Fistula Output Microorganism-Susceptible Antimicrobial Prophylaxis Is Associated with a Lower Risk of Surgical Site Infection in Gastrointestinal Fistula Patients Undergoing One-Stage Definitive Surgery

Abstract

Background:

Empiric broad-spectrum antimicrobial prophylaxis (AMP) may not be sufficient to minimize the risk of surgical site infections (SSIs) after definitive surgical treatment of gastrointestinal (GI) fistula. This study investigates whether AMP targeted toward fistula microbiology is associated with a lower risk of SSIs in GI fistula patients undergoing one-stage definitive surgery.

Methods:

Fistula output was sampled from the abdominal fistula opening for microbial growth and drug sensitivity prior to surgery. The primary outcome measure was the overall incidence rate of SSIs.

Results:

A total of 191 patients were examined. Pre-operative microbial culture identified microbial growth in 149 patients (76.0%). Post-operative SSIs occurred in 51 patients (26.7%). Risk index category, abdominal incision length, and time of peritoneal drain removal had significantly negative impacts on SSIs frequency. Sensitive AMP agents were associated with a significantly lower risk of SSIs, compared with insensitive AMP agents, but with a similar risk to indefinite AMP agents (23.2% vs. 45.2% vs. 23.1%; odds ratio [95% confidence interval]: 2.724 [1.063, 6.979], p=0.034; 1.008 [0.467–2.177], p=0.984).

Conclusions:

Antimicrobial prophylaxis targeted toward fistula output AMP may minimize the occurrence of SSIs after one-stage definitive surgical treatment of GI fistula.

Gastrointestinal (GI) fistula usually manifests as abnormal openings on the abdominal wall with concomitant leakage of GI content. The etiology of intestinal fistula is complex: the majority (75%–85%) of cases are secondary to iatrogenic injury, such as intra-abdominal operations for the treatment of inflammatory bowel disease [1]. The morbidity and mortality of GI fistula is variable, mainly depending on location of abnormal GI opening and underlying surgical or medical conditions [2].

Gastrointestinal fistula treatment requires a multimodal management strategy, including conservative measures, specific pharmacotherapy, and definitive surgical repair. Surgical intervention offers a definitive therapeutic effect but only applies in select patients, for whom the fistula may not or does not close after the conservative treatment. The operative procedure consists mainly of the removal of diseased intestinal segments and concomitant intra-peritoneal lesions, GI reconstruction, and abdominal wall wound closure. The treatment outcome is associated with the treating surgeon's experience and institute case load.

Surgical site infection (SSI) is a common post-operative complication in abdominal surgery involving the GI tract [3]. The primary risk factor of SSI is the pre-operative microbial burden, whereas the incidence of SSI is also associated with the synergistic effect of patient characteristics and operative characteristics [4]. Gastrointestinal fistula patients undergoing definitive surgery are expected to be prone to SSI, because a contaminated wound is known to be more susceptible to infection (15%–20%) than a clean (1%–2%) or clean-contaminated wound (8%–10%) [5]. Additionally, GI fistula patients often have concomitant medical or surgical conditions that contribute to the development of an SSI, such as poor nutritional status, long pre-operative hospital stay, and previous anti-microbial therapy [6]. Similar to other post-operative complications, an SSI results in an increase in the surgical morbidity and mortality rates, as well as a prolonged hospital stay and larger healthcare burden. Moreover, a severe SSI is a major contributing factor to fistula recurrence [7].

Modern aseptic techniques and the prophylactic use of antimicrobial agents contribute substantially to the reduction in SSI rates for every class of surgery, including class III/contaminated surgery. The U.S. Centers for Disease Control and Prevention (CDC) Guideline for the Prevention of Surgical Site Infection is the standard of practice for selecting an optimal anti-microbial prophylaxis (AMP) regimen [8]. Empiric broad-spectrum AMP, mainly with first- or second-generation cephalosporins, is administered in most cases, in the hope of targeting the most likely pathogens involved in a specific operative procedure.

Most studies regarding AMP for abdominal surgery have mainly focused on elective GI surgery [9], rather than class III/contaminated surgery (e.g., a definitive operation for GI fistula). The relatively high risk of SSIs in complex GI fistula patients suggests that the empirical administration of AMP, based on general microbiologic epidemiology, is not sufficient for controlling SSIs. Thus, we analyzed retrospectively the occurrences of SSIs in GI fistula patients undergoing one-stage definitive surgery at our academic tertiary care institute. The goal of this study was to determine whether AMP targeting the underlying fistula microbiology was associated with a lower risk of SSIs, in order to improve the treatment outcome of GI fistulae.

Patients and Methods

Ethical approval of study protocol

The study protocol was approved by the Institutional Review Board at Jin Ling Hospital, Nanjing, China, which is a national center specializing in the treatment of GI fistula with an annual volume of 200–300 patients. Gastrointestinal fistula inpatients were enrolled consecutively between November 2008 and November 2010. All patients volunteered to give informed consent in writing prior to the enrollment.

Patient selection

The inclusion criteria of patients were: being at least 18 yrs of age; having a clinically or radiographically confirmed diagnosis of GI fistula; having a complete control of their pre-existing intra-abdominal infection by the combination of peritoneal drainage and anti-microbial agents; exhibiting a well-maintained nutritional status on enteral nutritional support; and being scheduled for one-stage primary GI reconstruction after GI fistula resection.

Criteria for excluding patients were: Suffering from a malignant tumor-associated GI fistula; having concomitant remote infections (such as skin soft tissue infection on other sites, lung infection, or catheter-related infection); having a history of antimicrobial therapy within 1 wk prior to the enrollment; having a history of steroid or other immunosuppressant use within 3 mo prior to enrollment; having a history of previous abdominal surgery within 3 mo prior to enrollment; undergoing peritoneal irrigation/drainage, intestinal ostomy, or delayed GI reconstruction alone; or not completing the follow-up visits as scheduled.

Pre-operative assessment and preparation

Routine physical examination and laboratory tests were given to characterize the patient's nutritional status (body weight, body mass index, blood hemoglobin concentration, and serum albumin concentration). Where applicable, the patient's overall tolerance to anesthesia and surgery were evaluated by electrocardiography, chest radiograph, and pulmonary function testing. Additionally, GI fistula was examined fully for the number, location, and type of fistula, using a combination of fistula-contrast radiography, gastrointestinal (GI)-contrast radiography, and abdominal computed tomography (CT) scan. Routine pre-operative preparations, including pre-operative fasting, skin preparation, GI decompression, urethral catheterization, and skin allergy testing were given according to institutional guidelines.

Microbial culture and antimicrobial susceptibility test

The microbial population in the fistula output was sampled by swabbing the skin within 1 cm of the fistula opening. The culture's drug sensitivity was determined by a centralized microbiology laboratory within 1 wk prior to surgery. The sensitivity of bacterial isolates was classified into: Sensitive if the bacterial isolates were susceptible to the given AMP agent; resistant if the bacterial isolates were resistant to the given AMP agent; or indeterminate if the fistula output sampling or microbial growth failed, or the bacterial isolates exhibited an unknown susceptibility to the given AMP agent on the susceptibility testing.

Anti-microbial prophylaxis and operative procedure

All patients were treated by a surgical team led by the corresponding author, which consisted of attending surgeons, resident surgeons, anesthesiologists, clinical microbiologists, pathologists, radiologists, operating room staff, and research nurses. Intravenous infusion of the selected AMP agent was started 30–60 min before making the first surgical incision. The selection of the given AMP agent for each patient was at the discretion of the attending surgeon (corresponding author) in accordance with the institutional guidelines.

After the administration of general anesthesia via intubation, an abdominal skin incision was made through the previous abdominal surgical incision, directly through the fistula opening, or through the transverse abdominal crease. The incision location was chosen based on the outlining of the GI fistula, the previous incision (if applicable), and pre-operative CT findings. The definitive surgery consisted of the complete resection of the GI fistula and GI tract reconstruction. Gastrointestinal continuity was reconstructed using a mechanical stapler (Frankenman Medical Instrument Co., Ltd., Suzhou, China) in an end-to-side manner, proximally to distally. The peritoneum, linea alba, and rectus sheath were closed using absorbable PDS-II sutures (Ethicon, Inc., Somerville, NJ) in a continuous manner. The subcutaneous tissue and skin were closed using non-absorbable Mersilk sutures (Ethicon, Inc.) in an interrupted manner. Relaxation sutures were used in the case of high intra-abdominal pressure. A self-prepared double-lumen drainage tube was placed to drain the peritoneal cavity continuously. The mean operative time was 151 min (range, 40–350 min) and the mean volume of intra-operative blood loss was 287 mL (range, 50–2,500 mL).

Post-operative care and follow-up

Post-operative AMP was continued for an additional 24–48 h in all patients. Total parenteral nutrition was given until the time of first post-operative defecation and replaced stepwisely by enteral feeding. The peritoneal drain was removed following the resumption of normal bowel movement. The occurrence of SSIs was confirmed clinically or radiographically and documented in accordance with the CDC National Noscomial Infection Surveillance (NNIS) system. Any wound discharge or pus was sampled for microbial isolation and antimicrobial susceptibility testing, if applicable. A superficial incisional SSI was treated mainly with wound dressing care, whereas a deep incisional or organ/space SSI was treated with additional drainage of any discharge or pus. The empiric use of an intravenous antimicrobial agent was prolonged in the cases of a serious SSI, whereas a pathogen-sensitive anti-microbial agent was used, as determined on the antimicrobial susceptibility testing, if applicable. Second-look definitive surgery was undertaken 3–4 mo after the primary operation if an organ/space SSI occurred and remained refractory to medical treatment. Patients were followed up at weekly outpatient visits for 30 d after the definitive operation.

Outcome measures

The primary outcome measures were the overall incidence rate of SSIs and the frequency of specific types of SSI within 30 d of definitive surgery. The patients were assessed for the incidence of SSI, daily until the discharge and weekly after the discharge, as defined by the CDC guidelines. The secondary outcome measures included time of SSI occurrence, location of SSIs, length of post-operative hospital stay, and total medical costs.

Statistical analysis

The Kolmogorov-Smirnov test was used to examine the distribution normality of continuous data. Continuous data in a normal distribution were expressed as mean±standard deviation (SD) and were compared using the one-way analysis of variance (ANOVA) test; those in a non-normal distribution were expressed as the median (25th percentile, 75th percentile) and compared using the Mann-Whitney U testor Wilcoxon test. Categorical data were expressed as n (%) and compared using the Fisher exact probability test.

In a univariate analysis model, potential contributing factors (ASA class, risk index category [RIC] for SSI, length of abdominal incision, operative time, volume of blood loss, intra-operative blood transfusion, the use of vacuum-assisted closure [VAC] device, time of peritoneal drain removal, and time of post-operative enteral nutrition resumption) were included to determine their associations with the occurrence of SSIs. The clinical characteristics of AMP were also analyzed, including the starting time of AMP, the pharmacologic classification of the AMP, and the microbial isolate susceptibility to the given AMP agent. Moreover, logistic regression analysis was used to determine the correlation of pre-defined perioperative factors with SSIs, whereas multivariable analysis using the Cox regression model was used to determine the independent contributing factors for SSI risk. Odds ratios and 95 % confidence intervals are presented. A p value<0.05 was considered statistically significant.

Results

Baseline patient characteristics

The demographic and clinical characteristics of enrolled patients are shown in Table 1. During the 2-y recruitment period for this study, 760 GI fistula patients were assessed for eligibility. Of these patients, 569 patients were excluded because of receiving conservative treatment (n=236), ineligibility for definitive surgery (n=91), having peritoneal drainage alone (n=74), or receiving a follow-up examination (n=168) alone. Additionally, are patient was lost to follow-up on post-operative day 21 and excluded from the analysis. Thus, 191 patients, aged 45.4±14.2 y, were included in the study analysis, including 139 males (72.8%) and 52 females (27.2%).

Table 1.

Demographic and Clinical Characteristics of Eligible Gastrointestinal Patients (n=191) Undergoing One-Stage Definitive Surgery

Age (y, mean±SD)	45.4±14.2
Gender (M:F)	139:52
Height (m, mean±SD)	1.67±0.07
Body mass (kg, mean±SD)	54.8±9.6
Body mass index (kg/m², mean±SD)	19.6±3.0
Etiology of GI fistula, n (%)
Abdominal surgery	81 (42.4)
Abdominal trauma	46 (24.1)
Primary GI disorders	40 (20.9)
Bowel radiation injury	10 (5.2)
Other GI conditions	14 (7.3)
Concomitant medical conditions, n (%)
Essential hypertension	56 (29.3)
Coronary heart disease	31 (16.2)
Diabetes mellitus	104 (54.5)
ASA class, n (%)
I	83 (43.5)
II	95 (49.7)
III	13 (6.8)
Risk index category, n (%)
1	134 (70.2)
2	55 (28.8)
3	2 (1.0)

SD=standard deviation; M=male; F=female; GI=gastrointestinal; ASA, American Society of Anesthesiologists.

The primary etiologies of the GI fistulae were abdominal surgery (n=81, 42.4%), abdominal trauma (n=46, 24.1%), primary GI disorders (n=40, 20.9%), bowel radiation injury (n=10, 5.2%), and other GI conditions (n=14, 7.3%). Of the 191 patients, 87 were diagnosed with colonic fistula (45.5%), 93 with small intestine fistula (48.7%), two with gastric fistula (1.0%), two with small intestine and colonic fistula (1.0%), and seven with enterovaginal or enterovesical fistula (3.7%). Of these patients, 83 patients (43.5%) were classified as ASA class 1, 95 patients (49.7%) as ASA class 2, and 13 patients (6.8%) as ASA class 3. In terms of NNIS risk category (RIC), 134 patients (70.2%) were categorized as RIC 1, 55 patients (28.8%) as RIC 2, and two patients (1.0%) as RIC 3.

Pre-operative microbial culture and AMP agents

The microbiologic characteristics of the pre-operative fistula output are shown in Table 2. The pre-operative microbial culture identified microbial growth in 149 patients (149/191; 76.0%), including Staphylococcus aureus (35/191; 18.3%), Escherichia coli (32/191; 16.8%), Proteus spp. (22/191; 11.5%), Klebsiella pneumoniae (15/191; 7.9%), coagulase-negative Staphylococcus spp. (9/191; 4.7%) and Pseudomonas aeruginosa (8/191; 4.2%). No microbial growth was observed in 42 patients (42/191; 24%). Six types of antimicrobial agents were used for pre-operative AMP, including mezlocillin/sulbactam (22/191; 11.5%), piperacillin-tazobactam (16/191; 8.4%), cefmenoxime (44/191; 23.0%), moxifloxacin (41/191; 21.5%), ertapenem (49/191; 25.7%), and meropenem (19/191; 9.9%). On the pre-operative drug susceptibility test, the susceptibility of bacterial isolates to the given AMP agent was determined to be susceptible for 80 isolates (53.7%), resistant for 47 isolates (31.5%), and indeterminate for 22 isolates (14.8%), respectively. Of the included patients (n=191), 56 patients (29.3%) received susceptible AMP, 31 patients (16.2%) received resistant AMP, and 104 patients (54.5%) received indeterminate AMP.

Table 2.

Outcomes (n [%]) of Pre-Operative Microbial Culture From Gastronintestinal Fistula Output and Microbial Isolate Drug Susceptibility to the Given Anti-Microbial Prophylaxis Agent

	Suscepible	Resistant	Indeterminate
S. aureus (n=35)	17 (48.6)	8 (22.9)	10 (28.6)
MRSA (n=12)	2 (16.7)	4 (33.3)	6 (50.0)
MSSA (n=23)	15 (65.2)	4 (17.4)	4 (17.4)
E. coli (n=32)	12 (37.5)	16 (50.0)	4 (12.5)
ESBL+ (n=19)	6 (31.2)	12 (63.2)	1 (5.3)
ESBL- (n=13)	6 (46.2)	4 (30.8)	3 (23.1)
Proteus spp. (n=22)	18 (81.8)	4 (18.2)	0
K. pneumonia (n=15)	11 (73.3)	4 (26.7)	0
CoN Staphylococcus spp. (n=9)	2 (22.2)	4 (44.4)	3 (33.3)
P. aeruginosa (n=8)	4 (50.0)	3 (37.5)	1 (12.5)
Enterococcus spp. (n=7)	2 (28.6)	3 (42.9)	2 (28.6)
Aeromonas spp. (n=7)	6 (85.7)	0	1 (14.3)
Serratieae spp. (n=5)	2 (40.0)	2 (40.0)	1 (20.0)
Enterobacter spp. (n=5)	2 (50.0)	2 (50.0)	0
Morganella spp. (n=3)	2 (66.7)	1 (33.3)	0
A. baumannii (n=1)	1 (100.0)	0	0
Citrobacter spp.(n=1)	1 (100.0)	0	0
Overall (n=149)	80 (53.7)	47 (31.5)	22 (14.8)

MRSA=methicillin-resistant S. aureus; MSSA=methicillin-sensitive S. aureus; ESBL=extended-spectrum β-lactamase; CoN=coagulase-negative.

SSIs and other complications

Overall, 51 patients (51/91; 26.7%) experienced SSIs, including superficial incisional SSIs (36/191; 18.8%), deep incisional SSIs (8/191; 4.2%), and organ/space SSIs (7/191; 3.7%), mainly during post-operative day 1–21 (median, 5 d). These infections occurred primarily in the abdominal wall (other than the fistula opening or the previous incision; 28/51; 54.9%), in the previous incision (12/51; 23.5%), or in the abdominal fistula opening (11/51; 21.6%). None of these patients experienced catheter-related infections or remote site infections. All SSIs resolved with medical treatment, expect for four refractory organ/space SSI cases (4/7; 57.1%), which required a secondary surgical treatment. The patients experiencing SSIs were hospitalized for a significantly longer period than those experiencing no SSIs, in terms of both their entire (37 [31, 64] d vs. 33 [26, 46] d, p=0.003) and post-operative hospital stay (23 [17, 32] d vs. 16.5 [13, 21] d, p<0001). Moreover, the total medical cost was significantly higher in the patients experiencing SSIs than those experiencing no SSIs (158,149 [99,998, 213,561] CNY vs. 98,002 [77,445, 141,485] CNY, p<0.001). Seven patients (3.7%) had recurrent fistula and required further specific intervention during the follow-up period. The microbiologic results from the post-operative SSIs are shown in Table 3. Seventy-one bacterial isolates were grown in 46 of 51 patients (90.2%), including single isolates from 25 patients (49.0%) and multiple isolates from 21 patients (45.7%). The microorganisms mainly included E. coli (22/51; 43.1%), Enterococcus spp. (14/51; 27.5%), K. pneumoniae (9/51; 17.6%), S. aureus (8/51, 15.7%), Proteus spp. (7/ 51; 11.5%), and P. aeruginosa (4/51; 4.2%). In patients experiencing SSIs, the post-operative SSI microbiology was consistent with the pre-operative fistula microbiology in six patients (11.8%) as shown in Table 4, inconsistent in 11 patients (21.6%), and indeterminate in 34 patients (66.7%).

Table 3.

Outcomes (n [%]) of Post-operative Microbial Culture from Surgical Site Infections and Microbial Isolate Drug Susceptibility to the Given Anti-Microbial Prophylaxis agent

	Sensitive	Resistant	Indeterminate
E. coli (n=22)	8 (36.4)	5 (22.7)	9 (40.9)
ESBL+ (n=16)	7 (43.8)	2 (12.5)	7 (43.8)
ESBL- (n=6)	1 (16.7)	3 (50.0)	2 (33.3)
Enterococcus spp. (n=14)	6 (42.9)	1 (7.1)	7 (50.0)
K. pneumoniae (n=9)	2 (22.2)	2 (22.2)	5 (55.6)
S. aureus (n=8)	1 (12.5)	3 (37.5)	4 (50.0)
MRSA (n=7)	1 (14.3)	3 (42.9)	3 (42.9)
MSSA (n=1)	0	0	1 (100.0)
Proteus spp. (n=7)	3 (42.9)	2 (28.6)	2 (28.6)
P. aeruginosa (n=4)	1 (25.0)	1 (25.0)	2 (50.0)
Citrobacter spp. (n=2)	1 (50.0)	0	1 (50.0)
D-group Streptococcus spp. (n=2)	1 (50.0)	0	1 (50.0)
Morganella spp. (n=1)	0	0	1 (100.0)
Enterobacter spp. (n=1)	0	0	1 (100.0)
Aeromonas spp. (n=1)	1 (100.0)	0	0
Overall (n=71)	24 (33.8)	14 (19.7)	33 (46.5)

SSIs=surgical site infections; MRSA=methicillin-resistant S. aureus; MSSA=methicillin-sensitive S. aureus; ESBL=extended-spectrum β-lactamase; CoN=coagulase-negative.

Table 4.

Matched Microbiology Between Preoperative Fistula and Post-Operative Surgical Site Infection Microbial Isolates (n=6)

Patient	Pre-operative	Post-operative
1	E. coli (ESBL+); S. aureus (β-lactamase+); MSSA	E. coli (ESBL+); P. mirabilis
2	P. mirabilis; S. aureus (β-lactamase+); MSSA; E. faecalis	P. mirabilis
3	E. coli (ESBL+); K. pneumonia (ESBL-)	E. coli (ESBL+)
4	S. aureus (β-lactamase+); MSSA	S. aureus (β-lactamase+); MSSA
5	P. mirabilis	P. mirabilis; E. faecium; A. caviae
6	P. mirabilis; E. coli (ESBL+)	E. coli (ESBL-)

ESBL=extended-spectrum β-lactamase; MSSA=methicillin-sensitive S. Aureus.

Risk factor analysis

The potential contribution of pre-defined perioperative risk factors to the occurrence of SSIs is summarized in Table 5. Of these factors, ASA class, operative time, volume of intra-operative blood loss, intra-operative blood transfusion, and time of post-operative enteral nutrition resumption were determined to not contribute to the occurrence of SSIs. In contrast, RIC (RIC 1 vs. RIC 2–3, 21.6% [29/134] vs. 38.6% [22/57]; 2.276 [1.161–4.463], p=0.015), length of abdominal incision (≤15 cm vs. >15 cm, 10.4% [5/48] vs. 32.2% [46/143]; 4.078 [1.515–10.979], p=0.003), and time of peritoneal drain removal (≤10 d vs. >10 d, 22.2% [30/135] vs. 38.9% [21/54]; 5.438 [1.127–4.401], p=0.020) were all found to have a significantly negative impact on the frequency of SSIs.

Table 5.

Risk Factors for Surgical Site Infections in Gastrointestinal Fistula Patients Undergoing One-Stage Definitive Surgery

Variables (n=191)	SSI frequency, n (%)	Odds ratio [95% CI]	p
ASA class
I (n=83)	21 (25.3)	1.000
II–III (n=108)	30 (27.8)	0.881 [0.460–1.686]	0.744
RIC
1 (n=134)	29 (21.6)	1.000
2–3 (n=57)	22 (38.6)	2.276 [1.161–4.463]	0.015
Starting time of AMP, min
<30 (n=66)	18 (27.3)	1.000
30–60 (n=125)	33 (26.4)	0.957 [0.488–1.873]	0.897
Carbapenems as AMP agent
Yes (n=68)	20 (29.4)	1.000
No (n=123)	31 (25.2)	1.237 [0.638–2.396]	0.529
Susceptibility of fistula isolates to AMP
Susceptible (n=56)	13 (23.2).	1.000
Resistant (n=31)	14 (45.2)	2.724 [1.063–6.979]	0.034
Indeterminate (n=104)	24 (23.1)	1.008 [0.467–2.177]	0.984
Length of abdominal incision, cm
≤15 (n=48)	5 (10.4)	1.000	0.003
>15 (n=143)	46 (32.2)	4.078 [1.515–10.979]
Operative time, min
≤120 (n=66)	14 (21.2)	1.000
120–180 (n=78)	20 (25.6)	1.281 [0.588–2.791]	0.533
≥180 (n=47)	17 (36.2)	2.105 [0.910–4.866]	0.079
Volume of intra-operative blood loss, mL
≤200 (n=109)	27 (24.8)	1.000
200–400 (n=55)	12 (21.8)	0.848 [0.391–1.837]	0.675
400–800 (n=18)	8 (44.4)	2.430 [0.871–6.781]	0.084
≥800 (n=9)	4 (44.4)	2.430 [0.608–9.704]	0.197
Intra-operative blood transfusion
No (n=95)	21 (22.1)	1.000
Yes (n=96)	30 (31.3)	1.602 [0.837–3.065]	0.153
Use of VAC device
No (n=73)	16 (21.9)	1.000
Yes (n=118)	35 (29.7)	1.502 [0.760–2.968]	0.240
Time of post-operative EN resumption, d
≤5 (n=91)	23 (25.3)	1.000
5–10 (n=84)	23 (27.4)	1.115 [0.568–2.186]	0.752
≥10 (n=16)	5 (31.3)	1.344 [0.422–4.278]	0.616
Time of peritoneal drain removal, d
≤10 (n=135)	30 (22.2)	1.000
>10 (n=54)	21 (38.9)	5.438 [1.127–4.401]	0.020

AMP=anti-microbial prophylaxis; ASA=American Society of Anesthesiologists; EN=enteral nutrition; RIC=risk index category; SSIs=surgical site infections; VAC=vacuum-assisted closure.

The presence of pre-operative microbial growth appeared to be associated with a higher SSI rate (negative vs. positive vs. unknown, 18.8% [12/64] vs. 29.4% [30/102] vs. 36.0% [9/25], p>0.05). The starting time of AMP and pharmacologic classification were determined to be not associated with the occurrence of SSIs. However, AMP agents, to which fistula microbial isolates were susceptible, were associated with a significantly lower risk of SSIs compared with insensitive AMP agents, but with a risk similar to indefinite AMP agents (susceptible vs. resistant vs. indeterminate, 23.2% [13/56] vs. 45.2% [14/31] vs. 23.1% [24/104]; 2.724 [1.063–6.979], p=0.034; 1.008 [0.467–2.177], p=0.984).

Discussion

Surgical site infection is a major complication secondary to definitive treatment of GI fistulae in current practice. The incidence of SSI ranges up to 45%, even in the scenarios of well-prepared ileostomy and colostomy [10]. The rate of SSI was relatively lower in our patient cohort, probably due to a large case volume and experienced management at our institute. However, the occurrence of an SSI will prolong substantially a patient's duration of hospitalization and increase the overall healthcare burden, as shown in our study. Some patients experiencing SSIs also require second-look operations, and severe SSIs are also believed to be associated with a higher risk of fistula recurrence [7]. Our primary finding from this retrospective study shows that GI fistula patients experienced a lower frequency of SSIs following one-stage definitive surgery if they are given fistula microbiology-specific AMP agents.

The pre-existing microbial pathogens at the surgical site are believed to be the primary contributing factor of SSI occurrence. Such SSIs will occur usually when the bacterial concentration is greater than 10⁵ colony-forming units/g tissue [4]. The goal of using AMP is to suppress, rather than eradicate, microbial growth following surgery. The outcome, however, depends mainly on the sensitiveness of the specific colonizing pathogens to the given AMP agent. In current practice, the empiric selection of the AMP agent is expected to target the most probable site-specific microbial flora. Gram-negative microorganisms, such as E. coli and K. pneumonia, are the most common pathogens causative of SSIs following GI surgeries [11]. Additionally, gram-positive microorganisms, such as S. aureus, are well known as the primary pathogen of superficial SSIs [11]. Broad-spectrum cephalosporins are used most frequently (∼80%) for empirical AMP in our patients, as both gram-negative and gram-positive pathogens are usually sensitive to these agents, as shown in patients undergoing colorectal surgeries [12].

Our pre-operative fistula microbiologic study shows that S. aureus and E. coli are the two major microorganisms isolated from GI fistula output. However, only approximately 50% of microorganisms isolated from the fistula output were resistant to the AMP agents empirically given prior to operation. Subsequently, more than one-quarter of our patients experienced SSIs of various severities. The primary pathogens causative of SSIs in our patients were E. coli, Enterococcus spp., K. pneumoniae, and S. aureus. It is possible that GI fistula output contamination contributes primarily to the occurrence of SSIs in these patients. The susceptibility rate of these microbial pathogens to the given AMP agents is even lower, as shown on drug susceptibility testing. These findings thus suggest that empiric AMP is not sufficient for minimizing the risk of SSIs in GI fistula patients. It is likely that previous hospitalization, surgery, and antimicrobial medication alter the microbiology in GI fistula patients, compared with those undergoing general abdominal surgery.

The risk factors of SSIs are even more complex in GI fistula patients because of various complicating medical and surgical conditions. In our patient cohort, ASA class, operative time, the volume of intra-operative blood loss, intra-operative blood transfusion, the use of a VAC device, and time of post-operative enteral nutrition resumption did not contribute significantly to the risk of SSIs. It is unexpected that ASA class, a measure indicating the patient's overall physical wellness [13], was not able to predict the risk of SSIs in these patients. This result may be attributed to our selective inclusion criteria. However, RIC, an independent factor predictive of SSI risk validated in patients undergoing selective colorectal surgery [14], was found to be the primary risk factor for SSI occurrence. Moreover, long abdominal incision and delayed peritoneal drain removal were also identified to be risk factors of SSIs, probably because of a high likelihood of surgical site contamination.

More importantly, our results show that fistula output flora-susceptible AMP is associated with a significantly lower frequency of SSIs, regardless of starting time and the pharmacologic classification of AMP agents. Although an AMP regimen is designed typically in accordance with pharmacology, microbiology, clinical experience, and medical economy [15], surgical site microbiology has largely been overlooked in previous studies of AMP for abdominal or colorectal surgery. This is despite the technical feasibility and efficiency with which it is possible to isolate the potentially causative microorganisms of SSI from the fistula output, and to test them for for drug susceptibility. To the best of our knowledge, the present study is the first report to describe the fistula output microbiology and flora drug susceptibility. It is meaningful clinically to isolate fistula flora pre-operatively and administer flora-targeted AMP agents, in the hope of minimizing SSIs in GI fistula patients undergoing definitive surgery, although this process is time- and effort-consuming.

There are some limitations in the present study. First, it was a retrospective, observational study; the benefit of flora-targeted AMP may be confounded by a favorable medical condition. However, this bias can be excluded, as the patients receiving targeted AMP were comparable to those receiving non-targeted AMP in terms of comorbidities, ASA class, and RIC scale. Second, it remains unknown whether more than one-half of our patients were medicated with targeted or non-targeted AMP agents, as the microbial isolation from the fistula output was not successful or the fistula output isolates were beyond the spectrum of drug susceptibility testing. Third, the sample size was relatively small; only 51 patients experienced SSIs and even fewer patients suffered from serious SSIs. It is doubtable whether fistula output-targeted AMP can be clinically useful for reducing deep incisional or organ/space SSIs. Fourth, the pre-operative fistula output microbiology was not always consistent with the post-operative SSIs microbiology. This suggests that fistula output contamination may not be causative of SSIs in all cases and that targeted AMP did not necessarily prevent the occurrence of SSIs in some cases. Despite these limitations, our study results support the clinical usefulness of AMP specifically targeting fistula output microbiology.

In conclusion, the prevalence of SSIs in GI fistula patients undergoing one-stage definitive surgery is still high, even following empirical AMP that has been well established in current practice but fails to cover the majority of the fistula flora. This complication contributes to a longer hospital stay and higher medical costs. Surgical site infections in these patients have a complex risk factor profile. Of note, AMP agents, to which fistula microbial isolates are susceptible, are associated with a significantly lower risk of SSIs. This finding suggests that fistula output-targeted AMP may minimize the occurrence of SSIs in these patients. Large-scale randomized controlled studies are required to further validate the clinical benefits of fistula output-targeted AMP.

Footnotes

Acknowledgments

The authors thank Dr. Jun Chen for assistance with data collection, Dr. Yujie Yuan for reviewing the manuscript, and Dr. Gang Han for performing statistical analysis on the data.

Author Disclosure Statement

All authors declare that there were no conflicts of interest involved.

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