410 Original Article

Ertapenem versus Standard Triple Antibiotic

Therapy for the Treatment of Perforated
Appendicitis in Pediatric Patients: A Prospective
Randomized Trial
Nazan Dalgic1 Cetin Ali Karadag2 Banu Bayraktar3 Mesut Sancar4 Ozlem Kara2 Suleyman Pelit3
Suleyman Celebi2 Ihsan Kafadar1 Ali Ihsan Dokucu2

1 Division of Pediatric Infectious Diseases, Sisli Etfal Training and Address for correspondence Nazan Dalgic, MD, Division of Pediatric
Research Hospital, Istanbul, Turkey Infectious Diseases, Sisli Etfal Training and Research Hospital,

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
2 Division of Pediatric Surgery, Sisli Etfal Training and Research Halasgargazi Cad, Istanbul 34377, Turkey
Hospital, Istanbul, Turkey (e-mail: nazandalgic@ttmail.com).
3 Division of Microbiology, Sisli Etfal Training and Research Hospital,
Istanbul, Turkey
4 Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara
University, Istanbul, Turkey

Eur J Pediatr Surg 2014;24:410418.

Abstract Background The primary objective of this study was to compare triple therapy with
ertapenem treatments in pediatric patients with perforated appendicitis, especially in
terms of postoperative infectious complications. The secondary objective of this study
was to assess the relative impact of therapy with ertapenem and triple antibiotic
regimen on the emergence of resistant bacteria in bowel ora in the patients.
Materials and Methods Children aged 3 months to 17 years with perforated
appendicitis were randomized 1:1 to receive ertapenem or triple therapy. Serial rectal
cultures were obtained from participants enrolled in the study, allowing assessment of
the relative impact of therapy with ertapenem and triple therapy on bowel colonization
by resistant bacteria.
Results In this study, 107 patients were included. No difference existed in time to full
oral intake and regular diet, the length of antibiotic therapy, the length of the
postoperative hospitalization, or the length of hospital stay between the two groups.
Patients in the triple-therapy group were more likely to suffer from a postoperative
infectious complication than those in the ertapenem group (6/54 vs. 2/53, p > 0.05).
Bowel colonization with resistant organisms at the end of therapy in the triple-therapy
group was signicantly different than in the ertapenem group (35.2 vs. 11.3%,
Keywords p < 0.05).
perforated Conclusions Bowel colonization with resistant bacteria was less likely to occur after
appendicitis ertapenem treatment than triple therapy. The results of this trial suggest that
children ertapenem may be a useful option that could eliminate the need for combination
ertapenem and/or multidosed antibiotic regimens for the empiric treatment of perforated
bowel ora appendicitis in children.

received 2014 Georg Thieme Verlag KG DOI http://dx.doi.org/

January 30, 2013 Stuttgart New York 10.1055/s-0033-1352524.
accepted after revision ISSN 0939-7248.
July 2, 2013
published online
August 27, 2013
 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis Dalgic et al. 411

Introduction bial agent, it is prudent to be vigilant for the emergence of

resistance. Surveillance of clinical isolates should be used in
Complicated intra-abdominal infections are mainly caused by
such monitoring, but a considerable latent period may be
ruptured or gangrenous appendicitis with or without perito-
expected before the full impact of a new agent antimicrobial
nitis, and constitute an important cause of pediatric morbidi-
susceptibility pattern becomes apparent. Bowel ora may
ty.1,2 Surgical site infections or intra-abdominal abscesses
provide a signicant reservoir for nosocomial horizontal
often necessitate a prolonged hospital stay for children with
transmission of resistant organisms.1922 In addition, clinical
perforated appendicitis.3 Most series report complication
infection is often preceded by colonization with resistant
rates around 10%.46 Although intravenous (IV) antibiotic
organisms. Earlier evidence of emerging resistance may be
therapy is conventionally used to treat perforated appendici-
obtained by examining the effects of antimicrobial agents on
tis, there is no consensus on the optimal regimen of antibiotic
the susceptibility patterns of bowel ora from treated pa-
use following appendectomy in children with perforated
tients, and the development of later clinical problems may be
appendicitis.7
forecasted.23,24
The three-drug regimen of ampicillin, gentamicin, and
Most research presents data from clinical trials evaluating
clindamycin or metronidazole is still used in many institu-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
new agents. However, such trials are usually not statistically
tions and continues to be gold standard antibiotic strategy
powered to prove clinical superiority but rather noninfer-
as for treatment of perforated appendicitis in children.8,9
iority to standard agents. In the selection of antimicrobial
Triple antibiotic therapy has the advantage of broad-spec-
agents, given equivalent efcacy, cost of treatment and bowel
trum coverage of gram-positive, gram-negative, and anaero-
colonization with resistant organisms during therapy become
bic bacteria. Although their individual doses are not
an important consideration.
expensive, each of these medications is administered several
The primary objective of this study was to compare triple
times a day resulting in a difcult dosing schedule. Further,
therapy with ertapenem treatments in pediatric patients
gentamicin is known to be an aminoglycoside with renal and
with perforated appendicitis, especially in terms of postop-
ototoxic side effects. Thus, serum levels must be measured to
erative infectious complications. The secondary objective of
maintain therapeutic yet nontoxic levels. Although this regi-
this study was to assess the relative impact of therapy with
men has been reported to be safe and effective, the large array
ertapenem and triple antibiotic regimen on the emergence of
of antibiotics available today includes very few drugs that
resistant microorganisms in bowel ora in these patients.
necessitate such close monitoring. One of the most important
goals of current medical treatments is to create equal or
better effect with less toxicity, effort, and costs. Materials and Methods
Ertapenem is a recent carbapenem antibiotic approved by
Study Design
the United States Food and Drug Administration in 2001 for
This prospective, randomized, open-label, comparative-con-
the treatment of several community-acquired and mixed
trolled trial was conducted at the division of pediatric surgery
aerobic/anaerobic infections, including moderate-to-severe
in our hospital, the largest referral center in Turkey between
complicated intra-abdominal infections due to Escherichia
March 2009 and February 2010. We evaluated the safety,
coli, Clostridium clostridioforme, Eubacterium lentum, Peptos-
tolerability, efcacy, and bowel colonization with resistant
treptococcus spp., Bacteroides fragilis, Bacteroides distasonis,
pathogens after therapy of ertapenem versus triple antibiotic
Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacter-
therapy for treating children with perforated appendicitis.
oides uniformis.1013 Ertapenem seems to have equal effec-
The study was approved by the Institutional Ethics Commit-
tiveness to ceftriaxone in the treatment of urinary tract
tee (03.09/68). Written informed consent was obtained for
infections, skin and soft tissue infections, and community-
each patient from their parent or guardian.
acquired pneumonia in pediatric patients.14 It also has similar
effects to those of ticarcillin/clavulanate in the treatment of
Patients
pediatric intra-abdominal and pelvic infections.2 It is thus
The study population consisted of children between 3 months
considered a safe alternative by the Infectious Diseases
and 17 years of age with perforated appendicitis. Inclusion
Society of America for the treatment of community-acquired
criteria began with the operative nding of perforation. The
intra-abdominal infections in children, together with other
presence of perforation was accepted if one or more of the
antibiotics such as cephalosporins combined with metroni-
following criteria were met:
dazole, aminoglycosides combined with metronidazole or
clindamycin and with or without ampicillin and -lactam/ 1. An existing perforation was noted by the surgeon.
-lactamase inhibitor combinations.15 Although recommen- 2. Local or diffuse fecal peritonitis was diagnosed by the
dations and management guidelines have been circulated by surgeon or pathologist.
infectious diseases associations,15,16 the nal decision is 3. A perityphlic abscess was diagnosed by the surgeon or
determined by considering many factors such as effective- pathologist.
ness, expenses, adverse effects, and bacterial resistance.17
When antimicrobial agents broadly active against enteric Only patients with community-acquired infections de-
bacteria are used, resistant organisms may colonize the bowel ned by clinical manifestations before or within 48 hours
during therapy.18 Following introduction of a new antimicro- of hospitalization were enrolled in the study. Exclusion

European Journal of Pediatric Surgery Vol. 24 No. 5/2014

412 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
criteria included history of serious allergy to study drugs, a
rapidly progressive or terminal illness, any immunosuppres-
sive illness or therapy, a pathogen resistant to either study
drug, > 24 hours of systemic antimicrobial therapy effective
against presumed or documented pathogens.
Interventions
After determination of perforation at the time of operation,
children were included in the study. The choice of open or
laparoscopic technique was made by the attending surgeon.
In the triple-therapy group, patients received ampicillin 50
mg/kg every 6 hours (maximum 8 g), gentamicin 7.5 mg/kg
once a day, and metronidazole 10 mg/kg every 8 hours
(maximum 4 g). In the ertapenem (Invanz; Merck & Co.
Inc., Clermont-Ferrand, France) group, children aged
3 months to 12 years received 30 mg/kg/day divided into
two daily doses with a maximum total daily dose of 1 g.
Children 13 years of age or older received 1 g of ertapenem as
a single daily dose. Both groups received a minimum 5-day
course after the operation regardless of clinical course. A
white blood cell (WBC) count was drawn on postoperative
day 5 in all patients. If this was normal, the patient was not
febrile and was tolerating a regular diet, they were discharged
without oral antibiotics. If leukocytosis (WBC > 15,000/
mm3) was found, the patient received 2 additional days of
IV antibiotics based on the culture results, and the WBC count
evaluation was repeated. If the WBC count remained elevated,
they received another 3 days of IV antibiotics based on the
results of culture, and an ultrasound (US) and/or computed
tomography (CT) scan was obtained to evaluate for the
presence of an abscess. In addition, US/CT scans were ob-
tained if the patients clinical condition suggested an abdom-
inal abscess at any time after 7 days. All patients who
developed postoperative abscesses were treated with IV anti-
biotics based on the in vitro susceptibility of the causative
pathogen(s). Drainage and length of treatment of abscesses
were dictated by the individual treating surgeon.
Assessment
Safety was evaluated based on the incidence of clinical or
laboratory adverse events (AEs) as determined by the inves-
tigator. Children were monitored for AEs on a daily basis
during the parenteral therapy period and at the test-of-cure
visit 7 to 14 days posttherapy. The tolerability of the study
drugs at the local infusion site was evaluated daily by the
investigator. Clinical response was measured on days 3 to 5,
when parenteral therapy was completed, 7 to 14 days
posttherapy.
To assess the efcacy of two different antibiotic regimens,
we abstracted all postoperative infectious complications
either before or after leaving the hospital up until the
patients rst clinic visit (usually 1 to 2 weeks after discharge
from the hospital).
Culture and sensitivity assays of appropriate bacterial
specimens was requested at baseline, at any time that there
was clinical or laboratory evidence of persistence or progres-
sion of the infectious process (including persistent fever,
elevated WBC, or signicant changes in the patients clinical
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
Dalgic et al.
condition), and at the time of any surgical or drainage
procedure.
Sample Size
We estimated that the minimum sample size was 59 for each
group to detect statistical signicance with 80% power and 5%
signicance level. The sample size was calculated on the basis
of a 20% difference in the proportion of the postoperative
infectious complications for patients treated with the two
different antibiotic regimens according to previously pub-
lished prospective randomized trial by St Peter et al.25
Assignment
An individual unit randomization was used in an unblocked,
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
nonstratied sequence. Perforation was dened by the surgeon
at the time of the operation after which the family was
approached for consent. The randomization sequence was
accessed to identify the next allotment after the consent was
signed. The patients were randomized in a 1:1 ratio (ertapenem:
triple therapy) by a computer-generated allocation schedule.
Blinding
The study drugs were administered in an unblinded manner.
Because ertapenem and triple therapy have different dosing
frequencies, the design of study was by necessity open label
so that matching placebo infusions would not have to be
administered to acutely ill pediatric patients.
Data Collection
All data were collected prospectively. At the time of presen-
tation, the patients age, weight, sex, days of symptoms,
maximum temperature, and WBC count were collected.
Operative variables collected included the operative ap-
proach, operative and intraoperative complications, includ-
ing conversion to the open approach.
The primary outcome variable was the postoperative
infectious complications (abscess and wound infection)
rate. The other outcome variables included maximum daily
temperatures for each of the rst 5 postoperative days, time to
initial oral intake, time to regular diet, length of antibiotic
therapy, any abnormal ndings during postoperative or
follow-up visits, and length of hospitalization.
Design of Bowel Colonization with Resistant
Pathogens Subanalyses
Serial rectal cultures were obtained from participants of the
study, allowing assessment of the relative impact of therapy
with ertapenem and triple therapy on bowel colonization by
resistant gram-negative bacilli.
Rectal cultures were obtained using rayon-tipped swabs
(Copan, Diagnostic Inc., Brescia, Italy) before the start of the
study therapy (baseline) and at the end of the study. Baseline
specimens could be obtained starting from 2 days before until
1 day after the rst day of study therapy. End-of-therapy
specimens could be obtained from the day before until 3 days
after the discontinuation of study therapy. Rectal swabs were
immediately placed in Stuart, Amies, and Cary-Blair liquid
media, refrigerated at study sites, and transported to a central
 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
microbiology laboratory within 24 hours of collection. The
clinical microbiology laboratory was blinded to treatment
allocation. Upon receipt at the central laboratory, material
from the rectal swabs was immediately inoculated on Mac-
Conkey agar plates supplemented with ertapenem (0.5 g/
mL), piperacillintazobactam (0.5 g/mL), or ceftazidime
(1 g/mL). Representative bacterial colonies (up to 3) were
identied from each plate using routine laboratory techni-
ques. For gram-negative bacilli, the minimum inhibitory
concentrations (MICs) of the study drugs, ceftazidime, and
imipenem were determined by epsilometric (E) testing.
Susceptibility results were interpreted according to the Clin-
ical and Laboratory Standards Institute (CLSI) breakpoints.26
Escherichia coli and Klebsiella spp. colonies growing on
ceftazidime- or ceftriaxone-supplemented MacConkey agar
were specically tested for extended-spectrum -lactamase
(ESBL) production by double-disk test. Operationally, ESBL
production was dened as a
5 mm increase in the zone
diameter for ceftazidime or cefotaxime when tested in com-
bination with clavulanic acid versus the zone diameter when
tested alone.26 As recommended by the CLSI, ESBL-producing
E. coli and Klebsiella spp. were considered to be resistant to
ceftriaxone, regardless of the ceftriaxone MIC result. Pseudo-
monas aeruginosa isolates recovered from any of the antibi-
otic-containing plates were tested for susceptibility to
ceftazidime and imipenem and to piperacillintazobactam.
Specimens in Stuarts medium were plated on Enterococ-
cosel agar (BBL Microbiology Systems, Cockeysville, Maryland,
United States) containing 8 g of vancomycin/mL to screen for
vancomycin-resistant enterococci. If growth was detected,
identication and susceptibility testing of the isolate by Micro-
Scan was routinely conrmed with conventional methods.
Only conrmed Enterococcus faecalis and Enterococcus faecium
with a vancomycin MIC of
32 g/mL by E-test were regarded
as vancomycin-resistant enterococci in this analysis.
Statistical Analyses
Continuous variables with an approximately normal distri-
bution were compared by using an independent sample
Student t-test. The MannWhitney U test was used as to
Table 1 Baseline characteristics of patients
Standard triple therapy
(n 54)
Age (mo) 107.17  43.88
Number of male (%) 36 (33.64)
Weight (kg) 28.74  12.61
BMI (kg/m2) 16.54  1.15
Duration of presenting symptoms (d) 2.89  2.80
WBC count (/mm3) 16,687.41  4,881.17
CRP (mg/L) 116.05  69.01
Bowel colonization at the baseline (%) 9 (16.7)
Abbreviations: BMI, body mass index; CRP, C-reactive protein; d, day; mo, month; WBC, white blood cell.
a
Statistically signicant difference, p < 0.05.
Dalgic et al. 413
compare the variables that were not normally distributed. All
categorical variables were analyzed with chi-square test or
Fisher exact test. A p value of less than 0.05 was considered to
show a statistically signicant result. Statistical analyses were
performed using the Statistical Package for Social Sciences
(SPSS: an IBM company, New York, United States) version 16.0
for Windows. Data were expressed as means  standard
deviation. All patients were analyzed in an intention to treat
manner.
Results
From March 2009 to February 2010, 118 patients who were
diagnosed with perforated appendicitis and underwent op-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
erative appendectomy within 24 hours of diagnosis were
enrolled in the study. Eleven patients were excluded from the
analysis because of missing or inadequate specimens at the
baseline and/or the end of therapy. Thus, 107 children were
included in the analysis.
Demographics
There was no difference between the triple-therapy and
ertapenem groups with respect to age, gender, weight,
body mass index, fever, WBC count, C-reactive protein, and
bowel colonization with resistant organisms at baseline.
Duration of symptoms at presentation was longer for patients
in the ertapenem group than for those in the triple-therapy
group (p < 0.05) (Table 1).
Operation
There was no difference in operating time between the
groups. Forty patients underwent laparoscopic appendecto-
my (LA). In the laparoscopic group, there were two wound
infections and one postoperative abscess. Patients in the open
group had three wound infections and two postoperative
abscesses. There was no signicant difference in the rate of
postinfectious complications regarding the type of operation.
A single patient, from the triple-therapy group, required
conversion from the laparoscopic approach to an open
procedure.
Ertapenem therapy p value
(n 53)
118.62  36.01 0.180
38 (35.51) 0.573
34.28  15.45 0.054
16.62  1.66 0.9
3.15  1.57 0.026a
17,451.89  5,551.98 0.451
131.01  97.08 0.651
5 (9.3) 0.267
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
414 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
Fig. 1 The mean of maximum recorded temperatures for the two
groups on admission and each of the rst 5 postoperative days.
Microbiologic Findings
Peritoneal uids were sampled for the culture at the time of
surgery. Polymicrobial infection was documented in the
majority of microbiologically evaluable patients (90/107
[84.1%]), with gram-negative and anaerobic organisms
most prevalent. The most frequent isolates were E. coli,
B. fragilis, other Bacteroides spp., and Clostridium spp. The
pathogens were susceptible for the study drugs.
Outcome
In terms of postoperative infectious complications; three
(5.6%) patients in the triple-therapy group developed a
wound infection compared with two (3.8%) wound infections
in the ertapenem group (p > 0.05). Three (5.6%) patients in
the triple-therapy group developed an abscess compared
with no abscess in the ertapenem group (p > 0.05). Patients
who developed an abscess received an additional 14.1  4.3
days of IV antibiotics, one patient received another 10 days of
oral antibiotics, and two patients took oral antibiotics for
7 days. The overall infectious complication rate in the erta-
penem group was 3.8%. In contrast, patients in the triple-
therapy group had an overall infectious complication rate of
11.2%. Although it was not statistically signicant, patients in
the triple-therapy group were more likely to suffer from a
Table 2 Clinical outcomes
Standard triple therapy (n 54)
Time to initiation oral intake (h) 47.22  14.02
Time to regular diet (h) 72.78  11.08
Length of antibiotic therapy (d) 7.20  2.66
Bowel colonization at the end of therapy (%) 19 (35.2)
Length of hospital stay after operation (d) 5.91  2.42
Length of hospital stay (d) 7.11  2.52
Postoperative abscess (%) 3 (5.6)
Wound infections (%) 3 (5.6)
Abbreviations: d, day; h, hour.
a
Statistically signicant difference, p < 0.05.
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
Dalgic et al.
postinfectious complication than those in the ertapenem
group (6/54 vs. 2/53, p > 0.05).
There was no difference in the fever curves for the rst 5
postoperative days between the two groups (Fig. 1)
(p > 0.05). No difference existed in time to full oral intake
and regular diet, the length of antibiotic therapy, the length of
postoperative hospitalization, or the length of hospital stay
between the two groups. Bowel colonization with resistant
organisms at the end of therapy in the triple-therapy group
was signicantly different from the ertapenem group (35.2
vs. 11.3%, p < 0.05) (Table 2).
Regarding AEs, WBC count, renal, and liver function tests
were monitored while children were receiving parenteral
therapy. No laboratory or clinical side effects were observed
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
during the therapy period. In terms of tolerability, no child
discontinued therapy owing to local reaction at the infusion
or injection site. One patient in the ertapenem group experi-
enced local erythema related to infusion-related event.
Bowel Colonization with Resistant Organisms
Rectal swabs were obtained from both treatment groups at
baseline and at the end of therapy. The acquisition of bowel
colonization with resistant organisms to the treatment oc-
curred signicantly more often during the standard triple-
therapy treatment (18.5%) than during the ertapenem treat-
ment (1.9%) (p 0.005) (Table 3).
At the end of therapy in the triple-therapy group, ESBL-
producing Enterobacteriaceae (11 E. coli and 5 K. pneumo-
niae) were recovered from 16 rectal swabs obtained from 54
(29.6%) patients treated with triple therapy, compared with
7 (12.9%) swab (E. coli) at baseline (p 0.049) (Table 4). In
the ertapenem treatment group, 5 of 53 (9.4%) patients
harbored ESBL-producing Enterobacteriaceae (4 E. coli and
1 K. pneumoniae) at the end of therapy, compared with
4 (7.5%) patients who harbored producing E. coli at the
baseline (p > 0.05). The emergence of ESBL-producing Enter-
obacteriaceae during therapy occurred signicantly more
often in patients treated with the triple therapy than with
ertapenem (16/54 vs. 5/53, p 0.042).
Ertapenem therapy (n 53) p value
47.09  15.84 0.566
72.06  14.93 0.396
7.57  2.43 0.217
6 (11.3) 0.004a
6.57  2.45 0.119
7.55  2.45 0.230
0.109
2 (3.8) 0.194
 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis Dalgic et al. 415

Table 3 Number of assessablea patients with bowel colonization with resistant organisms

Treatment group Number of Baseline n (%) End of therapy n (%) Acquisition n (%) Effectivenessb (%)
patients
Standard triple therapy 54 9 (16.7) 19 (35.2) 10 (18.5) 81.5
Ertapenem therapy 53 5 (9.4) 6 (11.3) 1 (1.9) 98.1
p value 0.267 0.004c 0.005c
a
Assessable patients included all patients who received at least 5 days parenteral antibiotics therapy and had rectal swabs collected at both baseline
and the end of therapy.
b
Percentage of patients who had no bowel colonization at the end of study compare with the baseline.
c
Statistically signicant difference, p < 0.05.

Table 4 Frequency of assessable patients with resistant organisms isolated from rectal swabs at different time points during the
study by treatment groups

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Isolate Standard triple therapy (n 54) Ertapenem therapy (n 53)
Baseline End of therapy Baseline End of therapy
ESBL-producing E. coli or Klebsiella spp. (%) 7 (12.9) a
16 (29.6) 4 (7.5) 5a (9.4)
Imipenem-resistant P. aeruginosa (%) 1 (1.8) 2 (3.6) 1 (1.8) 0 (0)
Ertapenem-resistant Enterobacter spp. (%) 0 (0) 1 (1.8) 0 (0) 0 (0)
Vancomycin-resistant E. faecium (%) 0 (0) 0 (0) 0 (0) 1 (1.8)
Vancomycin-intermediate E. faecalis (%) 1 (1.8) 0 (0) 0 (0) 0 (0)
a
There is a signicant difference between standard triple therapy and ertapenem therapy at the end of therapy.

In the triple-therapy group, imipenem-resistant P. aerugi-
nosa was found in two recipients (3.6%) at the end of therapy,
one at the baseline versus one ertapenem recipient (1.8%) at
the baseline, none at the end of therapy.
Ertapenem-resistant Enterobacter spp. was recovered
from 1 of 54 (1.8%) patients in the triple-therapy group at
the end of therapy, none at the baseline, and no ertapenem-
resistant Enterobacteriaceae isolates were detected in the
ertapenem group. No vancomycin-resistant enterococci were
recovered from the 54 assessable triple-therapy recipients at
either baseline or end of therapy, but vancomycin resistance
was detected in an E. faecium isolated from one patient in the
ertapenem treatment group at the end of therapy, compared
with none at baseline. In the triple-therapy treatment group,
vancomycin-intermediate E. faecalis was isolated from one
patient (1.8%) at the baseline and none again at the end of
therapy. No vancomycin-intermediate enterococci isolates
were detected during the ertapenem therapy.
None of these patients received concomitant antibacterial
therapy.
Discussion
Appendicitis remains the most common indication for urgent
abdominal surgery among pediatric patients, and ruptured
appendicitis affects a large proportion of them.27 At present,
no consensus exists on the optimal antibiotic therapy after
appendectomy for children with perforated appendicitis.28
Indeed, there are many beliefs among pediatric surgeons on
the choice of antibiotics, duration of treatment, route of
administration, and duration of hospitalization.29,30 The pro-
claimed gold standard of postoperative antibiotic therapy
in children with perforated appendicitis was rst described in
1994 and recommended 10 days of IV ampicillin, gentamicin,
and clindamycin.5 Recently, though, monotherapy with
newer broad-spectrum agents such as piperacillin/tazobac-
tam has been shown to be as effective as traditional triple
therapy in intra-abdominal infections.31 Cefotaxime, a ceph-
alosporin with a similar prole to ceftriaxone, was shown to
be similar to the above-mentioned monotherapy schedule of
piperacillin/tazobactam in children with complicated perfo-
rated appendicitis when combined with metronidazole.32
Also, St Peter et al found a once-a-day regimen of ceftriaxone
and metronidazole to be an efcient, cost-effective treatment
for children with perforated appendicitis.25 Their study was
the rst study to show that triple antibiotic therapy was not
advantageous and that single daily dosing of antibiotics is just
as effective as multiple dosing per day of triple antibiotic
therapy. Such data cast doubt on the need for complicated
antibiotic regimens such as the ones used in conventional
triple therapy, which includes a toxic agent (gentamicin) with
a narrow therapeutic window that requires serum monitor-
ing to achieve adequate gram-negative coverage. On the other
hand, although monotherapy seems to be more attractive and
advanced than triple therapy such as the one used in this
study, the expense of such treatments must also be
considered.
Ertapenem, a once-a-day parenteral carbapenem, was
shown to be active in vitro against many aerobic and anaero-
bic bacteria present in complicated community-acquired
intra-abdominal infections. In vitro data against intra-ab-
dominal isolates and the success of ertapenem in the therapy

European Journal of Pediatric Surgery Vol. 24 No. 5/2014

416 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
of complicated intra-abdominal infections among adults in
comparative clinical trials throughout the world are evidence
that ertapenem is generally well tolerated and as effective as
either piperacillintazobactam or ceftriaxone plus metroni-
dazole in the therapy of community-acquired, complicated
intra-abdominal infections.33 In a randomized, open-label,
multicenter and comparative study, ertapenem was com-
pared with ticarcillin/clavulanate among 112 children with
complicated intra-abdominal or acute pelvic infections. Pa-
tients were treated with either ertapenem (15 mg/kg every
12 hours in patients 3 months to 12 years and 1 g once daily in
patients 13 to 17 years of age) or ticarcillin/clavulanate at
doses of 50 mg/kg in patients weighing under 60 kg and 3 g in
patients above 60 kg administered four to six times daily. The
clinical response rates in the children with intra-abdominal
infections were 87% (43/50) for ertapenem and 73% (11/15)
for ticarcillin/clavulanate. Those in patients with pelvic in-
fections were 100% (25/25) for ertapenem and 100% (8/8) for
ticarcillin/clavulanate.2 In our study, clinical efcacy response
rates were similar regarding time to initiation oral intake,
regular diet, length of antibiotic therapy, hospital stay after
operation, and length of hospital stay between pediatric
patients treated with triple therapy and patients treated
with ertapenem. At the same time, there were no serious
drug-related laboratory adverse experiences reported by
those receiving ertapenem therapy and no patients discon-
tinued the therapy as the result of an adverse laboratory
experience. There were no deaths reported during the study,
and the overall rate of serious adverse experiences was low
and of the type normally expected in pediatric patients
hospitalized for these types of infectious diseases. The results
of this trial suggest that ertapenem may be a useful alterna-
tive which may eliminate the need for combination and/or
multidosed antibiotic regimens for the empiric treatment of
perforated appendicitis in pediatric patients.
Broad-spectrum antimicrobial therapy has been linked to
the emergence of resistant bowel ora during or after thera-
py.34 Resistant organisms may emerge through genetic mu-
tation or induction, be acquired exogenously, or, if already
present in undetectably low concentrations, overgrow under
selective pressure.18,3537 Colonization with resistant micro-
organism in the colon often occurs before clinical infection
with resistant organisms, and may sometimes cause horizon-
tal spread of difcult-to-treat pathogens.20,23,24,38 Different
antimicrobial agents and classes impact bowel ora in differ-
ent ways, partially due to varying activity against normal
bowel ora as well as different excretion rates into the
bowel.20,36,3842 The present analysis prospectively com-
pared the frequency with which the standard use of triple
therapy or ertapenem for perforated appendicitis in children
was associated with bowel colonization by resistant bacteria
after antimicrobial therapy in patients enrolled in a random-
ized, comparative trial.
In this study, the prevalence of bowel colonization with
resistant bacteria to the study drug signicantly increased
from baseline to the end of therapy in the standard triple-
therapy group. The acquisition rate of resistant bacteria was
signicantly higher among participants treated with triple
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
Dalgic et al.
therapy (18.5%) than among those treated with ertapenem
(1.9%). Overall, no isolate of ertapenem-resistant Enterobac-
teriaceae emerged during therapy in ertapenem-treated
patients. In addition, the prevalence of ESBL-producing Enter-
obacteriaceae increased during therapy among triple-thera-
py recipients.
Clinical and epidemiological consequences of bowel colo-
nization with resistant bacteria cannot be drawn from our
data; however, rectal colonization with resistant microorgan-
isms may predict the nosocomial spread and subsequent
development of serious infections with bacteria that are
hard to treat.38,4349
Limitations of our study include the type of operative ap-
proach and the sample size. First, although our ndings do not
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
demonstrate a signicant difference in the rate of postinfectious
complications regarding the type of operation, recently pub-
lished an article by Galli et al demonstrated the superiority of LA
in patients with perforated appendicitis with regard to the
length of hospital stay and overall postoperative complica-
tions.50 Second, in the literature, there is limited information
about the rate of postoperative infectious complications after the
surgery of complicated appendicitis for children treated with the
triple-therapy and/or ertapenem regimens. In our study, we
estimated that the minimal sample size based on postoperative
infectious complications was 59 from each group from the article
published by St Peter et al.25 Further studies are needed to
establish the rate of overall postoperative complications in
children treated with these antibiotics.
Although there are numerous reports concerning the ideal
management of children with perforated appendicitis, there is
clearly need for more data. Ertapenem was generally well
tolerated and had a similar safety and tolerability prole to
triple therapy in this study. Bowel colonization with resistant
bacteria was also less likely to occur after ertapenem treatment
than triple therapy. The results of this study suggest that
ertapenem may be a useful option that could eliminate the
need for combination and/or multidosed antibiotic regimens for
the empiric treatment of perforated appendicitis in children.
Conict of Interest
None.
References
1 Dougherty SH, Sirinek KR, Schauer PR, et al. Ticarcillin/clavulanate
compared with clindamycin/gentamicin (with or without ampi-
cillin) for the treatment of intra-abdominal infections in pediatric
and adult patients. Am Surg 1995;61(4):297303
2 Yellin AE, Johnson J, Higareda I, et al. Ertapenem or ticarcillin/
clavulanate for the treatment of intra-abdominal infections or
acute pelvic infections in pediatric patients. Am J Surg 2007;194
(3):367374
3 Curran TJ, Muenchow SK. The treatment of complicated appendi-
citis in children using peritoneal drainage: results from a public
hospital. J Pediatr Surg 1993;28(2):204208
4 Gollin G, Abarbanell A, Moores D. Oral antibiotics in the manage-
ment of perforated appendicitis in children. Am Surg 2002;68
(12):10721074
 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
5 Lund DP, Murphy EU. Management of perforated appendicitis in
children: a decade of aggressive treatment. J Pediatr Surg 1994;29
(8):11301133, discussion 11331134
6 Fishman SJ, Pelosi L, Klavon SL, ORourke EJ. Perforated appendici-
tis: prospective outcome analysis for 150 children. J Pediatr Surg
2000;35(6):923926
7 Newman K, Ponsky T, Kittle K, et al. Appendicitis 2000: variability
in practice, outcomes, and resource utilization at thirty pediatric
hospitals. J Pediatr Surg 2003;38(3):372379, discussion 372379
8 Vane DW, Fernandez N. Role of interval appendectomy in the
management of complicated appendicitis in children. World J Surg
2006;30(1):5154
9 St Peter SD, Little DC, Calkins CM, et al. A simple and more cost-
effective antibiotic regimen for perforated appendicitis. J Pediatr
Surg 2006;41(5):10201024
10 Kohler J, Dorso KL, Young K, et al. In vitro activities of the potent,
broad-spectrum carbapenem MK-0826 (L-749,345) against broad-
spectrum beta-lactamase-and extended-spectrum beta-lactamase-
producing Klebsiella pneumoniae and Escherichia coli clinical iso-
lates. Antimicrob Agents Chemother 1999;43(5):11701176
11 Gill CJ, Jackson JJ, Gerckens LS, et al. In vivo activity and pharma-
cokinetic evaluation of a novel long-acting carbapenem antibiotic,
MK-826 (L-749,345). Antimicrob Agents Chemother 1998;42
(8):19962001
12 Goldstein EJ, Citron DM, Vreni Merriam C, Warren Y, Tyrrell KL.
Comparative in vitro activities of ertapenem (MK-0826) against
1,001 anaerobes isolated from human intra-abdominal infections.
Antimicrob Agents Chemother 2000;44(9):23892394
13 Pelak BA, Woods GL, Teppler H, Friedland I, Bartizal K, Motyl M.
Comparative in-vitro activities of ertapenem against aerobic
bacterial pathogens isolated from patients with complicated
intra-abdominal infections. J Chemother 2002;14(3):227233
14 Arguedas A, Cespedes J, Botet FA, et al; Protocol 036 Study Group.
Safety and tolerability of ertapenem versus ceftriaxone in a
double-blind study performed in children with complicated uri-
nary tract infection, community-acquired pneumonia or skin and
soft-tissue infection. Int J Antimicrob Agents 2009;33(2):163167
15 Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and manage-
ment of complicated intra-abdominal infection in adults and
children: guidelines by the Surgical Infection Society and the
Infectious Diseases Society of America. Clin Infect Dis 2010;50
(2):133164
16 Mazuski JE, Sawyer RG, Nathens AB, et al; Therapeutic Agents
Committee of the Surgical Infections Society. The Surgical Infec-
tion Society guidelines on antimicrobial therapy for intra-abdom-
inal infections: evidence for the recommendations. Surg Infect
(Larchmt) 2002;3(3):175233
17 Sanabria A. Decision-making analysis for selection of antibiotic
treatment in intra-abdominal infection using preference measure-
ments. Surg Infect (Larchmt) 2006;7(5):453462
18 Safdar N, Maki DG. The commonality of risk factors for nosocomial
colonization and infection with antimicrobial-resistant Staphylo-
coccus aureus, enterococcus, gram-negative bacilli, Clostridium
difcile, and Candida. Ann Intern Med 2002;136(11):834844
19 Bodey GP, Fainstein V, Garcia I, Rosenbaum B, Wong Y. Effect of
broad-spectrum cephalosporins on the microbial ora of recipi-
ents. J Infect Dis 1983;148(5):892897
20 Paterson DL. Collateral damage from cephalosporin or quinolone
antibiotic therapy. Clin Infect Dis 2004;38(Suppl 4):S341S345
21 Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic
therapy on the density of vancomycin-resistant enterococci in the
stool of colonized patients. N Engl J Med 2000;343(26):19251932
22 Hoyen CK, Pultz NJ, Paterson DL, Aron DC, Donskey CJ. Effect of
parenteral antibiotic administration on establishment of intestinal
colonization in mice by Klebsiella pneumoniae strains producing
extended-spectrum beta-lactamases. Antimicrob Agents Chemo-
ther 2003;47(11):36103612
Dalgic et al. 417
23 Donskey CJ. The role of the intestinal tract as a reservoir and source
for transmission of nosocomial pathogens. Clin Infect Dis 2004;39
(2):219226
24 Flynn DM, Weinstein RA, Nathan C, Gaston MA, Kabins SA.
Patients endogenous ora as the source of nosocomial Enter-
obacter in cardiac surgery. J Infect Dis 1987;156(2):363368
25 St Peter SD, Tsao K, Spilde TL, et al. Single daily dosing ceftriaxone
and metronidazole vs standard triple antibiotic regimen for
perforated appendicitis in children: a prospective randomized
trial. J Pediatr Surg 2008;43(6):981985
26 Clinical and Laboratory Standards Institute (CLSI). Performance
standards for antimicrobial susceptibility testing; Nineteenth
informational supplement, M100S19. Wayne, PA: Clinical and
Laboratory Standards Institute; 2009
27 Goldin AB, Sawin RS, Garrison MM, Zerr DM, Christakis DA.
Aminoglycoside-based triple-antibiotic therapy versus monother-
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
apy for children with ruptured appendicitis. Pediatrics 2007;119
(5):905911
28 Emil S, Laberge JM, Mikhail P, et al. Appendicitis in children: a ten-
year update of therapeutic recommendations. J Pediatr Surg 2003;
38(2):236242
29 Muehlstedt SG, Pham TQ, Schmeling DJ. The management of
pediatric appendicitis: a survey of North American Pediatric
Surgeons. J Pediatr Surg 2004;39(6):875879, discussion 875879
30 Chen C, Botelho C, Cooper A, Hibberd P, Parsons SK. Current
practice patterns in the treatment of perforated appendicitis in
children. J Am Coll Surg 2003;196(2):212221
31 Nadler EP, Reblock KK, Ford HR, Gaines BA. Monotherapy versus
multi-drug therapy for the treatment of perforated appendicitis in
children. Surg Infect (Larchmt) 2003;4(4):327333
32 Maltezou HC, Nikolaidis P, Lebesii E, Dimitriou L, Androulakakis E,
Kafetzis DA. Piperacillin/Tazobactam versus cefotaxime plus met-
ronidazole for treatment of children with intra-abdominal infec-
tions requiring surgery. Eur J Clin Microbiol Infect Dis 2001;20
(9):643646
33 Goldstein EJ, Snydman DR. Intra-abdominal infections: review of
the bacteriology, antimicrobial susceptibility and the role of
ertapenem in their therapy. J Antimicrob Chemother 2004;53
(Suppl 2):ii29ii36
34 DiNubile MJ, Friedland IR, Chan CY, et al. Bowel colonization with
vancomycin-resistant enterococci after antimicrobial therapy for
intra-abdominal infections: observations from 2 randomized
comparative clinical trials of ertapenem therapy. Diagn Microbiol
Infect Dis 2007;58(4):491494
35 Bhalla A, Pultz NJ, Ray AJ, Hoyen CK, Eckstein EC, Donskey CJ.
Antianaerobic antibiotic therapy promotes overgrowth of antibi-
otic-resistant, gram-negative bacilli and vancomycin-resistant
enterococci in the stool of colonized patients. Infect Control
Hosp Epidemiol 2003;24(9):644649
36 Lonard F, Andremont A, Leclerq B, Labia R, Tancrde C. Use of
beta-lactamase-producing anaerobes to prevent ceftriaxone from
degrading intestinal resistance to colonization. J Infect Dis 1989;
160(2):274280
37 Pletz MW, Rau M, Bulitta J, et al. Ertapenem pharmacokinetics and
impact on intestinal microora, in comparison to those of ceftri-
axone, after multiple dosing in male and female volunteers.
Antimicrob Agents Chemother 2004;48(10):37653772
38 Piroth L, Aub H, Doise JM, Vincent-Martin M. Spread of extended-
spectrum beta-lactamase-producing Klebsiella pneumoniae: are
beta-lactamase inhibitors of therapeutic value? Clin Infect Dis
1998;27(1):7680
39 Beaber JW, Hochhut B, Waldor MK. SOS response promotes
horizontal dissemination of antibiotic resistance genes. Nature
2004;427(6969):7274
40 Berkowitz FE, Metchock B. Third generation cephalosporin-resis-
tant gram-negative bacilli in the feces of hospitalized children.
Pediatr Infect Dis J 1995;14(2):97100
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
418 Ertapenem versus Standard Triple Antibiotic Therapy for the Treatment of Perforated Appendicitis
41 Cavallaro V, Catania V, Bonaccorso R, et al. Effect of a broad-spectrum
cephalosporin on the oral and intestinal microora in patients
undergoing colorectal surgery. J Chemother 1992;4(2):8287
42 Guggenbichler JP, Allerberger FJ, Dierich M. Inuence of cepha-
losporines III generation with varying biliary excretion on fecal
ora and emergence of resistant bacteria during and after cessa-
tion of therapy. Padiatr Padol 1986;21(4):335342
43 Cosgrove SE, Kaye KS, Eliopoulous GM, Carmeli Y. Health and
economic outcomes of the emergence of third-generation cepha-
losporin resistance in Enterobacter species. Arch Intern Med
2002;162(2):185190
44 Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial
treatment of infections: a risk factor for hospital mortality among
critically ill patients. Chest 1999;115(2):462474
45 Livermore DM. Multiple mechanisms of antimicrobial resistance
in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis
2002;34(5):634640
46 Ostrowsky BE, Venkataraman L, DAgata EM, Gold HS, DeGirolami
PC, Samore MH. Vancomycin-resistant enterococci in intensive
European Journal of Pediatric Surgery Vol. 24 No. 5/2014
Dalgic et al.
care units: high frequency of stool carriage during a non-outbreak
period. Arch Intern Med 1999;159(13):14671472
47 Paterson DL, Ko WC, Von Gottberg A, et al. Outcome of cephalo-
sporin treatment for serious infections due to apparently suscep-
tible organisms producing extended-spectrum beta-lactamases:
implications for the clinical microbiology laboratory. J Clin Micro-
biol 2001;39(6):22062212
48 Paterson DL, Ko WC, Von Gottberg A, et al. International prospec-
tive study of Klebsiella pneumoniae bacteremia: implications of
extended-spectrum beta-lactamase production in nosocomial
Infections. Ann Intern Med 2004;140(1):2632
49 Trouillet JL, Vuagnat A, Combes A, Kassis N, Chastre J, Gibert C.
Pseudomonas aeruginosa ventilator-associated pneumonia: com-
parison of episodes due to piperacillin-resistant versus pipera-
cillin-susceptible organisms. Clin Infect Dis 2002;34(8):1047
1054
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
50 Galli R, Banz V, Fenner H, Metzger J. Laparoscopic approach in
perforated appendicitis: increased incidence of surgical site infec-
tion? Surg Endosc 2013;27(8):29282933
Copyright of European Journal of Pediatric Surgery is the property of Georg Thieme Verlag
Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv
without the copyright holder's express written permission. However, users may print,
download, or email articles for individual use.