Download A Hospitalwide Intervention Program to Optimize the Quality of

MAJOR ARTICLE
A Hospitalwide Intervention Program
to Optimize the Quality of Antibiotic Use:
Impact on Prescribing Practice, Antibiotic
Consumption, Cost Savings, and Bacterial
Resistance
Carlos Bantar,1 Beatriz Sartori,2 Eduardo Vesco,3 Claudia Heft,2 Mariano Saúl,2 Francisco Salamone,4
and Marı́a Eugenia Oliva1
1
Committee for Prevention and Control of Nosocomial Infection and Departments of 2Pharmacy, 3Internal Medicine, and 4Microbiology,
Hospital San Martı́n, Paraná, Entre Rı́os, Argentina
Several findings from Argentina provide compelling evidence of the need for more rational use of antimicrobial
agents. Thus, a multidisciplinary antimicrobial treatment committee for the development of a hospital-wide
intervention program was formed to optimize the quality of antibiotic use in hospitals. Four successive steps
were developed during 6-month periods: baseline data collection, introduction of a prescription form, education, and prescribing control. Sustained reduction of drug consumption was shown during the study
(R 2 p 0.6885; P p .01). Total cost savings was US$913,236. To estimate the consumption of cefepime and
aminopenicillin-sulbactam in relation to that of the third-generation cephalosporins, 2 indices were calculated:
Icfp and Iams, respectively. Decreasing resistance to ceftriaxone by Proteus mirabilis and Enterobacter cloacae
proved to be associated with increasing Icfp. Decreasing rates of methicillin-resistant Staphylococcus aureus
were related to increasing Iams. The present study indicates that a systematic program performed by a
multidisciplinary team is a cost-effective strategy for optimizing antibiotic prescribing.
Appropriate antibiotic use is one of the main goals of
the medical community [1]. Overuse of antimicrobial
agents has been described worldwide in both community [2, 3] and hospital [4, 5] settings. In addition
to the effect on patients [6, 7], antibiotic misuse can
provoke the emergence of bacterial resistance [4, 8] and
increase health care costs [9]. It is evident that optimizing antibiotic use is a challenge that deserves to be
undertaken.
Received 17 December 2002; accepted 13 March 2003; electronically published
9 July 2003.
Reprints or correspondence: Dr. Carlos Bantar, Colón 128, (3100) Paraná, Entre
Rı́os, Argentina ([email protected]).
Clinical Infectious Diseases 2003; 37:180–6
2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3702-0004$15.00
180 • CID 2003:37 (15 July) • Bantar et al.
It has been observed that the infectious diseases physician plays a crucial role in controlling antibiotic use
in the hospital [10], as does a multidisciplinary team
approach, with the active involvement of clinical microbiologists and pharmacists [8, 9, 11–13]. Bantar et
al. [14] published alarming rates of bacterial resistance
in a surveillance study involving 27 Argentinean health
care centers, and Bantar and others have noted high
rates of nosocomial infection, surgical prophylaxis errors leading to unnecessary cost increases in the hospital
[15], and confirmation of misuse of antibiotics in the
same hospital [5]. These findings provide compelling
evidence of the need for more-rational use of antimicrobial agents in Argentina. To our knowledge, a systematic strategy for control of antibiotic use in our
country has not been published. Thus, we designed a
multidisciplinary antimicrobial treatment team for de-
veloping a hospital-wide intervention program to optimize antibiotic use in our hospital. Here, we report the impact of this
program on prescribing practice, antibiotic use, cost savings,
and bacterial resistance.
METHODS
Setting. The Hospital San Martı́n is a 250-bed public teaching
hospital for adult patients in Paraná, a city in Argentina of
∼350,000 inhabitants. It has a 10-bed intensive care unit (ICU)
and several surgical wards (including orthopedic, abdominal,
thoracic, gynecological, and neurological units) and lacks facilities for solid-organ or bone marrow transplantation and
cardiac surgery.
Program design. An antimicrobial treatment committee
(ATC), which comprised an infectious diseases physician
(M.E.O.), a clinical microbiologist with experience in pharmacokinetics and pharmacodynamics (C.B.), a laboratory microbiologist (F.S.), 2 pharmacists (B.S. and C.H.), an internal
medicine specialist (E.V.), and a computerized system analyst
(M.S.), was convened in 1999 to design a sequential intervention program to optimize antibiotic use within the hospital. By
early 1999 (before the study), specific computerized systems
for data recording and analysis were implemented in the departments of pharmacy, microbiology, and prevention and control of nosocomial infection. Thereafter, 4 successive intervention steps were developed during 6-month periods, as follows:
period 1 (the last 6 months of 1999; baseline), introduction of
an optional antibiotic order form and collection of baseline
data (i.e., data on bacterial resistance, antibiotic use, prescribing
practice, and nosocomial infection and crude mortality rates);
period 2 (the first 6 months of 2000; initial intervention period),
feedback activities, according to the baseline findings, and
transformation of the optional antibiotic order form into an
obligatory requirement for procuring the drug from the pharmacy; period 3 (the last 6 months of 2000; education phase),
like period 2, but with the addition of policy activity for every
antibiotic prescription (except for surgical prophylaxis, which
was already standardized) and bedside discussion among the
infectious diseases physicians, the clinical microbiologist, and
the attending physicians; and period 4 (the first 6 months of
2001; active control period), like period 3 but included modification of prescription, if necessary, by the ATC.
There were no restrictions on antibiotic-prescribing habits.
However, during the education phase, physicians were informed
about the increased risk for the selection of bacterial resistance
associated with the overuse of the third-generation cephalosporins and carbapenems, as well as the potential benefits of their
replacement (when appropriate) with aminopenicillin-sulbactam
or with the available fourth-generation cephalosporin, cefepime.
To evaluate the impact of the antimicrobial-control program, no
specific actions to control and prevent nosocomial infections
(beyond the standard precautions that were being undertaken
before starting the study) were introduced by the pertinent committee during the 24 months of the study.
Strategy and data collection. Use of antibiotics was recorded as total number of grams of the drug on a homemade
computerized system (SOUFARMA) [5] and then converted
into defined daily doses (DDDs) per 1000 patient-days, in accordance with the World Health Organization recommendation
[16]. Only the expenditure for drugs that are administered
intravenously was analyzed. Data regarding antibiotic use associated with surgical prophylaxis were excluded. To estimate
the rates of use of cefepime and aminopenicillin-sulbactam in
relation to that for the third-generation cephalosporins, 2 indices were calculated: Icfp and Iams. Icfp was calculated as
consumption of cefepime/consumption of ceftriaxone and ceftazidime ⫻ 100. Iams was calculated as consumption of aminopenicillin-sulbactam/consumption of ceftriaxone plus ceftazidime ⫻ 100. Consumption was measured in DDDs per 1000
patient-days.
Bacterial resistance rates were recorded and analyzed using
a homemade computerized system (SIR) described elsewhere
[14] that was developed by one of the authors (C.B.). The
antibiotic order form required the physician to state the certainty of infection diagnosis, as well as the most relevant epidemiological data. The infectious diseases physician filled out
a unique form with the same data as the antimicrobial order
form and additional data, such as any interruption or modification of treatment suggested by the ATC. Criteria used to
define the need for antimicrobial therapy were adopted from
the current edition of Principles and Practices of Infectious Diseases [17]. Therapy was considered appropriate if it was included in any of the primary or alternative regimens suggested
in The Sanford Guide to Antimicrobial Therapy [18]. Data were
finally recorded and analyzed using Epi Info software, version
6.0 (Centers for Disease Control and Prevention).
Density of nosocomial infection was estimated as described
elsewhere [15]. Data on the number of patient admissions and
discharges, number of patient-days, and crude mortality were
kindly supplied by S. Hayy from the Department of Statistics
(Hospital San Martı́n).
Bacterial resistance and antibiotic use. To evaluate the
impact of changes in antibiotic use on bacterial resistance, we
selected certain worrisome multidrug-resistant species detected
in the baseline period for analysis, such as third-generation
cephalosporin–resistant Escherichia coli, Enterobacter cloacae,
Klebsiella pneumoniae, and Proteus mirabilis; imipenem-resistant Pseudomonas aeruginosa; and methicillin-resistant Staphylococcus aureus (MRSA). In addition, 2 phenotypes were selected to assess the impact of the increase of Iams and Icfp
indices, aminopenicillin-sulbactam–resistant E. coli and cefeIntervention on Antibiotic Prescription • CID 2003:37 (15 July) • 181
pime-resistant P. aeruginosa. To date, vancomycin-resistant enterococci (VRE) has never been isolated in our hospital; thus,
this organism was not included in the analysis. Variations in
the resistance phenotype above, which were estimated as a 6month prevalence rate from each period, were compared with
those for every antibiotic showing any sustained trend over the
study period by linear regression analysis.
Statistical analysis. Rates were analyzed by comparison
of proportions with the x2 or Fisher’s exact tests using the Epi
Info statistical package. Trends over time and correlation among
variables were assessed by simple linear regression analysis, performed using Statistix software for Windows, version 2.0 (Analytical Software). P ⭐ .05 was regarded as statistically significant. All values are in US dollars.
RESULTS
Antibiotic use and cost savings. Variations in intravenous
antibiotic consumption during the different periods are shown
in table 1. The numbers of patient-days for periods 1, 2, 3, and
4 were 37,556, 38,086, 39,954, and 38,905, respectively. A sig-
nificant global decrease in the use of antibiotics was observed
between period 1 (baseline period) and period 2 (initial intervention period). Simple linear regression analysis showed that
this trend continued during the remaining periods (adjusted
R 2 p 0.6885; P p .01).
Linear regression analysis revealed a sustained increase in the
Icfp and Iams indices throughout the study (adjusted R 2 p
0.88 [P p .04] and 0.81 [P p .06], respectively). The evolution
of both indices along the 4 periods is shown in figure 1. Cost
savings from period 1 (baseline) to period 2, from period 2 to
period 3, and from period 3 to period 4 were $261,955, $57,245,
and $12,881, respectively. The cumulative total savings during
the 18 months of intervention was $913,236.
Prescribing practice. In all, 450 and 349 successive unique
antimicrobial order forms (corresponding to 1 patient each)
were analyzed during periods 1 and 4, respectively. Antibiotics
to be given orally were also included in this analysis. Because
the ATC members might modify a considerable number of
antimicrobial orders during period 4, prescription rates during
this period were divided between the prescribing intention and
definitive treatment (after correction by the ATC members).
Table 1. Variations in use of intravenous antibiotics after implementation of
successive intervention steps for optimizing the quality of antimicrobial prescription in the hospital.
Consumption, divided daily doses
a
per 1000 patient-days
Antibiotic
Period 1:
baseline
Period 2:
initial
intervention
Period 3:
education
phase
Period 4:
active
control
phase
P for
period 4
vs. period 1b
Amikacin
40.18
25.40c
26.22
32.04
NS
AMP-SUL
24.75
17.05
18.82
22.90
NS
Carbapenem
13.54
7.79
6.39
6.18
.03
3.86
3.31
8.96d
8.80
NS
Ceftazidime
29.46
21.67
24.60
30.50
NS
Ceftriaxone
62.85
35.63c
26.63
11.77
!.0001
Cefepime
Cefuroxime
9.48
4.83
4.77
2.88
Cephalothin
80.68
62.59
59.54
45.43
!.0001
Ciprofloxacin
16.02
14.11
12.75
17.54
NS
7.87
3.49
3.10
3.02
NS
Clindamycin
42.75
31.14
19.66
21.99
.003
Gentamicin
51.13
43.03
33.04
36.72
NS
Metronidazole
19.78
15.20
17.85
15.87
NS
Vancomycin
28.53
27.81
24.98
20.70
430.89
313.06c
287.31
276.35
Clarithromycin
Total
NOTE.
a
b
c
d
AMP-SUL, aminopenicillin-sulbactam; NS, not significant.
See the section “Program design” in Methods for detailed definitions.
Determined by x2 test.
Significant decrease was observed between period 1 and period 2 (P ! .05).
Significant increase was observed between period 2 and period 3 (P ! .05).
182 • CID 2003:37 (15 July) • Bantar et al.
.04
NS
!.0001
Figure 1. Variation of 2 antibiotics indices during a 4-period systematic
intervention program. Iams () and Icfp () represent the respective
ratios between the use (divided daily doses per 1000 patient-days) of
aminopenicillin-sulbactam or cefepime and third-generation cephalosporins (ceftriaxone and ceftazidime). See Methods for details.
Data are shown in table 2. An alarmingly high rate of carbapenem prescription (44%) was noted at baseline. In addition,
an appreciable use of ceftriaxone (17%) was observed. On the
other hand, cefepime and aminopenicillin-sulbactam were seldom ordered. After the education phase, a dramatic decrease
was observed in the prescribing intention of carbapenem and
ceftriaxone, as shown in period 4. On the other hand, prescription rates for cefepime and aminopenicillin-sulbactam and
the respective indices, Icfp and Iams, increased in this period.
All of these trends were reinforced by the active intervention
of the ATC members at the time of definitive treatment (table
2).
The characteristics of the control intervention by ATC members in the last period were also examined. A significant increase
was found in the rate of microbiologically based prescribing
intention in comparison with that of the baseline period (62.8%
vs. 27%, respectively; P ! .0001 ). In all, 87 (24.9%) of 349 prescriptions were modified, and 13 order forms (3.7%) were withdrawn by the ATC. Therapy was reduced, in terms of either
dose or duration, in 11.5% of cases. Furthermore, 86.1% of
the corrections involved less-expensive therapy, and 47% used
a drug with a narrower antimicrobial spectrum. Among the 87
order forms that were modified by the ATC, 5, 43, and 39
corresponded to mild, moderate, and severe infections, respectively. The presumed or documented sources of the infection corresponding to these orders were lower respiratory tract
(44.2%), abdomen (12.6%), catheter (12.6%), skin and soft
tissue (9.2%), urinary tract (8.0%), CNS (6.9%), bone (3.4%),
and other sources (3.1%).
Nosocomial infection, crude mortality rates, and hospital
and ICU stay. The nosocomial infection rates were 8.0, 8.5,
8.5, and 8.9 cases per 1000 patient-days for periods 1, 2, 3, and
4, respectively. The corresponding rates of crude mortality were
9.4, 7.3, 6.6, and 7.4 deaths per 1000 patient-days. The mean
lengths of hospital stay (SD) for infected patients decreased
significantly (P p .04 ) between period 1 and period 4, as follows: 47.4 40.4, 28.6 28.1, 25.9 24.6, and 25.5 23.3
days. The mean durations of total stay in the ICU (SD) were
261.7 52.8, 228.5 47.3, 233.2 43.1, and 218.8 40.5
days. Decreasing antibiotic use correlated with duration of both
hospital and ICU stay (R 2 p 0.99 [P p .004] and R 2 p 0.86
[P p .047], respectively), whereas a trend was observed for
crude mortality (R 2 p 0.82 [P p .06]).
Correlation between bacterial resistance and antibiotic
use. Data on bacterial resistance and antibiotic use are summarized in table 3. No correlation was found between variations
in antibiotic use and resistance to third-generation cephalosporins by E. coli or K. pneumoniae, whereas decreasing rates
of this kind of resistance for P. mirabilis and E. cloacae proved
to be associated with the increase in the Icfp index over time.
Likewise, decreasing rates of MRSA were related to an increasing Iams index, as well as to a sustained reduction in vancomycin use. No correlation was shown between bacterial resistance variations and the consumption of any one antibiotic
included in the formulas for the above indices. The frequency
of imipenem-resistant P. aeruginosa strains decreased to 0% in
the last period. This finding was strongly associated with a
reduction in carbapenem consumption over time. No changes
Table 2. Variation in the frequency of prescription of different
antibiotics during a systematic intervention program.
Frequency of prescription, %b
Period 1:
baseline
(n p 450)
a
Antibiotic
Period 4:
active control
(n p 349)
Prescribing
intention
Definitive
treatment
P for
period 1 vs.
definitive
treatmentc
Carbapenem
44
5d
2.3
!.0001
Ceftriaxone
17
9.4d
8
!.0001
Ceftazidime
8
8.4
6
NS
Cefepime
0.5
AMP-SUL
6
d
4.2
35.7d
7.3
!.0001
38
!.0001
Iams
24
190d
271
!.0001
Icfp
2
22d
52
!.0001
NOTE.
AMP-SUL, aminopenicillin-sulbactam; NS, not specific.
a
Icfp was calculated as frequency of prescription of cefepime/ceftriaxone
and ceftazidime ⫻ 100. Iams was calculated as frequency of prescription of
AMP-SUL/ceftriaxone plus ceftazidime ⫻ 100.
b
See the section “Program design” in Methods for detailed definitions of
periods.
c
Determined by x2 test.
d
P ⭐ .05 vs. baseline.
Intervention on Antibiotic Prescription • CID 2003:37 (15 July) • 183
Table 3. Variation of bacterial resistance rates after the implementation of successive intervention steps for optimizing the
quality of antimicrobial prescription and association with antibiotic use over time.
Resistance rate, % (total no. of strains)
Organism/phenotypic resistance
Escherichia coli/third-generation
cephalosporins
Period 1:
baseline
8 (204)
Period 2:
initial
intervention
7 (195)
Period 3:
education
phase
12 (128)
a
Period 4:
active
control
8 (131)
Associated antibiotic or index
(type of variation, adjusted R 2)b
P
None
—
E. coli/AMP-SUL
22 (204)
18 (195)
19 (128)
18 (131)
None
—
Klebsiellaspecies/third-generation
cephalosporins
45 (64)
63 (32)
21 (43)c
42 (50)
None
—
Proteus mirabilis/third-generation
cephalosporins
40 (47)
45 (49)
30 (46)
27 (41)
Icfp (increase, 0.85)
.05
Enterobacter cloacae/third-generation
cephalosporins
50 (16)
50 (6)
29 (17)
10 (10)
Iams (increase, 0.92)
Icfp (increase, 0.91)
.03
.03
Pseudomonas aeruginosa/imipenem
19 (88)
8 (62)
3 (100)
0 (56)
Carbapenem (decrease, 0.93)
.02
8 (88)
0 (62)
3 (100)
7 (56)
None
47 (165)
50 (150)
40 (199)
30 (101)
P. aeruginosa/cefepime
Staphylococcus aureus/methicillin
NOTE.
Iams (increase, 0.89)
Vancomycin (decrease, 0.94)
.04
.02
AMP-SUL, aminopenicillin-sulbactam.
a
See the section “Program design” in Methods for detailed definitions of periods.
b
Linear regression analysis between resistance rate evolution and antibiotic consumption throughout the study (table 1). Icfp was calculated as
consumption of cefepime/consumption of ceftriaxone and ceftazidime ⫻ 100 . Iams was calculated as consumption of AMP-SUL/consumption of ceftriaxone plus ceftazidime ⫻ 100. Consumption was measured in defined daily doses per 1000 patient-days.
c
P ! .05 for period 3 vs. period 2.
were observed in the resistance rates to aminopenicillin-sulbactam and cefepime by E. coli and P. aeruginosa, respectively.
DISCUSSION
Several strategies for regulating antimicrobial prescribing practices have been proposed, such as formulary replacement or
restriction [19], introduction of order forms [20], health care
provider education, feedback activities [21], and required approval from an infectious diseases physician for drug prescription [22]. Although most of these interventions have been assessed separately, data from prospective studies evaluating the
impact of the different strategies applied systematically over
time in the same hospital setting remain scarce. In addition,
results of a coordinated approach by a multidisciplinary team
composed of infectious diseases physicians, microbiologists,
and pharmacists have rarely been reported [13]. We have shown
a significant reduction in antibiotic use when feedback activities
were performed and when we made the optional antibiotic
order form obligatory for getting the drug from pharmacy (i.e.,
period 2, the initial intervention period). Our findings are opposite to those of Gyssens et al. [20], who reported a 25%
increase in antibiotic use after this kind of intervention at a
948-bed university hospital in The Netherlands. This is not
surprising, because we noted a number of unjustified prescriptions during the baseline phase. A further decrease in drug
consumption was reached during the last 2 intervention periods
184 • CID 2003:37 (15 July) • Bantar et al.
(education and active control phases). This fact might be attributable to the combination of both kinds of interventions.
Because of the alarming prevalence of bacterial resistance
found in the baseline period, our education strategy emphasized
3 major issues: making an effort to document the infection
microbiologically before starting antimicrobial therapy, avoiding use of certain antibiotics known to be associated with emergence of bacterial resistance [23, 24], and increasing the use of
antimicrobials thought to reduce the frequency of multidrugresistant organisms [25]. Our results challenge the connection
between heavy or inappropriate antibiotic use and bacterial
resistance. One of the antibiotics we wanted to use instead of
third-generation cephalosporins (when appropriate) was aminopenicillin-sulbactam, a drug active against anaerobic organisms. Although several authors have suggested that use of antibiotics with antianaerobic activity is a strong predictor for
VRE acquisition, most studies referred to clindamycin [26] and
metronidazole [27], rather than aminopenicillin-sulbactam, or
found that use of third-generation cephalosporins and vancomycin was an additional VRE predictor [27, 28]. During our
study, use of clindamycin, ceftriaxone, and vancomycin decreased, whereas use of metronidazole remained stable. However, because we did not detect VRE during any part of the
study period, we cannot assert that this situation had an impact
on selection of VRE.
We are unable to assert that the sole substitution of thirdgeneration cephalosporins by aminopenicillin-sulbactam or ce-
fepime results in cost containment. Nevertheless, an indirect
contribution to the cost savings by the association between this
switch and the sustained reduction of resistance rates over time
can be inferred. For instance, third-generation cephalosporin
resistance in P. mirabilis and E. cloacae was inversely associated
with the increase in the Icfp (also Iams for E. cloacae), whereas
no correlation was observed with the single components of the
index formula. These findings differ from those of Friedrich et
al. [29], who found a correlation between use of single antibiotics and changes in the susceptibility patterns of some gramnegative aerobes by using data analysis comparable to that of
our study (i.e., simple linear regression).
To our knowledge, the present article is the first report to
evaluate a ratio representing the relative consumption between
⭓2 antibiotics against variations in resistance rates over time.
Thus, our results suggest that, for certain antibiotics, demonstration of the relationship between drug use and a specific
phenotype of resistance may require the assessment of a ratio
relating to the opposite trends in consumption of different
antimicrobial agents. In fact, neither the sole decreasing use of
ceftriaxone nor the sole increasing consumption of cefepime
or aminopenicillin-sulbactam proved to be related to any variation in resistance rates over time.
Of interest, rates of MRSA were inversely associated with
increasing Iams, but not with the single drugs included in this
index formula. This finding is in agreement with that of Landman et al. [22], who described a reduction in the number of
patients infected with MRSA after a dramatic increase in use
of ampicillin-sulbactam in parallel with a reduction in thirdgeneration cephalosporin use. We hypothesize that the known
in vivo and in vitro inhibitory effect of aminopenicillin-sulbactam over that of the cephalosporins against several MRSA
strains might be a suitable explanation for this phenomenon
[30, 31].
In summary, the results of the present study support the
notion that a systematic program executed by a multidisciplinary team is a cost-effective strategy for optimizing antibiotic
use in a hospital and has an evident impact on prescribing
practice, antibiotic use, cost savings, and bacterial resistance.
Furthermore, this impact may be noted even where there are
high rates of bacterial resistance and irrespective of any additional precautions for controlling nosocomial infection.
Acknowledgment
We deeply thank Mary Forrest for her valuable technical
assistance in revising the manuscript.
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