Oral antibiotics for perforated appendicitis is not recommended

In Denmark more than 6,000 patients undergo appendicitis

surgery annually, and one third of these patients

have perforated appendicitis [1]. The treatment for perforated

appendicitis is usually intravenous (IV) antibiotic

therapy for a minimum of three days after surgery, i.e.

the patient will remain hospitalized for a minimum of

three days after surgery. Early conversion to oral (PO)

treatment has been attempted for various intra-abdominal

infections [2-7]. These studies have consistently

shown that early conversion from intravenous to PO

antibiotic therapy was at least as good as an IV antibiotic

therapy alone [2-7]. A common characteristic in these

studies has been an overall good effect of IV/PO antibiotic

therapy in all intra-abdominal infections, including

acute appendicitis. However, none of these studies provided

details for each intra-abdominal infection, but only

common, pooled data for all intra-abdominal infections.

An assessment of the effect of early conversion to PO

antibiotics for perforated appendicitis is therefore not

possible on the basis of these studies.

The purpose of this article was to provide an overview

of studies on perforated appendicitis that specifically

examined the differences between PO antibiotic

therapies and IV antibiotic therapy after surgery.

MATERIAL AND METHODS

A search was made on Medline, Embase and The Cochrane

Library. The following keywords were used individually

and in combination: acute/perforated appendicitis,

antibiotic, oral. The following MeSH-terms were used:

appendicitis, perforated, and antibiotic – both individ -

ually and in combination. All human studies published

in English on the treatment of perforated appendicitis

with PO antibiotics after surgery were included. In addition,

the reference lists of the individual articles were reviewed

manually to identify additional studies. The publication

date of the included studies ranged from 1966

to 15 September 2009.

RESULTS

The database search yielded five studies specifically addressing

the treatment of acute perforated appendicitis

with PO antibiotics [8-12]. In one study (PO-study), patients

received only PO antibiotics [8]. In the remaining

four studies (IV/PO studies), patients with perforated

appendicitis received IV antibiotics followed by PO antibiotics,

see Table 1 [9-12]. Four additional studies were

found on the treatment of intra-abdominal infections

generally with PO antibiotics. In these studies, however,

all types of intra-abdominal infections were included

without specific details about the underlying disease.

These four studies were therefore not included in this

review. Study details for the included studies are given

in Table 1. Two of the studies were randomized [8, 10],

two were prospective [11, 12] and one was retrospective

[9]. The study periods were two to three years for

four of the studies [8-11], and the study period was not

specified in the fourth study [12].

ORAL ANTIBIOTIC STUDIES

Banani et al [8] included 114 patients (PO group) receiving

exclusively PO metronidazole 500 mg every eight

hours both pre- and postoperatively. The control group

(IV group) included 120 patients who preoperatively received

IV ceftizoxime four times per day (750-1,000 mg/

dose for adults and 20-25 mg/kg/dose for children under

the age of 15 years) if there was no pus in the abdomen,

or postoperative triple-drug therapy consisting of IV

penicillin (100,000 units/kg/day), chloramphenicol (50-

80 mg/kg/day) and gentamicin (5-6 mg/kg/day) if there

was visible pus during surgery. In both groups, the duration

of antibiotic therapy was 3-6 days, depending on

the classification of the acute perforated appendicitis.

The exclusion criteria comprised: patients with generalized

peritonitis, immunosuppressive patients, allergy

to antibiotics, children < 4 years and adults > 50 years,

pregnancy and patients who received antibiotics before

they were admitted to the hospital.

The complication rates were 19% in the PO group and 18% in the IV group. Intra-abdominal abscesses

occurred in four (4%) patients in the PO group and five

(4%) in the IV group. The treatment was re-laparotomy

in three patients from the PO group and four from the IV

group. The remaining patients recovered with PO metronidazole

for two weeks or IV gentamicin for 6-7 days.

INTRAVENOUS/ORAL ANTIBIOTIC STUDIES

The four IV/PO studies were heterogeneous, but patients

with acute perforated appendicitis underwent

appendectomy in all of the studies, and initially they

received intravenous antibiotics, typically for 4-5 days.

Subsequently, patients were divided into one of two

groups receiving PO antibiotics/continued IV antibiotics,

placebo or no antibiotics (see Table 1). On average, the

initial IV administration lasted 4-5 days, while the average

period of subsequent PO treatment was 5-7 days.

In the study by Adibe et al, patients received IV

ampicillin-sulbactam alone or in combination with

gentamicin, and PO antibiotics consisted of trimethoprim-

sulphamethoxazole and metronidazole [9].

Rice et al gave PO amoxicillin-clavulanate potassium

(40 mg/kg/day) and IV treatment consisted of ampicillin

(400 mg/kg/day), gentamicin (7.5 mg/kg/day) and clindamycin

(40 mg/kg/day) [10]. In the study by Taylor et

al, patients received IV amoxicillin/sulbactam and the

PO antibiotics consisted of amoxicillin/clavulanate for

patients over 18 years and levofloxacin for patients

under 18 years [11]. Gollin et al gave IV ampicillin

(200 mg/kg/day), gentamicin (7.5 mg/kg/day) and

metronidazole (30 mg/kg/day), while the PO antibiotic

regimen consisted of trimethoprim/sulphamethoxazole

(10 mg/kg/day) and metronidazole (30 mg/kg/day) [12].

The criteria for conversion to PO therapy varied

between the four studies, although a common criterion

was that enteral feeding should be tolerated for PO

therapy to be initiated. In two of the studies, conversion

from IV to PO antibiotics was made regardless of fever

or leucocytosis [10, 12]. In two other studies, PO antibiotics

were initiated when there was a resolution in

abdominal pain, tenderness, distension, fever [9, 11]

and a decrease in the white blood cell count [11].

Exclusion criteria also varied between studies and

were, e.g. presence of gangrenous appendicitis, intraoperative

bowel perforation, laparoscopic surgery, other

infections, allergy to antibiotics, immunosuppression,

renal failure, neutropenia, pregnancy, development of

intra-abdominal abscess or wound infection before conversion

to PO antibiotics. The total number of patients

who had received antibiotic therapy with initial IV administration

and subsequent conversion to PO administration

was 152, and the typical age group in the studies

was been between one and 22 years [9-12].

Complications during PO treatment were found in

all four studies, and the complication rate was 0-30% in

the control groups and 4-26% in the intervention groups.

None of these studies saw a significant difference in

complication rate between the groups. Eight patients

developed wound infections: four were treated with incision,

drainage and oral antibiotics during hospitalization

[11], three were given with antibiotics as outpatients

[12], and the treatment afforded the last patient

was not stated [10]. Postoperative intra-abdominal abscesses

were observed in four patients, one patient was

treated with percutaneous drainage and IV antibiotics

[11], while three other patients received only IV antibiotics

[9].

Complications in the control groups were found

in 22 (14%) patients: six with abscesses, three with

wound infections, two with Clostridium difficile colitis,

one had a phlegmonous infection, two had problems

with peripherally inserted central catheters, one was dehydrated,

two had small bowel obstructions, one patient

experienced a toxic reaction due to the antibiotics, and

three had persistent fever for more than three days.

Conversion of the scheduled PO antibiotic therapy

to IV treatment occurred in two of the four studies

[10, 11]. In total, three patients (2%) had their treatments

converted. The reason was that one patient developed a wound infection [10], and two patients

developed intra-abdominal abscesses [11].

EXPENSES

The differences in cost associated with the use of PO antibiotics

compared with IV antibiotics were also studied.

In two of the IV/PO studies, a difference in cost associated

with the two antibiotic therapies was found [9, 10].

Rice et al found that conversion to PO treatment resulted

in savings of $1,500 per patient, while the corresponding

savings were $4,000 per patient in the study

by Adibe et al. The PO study found a 30% reduction in

cost when only PO antibiotics were used [8]. Calculations

were based on the price of antibiotics, the construction

of intravenous access, nursing care expenses

and hospital stay.

DISCUSSION

The available literature is sparse and the applied regimens

cannot be readily transferred to a Danish context.

Thus, in some studies patients received IV therapy for

4-5 days before they received PO treatment, whereas

our usual routine for perforated appendicitis is IV antibiotics

for three days after surgery. The objective of the

current literature review was, on the basis of the current

evidence to assess whether a switch to PO therapy alone

after surgery may be made, and as a result whether the

patient could be discharged sooner after the operation

than is currently the case. However, the current evidence

does not support a conclusion of this nature.

The usual treatment for patients with acute perforated

appendicitis is appendectomy combined with

antibiotic therapy. Such treatment is supported by

numerous controlled trials and a Cochrane review [13].

Patients with acute appendicitis undergoing surgery

and antibiotic therapy have fewer wound infections

and intra-abdominal abscesses than patients receiving

placebo [13]. In recent years, it has been debated

whether the optimal method of administration of antibiotics

in these patients is by the IV route. The usual

method in Denmark is IV administration of antibiotics

(a single, two or three drugs, depending on local policy)

given as a single dose during surgery, and if there has

been visible pus or faeces in the abdomen, the antibiotic

therapy continues for three days, also IV therapy.

In the randomized study by Banani et al, in which

the use of PO antibiotics was compared with IV antibiotics,

no significant differences were found in the two

groups’ outcomes in terms of infectious complications

[8]. This study is encouraging, but unfortunately did

not use a regimen comparable to our usual routine.

A change of the IV antibiotic therapy for PO therapy

alone would be a big step towards minimizing the use of

medication and the need for hospitalization after surgery.

Rescheduling IV to PO therapy is therefore an important

step in development of optimized patient treatment

in this patient group. However, to our knowledge

no studies specifically address this issue, and we therefore

need to examine the current Danish regimen with

three days of IV treatment against a group that receives

an intra operative IV single-dose intravenous therapy

followed by PO treatment alone.

Other studies have examined different antibiotic

treatment regimens, consisting of an initial IV antibiotic

administered over a period of several days with subsequent

conversion to PO administration [9-12]. The results

from these trials were that patients with a combined

regimen had fewer complications and shorter

hospitalization periods than patients in the group receiving

only IV therapy, while the economic costs were lower

in the combined regimen groups. The investigated

regimens are, however, far from usual clinical practice,

where the maximum treatment duration is typically

three days for complicated cases. Furthermore, the designs

of the four trials were not similar and the inclusion

and exclusion criteria used were not standardized.

The prolonged treatment with IV antibiotics used in

the IV/PO studies was probably based on recommendations

from past publications, that patients with acute

perforated appendicitis should receive a minimum of

ten days of IV antibiotics [14-16]. Other studies have

recommended at least 5-7 days of IV antibiotics until

there is no fever or leucocytosis for 24 hours [17]. In a

recent study of 272 patients with perforated appendicitis,

it was shown that halving the period during which

patients received intravenously administered antibiotics

was not associated with an increase in the complication

rate [18]. Considering that the vast majority of hospitals

in Denmark treat these patients with three days of IV

antibiotics, the basis for comparison with the available

scientific literature is not optimal. Denmark has a good

tradition of general caution with the use of antibiotics

with a view to reducing the risk of resistance and unnecessary

side effects.

CONCLUSION

There is presently not sufficient evidence to support

shifting the currently preferred three days of IV antibiotic

treatment for perforated appendicitis in Denmark

to a PO regimen immediately after surgery. Controlled

randomized studies should be performed comparing the

current regimen for perforated appendicitis (IV antibiotics

starting during operation and continuing for three

days) with a regimen consisting of IV antibiotics during

surgery and a PO regimen in the convalescence period.

CORRESPONDENCE: Mahdi Alamili, Gastroenheden, Herlev Hospital, 2730

Herlev, Denmark. E-mail: Mahdi_alamili@hotmail.com

ACCEPTED: 16 June 2010

CONFLICTS OF INTEREST: None