Pharmacoepidemiology and Drug Safety
Original report
Antimicrobial use at a university hospital: appropriate or misused?
A qualitative study
Vera Vlahović-Palčevski, MD, PhD1; Igor Francetić, MD, PhD2; Goran Palčevski,
MD, PhD3; Srđan Novak, MD, PhD4; Maja Abram, MD, PhD5 Ulf Bergman, MD,
PhD6
1
Department for Clinical Pharmacology, University Hospital Center Rijeka, University
of Rijeka Medical School, Rijeka, Croatia
2
Unit for Clinical Pharmacology, Department of Medicine, University Hospital Center
Rebro, Zagreb, University of Zagreb Medical School, Croatia
3
Pediatric Clinic, University Hospital Center Rijeka, Croatia
4
Department of Medicine, University Hospital Center Rijeka, University of Rijeka
Medical School, Croatia
5
Department for Clinical Microbiology, University Hospital Center Rijeka, University
of Rijeka Medical School, Croatia
6
Division of Clinical Pharmacology, Department of Laboratory Medicine, WHO
Collaboration Centre for Drug Utilisation Research and Clinical Pharmacological
Services, Karolinska Institute, Karolinska University Hospital- Huddinge, Stockholm,
Sweden
Acknowledgments: This work was supported by a grant from the Ministry of Science
and Technology, Croatia (Grant No 0069062). We acknowledge the Swedish Institute
for a scholarship and Pharmacia Corp. for an unrestricted grant to Vera VlahovićPalčevski. We also thank Paolo Bajčić, MD, for his assistance in data collection.
Corresponding author:
Vera Vlahović-Palčevski, MD, PhD
Department of Clinical Pharmacology
University Hospital Center Rijeka
Krešimirova 42
51000 Rijeka
Croatia
Email: vvlahovic@inet.hr
Telephone: +385 51 658 805
Fax: + 385 51 658 826
Short title: The quality of antimicrobial use in hospital
Key words: antimicrobial use, quality, hospital, Kunin’s quality criteria
Abstract
Objective: To evaluate the quality of antimicrobial drug use at the Department of
Medicine with 270 patient beds at the University Hospital Rijeka, Croatia.
Methods: The appropriateness of antimicrobial treatment was assessed in a prospective,
longitudinal survey, during a 21-week period using modified Kunin’s criteria. Criteria
were categorized as follows:
I. Agree with the use of antimicrobial therapy, the protocol is appropriate; II. Agree
with the use of antimicrobial therapy, the protocol is probably appropriate; III. Agree
with the use of antimicrobial therapy, but a different antimicrobial is preferred;
IV. Agree with the use of antimicrobial therapy but a different mode of use is preferred;
and V. Disagree with the use of antimicrobial therapy, administration is unjustified.
Categories I. and II. indicate “appropriate therapy”, categories III. and IV. indicate
some major deficiency in the choice or use of antimicrobials.
Results: During the study period 438 patients were treated with antimicrobials at the
Department of Medicine. Of these, 159 (36%) had received antimicrobials
appropriately (category I and II), 180 (41%) needed antimicrobials (category III and
IV) but they should have been prescribed differently. The main reason for inapproprite
antimicrobial treatment was the wrong choice of animicrobials (broad-spectrum where
a narrow spectrum would suffice). Ninty-nine patients (23%) did not need
antimicrobials at all (category V).
Conclusion: The main reason for suboptimal use of antimicrobials was overprescribing of broad-spectrum antimicrobials, and its reduction should be a major goal
of the stewardship program in the Department of medicine in our institution.
Key points:

Appropriate antimicrobial drug use is the one that maximizes therapeutic impact
while minimizing toxicity and development of resistance. It means prescribing
an antimicrobial only when it is beneficial to the patient, targeting therapy to the
likely or defined pathogen and using adequete drug, in optimal dose, duration
and intervals.


Before prescribing an antimicrobial a physician should answer these questions:
-
Is antimicrobial treatment really necessary?
-
Which antimicrobial is the most suitable for the patient?
-
How to use it (route, dose, interval and duration)?
Kunin’s criteria for the evaluation of the appropriateness of antimicrobial
treatment represent a simple quality assessment method that covers almost all
aspects of antimicrobial therapy.

Hospital antimicrobial stewardship program should be based on local qualitative
assessment of antimicrobial drug use including data on resistance patterns.
Introduction
Many surveys during the past decades have demonstrated that more than half of
antimicrobial use in hospitals is inappropriate (1-7). The major issue in promoting
rational antimicrobial use is the growing concern about antimicrobial resistance and
patient safety. Appropriate antimicrobial drug use is defined as the use that maximizes
therapeutic impact while minimizing toxicity and development of resistance. It means
prescribing an antimicrobial only when it is beneficial to the patient, targeting therapy
to the desired pathogen, and using the appropriate drug, in optimal dose and duration.
We have previously reported on the results of a survey assessing the necessity of
antimicrobial drug prescribing at the Department of Medicine at the University Hospital
Rijeka by using a point scoring system as a key quality indicator (5). We found that as
much as one third of all antimicrobials were prescribed to patients without clear
indications. As a sequele to that we now report on the quality of antimicrobial drug
prescribing by assesing the appropriateness of its use in the same study population.
Methods
Setting
The University Hospital Centre Rijeka is an 1191-patient-bed teaching hospital in
Croatia comprised of departments covering all major specialities. The Department of
Medicine
had
279
hospital-beds
with
wards
representing
endocrinology,
gastroenterology, hematology, clinical immunology, cardiology and coronary care unit,
nephrology and pulmonology (5).
Study design
We prospectively examined the appropriateness of antimicrobial treatment of adult inpatients at the Department of Medicine, for whom new antimicrobials were prescribed
during a 21-week period, between January 17th and June 13th 2003.
The medical records of all hospitalized patients were reviewed daily during the survey
period. The diagnosis and relevant clinical data of each patient receiving an
antimicrobial were recorded into a patient-specific form. The substance prescribed, the
duration of treatment, the dosage, the route and interval of antimicrobial administration
were also recorded. Prophylactic use of antimicrobials was not evaluated. The data
were analysed by specialists in Internal Medicine, Clinical Pharmacology and Clinical
Microbiology (5).
The appropriateness of antimicrobial treatment was evaluated by using modified
Kunin’s criteria (6).
The following categories were used:
I. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration, and
dosage) is appropriate.
II. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration,
and dosage) is probably appropriate. Usually a microbiology report is missing to
classify the protocol in another category.
III. Agree with the use of antimicrobial therapy, but a different antimicrobial (less
expensive, less toxic, narrower spectrum, other combination) is preferred.
IV. Agree with the use of antimicrobial therapy but a modified dose, interval, duration
or route of administration is preferred.
V. Disagree with the use of antimicrobial therapy, administration is unjustified.
Categories I. and II. indicate “appropriate therapy”, categories III. and IV. indicate that
there was some major deficiency in the choice or use of antimicrobials (6). Category V.
indicates unnecessary antimicrobial use and corresponds to the score less than 3
according to the scoring system presented in our earlier study (5).
These Kunin´s categories are illustrated by clinical examples in Table 1.
The evaluation and categorization of antimicrobial treatment was carried out upon the
agreement between the authors. It was based on the microbiology reports, major
published guidelines and recommendations for antimicrobial drug use and the
knowledge on local resistance patterns (8-21). Local guidelines on antimicrobial drug
use did not exist except for the ruling of restricted release antimicrobial described in the
previous study (5).
Statistical evaluation of data was performed using Statistica 6.0. software. The
comparisons were made using appropriate statistical tests with the significance level at
0.05.
Ethical considerations
This survey is a part of quality control of drug utilization, and therefore does not
require the Hospital Ethics Committee approval.
Results
During the study period 438 patients were treated with antimicrobial agents at the
Department of Medicine. One hundred fifty-nine (36%) had received antimicrobials
appropriately (cat. I. and II), 180 (41%) needed antimicrobials, but prescribed
differently with regard to the choice, dosage, route, interval or duration of treatment
(cat. III. and IV.) and 99 (23%) did not need antimicrobials, but had received it (Table
2).
We have not found significant difference in the appropriateness of antimicrobial drug
use (expressed as categories I-V) between the wards. The median category in all wards
was III (Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test: H(6, N=438) =
8,125001 p=0,2291) (Table 2A).
The appropriateness of antimicrobial drug use according to diagnoses showed
significant difference, with sepsis being treated most appropriately (Table 2B)
(Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test: H (9, N=438) =39,61257
P<0,001).
A significant difference was found also in the appropriateness of use of selected
substances, with broad spectrum agents being used inappropriately more often than the
narrow spectrum (Table 2C.) ( Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test:
H (27, N=438) =57,76266 p=0,0005).
Discussion
Strategies to prevent and control emergence and spread of antibiotic-resistant pathogens
in hospitals are based mainly on effective infection control and prevention measures
and antimicrobial stewardship programs. It has been shown that despite these efforts,
nearly one third of antimicrobials prescribed for hospitalized patients are not necessary
(5,7).
In this study we have addressed the question of the quality (appropriateness) of
antimicrobial drug use for hospitalized patients.
We used modified Kunin’s criteria because the method is simple and covers almost all
aspects of antimicrobial therapy (8).
We tried to find out the proportion of patients receiving antimicrobials inappropriately,
and the most probable reason for it. The hypothesis was that if these drugs were not
used appropriately in some wards more often than in others, the most probable reason
would be local prescribing habits, policy or management. If certain illnesses were not
treated appropriately, the most probable reason would be lack of treatment guidelines,
and finally if a certain antimicrobial was misused more often than the others, in
addition to the lack of guidelines, possible reasons could be diagnostic uncertainty and
industry pressure. Each of these deviations should be approached differently!
Forty-one percent of the patients treated with antimicrobials should have received them
differently, but their distribution according to different wards was similar, meaning that
a single ward was not responsible for the antibiotic misuse. The main reason for
inappropriate antimicrobial treatment was the wrong choice of antimicrobials (Kunin’s
cat. III). One half of the patients were prescribed antimicrobials for respiratory tract
infections, of which 42% inappropriately (the wrong choice). Also, more than half of
the patients treated for abdominal and skin and soft tissue infections were not treated
correctly for the same reason. Improving adherence to major published guidelines for
antimicrobial treatment, or publishing local ones would be the most effective means to
reduce this type of misuse. In addition, a feedback program to prescribing clinicians, as
a part of quality circle has been accepted as a simple intervention on prescribing
behavior. The feedback summary may also include recommendations for clinical action
(22).
Aminoglycosides and vancomycin were given to more than 2/3 of the patients when
they should not have been used. As these are old drugs, and have narrow spectrum,
pharmaceutical pressure probably did not play a major role in their misuse. We assume
that it is due to diagnostic uncertainty, and prescribing by inexperienced physicians.
Therapeutic guidelines and educational efforts should be strongly encouraged to
improve this.
Mostly misused broad-spectrum agents were 3rd and 4th generation cephalosporins and
co-amoxiclav. Physicians often opt for broad-spectrum antibiotics because of
diagnostic uncertainty, but the role of pharmaceutical industry should not be neglected,
as these newer agents are costly.
Our findings suggest that the main reason for suboptimal use of antimicrobials was
over-reliance on broad-spectrum antimicrobials, and its reduction should be a major
goal of the stewardship program in our institution.
Appropriate antimicrobial stewardship that includes optimal selection, dose and
duration of treatment, as well as control of antimicrobial drug use, will prevent or slow
the emergence of resistance among microorganisms. In addition, optimizing
antimicrobial use may reduce pharmacy expenditures.
Further work is required to define the most efficient means to improve hospital
antimicrobial drug use.
Based on the results of this study, local guidelines for antimicrobial drug use will be
developed as well as measures to promote their implementation.
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Table 1. Examples of clinical scenarios in each category of appropriateness of
antimicrobial treatment
Antimicrobial therapy is:
- appropriate (Category I)
An 82-year old woman was admitted with fever 38,2ºC, chills, malaise and back pain,
which started three days before admission. The examination showed a systolic aortic murmur,
sedimentation rate 53 mm/hour and leukocytosis 11.000/mm3. Urine and blood cultures were
taken and antimicrobial treatment was started (benzylpenicillin 2 MIU every 4 hours plus
gentamycin 160mg once daily). Urine culture was negative. Blood culture confirmed the
suspected Streptococcus viridans endocarditis.
- probably appropriate (Category II).
A 69-year old woman with ischemic heart disease was admitted from home with signs
and symptoms of pneumonia, which was confirmed radiografically. Microbiology testing was
not performed. The presumed pathogen was Haemophilus influenzae. She was treated with
cefuroxime, 750 mg every 8 hours intravenously for six days. As the symptoms subsided, the
regimen was switched to oral, 500 mg every 12 hours for another 7 days.
Comment: Microbiology testing was not performed to confirm diagnose. Clinical improvement
speaks in favor of correct empiric treatment.
- agree with the use ofantimicrobial, but a different agent is suggested/preferred
(Category III).
A 35-year old woman was admitted with signs and symptoms of community acquired
pneumonia. She was prescribed empirically a combination of co-amoxiclav intravenously 1,2 g
every 8 hours and doxycycline orally 100 mg daily, for 10 days. The symptoms persisted and
the therapy was switched to ciprofloxacin intravenously 500 mg every 12 hours for 21 day. On
the 12th day of ciprofloxacin therapy, oral clarythromycin, 250mg every 12 hours was added to
the regimen.
Comment: The most common pathogens in community-acquired pneumonia in young adults are
Streptococcus pneumoniae or Mycoplasma pneumoniae and less likely H. influenzae and
Legionella spp. An example of adequate empiric treatment would be azithromycin (good
coverage of likely atypical pathogens or pneumococci and H. influenzae), or a floroquinolone.
In addition penicillin and a tetracycline should not be given simultaneously because of their
antagonistic activity.
- agree with the use of antimicrobial, but a modified dose, interval, duration or route of
administration is suggested/preferred (Category IV)
A 70-year old woman with a history of ischemic heart disease and normal renal
function was admitted to regular ward with signs and symptoms of lower respiratory tract
infection (acute exacerbation of chronic bronchitis). She was treated empirically with
amoxicillin 500 mg orally, once daily for 22 days.
Comment: amoxicillin should be given 3 times daily
- unnecessary (Category V)
A 59-year old man was admitted due to gastrointestinal bleeding (duodenal peptic
ulcer). Two hours after a single blood transfusion he got chills and his body temperature rose to
38,1ºC. He was otherwise asymptomatic, with no evidence of infection but was treated
empirically with co-amoxiclav for 7 days.
Comment: the transfusion, not an infection, caused the fever reaction.
Appropriate
Therapy
A Ward
Cardiology
Endocrinology
Gastroenterology
Hematology
Immunology
Nephrology
Pulmonology
B Diagnosis
Abdominal infection
Endocarditis
Malignancy
Pericarditis
RTI
Sepsis
Skin and soft
tissue infection
Tuberculosis
Unclear
UTI
I
(57)
II
(102)
13
10
11
1
1
9
12
14
4
13
5
4
8
54
9
1
11
%
(36)
Inappropriate
Therapy
III
(162)
IV
(18)
41
48
25
27
31
35
41
15
9
44
10
8
13
63
4
2
1
8
39
33
62
19
2
3
55
2
5
46
100
35
32
2
5
1
81
1
5
50
%
(41)
Unnecessary
Treatment
V
(99)
%
(23)
Total
(438)
29
38
47
45
56
47
39
20
4
26
6
2
9
32
30
14
27
27
13
18
20
66
29
95
22
16
49
161
42
67
25
25
32
7
35
7
42
49
23
11
4
52
6
21
77
3
20
1
211
4
29
1
6
43
25
41
2
6
4
14
75
6
14
8
71
1
10
22
16
57
6
1
23
10
44
7
5
35
7
21
1
5
7
4
18
17
1
64
5
18
34
7
28
21
26
51
19
4
25
23
25
93
3
2
7
16
5
25
15
36
1
5
60
58
43
6
31
3
15
26
21
9
19
1
3
47
52
29
56
23
64
6
1
1
17
4
3
5
28
57
33
9
13
1
1
47
19
14
11
40
118
14
2
19
67
7
9
C Antimicrobial
Aminopenicillins
Antituberculotics
Aminoglycosides
1st and 2nd generation
cephalosporins
3rd and 4th generation
cephalosporins
Co-amoxiclav
Macrolides
Penicillin
Tetracyclines
Quinolones
Vancomycin
Other
1
16
1
2
2
Table 2 A-C. Appropriateness of antimicrobial treatment in different wards, in different indications
and by selected substances. (Cat. I. Agree with the use of antimicrobial therapy, the protocol (choice,
route, duration, and dosage) is appropriate. Cat. II. Agree with the use of antimicrobial therapy, the
protocol (choice, route, duration, and dosage) is probably appropriate. Cat. III. Agree with the use of
antimicrobial therapy, but a different antimicrobial (less expensive, less toxic, narrower spectrum, other
combination) is preferred. Cat. IV. Agree with the use of antimicrobial therapy but a modified dose,
interval, duration or route of administration is preferred. Cat.V. Disagree with the use of antimicrobial
therapy, administration is unjustified.).