statistically significant differences between EU and non-EU countries. This is in the rank of other reports published previously1,3,14-16.

On pan-European basis this study confirms the shift in the etiologic spectrum of bacteremia observed in recent years in different institutions4,6,9,17. Gram-positives represented 52.9% of all isolates, while gram-negative, fungi and anaerobes represented 41.2%, 4.6% and 1.3% respectively. The most frequent microorganism isolated was S. aureus (15.1%) but Staphylococcus coagulase negative (CNS) and S. epidermidis both constitute 17.8% of all isolates. This number of gram-positives can be explained by the appearance of new mechanisms of resistance in some cases, better control and treatment of gram-negatives, and the appearance of population groups susceptible to this type of infection, such as IVDU, patients with prosthetic material and patients with indwelling intravenous catheters4,17-20.

Gram-negatives represented the second biggest group of isolates, E. coli being the second most frequent microorganism overall (14.5%), followed by P. aeruginosa and Klebsiella pneumoniae. These results are in agreement with other studies previously published6,21-23.

Regarding fungemia, Candida is the etiologic agent in the vast majority of episodes. In recent years, an increasing trend in the incidence of episodes of candidemia has been reported24-32. They reached 8% of all episodes of significant bloodstream infections in the SCOPE Program in the U.S.A.32. At the same time, many institutions reported a shift to non-albicans species which now represent at least 50% of the isolates in many reports24-26,29. In our study, 4.6% of overall isolates belonged to the genus Candida, but only seven out of 14 were C. albicans. This may be partly due to the more widespread use of antifungal drugs, especially imidazols, not only as treatment but also as prophylaxis.

During the last decade there has been a progressive decline in the incidence of anaerobic bacteremias. At present, anaerobes represent less than 5% of all documented bloodstream infections4,33-35 and the systematic convenience of an anaerobic bottle in all sets of blood cultures has been questioned. Our study also shows in Europe a very low percentage (1.3%) of anaerobic bloodstream infections.

The incidence of polymicrobial bacteremia has also been increasing in recent decades with a frequency which varies between 5 and 22% of all bacteremias3,36-38. The information collected in our study is comparable to that already reported showing a figure of 11% with no significant differences between EU and non-EU countries.

The ESGNI-001 Study was not designed to study in detail the prevalence of antibiotic resistance among the different organisms obtained from bloodstream infections, due to the limited number of isolates obtained and the absence of a uniform methodology in the antimicrobial resistance assays. Nevertheless, some data deserve special attention. Methicillin resistance appears widespread and high among S. aureus (42.8%), S. epidermidis and other CNS (63.0%) collected in our Study. Prior European data are scarce and show a wide variation of MRSA among countries and institutions in Europe39-44.

The number of isolates in other microorganisms does not permit any firm conclusion regarding antimicrobial resistance. Several studies have tried to assess the issue of European antimicrobial resistance in different microorganisms in recent years39-49.

Clinical data obtained in this study showed a non-surprising age and sex distribution of patients with bloodstream infections. Bacteremia can occur in patients of any age group, but the classic pattern involves two large peaks of incidence. One represents bacteremia during the first years of life and the other usually appears from age fifty on. Neither demographic characteristics nor predisposing factors to developing bacteremia were different in EU and non-EU countries. The most frequently observed predisposing factors in our study implied the rupture of natural barriers: I.V. catheter, bladder catheter, surgery and intubation. The second largest group involved factors that impaired the general mechanisms of defense such as the use of corticosteroids, cytotoxic therapy or neutropenia. To our surprise, only 1.3% of all episodes detected in a single day occurred in HIV-positive patients.

The acquisition of bloodstream infections is also shifting from a predominantly nosocomial origin to an increasingly frequent community acquisition1,3,6. This is probably due to shorter periods of hospital stay even in severely ill patients. The pan-European data of 73% nosocomial-acquisition show significant differences between EU (68% nosocomial) and non EU countries (86.5% nosocomial; p=0.003).

There is not an unquestionably established duration of treatment for bloodstream infections which usually varies from 5 to 14 days. Our data show 10 days as the median period of therapy in European hospitals. Our data show also a more striking feature regarding therapy. Overall, almost 23% of our patients did not live long enough to receive adequate treatment or were treated with inadequate antimicrobial agents. This is clearly a variable for intervention. It is a responsibility of clinical microbiologists to delineate better procedures for conveying rapidly to the bedside information regarding etiology and antimicrobial susceptibility patterns of isolates from bloodstream infections50, 51.

The death of a patient with bacteremia is not infrequent and occurs in 0% to 45% of cases1, 3, 14, 52, 53. The apparent discrepancy in the figures is due to the populations selected in the studies. The lowest rates are observed in gyne-obstetric patients, who are generally younger and have no underlying illness and a better prognosis52, 54. At the other extreme we can find patients admitted to the intensive care unit or patients with a serious underlying disease14, 55.

In our study, overall mortality was 19% whereas death attributable to bacteremia was 7.1% with no differences observed between both groups of countries. Mortality was independently associated with advanced age, poor status of health previous to the bacteremic episode and a higher severity of illness. Regarding this last issue, risk for mortality was 6.5, 12.02 and 99.43 times higher for patients with severe sepsis, septic shock and multiorgan failure respectively compared to patients with sepsis only. Furthermore, when we studied the mortality rate for each category, we noticed that patients with sepsis presented 10.4% mortality and this proportion increased with severity: severe sepsis 31.2%, septic shock 58.3% and multiorgan failure 81.8%. This correlation between progressively more severe situations and growing mortality has also been well documented elsewhere55, 56.

On the other hand, in cases where antibiotic treatment was considered inadequate in the terms defined in the protocol, mortality was significantly higher than when it was considered adequate (29.4% vs 16.7%; p=0.041). This may reflect not only inappropriate antibiotic treatment, but also a situation where patients did not survive long enough to receive a complete course of antibiotic treatment. In this way, adequacy of treatment was not an independent predictor of mortality, maybe because it was related to more severly ill patients rather than being the optimal treatment. This was corrected in the LR model according to severity.

On a broad European basis, our survey shows, the situation of bloodstream infections in Europe, their laboratory workload, shift in etiology and significant morbidity and mortality which leave clear spaces for future intervention.
 

Appendix: ESGNI-001 and ESGNI-002 authors:

Dr. Adan, Dieter (Universty Children's Hospital. Germany); Dra. Afonso, Teresa (Centro Hospitalar Du Funchal. Portugal); Dr. Agius, Gerard (C.H.U. La Miletrie. France); Dr. Agostini, Dragana (Health Protection Institute. Yugoslavia); Dr. Agulla, Andres (C.H. A. Marcide. Spain); Dr. Alcoba Flores, Julia (Hospital Ntra. Sra. Candelaria. Spain); Dr. Alexandrova, Irina A. (Burdenko Neurosurgical Institute. Russia); Dr. Alfandari, Serge (Centre Hospitalier G. DRON. France); Dr. Allerberger, Franz (Universitat Sklinniken Innsbruck. Austria); MD Arends, J.P. (Academsich Ziekenhuis Groningen. The Netherlands); Dr. Arman, (Gazi Universitesi Tip Fakultesi. Turkey); Dr. Auckenthaler, Raymond (Hospital Cantonal Universitaire de Geneve. Suisse); Dr. Avlamis, Athina (Laikon General Hospital. Greece); Dr. Balode, Arta (AML P. Stradina Clinical Hospital. Latvia); Dr. Baraia-Echaburu Arteche, Josu (Hospital de Basurto. Spain); Dr. Barbro, Isaksson (University Hospital Linköping. Sweden); Dra. Barros, Rosa Maria (D. Estefânia. Portugal); Dr. Beaujeau, Desiree (University Hospital Utrecht. The Netherlands); Dr. Beovic, Bojana (University Medical Centre. Slovenia); Dra. Berberova, Tamara (Universty Hospital Plzen. Czech Rep.); Dr. Bethimonti, Katerina (Red Cross Hospital. Greece); Prof.Dr. Bille, Jacques (Centre Hospitalier Universitaire Vaudois. Switzerland); Dr. Binder, Lotharr (Elisabethinen Hospital. Austria); Dr. Blasco, Marco (Hospital Miguel Servet. Spain); Dr. Bou-Hoi, Annie (Broussais Hospital. France); Prof. Bouza, Emilio (Hospital Gregorio Marañón. Spain); Dr. Bremmelgaard, Annie (Bispebjerg Hospital. Denmark); Dr. Carvalho Ribeiro, Maria da Graca (Hospital Da Universidade De Coimbra. Portugal); Dra. Catherine, Kalahani-Lazou (Evangelismos Hospital. Greece); Dr. Cermak, Pavel (University Hospital. Czech Republic); Dr. Chavanet, Pascal (Hospital du Bocag. France); Dr. Cisterna, Ramon (Hospital de Basurto. Spain); Dra. Collegnon, Anne (Hospital Jean Verduer. France); Dr. Croix, Jean-Claude (Centre Hospitalier. France); Dr. Dannenberg, Lutz (Chest Hospital Heckbshorn. Germany); Dr. Danuta, Dzierzanowska (The Childrens Memorial Health Institute. Poland); Prof Daschner, (Klinikum der Albert-Ludwigs-Universitaet. Germany); Dr. Davila, Neda (Zagreb Institute of Public Health . Croatia); Dr. Daw, Mohamed Ali (Facultay of Medicine. Central Hospital Aljala Hospital. Libya); Dr. Dechamps, Chistopher (Faculte de Medecine. France); Prof. Delmee, Michel (Universite Catholique de Louvain. Belgica); Dr. Digranes, Asbouorn (Haukland Hospital. Norway); Dr. Dimitracopoulos, George (University Hospital of Patras. Greece); Dr. Dogamay, Mehmet (Erciyes University Hospital. Turkey); Dr. Elisabeth, Nagy (Albert Szent-Gyorgyi Medical University. Hungary); Dr. Ena, Javier (Hospital Marina Baixa. Spain); Dr. Ezpeleta, Carmen (Hospital de Basurto. Spain); Dr. Fadda, Giovanni (Hospital Policlinico "Agostino Gemmelli". Italy); Dr. Fameree, Dominique (Belgium); Dr. Ferretto, Roberto (Universita e Azienda Ospedaliera Di Verona. Italy);Dr. Fiser, Jerneja (Zavod Za Zdraustveno. Slovenia); MD Fontana, Roberta (Ospedale Civile Maggiore. Italy); Dr. Francetic, Igor (Clinical Hospital Center Rebro. Croatia); Dr. Francine, Pepersack (Hospital de Braine L'Alleud. Belgium); Dr. Francioli, Patrick (Centre Hospitaleier Universitaire Vadois. Switzerland); Dr. Freitas, Ema (Portugal); Dr. Frestschner, Reinhold (Universitaets Klinikum Tuebingen. Germany); Dr. Garrino, Maria Grazia (University Hospital UCL Mont-Godinne. Belgium); Dr. Gastaud, Peter (National Hospital, University of Oslo. Norway); Dr. Gedikoglu, Suna (Uladag University of Medical Faculty. Turkey); Dr. Gesu, Giovanni (Laboratory Medicine. Italy); Dr. Giamarellou, Helen (Laikon General Hospital. Greece); Dr. Gil Aguado, A. (Hospital "La Paz". Spain); Dra. Gismondo, Maria Rita (Hospital Luigi Sacco-Polo Universitario. Italy); Dr. Glupczynski, Youri (University Hospital UCL Mont-Godinne. Belgium); Dr. Gobernado, Miguel (Hospital La Fe. Spain); Dr. Gomis, Manuel (Hospital del Aire. Spain); Dra. Gualterotti, Silvia (Hospital Bassini. Italy); Dra. Gubina, Marija (Medical Faculty, University of Ljubljana. Slovenia); Dr. Guerrero, Antonio (Complejo Hospitalario Juan Canalejo. Spain); Dra. Guerrero, Carmen (Hospital Morales Meseguer. Spain); Dr. Guillaume, Kac (Hospital Broussais. France); Dr. Haas, Bernhard (Vienna General Hospital (AKH-Wien). Austria); Dr. Halabi, Milo (Krankenhaus Ried/Innkreis. Austria); Dr. Hamilton-Miller, Jeremy (Royal Free Hospital. United Kingdom); Dr. Hansen, Dennis Schroder (Hvidovre Hospital. Denmark); Dr. Harthug, Stig (Hanhcland University Hospital. Norway); Dr. Haydouchka, Irina (Ploudiv Med. University. Bulgaria); Dr. Hertel, Roland (Kinderspital Basel. Checolovaquia); Dr. Hocqueloux, Laurent (Hospital Bichat-Claude Bernard. France); Dra. Hupkova, Helene (St. Cyril And Method Hospital. Slovakia); Dr. Isaksson, Barbro (University Hospital. Sweden); Dr. Jan, Arends (Academic Hospital Goningen. Netherlands); Dr. Janes, Vlatka (Pablic Helth Dept. Koprivhica. Croatia); Dr. Janusz, Jeljaszawicz (National Institute of Hygiene. Poland); Dr. Jebavy, Ladislav (Charles University Faculty Hospital. Czech Republic); Dr. Just, Heinz-Michael (Klinikum Nürnberg. Germany); Dr. Kada, Helen ("El Venizelon" General and Maternity Hospital. Greece); Dr. Kalenic, Smila (Clinical Hospital Center Rebro. Croatia); Dr. Kaltenis, Petras (Vilnius University Children's Hospital. Lithuania); Dr. Kansouzidou, Athina (Infectious Diseases Hospital. Greece); Dr. Kitsou, Spyridoula (Agia Olga Koustadopouli o Complex. Greece); Dr. Kluytmans, Jan (Ignatius Hospital Breda. Netherlands); Dr. Koeleman, Johannes G.M. (Sint Franciscus Gasthuis. The Netherlands); Dr. Korn, Stefan (University Hospital Frankfurt. Germany); Dr. Kouppari, Georgia (Amalia Fleming General Hospital. Greece); Dr. Kozlov, Roman (Hospital Smolensk State Medical Academy. Russia); Dr. Krcmery Jr., Vladimir (Slovak Republic); Dr. Krueger, Wolfrang (Tuebingen University Hospital. Germany); Dr. Krugmann, Kristine (Universitat Sklinniken Innsbruck. Austria); Dr. Ktenidoy-Katarli, Sofia (Regional General Hospital. Greece);Dr. Kucisec-Tepes, Nastja (General Hospital "Sveti Duh". Croatia); Dr. Lauterbach, Ryszard (Medical College Jagielonain University. Poland); Dra. Lazaric-Stefanovic, Lorena (Public Health Institute of Istrian Conty. Croatia); Dr. Lejko, Tatjana (Slovenia); MD Lewis, Ann (Singleton Hospital. United Kindong/Wales); Dra. Liñares, Josefina (Hospital de Bellvitge. Spain); Dr. Liskova, Anna (Dept. of Clinical Microbiology / Hospital Nitra. Slovakia); Dr. Llinares, Pedro (Hospital Juan Canalejos. Spain); Dr. Looker, Nick (Glan Clwyd Hospital. Great Britain); Dr. López Brea, Manuel (Hospital de La Princesa. Spain); Dr. Luca, Vasile (Universite de Medicine & Pharmacie. Romania); Dr. Ludurig-Serge, Amo (C.H.U. de Dijon. France); Dr. Magina, Nina (Agia Olga General Hospital. Greece); Dr. Mararic, Vesna (The General Hospital. Croatia); Dra. Marco, Mª Luisa (Hospital Miguel Servet. Spain); Dr. Marie, Vackova (Purkynje Military Medical Academy. Czech Republic); Dr Marroni, Massimo (Institute of Infectious Diseases Perugia University. Italy); Dr. Mavridis, Anestis (General hospital "G.Hatzikosta". Greece); MD Mc Cracken, Diane (University Hospital of Wales. United Kingdom); Dr. Melo-Cristino, Jose (Hospital Santa Maria. Portugal); Dr. Meurman, Olli (Torku University Hospital. Finland); Dr. Michel, Aoun (Institute Jules Border. Belgium); Dr. Michelle, Rossier (Hospital de Zone. Switzerland); Dr. Mittermayer, Helmut (Elisabethinen Hospital . Austria); MD Mlangeni, Dennis (University Hospital Freiburg. Germany); Dr. Moreno Guillen, Santiago (Hospital Morales Meseguer. Spain); Dr. Mueller-Uir, Peter S. (Hospital Landes Nerven Klinik. Austria); MD Mullerova, Lenka (Purkynje military Medical Academy. Czech Republic); Dr. Munzinger, J. (Kantonsspital. Switerland); Dr. Muzlovic, Igor (Clinic for Infectious Diseases. Slovenia); Dr. Nagy, Elisabeth (Medical University Srego. Hungary); Dr. Nicoletti, Pierluigi (Azienda Ospedaliera Careggi. Italy); MD Ossi, Cristina (Hospital San Raffaele. Italy); Dr. Oteo, Jose Antonio (Hospital de la Rioja. Spain); Dr. Pallares, Roman (Hospital de Bellvitge. Spain); Dra. Paniara, Olga (General Hospital "Evangelimos". Greece); Dr. Paradisi, Franco (Nuovo Ospedale S. Giovanni di Dio. Italy); Dr. Pascual, Alvaro (Hospital Virgen de la Macarena. Spain); Dra. Peña Garcia, Pilar (Hospital La Paz. Spain); Dr. Perea, Evelio (Hospital U. Virgen de la Macarena. Spain); Dr. Pérez Molina, José A. (Hospital Gregorio Marañón. Spain); Dr. Peterslund, Niels (Aarhus Amtssygehus. Denmark); Dr Pina, Elaine (C.C.I.H.. Portugal); Dr. Pombo, Victor (Hospital Da Universidade de Coimbra. Portugal); Dr. Popescu, Irina (Uniklinik Freiburg. Deutschland); Dr. Prammer, Wolfrang (Hospital Wels. Austria); Dr. Praz, Gerard (Institut Central des Hôspitaux Valaisans. Switzerland); Dr. Punda-Polic, Volga (University Hospital Split. Croatia); Dra. Radulescu, Amanda (Clinic of Infectious Diseases. Romania); Dr Ransjö, Ulrika (Karolinska Hospital. Sweden); Dr. Reder, Bent (Hospital Hillerod Sygemus. Denmark); Dr. Reid, T.M.S. (Hospital Aberdeen Royal Infirmary. Scotland); Dr. Rivero Marcotegui, Maria (Hospital Virgen del Camino. Spain); Dr. Rodríguez Créixems, Marta (Hospital Gregorio Marañón. Spain); Dr. Roilides, Emmanuel (Hippokration hospital. Greece); Dr. Ros, A. (Hospital Nord. France); Dr. Rozgoyi, Ferenc (Semmelweis University of Medicine. Hungary); Prof. Rueden, (Hygiene-Institu. Germany); Dr. Ruef, Christian (University of Zurich. Switherland); Dr. Saroglou, George (Evagelismos Hospital. Greece); Dr. Sasca, Nadia (Clinic of Infectious Diseases. Romania); Prof. Shah, Pramod (Johann Wolfgang Goethe-Universität. Germany); MD Simmons, Michael (Public Health Laboratory. WALES/UK); Dra. Simon, Anne (St.Lluc University Hospital. Belgium); Dr. S'kerl, Marjeta (University Medical Center. Slovenia); Dr. Smyth, Edmond (Beaumont Hospital. Ireland); Dr. Sofianou, Danair ("Hippokration" General Hospital. Grecia); Dr. Soukup, Josef (Purkynje Military Medical Academy. Czech Republic); Dr. Spanjaard, Lodewyk (Academic Medical Center. The Netherlands); Dr. Spencer, Robert C. (Public Health Laboratory, Level 8. United Kindom); Dr. Spiliopoulou, Iris (University Hospital of Patras. Greece); Dr. Splino, Miroslav (Purkynje Military Medcial Academy. Czech Republic); Dr. Stablova, Vera (Purkynje Military Medcial Academy. Czech Republic); Dr. Stobberingl, E.E. (University Hospital Maastricht. The Netherlands); Dr. Stratchounski, Leonid (Smolensk State Medical Academy. Russia); Dr. Struelens, Marc (Erame. Belgium); Dr. Sumerkan, Bulent (Erciyes University Hospital. Turkey); Dr. Tabakova, Vera (University Hospital "St. Ekaterina". Bulgaria); Dr. Tambic, Arjana (Children's Hospital Zagreb. Crotia); MD Thorsteinssan, Geir (Landspitalium- Nacional University Hospital. Iceland); Dr. Torroba Alvarez, Luis (Hospital Virgen del Camino. Spain); Dr. Trupl, Jan (National Cancer Institue. Slovakia); Dr. Tvede, Michael (Rigshospitalet, Afsnit 9301. Denmark); Dr. Tveten, Yngvar (Telemark County Hospital. Norway); Dr. Vam De Vyvere, Martine (Az Stulvemberg. Belgium); Dr. Van Den Broeck, Hans L.M. (Hospital Val Helmont. Belgium); Dr. Van Der Zwet, Wil (Clinical Microbiology and Infection Control. The Netherlands); Dra. Vandenbroucke-Grauls, Chistinia M.J.E. (Academic Hospital "Vrije Universiteit". The Netherlands); Dr. Von Wulffen, Hinrik (Hospital Allgemeines Krankenhans Barmbek. Germany); Dr. Vos, Margreet C. (Erasmus Medical Center Rotterdan. The Netherlands); Dr. Voss, Andreas (University Hospital St. Radboud. The Netherlands); Dr. Votava, Miroslav (St. Anna Hospital. Czech Rep); Dr. Vundelinckx, Guy (Belgium); Dr Wagenvoort, J.H.T. (The Netherlands); Prof. Dr. Waleria, Hryniewicz (Sera and Vaccines Laboratory. Poland); MD Walker, Mark (Public Health Laboratory Bangor. United Kingdom); Dr. Weber, Michele (Hospital Central. France); MD Williams, A (Hospital Llandought. United Kingdom); Dr. Willke, Ayse (Ibn-i Sina Hospital. Turkey); Dr. Wishrom, Johan (University Hospital Umea. Sweden); Dr. Zbinden, Reinhard (University of Zurich. Switzerland).
 
 

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