Int J Clin Pharm (2012) 34:120126

DOI 10.1007/s11096-011-9601-3

RESEARCH ARTICLE

Application of ATC/DDD methodology to evaluate perioperative

antimicrobial prophylaxis
Serife Akalin Selda Sayin Kutlu Bayram Cirak
Saadettin Yilmaz Eskicorapc Dilek Bagdatli
Semih Akkaya

Received: 22 July 2011 / Accepted: 19 December 2011 / Published online: 30 December 2011
 Springer Science+Business Media B.V. 2011

Abstract Objective To evaluate quality of perioperative

antibiotic prophylaxis (PAP) and to calculate the cost per
procedure in a Turkish university hospital. Setting A
352-bed teaching hospital in Denizli, Turkey. Method An
prospective audit was performed between July and October
2010. All clean, clean-contaminated and contaminated
elective surgical procedures in ten surgical wards were
recorded. Antimicrobial use was calculated per procedure
using the ATC-DDD system. The appropriateness of antibiotic use for each procedure was evaluated according to
international guidelines on PAP. In addition, the cost per
procedure was calculated. Results Overall, in 577 of the
625 (92.3%) of the studied procedures, PAP was used. PAP
was indicated in 12.5% of the group where it was not used,
and not indicated in 7.1% of the group where it was used.
Unnecessarily prolonged antimicrobial prophylaxis was

observed in 56.9% of the procedures, mean duration was

2.6 2.7 days. The most frequently used antimicrobials
were cefazolin (117.9 DDD/100-operation) and sulbactam/
ampicillin (102.2 DDD/100-operation). The timing of the
starting dose was appropriate in 545 procedures (94.5%). In
the group that received PAP, only 80 (13.7%) of the procedures were found to be fully appropriate and correct. The
density of antimicrobial use per operation was 2.8 DDD.
The mean cost of the use of prophylactic antimicrobials
18.6 per procedure. Conclusion The density of antimicrobial use in PAP was found to be very high in our hospital. Antibiotic overuse extended into the postoperative
period.
Keywords Appropriateness
Audit
ATC-DDD index

Cost
Perioperative antimicrobial prophylaxis
Turkey

S. Akalin (&)
S. S. Kutlu

Faculty of Medicine, Department of Infectious Diseases and
Clinical Microbiology, Kinikli Kampusu,
Pamukkale University, 20070 Denizli, Turkey
e-mail: akalinse@hotmail.com

Impact of findings on practice

B. Cirak
Faculty of Medicine, Department of Neurosurgery,
Pamukkale University, Denizli, Turkey

S. Y. Eskicorapc
Faculty of Medicine, Department of Urology,
Pamukkale University, Denizli, Turkey
D. Bagdatli
Faculty of Medicine, Department of Plastics Surgery,
Pamukkale University, Denizli, Turkey
S. Akkaya
Faculty of Medicine, Department of Orthopedics,
Pamukkale University, Denizli, Turkey

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Evaluating perioperative antibiotic prophylaxis is useful and uncovers possible inappropriate antibiotic use
as well as too high costs.
The ATC-DDD system is useful for comparing antibiotic use of departments and hospitals, within as well as
between countries.

Introduction
In many surgical procedures, perioperative antimicrobial
prophylaxis (PAP) has been found to be effective in
reducing the incidence of surgical site infections (SSI)
[1, 2]. In many countries, the guidelines for PAP have been
improved, based on international experiences and guidelines [35]. Despite the availability of local and national

Int J Clin Pharm (2012) 34:120126

guidelines, many studies of the current practice of PAP

reported that unnecessary utilization of surgical antibiotic
prophylaxis is still a common practice worldwide [6, 7].
This problem includes unnecessary use of broad-spectrum
antibacterial, prolonged duration of PAP, incorrect timing
of prophylaxis, which causes the development of bacterial
resistance and increasing costs for the healthcare system
[69]. Hence, the density and quality of PAP has been the
subject of many audits and studies. Drug utilization studies
can provide useful information for improvement of the
appropriate and effective use of PAP in surgical practice.
Although some studies have reported costs and misuse
of antibiotics in Turkish hospitals, there are insufficient
studies of the costs, quality, and density of surgical prophylaxis in Turkey [1014].

Aim of the study

The aim of this study was to analyze the quality, density,
and cost of PAP prescriptions according to international
guidelines at a university hospital in Turkey.

Methods
An observational study was conducted between July and
October 2010 at Pamukkale University Hospital, which is a
352-bed tertiary-care university hospital in Denizli, Turkey.
In a prospective approach, all clean, clean-contaminated, and contaminated elective surgical procedures were
evaluated in surgical wards for quality and density of PAP
without any intervention. The modified National Research
Council wound classification criteria were used for surgical
wound classification [3, 4]. These criteria are as follows:

Clean surgical procedures (primarily closed, elective

procedures involving no acute inflammation, no breakin technique, and no transection of gastrointestinal (GI),
oropharyngeal, genitourinary (GU), biliary, or tracheobronchial tracts);
Clean-contaminated procedures (procedures involving
transection of GI, oropharyngeal, GU, biliary, or
tracheobronchial tracts with minimal spillage or with
minor break-in techniques; clean procedures performed
emergently or with major break-in techniques; reoperation of clean surgery within 7 days; or procedures
following blunt trauma);
Contaminated procedures (clean-contaminated procedures during which acute, non-purulent inflammation is
encountered or major spillage or technique break
occurs; procedures performed within 4 h of penetrating
trauma or involving a chronic open wound);

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Typically, prophylactic antimicrobials are not indicated

for clean surgical procedures. However, prophylaxis is
justified for procedures involving prosthetic placement
because of the potential for severe complications if postoperative infections involve a prosthesis [35, 15]. Antimicrobial prophylaxis is justified for the following types of
surgical procedures: cardiothoracic, GI tract (colorectal and
biliary tract operations), head and neck (except clean procedures), neurosurgical, obstetric or gynaecologic, orthopaedic (except clean procedures), urologic, and vascular
[35, 15].
All operations in neurosurgery, urology, plastic surgery, orthopaedics, obstetrics and gynaecology, paediatric
surgery, cardiovascular surgery, otolaryngology, thoracic
surgery and general surgery were monitored. The following parameters of patients and procedures were
recorded: dates of admission and discharge, date of surgery, type and duration of surgical procedure, wound
contamination class, selection of antibiotic, unit doses of
used antibiotics, the number of total prophylaxis doses,
duration of prophylaxis, administration time of the first
and subsequent doses. The cost of antibiotics for each
perioperative surgical prophylaxis was calculated based
on daily pharmacy prices in Turkish currency (Turkish
Lira = TL). Total costs were expressed as Euros () by
taking 1 as 2.06 TL at the time of the study. Patients
with pre-existing infections and dirty surgical procedures
were excluded from the study.
Antimicrobial prophylaxis administration and the accuracy of antimicrobial prophylaxis management was analyzed in accordance with international guidelines regarding
the types of antibiotics prescribed, dosage, administration
time and duration of prophylaxis relative to time of surgery
[35, 15]. The guidelines recommend a single intravenous
dose of an inexpensive, non-toxic, and limited-spectrum
antibiotic be administered within 3060 min before the
first incision. However, vancomycin or fluoroquinolone
antibiotics should be given 2 h before the first surgical skin
incision. Cefazolin or cefuroxime, if the patient is allergic
to beta-lactams, vancomycin or clindamycin, (combined
with metronidazole if activity against anaerobic microorganisms is necessary) is the first choice drug, as it possesses many of the mentioned characteristics. Cefazolin
and cefuroxime were accepted as the only appropriate
choices for non-allergic individuals. The only situations in
which vancomycin is appropriate for surgical prophylaxis
are major surgical procedures involving the implantation of
prosthetic materials or devices at institutions that have a
high rate of infections caused by Methicillin-resistant
Staphylococcus aureus or Methicillin-resistant Staphylococcus epidermidis, or in patients who have a life-threatening allergy to b-lactam antimicrobials. Repeated dosing
is recommended when surgery is prolonged beyond two

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times the half-life of the administered antibiotic or when

blood loss exceeds 1,500 mL during the procedure. For
most procedures, the duration of antimicrobial prophylaxis
should be 24 h or less, with the exception of cardiothoracic
procedures (up to 72 h duration).
An Infectious Diseases physician (first author) and a
resident from the surgical department evaluated the
appropriateness of the surgical antimicrobial prophylaxis
according to international guidelines [35, 15]. The
appropriateness of surgical prophylaxis was evaluated
based on five steps: (1) Justifying the use of PAP in the
surgical procedure; (2) Choosing an appropriate antimicrobial agent; (3) Optimal timing of PAP; (4) Adjusting the
duration of PAP; (5) Finding an appropriate route for
administration.
Antibiotic prophylaxis prescriptions were considered as
inappropriate if any of the assessed criteria appeared
unacceptable. If an antibiotic prophylactic procedure was
performed appropriately in every respect according to
current international guidelines, it was recorded as definitely appropriate.
Antimicrobial utilization was analyzed quantitatively by
calculating the defined daily doses (DDDs) per 100-procedures. DDDs were obtained from the Anatomic Therapeutic Chemical/defined daily doses (ATC/DDD) Index
(2010) of the WHO Collaborating Centre for Drugs Statistics Methodology [18]. DDDs are normally assigned
based on usage in adults. For products approved for use in
children, the dose recommendations will differ according
to age and body weight. Many medical products used in
children are not approved for such use, and documentation
regarding dose regimens is not available [16]. One limitation of the DDD methodology is that it does not account
for dose adaptation in childhood [17]. In our hospital,
paediatricians evaluate paediatric patients as being aged
15 years or younger. Therefore, patients under the age of
15 were excluded when calculating DDD.
The study was carried out in accordance with the ethical
guidelines of Pamukkale Universitys Medical Ethics
Committee.

Int J Clin Pharm (2012) 34:120126

Assessment of PAP
PAP indication
A total of 577 cases received PAP (92.3%) and the
remaining 48 did not (7.7%). PAP implementation was
indicated in 6 of the non-PAP group (12.5%). PAP was not
indicated in 41 patients (7.1%) in the PAP group (Table 1).
Antibiotic choice
In 542 procedures (93.9%), a single antimicrobial was used
for PAP (Table 1). The most frequently used antimicrobial

Table 1 The results of perioperative antimicrobial prophylaxis in

surgical procedures
No. of
recorded
(%)a

No. of
appropriate
(%)b

Yes

577 (92.3)

536 (92.9)

No

48 (7.7)

Parameter

Antibiotic usage

Total
PAP indication
Yes
No

123

536 (98.9)
42 (50.6)
536 (98.9)

Antibiotic choice
Cefazolin

195 (33.8)

SAM

192 (33.3)

Ceftriaxone

108 (18.7)

12 (11.1)

Cefuroxime

76 (13.2)

76 (100)

Others

42 (7.3)

Total
Single antimicrobial agent
Combination (2 antimicrobials)

195 (100)
0 (0)

3 (7.1)
286 (49.5)

542 (93.9)

275 (50.7)

35 (6.1)

0 (0)

Timing of first dose

At the time of induction of anesthesia
Postoperative

In a four-month period, 639 operations were reviewed, of

which 625 fulfilled the inclusion criteria and were evaluated in the study. The cases followed were within ten
different surgical departments. Of these 625 patients, 274
(43.8%) were women. The mean age (SD) of the patients
was 43.4 22.7 years. Approximately 382 (61.1%) were
clean surgery, 232 (37.1%) clean-contaminated, and 11
(1.8%) contaminated.

542 (86.7)
83 (13.3)

Total

3060 min before incision

Results

42 (87.5)
536 (92.9)

68 (11.8)

68 (100)

477 (82.7)

477 (100.0)

32 (5.5)

Total
Duration of PAP
Single dose (h)

74 (12.82)

\24

175 (30.3)

[24

328 (56.9)

Total
Total recorded patients

0 (0)
545 (94.5)
74 (100)
175 (100)
0 (0)
249 (43)

577 (100)

SAM sulbactam/ampicillin
a

The denominators are the total recorded procedures

The denominators are the recorded procedures

80 (13.9)

Int J Clin Pharm (2012) 34:120126

123

during the study was cefazolin (in 195 procedures, 33.8%;

(Table 1).
Timing and route
The route of administration was intravenous in all procedures (100.0%). PAP was administered within the recommended period (3060 min prior to incision and at the time
of induction of anaesthesia) in 94.5% of cases (Table 1).
Timing was considered inappropriate in 32 (5.5%)
patients:prophylactic antibiotics received more than 2 h
before the incision or after the surgery.
Duration
The mean duration of PAP was 2.6 2.7 days. Unnecessarily prolonged antimicrobial prophylaxis was observed in
most of the procedures. In total, 328 of the 577 PAPs
(56.9%) were of inappropriate duration.
Total assessment of appropriateness
All steps of PAP were found to be correct in 112 of 625
patients (17.9%). In the group that received PAP, only 80
(13.9%) procedures were found to be appropriate and
correct in all steps of PAP (Table 1).
Density calculation of DDD per operation
The mean dosage per operation was 7.9 9.2 doses.
According to the ATC-DDD system, the density of antimicrobial use was calculated as 282.3 DDD/100-operation.
The density of antimicrobial use per operation was 2.8
DDD. Antimicrobial density in surgical prophylaxis was
found to be higher in cardiovascular surgery, neurosurgery,

thoracic surgery, and orthopaedics (700.5 DDD/operation,

529 DDD/operation, 386 DDD/operation, and 350 DDD/
operation, respectively) than in other surgical wards
(Table 2). The most frequently used antimicrobials were
cefazolin (117.9 DDD/100-operation) followed by sulbactam/ampicillin (102.2 DDD/100-operation), cefuroxime
(29.8 DDD/100-operation), and ceftriaxone (23.6 DDD/
100-operation) (Table 2).
Costs
The mean cost of prophylactic antimicrobial use was 18.6
per procedure (total cost 11,629 for all patients during the
study). If PAP administrations were implemented according to international guidelines, the mean cost per procedure
would have been 2.25. If PAP administrations were
implemented as a single cefazolin dose per procedure in all
patients, the total cost would have been 1,406.3, a
reduction of 88%. If PAP administrations were implemented as four cefazolin doses per procedure in all
patients, the total cost would have been 5,625.2, a
reduction of 51.6%.

Discussion
Antibiotic prophylaxis in surgery is one of the most controversial topics in healthcare, since surgical procedures are
often associated with the unnecessary prescription of
antibiotics [17]. Most of the consensus guidelines for PAP
in developed countries were improved and such guidelines
have become more common in recent years [35, 15]. PAP
is crucial for preventing or reducing postoperative infections. It is well-known that inappropriate implementations
can be wholly ineffective in many procedures. On the other

Table 2 The number of DDD/100-operation in surgical wards

ATC

NS

Urology

Cefazolin

J01DB04

164.3

3.5

Cefuroxime

J01DC02

PS

Orthopedics

Obst/Gyne

CVS

HNS

336.4

175

663.6

386

97.3

TS

GS

Total

36

117.9
29.89

Ceftriaxone

J01DD04

96.5

98.7

23.6

SAM

J01CR01

363.8

2.2

190.5

188.2

102.29

Ciprofloxacin

J01MA02

2.09

6.4

0.89

Amikacin

J01GB06

1.7

0.39

Gentamicin

J01GB03

3.5

11.9

1.4

Ornidazole

J01XD03

39.7

25

5.5

Clindamycin

J01FF01

7.5

0.5

Vancomycin

J01XA01

1.2

109.5

230.2

350.3

700.5

188.2

Total

529

175

386

0.3

231.9

282.3

NS neurosurgery, PS plastics surgery, Obst/Gyne obstetrics and gynecology, CVS cardiovascular surgery, HNS head and neck surgery, TS
thoracic surgery, GS general surgery, SAM sulbactam/ampicillin

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hand, inappropriate and excessive use of antibiotics for

surgical prophylaxis can give rise to resistance problems
and leads to an exhausting of the countrys economy [11].
Currently, some Turkish hospitals have guidelines on PAP
but these are not common nationally. In most Turkish
hospitals, there is no effective enforcement to improve the
quality of PAP. This study provides new data from Turkey
regarding use of the ATC-DDD system for calculation of
antimicrobial density in surgical prophylaxis.
In the PAP-received group in this study, few procedures
complied entirely with PAP guidelines (13.9%). In another
study from Turkey, all steps of the PAP-received group
were found to be correct in 34.3% of cases before intervention and 28.5% after intervention [13]. In a Dutch
study, prophylaxis was completely administered 0.4%
before intervention and 25% after intervention [18]. These
prospective studies reported the results of interventions in
order to promote improvement. In the study from Turkey,
compliance decreased non-significantly after intervention.
In the Dutch study, compliance increased after intervention. Our study was not an intervention study, and therefore
potential changes could not be evaluated.
Calculation of antimicrobial density in surgical prophylaxis with ATC-DDD provides a practical method of
comparing various hospitals or countries. In a Dutch study,
the authors reported the density of antimicrobial use per
operation as 1.21 DDD before intervention and 0.79 DDD
after intervention [18]. In another Dutch study, prophylactic antibiotic consumption decreased from 0.75 to 0.53
DDD per operation [21]. In a Japanese study, DDD per 100
procedures decreased from 160.6 to 129 following intervention [1]. Hosoglu et al. calculated the density of PAP as
330.2 DDD/100-operation at a general hospital in central
Diyarbakir, a city in south-eastern Turkey [11]. The density
of antimicrobial use was considerably higher in our study
compared with the Dutch studies (2.8 DDD/operation vs.
0.53 DDD/operation, respectively). On the other hand, our
result was slightly lower than the other Turkish study from
Diyarbakir (2.8 DDD/operation vs. 3.3 DDD/operation,
respectively).
In our study, antimicrobial density in surgical prophylaxis was found to be higher in cardiovascular surgery,
neurosurgery, thoracic surgery, and orthopaedics (700.5
DDD/operation, 529 DDD/operation, 386 DDD/operation,
and 350 DDD/operation, respectively) than in other surgical wards. The high antibiotic usage observed in cardiovascular surgery is not surprising, as the surgeons prefer to
continue with antimicrobial therapy for over 72 h (72.7%).
In contrast, prophylaxis durations within the urology unit
were less than 24 h (84.1%).
Despite prolonged duration of surgical antimicrobial
prophylaxis, it does not reduce the rate of SSI; many surgeons have a tendency to use prophylaxis longer than

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Int J Clin Pharm (2012) 34:120126

recommended [1, 7, 10, 11, 20, 21]. In studies conducted in

2001 and 2002 in our hospital, Yalcin et al. found that
duration of prophylaxis was appropriate only in 47.7 and
29.0% of all cases, respectively [12, 14]. The results of the
present study therefore indicate no change in duration of
surgical prophylaxis for approximately 9 years in our
hospital. In other studies, the incorrect duration of surgical
prophylaxis ranged between 45 and 87.9% [1, 2, 20]. In
another study from Turkey, the duration of surgical antimicrobial prophylaxis was reported as being less than 24 h
for only 20% of the selected procedures [10]. In contrast,
studies from other countries have found the duration of
perioperative antibiotic prophylaxis was less than 24 h for
7592% of procedures [8, 19, 22]. The number of doses of
PAP is related to the duration of prophylaxis. In our study,
12.8% of procedures used a single dose of antibiotic.
Similarly, Hosoglu et al. reported that 12% of surgeons
used a single dose of antibiotic in their practice [10]. In
contrast, a French study found that in 93% of all procedures, the first dose of antibiotic was administered at the
time of induction of anaesthesia, as recommended by
French guidelines [21]. A single dose of antibiotic before
surgery is sufficient prophylaxis for most surgical procedures [35, 15].
In our study, the timing of prophylaxis was found to be
appropriate in 94.5% of all procedures. In other Turkish
studies, the timing of prophylaxis was appropriate in
59.2100% of all procedures [1012, 14].
One of the most critical issues for correct PAP implementation is choosing an appropriate antibiotic. First- and
second-generation cephalosporins have generally been
recommended for surgical prophylaxis [35, 15], but were
chosen in only 47% of procedures in our study. Previous
studies reported a wide range of first-generation cephalosporin use in PAP practice, from 11 to 85.8% [1013]. In
our study, although the most frequently used antimicrobial
was cefazolin, inappropriate antibiotic choice was one of
the most important errors.
In previous Turkish studies, the average cost of each
perioperative antibiotic prophylaxis was reported as
between 45.6 USD and 62.0 USD per patient [12, 13].
Similarly, in a study from Taiwan, the mean cost of prophylactic antibiotics was reported as 55 USD [23]. In a
Brazilian study, before the adoption of a protocol, the
median cost of PAP was 7.4 USD per surgery, compared
with 4.4 USD per surgery after the protocol (a 40.5%
reduction in the cost of PAP) [24]. In a Dutch study, the
antibiotic cost per procedure decreased by 25%, from 11.0
to 8.2 [18]. In our study, the mean cost of PAP use was
18.6 (25.4 USD) per procedure. In a previous study in our
hospital, Yalcin et al. [14] found the average cost of PAP
use was 62 USD per patient [12]. The reduced cost per
procedure compared with the previous findings could be

Int J Clin Pharm (2012) 34:120126

related to the decrease in medicine prices in Turkey. When

prophylactic administrations are compared with international guidelines, the mean cost per procedure should be
2.3. If PAP administrations had been implemented as a
single cefazolin dose per procedure for all patients, the total
cost would have been 1,406.3, representing a reduction of
88%. The remarkable decrease in antibiotic use and costs
per procedure was due to a reduction in the number of postoperative doses, the use of less costly antibiotics and, to a
small extent, the use of lower dosages [18].
The improvement in antibiotic use in surgical prophylaxis provided a better quality of health care and resulted in
a reduction in the cost of PAP per surgery, resulting in a
predicted annual saving [24]. National guidelines on surgical prophylaxis would be useful in improving local
consensus and increasing the quality of antibiotic use.
Some Turkish hospitals have adopted surgical prophylaxis
guidelines, but presently there is no national guidance.
Unfortunately, our hospital does not have any local
guidelines on surgical antibiotic prophylaxis. In order to
ensure the correct and restrictive use of antibiotics,
development of hospital guidelines for rational antibiotic
use are now included in our hospitals infection control
programme.
There are some limitations to our study. One limitation
is that this study was a single-centre study. Another limitation is the lack of information about SSI rates during the
study. However, we focused on quality of PAP and there is
no intervention in that study.

Conclusion
In this prospective survey, only 17.9% of the reviewed procedures were correct in all steps of PAP. We found a strong
tendency towards excessive use of antibiotics in preoperative
prophylaxis. This tendency contributes to antibiotic resistance and leads to an economic burden. Therefore, evaluation of PAP density could be useful to draw attention to the
quality of surgical antibiotic prophylaxis.
Acknowledgments We are grateful to the Perioperative Antimicrobial Prophylaxis Study Group of the participating hospital for
retrieving the surgical prophylaxis data. Members of the Perioperative
Antimicrobial Prophylaxis Study Group: Ozer Oztekin, Ugur Koltuksuz, Ali Vefa Ozcan, Funda Tumkaya, Gokhan Yuncu, Koray
Tekin, Ilkay Sitti, Gungor Bingolo, Orhan Aydin, Veysel Baskan,
Umit Cabus, Firat Durna, Bulent Kamil Akyol, Yasin Ekinci and Seda
Arzuman.
Funding

No financial support was provided for this study.

Conflicts of interest The authors declare no conflicts of interest or

financial interests in any product or service mentioned in this article.

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