Multi-Center Prospective Study of Restrictive Post-Operative Antibiotic Treatment of Children with Complicated Appendicitis

Abstract

Background:

No consensus has been reached regarding the most advantageous duration of antibiotic prophylaxis to decrease post-operative infection complications of appendectomy for acute complex appendicitis. This study aimed to determine the efficacy of short-term antibiotic treatment on post-operative complications in children with complex appendicitis.

Methods:

A multi-center, parallel group, randomized study was conducted in patients younger than 14 years of age with complicated appendicitis at three hospitals in China. The qualified patients were randomized prospectively to either the restrictive 72-hour short-term antibiotic strategy or the standard antibiotic usage. A comparison of the complications within 24 months, including infectious complications and long-term results, were conducted between the two groups. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR), number ChiCTR1900023941 and is complete.

Results:

A shorter duration of antibiotic treatment had no effect on intestinal function recovery, antibiotic-associated diarrhea, and health-care–associated Clostridium difficile infection and infectious complication, including intra-abdominal abscess development (17.9% vs. 18.0%, p = 0.52). Furthermore, no substantial difference for re-admission requirement and re-operation were found between the two treatment strategies. A sizeable decrease in total duration of hospitalization (p < 0.001) and average total antibiotic duration (p < 0.001) were observed for the restrictive antibiotic strategy group.

Conclusion:

In complicated appendicitis, the restrictive antibiotic usage was equivalent to standard antibiotic usage in terms of short- and long-term outcomes, but with shorter hospital stays and fewer antibiotic agents.

Acute appendicitis is one of the most common abdominal emergencies managed in pediatric populations throughout the world [1,2]. Many of these children presented with complex appendicitis, including perforated and gangrenous appendicitis and any appendicitis accompanied by an intra-abdominal or pelvic abscess, which is associated with most of the post-operative intra-peritoneal abscesses or incision infections [3,4]. Currently, there are differences in the care of children with this disease, including different antibiotic treatment regimens, and the duration of post-operative antibiotic therapy, which is based mainly on the individual surgeon's preference and experience [5]. In terms of complex appendicitis, the recommended duration of antibiotic treatment is inconsistent. There are not yet consistent practice guidelines to guide decision making concerning the best duration of post-operative antibiotic administration after appendectomy [6]. Some studies follow institutional clinical guidelines whereas others support a defined length of antibiotic treatment [7]. Recent research showed that it is perhaps better to discontinue antibiotic administration even earlier than three days of post-operative antibiotic treatment; no benefit was found for extending treatment longer than three days in terms of the incidence of post-operative complications [8,9]. Furthermore, antimicrobial resistance and restricting antibiotic therapy are indicated resulting from antibiotic overtreatment by the World Health Organization. In the pediatric population, to our knowledge, the duration of antibiotic usage is seldom restricted to fewer than three days after an operation for complicated appendicitis.

The purpose of our study was to assess the effect of limiting a course of post-operative antibiotic treatment for complex appendicitis in term of abscess, incision infection rate, and re-admission rate. We hypothesized that restrictive post-operative antibiotic administration is equivalent to the standard regimen after surgery for complicated pediatric appendicitis.

Patients and Methods

We performed a randomized, controlled, parallel group, multi-center analysis regarding two managements (restrictive antibiotic agent usage or standard antibiotic agent usage) for patients with complex appendicitis who underwent surgical intervention in a collaborative multidisciplinary program among three pediatric general surgical departments at Qingdao Maternity and Child Care Hospital, Jinan Maternity and Child Care Hospital, and Chongqing Children's Hospital from July 1, 2017 to June 30, 2019. The Chongqing Children's Hospital of Chongqing Medical University is the largest children's hospital in the region. The current research protocol was approved by the Institutional Review Board (IRB) of the Chongqing Medical University (approval no. 108/2018) and the IRBs at other sites. Patients were eligible for entry into the research with the following inclusion criteria: clinically defined as a patient with gangrenous or perforated appendicitis by the attending surgeon; younger than 14 years old; normal renal and hepatic function. The subjects were excluded if they presented with clinical suspicion of severe sepsis, complex appendicitis with abscess formation and were treated with interval appendectomy. Patients who were not available for post-operative follow-up within two months of the first admission were also excluded. Furthermore, patients were excluded if they were managed with open appendectomy to achieve a more homogenous cohort of patients. Patients who met the inclusion criteria and provided informed consent were allocated prospectively and randomly to either the restrictive antibiotic agent usage or standard antibiotic agent group. After providing informed consent, the independent party immediately extracted a sealed, unlabeled, random envelope from the container for random assignment.

Medication and management

The same treatment surgical protocol was performed for all the patients in different institutes, including operation intervention method, prophylactic drain placement, post-operative management, intra-operative cultures, etc. According to the antibiotic regimen design, participants would be assigned randomly (1:1) to either the restrictive group receiving a 72-hour short-term course or the standard group receiving a standard protocol of post-operative antibiotic treatment. All patients received a fluid bolus of broad-spectrum antibiotic therapy with either piperacillin-tazobactam (100–150 mg/kg per day in two divided doses) or cefoperazone sodium and sulbactam (100–150 mg/kg per dose in two divided doses) as well as metronidazole (30 mg/kg per dose in two divided doses).

The standard protocol included that patients received intravenous antibiotic agents and continued to do so until the leukocyte count and temperature returned to normal or for a minimum of five days. The intravenous doses of antibiotic and dose interval were identical except the treatment duration between the two groups. Patients were discharged with oral amoxicillin-clavulanate to complete a 10-day treatment. At least two assessments were performed on all patients every morning and afternoon to determine whether they met discharge criteria.

Follow-up

After discharge, all patients were followed-up systematically at the outpatient department at two- to four-week intervals throughout the six-month study by the operating surgeon according to local hospital policy. The patients were then asked to follow-up at approximately two-month intervals throughout the six-month study period either by telephone or onsite visit. Patients would undergo imaging studies, laboratory tests, and blood cultures only when there were clinical indications. All patient outcome measures would be enrolled directly from the electronic medical records. The primary end points for the study were a composite of infectious complications occurring within six months, including post-operative abdominal or pelvic abscess and surgical site infection (SSI) after appendectomy as defined by published US Centers for Disease Control and Infection (CDC) criteria. Secondary outcomes included length of hospital stay (LOS), re-hospitalization rate, duration of antibiotic treatment, numbers of re-visits to either the inpatient and emergency department or outpatient clinic setting from any cause.

Statistical analysis

All statistical analyses were performed by using the SPSS 20.0 (version 17.0, SPSS Inc., Chicago, IL) software. Continuous variables were reported as the median (range) or as the means ± standard deviations as appropriate and tested statistically with Mann-Whitney U test, Student t-test, or Wilcoxon rank-sum test. Categorical variables were expressed as frequencies (percentages) and analyzed with χ² test or Fisher exact test as appropriate. A result was considered statistically significant if it had a p value <0.05 (a two-tailed 95% confidence interval [CI]).

Results

Patient characteristics

During the study period, 747 patients met inclusion criteria. Among them, 37 were excluded because they were unavailable for post-operative follow-up and 24 for other exclusion criteria. The final evaluated study cohort included 686 patients, of whom 350 patients were confirmed as managed with the restrictive post-operative antibiotic agents. Among them, 32 cases were discharged as early as post-operative day 1 or 2 and followed the short duration of home oral antibiotics. To collect as many as cases as possible, we included these patients in the restrictive group. The baseline characteristics between the two groups are presented in Table 1. As shown in Table 1, the distribution of demographics and the features of severity covariables were comparable, including gender distribution, clinical symptoms, imaging finding, and inflammation parameters at admission, indicating that there were no systematic differences in baseline characteristics between the two groups in this study. The operative magnitude was assessed by measuring the operation time and estimating the amount of blood loss during the operation and there were no different from the two groups. There was also no discrepancy in the number of peritoneal drainages performed.

Table 1.

Baseline Characteristics of Eligible Patients and Surgical Parameters

	Standard group	Restrictive group
Baseline characteristics	(336)	(350)	p
Age (y)	6.3 ± 3.6	6.2 ± 3.4	0.24
Duration of clinical symptoms, days, mean ± SD	4.3 ± 2.6	4.2 ± 2.7	0.41
Clinical symptoms, n (%)
Abdominal pain	306 (91.1%)	322 (92.0%)	0.38
Vomiting	173 (51.5%)	182 (52.0%)	0.48
Fever	266 (79.2%)	273 (78.0%)	0.39
Male:female	153:183	159:191	0.52
Mean body weight (kg)	22.3 ± 7.3	22.7 ± 7.9	0.32
Abscess 2 cm or more, n (%)	143 (42.6%)	152 (43.4%)	0.44
WBC (10⁹/L)	15.3 ± 3.5	15.6 ± 4.1	0.14
PCT (ng/mL, normal value: 0–0.5)	7.9 ± 3.6	7.5 ± 3.5	0.38
CRP (mg/L, normal value: 0–8)	22.6 ± 5.7	22.8 ± 5.6	0.41
Albumin (g/L, normal range, 35–50)	32.4 ± 8.6	31.8 ± 8.7	0.51
Operative time	46.4 ± 26.7	46.8 ± 25.9	0.27
Estimated blood loss	10.2 ± 3.9	10.9 ± 3.8	0.33
Peritoneal drains	188 (56.0%)	192 (54.9%)	0.42
Microbiologic positive	85 (25.3%)	89 (25.3%)	0.43
Source of patients
Chongqing Children's Hospital	189 (56.3%)	195 (55.7%)
Qingdao Maternity and Child Care Hospital	85 (25.3%)	90 (25.7%)
Jinan Maternity and Child Care Hospital	62 (18.4%)	65 (18.6%)
Diagnosis
Gangrenous	123 (36.6%)	127 (36.3%)
Perforated appendicitis	213 (63.4%)	223 (63.7%)	0.47

SD = standard deviation; WBC = white blood cell count; PCT = procalcitonin; CRP = C-reactive protein.

Post-operative outcome

There was no difference in the formation of post-operative intra-abdominal abscess and post-operative SSI between the two antibiotic regime cohorts (Table 2). A total of 123 children developed a post-operative abscess including 63 in the restrictive post-operative antibiotic administration group (18.0%) and 60 in the standard criteria group (17.9%; p = 0.52). For the 63 cases of post-operative abscess in the restrictive post-operative antibiotic administration group, all patients had been discharged home without oral antibiotic agents. For the standard criteria, the post-operative abscess should be smaller than 2 cm for discharge and oral antibiotic agents should be continued until the abscess disappeared. No differences were found in inflammation parameters between the two groups at post-operative day 5 (Table 2).

Table 2.

Outcome Characteristics in the Matched Population: Multivariable Logistic Regression

Treatment	Standard group (336)	Restrictive group (350)	p	Risk ratio (95% CI)
Post-operative intra-abdominal abscess	60 (17.9%)	63 (18.0%)	0.52
Time from surgery to diagnosis (d)	6.8 ± 1.7	6.9 ± 1.6	0.48
Post-operative surgical site infection	23 (6.8%)	24 (6.9%)	0.56
WBC (10⁹/L) on POD 5	8.8 ± 3.9 (n = 139)	9.2 ± 3.7 (n = 216)	0.41
PCT (ng/mL, normal value: 0–0.5) on POD 5	1.8 ± 0.7 (n = 139)	1.7 ± 0.6 (n = 216)	0.32
CRP (mg/L, normal value: 0–8) on POD 5	9.4 ± 3.8 (n = 139)	9.5 ± 4.2 (n = 216)	0.31
Feeding within POD 1	276 (82.1)	292 (83.4)	0.37
Clostridium difficile infection	6 (1.8%)	4 (1.1%)	0.35
MRSA infection	3 (0.9%)	2 (0.6%)	0.48
Abdominal cramps	58 (17.3%)	55 (15.7%)	0.33
Abdominal distention	66 (19.6%)	68 (19.4%)	0.51
Diarrhea	83 (24.7%)	86 (24.6%)	0.52
Early ileus	94 (28.0%)	88 (25.1%)	0.23
Discharge home without antibiotic agents	104 (31.0%)	318 (90.9%)	<0.001	0.045 (0.029–0.069)
Duration of IV antibiotics, days, mean ± SD	6.8 ± 1.3	2.5 ± 0.6	<0.001	0.54 (0.45–0.72)
Mean days of home oral antibiotic agents	4.6 ± 2.8 (n = 232)	3.3 ± 1.2 (n = 32)	<0.001
Length of hospitalizations	5.6 ± 1.7	3.4 ± 1.1	<0.001	0.33 (0.15–0.81)

CI = confidence interval; POD = post-operative day; SD = standard deviation; WBC = white blood cell count; PCT = procalcitonin; CRP = C-reactive protein; MRSA = methicillin-resistant Staphylococcus aureus; IV = intravenous.

No differences were found in post-operative feeding time between the two groups (Table 2). Although the longer average duration of total antibiotic therapy, for the standard criteria group, there were no different in terms of multi-resistant bacterium, such as Clostricium difficile or methicillin-resistant Staphylococcus areus (MRSA). The incidences of diarrhea, abdominal cramps, and abdominal distention within five days post-operative in patients with restrictive antibiotic agent treatment were similar to patients with standard antibiotic treatment. Early ileus within five days post-operative was reduced in patients with restrictive antibiotic treatment compared with patients who received standard antibiotic treatment, but this difference was not statistically significant (p = 0.23). However, those who were discharged with restrictive antibiotic treatment did have a shorter average duration of total antibiotic therapy (p < 0.001; odds ratio [OR], 0.54; 95% CI, [0.45–0.72]) and initial LOS (p < 0.001; OR, 0.33; 95% CI, [0.15–0.81]) compared with the standard criteria group, which would be expected (Table 2).

Follow-up and adhesive small bowel obstruction (ASBO) incidence

During follow-up, the total number of re-visits, which included emergency department visits, surgery clinic visits, and other clinic visits such as infectious disease or gastrointestinal, was 28.6 % in the standard criteria group and 29.4% in the standard criteria group (p = 0.44). Three (0.8%) patients with restrictive antibiotic treatment required surgical intervention for suspected bowel strangulation. Bowel strangulation was confirmed in two patients, and no cases of strangulation were observed in the restrictive antibiotic treatment group (Table 3).

Table 3.

Follow-Up Outcomes in Pediatric Patients Based on Conservative Management or Surgical Intervention

Treatment	Standard group (336)	Restrictive group (350)	p	Risk ratio (95% CI)
Total number of re-visits	96 (28.6%)	103 (29.4%)	0.44
Re-admissions	22 (6.5%)	10 (2.9%)	0.017	2.38 (1.11–5.11)

CI = confidence interval.

There was substantial difference in post-operative re-admission rate (6.5% vs. 2.9%). Only 10 patients with restrictive post-operative antibiotic administration reported re-admissions versus 22 patients with standard protocol (p = 0.017; OR, 2.38; 95% CI, [1.11-5.11]) (Table 3).

Discussion

The major findings in this large-scale prospective cohort demonstrates that among children with complicated appendicitis, less antibiotic administration offers equivalent outcomes to the five-day standard treatment in terms of the infectious complications or hospital re-admission. This conversely may reduce the hospitalization time and may decrease hospital cost, thereby supporting the reduction of antibiotic use in children with complex appendicitis in the future. In the long term, the rate of emergence of antibiotic resistance may be slowed because of reducing the use of antibiotic agents.

For most practices in China, no matter how long the duration of treatment, some surgeons and pediatricians stop the use of antibiotic agents according to the patient's clinical signs. Because delayed clinical improvement may not accurately reflect an infectious focus, the clinical parameters resolution for the termination point for antimicrobial therapy may cause overtreatment with antibiotics [10]. On the contrary, early cessation of antibiotic agents regardless of whether signs of clinical improvement are present was advocated in a growing body of evidence [11 –13]. Previous research suggested that no difference in SSI and intra-abdominal abscess rates for complex appendicitis for post-operative prophylaxis of antibiotic administration even less than 24 hours [14]. However, when interpreting the results, the retrospective nature and small sample sizes included in these studies must be recognized. The present study is designed against this backdrop to answer the question whether early cessation of post-operative antibiotic agents is valuable to the standard post-operative treatment of complex appendicitis in pediatric patients.

Post-operative intra-abdominal abscess is a serious and life-threatening complication event after appendectomy [15,16]. Because of the inconsistent definition of intra-abdominal abscess among different institutes, there is a high degree of variability of reported intra-abdominal abscess rates in the literature [17 –21]. In the current study, we assembled a relative homogeneous population to reduce the scope of the disease, only pediatric patients with gangrenous as well as perforated appendicitis who underwent laparoscopic appendectomy were included, which is most likely to form abscesses in the abdominal cavity. By screening this susceptible group, we sought to examine the possible efficacy of different antibiotic treatments in these population. In the current research, both patient groups were identical regarding the baseline characteristics, such as peritoneal drain placement, onset, and type of antibiotic agent usage. The excessive irrigation fluids residual in the abdominal cavity have been suggested to be related to intra-abdominal abscess [22,23]. At our institution, to remove fluids that may collect, peritoneal drains are widely placed in the abdominal cavity, usually in the pouch of Douglas. We believe that we could compare the two antibiotic regimens, although antibiotic regimens were administered in different hospitals, which supports the local antimicrobial policy.

Although it is noteworthy that the rate of intra-abdominal abscess found in the current study is relatively high (comparatively high), it is still within the scope of the pediatric patients with appendix perforation as reported previously [17 –21], with moderate heterogeneity between studies. Our results are not unprecedented because of the well-defined perforative appendicitis, which might reduce the incidence of abscesses in this population. In our series, no difference in outcomes was found when comparing the two antibiotic administration regime groups. Eleven children treated with restrictive antibiotic administration developed an abscess after initial hospital discharge and were treated without antibiotic agents. This finding suggests that pre-defined short-term duration of antimicrobial treatment does not increase the incidence of infection complications, including the infection of operative site as well as intra-abdominal abscesses.

We also conducted this research to determine whether restrictive post-operative antibiotic treatment is beneficial for intestinal function recovery, which has not been reported previously. The difficulty of evaluating patients is that intestinal function cannot be monitored adequately. Our analysis involves frequent nursing evaluations and continuous monitoring of intestinal function in a closely monitored hospital environment. Accordingly, any clinically important intestinal discomfort would likely be caught. Our results indicate the insignificant beneficial effects of restrictive post-operative antibiotic agents on intestinal function. Similarly, patients who received restrictive post-operative antibiotic demonstrated similar recovery of inflammatory markers within five postoperative, which might explain the current clinical results. Previous studies suggested that long-term antibiotic therapy is a risk factor for antibiotic-associated diarrhea and health-care–associated Clostridium difficile infection [24,25]. Here we did not find these associations. In the current research, microbiologic analysis of the data is difficult because routine peritoneal sampling was not widely performed because of the high proportion of negative samples. Furthermore, antibiotic-associated diarrhea was difficult to define. To achieve a greater objectivity in the assessment, four definitions of diarrhea were included, including the combination of the consistency of feces and the number of stools. A tendency to a lower number of daily stools could be seen in the group treated with the restrictive post-operative antibiotic therapy compared with the standard protocol, although without statistical significance, probably because of the small sample size during the 30-day period of the study.

We found that patients treated with 72 hours of post-operative antibiotic agents had shorter length of hospital stay and less antibiotic agent administration once discharged. In this study, 1,086 patients received post-operative antibiotic treatment for a maximum of three days and the mean duration of antibiotic treatment in these patients was 2.54 days. It is shorter than that reported in a recent study, which recommended four days of antibiotic treatment for patients with adequate source control [26,27]. With these considerations, the results of our study suggest that restrictive post-operative antibiotic administration may be not only good for the patient, but also the shorter hospital stay can result in a reduction in costs, even though there were no cost analyses in this study. According to our management protocol, patients who were administered restrictive post-operative antibiotic agents had identical overall need for re-admission compared with the control, which is identical to previous reports [28,29].

The current results must be considered in the context of its limitations and should be interpreted cautiously. It is important to minimize the risk of bias but blinding in this trial would not be practical or advisable. Another limitation is that different surgeons and clinicians were included in the study. The study was a multi-center design investigation, the diagnosis and intra-operative classification of complicated appendicitis might be more subjective and dependent on the opinion of individual surgeon, which introduces the possibility of overclassification or underclassification of the degree of appendix pathology, allowing variation in practice to be introduced. In order to conduct a powerful study that specifically aimed at differences in complication rates, many more patients would need to be recruited.

In conclusion, the results of this study favor the premise that antibiotic treatment for three days was sufficient and may be suitable for treatment of children with complicated appendicitis. Shorter antibiotic administration was not correlative with intra-peritoneal abscesses. The advantage of this practice is less antibiotic administration and possible early discharge. To date, no other study has addressed this issue specifically in pediatric with appendicitis.

Footnotes

Acknowledgments

Qianyang Liu designed and evaluated the manuscript. Fabao Hao performed the statistical measurements and analyzed the data. Bailin Chen, Lei Li, and Chunbao Guo analyzed the data and wrote the article.

We thank Prof. Xianqing Jin for providing an in-depth discussion on the manuscript. We are grateful to Dr. Xiaoyong Zhang, Wistar Institute for the language revision of the manuscript.

The Institutional Review Board of Chongqing Medical University exempted the review of this study, and no informed consent is required given the retrospective design of the study.

The data sets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding Information

This study was supported by the grants from the National Natural Science Foundation of China (No: 30973440, 30770950) in designing the study, the Key Project of the Chongqing Natural Science Foundation (CSTC, 2008BA0021, cstc2012jjA0155) for collecting, analyzing and interpreting the data and Chongqing Health Planning Commission of Research Fund (No: 2016MSXM044) in writing the manuscript.

Author Disclosure Statement

No potential conflicts of interest relevant to this article are reported.

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