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ORIGINAL ARTICLE
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UDC 573.4021.484::615.33
Abstract
Apstrakt
Key words:
anti-bacterial agents; drug utilization; drug resistance,
bacterial; therapeutics; quality control.
Kljune rei:
antibiotici; lekovi, korienje; lekovi, rezistencija
bakterija; leenje; kvalitet, kontrola.
Correspondence to: Radmila M. Velikovi-Radovanovi, Clinical Centre Ni, Department of Clinical Pharmacology, Zorana inia
48, 18 000 Ni, Serbia. Phone +381 18 53 39 57. E-mail: farmakoterapija@yahoo.com
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Introduction
Antibiotics are the most frequently used medications in
hospitalized patients (1530% of all prescribed drugs). It has
been estimated that 3050% of hospitalized patients receive
antimicrobial agents, and that up to 50% of prescribed antimicrobial agents are not prescribed optimally 13. It has been
shown that inappropriate antibiotic use significantly contributes to increasing rates of resistant pathogens 4, 5. Bacteral resistance is now being recognized as a major factor determining morbidity, mortality and costs in the hospital. It has
been generally recognized that the prevalence of bacterial resistance among bacteria is an unavoidable consequence of
antibiotics use and that it correlates with the overall use of
antimicrobial drugs 2, 5. Several lines of evidence suggest that
there is a causal association between the use of antimicrobial
agents and the prevalence of drug resistance in microorganisms 68. Taking into account this escalation in bacterial resistance and the large body of evidence considering the
overuse of antibiotics a rational approach is a strict control of
antibiotic use. Factors that promote the emergence of resistance include frequent use of broad-spectrum antimicrobial
agents, prolonged use of antimicrobial agents, more frequent
use of invasive devices and procedures 9,10. However, there
are reasons for optimism, as studies in various centers show
rapid reversal of resistance 7, 8. The 1998 European Conference entitled The Microbial Threat emphasized the importance of collecting and comparing data of antibiotic use
and bacterial resistance from different countries 11, 12. Information about antibiotic utilization and sensitivity among inpatients in Serbia is scanty, and there are no available publications on the topic. The purpose of this study was to investigate the extent of antimicrobial usage and to evaluate the
bacterial resistance in the Clinical Center Ni, one of the
biggest hospitals in Serbia. This study generally used the
World Health Organization (WHO) Anatiomical Therapeutic
Chemical (ATC) Classification System and the volume unit
Defined Daily Doses (DDD) 13, 14.
Methods
In this survey antibiotic consumption and bacterial susceptibility were monitored in the period 2003-2007. The results were analyzed in the Clinical Center Ni, a 1460- bed,
3rd tertiary health care university hospital in Serbia, that
comprises departments covering all major specialties except
for infectious diseases, kidney transplantation, hematology,
oncology, surgery and tuberculosis. The study period extended from 2003 2007. In 2003 2005, the Clinical Center had 417 357, 452 993 bed-days per year.
As this study did not collect any data on individual patients and surveillance was a part of quality assurance, an
approval by Ethical Committee was not considered necessary.
Utilization of antibiotics in Clinical Center Ni in the
period followed was obtained from the computerized database of the Department of Pharmacotherapy and expressed as
DDD per 100 bed/days (DBD). Defined Daily Doses of anti-
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DBD (%)
2005
3.60
(6.87)
4.21
(8.04)
2.40
(4.58)
4.68
(10.84)
2.21
(4.22)
2.80
(5.35)
1.65
(3.15)
2.26
(4.32)
4.79
(9.14)
3.82
(7.29)
18.96
(36.90)
51.38
(100)
2003
8.18 (13.14)
7.42 (11.92)
5.94
(9.55)
2.12
(3.41)
5.47
(8.79)
5.09
(8.18)
4.94
(7.94)
4.26
(6.85)
3.69
(5.93)
0.96
(1.54)
14.16 (22.75)
62.23
(100)
Ceftriaxone
Gentamicin
Bipenicillins
Ciprofloxacin
Amikacin
Coamoxiclav
Cefotaxime
Cotrimoxazole
Ampicillin
Cefuroxime
Other
Total
2007
6.09
3.33
1.63
5.30
2.20
1.19
1.28
1.87
1.57
5.97
13.76
47.92*
(12.7)
(6.95)
(3.40)
(11.06)
(4.59)
(2.48)
(2.67)
(3.96)
(3.28)
(12.40)
(28.71)
(100)
*Consumption of antibiotics had a significant decrease from 2003 to 2007 (p < 0.01)
DBD defined daily doses per 100 bed-days
The most frequently used antibiotics were cephalosporins, followed by penicillins, aminoglycosides and quinolones.
In 2003, ceftriaxone was the most frequently prescribed antibiotic and made up a quarter of the use (Figure 1).
ence of the reduction of E. coli resistance to amoxicillin+clavulanic on their utilization in Clinical Center Ni is
shown in Figure 2. A significant correlation was found
(r = 0.924; p < 0.05).
2003
DBD
2005
2007
n*
ac
i
am
ik
n*
ic
i
ge
nt
am
ci
p
ro
flo
xa
ci
n
ci
lin
am
pi
co
am
ox
ic
l
av
ns
ill
i
ic
pe
n
bi
ta
xi
m
e
fo
ce
ce
ft r
ia
xo
ne
9
8
7
6
5
4
3
2
1
0
*Hospital aminoglycosides consumption was significantly reduced from 2003 to 2007 (p < 0.001).
Fig. 1 Trends in antibiotic consumption in defined daily doses per 100 bed-days (DBD)
in the Clinical Center Ni from 2003 to 2007
Escherichia coli was a most frequently isolated bacteria (15.7119.19%), followed by Staphylococcus aureus,
Staphylococcus epidermidis, Pseudomonas aeruginosa and
During the same period, there was a substantial decrease in the use of ceftriaxone, while the resistance for all
isolates was reduced from 58.2% to 48.86%.
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Table 2
Types and frequency of appearance of bacterial strains in the Clinical Center Ni
from 2005 to 2007
Number of bacterial strains (%)
2003
2005
2007
490 (15.71)
500 (18.70)
678 (19.19)
450 (14.42)
370 (13.85)
264
(7.47)
410 (13.14)
236
(8.84)
241
(6.82)
290
(9.29)
142
(5.32)
342
(9.68)
210
(6.73)
154
(5.77)
177
(5.01)
200
(6.41)
198
(7.41)
304
(8.80)
160
(5.13)
118
(4.42)
201
(7.11)
215
(6.78)
146
(5.46)
142
(4.08)
132
(4.23)
132
(4.94)
138
(3.91)
120
(3.85)
83
(3.11)
106
(3.74)
443 (14.19)
592 (22.16)
941 (26.62)
3120
(100)
2671
(100)
3534
(100)
Bacterials strains
Echerichia coli
Staphylococcus aureus
Staphylococcus epid.
Enterococcus
Proteus mirabilis
Pseudomonas aeuriginosa
Klepsiella
Eneterobacter
Citrobacter
Acinetobacter
Other
Total
Table 3
Resistance of bacterial strains isolated in inpatients in the Clinical Center Ni in 2003 and 2007
Antibiotics
Ampicillin
Amoxicillin+ clavulanic acid
Cefuroxime
Cefotaxime
Ceftriaxone
Imipenem
Meropenem
Gentamicin
Amikacin
Ciprofloxacin
Number of isolates
E.coli
2003
2007
73.08
57.61
Klebsiella sp.
2003
2007
Acinetobacter sp.
2003
2007
P. mirabilis
2003
2007
77.27
51.47
52.16
24.40
80.00
73.47
83.33
81.18
79.22
78.86
42.74
28.57
27.50
26.46
29.14
2.50
3.70
30.34
40.20
15.63
490
23.88
22.42
46.08
1.92
3.7
20.10
19.74
28.33
678
66.67
0
0
71.13
58.94
40.00
160
69.74
77.62
75.59
6.98
1.66
57.14
39.56
69.74
201
80.00
85.46
8.97
15.72
75.97
54.32
44.20
200
76.19
91.50
9.77
11.37
53.49
43.19
58.64
304
73.20
68.21
61.21
8.57
0
70.23
53.10
40.52
215
64.93
69.57
62.71
2.7
50.64
28.7
52.94
142
85.71
87.84
3.95
4.41
83.12
78.38
75.32
120
90.48
92.80
12.71
13.22
80.30
70.42
77.48
106
38.67
18.99
31.34
12.50
0
35.04
17.60
11.01
210
27.56
24.19
26.32
10.53
5.26
27.68
14.46
30.09
177
development of E. coli resistance to ciprofloxacin on their utilization in the Clinical center Ni is shown in Figure 3. A significant correlation was found (r = 0.827, p = 0,025).
VOJNOSANITETSKI PREGLED
S. aureus resistant to vancomycin and the vancomycinresistant enterococcus were not detected.
Discussion
Utilization of antibiotics in Serbia is among the highest
in Europe, mostly due to overuse of cephalosporines and
aminoglycosides. The European Surveillance of Antibiotic
Consumption (ESAC) found large differences in antibiotic
use in inpatients. Utilization of antibiotics in the world varied
greatly, from the extremely high in Croatia and Greece, next
rate in France and to the lowest one was in the Netherland. In
this study we found high antibiotic utilization and high resistance rates in our hospital compared with other countries 1, 11, 12, 18. A survey carried out at three university hospitals, in another country, showed lower total antibiotic consumption to that found at our hospital l6, 19. Unfortunately, no
resistance data were included in these studies.
We found high rate of resistance among the most commonly used antibiotics (aminoglycosides, cephalosporines,
fluoroquinolones) 20. Here it was found that resistance of P.
aeruginosa to gentamicin, was changed from 75.9% of resistant strains in 2005, to 53.5% in 2007. This means that for
P. aeruginosa infections change led to improved sensitivity,
though it is clear that gentamicin cannot be used for this kind
of infection 1, 17. Goryachkina et al. 11 showed the decreased
resistance level for gentamicin (80% to 40%) in Russia from
20032005.
At the same time, we showed a decreased resistance
level for amoxicillin+clavulanic acid (61.58 to 46.36%; same
strains were tested). This provides an overall impression on
coincidence of resistance and antibiotic overuse. The resistance of E. coli was decreased significantly from 52.16% of
resistant strains in 2005, to 24.40% in 2007.
At the beginning of this study, utilization of ciprofloxacin
was low in our hospital (2.12 DBD). The resistance of E.coli
in inpatients was at a level of 15.5%. In the study period ciprofloxacin utilization increased significantly (p < 0.001). Bacte-
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