Bloodstream Infections

Evolution and Trends in the Microbiology Workload, Incidence,

and Etiology, 1985–2006
Marta Rodrı́guez-Créixems, MD, PhD, Luis Alcalá, PharmD, Patricia Muñoz, MD, PhD,
Emilia Cercenado, PharmD, Teresa Vicente, MD, and Emilio Bouza, MD, PhD

Abstract: Information available on bloodstream infection (BSI) is Abbreviations: AIDS = acquired immunodeficiency syndrome, BSI =
usually restricted to short periods of time, certain clinical bloodstream infection, ESBL = extended-spectrum beta-lactamase,
HAART = highly active antiretroviral therapy, HIV = human
backgrounds, or specific pathogens, or is just outdated. We immunodeficiency virus, MRSA = methicillin-resistant Staphylococcus
conducted the current prospective study of patients with BSI in a aureus.
1750-bed teaching hospital to evaluate workload trends and the
incidence and etiology of BSI in a general hospital during the last
22 years, including the acquired immunodeficiency syndrome
(AIDS) era. The main outcome measures were laboratory workload, INTRODUCTION
trends in incidence per 1000 admissions and per 100,000 population
of different microorganisms, and the impact of the human
immunodeficiency virus (HIV) epidemic in the period 1985–2006.
B loodstream infection (BSI) remains one of the more
severe diseases affecting humans. Fragmented data
suggest important changes in the underlying conditions,
From 1985 to 2006 we had 27,419 episodes of significant BSI
etiology, and prognosis of BSI in recent years. However, the
(22,626 patients). BSI incidence evolved from 16.0 episodes to
information available is usually restricted to short periods
31.2/1000 admissions showing an annual increase of 0.83 episodes/
of time, to patients with certain underlying clinical condi-
1000 admissions (95% confidence interval, 0.61–1.05; p < 0.0001).
tions, or to specific pathogens, or the information is just
The evolution of the incidence per 1000 admissions and per 100,000
outdated6,11,14,16–18,36,37,39,42,45,51,52,55,59,65,72,74,84,91,100,101,120.
population of different groups of microorganisms was as follows:
Large series of BSI with nonselected types of
Gram positives 8.2 to 15.7/1000 admissions and 66.8 to 138.3/
patients or specific pathogens are scarce and are mainly
100,000 population; Gram negatives 7.8 to 16.2/1000 admissions
based on the perspective of clinicians, not microbiolo-
and 63.5 to 141.9/100,000 population; anaerobes 0.5 to 1.3/1000
gists21,31,42,66,78,88,102,112,114,117. Reliable data assessing the
admissions and 4.1 to 11.7/100,000 population; and fungi 0.2 to 1.5/
trends of the microbiology laboratory workload, the inci-
1000 admissions and 1.7 to 12.5/100,000 population. All those
dence, and the etiologic changes of BSI are, accordingly,
differences were statistically significant.
difficult to find in the literature.
We observed the emergence of multiresistant Gram-positive and
Similarly, the contribution of HIV-infected patients to
Gram-negative microorganisms. At least 2484 episodes of BSI
both the workload and the etiology of bacteremia has not
(9.1%) occurred in 1822 patients infected with HIV. The incidence
been studied in depth31,68,82,85,108. We conducted the current
of BSI in HIV-infected patients increased from 1985 and reached a
study to report the trends in the workload, incidence, and
peak in 1995 (17.6% of BSI). Since 1995, the decrease was
etiology of BSI in a general hospital from the perspective of
continuous, and in 2006 only 3.9% of all BSI episodes occurred in
the clinical microbiology department during the last 22
HIV-positive patients in our institution.
We conclude that the BSI workload has increased in modern
years, thus including the AIDS era.
microbiology laboratories. Gram-positive pathogens have overtaken
other etiologic agents of BSI. Our observation shows the PATIENTS AND METHODS
remarkable escalation of some resistant pathogens, and the rise Ours is a general teaching hospital serving a population
and relative fall of BSI in patients with HIV. that ranged during the 22 years of study from approximately
650,000 to 750,000 inhabitants of a large city. During the
(Medicine 2008;87:234–249) study period the number of beds available was reduced
from 2500 to approximately 1750. We have all the
From Microbiology and Infectious Disease Department, Hospital General services of a general hospital, with active programs
Universitario ‘‘Gregorio Marañón,’’ Ciber de Enfermedades Respiratorias directed to HIV-infected patients, transplant recipients, and
(CIBERES), Universidad Complutense, Madrid, Spain. immunosuppressed hosts, and dynamic and sophisticated
Address reprint requests to: Patricia Muñoz, MD, PhD, Servicio de
Microbiologı́a Clı́nica y E. Infecciosas, Hospital General Universitario surgical programs.
‘‘Gregorio Marañón,’’ Dr. Esquerdo, 46 28007 Madrid, Spain. Fax:
34-91-3721721; e-mail: pmunoz@micro.hggm.es. Study Period
Copyright n 2008 by Lippincott Williams & Wilkins
ISSN: 0025-7974/08/8704-234 We included all blood samples sent for bacterial and
DOI: 10.1097/MD.0b013e318182119b fungal culture to our laboratory from January 1985 to

234 Medicine
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Medicine
Volume 87, Number 4, July 2008 Evolution of Bloodstream Infections

December 2006 (22 years). We excluded bacteremia by
Mycobacterium species from our analysis.
Blood Culture Systems
Given the length of the study period, 3 major changes
were made in the laboratory processing of blood cultures.
From January 1985 to April 1986, we used the Vacutainer
System (Becton Dickinson Co, Rutherford, NJ) with manual
reading. Acridine orange was systematically used, and the
regular incubation period was 7 days (30 days for cases with
suspected endocarditis, brucellosis, or mycoses). From May
1986 to October 1995, the manual system was changed to a
semiautomatic procedure (BACTEC-NR 640, Johnston
Laboratories). Negative samples were discarded after 5 days
of incubation, when reading was less than 30 U according to
the manufacturer’s instructions.
From November 1995 to the end of the study period
(December 2006), blood cultures were processed using the
BACTEC 9240 (Becton Dickinson Microbiology Systems),
which is more automatic and includes continuous shaking.
Sampling and transportation of blood cultures were
performed by standard procedures. During the whole study
period we recommended 3 samples of blood (approximately
10 mL in each for adults) to evaluate each episode of
suspected bacteremia. Blood from each extraction was
divided between an aerobic and anaerobic atmosphere bottle.
All positive samples were subcultured and Gram stained.
Methods for processing positive blood cultures, identifica-
tion of isolates, and antimicrobial susceptibility testing were
standard8,119.
Definitions
We used the following definitions:
Blood culture (often referred to as a culture set): a
volume of blood obtained under aseptic conditions, inocu-
lated to 1 or more bottles or vials for microbiologic isolation.

TABLE 1. Evolution of Blood Culture Laboratory Workload During a 22-Year Period

No. of Blood Episodes Episodes
Cultures of BSI of BSI %
(per 1000 % % (per 1000 per 100,000 Polymicrobial
Year Inhabitants Admissions Admissions) Positivity Contamination Admissions) Inhabitants Episodes
1985 604,904 49,332 14,736 (299) 19.9 7.4 788 (16.0) 130.3 10.0
1986 608,594 50,365 15,590 (310) 19.1 7.5 770 (15.3) 126.5 7.7
1987 612,284 49,367 16,051 (325) 18.8 6.5 809 (16.4) 132.1 6.8
1988 615,974 48,558 16,950 (349) 18.9 7.1 840 (17.3) 136.4 13.0
1989 619,664 47,789 18,982 (397) 19.1 7.1 1005 (21.0) 162.2 12.8
1990 623,354 46,443 21,352 (460) 18.4 7.1 1075 (23.2) 172.5 11.6
1991 627,043 45,792 23,629 (516) 17.5 7.0 978 (21.4) 156.0 9.7
1992 629,040 45,565 25,290 (555) 16.0 6.2 1038 (22.8) 165.0 9.5
1993 631,037 48,582 27,807 (572) 16.1 6.1 1130 (23.3) 179.1 8.5
1994 633,034 48,275 28,496 (590) 13.3 4.6 1053 (21.8) 166.3 8.5
1995 635,031 47,972 29,574 (617) 16.5 6.3 1265 (26.4) 199.2 12.5
1996 637,028 49,687 28,292 (569) 16.9 5.9 1388 (27.9) 217.9 11.5
1997 642,091 51,604 30,467 (590) 14.5 5.5 1326 (25.7) 206.5 10.9
1998 647,154 50,371 29,309 (582) 17.2 5.3 1306 (25.9) 201.8 12.6
1999 650,597 49,097 28,426 (579) 15.1 4.9 1262 (25.7) 194.0 11.7
2000 653,849 50,873 28,912 (568) 21.5 4.8 1365 (26.8) 208.8 11.6
2001 668,942 52,249 31,879 (610) 15.7 4.6 1396 (26.7) 208.7 13.0
2002 684,754 52,889 34,285 (648) 15.4 4.1 1557 (29.4) 227.4 10.5
2003 704,030 54,781 38,796 (708) 13.4 4.3 1613 (29.4) 229.1 12.7
2004 717,326 61,299 40,713 (664) 12.7 4.1 1642 (26.8) 228.9 11.8
2005 738,481 62,773 44,187 (706) 12.4 3.8 1773 (28.5) 240.1 8.5
2006 743,387 65,681 47,101 (720) 13.3 3.7 2040 (31.2) 269.8 9.5
Annual average 651,254 51,334 28,219 (549.7) 15.8 5.3 1246 (24.3) 191.2 10.7
Annual increase — 61.5 18.4* — — 0.83y — —
(95% CI) (25.7–97.4) (15.3–21.5) (0.61–1.05)
Annual decrease — — — 0.32 0.22 — — —
(95% CI) (0.14–0.50) (0.16–0.28)
p Value — 0.0009 <0.0001 0.0004 <0.0001 <0.0001 — NS
* Referred to number of blood cultures per 1000 admissions.
y
Referred to episodes per 1000 admissions.

n 2008 Lippincott Williams & Wilkins 235

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Rodrı́guez-Créixems et al Medicine
Volume 87, Number 4, July 2008

FIGURE 1. Evolution of bacteremia in pediatric patients and neonates (‘‘Neont.’’), 1985–2006.

BSI episode: episodes of bacteremia, or fungemia,
refer only to patients, not to number of blood cultures. All
microorganisms isolated from blood from the same patient
within 1 week were considered as a single episode. Clinical
significance of each episode was discussed with the
attending clinicians when doubtful.
Recurrent bacteremia: an episode of bacteremia was
considered recurrent when the patient already had a prior
episode in our records with an interval of at least 10 days
between the prior and the present episode, and with previous
clearing of the clinical manifestations attributable to the first
BSI episode.
Contaminant microorganisms: the following micro-
organisms were categorized as probable contaminants, unless
proven otherwise: Bacillus species, Corynebacterium species
(except Corynebacterium jeikeium), Lactobacillus species,
and Propionibacterium species. Coagulase-negative Staphy-
lococcus, or viridans group Streptococcus isolates and
Clostridium perfringens were considered to be probable
pathogens only if they were recovered from 2 samples (2
separate needle sticks). In the case of neonates, due to the
difficulty in obtaining blood from these patients and
following standard recommendations, we accepted as
significant the presence of coagulase-negative Staphylococ-
cus or other potential contaminants in both bottles of a single
venous puncture.
Polymicrobial bacteremia: was defined as isolation of
more than 1 microorganism during a single bacteremic
episode.
Database and Statistical Analysis
The database of the episodes of significant BSI was
prospectively maintained on a daily basis by a staff member
of the microbiology laboratory (MRC) from the beginning of
the study. The database includes the following information:
identification of the patient, unit of admission, data of
extraction of blood cultures, number of blood cultures
obtained, number of positive blood cultures, date of
positivity, microorganisms identified, antimicrobial suscep-
tibility, and HIV condition (if available). Global incidence of

FIGURE 2. Evolution of the etiology of BSI episodes in a general hospital during a 22-year period.

236 n 2008 Lippincott Williams & Wilkins

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 TABLE 2. Evolution of Episodes of BSI Caused by Gram-Positive Microorganisms During a 22-Year Period*
Episodes of Staph. Str. Str. Str. Str. viridans Enterococcus Listeria
Gram (+) aureus MRSA MSSA CNS pneumoniae agalactiae pyogenes group spp. spp.
(per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000
Year Admissions) Admissions Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions)
1985 404 (8.2) 147 (3.0) 0 (0.0) 147 (3.0) 107 (2.2) 44 (0.9) 6 (0.1) 11 (0.2) 12 (0.2) 59 (1.2) 0 (0.0)
1986 370 (7.3) 133 (2.6) 0 (0.0) 133 (2.6) 79 (1.6) 42 (0.8) 9 (0.2) 11 (0.2) 25 (0.5) 63 (1.3) 3 (0.06)
1987 393 (8.0) 131 (2.7) 0 (0.0) 131 (2.7) 112 (2.3) 54 (1.1) 8 (0.2) 6 (0.1) 24 (0.5) 56 (1.1) 6 (0.12)
1988 467 (9.6) 164 (3.4) 0 (0.0) 164 (3.4) 148 (3.0) 51 (1.1) 3 (0.1) 9 (0.2) 30 (0.6) 67 (1.4) 3 (0.06)

n 2008 Lippincott Williams & Wilkins

1989 616 (12.9) 220 (4.6) 22 (0.5) 198 (4.1) 214 (4.5) 55 (1.2) 12 (0.3) 6 (0.1) 41 (0.9) 83 (1.7) 2 (0.04)
1990 660 (14.2) 278 (6.0) 69 (1.5) 209 (4.5) 207 (4.5) 58 (1.2) 8 (0.2) 16 (0.3) 40 (0.9) 81 (1.7) 2 (0.04)
1991 598 (13.1) 217 (4.7) 65 (1.4) 152 (3.3) 153 (3.3) 71 (1.6) 8 (0.2) 25 (0.5) 43 (0.9) 95 (2.1) 1 (0.02)
1992 647 (14.2) 234 (5.1) 52 (1.1) 182 (4.0) 186 (4.1) 106 (2.3) 12 (0.3) 10 (0.2) 43 (0.9) 75 (1.6) 4 (0.09)
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1993 644 (13.3) 215 (4.4) 38 (0.8) 177 (3.6) 225 (4.6) 72 (1.5) 15 (0.3) 0 (0.0) 36 (0.7) 92 (1.9) 5 (0.10)
1994 604 (12.5) 196 (4.1) 36 (0.7) 160 (3.3) 238 (4.9) 66 (1.4) 14 (0.3) 2 (0.1) 15 (0.3) 90 (1.9) 3 (0.06)
1995 741 (15.4) 197 (4.1) 42 (0.9) 155 (3.2) 314 (6.5) 84 (1.8) 7 (0.1) 7 (0.1) 30 (0.6) 108 (2.3) 3 (0.06)
1996 793 (16.0) 250 (5.0) 108 (2.2) 142 (2.9) 305 (6.1) 89 (1.8) 5 (0.1) 18 (0.4) 36 (0.7) 110 (2.2) 2 (0.04)
1997 774 (15.0) 234 (4.5) 89 (1.7) 145 (2.8) 324 (6.3) 67 (1.3) 17 (0.3) 8 (0.2) 34 (0.7) 105 (2.0) 3 (0.06)
1998 748 (14.8) 231 (4.6) 81 (1.6) 150 (3.0) 309 (6.1) 84 (1.7) 19 (0.4) 13 (0.3) 30 (0.6) 92 (1.8) 4 (0.08)
1999 714 (14.5) 189 (3.8) 58 (1.2) 131 (2.7) 263 (5.4) 97 (2.0) 16 (0.3) 22 (0.4) 34 (0.7) 102 (2.1) 1 (0.02)
2000 767 (15.1) 196 (3.9) 65 (1.3) 131 (2.6) 304 (6.0) 103 (2.0) 10 (0.2) 14 (0.3) 35 (0.7) 111 (2.2) 10 (0.20)
2001 735 (14.1) 206 (3.9) 79 (1.5) 127 (2.4) 302 (5.8) 90 (1.7) 19 (0.4) 4 (0.1) 26 (0.5) 97 (1.9) 10 (0.19)
2002 777 (14.7) 212 (4.0) 78 (1.5) 134 (2.5) 310 (5.9) 95 (1.8) 15 (0.3) 11 (0.2) 53 (1.0) 92 (1.7) 7 (0.13)
2003 880 (16.1) 250 (4.6) 104 (1.9) 146 (2.7) 351 (6.4) 110 (2.0) 16 (0.3) 18 (0.3) 44 (0.8) 109 (2.0) 9 (0.16)
2004 779 (12.7) 188 (3.1) 77 (1.3) 111 (1.8) 293 (4.8) 99 (1.6) 21 (0.3) 20 (0.3) 51 (0.8) 115 (1.9) 8 (0.13)
2005 888 (14.2) 199 (3.2) 78 (1.2) 121 (1.9) 335 (5.4) 122 (1.9) 24 (0.4) 20 (0.3) 33 (0.5) 129 (2.1) 5 (0.08)
2006 1028 (15.7) 229 (3.5) 69 (1.1) 160 (2.4) 386 (5.9) 142 (2.1) 24 (0.4) 22 (0.3) 50 (0.8) 150 (2.3) 9 (0.14)
Annual 683.1 (13.31) 205.3 (4.00) 55.0 (1.07) 150.3 (2.93) 248.4 (4.84) 81.9 (1.59) 13.1 (0.26) 12.4 (0.24) 34.8 (0.68) 94.6 (1.84) 4.5 (0.09)
average
Annual 0.49 0.09 — — 0.20 0.08 0.02 — — 0.07 0.01
increasey (0.31–0.66) (0.01–0.17) (0.11–0.29) 0.04–0.11 (0.01–0.03) (0.03–0.11) (0.01–0.02)
(95% CI)
Annual — — — — — — — — — — —
decreasey
(95% CI)
p Value <0.0001 0.0330 NS NS <0.0001 <0.0001 0.0043 NS NS 0.0009 0.0032

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Abbreviations: MSSA = methicillin-susceptible Staph. aureus, CNS = coagulase-negative staphylococci.
*Data on incidence per 100,000 inhabitants are provided in the text.
y
Referred to episodes per 1000 admissions.
Evolution of Bloodstream Infections

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Rodrı́guez-Créixems et al Medicine
Volume 87, Number 4, July 2008

FIGURE 3. Evolution of methicillin-susceptible (MSSA) and methicillin-resistant Staph. aureus (MRSA) BSI from 1985 to 2006.

BSI episodes, provided as episodes per 1000 admissions, was
calculated as the number of episodes detected during the 22
years divided by the number of admissions (in thousands) of
the institution over this period. The evolution of variables
along the study period was performed by means of the
autoregressive integrated moving average test (ARIMA)
with data in monthly intervals. For the analysis of BSI
episodes per 1000 admissions, the ARIMA model was
adjusted by the blood culture system used in each period and
the percentage of blood cultures with growth of significant
microorganisms (as a measurement of index of suspicion).
Comparison of 2 proportions (such as BSI incidence per
100,000 inhabitants in 2 different years) was performed
using the Fisher exact test with 2 tails. A p value < 0.05 was
considered significant. The analysis was carried out with
SPSS 15.0 (SPSS, Chicago, IL).
RESULTS
Evolution of Blood Culture Laboratory Workload
The evolution of the main parameters of the laboratory
workload of BSI in our institution is summarized in Table 1.
Our institution had 1,129,344 admissions during the 22 years
of the study (mean, 51,334 admissions/year).
Blood cultures increased progressively in our institu-
tion during the study period, ranging from 299 blood
cultures/1000 admissions in the year 1985 to 720/1000
admissions in 2006. This represents a yearly increase of 18.4
blood cultures per 1000 admissions (95% confidence interval
[CI], 15.37–21.5; p < 0.0001). The population-based data on
blood cultures requested in our area show that the number of
blood cultures obtained per 100,000 inhabitants increased
from 2436 in 1985 to 6336 in 2006 (p < 0.0001).
The number of blood cultures with growth of 1 or more
microorganisms was 98,216 (global positivity rate, 15.8%).
Of these, 32,741 (5.3%) were considered contaminated
according to our definitions. The evolution of the rate of
contamination in our blood cultures decreased from 7.4% of
all blood cultures in 1986 to 3.7% in 2006 (mean annual
decrease of 0.22% [95% CI, 0.16–0.28; p < 0.0001]).
The 65,475 blood cultures with recovery of signifi-
cant microorganisms represent 27,419 episodes of signifi-
cant BSI (22,626 patients), and constitute the figures to
which we will refer in the rest of the results section. The

FIGURE 4. Evolution of the episodes of Str. pneumoniae BSI/1000 admissions.

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Medicine
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range of BSI episodes per 1000 admissions in our institu-
tion evolved from 16.0 episodes in 1986 to 31.2 in 2006
(mean, 24.3 episodes of BSI/1000 admissions during the
whole study period). There was an annual increase of 0.83
episodes of BSI per 1000 admissions (95% CI, 0.61–1.05;
p < 0.0001). Overall, 3365 patients had more than 1 episode
of BSI detected in our institution (14.9% of recurrences).
Of all the significant episodes, 2955 were polymicrobial
(10.7%) (see Table 1). Of all the episodes of bacteremia,
2930 (10.7%) occurred in the pediatric population during the
study period (Figure 1).
Etiology
Overall, 54.8% episodes were caused by Gram-
positive microorganisms, 43.7% by Gram-negative micro-
organisms, 4.1% by anaerobic bacteria, and 3.04% by fungi.
Figure 2 shows the evolution of the major groups of
microorganisms causing BSI in our institution during the 22
years of the study.
Gram-Positive Microorganisms
Gram-positive bacteria were the most frequent cause
of BSI episodes in our institution with an annual average
of 683 episodes (13.31 episodes per 1000 admissions).
These episodes increased at an annual rate of 0.49 episodes/
1000 admissions (95% CI, 0.31–0.66; p < 0.0001) (Table 2).
(From now on we will provide data per 1000 admis-
sions in the tables and incidence per 100,000 inhabitants in
the text.)
The incidence of BSI caused by Gram-positive bacteria
in our population increased from 66.8 episodes/100,000
inhabitants in 1985 to 138.3/100,000 in 2006 (p < 0.0001).
Staph. aureus caused 4516 episodes of BSI in 3980 patients
with a mean annual incidence of 205 episodes (4.0 episodes/
1000 admissions). The incidence of Staph. aureus BSI
episodes during the study period has shown a yearly increase
of 0.09 episodes/1000 admissions (95% CI, 0.01-0.17; p =
0.0330). We had 24.3 episodes per 100,000 population in
1985 and 30.8 in 2006 (p = 0.0260). Methicillin-resistant
Staph. aureus (MRSA) emerged as a cause of BSI in 1989
(22 episodes), and has increased since then. In 2006, 30.1%
of all episodes of Staph. aureus BSI were caused by MRSA
isolates (69 episodes) (Figure 3).
Another microorganism of particular interest is Strep-
tococcus pneumoniae. The incidence of BSI caused by Str.
pneumoniae grew significantly during the study period, from
7.3 episodes/100,000 population in 1985 to 19.1/100,000
episodes in 2006 (p < 0.0001). This represents a significant
increase of 0.08 episodes per 1000 admissions/year (95% CI,
0.04–0.11; p < 0.0001) (Figure 4).The percentage of Str.
pneumoniae isolates nonsusceptible to penicillin evolved
from 36% and 49% in 1995 and 1996, respectively, to 23%
and 19% in 2005 and 2006, respectively. The evolution of
other Gram-positive microorganisms is shown in Table 2.
Gram-Negative Microorganisms
Gram-negative bacteria caused an annual mean of
544.9 episodes (10.61 episodes/1000 admissions). Their
n 2008 Lippincott Williams & Wilkins
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Evolution of Bloodstream Infections
incidence significantly increased in 0.49 episodes per 1000
admissions and year (95% CI, 0.37–0.61; p < 0.0001),
evolving from 63.5 episodes (1985) to 141.9 (2006) per
100,000 inhabitants (p < 0.0001). The incidences per 1000
admissions of Escherichia coli, Klebsiella species, Citro-
bacter species, Enterobacter species, Morganella species,
and other Enterobacteriaceae are shown in Table 3.
Overall, we collected 5888 episodes of E. coli BSI in
5434 patients, with an annual mean of 267.6 episodes (5.2
episodes/1000 admissions). The incidence increased pro-
gressively from 23.5 episodes/100,000 inhabitants in 1985 to
79.1 episodes/100,000 population in 2006 (p < 0.0001).
Accordingly, E. coli BSI increased a mean of 0.36 episodes/
1000 admissions and year (95% CI, 0.29–0.42; p < 0.0001).
In 1995, strains of E. coli able to produce extended-
spectrum beta-lactamase (ESBL) began to appear in our
institution, and those strains recently increased considerably,
going from 1–5 episodes per year from 1995 to 2003, to 46
episodes in 2006 (Figure 5). Resistance of E. coli to
ciprofloxacin increased significantly, going from a propor-
tion of 3% of all E. coli isolated from BSI in 1991 to 32% in
2006 (p < 0.0001). Regarding nonfermenting Gram-negative
bacilli, Pseudomonas aeruginosa produced 957 episodes
(906 patients), with an annual mean of 43.5 episodes (0.85
episodes/1000 admissions). The trend of P. aeruginosa BSI
can be seen in Table 3, with a mean increase per year of 0.05
episodes/1000 admissions (95% CI, 0.02–0.07; p = 0.0007).
The evolution of episodes of BSI caused by other fastidious
Gram-negative microorganisms such as Haemophilus spe-
cies, Neisseria meningitidis, Brucella species, or Campylo-
bacter species is also shown in Table 3.
Haemophilus species caused 305 episodes of BSI in
our institution during the study period. H. influenzae was the
most common species isolated (267 episodes). Of these, 75%
occurred in adult patients. Neither the trend to decrease in
the incidence in pediatric patients nor the trend to increase in
the adult population reached a statistically significant
difference (Figure 6).
The incidence of episodes caused by Acinetobacter
species and Neisseria meningitidis significantly decreased by
0.02 episodes/1000 admissions per year (95% CI, 0.01–
0.03), while the incidence of BSI caused by Proteus species,
Salmonella species, Serratia species, Brucella species, and
Campylobacter species remained stable.
Anaerobic Bacteria
Episodes of BSI in which 1 or more anaerobic
microorganisms were present occurred at an annual mean
of 51.4 episodes (1.00 episode/1000 admissions) (Table 4).
The evolution of the incidence of anaerobic BSI grew in our
institution, going from 0.5 episodes/1000 admissions in 1985
to 1.3/1000 admissions in 2006. The mean increase in
incidence was 0.03 episodes/1000 admissions per year (95%
CI, 0.01–0.06; p = 0.0019). Episodes of anaerobic BSI
evolved from 4.1/100,000 population in 1985 to 11.7/
100,000 population in 2006 (p < 0.0001).
Anaerobic microorganisms most frequently isolated
from BSI included those belonging to the genus Bacteroides,
239
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with 617 overall episodes and a mean annual rate of 28.1
episodes (0.55/1000 admissions).
Fungemias
Fungal BSI presented an annual mean of 37.9 episodes
(0.74 episodes/1000 admissions) and a mean yearly increase
of 0.04 episodes/1000 admissions (95% CI, 0.01–0.06; p =
0.0092) (Table 5). The incidence of fungal BSI per 100,000
population evolved from 1.7 episodes in 1985 to 12.5 in 2006
(p < 0.0001). A progressive increase in non-albicans species
of the genus Candida was particularly remarkable. Candida
parapsilosis was by far the most common non-albicans
species of Candida causing BSI, followed by a miscellany of
other species (Figure 7).
BSI in HIV-Infected Patients
During the study period, at least 2484 episodes of BSI
(9.1%) occurred in 1822 patients infected with HIV. Overall,
23.5% of these patients had more than 1 episode of BSI
registered in our records (429 patients).
Figure 8 shows the evolution during the 22 years of the
study of BSI in HIV-infected patients. The incidence
increased progressively from 1985 and reached a peak in
1995, when there were 223 episodes (17.6% of all episodes
of BSI). From 1995 on, the decrease was continuous, and in
the year 2006 only 3.9% of all BSI episodes occurred in
HIV-positive patients.
HIV-infected patients accounted for 15.1% (681 epi-
sodes) of all Staph. aureus BSI, 23.7% (427 episodes) of all

TABLE 3. Evolution of Episodes of BSI Caused by Gram-Negative Microorganisms During a 22-Year Period*
Episodes Klebsiella Citrobacter Enterobacter Morganella Proteus Salmonella
of Gram (–) E. coli spp. spp. spp. spp. spp. spp.
(per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000
Year Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions)
1985 384 (7.8) 142 (2.9) 58 (1.2) 5 (0.1) 37 (0.8) 9 (0.2) 34 (0.7) 31 (0.6)
1986 376 (7.5) 152 (3.0) 25 (0.5) 2 (0.1) 28 (0.6) 2 (0.1) 26 (0.5) 47 (0.9)
1987 405 (8.2) 156 (3.2) 31 (0.6) 5 (0.1) 31 (0.6) 3 (0.1) 25 (0.5) 49 (1.0)
1988 377 (7.8) 139 (2.9) 33 (0.7) 6 (0.1) 28 (0.6) 2 (0.1) 30 (0.6) 34 (0.7)
1989 385 (8.1) 173 (3.6) 24 (0.5) 3 (0.1) 27 (0.6) 4 (0.1) 23 (0.5) 31 (0.6)
1990 390 (8.4) 138 (3.0) 27 (0.6) 5 (0.1) 30 (0.6) 5 (0.1) 33 (0.7) 47 (1.0)
1991 353 (7.7) 140 (3.1) 51 (1.1) 9 (0.2) 20 (0.4) 2 (0.1) 22 (0.5) 28 (0.6)
1992 368 (8.1) 177 (3.9) 21 (0.5) 4 (0.1) 18 (0.4) 3 (0.1) 19 (0.4) 31 (0.7)
1993 472 (9.7) 228 (4.7) 36 (0.7) 5 (0.1) 33 (0.7) 4 (0.1) 28 (0.6) 33 (0.7)
1994 416 (8.6) 209 (4.3) 49 (1.0) 6 (0.1) 27 (0.6) 1 (0.1) 14 (0.3) 28 (0.6)
1995 501 (10.4) 227 (4.7) 49 (1.0) 5 (0.1) 35 (0.7) 5 (0.1) 24 (0.5) 37 (0.8)
1996 566 (11.4) 274 (5.5) 81 (1.6) 6 (0.1) 32 (0.6) 2 (0.1) 33 (0.7) 24 (0.5)
1997 523 (10.1) 251 (4.9) 51 (1.0) 3 (0.1) 29 (0.6) 10 (0.2) 23 (0.4) 25 (0.5)
1998 524 (10.4) 278 (5.5) 48 (1.0) 8 (0.2) 22 (0.4) 3 (0.1) 35 (0.7) 31 (0.6)
1999 531 (10.8) 256 (5.2) 59 (1.2) 6 (0.1) 28 (0.6) 13 (0.3) 37 (0.8) 16 (0.3)
2000 574 (11.3) 277 (5.4) 81 (1.6) 5 (0.1) 39 (0.8) 6 (0.1) 44 (0.9) 29 (0.6)
2001 624 (11.9) 352 (6.7) 96 (1.8) 4 (0.1) 27 (0.5) 11 (0.2) 32 (0.6) 27 (0.5)
2002 736 (13.9) 413 (7.8) 120 (2.3) 6 (0.1) 35 (0.7) 11 (0.2) 32 (0.6) 38 (0.7)
2003 699 (12.8) 381 (7.0) 102 (1.9) 4 (0.1) 33 (0.6) 12 (0.2) 37 (0.7) 26 (0.5)
2004 818 (13.3) 472 (7.7) 127 (2.1) 12 (0.2) 43 (0.7) 12 (0.2) 36 (0.6) 34 (0.6)
2005 910 (14.7) 495 (7.9) 104 (1.7) 4 (0.1) 52 (0.9) 15 (0.2) 46 (0.7) 33 (0.5)
2006 1,055 (16.2) 588 (8.5) 117 (1.8) 22 (0.4) 77 (1.2) 19 (0.3) 58 (0.9) 28 (0.4)
Annual 544.9 (10.61) 267.6 (5.21) 63.2 (1.23) 6.1 (0.12) 33.2 (0.65) 7.0 (0.14) 31.4 (0.61) 32.1 (0.63)
average
Annual 0.49 0.36 0.09 0.01 0.04 0.01 — —
increasey (0.37–0.61) (0.29–0.42) (0.06–0.12) (0.01–0.02) (0.02–0.06) (0.01–0.02)
(95% CI)
Annual — — — — — — — —
decreasey
(95% CI)
p Value <0.0001 <0.0001 <0.0001 0.0150 0.0003 0.0016 NS NS
*Data on incidence per 100,000 inhabitants are provided in the text.
y
Referred to episodes per 1000 admissions.

continued next page

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Medicine
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Str. pneumoniae BSI, and 23% of all Salmonella species BSI.
The evolution of the percentage of BSI caused by these
microorganisms in HIV-infected patients during the study
period is shown in Figure 9.
DISCUSSION
The current study shows the increasing laboratory
workload that BSI generates in the microbiology laboratory
of a modern hospital. BSI caused by all major groups of
microorganisms are increasing, but the Gram-positive
pathogens have overcome other etiologic agents of BSI.
Our long period of observation shows the remarkable
escalation of some resistant pathogens and the rise and
subsequent relative fall of BSI in HIV-infected patients.
Laboratory Workload
The indications and methods for obtaining blood
cultures are well accepted now8; however, no evidence-
based data permit us to establish what is and what is not a
proper laboratory and hospital workload of blood culture
requests. The acceptable limits of blood cultures obtained per
1000 admissions or per 1000 days of hospital stay have to be
determined. During the study period, there was an increase
from 299 to 720 blood cultures/1000 admissions. Data
collected in 1998 in a broad European-based study involving
128 hospitals and 28 countries provided an overall figure of
242.4 blood cultures obtained per 1000 admission18.
Rates of positivity of blood cultures are an indirect
index of the rate of suspicion of BSI in a given institution.

TABLE 3. Continued
Salmonella Acinetobacter Haemophilus Campylobacter
typhi P. aeruginosa spp. spp. H. influenzae N. meningitidis Brucella spp. spp.
(per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000 (per 1000
Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions) Admissions)
6 (0.1) 26 (0.5) 4 (0.1) 6 (0.1) 4 (0.1) 13 (0.3) 8 (0.2) 1 (0.1)
5 (0.1) 22 (0.4) 9 (0.2) 8 (0.2) 4 (0.1) 25 (0.5) 3 (0.1) 8 (0.2)
14 (0.3) 24 (0.5) 33 (0.7) 10 (0.2) 6 (0.1) 14 (0.3) 7 (0.1) 3 (0.1)
5 (0.1) 21 (0.4) 20 (0.4) 19 (0.4) 15 (0.3) 17 (0.4) 2 (0.1) 2 (0.1)
4 (0.1) 26 (0.5) 16 (0.3) 17 (0.3) 15 (0.3) 3 (0.1) 6 (0.1) 2 (0.1)
4 (0.1) 58 (1.2) 15 (0.3) 15 (0.3) 11 (0.2) 5 (0.1) 2 (0.1) 2 (0.1)
4 (0.1) 42 (0.9) 12 (0.3) 13 (0.3) 12 (0.3) 4 (0.1) 1 (0.1) 4 (0.1)
4 (0.1) 35 (0.8) 12 (0.3) 18 (0.4) 17 (0.4) 4 (0.1) 8 (0.2) 5 (0.1)
6 (0.1) 41 (0.8) 12 (0.2) 19 (0.4) 18 (0.4) 9 (0.2) 3 (0.1) 4 (0.1)
4 (0.1) 24 (0.5) 22 (0.5) 7 (0.1) 7 (0.1) 5 (0.1) 4 (0.1) 1 (0.1)
1 (0.1) 52 (1.1) 6 (0.1) 16 (0.3) 15 (0.3) 12 (0.3) 9 (0.2) 7 (0.1)
4 (0.1) 46 (0.9) 10 (0.2) 18 (0.4) 18 (0.4) 10 (0.2) 8 (0.2) 3 (0.1)
1 (0.1) 40 (0.8) 9 (0.2) 15 (0.3) 15 (0.3) 16 (0.3) 3 (0.1) 1 (0.1)
6 (0.1) 30 (0.6) 11 (0.2) 17 (0.3) 15 (0.3) 7 (0.1) 1 (0.1) 1 (0.1)
3 (0.1) 38 (0.8) 13 (0.3) 16 (0.3) 13 (0.3) 6 (0.1) 6 (0.1) 0 (0.0)
1 (0.1) 53 (1.0) 10 (0.2) 8 (0.2) 6 (0.1) 8 (0.2) 3 (0.1) 6 (0.1)
2 (0.1) 57 (1.1) 4 (0.1) 11 (0.2) 9 (0.2) 9 (0.2) 0 (0.0) 5 (0.1)
2 (0.1) 53 (1.0) 4 (0.1) 4 (0.1) 2 (0.1) 13 (0.2) 0 (0.0) 4 (0.1)
2 (0.1) 70 (1.3) 9 (0.2) 12 (0.2) 10 (0.2) 4 (0.1) 4 (0.1) 0 (0.0)
2 (0.1) 59 (1.0) 6 (0.1) 17 (0.3) 16 (0.3) 6 (0.1) 4 (0.1) 3 (0.1)
2 (0.1) 70 (1.1) 11 (0.2) 18 (0.4) 18 (0.3) 8 (0.1) 0 (0.0) 1 (0.1)
2 (0.1) 70 (1.1) 11 (0.2) 21 (0.4) 21 (0.3) 5 (0.1) 1 (0.1) 4 (0.1)
3.8 (0.07) 43.5 (0.85) 11.8 (0.23) 13.9 (0.27) 12.1 (0.24) 9.2 (0.18) 3.8 (0.07) 3.1 (0.06)

— 0.05 — — — — — —
(0.02–0.07)

— — 0.02 — — 0.02 — —
(0.01–0.03) (0.01–0.03)

NS 0.0007 0.0066 NS NS 0.0014 NS NS

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Rodrı́guez-Créixems et al Medicine
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FIGURE 5. Evolution of BSI caused by ESBL-producing and ciprofloxacin-resistant (CIP-R) E. coli.

Data from European nations showed a rate of blood culture
positivity of 14% and 19% in ESGNI 1 and ESGNI 2 studies,
respectively18. The American Society for Microbiology
Cumitech establishes that if the proportion of positive
samples of the total obtained drops below 5% or rises above
15%, an investigation should be initiated into whether
physicians are ordering blood cultures appropriately.
Blood culture contamination represents an ongoing
source of frustration for clinicians and microbiologists
alike41. Blood contamination has been reported to occur in
0.5%–15% of all blood cultures drawn35,64, and target
rates for contamination are usually set at 2%–3%30,111. Our
data conclusively show the efficacy of a policy of continuous
education during a long-term period of study on the
contamination rate of blood cultures in a large institution.
Incidence
The incidence of BSI is traditionally reported as cases
per 1000 hospital admissions. The classic data from the
Boston City Hospital reported 7.4 episodes/1000 admissions
in 1935 and 12.1 episodes/1000 admissions in 195166. The
same institution had figures close to 30 episodes/1000
admissions during the 1970s65. Our data provide a figure of
24.3 episodes of significant BSI episodes/1000 admissions
during the 22 years of the current study, with a significant
increase from 16 episodes in 1985 to 31.2 episodes in 2006.
A similar trend has been reported in Europe and the United
States110. The change in policies for admission to hospitals
and health care institutions during the last 2 decades,
however, may be a source of bias when reporting BSI
episodes on a 1000 admissions-denominator basis.
Incidence of bacteremia is rarely provided in population-
based studies102,110. Our data show an overall incidence of
nosocomial and community-acquired BSI that ranged from
130 episodes/100,000 inhabitants in 1985 to 270 episodes/
100,000 inhabitants in 2006. Data from the United States,
Canada, and Europe report figures ranging from 104 to
109 cases/100,000 inhabitants with increases in recent

FIGURE 6. Evolution of the episodes of H. influenzae BSI in adult and pediatric patients.

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Medicine
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TABLE 4. Evolution of Episodes of BSI Caused by Anaerobic Microorganisms During a 22-Year Period*
Anaerobes Gram-Negative Fusobacterium Bacteroides spp. Gram-Positive Clostridium
(per 1000 Rods (per 1000 spp. (per 1000 (per 1000 Rods (per 1000 spp. (per 1000
Year Admissions) Admissions) Admissions) Admissions) Admissions) Admissions)
1985 25 (0.5) 16 (0.3) 2 (0.1) 15 (0.3) 9 (0.2) 5 (0.1)
1986 41 (0.8) 30 (0.6) 3 (0.1) 27 (0.5) 10 (0.2) 6 (0.1)
1987 32 (0.6) 27 (0.5) 5 (0.1) 22 (0.4) 5 (0.1) 3 (0.1)
1988 35 (0.7) 31 (0.6) 5 (0.1) 28 (0.6) 3 (0.1) 2 (0.1)
1989 54 (1.1) 42 (0.9) 3 (0.1) 39 (0.8) 11 (0.2) 7 (0.1)
1990 36 (0.8) 26 (0.6) 2 (0.1) 25 (0.5) 7 (0.2) 4 (0.1)
1991 49 (1.1) 34 (0.7) 2 (0.1) 31 (0.7) 14 (0.3) 8 (0.2)
1992 48 (1.1) 33 (0.7) 1 (0.1) 31 (0.7) 16 (0.4) 8 (0.2)
1993 31 (0.6) 27 (0.6) 2 (0.1) 24 (0.5) 5 (0.1) 2 (0.1)
1994 36 (0.7) 28 (0.6) 4 (0.1) 24 (0.5) 8 (0.2) 3 (0.1)
1995 52 (1.1) 33 (0.7) 2 (0.1) 27 (0.6) 12 (0.3) 4 (0.1)
1996 45 (0.9) 31 (0.6) 6 (0.1) 24 (0.5) 14 (0.3) 6 (0.1)
1997 52 (1.0) 33 (0.6) 1 (0.1) 27 (0.5) 16 (0.3) 11 (0.2)
1998 46 (0.9) 33 (0.7) 5 (0.1) 25 (0.5) 13 (0.3) 12 (0.2)
1999 41 (0.8) 31 (0.6) 2 (0.1) 26 (0.5) 16 (0.3) 15 (0.3)
2000 53 (1.0) 34 (0.7) 3 (0.1) 26 (0.5) 16 (0.3) 11 (0.2)
2001 66 (1.3) 51 (1.0) 12 (0.2) 36 (0.7) 13 (0.2) 12 (0.2)
2002 62 (1.2) 40 (0.8) 11 (0.2) 24 (0.5) 19 (0.4) 14 (0.3)
2003 63 (1.2) 31 (0.6) 4 (0.1) 25 (0.5) 27 (0.5) 19 (0.3)
2004 84 (1.4) 52 (0.8) 14 (0.2) 33 (0.5) 28 (0.5) 18 (0.3)
2005 92 (1.5) 58 (0.9) 10 (0.2) 41 (0.6) 23 (0.4) 19 (0.3)
2006 87 (1.3) 53 (0.8) 8 (0.1) 37 (0.6) 27 (0.4) 22 (0.3)
Annual average 51.4 (1.00) 35.2 (0.69) 4.9 (0.09) 28.1 (0.55) 14.8 (0.28) 9.6 (0.19)
Annual increasey 0.03 — — — 0.02 0.01
(95% CI) (0.01–0.06) (0.01–0.03) (0.01–0.02)
Annual decrease y — — — — — —
(95% CI)
p Value 0.0019 NS NS NS 0.0100 0.0074
*Data on incidence per 100,000 inhabitants are provided in the text.
y
Referred to episodes per 1000 admissions.

years and important differences according to age and sex
of the population56,62,102,110.
The increases in the incidence of sepsis and BSI are
not easily explained by a single factor. Related factors
include the aging of the population, the more extensive use
of invasive procedures, the increase in the immunosup-
pressed population, the epidemic of HIV infection, and the
increase in antimicrobial resistance. The new, automatic
blood-culturing machines, with agitation and continuous
monitoring, have been associated with a better yield of
positive results80, and may also be contributing to the
increased number of BSI cases in recent years.
Etiologic Change and Change in Susceptibility
A switch in the etiology of BSI, with an increase
in the proportion of episodes caused by Gram-positive
microorganisms, has been reported in several publications, but
reports have mainly focused on selected groups of popula-
tion3,42,65,83,95,118,121. Data regarding the change in etiology
during a long period of time in an unselected general hospital
population are scarce34a. Our data demonstrate that this
increasing trend affects all groups of Gram-positive micro-
organisms during a long period of time in an unselected general
hospital population. This is probably a consequence of the
massive use of intravascular catheters and other devices, other
invasive procedures, and, in specific populations, the use of
fluoroquinolones prophylaxis, and high-dose chemotherapy-
induced mucositis29,37,47,49,53,54,58,72,75,77,89,93,96,109.
The most remarkable and significant problem in the
evolution of resistance of Gram-positive bacteria is the
emergence of MRSA. The current series may be represen-
tative of this worldwide phenomenon, and shows a
progressive increase in the incidence of BSI caused by
MRSA in the population receiving care at a general hospital.
Proportions of 20%–55% of all Staph. aureus isolates in
Europe and in the United States are now MRSA4,12,18,79.
BSI caused by Enterococcus species is also a cause of
concern, but it is difficult to find trends in figures of

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Rodrı́guez-Créixems et al Medicine
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TABLE 5. Evolution of Episodes of BSI Caused by Fungi During a 22-Year Period*

Fungi Candida spp. C. albicans C. parapsilosis Candida non CA C. neoformans
(per 1000 (per 1000 (per 1000 (per 1000 not CP (per 1000 (per 1000
Year Admissions) Admissions) Admissions) Admissions) Admissions) Admissions)
1985 10 (0.2) 10 (0.2) 8 (0.2) 0 (0.0) 2 (0.1) 0 (0.0)
1986 17 (0.3) 17 (0.3) 14 (0.3) 0 (0.0) 3 (0.1) 0 (0.0)
1987 15 (0.3) 14 (0.3) 11 (0.2) 0 (0.0) 3 (0.1) 0 (0.0)
1988 17 (0.4) 16 (0.3) 6 (0.1) 5 (0.1) 5 (0.1) 0 (0.0)
1989 13 (0.3) 13 (0.3) 10 (0.2) 2 (0.1) 1 (0.1) 0 (0.0)
1990 37 (0.8) 35 (0.8) 18 (0.4) 6 (0.1) 11 (0.2) 2 (0.1)
1991 20 (0.4) 19 (0.4) 14 (0.3) 3 (0.1) 2 (0.1) 0 (0.0)
1992 17 (0.4) 15 (0.3) 7 (0.2) 3 (0.1) 5 (0.1) 0 (0.0)
1993 42 (0.9) 32 (0.7) 19 (0.4) 11 (0.2) 2 (0.1) 7 (0.1)
1994 34 (0.7) 29 (0.6) 11 (0.2) 8 (0.2) 10 (0.2) 2 (0.1)
1995 41 (0.9) 31 (0.6) 17 (0.4) 9 (0.2) 5 (0.1) 9 (0.2)
1996 48 (1.0) 42 (0.8) 12 (0.2) 17 (0.3) 13 (0.3) 4 (0.1)
1997 38 (0.7) 34 (0.7) 9 (0.2) 12 (0.2) 14 (0.3) 2 (0.1)
1998 47 (0.9) 43 (0.9) 20 (0.4) 9 (0.2) 14 (0.3) 1 (0.1)
1999 52 (1.1) 46 (0.9) 21 (0.4) 13 (0.3) 12 (0.2) 4 (0.1)
2000 35 (0.7) 31 (0.6) 13 (0.3) 9 (0.2) 10 (0.2) 2 (0.1)
2001 45 (0.9) 40 (0.8) 16 (0.3) 19 (0.4) 7 (0.1) 1 (0.1)
2002 61 (1.2) 57 (1.1) 24 (0.5) 27 (0.5) 7 (0.1) 1 (0.1)
2003 53 (1.0) 45 (0.8) 21 (0.4) 20 (0.4) 7 (0.1) 1 (0.1)
2004 50 (0.8) 47 (0.8) 20 (0.3) 17 (0.3) 13 (0.2) 0 (0.0)
2005 49 (0.8) 47 (0.8) 24 (0.4) 20 (0.3) 3 (0.1) 1 (0.1)
2006 93 (1.5) 87 (1.4) 33 (0.5) 35 (0.6) 19 (0.3) 0 (0.0)
Annual average 37.9 (0.74) 34.1 (0.66) 15.8 (0.31) 11.1 (0.22) 7.6 (0.15) 1.7 (0.03)
Annual increasey 0.04 0.03 0.02 0.02 — —
(95% CI) (0.01–0.06) (0.01–0.06) (0.01–0.03) (0.01–0.04)
Annual decreasey — — — — — —
(95% CI)
p Value 0.0092 0.0087 0.0136 0.0024 NS NS
Abbreviations: CA = Candida albicans, CP = Candida parapsilosis.
*Data on incidence per 100,000 inhabitants are provided in the text.
y
Referred to episodes per 1000 admissions.

enterococcal BSI in recent years24,117. Our data show that rates
of enterococcal BSI, both per 1000 admissions and population
based, are clearly increasing. It is particularly troubling to note
the presence of strains resistant to vancomycin2,23 and amino-
glycosides, and even ampicillin25,86.
The evolution of the incidence of invasive pneumo-
coccal disease in recent years is particularly important. The
introduction of a heptavalent conjugated pneumococcal
vaccine for children has been associated with a decrease in
the incidence of invasive pneumococcal disease caused by
the serotypes included in the vaccine in several reports5,116.
However, the overall impact of this vaccine on invasive
pneumococcal disease caused by serotypes both included and
not included in the vaccine is still under discussion9,26,40,67.
The conjugated vaccine could not only have an effect in
vaccinated children, but could also have a herd effect in
unvaccinated children and adults40. The vaccine could,
however, increase the rate of invasive pneumococcal disease
caused by strains of Str. pneumoniae not included in the
vaccine22,38,104,105. The conjugated pneumococcal vaccine
was introduced on the market in our area of Spain in 2001 on
a voluntary basis, paid for by parents. The cost of
vaccination was fully supported by the Community of
Madrid only beginning in November 2006. Unfortunately,
the rates of conjugated pneumococcal vaccination use in our
area are not available to us. Despite the voluntary use of the
conjugated vaccine, our data suggest that from 2001 to 2006
there was no reduction of pneumococcal BSI in our
institution, in children or in adults. Reports from other areas
of Spain show only a nonsignificant or slightly significant
reduction in the incidence of invasive pneumococcal
disease9,26.
Information regarding the evolution of aerobic and
facultative Gram-negative BSI is either partial or lacking in
recent years63,81. The available studies usually are biased by
a previous selection of patients46,48,103,115. Some references

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Medicine
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FIGURE 7. Evolution of the episodes of candidemia caused by different Candida species.

report a decrease in the proportion of BSI caused by Gram-
negative bacteria (compared with other microorganisms),
which may mislead readers by suggesting a purported
decrease of the overall incidence of this problem. The
current study shows the progressive increase in the incidence
of Gram-negative BSI over the last 22 years, without a
selection of patients.
One of the main causes of concern regarding Gram-
negative BSI is the emergence and dissemination of Enter-
obacteriaceae producing ESBL, due to a higher chance of
inadequate empirical antimicrobial therapy and a consequent
higher mortality61,107. The current study shows the evolution
of BSI caused by E. coli-producing ESBL in our institution.
The problem represented <1% of the E. coli BSI episodes
from 1994 to 2001 and progressively increased since then,
reaching a troubling proportion of 9% of the E. coli BSI
in 2006, higher than the 6.7% reported in the SENTRY
study94.
Data on the incidence of P. aeruginosa BSI in large
teaching hospitals are scarce. Wisplinghoff et al117 report an
incidence of 0.21 episodes/1000 admissions in United States
hospitals. In our institution, we had an overall incidence
of 0.85/1000 admissions. This figure evolved from 0.4 to
1.3/1000 admissions in the more recent years.
After multiple reports34,57,71a,76,98,99,113 showing the
decrease of anaerobic BSI during the 1970s and 1980s, recent
reports from the Mayo Clinic and other centers27,42,50,55,90 show
that anaerobic bacteremia has re-emerged as a significant
clinical problem, and we probably are back where we started43.
Anaerobic bacteria were present in 3.3% of positive blood
cultures in a Belgium center13, with an overall incidence of
clinically significant anaerobic bacteremia of 0.51 cases/1000
patient admissions. The incidence was significantly higher in
patients with active hematologic malignancies than in other
groups. Our data confirm a progressive increase of anaerobic
BSI. We continued routine blood cultures in anaerobiosis
throughout the current study, and anaerobic BSI never
decreased in our center during that long period of time.
Many researchers in the last 2 decades have tried to
assess the trends in the incidence of candidemia in different
settings. The studies, mainly from Europe and the United
States, have widely variable methodology and results, but
they can be biased by the selection of certain populations
(hematology, nonhematology, intensive care unit patients) or
by the evaluation of very short periods of time7,28,44,71.
Studies from different European countries and the United
States have shown incidence rates of candidemia ranging
from 0.17 to 0.76 and 0.28 to 0.96 per 1000 admissions,

FIGURE 8. Evolution of the number of episodes of BSI in HIV-infected patients and percentage of the overall episodes of BSI.

n 2008 Lippincott Williams & Wilkins 245

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Rodrı́guez-Créixems et al
FIGURE 9. Evolution of the percentage of BSI caused by Staph. aureus, Str. pneumoniae, Salmonella species, and P. aeruginosa.
respectively106. Our data show a clear increasing trend in
incidence, with an overall figure of 0.66 cases/1000
admissions that ranged from 0.2 episodes/1000 admissions
in 1985 to 1.4 episodes/1000 admissions in 2006. Our data
also nicely reflect the shift in the epidemiology of the species
causing candidemia, with a progressive increase in the non-
albicans species, mainly Candida parapsilosis and other
species as reported by other authors1,32,60,70,87,97.
BSI in HIV-Infected Patients
It is well known that the incidence of bacterial and
fungal BSI was dramatically high in patients infected with
HIV before the introduction of highly active antiretroviral
therapy (HAART) in general practice. Staphylococcus, Group
A Streptococcus, Str. pneumoniae, Listeria, Salmonella, P.
aeruginosa, Mycobacterium avium complex, and other micro-
organisms had a higher incidence in the HIV population, but
most of the reported data were collected from clinical
departments against a background of the HIV populations
served by specific hospital units10,11,15,19,20,68,73,74,92.
The introduction of HAART has been associated with
a significant fall in the occurrence of bacteremia, but only a
few series compare pre- and postHAART incidence of BSI in
HIV-infected patients. Most of them study only short periods
of time or particular microorganisms, and are not based on
the whole experience of the microbiologic data of a large
teaching hospital33,69. The scarce data available concur with
a clear reduction in incidence after the widespread use of
HAART10,11,15,19,20,73,74,92. The trends in the current series,
before and after the introduction of HAART, also show a
clear reduction in the proportion of all BSI episodes
occurring in patients with HIV.
In summary, in the current study, which is to our
knowledge the largest series of BSI collected to date by a
single institution, we highlight the continuous and progres-
sive increase in the workload related to BSI in modern
healthcare institutions and the important shifts in the
microorganisms causing BSI. The tremendous impact of
the HIV epidemic before and after the introduction of
HAART shows how adequate interventions aimed at the
246
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Medicine
Volume 87, Number 4, July 2008
underlying diseases of the population can affect the
incidence of secondary infections.
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