ABSTRACT
Background
Appendectomy is the current standard of care for acute appendicitis. However, accumulating international evidence suggests that medical antibiotic therapy is not inferior to appendectomy. Local factors may work for and against a medical approach. While prospective randomized trials are still to be performed in a South African setting, this study aimed to describe existing data within a geographically defined area.
Materials and Methods
A retrospective audit from 01/01/2018–31/12/2023 was performed at George Regional Hospital, South Africa. All adults and children over 12 years with a clinical or radiological diagnosis of acute appendicitis, without complicated disease mandating direct surgical appendectomy, were identified and separated into two groups, namely, those with initial medical management and those who underwent direct appendectomy. The primary aims were to compare the presentations and outcomes of acute appendicitis managed by antibiotic therapy or appendectomy. Secondary aims included describing the proportion of cases eligible for medical management, as well as post‐treatment complications, including the recurrence rate. Analysis was descriptive and comparative with patients grouped as Direct Surgery (DS), Antibiotics Successful (AS) and Antibiotics Unsuccessful (AU).
Results
Direct surgical appendectomy was performed on 44% of the 650 cases. Of 365 (56%) cases that received antibiotic therapy, 190 (52%) were discharged without symptoms (AS), while 175 (48%) failed antibiotic therapy and underwent surgical appendectomy (AU) during first admission. Of the 190 patients who were discharged after antibiotic therapy only, 16 had recurrent symptoms, of which 14 underwent surgery and 2 had repeat antibiotic therapy. When comparing the AS to AU group, AS cases had a lower median heart rate (89 vs. 95 bpm; p < 0.05), lower C‐reactive protein level (51 vs. 108 mg/L; p < 0.01) and lower Alvarado score (6 vs. 7; p < 0.01). Patients in the AS group had a median hospitalization of one day less than the DS group (p < 0.001), and two days less than the AU group (p < 0.001). When compared with DS, patients in the AU group experienced significantly fewer (p < 0.001) Clavien‐Dindo grade 3–5 events.
Conclusion
Half of patients with acute appendicitis treated medically, safely avoided appendectomy. In this context, antibiotic therapy may be considered in selected patients.
Keywords: antibiotic, appendectomy, appendicitis, medical therapy, recurrence
Appendectomy is the current standard of care for acute appendicitis. However, accumulating international evidence suggests that medical antibiotic therapy is not inferior to appendectomy. Local factors may work for and against a medical approach. While prospective randomized trials are still to be performed in a South African setting, this study aimed to describe existing data within a geographically defined area.
1. Introduction
Appendicitis is one of the most common surgical emergencies worldwide [1]. The current standard of care is surgical appendectomy, however there is a growing body of international evidence suggesting that medical antibiotic therapy is not inferior to appendectomy and does not increase the risk of complications [2, 3, 4, 5]. In a randomized clinical trial comparing antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis, Salminen et al., reported a recurrence rate of 27% within one year (thus 73% of medically treated patients did not require surgery), while the rate after 5 years rose to 39% (61% avoiding surgery) [2, 6]. Although antibiotic treatment alone presented a feasible alternative to surgery, it is important to consider the context of the study, namely Finland, a High Income Country (HIC). Similarly, the CODA collaborative found antibiotics non‐inferior to appendectomy, but with a 30% conversion to appendectomy within 90 days [5]. A meta‐analysis by van Dijk et al., showed that delaying appendectomy for presumed uncomplicated appendicitis for up to 24 h after admission does not appear to be a risk factor for complicated appendicitis, post‐operative surgical site infection or morbidity [7].
Although the medical management of acute appendicitis has been discussed in South African literature [8, 9, 10], there is, to the best of the author's knowledge, no data from South Africa. Rather, opinions are based on published studies originating from HICs.
Social determinants of health make it difficult to extrapolate findings of studies from HICs to Low and Middle Income Countries (LMICs) where existing factors argue both for and against a medical approach. Ready access to medical care in LMICs is often constrained, with care only sought when the disease process is more advanced. This may limit treatment options, make treatment more difficult or diminish the success of medical management. Additional confounding variables include immune compromised conditions and obesity [11, 12]. On the other hand, district hospitals in LMICs are frequently overburdened, or lack the capacity to deliver safe surgical care, resulting in onward referral and long waiting times at regional hospitals with specialist services. Medical therapy avoids general anesthesia, surgery, and long hospital stays, and has been shown as cost effective [4, 13].
A local study investigating the knowledge and skills gap of medical practitioners delivering district hospital services in the Western Cape Province reported that even though district doctors rated themselves competent in performing a laparotomy, they did not perform this procedure. Rather, patients requiring a laparotomy were referred for specialist care as medical officers were not sufficiently confident to deal with unexpected complications, while also being concerned about medico‐legal implications [14]. Therefore, early medical treatment of acute uncomplicated appendicitis at district level, if effective, could benefit both the patient and healthcare system.
Currently there are no published guidelines for medical management of acute appendicitis in South Africa, a LMIC. Therefore, units that have adopted an antibiotic first approach in managing acute uncomplicated appendicitis have a moral obligation to publish their findings in order to inform management. The primary aims of this study were to compare the presentations and outcomes of acute appendicitis managed by medical antibiotic therapy, with standard appendectomy. The secondary aims were to describe the proportion of cases deemed eligible for medical management, as well as the complications and predictive factors for recurrence and post‐medical antibiotic therapy appendectomy.
2. Material and Methods
A retrospective audit over a period of six years (01/01/2018–31/12/2023) was performed at George Regional Hospital in the Western Cape Province of South Africa. This hospital serves as a primary and secondary level referral center, with a drainage area stretching from Murraysburg (399 km) in the north, to Plettenberg Bay (96 km) in the east and Riversdale (138 km) to the west, with a total triangulated service drainage area of 22,780 km2. The Surgery Department consisted of four consultants and six medical officers with an in‐patient capacity of 40 adult beds. A shared emergency theater was available 24 h/day. The names and hospital numbers of patients are held in the clinic records of the hospital. All patients (adults and children over 12 years) with a clinical or radiological diagnosis of acute appendicitis were identified and separated into two groups, namely, those who underwent initial medical antibiotic management and those who underwent direct surgical appendectomy. Patients with complicated disease on admission (including abscess > 5 cm, appendicolith and abdominal free fluid), were excluded by the treating team from antibiotic therapy. Thereafter, patients proceeded to direct surgery or antibiotic therapy according to the managing clinician. Pregnant women were not included in the study.
The diagnosis of appendicitis was made on history and clinical examination, and also included the Alvardo score, ultrasound imaging and abdominal computerized tomography (CT) when available. The Alvarado score is a clinical scoring system used to assess the likelihood of acute appendicitis. This assists in determining the need for further surgical consultation or diagnostic tests such as CT scans, in emergency settings. The score ranges from 0 to 10, with higher scores indicating a greater probability of appendicitis. Surgical appendectomy included both open (laparotomy and McBurney incision) and laparoscopic approaches, while conservative antibiotic therapy comprised a course of co‐amoxicillin and clavulanic acid (combination) 1.2 g IV 8‐hrly, converted to oral therapy (1 g 12‐hrly) at (24–48 h) for a total 10 days course. Clindamycin 600 mg IV 8‐hrly, converted to oral therapy (450 mg 8‐hrly) at (24–48 h) for a total of 10 days with addition of metronidazole 500 mg IV 12‐hrly, converted to oral therapy (400 mg 12‐hrly) at (24–48 h) for the total of 10 days was administered to patients with penicillin allergy. The decision to proceed to surgery after initial antibiotic therapy was made by the treating clinical team, taking the following combination of parameters into account after 24–48 h: no improvement or worsening of abdominal pain, feeding intolerance—nausea and/or vomiting, and no improvement or deterioration of vital parameters including heart rate and temperature. Successful antibiotic therapy was regarded as the discharge of an asymptomatic patient without surgical intervention.
Complications were sought up to discharge from hospital, while recurrence rate was determined by patients returning to the hospital with appendicitis, within 15 months. The Clavien‐Dindo classification system was utilized for grading the severity of postoperative complications. It provides a standardized, reproducible and objective method for reporting and comparing surgical outcomes across studies and institutions, based on the therapeutic consequences of the complication rather than subjective assessment. Grades 3–5 are considered major complications.
All relevant data was collected from the hospital's electronic health records and entered onto an anonymized Excel spreadsheet for statistical analysis. A separate log linking case numbers to patient names and hospital numbers was kept by the Principal Investigator in a secure location. Descriptive statistics were generated to characterize the populations and determine possible confounding differences. The normal distribution of data was determined using the Shapiro‐Wilk test and confirmed using the Kilmogorov‐Smirnov test. Results are reported as n (%) and categorical comparisons using the Fisher's exact (X 2) test. Special investigations are reported using the means (SD) and/or median (range and/or quartiles) according to the distribution of the data. Continuous variables were compared using either the One‐way ANOVA with Tukey's (normally distributed variables) or Kruskal‐Wallis test (non‐parametric variables). The Kaplan‐Meier curve was used to determine probability and the Receiver Operator Curve (ROC) used to determine diagnostic accuracy based on sensitivity/specificity. The threshold for significance was accepted at p < 0.05. All statistical analysis was performed using GraphPad Prism (version 10). The study was approved by the Human Research Ethics Committee of the University of Cape Town (655/2024) which granted a waiver of consent due to the retrospective, audit design.
3. Results
A total of 774 patients with a clinical or radiological diagnosis of acute appendicitis were identified. Of these, 124 were excluded from this analysis due to having complicated disease on admission, leaving 650 patients with uncomplicated appendicitis for inclusion in the study. Three hundred and sixty‐five (56.1%) received medical antibiotic therapy, while 285 (43.9%) underwent direct surgical appendectomy. Asymptomatic discharge, without surgery, was achieved in 52% of the antibiotic therapy group. These totals and outcomes are depicted in Figures 1 and 2; A1.
FIGURE 1.
Overview of patients with acute uncomplicated appendicitis and outcomes. Patients with an abscess > 5 cm, appendicolith or abdominal free fluid were excluded.
FIGURE 2.
Graphical depiction of outcomes. (A.1 & A.2)—Kaplan‐Meier survival charts; (C)—Receiver operating characteristic (ROC) curve.
The descriptive clinical characteristics, laboratory and imaging investigations on admission for all patients grouped as Direct Surgery, Antibiotics Successful and Antibiotics Unsuccessful are shown in Table 1. The median age of patients in the Direct Surgery group was significantly lower (p < 0.05) than that in the Antibiotics Unsuccessful group. The median duration of symptoms in the Direct Surgery group was significantly longer than the Antibiotics Successful (p < 0.01) and Antibiotics Unsuccessful (p < 0.05) groups. The mean heart rate of the Direct Surgery group was also higher than the Antibiotics Successful (p < 0.001) and Antibiotics Unsuccessful (p < 0.01) groups. The administration of pre‐admission antibiotics was similar in all three groups (12%, 16% & 14%). On admission, the median Alvarado score of the Direct Surgery Group was higher than the Antibiotics Successful group (p < 0.01). When comparing the Antibiotics Successful and Antibiotics Unsuccessful groups the Alvarado score was significantly higher in the Antibiotics Unsuccessful (p < 0.05) group. Patients in the Direct Surgery Group had significantly more abdominal pain than both Antibiotics groups (34% vs. 10% & 21%; p < 0.001). The median C‐reactive protein level of the Direct Surgery Group was significantly higher than the Antibiotics Successful group (175 vs. 51 mg/L); p < 0.001), while in similar fashion the median C‐reactive protein level of the Antibiotics Unsuccessful group was significantly higher than the Antibiotics Successful group (108 vs. 51 mg/L; p < 0.01; Figure 2B). These results are also shown graphically in Figure 2B,C. The frequencies and types of imaging tests are also shown in Table 1.
TABLE 1.
Clinical characteristics, laboratory and imaging of patients on admission.
| Direct surgery (N = 285) (a) | Antibiotics (N = 365) | Significance | ||
|---|---|---|---|---|
| Successful (n = 190) (b) | Unsuccessful (n = 175) (c) | |||
| Age (years) c | 26 (16–39) | 28 (20–37) | 29 (19–43) | a versus c * |
| Sex a | ||||
| Male | 165 (58%) | 91 (48%) | 89 (51%) | — |
| Female | 120 (42%) | 99 (52%) | 87 (49%) | |
| Pre‐admission antibiotics a | 35 (12%) | 31 (16%) | 25 (14%) | — |
| Duration of symptoms (days) c | 3 (2–5) | 2 (1–4) | 2 (1–4) | a versus b ** |
| a versus c * | ||||
| On Admission | ||||
| Heart rate (bpm) b | 102 ± 21 | 89 ± 19 | 95 ± 19 | a versus b *** |
| a versus c ** | ||||
| b versus c * | ||||
| Temperature (0C) c | 36.5 (36–37.3) | 36.3 (35.8–36.9) | 36.4 (35.9–37.1) | a versus b * |
| Respiratory rate (pm) c | 16 (14–19) | 16 (14–18) | 16 (14–18) | — |
| Alvarado score c | 7 (6–8) | 6 (5–8) | 7 (5–8) | a versus b ** |
| b versus c * | ||||
| Abdominal pain a | 98 (34%) | 10 (5%) | 21 (12%) | ### |
| C‐reactive protein (mg/L) c | 175 (59–253) | 51 (11–124) | 108 (36–228) | a versus b *** |
| b versus c ** | ||||
| White cell count (× 109/L) c | 14.9 (11.8–19.3) | 13.4 (10.3–17.3) | 14.8 (11.3–18.6) | a versus b * |
| Imaging performed a | ||||
| None | 100 (35%) | 13 (7%) | 40 (23%) | — |
| Abdominal X‐ray | 97 (34%) | 15 (8%) | 28 (16%) | |
| Ultrasound | 80 (28%) | 159 (83%) | 95 (54%) | |
| CT scan | 4 (1.5%) | 3 (2%) | 12 (7%) | |
| Not reported | 4 (1.5%) | 0 (0%) | 0 (0%) | |
Note: Successful antibiotic treatment is defined as asymptomatic discharge of a patient. Unsuccessful antibiotic treatment is defined as a patient that did not improve on antibiotics whilst within hospital and required subsequent appendectomy. Alvarado scores range from 0 to 10, with higher scores indicating a higher likelihood of appendicitis Statistical analysis: One‐way ANOVA with Tukey's (parametric) or Kruskal‐Wallis test (non‐parametric). Fishers exact test for categorical predictors. ###p < 0.001.
Data is presented as n (%).
Mean (SD).
Median (IQR).
p < 0.05.
p < 0.01.
p < 0.001.
The clinical and surgical outcomes are shown in Table 2 with types and numbers of surgical procedures shown in Figure 1. Patients in the Antibiotics Successful group had a median hospitalization of one day less than the Direct Surgery group (p < 0.001), and two days less than the Antibiotics Unsuccessful group (p < 0.001). Patients not responding to antibiotics were operated one day (median 1; IQR 1–2) after first admission, and experienced significantly fewer (4.6 vs. 15.8%; p < 0.001) Clavien‐Dindo grade 3–5 events than patients who underwent direct surgery. Sixteen patients (8.4%) experienced recurrence of acute appendicitis after initial successful discharge, at a median of 1.89 (0.52–7.25) months (Figure 2A.2). Taking these cases into account, the overall successful response to antibiotics in this study was 176 (48.2%) of patients, but when antibiotics failed, 175/189 (92.6%) did so during the initial admission. There were two deaths in the Direct Surgery group (thus not considered for primary antibiotic therapy). One case arrived after 7 days of symptoms, critically ill with generalized peritonitis. Despite appendectomy and relook laparotomy within 24 h the patient succumbed to sepsis two days later. The other case presented with septic shock. After appendectomy and two relook procedures, the patient died in the Intensive Care Unit 15 days after the primary surgery.
TABLE 2.
Clinical and surgical outcomes.
| Direct surgery (N = 285) (a) | Antibiotics (N = 365) | Significance | ||
|---|---|---|---|---|
| Successful (n = 190) (b) | Unsuccessful (n = 175) (c) | |||
| Length of hospitalization (days) b | 3 (2–5) | 2 (1–3) | 4 (3–6) | a versus b *** |
| b versus c *** | ||||
| Interval from first admission to surgery (days) b | 0 | — | 1 (1–2) | — |
| Clavien–Dindo grade 3–5 events a | 45 (15.8%) | — | 8 (4.6%) | ### |
| Death a | 2 (< 1%) | 0 (0%) | 0 (0%) | — |
| Recurrence after discharge a | — | 16 (8.4%) | — | — |
| Interval from discharge to recurrence (months) b | — | 1.89 (0.52–7.25) | — | — |
Note: Successful antibiotic treatment is defined as asymptomatic discharge of a patient. Unsuccessful antibiotic treatment is defined as a patient that did not improve on antibiotics whilst within hospital and required subsequent appendectomy. The Clavien‐Dindo classification for grading postoperative complications; grades 3–5 considered major complications. Statistical analysis: One‐way ANOVA with Tukey's (parametric) or Kruskal‐Wallis test (non‐parametric). Fishers exact test for categorical predictors. ###p < 0.001.
Data is presented as n (%).
Median (IQR).
p < 0.001.
4. Discussion
Appendicitis is a common surgical emergency for which the current standard of care is surgical appendectomy. However, a growing body of evidence from HICs suggests that medical antibiotic therapy is not inferior to appendectomy and does not increase the risk of complications. In LMICs there are factors that argue both for and against a medical approach. This medium‐sized study performed in South Africa, a middle‐income country, showed that after excluding complicated appendicitis mandating direct surgical appendectomy, more of the remaining patients were assigned to antibiotic therapy than direct surgery (56 vs. 44%). In the antibiotic therapy group, half (52%) were treated safely and successfully during the first admission period, thereby avoiding surgery, although 14 more cases required appendectomy after discharge within one year, thereby lowering antibiotic success to 48%.
As this was not a randomized trial it is important to compare the clinical and laboratory findings at admission, of the those assigned to direct surgery with those assigned to antibiotic therapy, as subtle biases can occur. Although the results in Table 1 indicate some statistically significant differences, showing the direct surgery group to be sicker, these differences may not be clinically significant or easily distinguishable. However, the C‐reactive protein levels were clearly highest in those assigned to direct surgery. Although we believe that the direct surgery and antibiotic therapy groups were largely comparable, receiving similar proportions of pre‐admission antibiotics, it is possible that doctors identified nuances marking sicker patients and assigned them to direct surgery, even when the defined complications were absent.
When antibiotics were prescribed but then deemed unsuccessful, the decision to proceed to surgery was taken within 24–48 h and major complications (Clavien‐Dindo grade 3–5 events) were significantly fewer compared to the direct surgery group (5% vs. 16%; p < 0.001). This is reassuring and important information to convey when counseling patients. In a large meta‐analysis that investigated the diagnosis to surgery interval in patients with acute appendicitis without complications, Van Dijk et al., found that delaying appendectomy for 24 h did not increase risks significantly [7].
Although antibiotic therapy of uncomplicated appendicitis has several evidence‐based advantages, such as fewer complications, shorter sick leave and lower costs [15], the recurrence rates have remained a cause for concern [16]. These data have informed the opinion of some that appendectomy remains the treatment of choice [17]. An open randomized clinical trial conducted in Finland, that compared antibiotic therapy to appendectomy as treatment for uncomplicated appendicitis, reported a recurrence rate (requiring appendectomy) of 27% within one year [2]. Importantly the same trial also demonstrated that when recurrence required appendectomy, the complication rate was three‐fold lower than those undergoing primary surgery (7% vs. 20%) [2]. A more recent and larger pragmatic, non‐blinded, non‐inferiority randomized trial comparing antibiotic therapy to appendectomy, found antibiotics non‐inferior to appendectomy, but with a 30% conversion to appendectomy within 90 days [5]. In our study the recurrence rate was much lower (7%), but our study structure was less robust and contextual factors within South Africa differ markedly from HICs. Another important difference is that the Coda Collaborative trial included patients with an appendicolith and found that these cases were at higher risk for appendectomy and complications [5], while our study excluded patients with an appendicolith. In a small prospective cohort study involving children from 6 to 12 years old presenting with acute uncomplicated appendicitis, Alsaggaf et al., investigated non‐operative treatment compared to endo‐surgery appendectomy [4]. Their exclusions were similar to our study in that non‐operative treatment was only offered when there was no appendicolith or fluid collection and symptoms < 48 h. Only 17% of the non‐operative treatment cases converted to surgery in the first 6 months [4].
The C‐reactive protein (CRP) levels were highest in patients that underwent direct surgery. These patients were not considered for primary antibiotic therapy. Amongst the patients who underwent antibiotic therapy, the median CRP level of the Antibiotics Unsuccessful group was double that of the Antibiotics Successful group (108 vs. 51; p < 0.01). This may be useful as part of the composite picture for predicting outcome. When evaluated on a Receiver operating characteristic (ROC) curve the area under the curve was a moderate 0,65 (p = 0.0005). Specific CRP levels are not reported in some of the larger trials, but in the randomized clinical trial comparing antibiotic therapy to appendectomy for treatment of uncomplicated appendicitis, by Salminen et al., the median CRP values at baseline were raised as expected, but clinically similar (surgical Group 36 mg/L [IQR 14–61]; antibiotic Group 29 mg/L [IQR 11–63]) [2].
As the burden of health care increases on the regional hospitals, patients wait longer for operative procedures, as elective surgery is curtailed by emergency cases. Safe medical treatment of appendicitis at district level, if effective, would therefore benefit both the patient and healthcare system. Our study makes an important contribution to the existing literature on this topic due to the relevance and paucity of information from LMICs and similar resource‐constrained facilities.
Although this study was subject to known methodological weaknesses of retrospective audit, it was conducted in a single, large referral hospital with stable consultant staff. A pragmatic approach to diagnosis was followed, patients in the antibiotic therapy group obviously lacked a pathology‐based diagnosis of appendicitis. The relatively low imaging rate (65%–70%) applied to both the direct surgery and antibiotic therapy groups. Thus, sub‐clinical, complicated disease might have been missed in the antibiotic therapy group. Within the South African context, the diagnosis of acute appendicitis is largely clinical, and ultrasound is more readily available imaging option. Junior doctors are at the forefront of peripheral clinical services and costly transfers warrant careful consideration, especially if surgery can be avoided or safely postponed. In our study, after excluding the complications associated with a higher risk of antibiotic failure such as an abscess > 5 cm, appendicolith and abdominal free fluid, half of the patients treated with antibiotics avoided surgery, thereby accruing several other substantive advantages in a resource‐constrained environment. The low recurrence rate within one year is encouraging, but needs to be confirmed in other studies.
5. Conclusion
In this study half of all patients with acute appendicitis treated with antibiotics, safely avoided surgical intervention. Medical therapy may therefore be considered in selected patients within this healthcare context.
Author Contributions
J. D. Hall: conceptualization (lead), data curation, investigation, writing – original draft (lead), methodology (lead), writing – review and editing (lead), project administration. D. Nel: supervision, writing – review and editing (equal). A. H. Stark: writing – review and editing (supporting). M. van de Vyver: formal analysis (lead), software (lead). P. Nguyen: data curation, investigation (supporting). N. Seedat: data curation, investigation (supporting). D. R. Hall: conceptualization (equal), writing – original draft (equal), writing – review and editing (equal), methodology (supporting), supervision.
Funding
The authors have nothing to report.
Ethics Statement
The study was approved by the Human Research Ethics Committee of the University of Cape Town (655/2024) which granted a waiver of consent due to the retrospective, audit design.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
This study was reported according to STROBE guidelines.
Data Availability Statement
Data available from corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data available from corresponding author on reasonable request.