Antibiotics vs. Appendectomy for Acute Uncomplicated Appendicitis in Adults: Review of the Evidence and Future Directions

Abstract

Background:

Acute appendicitis is the most common abdominal surgical emergency in the United States, with a lifetime risk of 7%–8%. The treatment paradigm for complicated appendicitis has evolved over the past decade, and many cases now are managed by broad-spectrum antibiotics. We determined the role of non-operative and operative management in adult patients with uncomplicated appendicitis.

Methods:

Several meta-analyses have attempted to clarify the debate. Arguably the most influential is the Appendicitis Acuta (APPAC) Trial.

Results:

According to the non-inferiority analysis and a pre-specified non-inferiority margin of −24%, the APPAC did not demonstrate non-inferiority of antibiotics vs. appendectomy. Significantly, however, the operations were nearly always open, whereas the majority of appendectomies in the United States are done laparoscopically; and laparoscopic and open appendectomies are not equivalent operations. Treatment with antibiotics is efficacious more than 70% of the time. However, a switch to an antimicrobial-only approach may result in a greater probability of antimicrobial-associated collateral damage, both to the host patient and to antibiotic susceptibility patterns. A surgery-only approach would result in a reduction in antibiotic exposure, a consideration in these days of focus on antimicrobial stewardship.

Conclusion:

Future studies should focus on isolating the characteristics of appendicitis most susceptible to antibiotics, using laparoscopic operations as controls and identifying long-term side effects such as antibiotic resistance or Clostridium difficile colitis.

Acute appendicitis is the most common abdominal surgical emergency in the United States [1]. With a lifetime risk of 7%–8%, it is not surprising that a significant portion of healthcare dollars is spent treating this disease.

Acute appendicitis is classified as complicated or uncomplicated. Complicated appendicitis describes the presence of an abscess, phlegmon, or perforation. The treatment paradigm for complicated appendicitis has evolved over the past decade, primarily on the basis of the greater operative morbidity associated with the disease [2,3]. Many cases now are managed non-operatively with broad-spectrum antibiotics. Similar to the treatment of acute colonic diverticulitis, this approach has resulted in acceptable rates of cure, recurrence, and morbidity [2,3]. It is worthwhile to mention, however, that the motivation to treat diverticulitis non-operatively is avoidance of a colostomy and the need for a second laparotomy in the future rather than the clear superiority of antibiotic therapy.

As treatment for complicated appendicitis has evolved to a less invasive approach, management of uncomplicated appendicitis may require re-evaluation as well. In contrast to complicated appendicitis, treatment of uncomplicated appendicitis remains surgical. Indeed, operative management has been considered the gold standard therapy for more than 125 years. This approach originated in 1886 with the publication of autopsy data on the subject by the American pathologist Reginald Fitz [4]. He reported that most appendiceal infections ultimately progress to gangrene, perforation, and pelvic abscesses. These pelvic abscesses were highly lethal at that time, especially considering the paper's predating Alexander Fleming's discovery of penicillin by more than 40 years. Three years after Fitz, the surgeon Charles McBurney presented his groundbreaking work showing that early appendectomy prevents pelvic abscess [5]. His findings were so convincing that for more than a century, appendectomy has been the gold standard treatment for treatment of acute appendicitis.

Despite its near-universal acceptance in the surgical community, various reports have suggested that a diagnosis of appendicitis may not mandate operative intervention. In 1959, Coldrey described a five-year experience with non-operative management of appendicitis in more than 400 patients [6]. It also is recognized that as many as 20% of appendicitis cases resolve spontaneously [7]. The purpose of this review was to determine the role of non-operative vs. operative management in adult patients with uncomplicated appendicitis.

Clinical Outcomes

Several meta-analyses have attempted to clarify the debate. In 2011, a Cochrane Systematic Review of appendectomy vs. antibiotic treatment for acute uncomplicated appendicitis evaluated five randomized controlled trials (RCTs) conducted over the previous 15 years [8]. Unfortunately, the quality of the studies was only low to moderate. Using non-inferiority analysis, the authors could not draw any definite conclusions other than that appendectomy remains the gold standard for acute appendicitis. A subsequent meta-analysis in 2012 presented a more favorable conclusion about the safety and efficacy of antibiotics vs. appendectomy to treat uncomplicated acute appendicitis [9]. Nevertheless, its findings are based on the same low- to moderate-quality studies as the Cochrane review.

Arguably the most influential recent study on this topic, at least in terms of media coverage, is the Appendicitis Acuta (APPAC) Trial, published in JAMA in 2015 [10]. This trial was a multicenter, randomized, open-label study comparing antibiotic therapy with appendectomy for the treatment of acute uncomplicated appendicitis. The study was conducted in Finland from November 2009 through June 2012. Importantly, the study incorporated a non-inferiority design. The aim was to determine whether antibiotics are as effective as or only slightly less effective than surgery rather than whether antibiotics are superior.

The authors enrolled 530 patients between the ages of 18 to 60 who had acute uncomplicated appendicitis, which was defined as the absence of perforation, abscess, appendicolith, or suspicion of tumor. The authors utilized this definition because all patients had uncomplicated appendicitis confirmed by computed tomography (CT) before enrollment. This CT criterion is an improvement over other trials in the literature that relied on somewhat inaccurate methods to confirm the diagnosis, such as laboratory values and physical examination.

Randomization of the 530 enrolled subjects resulted in 273 subjects undergoing surgery and 257 receiving antibiotics. Open appendectomy was performed in 95% of the patients assigned to surgery. Antibiotic therapy consisted of three days of inpatient intravenous (IV) ertapenem (1 g/d), followed by seven days of oral levofloxacin (500 mg/d) and metronidazole (500 mg/tid). The primary endpoints were completion of the appendectomy in the surgical group and discharge of the patient without need for surgery and no recurrence of appendicitis for one year in the antibiotic group.

Appendectomy was completed successfully in 99.6% (95% confidence interval [CI] 98.0%–100.0%) of the patients in the surgical group. Treatment without a need for surgery and no recurrence for one year was seen in 72.7% (95% CI 66.8–78.0%) of the subjects in the antibiotic group. Of the 27.3% (95% CI 22.0–33.2%) of the patients in the antibiotic group who underwent an appendectomy within one year, 82.9% had uncomplicated appendicitis at the second presentation. There were no other major complications in this treatment group. The difference in treatment efficacy between groups was −26.9%, and the lower 95% CI was −31.6%. Based on the non-inferiority analysis and the specified non-inferiority margin of −24%, the study failed to demonstrate non-inferiority of antibiotics vs. appendectomy for the treatment of acute uncomplicated appendicitis.

In addition to the statistically inconclusive findings, there are a number of logistical concerns with the design and conduct of this study. First, the majority of appendectomies performed in the United States are done laparoscopically, whereas 95% of the operations in the trial were open [11]. Not only does this limit the external validity of the conclusions, but laparoscopic and open appendectomies are not equivalent operations. Laparoscopic appendectomy is associated with less post-operative pain, fewer surgical site infections (SSIs), shorter hospital stays, and faster return to normal activity [12,13]. Considering that secondary endpoints of the APPAC trial included pain scores, use of pain medication, length of hospital stay, amount of sick leave used by the patient, and SSI within 30 days of surgery, reconciling this source of potential bias is difficult. Indeed, because of the rates of SSI and incisional pain, the authors reported a significantly higher complication rate in the surgery group. Interestingly, the median length of the primary hospital stay still was significantly shorter in the surgery group. Second, the original power calculations called for 275 subjects per group (550 total), but recruitment challenges resulted in enrollment of only 530 patients. Thus, the study remains at risk for being underpowered, even after revised power calculations. Furthermore, 18% of the eligible patients refused enrollment in the study. This resulted in the performance of 4,380 appendectomies in the study hospitals outside of the trial. Third, ertapenem is not available everywhere, and other more accessible antibiotic regimens may not have similar efficacy. Fourth, the authors chose to include pain and SSI as secondary endpoints, which clearly are more common complications in a surgical cohort. In contrast, the authors chose not to include recurrent appendicitis as a complication but rather as part of the primary endpoint. This practice tends to minimize the perceived complications attributable to antibiotic therapy.

Despite these concerns about the APPAC trial, proponents of an initial non-operative management strategy cite several reasons antibiotics alone are a reasonable choice for uncomplicated appendicitis [14]. These arguments include a more liberal interpretation of the results of the APPAC trial, improvements in patient-reported outcomes, incorporation of patients' preferences and values into decision-making, consideration of cost-effectiveness, and arguments for preserving the appendix based on a biological rationale.

The primary outcome in the APPAC trial was treatment success or no appendectomy within a year after discharge for the non-operative antibiotics group. The sample size for the APPAC trial was powered to show non-inferiority of antibiotics with a margin of 24% difference in efficacy between the treatment arms. Because the difference in efficacy was 27%, the trial did not meet the criteria for declaring non-inferiority. However, the margin of 24%, presumed to be the minimal clinically important difference, was arbitrarily set by the investigators [15]. In reality, there is little clinical difference between 24% and 27% treatment failure at one y. Furthermore, the acceptable rate of one-year treatment failure likely differs among patients and clinicians on the basis of multiple factors such as perceived risks vs. benefits of the two strategies for each individual as well as individual preferences and values.

Multiple recent meta-analyses comparing antibiotics with appendectomy report a failure rate consistent with that noted in the APPAC trial, perhaps because the latter trial contributed approximately one-third of the patients to these meta-analyses [15 -17]. In other diseases where there is an option for surgical vs. medical management with antibiotics such as diverticulitis, similar rates of recurrence are accepted as justification for non-operative management. For example, in a systematic review of diverticulitis, Regenbogen et al. stated that: “the recurrence rates ranged from 10% to 35%, meaning that most patients never had another episode and would have no opportunity to benefit from surgery” [18]. Although the overall complication rates for surgery for diverticulitis are significantly higher than those for appendectomy, this discordance in interpretation is something to consider.

As already noted, comparing complications for a non-operative and an operative strategy for acute appendicitis can be challenging. Combining data from multiple studies can be misleading, given the differences between studies in definitions and outcome assessments. Conclusions in different meta-analyses have been no difference [16], fewer complications with initial non-operative management [19, 20], and fewer complications with appendectomy [15,21].

Despite the statistically inconclusive results, it deserves mention that for patients and surgeons looking to avoid surgery, treatment with antibiotics is efficacious more than 70% of the time. Moreover, patients who have a recurrence in the first year are unlikely to develop complicated appendicitis. It also is reassuring to know that patients avoiding surgery do not develop major complications. Not surprisingly, foregoing open surgery helps reduce pain scores and narcotic usage, which can prove troublesome for some individuals at risk for addiction.

Patient Factors

Patient-reported outcomes

Since the Patient-Centered Outcomes Research Institute was established in 2010, there has been more engagement of patients and all relevant stakeholders in comparative effectiveness research whereby two or more commonly used treatments are evaluated to determine which works best for which patients. In order to answer questions of comparative effectiveness, outcomes beyond the traditionally reported morbidity and mortality rates must be considered. Patient-reported outcomes such as health status, quality of life, and satisfaction are being reported increasingly as secondary outcomes in comparative effectiveness research [22].

Unfortunately, no randomized trials or meta-analyses comparing appendectomy with antibiotics included a health status or quality of life assessment. The paucity of patient-reported and patient-centered outcomes in appendicitis research has been noted previously. The available literature includes studies focused on pediatric appendicitis, including a limited number of studies describing “Life Impact” outcomes, with only one RCT utilizing a validated patient or parent quality-of-life assessment tool [23]. In a non-randomized, patient-preference pediatric study, there were no differences between treatment strategies in health-related quality of life, as measured directly from the child or from a parent proxy [24]. Taken together, these studies illustrate the overall paucity of data, especially in adults, regarding quality-of-life outcomes in appendicitis trials comparing appendectomy with antibiotic intervention.

In the above review of appendicitis trials, other “Life Impact” outcome measures included validated pain score, time away from normal activities or school, recovery to full activity, time to ambulation, cosmesis, and other patient-reported outcome measures [23]. Only a few of these measures are reported in the meta-analyses comparing antibiotics with appendectomy (Table 1). For example, pain is mentioned in two systematic reviews/meta-analyses that are recent enough to have included the APPAC trial [16,20]. Both meta-analyses report that quantitative synthesis was not possible for pain but described the results of individual trials. One trial found no difference in the duration of pain in the short term [25]. Three trials supported either less pain, as measured on specific post-operative days [26], or shorter duration of pain with antibiotics [10,27]. The latter two trials also demonstrated that any initial difference in pain disappeared in the longer term [10,27].

Table 1.

Data Provided in Meta-Analyses of Randomized Controlled Trials (RCTs) Comparing Antibiotics with Appendectomy for Acute Uncomplicated Appendicitis

Series	Number and types of studies	Efficacy/ adverse events	Pathophysiological manifestations	Resource use	Life impact
Findlay et al. (2016) [16]	6 RCTs	X	X	X	X
Rollins et al. (2016) [20]	5 RCTs	X	–	X	X
Sallinen et al. (2016) [17]	5 RCTs and 1 quasi-RCT	X	–	X	X
Harnoss et al. (2016) [15]	4 RCTs and 4 non-RCTs	X	X	X	–
Rocha et al. (2015) [19]	8 Meta-analyses	X	X	X	X
Kirby et al. (2015) [21]	3 RCTs	X	–	–	–
Liu et al. (2014) [55]	5 RCTs	X	–	–	X
Varadhan et al. (2012) [9]	4 RCTs	X	–	X	X
Mason et al. (2012) [56]	5 RCTs	X	–	X	X
Wilms et al. (2011) [8]	5 RCTs	X	–	X	X
Ansaloni et al. (2011) [57]	4 RCTs	X	X	X	X
Liu and Fogg (2011) [7]	4 RCTs and 2 non-RCTs	X	–	–	–
Varadhan et al. (2010) [58]	3 RCTs	X	–	–	–

Reported outcomes included efficacy (i.e., recurrence of symptoms) and adverse events, pathophysiological manifestations (i.e., blood markers of inflammation, histopathologic progression), resource use (i.e., costs, length of stay), and life impact (i.e., pain and sick days or time away from work).

Similarly, four trials described sick leave, return to work, or both. Two trials favored antibiotics with regard to duration of sick leave [10, 27], whereas two trials showed no difference [25,28]. No quantitative synthesis of these individual trials was performed in the systematic review and meta-analysis by Rollins et al. [20]. Sallinen et al. analyzed three trials [10,25,28] but excluded one because it enrolled only children; they found no difference in sick leave [17]. Findlay et al. included all four trials but found a shorter sick leave only with intention-to-treat but not per-protocol analyses [16].

Further research is necessary to identify and quantify whether differences in patient-reported outcomes exist with the different strategies for managing uncomplicated acute appendicitis. Although currently available data suggest that there may be benefits in terms of short-term pain severity and duration as well as sick leave, these data are marred by inconsistency and risk of bias.

Patient knowledge, perceptions, preferences, and values

The Affordable Care Act (ACA) mandated that patients be engaged in shared decision-making, meaning that they should be provided with all relevant clinical evidence and treated as stakeholders in management decisions [29]. In order for patients to be able to make informed choices, they must have adequate knowledge about the epidemiology, treatment, and outcome of their disease. However, patient and parent perceptions may stem from poor underlying knowledge about appendicitis.

Kadera et al. performed a prospective survey of patients, visitors, and medical center staff at the Los Angeles County Public Teaching Hospital. Among 129 participants, only half of patients (51%) knew what and where the appendix was, and fewer than half (43%) correctly defined appendicitis [30]. In another prospective survey of caregivers and patients over the age of 14 years presenting to a children's hospital emergency department with suspected appendicitis, a minority of participants (14%) could correctly rank the risk of death when compared in magnitude with deaths from accidents or natural disasters such as lightening. Furthermore, the majority of patients believed that delay in operation was “likely” or “very likely” to result in appendiceal rupture (82%) and therefore to lead to severe complications and death (81%) [31]. In this study, a short, tablet-based educational intervention was able to reduce the percentage holding these beliefs only to 53 and 47, respectively. Furthermore, after education, a similar percentage of patients considered immediate appendectomy (74%) and antibiotics only (68%) to be reasonable choices.

In the study by Kadera et al., the authors also identified participants' preferred treatment strategy given current evidence for antibiotics for acute appendicitis and a hypothetical scenario [30]. Of 110 patients without prior appendectomy, more than half (55%) had a preference for antibiotic therapy, whereas only 37% had a preference for surgery. Of 19 patients with prior appendectomy, the majority (74%) indicated that they would now choose antibiotics. The most frequently mentioned reasons for the decision were concerns about dying, surgical complications, missing school or work, inability to perform normal activities, pain, and costs. The primary drivers for the decision differed according to whether the participants had had an appendectomy. Concerns about dying, pain, and cost ranked highest among those without prior appendectomy, and pain and inability to perform normal activities ranked highest among those with prior appendectomy.

Nevertheless, more than 27% of patients treated with antibiotics have a recurrence within a year and ultimately require surgery. For a college student having to miss classes or a single working parent trying to support a family, this can represent a substantial life burden. Combined with an undetermined but potentially higher recurrence rate in subsequent years, the risks of antibiotic therapy loom even larger. In contrast, patients undergoing appendectomy have received a definitive, curative therapy and return to work or school within several days.

Patient compliance

Effective out-patient treatment with antimicrobial therapy relies heavily on patient compliance with prescribed enteral antibiotics. Non-compliance may lead to failure, whereas a surgical intervention is a definitive approach. The treatment of other infectious diseases demonstrates that patient compliance may be as low as approximately 50% with antimicrobial therapy, even for short courses [32]. Despite the potential for compliance issues playing a role in out-patient treatment consideration, the out-patient management of uncomplicated diverticulitis remains a feasible and effective strategy [33]. Patient compliance remains a significant consideration when choosing a treatment strategy.

Costs

When comparing the costs of different management strategies for acute uncomplicated appendicitis, the costs beyond the initial hospitalization must be included. The costs of complications and management failure (i.e., need for appendectomy after antibiotics) have not been reported in randomized trials and therefore have not been included in meta-analyses [16]. As noted above, the patient preference cohort study did evaluate healthcare-related costs of appendicitis out to one y, and the costs were ∼$1,200 higher in the appendectomy group [34].

Because there are no randomized trials comparing costs, cost-effectiveness analyses informed by the best available evidence and data are the next best option for determining which management strategy should be preferred. Wu et al. performed decision and cost-effectiveness analyses comparing laparoscopic appendectomy with non-operative management for acute uncomplicated appendicitis in both adults and children [35,36]. For adults, three strategies were compared: (1) Immediate laparoscopic appendectomy; (2) non-operative management without subsequent interval appendectomy; and (3) non-operative management with subsequent interval appendectomy [35]. For children, laparoscopic appendectomy was compared with non-operative management (with interval appendectomy occurring in 10% of cases) [36]. Both analyses were informed by literature review, the Healthcare Cost and Utilization Project data, and the Medicare Physician Fee schedule. For the analysis in adults, the American College of Surgeons National Surgical Quality Improvement Project Risk Calculator also was utilized. Both analyses included a societal perspective in the costs analysis.

Non-operative management without interval appendectomy was the preferred strategy in 96% of adult cases, and non-operative management was cost-effective in 92% of simulations of children with acute, uncomplicated appendicitis. Furthermore, sensitivity analysis showed that the one-year recurrence rate for appendicitis would have to be ∼40% for laparoscopic appendectomy to be preferred in adults. Furthermore, if the total cost of appendectomy were less than $5,468 in adults, then laparoscopic appendectomy would be preferred.

The limitations of these cost-effectiveness analyses should be considered. First, the utilities were extrapolated from studies of patients with diverticulitis or undergoing other abdominal operations. Second, several assumptions were made about costs. Given that the model was sensitive to changes in costs, this may have affected the results. Third, costs related to antibiotic resistance or Clostridium difficile infections (CDIs) related to antibiotic administration were not factored into the models. Fourth, outcomes were considered only out to one y, so longer-term outcomes were not included. Furthermore, rare outcomes such as a missed appendiceal malignancy were not included. Lastly, these analyses were performed from a societal rather than from a patient's perspective.

Biological Impact

Antimicrobial collateral damage

Widespread and unfocused antibiotic use results in collateral damage, including antimicrobial resistance, CDI, altered microbiome, and adverse drug reactions [37,38]. A switch to an antimicrobial treatment-only approach may result in a greater probability of antimicrobial-associated collateral damage, both to the host patient and to antibiotic susceptibility patterns. In particular, an antibiotics-only approach commonly utilizes a fluoroquinolone [10, 28]. This class of antibiotics has received more focus because of the recent increased resistance, adverse reactions, and a propensity to cause CDI with hypervirulent strains [39,40]. A recent FDA communication supports the selective utilization of these agents to avoid untoward effects [41]. A surgical-only approach would result in a reduction in antibiotic exposure to selective pre-operative or peri-operative prophylaxis [42]. Antimicrobial stewardship has become a focus in the surgical arena [43] and should be considered strongly as a deciding factor in the debate and study design of antibiotic-only vs. surgical approaches.

Biologic rationale

Although the appendix traditionally has been thought of as a vestigial organ, recent data suggest that it plays an immune-mediated role in the maintenance of gut flora, supporting the retention of the organ whenever possible [44].

Ongoing Studies

Critics of an antibiotic-first strategy for acute uncomplicated appendicitis argue against the use of intravenous broad-spectrum antibiotics (i.e., ertapenem) requiring several days in the hospital. A pilot trial was conducted recently for planning purposes for a multicenter randomized trial; 30 patients were randomized to outpatient antibiotic management or appendectomy for acute uncomplicated appendicitis [45]. This single-center pilot trial demonstrated the feasibility of the outpatient approach, although short- and long-term effectiveness and safety have yet to be established.

Future Directions

Predictors of antibiotic success

There is a modest amount of data on predictors of antibiotic success. Age <60 y, serum C-reactive protein (CRP) concentration <60 g/L, and white blood cell (WBC) count <12 × 10⁻⁹/L were significant predictors of uncomplicated appendicitis and antibiotic success [46]. Elevated CRP (>4 mg/dL) [25] and the presence of an appendicolith were significant risk factors for failed antibiotic treatment [47]. Appendicoliths are significantly more common in perforated appendicitis, with a 39.4% prevalence vs. 14.6% in non-perforated appendicitis [48]. Some experts believe the presence of an appendicolith combined with inflammatory changes on CT indicate perforation or impending perforation [49]. Vons et al. found the presence of an appendicolith on CT to be the only factor significantly associated with complicated appendicitis and associated with the failure of antibiotic treatment. [25] We believe the above-mentioned factors are surrogates for either severe infection or complicated appendicitis and thus are predictors of antibiotic failure.

The APPAC is the most recent RCT on this topic, and their inclusion criteria were a CT diameter of >6 mm and abnormal contrast enhancement of the appendiceal wall, inflammatory edema, or fluid collection; with exclusion criteria of appendicolith on CT, perforation, abscess, suspicion of tumor, or age >60 y. Compared with other recent clinical trials, the APPAC inclusion and exclusion criteria yielded the highest accuracy (98.7%) (Table 2) in predicting uncomplicated appendicitis and correlated with the lowest initial antibiotic failure rate (5.8%) (Table 3) [10,25,28]. We believe that excluding patients with appendicoliths, perforation, abscess, suspicion of tumor, or age >60 y will best predict initial treatment success; however, more trials are needed to isolate additional factors correlating with initial antibiotic success and minimizing the long-term recurrence rate.

Table 2.

Efficacy of Exclusion Criteria in Predicting Complicated Appendicitis

Series	Inclusion	Exclusion	Complicated appendicitis
Styrud et al. (2006) [28]	Clinical	Clinical suspicion of perforation; CRP <10 mg/dL	5% of Surg arm perforation 5% of Antibiotic arm perforation
Vons et al. (2011) [25]	CT imaging	CT: complicated appendicitis	18% of Surg arm
APPAC [10]	CT imaging	CT: complicated appendicitis or appendicolith	0 in Surg arm^a 2.7% Antibiotic arm

Note: In APPAC, 1.5% of patients in surgical arm ended up having complicated appendicitis. However, upon further review, the authors discovered that these patients had violated the protocol, and all had appendicoliths visible on CT at the time of inclusion.

CT = computed tomography; CRP = C-reactive protein; Surg = surgery.

Table 3.

Failure Rate, Hospital Length of Stay, and Complication Rate of Surgery vs. Antibiotic Treatment

Series	Inclusion	Exclusion	Study arms	Short-term failure	Re- currence	Abx duration (IV + PO)	Hospitalization (d)	Complications
Styrud et al. (2006) [28]	Clinical	Clinical suspicion of perforation, CRP <10 mg/dL	Abx^a	12%	14%	2 + 10 d	3	N/A
			Surg	0	0	N/A	2.6	14%
Vons et al. (2011) [25]	CT	CT: complicated appendicitis	Abx^b	12%	29%	2 + 8 d	3.96	8%
			Surg	0	0	One time	3.04	2%
APPAC [10]	CT	CT: complicated appendicitis or appendicolith	Abx^c	5.8%	21.5%	3 + 7 d	3	2.8%
			Surg	0	0	One time	3	20.5%

Cefotaxime + tinidazole (two days IV), then ofloxacin + tinidazole (10 days PO).

Amoxicillin/clavulanic acid (2 days IV or PO + 8 days PO).

Ertapenem (3 days IV) then levofloxacin + metronidazole (7 days PO).

Abx = antibiotic; CT = computed tomography; CRP = C-reactive protein; IV = intravenously; N/A = not available; PO = by mouth; Surg = surgery.

Comparative effectiveness of antibiotics

There are no trials comparing the efficacy of different antibiotics in the treatment of appendicitis. The appendiceal flora includes facultative and aerobic gram-negative organisms and anaerobic organisms. From the RCTs, we currently have evidence only of good results from cefotaxime plus tinidazole (Styrud et al.) and ertapenem (APPAC) [10,28]. In addition to these two antibiotic regimens, we recommend the regimens in the Surgical Infection Society's Guideline for Intra-abdominal infection (Table 4) [50]. Ampicillin/sulbactam is no longer recommended because of the proliferation of β-lactamase-producing Escherichia coli strains, resulting in a reduction in susceptibility [51].

Table 4.

Initial Empiric Treatment of Adult Patients with Community-Acquired Intra-Abdominal Infections [ 50 ]

Lower risk or severity	Higher risk or severity
Cefotaxime or ceftriaxone + metronidazole	Piperacillin/tazobactam
Ertapenem	Cefepime or ceftazidime + metronidazole
Moxifloxacin or ciprofloxacin + metronidazole (if severe β-lactam allergy or local susceptibility demonstrated per antibiogram)	Doripenem or imipenem/cilastatin or meropenem
	Aztreonem + vancomycin + metronidazole (if severe β-lactam allergy)

Whereas Vons et al. showed a lower complication rate in the surgical group, both Styrud et al. and the APPAC studies showed more complications with surgery (see Table 2) [10,25,28]. Hospitalization times were similar in all three trials in the antibiotic and surgery groups. Several studies have shown patients assigned to the antibiotic group report less pain and quicker return to work [10,25-27].

However, a major limitation is that most of these trials were performed in Europe with the nearly all using open appendectomies, which may over-represent surgical complication rates. In the U.S., as many as 80% of appendectomies are performed laparoscopically with hospitalization of 1–2 d and complication rates of 1%–3% [52,53]. Laparoscopic appendectomies shorten hospitalization by 1.1 days and produce half the rate of skin infections as open appendectomies [12,13]. We believe that the surgical group complication rates and hospitalization time would decrease if the same studies were performed using laparoscopic appendectomies, especially given that half of the APPAC trial's surgical complications were incision infections [10]. Therefore, we encourage future U.S. trials using the laparoscopic technique.

Another limitation is that the current RCTs followed patients only out to one y [10,25,28]. This may limit the complications and costs of complications of both treatment groups such as small bowel obstruction caused by an operation and the negative effects of antibiotics such as increased resistance and Clostridium difficile colitis caused by the implementation of empiric antibiotics.

Subgroups in whom antibiotics may be the preferred treatment strategy

The incidence of perforation, abscess, or any major complication is not higher in the antibiotic group who underwent delayed appendectomy [10,25,28]. Therefore, the use of antibiotics may be especially beneficial in specific populations such as patients with a hostile abdomen, severe co-morbidities of the heart and lungs that make surgery high risk, equivocal findings mimicking appendicitis such as ruptured right ovarian cyst, and patients without ready access to surgery such as maritime military personnel [54] or citizens of developing countries. There is no current evidence on the effects of antibiotic therapy in these specific patient populations.

Conclusion

Current evidence suggests antibiotic therapy may be used safely in a select group of patients with uncomplicated appendicitis. Selection of these patients should include clinical findings as well as patient preference. It is controversial whether antibiotic therapy is non-inferior to the gold standard of appendectomy. Future studies should focus on isolating the characteristics of appendicitis most susceptible to antibiotics, using laparoscopic operations as controls for comparison, identifying long-term side effects such as antibiotic resistance or Clostridium difficile colitis, documenting the difficulty of operating on recurrent appendicitis, and analyzing the efficacy of antibiotic treatment in non-surgical candidates. Furthermore, patient compliance with therapy, particularly in the non-operative group, must be evaluated to optimize patient selection and outcome.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Addiss

, Shaffer

, Fowler

, Tauxe

. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol, 1990; 132:910–925.

Andersson

, Petzold

. Nonsurgical treatment of appendiceal abscess or phlegmon: A systematic review and meta-analysis. Ann Surg, 2007:246:741–748.

Simillis

, Symeonides

, Shorthouse

, Tekkis

. A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon). Surgery, 2010; 147:818–829.

Fitz

. Perforating inflammation of the vermiform appendix; with special reference to its early diagnosis and treatment. Am J Med Sci, 1886; 92:321–346.

McBurney

. Experience with early operative interference in cases of disease of the vermiform appendix. NY Med J, 1889; 50:676–684.

Coldrey

. Five years of conservative treatment of appendicitis. J Int Coll Surg, 1959; 32:255–261.

Liu

, Fogg

. Use of antibiotics alone for treatment of uncomplicated acute appendicitis: A systematic review and meta-analysis. Surgery, 2011; 150:673–683.

Wilms

I.M

, de Hogg

, de Visser

, Junzing

. Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane Database Syst Rev, 2011(11):CD008359.

Varadhan

, Neal

, Lobo

. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: Meta-analysis of randomised controlled trials. BMJ, 2012; 344:e2156.

10.

Salminen

, Paajdnen

, Rautio

, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: The APPAC randomized clinical trial. JAMA, 2015; 313:2340–2348.

11.

Masoomi

, Nguyen

, Dolich

, et al. Laparoscopic appendectomy trends and outcomes in the United States: Data from the Nationwide Inpatient Sample (NIS), 2004–2011. Am Surg, 2014:80:1074–1077.

12.

Ingraham

, Cohen

, Bilimorin

, et al. Comparison of outcomes after laparoscopic versus open appendectomy for acute appendicitis at 222 ACS NSQIP hospitals. Surgery, 2010; 148:625–635.

13.

Sauerland

, Jaschinski

, Neugebauer

. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev, 2010(10):CD001546.

14.

Livingston

, Vons

. Treating appendicitis without surgery. JAMA, 2015; 313:2327–2328.

15.

Harnoss

, Zelienkap

, Probst

, et al. Antibiotics versus surgical therapy for uncomplicated appendicitis: Systematic review and meta-analysis of controlled trials (PROSPERO 2015: CRD42015016882). Ann Surg, 2017; 265:889–900.

16.

Findlay

, Kufsi

, Hammer

, et al. Nonoperative management of appendicitis in adults: A systematic review and meta-analysis of randomized controlled trials. J Am Coll Surg, 2016; 223:814–824.

17.

Sallinen

, Akl

, You

, et al. Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis. Br J Surg, 2016; 103:656–667.

18.

Regenbogen

, Hardiman

, Hendren

, Morris

. Surgery for diverticulitis in the 21st century: A systematic review. JAMA Surg, 2014; 149:292–303.

19.

Rocha

, Rossi

, Pessoa

, et al. Antibiotics alone versus appendectomy to treat uncomplicated acute appendicitis in adults: What do meta-analyses say?. World J Emerg Surg, 2015; 10:51.

20.

Rollins

, Varadhan

, Neal

, Lobe

. Antibiotics versus appendicectomy for the treatment of uncomplicated acute appendicitis: An updated meta-analysis of randomised controlled trials. World J Surg, 2016; 40:2305–2318.

21.

Kirby

, Hobson

, Burke

, et al. Appendicectomy for suspected uncomplicated appendicitis is associated with fewer complications than conservative antibiotic management: A meta-analysis of post-intervention complications. J Infect, 2015; 70:105–110.

22.

Calvert

, Blazeby

, Revicki

, et al. Reporting of patient-reported outcomes in randomized trials: The CONSORT PRO extension. JAMA, 2013; 309:814–822.

23.

Hall

, Kapedia

, Eaton

, et al. Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: A systematic review. Trials, 2015; 16:275.

24.

Minneci

, Deans

. Is an RCT the best way to investigate the effectiveness of nonoperative management of pediatric appendicitis?. Ann Surg, 2015. November 18. Epub ahead of print.

25.

Vons

, Barry

, Maitre

, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: An open-label, non-inferiority, randomised controlled trial. Lancet, 2011; 377:1573–1579.

26.

Eriksson

, Granstrom

. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg, 1995; 82:166–169.

27.

Hansson

, Körner

, Khorr

, Manesh

. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg,, 2009; 96:473–481.

28.

Styrud

, Eriksson

, Nilsson

, et al. Appendectomy versus antibiotic treatment in acute appendicitis: A prospective multicenter randomized controlled trial. World J Surg, 2006; 30:1033–1037.

29.

Telem

. Shared decision making in uncomplicated appendicitis: Is it time to include nonoperative management?. JAMA, 2016; 315:811–812.

30.

Kadera

, Mower

, Krishnadasan

, Talan

. Patient perspectives on antibiotics for appendicitis at one hospital. J Surg Res, 2016; 201:253–257.

31.

Chau

, Ciullo

, Watson-Smith

, et al. Patient-centered outcomes research in appendicitis in children: Bridging the knowledge gap. J Pediatr Surg, 2016; 51:117–121.

32.

Eells

, Nguyen

, Jung

, et al. Relationship between adherence to oral antibiotics and postdischarge clinical outcomes among patients hospitalized with Staphylococcus aureus skin infections. Antimicrob Agents Chemother, 2016; 60:2941–2948.

33.

Lue

, Laredo

, Lanas

. Medical treatment of diverticular disease: Antibiotics. J Clin Gastroenterol, 2016; 50(Suppl 1):S57–S59.

34.

Minneci

, Mahida

, Lodwick

, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis. JAMA Surg, 2016; 151:408–415.

35.

, Dawes

, Sacks

, et al. Cost effectiveness of nonoperative management versus laparoscopic appendectomy for acute uncomplicated appendicitis. Surgery, 2015; 158:712–721.

36.

, Sacks

, et al. The cost-effectiveness of nonoperative management versus laparoscopic appendectomy for the treatment of acute, uncomplicated appendicitis in children. J Pediatr Surg, 2016 DOI 10.1016/j surg 2015;06.021

37.

Hensgens

, Goorhuis

, Dekkers

, Kujper

. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother, 2012; 67:742–748.

38.

Dellit

, Owens

, McGowan

Jr , et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis, 2007; 44:159–177.

39.

Pepin

, Saheb

, Coulombe

, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: A cohort study during an epidemic in Québec. Clin Infect Dis, 2005; 41:1254–1260.

40.

Hawser

, Hoban

, Badalsk

, et al. Epidemiology and antimicrobial susceptibility of gram-negative aerobic bacteria causing intra-abdominal infections during 2010–2011. J Chemother, 2015; 27:67–73.

41.

FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. Bethesda, Md. July 26, 2016. (Accessed February 28, 2017).

42.

Bratzler

, Dellinger

, Olsen

, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect, 2013; 14:73–156.

43.

Sartelli

, Duane

, Catena

, et al. Antimicrobial stewardship: A call to action for surgeons. Surg Infect, 2016; 17:625–631.

44.

Bollinger

, Barbas

, Bush

, et al. Biofilms in the normal human large bowel: Fact rather than fiction. Gut, 2007; 56:1481–1482.

45.

Talan

, Saltzman

, Mower

, et al. Antibiotics-first versus surgery for appendicitis: A US pilot randomized controlled trial allowing outpatient antibiotic management. Ann Emerg Med [Epub ahead of print]. DOIII: 10.1016/j annemergmed 2016.08.446.

46.

Hansson

, Khorram-Manes

, Alwindawe

, Lundholm

. A model to select patients who may benefit from antibiotic therapy as the first line treatment of acute appendicitis at high probability. J Gastrointest Surg, 2014; 18:961–967.

47.

Shindoh

, Niwah

, Kawai

, et al. Predictive factors for negative outcomes in initial non-operative management of suspected appendicitis. J Gastrointest Surg, 2010; 14:309–314.

48.

Singh

, Mariadason

. Role of the faecolith in modern-day appendicitis. Ann R Coll Surg Engl, 2013; 95:48–51.

49.

Pinto Leite

, Pereira

, Cunha

, Sirlin

. CT evaluation of appendicitis and its complications: Imaging techniques and key diagnostic findings. AJR Am J Roentgenol, 2005; 185:406–417.

50.

Mazuski

, Tessier

, May

, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect, 2017; 18:1–76.

51.

Pitout

, Laupland

. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: An emerging public-health concern. Lancet Infect Dis, 2008; 8:159–166.

52.

Andersson

. Short-term complications and long-term morbidity of laparoscopic and open appendicectomy in a national cohort. Br J Surg, 2014; 101:1135–1142.

53.

Papandria

, Lardaro

, Rhee

, et al. Risk factors for conversion from laparoscopic to open surgery: Analysis of 2138 converted operations in the American College of Surgeons National Surgical Quality Improvement Program. Am Surg, 2013; 79:914–921.

54.

Wojciechowicz

, Hoffkamp

, van Hulst

. Conservative treatment of acute appendicitis: An overview. Int Marit Health, 2010; 62:265–272.

55.

Liu

, Li

, Zhang

, et al. Meta-analysis of the therapeutic effects of antibiotic versus appendicectomy for the treatment of acute appendicitis. Exp Ther Med, 2014; 7: 1181–1186.

56.

Mason

, Mouzzeza

, Moroney

, Katkhouda

. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect, 2012; 13:74–84.

57.

Ansaloni

, Catena

, Coccolini

, et al. Surgery versus conservative antibiotic treatment in acute appendicitis: A systematic review and meta-analysis of randomized controlled trials. Dig Surg, 2011; 28:210–221.

58.

Varadhan

, Hmumes

, Neal

, Lobo

. Antibiotic therapy versus appendectomy for acute appendicitis: A meta-analysis. World J Surg, 2010; 34:199–209.