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7433 SJS103110.1177/1457496913497433Use of pre- or postoperative antibiotics for appendicitis K. Daskalakis, et al.

SYSTEMATIC REVIEW Scandinavian Journal of Surgery  103:  14­–20,  2013

The use of pre- or postoperative antibiotics in surgery


for appendicitis: A systematic review

K. Daskalakis, C. Juhlin and L. Påhlman


Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden

Abstract
Background and Aim: The aim of this study was to review the literature regarding the use
of pre- and/or postoperative antibiotics in the management of appendicitis, using data
obtained from PubMed and the Cochrane Library.
Material and Methods: A literature search was conducted using the terms “appendicitis”
combined with “antibiotics.” Studies were selected based on relevance for the evidence
on prophylactic and postoperative treatment with regard to the route and duration of drug
administration and the findings of surgery.
Results: Patients with acute appendicitis should receive preoperative, broad-spectrum
antibiotics. The use of postoperative antibiotics is only recommended in cases of
perforation, and treatment should then be given intravenously, for a minimum period
of 3–5 days for adult patients, until clinical signs such as fever resolve and laboratory
parameters such as C-reactive protein curve and white blood cell (WBC) start to decline.
Conclusion: Preoperative antibiotic prophylaxis is recommended in all patients with
acute appendicitis, whereas postoperative antibiotics only in cases of perforation.

Key words: Acute appendicitis; perforated appendicitis; appendectomy; antibiotic prophylaxis; antibiotic
treatment; oral antibiotics; intravenous antibiotics

Introduction accumulative life risk is 7% (1). The result of appen-


dectomy after clinically suspected appendicitis has
Appendicitis is the most common cause of acute
historically shown a “correct” diagnosis in 70%–
abdominal pain requiring surgical intervention. The
75% of cases, and the frequency of appendicitis with
incidence of appendicitis is generally reported in
perforation has been 15%–30% (1). More recently,
100 out of 100,000 inhabitants annually, and the
introduction of diagnostic imaging aids, specifically
computed tomography (CT), has allowed more
accurate diagnosis of appendicitis (2). The rates of
Correspondence: finding a normal appendix at surgery, in studies
Kosmas Daskalakis, M.D. where CT was part of the diagnostic process, were
Department of Surgical Science 3.3%–7.2%, compared to rates of 3.2%–15% for the
Uppsala University patients who were immediately referred for appen-
University Hospital dectomy. At the same time, the liberal use of CT
scanning and laparoscopy has led to an increase in
Geijersgatan 18b
the number of cases with detected appendicitis,
75226 Uppsala with a subsequent higher appendectomy rate,
Sweden implying that the disease may heal by itself
Email: kosmas.daskalakis@akademiska.se (3). Although antibiotics may be used as primary
Use of pre- or postoperative antibiotics for appendicitis 15

English, with a publication date ranging from 1994 to


Titles identiied through December 2011 were included. The selection was
database searching n=633
based on relevance for the following questions:
Titles excluded n=572
1a. Should preoperative antibiotics be used for
patients with suspicious acute appendicitis prior
Abstracts screened n=61
to surgery?
1b. What preoperative antibiotics should then be
used?
Abstracts excluded n=25
2a. Is there any benefit in treating patients postopera-
tive with antibiotics in case of phlegmonous, gan-
grenous, or perforated appendicitis, respectively?
Full-text artiles assesed for 2b. What postoperative antibiotics should then be
eligibility n=36 used, what route, and for how long?
Full text articles exluded (Pediatric
RCTs and trials on intra-abdominal A total of 633 study titles were identified by the ini-
infections) n=23
tial search strategy, and of these, 572 were excluded
after title searching, based on the relevance for the
Studies eligible for inclusion in the questions mentioned above. A total of 61 potential
review n=13 (twelve RCTs and one
Cochrane Database review).
articles were selected. In the next stage, abstracts were
reviewed and 36 articles were selected for further
review of full text publications. 79 study titles, report-
Fig. 1. Flowchart. ing patients with periappendicular abscess not oper-
RCTs: randomized controlled trials. ated upon, are excluded from this review. All
potentially eligible studies were randomized con-
trolled trials (RCTs). Of these, 17 trials addressing to
definitive treatment for selected patients with sus- intra-abdominal infections were identified, but not
pected uncomplicated appendicitis, appendectomy included as they did not provide data on acute appen-
is still the gold standard therapy (4). dicitis alone. Six pediatric RCTs were excluded as ado-
Appendiceal abscess or phlegmon is found in 3.8% lescents are not directly comparable with adults,
of patients with appendicitis. These patients are especially regarding the clinical course of acute appen-
treated conservatively as immediate surgery is associ- dicitis. Finally, 12 trials, plus one Cochrane Database
ated with higher morbidity (5). Moreover, the devel- meta-analysis addressing acute appendicitis, were
opment of CT and ultrasound (US) has improved the included in this analysis (Fig. 1).
diagnosis of enclosed inflammation and made drain- Of these 12 trials, 8 had two treatment arms and
age of intra-abdominal abscesses easier. The risk of 4 had three or more arms. Age of the included
recurrence with nonsurgical treatment is 7.4%, and a patients ranged from 4 to 80 years. Eleven studies
malignant disease is detected in 1.2% of patients dur- reported the male/female ratio. Five of the studies
ing follow-up (5). Interval appendectomy is not rec- classified the appendicitis either as simple or
ommended as a routine, and it should be done only uncomplicated and advanced or complicated. Ten
for special indications such as persisting complaints studies reported wound infection, six studies
that suggest appendicitis. reported intra-abdominal abscess and eight studies
With respect to antibiotic therapy, there is consider- reported length of stay in hospital.
able variability in the choice, duration, and route of The classification into phlegmonous, gangrenous,
administration in acute appendicitis treated opera- and perforated appendicitis was used for the purposes
tively. Moreover, there is an escalating problem with of this review. In several studies, the terms simple/
antibiotic resistance among bowel pathogens (6, 7), uncomplicated and complicated/advanced were
with an increased rate of antibiotic resistant bacteria. encountered, applying for phlegmonous and gangre-
Even after short course of antibiotic therapy, extended- nous/perforated appendicitis, respectively. In three
spectrum beta-lactamase (ESBL) resistance has been trials, the specimens were sent to pathology for the
found with increased costs, prolonged hospitalization, final diagnosis, whereas in the others, the classifica-
and increased mortality (8). Since antimicrobial use tion was based on the macroscopic appearance of the
proceeds to the emergence of antimicrobial resistance, appendix peroperatively. In none of the studies, pre-
optimized use of antibiotics is required. The purpose operative standardized radiological assessment was
of this review is to provide an overview of studies on performed. Seven studies reported an open McBurney
antibiotics for acute appendicitis treated operatively incision as the standardized method of surgery,
and to see whether evidence-based recommendation whereas in none of the studies was laparoscopy stand-
can be suggested. ardized.

Material and Methods Results


A search was made using PubMed and the Cochrane 1a. Should preoperative antibiotics be used for
Library database. Appendicitis and antibiotics were patients with suspicious acute appendicitis prior
selected as search terms. All studies, published in to surgery?
16 K. Daskalakis, et al.

Table 1
Summary of Cochrane Database review regarding use of antibiotics for appendicitis. Systemic antibiotics versus placebo.

Outcome No. of No. of Statistical method Effect size


studies participants

1. Wound infection 47 8812 Peto odds ratio (Peto,   0.33 (0.29, 0.38)
fixed, 95% CI)
2. Postoperative intra- 16 4468 Peto odds ratio (Peto,   0.43 (0.25, 0.73)
abdominal abscess fixed, 95% CI)
3. Length of stay in  8 1200 Mean, difference (IV, −1.69 (−1.78, −1.61)
hospital fixed, 95% CI)

CI: confidence interval.

Table 2
Data in studies on different regimens of antibiotic prophylaxis in acute appendicitis (11–14) and duration of IV antibiotics in cases of non-perforated
appendicitis (14, 15).

Studies Regimens n Wound infection Hospital stay

Ravari et al. (11) PO metronidazole 102 6% 2.3 ± 0.8


IV metronidazole 102 4% 2.7 ± 1.1
Kumarakrishnan IV metronidazole and gentamycin 60 n = 13 7.4 (not infected)−7.5
et al. (12) (infected)
IV metronidazole and ciprofloxacin 60 n=5 7.1 (not infected)−10.5
(infected)
IV metronidazole and cefotaxime 60 n=3 6.9 (not infected)−9
(infected)
Salam et al. (13) IV cefoxitin 124 2.4% (n = 3) 4–8 (not infected); 12–21
(infected)
IV piperacillin 126 4% (n = 5) 4–8 (not infected); 12–21
(infected)
Liberman et al. IV cefotetan 37 0 No data
(14) IV cefoxitin 45 11.1% (n = 5) No data
Three-dose (1-day) IV cefoxitin 54 1.9% (n = 1 patient No data
with abscess)
Mui et al. (15) Single-dose, preoperative IV 92 6.5% (n = 6) 4.3
cefuroxime and metronidazole
Three-dose (1-day) IV cefuroxime 94 6.4% (n = 6) 4.6
and metronidazole
5-day course of IV cefuroxime and 83 3.6% (n = 3) 4.8
metronidazole

PO: oral; IV: intravenous.

The Cochrane Database review supports that broad- In Andersen et  al. Cochrane meta-analysis (9), the
spectrum antibiotics given preoperatively are effective in most common antibiotics used were cephalosporin
decreasing wound infection and abscesses (9; Table 1). and imidazole derivatives.
This meta-analysis includes 45 studies and confirms an Four RCTs (Table 2; 11–14) have compared differ-
overall effect of antibiotics on reduction of infectious com- ent antibiotic regimens as prophylaxis for non-
plications, regardless of whether administered prophylac- perforated appendicitis. Ravari et al. (11) showed that
tically (a single-dose administration in case of normal single dose of oral metronidazole prior to operation
removed appendix or phlegmonous appendicitis) or as can provide a sufficient prophylaxis for non-perfo-
repetitive treatment in case of complicated appendicitis. rated appendicitis, when compared to single dose of
Regarding the timing of antibiotic treatment, intravenous (IV) metronidazole before surgery.
Almqvist et  al. (10) conducted a prospective rand- Kumarakrishnan et al. (12) showed that the combina-
omized trial on patients with gangrenous appendicitis tion of cefotaxime–metronidazole had the lowest
and showed that antibiotic treatment started during wound infection rate compared to metronidazole–
the operation is not significantly less effective, at pre- gentamycin and metronidazole–ciprofloxacin. Salam
venting infectious complications, than started prior to et al. (13) showed that prophylactic cefoxitin or piper-
surgery. acillin were similarly effective in minimizing the rate
of wound infections. A single-dose cefotetan was
1b. What preoperative antibiotics should then be equally effective as multiple-dose cefoxitin according
used? to the study by Liberman et al. (14).
Use of pre- or postoperative antibiotics for appendicitis 17

Table 3
Data in studies on IV regimens (16–18) and IV versus PO regimens (19, 20) in perforated appendicitis.

Group n Age IV days PO days Complications

Allo et al. (16) IV ticarcillin–clavulanate 64 12–76 3–5 – 2 (3.1%)


IV imipenem–cilastatin 73 12–59 3–5 – 3 (4.1%)
Hopkins et al. IV cefotetan 40 18–60 6.9 ± 1.7 – 4
(17) IV clindamycin–amikacin 36 18–55 6.5 ± 2.4 – 5
Berne et al. IV meropenem 63 18–59 6.1 ± 1.6 – 5
(18) IV tobramycin–clindamycin 66 18–57 7.3 ± 2.2 – 6
Banani and IV ceftizoxime (no pus) or IV ceftizoxime 120  4–50 3–6 – 17 (14.16%)
Talei (19) preoperatively and penicillin, chloramphenicol,
and gentamycin postoperatively (pus)
PO metronidazole 114  4–50 – 3–6 18 (15.78%)
Taylor et al. IV ampicillin–sulbactam—PO placebo 22 21.7 ± 11.8 4.3 7 6 (27.3%)
(20) IV ampicillin–sulbactam—PO amoxicillin– 23 19.9 ± 12.6 4.3 7 6 (26.1%)
clavulanic (<18 years) or levofloxacin (>18 years)

IV: intravenous; PO: oral.

There were no RCTs found comparing different Three RCTs (16–18) could be found comparing
regimens of antibiotic prophylaxis specifically regard- postoperative IV antibiotic regimens on patients with
ing perforated appendicitis. perforated appendicitis (Table 3; 16–18). Allo et al. (16)
showed that ticarcillin–clavulanate is as effective and
2a. Is there any benefit in treating patients postopera- safe as imipenem–cilastatin. Hopkins et  al. (17)
tive with antibiotics in case of phlegmonous, gan- showed that monotherapy with a second generation,
grenous, or perforated appendicitis, respectively? broad-spectrum cephalosporin, such as cefotetan, is
an effective regimen, and aminoglycosides as well as
Only two RCTs were designed to evaluate the effi- other more potent antimicrobials should be reserved
cacy of postoperative antibiotics in addition to pre- for resistant organisms or nosocomial infections. Berne
operative antibiotics in non-perforated appendicitis et al. (18) showed that meropenem was more effective
(Table 2; 14, 15). In the Liberman et  al. study (14), than tobramycin–clindamycin.
patients with phlegmonous appendicitis were rand- Antimicrobial therapy in studies mentioned above
omized to receive either preoperative cefotetan (n = commonly includes broad-spectrum agents effective
37), preoperative cefoxitin (n = 45), or preoperative against aerobic gram-negative and anaerobic organ-
cefoxitin followed by three postoperative doses isms.
of cefoxitin (n = 54). The single preoperative dose of Two studies (Table 3; 19, 20) were found address-
cefoxitin had a significantly higher wound infection ing to the treatment of acute perforated appendicitis
rate (11.1%) compared with the group that received with oral (PO) antibiotics. Banani and Talei (19) con-
both preoperative and postoperative cefoxitin (1.9%). ducted a trial comparing PO metronidazole both pre-
However, a single dose of cefotetan was as effica- and postoperatively versus IV ceftizoxime if there
cious as the combined course of preoperative and was no pus in the abdomen or postoperative triple
postoperative cefoxitin. Mui et  al. (15) investigated drug therapy with IV penicillin, chloramphenicol,
wound infection rates in a three-armed RCT includ- and gentamycin if there was visible pus during sur-
ing patients with non-perforated (both phlegmonous gery. The difference in complication rate was not sta-
and gangrenous) appendicitis. One group (n = 92) tistically significant. In the study by Taylor et al. (20),
received one preoperative dose of cefuroxime and patients received 2–5 days IV ampicillin–sulbactam
metronidazole, another group (n = 94) received an and were subsequently randomized to placebo or PO
additional three postoperative doses, and a third antibiotics consisting of amoxicillin–clavulanate for
group (n = 83) received postoperative antibiotics for patients above 18 years and levofloxacin for patients
an additional five consecutive days. No statistically below 18 years. No statistically significant difference
significant difference was found in the wound infec- for infectious complications was found in the two
tion rates between the three groups (6.5, 6.4, and 3.6, groups.
respectively). Studies (16–18) comparing different IV antibiotic
regimens for perforated appendicitis demonstrate a
2b. Which postoperative antibiotics should then be variation in the duration of treatment. Allo et al. (16)
used, what route, and for how long? used a protocol of 3–5 days, Hopkins et al. (17) a mini-
mum of 5 days, and Berne et al. (18) 5–9 days. All the
Postoperative antibiotic treatment is considered stand- above-mentioned studies commonly used the white
ard of care in cases of perforated appendicitis. blood cell (WBC) normalization and a period of 24–48
Subsequently, in all reviewed RCTs (16–21), all patients h without fever as criteria for the discontinuation of IV
received postoperative antibiotics. treatment.
18 K. Daskalakis, et al.

In the study by Taylor et  al. (21), a minimum IV Since the diagnostic approach was similar in all the
5-days antibiotic regimen versus no minimum IV regi- included RCTs, without CT scans or US scans in the
men was studied in patients with complicated appen- preoperative assessment, the diagnostic procedure
dicitis and showed no statistically significant does not have any impact on the results.
difference regarding infectious complications and Open surgery was the standard procedure in seven
average hospital stay. Clinical criteria for discontinu- trials, whereas laparoscopy in none. In all others, the
ing IV antibiotics in both groups included resolution method of surgery was not standardized. A Cochrane
of fever, improved abdominal signs and symptoms, Database systematic review by Sauerland et  al. (23)
and return of bowel function, with some surgeons also showed that diagnostic laparoscopy and laparoscopic
using a decrease in leukocytosis. appendectomy (either in combination or separately)
seem to have various advantages over open surgery.
Wound infections were less likely after laparoscopic
Discussion
than after open appendectomy, but the incidence of
This review is focused on the use of antibiotics in surgi- intra-abdominal abscesses increased. Diagnostic lapa-
cally treated appendicitis. Although conservative anti- roscopy reduced the risk of a negative appendectomy,
biotic treatment of acute appendicitis has been but this effect was stronger in fertile women as com-
investigated in several studies, appendectomy remains pared to unselected adults.
the standard treatment. This is supported by a Cochrane Based on this Cochrane Database review by
Database review by Wilms et  al. (4). Nonoperative Sauerland et al. (23), the use of laparoscopy and lapa-
management of uncomplicated appendicitis with anti- roscopic appendectomy is generally recommended in
biotics was associated with significantly fewer compli- patients with suspected uncomplicated appendicitis,
cations, but antibiotics alone had lower efficacy especially in young female, obese, and employed
compared to appendectomy. Moreover, the quality of patients. In cases of perforated appendicitis, intra-
RCTs on definitive antibiotic treatment of acute appen- abdominal abscesses are more likely to occur after
dicitis was low to moderate. laparoscopic surgery, and an open procedure or con-
Based on this meta-analysis (4), antibiotic treatment verting to open surgery after diagnostic laparoscopy
might be used as an alternative treatment in a good- should be considered.
quality RCT or in specific patients or conditions where Implications for clinical practice on the use of anti-
surgery is contraindicated, but this was not the scope biotics regarding the surgical technique cannot be
of this report. made based on this meta-analysis and no RCTs on
Data strongly support that patients with acute adult patients could be found on the subject, but the
appendicitis should receive preoperative, broad- principles used in open surgery are still valid for lapa-
spectrum antibiotics. For non-perforated (phlegmon- roscopic appendectomy.
ous or gangrenous) appendicitis, preoperative treat- A Cochrane Database meta-analysis (9) supports
ment is enough. If the appendicitis is perforated, the use of broad-spectrum IV antibiotic prophylaxis in
postoperative, broad-spectrum antibiotics are recom- acute appendicitis. The positive overall effect of anti-
mended. The period is still not defined, but a period of biotic prophylaxis on reduction of infectious compli-
3–5 days for adult patients is recommended. cations was seen even in cases of removed normal
Discontinuation of the IV treatment has been based on appendix, which supports the use of IV preoperative
clinical and laboratory criteria in all studied series, but antibiotic prophylaxis in all appendectomies (9).
the present knowledge does not support the use of oral Moreover, the Cochrane Database meta-analysis
antibiotics after the initial IV treatment. One large RCT results indicate that single doses have the same impact
on oral versus IV antibiotic postoperative treatment as multiple doses (9). In order to reduce cost, toxicity,
and one large RCT on the duration of postoperative and the risk of developing bacterial resistance, it is
treatment in perforated appendicitis are necessary. desirable to establish the shortest, effective prophy-
However, there are several important limitations. laxis for postoperative complications. Oral prophy-
The number of prospective RCTs on antibiotic treat- laxis prior to surgery in cases of non-perforated
ment of patients with acute appendicitis is too small appendicitis can be considered according to the study
and subsequently underpowered. Furthermore, this by Ravari et al. (11), but more RCTs on the subject are
review was neither addressing differences among necessary.
antibiotic types nor differences in local antibiotic For gangrenous appendicitis, it is difficult to draw
resistance. firm conclusions since several studies combine gan-
Another important limitation is that the classifica- grenous and perforated appendicitis. Studies that sep-
tion of acute appendicitis into phlegmonous, gangre- arate simple or advanced/complicated appendicitis
nous, and perforated is not followed by all the commonly include gangrenous appendicitis in the
reviewed RCTs. Current pathology reporting terms second group. On the contrary, the Mui et al. trial (15)
lack the necessary specificity to differentiate cases of pooled together phlegmonous and gangrenous appen-
clinically significant inflammation from clinically dicitis. There was no study providing data on dura-
unimportant mild inflammation in patients with tion of antibiotic treatment of gangrenous appendicitis
phlegmonous appendicitis and incidentally removed alone. Based on the studies of Liberman et al. (14), Mui
appendix (22). In this meta-analysis, the majority of et al. (15), and Andersen et al. (9), single-dose preop-
eligible RCTs used only a clinical classification based eratively administrated antibiotic treatment for phleg-
on the appearance of the appendix peroperatively. monous and gangrenous appendicitis is recommended.
Use of pre- or postoperative antibiotics for appendicitis 19

Table 4
Regimens that may be used for the treatment of perforated or abscessed appendicitis according to guidelines by the Surgical Infection Society and the
Infectious Diseases Society of America.

Regimen Mild-to-moderate severity: High risk or severity: severe


perforated or abscessed physiologic disturbance, advanced
appendicitis age, or immunocompromised state

Single agent •  Cefoxitin •  Imipenem–cilastatin


•  Ertapenem •  Meropenem
•  Moxifloxacin •  Doripenem
•  Tigecycline •  Piperacillin–tazobactam
•  Ticarcillin–clavulanic acid
Combinations •  Cefazolin •  Cefepime
•  Cefuroxime •  Ceftazidime
•  Ceftriaxone •  Ciprofloxacin
•  Cefotaxime •  Levofloxacin
•  Ciprofloxacin  each in combination with
•  Levofloxacin metronidazole
 each in combination with
metronidazole

Regarding perforated appendicitis and the selec- appendicitis, who received antibiotics in the postop-
tion of antibiotic prophylaxis and antibiotic treat- erative course, and in the study by Banani et al. (19),
ment in the postoperative course, broad-spectrum patients older than 50 years of age and cases with
regimens effective against aerobic gram-negative generalized peritonitis were excluded. Adding a
organisms and anaerobic organisms are recom- course of outpatient PO antibiotics does not decrease
mended according to guidelines by the Surgical postoperative infectious complications in appendici-
Infection Society and the Infectious Diseases Society tis patients but increases the treatment cost (21).
of America (24; Table 4). These guidelines apply Therefore, oral antibiotics, alone or following IV regi-
even for cases of abscessed appendicitis treated con- mens, for the treatment of perforated appendicitis
servatively. cannot be recommended.
Regarding the length of IV antibiotic treatment in
patients with perforated appendicitis, numerous stud-
Summary
ies on complicated intra-abdominal infections could
be found comparing various antibiotic regimens, but The evidence is strong supporting preoperative,
they do not provide data for each intra-abdominal broad-spectrum antibiotics to patients with acute
infection separately. appendicitis. In patients with non-perforated (phleg-
Based on studies (16–20) on perforated appendicitis monous or gangrenous) appendicitis, the use of post-
and postoperative antibiotics, a minimum 3- to 5-days operative antibiotic treatment is not recommended.
treatment is recommended for adult patients. In cases of perforated appendicitis, postoperative,
According to the study by Taylor et al. (21), the discon- broad-spectrum antibiotics are recommended for a
tinuation of IV antibiotics based on resolution of clini- minimum period of 3–5 days for adult patients. No
cal findings as compared to a required minimum good recommendations exist for how discontinua-
postoperative IV antibiotic duration yielded similar tion of IV treatment should be done, since the major-
outcome and saved antibiotic costs and potential hos- ity of trials were done during an era with little focus
pital days. Discontinuation of IV therapy is arbitrary on resistance to drugs. However, the present evi-
based on clinical criteria, such as absence of pyrexia, dence does not support the use of oral antibiotics
and supported by a decrease in leukocytosis and after the initial postoperative IV treatment in acute
C-reactive protein (CRP). perforated appendicitis and further trials are awaited.
Regarding the importance of inflammatory
response variables, only one prospective trial by
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