Effect of a Standardized Protocol of Antibiotic Therapy on Surgical Site Infection after Laparoscopic Surgery for Complicated Appendicitis

Abstract

Background:

Although it is accepted that complicated appendicitis requires antibiotic therapy to prevent post-operative surgical infections, consensus protocols on the duration and regimens of treatment are not well established. This study aimed to compare the outcome of post-operative infectious complications in patients receiving old non-standardized and new standard antibiotic protocols, involving either 5 or 10 days of treatment, respectively.

Methods:

We enrolled 1,343 patients who underwent laparoscopic surgery for complicated appendicitis between January 2009 and December 2014. At the beginning of the new protocol, the patients were divided into two groups; 10 days of various antibiotic regimens (between January 2009 and June 2012, called the non-standardized protocol; n = 730) and five days of cefuroxime and metronidazole regimen (between July 2012 and December 2014; standardized protocol; n = 613). We compared the clinical outcomes, including surgical site infection (SSI) (superficial and deep organ/space infections) in the two groups.

Results:

The standardized protocol group had a slightly shorter operative time (67 vs. 69 min), a shorter hospital stay (5 vs. 5.4 d), and lower medical cost (US$1,564 vs. US$1,654). Otherwise, there was no difference between the groups. No differences were found in the non-standardized and standard protocol groups with regard to the rate of superficial infection (10.3% vs. 12.7%; p = 0.488) or deep organ/space infection (2.3% vs. 2.1%; p = 0.797).

Conclusions:

In patients undergoing laparoscopic surgery for complicated appendicitis, five days of cefuroxime and metronidazole did not lead to more SSIs, and it decreased the medical costs compared with non-standardized antibiotic regimens.

Acute appendicitis is the most common medical condition requiring emergency surgical management. Complicated cases of appendicitis may be associated with a higher surgical site infection (SSI) rate; hence, patients with complicated appendicitis generally receive antibiotics post-operatively. However, there are limited data available to guide clinical practice regarding effective antibiotic regimens and the appropriate duration of treatment. Study has already established that in patients with intra-abdominal infections, after adequate control of the infectious source, short-course antibiotic therapy leads to outcomes similar to longer courses of therapy [1].

In order to reduce SSI, various antibiotic regimens have been administered via the intravenous or oral route for a long duration and were prescribed to patients who had undergone laparoscopic surgery for complicated appendicitis (non-standardized treatment). However, a Diagnosis-Related Group (DRG)-based payment system for appendicitis, including complicated cases, has been prevalent in our country since July 2012. To reduce the cost of treatment and shorten the hospital stay, we introduced a new protocol for complicated appendicitis using a recommended antibiotic regimen for a short duration (standardized treatment). Considering the recent trends in post-operative antibiotic therapy, we compared the clinical outcome, in terms of SSI rate, between the old non-standardized and the new standardized antibiotic protocol with regard to the time period in patients undergoing laparoscopic surgery for complicated appendicitis.

Patients and Methods

This observational cohort study was conducted with the approval of the Institutional Review Board (Protocol No. 11-1026). A total of 3,946 patients aged 18–69 y suffering from acute appendicitis (seen from 2009 to 2014) were managed surgically, of whom 1,343 (34%) underwent laparoscopic surgery for complicated appendicitis. This condition was defined as comprehensive gangrenous change with pus or dirty ascites or a perforated appendix with or without abscesses, as judged by both intra-operative findings and pathologic examination, which usually were reported within two d after surgery.

We excluded 191 patients who had simple gangrenous appendicitis that was not combined with pus or dirty ascites, and 32 patients with a discrepancy between the intra-operative findings and the pathologic examination. We also excluded 72 patients who they underwent open appendectomy initially (n = 28), had percutaneous drainage initially and underwent delayed surgery (37), or had cephalosporin allergy (7).

Laparoscopic surgery was performed either with the conventional three incisions (n = 1,135) or with a single port (208). The abscesses were drained by suction and saline irrigation. The decision regarding insertion of a closed suction drain (347 cases) was left to the discretion of the surgeon. Two endoloop ties were used for appendiceal closure, and staplers usually were applied in cases of partial cecectomy or bowel resection. All specimens of the appendix were examined by a pathologist.

For prophylactic antibiotic therapy, all patients received a first-generation cephalosporin before surgery. For the therapeutic antibiotics in complicated cases, from January 2009 to June 2012, we commonly treated patients with intravenous antibiotics during the immediate post-operative period and then continued treatment with oral antibiotics after hospital discharge for a total treatment span of 10 d. Various antibiotic regimens, such as quinolones, carbapenem, or tigecycline with metronidazole, were used.

From July 2012 to December 2014, under the DRG system, we practiced a new standardized antibiotic protocol for complicated appendicitis, using a recommended regimen (cefuroxime with metronidazole)[2] for a total of five d, including oral agents. If the patients demonstrated fever or abnormal blood test results, we employed active observation without antibiotic therapy. The discharge criteria were that the patient was afebrile and had normal blood test reports. Post-operative computed tomography (CT) was performed on patients who demonstrated clinical deterioration or abnormal blood test reports after discharge.

We divided the patients into two groups (non-standardized and standardized protocol) and compared the clinical outcomes, including infectious complications, in the two groups. The primary objective of the study was to discover any difference in the incidence of SSIs (either superficial or deep organ/space infections) within 30 d after surgery. Deep organ/space infections were defined as fluid collections or abscess formation in the peritoneal cavity. All statistical analyses were performed using Pearson's χ² test or an independent t-test.

Results

This study included 727 men and 626 women with a mean age of 37.5 ± 12.4 standard deviation (SD) y. The most common presenting symptom of appendicitis was right lower-quadrant pain with tenderness, although 132 patients presented with other symptoms (epigastric discomfort, vomiting, indigestion, or pain across the entire abdomen). There were 168 patients (12.5%) with a history of abdominal surgery.

A total of 266 patients (19.8%) had fever (body temperature ≥38.3°C). The mean time between admission and surgery was 11.3 ± 6.4 h (SD), the range being 3–42 h. No deaths were reported within 30 d of surgery.

Co-morbidities were recorded in 227 patients (16.9%). The most common were diabetes mellitus and hypertension. Others were cardiac, neurologic, renal, or cerebrovascular disease; asthma; rheumatoid arthritis; or history of malignancy.

Clinical features and laboratory findings were similar in the two groups. The operating time was shorter in the standardized than in the non-standardized group (66.8 vs. 68.9 min; p = 0.044).

We assessed all patients' histopathology reports: 696 (51.8%) had gangrenous or necrotic appendicitis, 483 (36%) had perforated appendicitis, and 164 (12.2%) had perforated appendicitis with an abscess. The surgical procedures were appendectomy (1,278; 95.2%), bowel resection including the appendix (43; 3.2%); and partial cecectomy (22; 1.6%) (Table 1). Most cases of partial cecectomy were performed as extended appendectomy with staples across a small portion of the cecum.

Table 1.

Comparison of Clinicopathologic Characteristics of Two Treatment Groups

Variable	Non-standardized protocol (n = 730)	Standardized protocol (n = 613)	P ^a
Age (y)	37.8 ± 12.4	37.1 ± 12.4	0.249
Male/female	383/347	334/279	0.460^b
Alvarado score	6.9 ± 1.3	7.0 ± 1.2	0.303
Body mass index (kg/m²)	23.4 ± 3.1	23.3 ± 3.2	0.722
Co-morbidities (%)	116 (15.9)	111 (18.1)	0.281^b
White blood cell count (10³/μL)	12.0 ± 4.5	12.3 ± 4.3	0.229
Neutrophils (%)	75.2 ± 10.7	74.6 ± 10.4	0.294
Body temperature (°C)	37.3 ± 1.2	37.4 ± 1.4	0.173
C-reactive protein (mg/dL)	47.5 ± 54.6	44.7 ± 48.8	0.323
Time to surgery (h)	11.1 ± 6.2	11.5 ± 6.7	0.293
Operative time (min)	68.9 ± 20.0	66.8 ± 19.3	0.044
Hospital stay (d)	5.4 ± 1.8	5.0 ± 1.6	<0.001
Medical cost (US$)	1,654 ± 315.9	1,564 ± 262.2	<0.001
Pathologic grade			0.888^b
Gangrenous	326 (44.6)	290 (47.3)
Perforation	305 (41.8)	219 (35.7)
Abscess formation	99 (13.6)	104 (17)
Operative procedure			0.545^b
Appendectomy	697 (95.5)	581 (94.8)
Partial cecectomy	12 (1.6)	10 (1.6)
Bowel resection	21 (2.9)	22 (3.6)

Values are expressed as mean ± SD or number (%).

P value calculated by the independent t-test.

P value calculated by the χ² test.

The rate of superficial infection and deep organ/space infection did not differ in the non-standardized and standardized protocol groups (10.3% vs. 12.7%; p = 0.488 and 2.3% vs. 2.1%; p = 0.797, respectively) (Table 2). When additional analyses were carried out of the cases with perforated appendicitis (404 in the non-standardized protocol and 323 in the standardized protocol), there were no differences in the SSI rates (17.1% vs. 14.2%; p = 0.298 and 3.7% vs. 3.1%; p = 0.651; Table 3).

Table 2.

Comparison of Post-Operative Surgical Infections between Groups (N [%])

Variable	Non-standardized protocol (n = 730)	Standardized protocol (n = 613)	p
Total infection	92 (12.6)	91 (14.8)	0.650
Superficial infection	75 (10.3)	78 (12.7)	0.488
Intra-abdominal abscess	17 (2.3)	13 (2.1)	0.797

Table 3.

Comparison of Post-Operative Surgical Infections between Groups in Patients with Perforated Appendicitis, Abscess, or Both (N [%])

Variable	Non-standardized protocol (n = 404)	Standardized protocol (n = 323)	p
Total infection	84 (20.8)	56 (17.3)	0.241
Superficial infection	69 (17.1)	46 (14.2)	0.298
Intra-abdominal abscess	15 (3.7)	10 (3.1)	0.651

For the treatment of SSIs, the additional antibiotics were not used in cases of superficial infection. These patients received intermittent dressing changes until the site was completely healed. In patients with intra-abdominal abscess, additional antibiotic therapy (other regimens) was given until symptomatic relief and normalization of laboratory values were confirmed. There were no cases of sepsis or need for related surgery as a result of intra-abdominal infection.

Prolonged surgery and perforated appendicitis were associated with a higher risk of SSI (Table 4).

Table 4.

Hazard Ratio (HR) of Risk Factors for Surgical Infection Rate

Variable		Adjusted HR (95% CI)	p
Time to surgery (h)	<10	1 (reference)	0.013
	≥10	1.49 (1.09–2.04)
Pathologic grade	Gangrenous	1 (reference)	<0.001
	Perforated or abscess	3.06 (2.17–4.31)

CI = confidence interval.

Beyond the SSIs, there were 46 operation-related morbidities. Post-operative ileus beyond d 5 developed in 32 patients, all of whom were treated conservatively. The other morbidities were pneumonia, bleeding, difficulty in glucose control, and adhesive ileus after 1 mo.

Discussion

We established that among adults with all type of complicated appendicitis who underwent laparoscopic surgery, the surgical infection rates do not differ between those who received various antibiotic regimens for a long time and those who received the recommended standardized regimen for a shorter time.

Antibiotics are not necessarily prescribed during the post-operative period in patients with non-complicated appendicitis because of the lower risk of surgical infection. In contrast to this, patients with complicated appendicitis require antibiotic treatment post-operatively, as the risk of SSI is greater. It is necessary to guide the clinician in antibiotic prescription, especially with regard to the duration of use. Broad-spectrum or single- or double-agent therapy is as efficacious as triple-agent therapy and is more cost-effective. The total duration of antibiotic therapy, including oral antibiotics, should be seven days [3].

Traditionally, triple-agent therapy was composed of antibiotics covering gram-positive, gram-negative, and anaerobic bacteria and was administered for as long as 10 days. Use of newer antibiotics, such as ceftriaxone, piperacillin/tazobactam, or ertapenem, may decrease the required duration of therapy [4 –8]. In the past, the duration of therapy for complicated appendicitis usually was more than seven days. Empirical drug therapy might be responsible for unnecessary prolongation of treatment to prevent SSI. At present, three to five days of post-operative intravenous antibiotic is recommended for complicated or perforated appendicitis. Observational data suggest that three days of antibiotics is as effective as five days in preventing surgical infection [9]. Investigators also recommend that further shortening of treatment duration could be considered in non-perforated complicated appendicitis, usually gangrenous or necrotic change [10].

We have a tendency to perform early surgery for complicated appendicitis. Although there are some controversies, early surgery has the advantage of being curative on admission and ensures early return to society provided a higher degree of patient compliance has been maintained.

Use of drainage initially for complicated appendicitis followed by interval appendectomy is an effective alternative approach. However, this procedure is not always technically feasible and may lead to additional morbidity as a result of treatment failure and disease aggravation. This form of disease management has several risks and requires considerable resources. In addition, the data suggest no significant difference in outcomes between early appendectomy and interval appendectomy, even in patients with an abscess [11].

Most patients with complicated appendicitis underwent laparoscopic appendectomy. Only a small portion of patients required extensive surgery, such as partial cecectomy or ileocolic resection. When complicated by adjacent abscesses or phlegmon, as is common, the site is not amenable to secure appendiceal stump closure. These procedures seem to control the source of intra-abdominal infections adequately and may have the effect of a lower intra-abdominal infection rate (2.2%), as in this study.

The operative time in the standardized protocol group was shorter (66.8 vs. 68.9 min). This may be the result of the procedures being performed more recently, after many surgeons had acquired facility with laparoscopic procedures. The standardized protocol group also had shorter hospital stays (5 vs. 5.4 d) and lower medical costs (US$1,564 vs. US$1,654) than the non-standardized group. The patients with longer antibiotic use had a tendency to have delayed discharge, and the various antibiotic regimens were more expensive than the standardized regimens.

Post-operative surgical infections were related to the time until surgery and appendiceal pathologic grade. Some studies show that a short delay (within 24 h) did not increase the risk of advanced disease but did increase the risk of SSI or adverse events within 30 d post-operatively [12,13]. Another study reported that appendectomies performed more than 24 h after admission often had disadvantageous outcomes [14]. According to our results, a prolonged pre-operative delay (more than 10 h) is likely to lead to infectious complications when managing complicated appendicitis.

Perforated appendicitis and abscess formation were associated with a higher surgical infection rate than were whole gangrenous organs with pus or dirty ascites. Compared with the uncomplicated group, the difference was more prominent. The rate of intra-abdominal abscess was 1.3% (31/2,308), and the rate of superficial infection was 5.4% (124/2,308) in the uncomplicated appendicitis group at our institution. Most of the wound infections developed in the umbilical port site. Accordingly, there was no difference in the superficial infection rate between triple- and single-port laparoscopic surgery.

Patients with co-morbidities often undergo delayed surgery because of their complex pre-operative evaluation and the need to consult with other medical departments. Although short-term antibiotic therapy seems to be effective in preventing infectious complications, other antibiotic protocols should be considered for high-risk patients, such as those who are affected by major co-morbidities.

The use of antibiotics for complicated appendicitis should be individualized, considering the disease severity and the clinical conditions. However, it might be appropriate to reduce the duration of antibiotic therapy for most patients.

This study was retrospective, with the inherent limitations of that design. However, the diagnostic tools based on the CT findings and post-operative care were not different in terms of time intervals. Finally, although infectious complications after laparoscopic surgery in patients with complicated appendicitis must be assessed carefully, the recently reported intra-abdominal or organ/space infection rate has decreased to 3% [15 –17].

Conclusion

Five days of cefuroxime and metronidazole treatment for complicated appendicitis after laparoscopic surgery may not increase the rate of SSI compared with various non-standardized antibiotic regimens with a longer duration of therapy.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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