A complete course of intravenous antibiotics vs a
combination of intravenous and oral antibiotics for
perforated appendicitis in children: a prospective,
Jason D. Fraser, Pablo Aguayo, Charles M. Leys, Scott J. Keckler, Jason G. Newland,
Susan W. Sharp, John P. Murphy, Charles L. Snyder, Ronald J. Sharp,
Walter S. Andrews, George W. Holcomb III, Daniel J. Ostlie, Shawn D. St. Peter⁎
Department of Surgery, The Children's Mercy Hospital, Kansas City, MO 64108, USA
Received 13 February 2010; accepted 22 February 2010
Introduction: In a previous prospective randomized trial, we found a once-a-day regimen of ceftriaxone
and metronidazole to be an efficient, cost-effective treatment for children with perforated appendicitis.
In this study, we evaluated the safety of discharging patients to complete an oral course of antibiotics.
Methods: Children found to have perforated appendicitis at the time of laparoscopic appendectomy were
enrolled in the study. Perforation was defined as a hole in the appendix or fecalith in the abdomen.
Patients were randomized to antibiotic treatment with either once daily dosing of ceftriaxone and
metronidazole for a minimum of 5 days (intravenous [IV] arm) or discharge to home on oral
amoxicillin/clavulanate when tolerating a regular diet (IV/PO arm) to complete 7 days.
Results: One hundred two patients underwent laparoscopic appendectomy for perforated appendicitis.
On presentation, there were no differences in age, weight, sex distribution, days of symptoms, maximum
temperature, or leukocyte count between the 2 groups. There was no difference in the postoperative
abscess rate between the two treatment groups. Discharge was possible before day 5 in 42% of the
patients in the IV/PO arm.
Conclusions: When patients are able to tolerate a regular diet, completing the course of antibiotics orally
decreases hospitalization with no effect on the risk of postoperative abscess formation.
© 2010 Elsevier Inc. All rights reserved.
Intravenous antibiotics are standard medical management
during the recovery period after an operation for perforated
appendicitis. However, several parameters of this therapy
vary among pediatric surgeons including choice of
antibiotic, route of antibiotic administration and length of
treatment [1-3]. Many surgeons treat perforated appendicitis
⁎Corresponding author. Center for Prospective Clinical Trials,
Department of Surgery, Children's Mercy Hospital, Kansas City, MO
64108, USA. Tel.: +1 816 983 3575; fax: +1 816 983 6885.
E-mail address: firstname.lastname@example.org (S.D. St. Peter).
0022-3468/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
Journal of Pediatric Surgery (2010) 45, 1198–1202
postoperatively initially with intravenous (IV) antibiotics
and then continue treatment with oral antibiotics at
discharge [4-7]. In a previous prospective randomized
trial, we found a once-a-day regimen of ceftriaxone and
metronidazole (CM) to be an efficient, safe, and cost-
effective treatment for children with perforated appendicitis.
Under that protocol, a 5-day inpatient course of IV
antibiotic therapy was utilized after which patients were
discharged without oral antibiotics . In the current study,
we evaluated the efficacy and impact of allowing patients to
complete an oral course of antibiotics at home when they
were tolerating a regular diet and afebrile before the fifth
Approval was obtained from the Children's Mercy
Hospital Internal Review Board (IRB) (IRB# 07 02-031)
before enrolling patients in this study. Patients were
subsequently enrolled only after obtaining consent from the
patient's legal guardian. The consent forms and consent
process were carefully evaluated by the IRB on a continual
basis. The study was registered with clinicaltrials.gov at the
inception of enrollment (NCT# 00462020).
The study population consisted of children with perforat-
ed appendicitis. Inclusion criteria began with the operative
finding of perforation. Perforation was defined as an
identifiable hole in the appendix or a fecalith in the
abdomen. In cases where this was not obvious at
laparoscopic appendectomy, the extracted specimen was
carefully inspected for the presence of hole . Patients with
documented allergies to the study antibiotics received an
alternative regimen and were not excluded.
Patients with a known severe concomitant process were
excluded. Those with an abscess identified by computed
tomographic (CT) scan before surgery were not included in
the study as they were eligible for another concurrent
After determination of perforation, patients were random-
izedto receive either ceftriaxone and metronidazole (CM) for
a minimum of 5 days (IV arm) or allowed the opportunity to
complete an oral course of amoxicillin/clavulanate at home
when tolerating a regular diet before day 5 (IV/PO arm). The
total length of antibiotic therapy in the IV/PO arm was 7 days
after appendectomy. Resuscitation fluid in all cases was
normal saline because of the concern about precipitation with
the use of the calcium-containing Lactated Ringers solution
when used with ceftriaxone.
1.3. Sample size
The power calculation for this study of 0.8 was based
on the post-operative abscess rate of 20% established from
our previously published prospective randomized trial
comparing once daily dosing of ceftriaxone and metroni-
dazole with ampicillin/gentamicin/clindamycin . A
sample size of 75 patients in each arm was calculated
with an α of .05.
An individual unit of randomization was utilized in a non-
stratified sequence in blocks of 10. Following the operative
finding of perforation, the family was approached for
consent. The randomization sequence was then accessed to
identify the next allotment after the consent was signed.
Appendectomies were performed by one of the 7
institutional staff surgeons as dictated by the call schedule.
All of the appendectomies were initiated laparoscopically
and performed with a 3-port technique. Nasogastric tubes
were not used after the operation .
Postoperative orders were controlled using a standard
electronic order setfor all operations. All patients received an
IV dose of CM preoperatively and until the time of discharge
according to the protocol that was validated in a previous
prospective trial .
In the IV arm, patients received at least 5 days of IV
CM at which point a white blood cell count was obtained.
If this was normal, they were discharged without further
antibiotics. If abnormal, they received a minimum 2
additional days of IV therapy with a repeat white blood
In the IV/PO arm, patients received CM until they were
able to tolerate a regular diet and were afebrile for the
previous 12 hours. If this occurred by the afternoon of
postoperative day 4, then they were discharged home on
oral amoxicillin/clavulanate to complete a total 7-day
course of antibiotics. If they were in the hospital on the
morning of postoperative day 5, then treatment was
identical to the IV group.
Patients who were still in the hospital in either group
with fever and elevated white blood cell count at or after
day 7 underwent CT to identify an abscess. Patients
returning to the hospital after discharge with abdominal
pain and an elevated white blood cell count also underwent
a CT scan. All patients with an abscess were treated with
2 weeks of IV CM with percutaneous drainage when the
radiologist felt this was feasible. All patients were seen by
the surgeon performing the appendectomy 2 to 4 weeks
after discharge or after the completion of outpatient therapy
for an abscess.
1199 Intravenous and oral antibiotics for perforated appendicitis
1.6. Data collection
All data were collected prospectively. At the time of
presentation, the patient's age, weight, body mass index, sex,
days of symptoms, maximum temperature, and leukocyte
count were collected.
Operative variables collected included the operative
approach, and all intraoperative and postoperative complica-
tions including conversion to the open approach.
The primary outcome variable was the postoperative
abscess rate. The other outcome variables included maxi-
mum daily temperatures for each of the first 5 post-operative
days, time to initial oral intake, time to regular diet, length of
postoperative hospitalization, length of antibiotic therapy,
medication charges, abscess rate, wound infection rate, total
healthcare visits, rehospitalizations, and any abnormal
findings during the postoperative or follow-up visits.
1.7. Statistical analysis
Continuous variables were compared using an indepen-
dent sample, two-tailed Student t test. Discrete variables
were analyzed with Fisher exact test. Significance was
defined as P ≤ .05. Descriptive statistics were calculated as
mean ± SD. All patients were analyzed in an intention to treat
manner. An interim analysis was planned after 100 patients
From March 2007 through October 2008, 102 patients
were enrolled in the study. Accrual of patients was
terminated after the interim analysis when the primary
outcome variable (postoperative abscess rate) was found to
be identical between the 2 groups.
There was no difference between the 2 groups in age,
weight, sex, or mean maximum temperature on admission
There was no difference in operating time between the
groups (Table 2). There were no conversions to an open
procedure and no intraoperative or immediate postoperative
No difference existed in the time to full oral intake, length
of postoperative hospitalization, total health care visits, or
abscess rate between the 2 groups. Patients in the IV/PO
group had significantly shorter hospital stays (Table 2), and
discharge was possible before 5 days in 42% of patients in
the IV/PO group.
Despite the large volume of children with perforated
appendicitis, there is a paucity of prospective data on which
management strategies can be based. As a result, wide
variability exists in the postoperative management of these
patients. A survey of APSA members in 2003 showed that
63.4% use 4 to 7 days of IV antibiotics, while only 3.2% use
1 to 3 days of IV antibiotics . This still leaves a significant
portion of pediatric surgeons who routinely employ at least
8 days of IV antibiotics. A database review from 2000
showed that the median length of the antibiotic course for
children with perforated appendicitis was 5.9 days . Some
clinicians use a predetermined length of antibiotic therapy,
whereas others base the length of therapy on clinical
parameters and the patient's condition [5,7,10,11]. Three
days of antibiotics has been suggested to be sufficient by
some but others have used a 10-day course of IV antibiotics
The use of oral antibiotics after discharge in patients with
perforated appendicitis with a relative attenuated course of
IV antibiotics has been demonstrated to be effective in
smaller series. A 14-day course combining IV antibiotics and
oral trimethoprim/sulfamethoxazole and metronidazole has
IV (n = 52) IV/PO (n = 50)P
Mean age (y)
Mean weight (kg)
Mean duration of
9.7 ± 4.2
41.2 ± 23.3
37.9 ± 1.0
10.1 ± 4.6
43.2 ± 24.1
38.1 ± 1.0
2.6 ± 1.33.0 ± 1.5 .36
IV (n = 52) IV/PO (n = 50) P value
Mean operative time
Mean time to regular
Mean length of stay
after operation (d:h)
41:06 ± 15:36 46:30 ± 19:42.13
68:00 ± 35:06 61:42 ± 32:12 .36
6:06 ± 2:00 4:48 ± 2:36 .01
3.1 ± 1.4
3.1 ± 1.2
1200 J.D. Fraser et al.
been demonstrated in a retrospective series to be as safe as
and more cost-effective than a 14-day course of IV
antibiotics . Similarly, a small prospective randomized
pilot study demonstrated that discharge of patients on return
of gastrointestinal function with oral amoxicillin/clavulanate
and metronidazole to complete a total 10-day course of
antibiotics was as safe as a standard 10-day IV antibiotic
course . An even more aggressive management strategy of
discharging patients with a 7-day course of oral trimetho-
prim/sulfamethoxazole and metronidazole when oral intake
was tolerated, regardless of the presence of leukocytosis or
fever, was deemed to be safe . At present, we would
caution about discharging patients with fever or leukocyto-
sis, even if discharged on antibiotics because we have found
both the presence of an elevated leukocyte count and fever
on postoperative day 5 to be predictive of a postoperative
abscess in children with perforated appendicitis .
Although the aforementioned studies on perforated
appendicitis center on the appropriate antibiotic regimen,
they are not necessarily generalizable in that there is no
consistent definition of what constitutes perforated appen-
dicitis. These series may contain patients with purulent
disease (without a definite hole in the appendix) which we
have previously shown to possess an extremely low risk
(b1%) of developing a postoperative abscess . An
important consideration for these data is the use of an
evidence-based definition of perforation of a hole in the
appendix or stool in the abdomen, which clearly separates
those at risk for developing an intraabdominal abscess from
those that are not . This definition allows the results of
this trial to be generalizable and reproducible while
removing interrater variability.
Clearly from the available literature, a variety of
treatment options exist, but none of these is based on
prospective randomized data. In our previous randomized
trial, the postoperative antibiotic length was set at 5 days. In
our current trial, 42% of patients were able to be discharged
home before 5 days when they were able to tolerate a diet
and were afebrile. Another way to look at these data is that
more than half of the patients with perforated appendicitis
require at least 5 days before tolerating a regular diet and
becoming afebrile. This study simply shows that discharge
to home on oral antibiotics when the patient is tolerating a
regular diet and is afebrile does not affect outcome. The
next logical step would be to examine whether the home
course of oral antibiotics influences the postoperative
abscess rate or if this is unnecessary. Cognizant of the
concerns over the development of resistant organisms and
excess healthcare costs, a prospective study examining this
question is under way.
 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
 Chen C, Botelho C, Cooper A, et al. Current practice patterns in the
treatment of perforated appendicitis in children. J Am Coll Surg
 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;38:372-9.
 Gollin G, Abarbanell A, Moores D. Oral antibiotics in the management
of perforated appendicitis in children. Am Surg 2002;68:1072-4.
 Snelling CM, Poenaru D, Drover JW. Minimum postoperative
antibiotic duration in advanced appendicitis in children: a review.
Pediatr Surg Int 2004;20:838-45.
 Rice HE, Brown RL, Gollin G, et al. Results of a pilot trial comparing
prolonged intravenous antibiotics with sequential intravenous/oral
antibiotics for children with perforated appendicitis. Arch Surg
 Adibe OO, Barnaby K, Dobies J, et al. Postoperative antibiotic therapy
for children with perforated appendicitis: long course of intravenous
antibiotics versus early conversion to an oral regimen. Am J Surg
 St Peter SD, Sharp SW, Holcomb III GW, et al. An evidence-based
definition for perforated appendicitis derived from a prospective
randomized trial. J Pediatr Surg 2008;43:2242-5.
 St Peter SD, Little DC, Calkins CM, et al. Does routine nasogastric
tube placement after an operation for perforated appendicitis make a
difference? J Surg Res 2007;143:66-9.
 Fishman SJ, Pelosi L, Klavon SL, et al. Perforated appendicitis:
prospective outcome analysis for 150 children. J Pediatr Surg 2000;35:
 Emil S, Taylor M, Ndiforchu F, et al. What are the true advantages of a
pediatric appendicitis clinical pathway? Am Surg 2006;72:885-9.
 Fraser JD, Aguayo P, Sharp SW, et al. Physiologic predictors of
post-operative abscess in children with perforated appendicitis:
Subset analysis from a prospective randomized trial. J Surg Res
Kurt Heiss, MD (Atlanta, GA): Did patients who underwent
a CT scan because of an abnormal WBC have some
intervention that actually made the CT scan necessary at
that point? Was the CT scan useful in making treatment
decisions or interventions?
Jason Fraser, MD (Kansas City, MO): The decision to
obtain CT scans was based upon clinical criteria. The
patients either had an elevated white blood cell count or
fever suggesting that they had an intra-abdominal abscess
or were still sick. If they did have an abscess they were
percutaneously drained. If abscesses were not amenable
to percutaneous drainage, assuming that they had an
abscess, patients were continued on IV antibiotics and
sometimes discharged home with a prolonged course of
Mary Brandt, MD (Houston, TX): How did you power the
study ahead of time to determine the numbers?
Jason Fraser, MD: The power was studied based upon the
primary outcome variable in the study, which was the
1201Intravenous and oral antibiotics for perforated appendicitis
postoperative abscess rate. We used our 20% postoper- Download full-text
ative abscess rate from the previous prospective trial of
20% using a power of 0.8 and an alpha of 0.05 that gave
us a total of 150 patients, where the interim analysis
plan did 100 patients. At that time, the difference
between the two groups, the P value was one, and so,
continuing beyond that would be a moot point.
Therefore, our study was stopped at 100 patients but
the total goal was 150 patients until the interim analysis
Mary Brandt, MD: I have a question regarding problems
with Clostridium difficile colitis and with MRSA. I just
wondered if you saw either of these infections or if that
was one of the endpoints you looked at?
Jason Fraser, MD: We did not look at this particular
endpoint. Infections with C. diff and MRSA are very
reasonable issues to think about. I think minimizing
antibiotics is a very important factor to consider. A future
study may evaluate the necessity of whether these patients
actually need to go home on antibiotics.
Daniel Robie, MD (Jacksonville, FL): I'm not aware of any
data that support the use of oral antibiotics in the setting of
appendicitis. We just reviewed this at my institution; we
couldn't find any real convincing data.
Jason Fraser, MD: No, the data is very scarce and mostly
retrospective. Hopefully, this will help clarify some of
that data. A future question may be whether they need the
antibiotics at all.
Daniel Robie, MD: How did you choose five days for your
IV group? Was that just an arbitrary choice?
Jason Fraser, MD: No, the five days was the same
treatment duration from the protocol we had used in our
previous prospective trial. Since the postoperative abscess
rate remained our primary outcome measure, we felt that
we could use the same duration of time for the IV therapy
for this study.
Daniel Robie, MD: Many of us base the duration of
antibiotics on clinical criteria, such as 24 or 48 hours of
being afebrile, normal white count, normal differential.
If these happen by post-op day three or four, we'll let
them go home. I find it interesting that are many
references on using five days as an arbitrary duration of
IV antibiotic therapy.
1202 J.D. Fraser et al.