Does Isolation of Enterococcus Affect Outcomes in Intra-Abdominal Infections?

Abstract

Background:

Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment.

Patients and Methods:

The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus. Fifty subjects of the cohort (n = 518) had Enterococcus isolated. Uni-variable and multi-variable analyses were conducted to determine whether isolation of Enterococcus constituted an independent predictor of the pre-defined STOP-IT composite outcome (surgical site infection, recurrent IAI, or death) and the individual components of the composite outcome.

Results:

From the cohort of 50 subjects, we identified 52 isolates of Enterococcus spp. with a predominance of Enterococcus faecalis (40%) followed by other Enterococcus spp. (37%) and Enterococcus faecium (17%). Baseline demographic characteristics were statistically similar between the two groups. Antibiotic utilization distribution remained balanced between the Enterococcus and no Enterococcus groups with the majority receiving piperacillin-tazobactam (62% and 54%, respectively). The groups had comparable infection characteristics including setting of acquisition (>50% community acquired) and origin of infection (predominantly colon or rectum). Individual and composite clinical outcomes were not different statistically between the Enterococcus and no Enterococcus groups: surgical site infection (10% vs. 7.5%; p = 0.53), recurrent IAI (20% vs. 14.1%; p = 0.26), death (2% vs. 1%; p = 0.40), and composite of all three (30% vs. 20.9%; p = 0.14], respectively. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (odds ratio [OR] 1.53 [95% confidence interval {CI} = 0.78–3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71).

Conclusions:

Enterococcus was not a more common pathogen in health-care–associated IAIs and was not an independent risk factor for the composite outcome. The isolation of Enterococcus from IAIs may not warrant an alternative treatment approach but larger studies are needed to validate these findings.

Intra-abdominal infections (IAIs) result from a variety of pathogens, most commonly from enteric organisms including gram-positive and gram-negative aerobic and anaerobic bacteria [1,2]. In particular, the isolation of Enterococcus spp. occurs in more than one-third of patients, often as a polymicrobial infection in post-operative infections [3 –6]. Because of the intrinsic resistance of enterococci to many antibiotic agents, it is unclear whether these pathogens warrant an alternative treatment approach with regard to empiric or definitive treatment. Currently, the Surgical Infection Society guidelines for the treatment of IAIs recommend reserving empiric coverage of Enterococcus to patients with high-risk community infections and health-care–associated infections meeting the following criteria: post-operative, recent broad spectrum antimicrobial exposure, signs of severe sepsis or shock, or known or suspected colonization with vancomycin-resistant enterococci (VRE) [1].

Post-operative IAIs result frequently in the isolation of Enterococcus in contrast to infections presenting from the community, and the isolation of this organism may portend treatment failure and death [3,7 –9]. In particular, a post hoc analysis of a randomized trial comparing ciprofloxacin plus metronidazole versus imipenem-cilastatin, found that isolation of Enterococcus from surgical cultures was an independent predictor of treatment failure [8]. Second, it was found that increases in age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, acute physiology score, pre-infection hospital length of stay, and post-operative infection rates were disproportionately higher in patients in whom Enterococcus was isolated [8]. In addition to the isolation of this organism predicting unfavorable outcomes, inappropriate antimicrobial coverage may result in increased post-operative infections, despite having no influence on mortality [9]. Last, the isolation of Enterococcus is associated with non-infectious complications, including wound dehiscence and development of venous thromboembolism [3].

Controversy exists regarding the relevance of enterococci for clinical IAI outcomes, as well as the importance of utilizing antibacterial agents with activity against enterococci in patients with these infections. The current study sought to delineate further whether the isolation of Enterococcus affects clinical outcomes in IAIs through a post hoc analysis of a recent study on the duration of antimicrobial therapy in IAI [10].

Patients and Methods

Study design

The cohort included for selection were collected from a database generated from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial. The original trial constituted an open-label, multi-center, randomized controlled trial designed to investigate the effectiveness of short course antimicrobial therapy (i.e., 4 d) to treat IAIs in tandem with source control. A detailed description of the design of the STOP-IT trial may be found within the original STOP-IT publication [10]. The subjects from the STOP-IT database were stratified based on isolation of Enterococcus. Subjects were assigned to those with isolation of Enterococcus from at least one site (Enterococcus) and those without isolation of Enterococcus (no Enterococcus). A sub-group analysis was conducted to include only patients with hospital-acquired or health-care–associated infections to determine the effect of isolating Enterococcus in this subset.

Data collection and outcomes

Baseline demographics, comorbidities, therapeutic interventions (i.e., surgical and antimicrobial therapy), and infection characteristics (i.e., systemic signs of infections, acquisition site, and site of infection) were derived from the STOP-IT database and stratified by isolation of Enterococcus. The isolation of Enterococcus was a documented positive culture at any time during the study period. The pre-defined STOP-IT outcomes that were assessed at 30 d were compared between subjects with and without isolation of Enterococcus and included surgical site infection (SSI), recurrent IAI, death, and a composite metric of all three outcomes [10].

Statistical analysis

Baseline characteristics, infection characteristics and outcomes, composite and individual, were analyzed via uni-variable statistics. Pearson χ² testing or Fisher exact test (small cell sizes) were used for categorical parameters. Two-tailed, independent samples t-tests were used for continuous parameters. Uni-variable and multi-variable logistic regression models were performed to determine the effect that isolation of Enterococcus had on the composite outcome. The multi-variable model used the composite outcome as the dependent parameter and isolation of Enterococcus as the key independent parameter. Only parameters that were measured in 20 or more patients were considered for model inclusion. Models were constructed iteratively, beginning with stepwise regression and followed by clinical and statistical judgment for ultimate inclusion in the model. Stepwise regression was executed through the forward method with probability to enter set at 0.15 and probability to remove at 0.20. A total of 55 additional parameters, including those given in Tables 1 –3, were examined for possible inclusion in the model based on criteria described. Goodness of fit for the models used the Hosmer-Lameshow procedure. The coefficient for Enterococcus in a model was a measure of its effect on the outcome after adjustment for patient differences in covariates.

Table 1.

Baseline Characteristics Stratified by Isolation of Enterococcus

Characteristic	Enterococcus (n = 50)	No Enterococcus (n = 468)	p ^a
Age, year, mean ± SD	54.5 ± 15.5	52.0 ± 16.1	0.28
Gender, no. (%)
Male	24 (48.0)	265 (56.6)	0.24
Body mass index, mean ± SD	28.3 ± 9.2	29.0 ± 8.8	0.59
STOP-IT treatment group			0.25
Control	29 (58.0)	231 (49.4)
Experimental	21 (42.0)	237 (50.6)
Race, no. (%)			0.89
White	40 (80.0)	364 (77.8)
Black	9 (18.0)	85 (18.2)
Asian	0 (0.0)	11 (2.4)
Other/Unknown	1 (2.0)	8 (1.7)
Hispanic, no. (%)	4 (8.0)	31 (6.8)	0.77
Comorbid conditions, no. (%)
Diabetes mellitus	9 (18.0)	69 (14.7)	0.54
Steroid use	1 (2.0)	15 (3.2)	1.00
Malignancy	5 (10.0)	54 (11.5)	0.75
Chronic kidney disease	1 (2.0)	15 (3.2)	1.00
Dialysis dependence	0 (0.0)	9 (1.9)	1.00
Chronic liver disease	2 (4.0)	15 (3.2)	0.68
Chronic pulmonary disease	3 (6.0)	25 (5.3)	0.75
Red blood cell transfusion	6 (12.0)	37 (7.9)	0.32
Cardiac disease	11 (22.0)	59 (12.6)	0.07
Inflammation of bowel	5 (10.0)	48 (10.3)	0.96
Lung disease	3 (6.0)	21 (4.5)	0.50
Vascular disease	1 (2.0)	25 (5.3)	0.50
APACHE II score, mean ± SD	12.6 ± 7.1	9.8 ± 5.8	0.01

t-test used for body mass index and age. χ² used for all other variables except where cell <5 in which Fisher exact test used.

SD = standard deviation; STOP-IT = Study to Optimize Peritoneal Infection Therapy.

Table 2.

Infection Characteristics Stratified by Isolation of Enterococcus

Characteristic	Enterococcus (n = 50)	No Enterococcus (n = 468)	p ^a
Maximum white blood cell count, per mm³,mean ± SD	16.5 ± 7.0	16.4 ± 9.8	0.89
Maximum body temperature, °C, mean ± SD	37.9 ± 0.8	37.7 ± 0.9	0.18
Setting of acquisition of cIAI, no. (%)
Community-acquired	26 (52.0)	295 (63.2)	0.13
Health-care–associated	17 (34.0)	110 (23.5)	0.10
Hospital-acquired	7 (14.0)	62 (13.3)	0.88
Origin of Infection, no. (%)
Colon or rectum	20 (40.0)	157 (33.5)	0.36
Small intestine	7 (14.0)	66 (14.1)	0.98
Appendix	4 (8.0)	69 (14.7)	0.28
Biliary tree (including gallbladder)	6 (12.0)	50 (10.7)	0.78
Duodenum	0 (0.0)	23 (4.9)	0.15
Esophagus	0 (0.0)	3 (0.6)	1.00
Stomach	2 (4.0)	29 (6.2)	0.76
Pancreas	2 (4.0)	14 (3.0)	0.66
Liver	3 (6.0)	15 (3.2)	0.40
Abdominal wall surgical site	1 (2.0)	12 (2.6)	1.00

t-test used for white blood cell count and body temperature. χ² used for all other variables except where cell <5 in which Fisher exact test used.

SD = standard deviation; cIAI = complicated intra-abdominal infection.

Table 3.

Treatment Strategies Stratified by Isolation of Enterococcus

Characteristic	Enterococcus (n = 50)	No Enterococcus (n = 468)^b	p ^a
Source-control procedure, no. (%)
Percutaneous drainage	20 (40.0)	152 (32.5)	0.28
Resection and anastomosis or closure	13 (26.0)	120 (25.6)	0.96
Surgical drainage only	7 (14.0)	102 (21.8)	0.20
Resection and proximal diversion	10 (20.0)	54 (11.5)	0.08
Simple closure	0 (0.0)	32 (6.8)	0.06
Surgical drainage and diversion	0 (0.0)	7 (1.5)	1.00
Antibiotic prescriptions, no. (%)
Ampicillin	3 (6.0)	14 (3.0)	0.22
Amoxicillin/amoxicillin-clavulanate	7 (14.0)	43 (9.2)	0.27
Ciprofloxacin	18 (36.0)	123 (26.3)	0.14
Carbapenems
Ertapenem	2 (4.0)	51 (10.9)	0.15
Meropenem	5 (10.0)	15 (3.2)	0.02
Imipenem-cilastatin	1 (2.0)	4 (0.9)	0.40
Daptomycin	3 (6.0)	3 (0.6)	0.01
Levofloxacin	0 (0.0)	14 (3.0)	0.38
Linezolid	3 (6.0)	6 (1.3)	0.05
Piperacillin/piperacillin-tazobactam	31 (62.0)	253 (54.1)	0.28
Vancomycin	19 (38.0)	112 (23.9)	0.03
Anti-enterococcal coverage^c	39 (78.0)	311 (66.5)	0.10
Total antibiotic days, mean ± SD	9.3 ± 6.3	7.3 ± 5.3	0.5
Total hospital days, mean ± SD	10.4 ± 8.0	9.1 ± 8.9	0.28

t-test used for total antibiotic days and total hospital days. χ² used for all other variables except where cell <5 in which Fisher exact test used.

One patient had no documented source-control procedure.

Anti-enterococcal coverage defined as patients receiving amoxicillin/amoxicillin-clavulanate, ampicillin, daptomycin, imipenem-cilastatin, linezolid, piperacillin/piperacillin-tazobactam, tigecycline, vancomycin.

SD = standard deviation.

An exploratory prediction model with Enterococcus was conducted to identify potential predictors for isolation of Enterococcus. This analysis was conducted in similar fashion to aforementioned multi-variable analyses except for Enterococcus serving as the dependent parameter. For all analyses, a significance level of 0.05, two tailed, was assumed. Power analysis, utilizing β = 0.80, α = 0.05, with fixed effect of 30% for the Enterococcus, yielded a required sample size of 678 (15% reduced composite outcome) and 1,657 (10% reduced composite outcome). Data were analyzed using Stata MP 13 (StataCorp, College Station, TX)

Results

Microbiology

Within the STOP-IT cohort (n = 518), 50 (9.7%) subjects had 52 Enterococcus spp. isolates documented. The speciation revealed 21 Enterococcus faecalis, 9 Enterococcus faecium, and 3 Enterococcus avium isolates and the remainder being a mixture of other 19 Enterococcus spp. isolates. Of these isolates, 8 were found to be VRE with 5 of these speciated as Enterococcus faecium and 3 as Enterococcus faecalis.

Baseline patient and infection characteristics

Baseline characteristics were similar between the two groups as shown in Table 1. On average the subjects were approximatively 50 years of age, white, and had limited comorbidities. The original study assignment to short-term antimicrobial therapy or control therapy was not different significantly between the groups (p = 0.25). Disease severity, as denoted by APACHE II score, was significantly higher, 12.6 ± 7.1 versus 9.8 ± 5.8; p = 0.01, for the Enterococcus and no Enterococcus groups, respectively. Systemic markers of infection, setting of acquisition, and origin of infection were not statistically different between the two groups as shown in Table 2. The majority of infections originated from the community setting followed by health-care–associated IAIs. The number of subjects with Enterococcus isolated compared with those without Enterococcus isolated was similar in the health-care–associated IAI group. Approximatively one-third of the infections were from the colon or rectum.

Treatment strategies

Table 3 summarizes treatment strategies, including source-control procedure, antibiotic agents, total antibiotic days, and total hospital days stratified by isolation of Enterococcus. Most subjects received source-control via percutaneous drain or resection and anastomosis or closure. Inclusion of anti-enterococcal coverage in the subjects treatment regimen was similar between the Enterococcus and no Enterococcus groups at 78% and 66.5%, respectively (p = 0.10). A majority of subjects received piperacillin-tazobactam, an agent with activity against Enterococcus, as part of their treatment course and this was similar between the Enterococcus and no Enterococcus groups at 62% and 54%, respectively (p = 0.28). More patients received meropenem, daptomycin, and vancomycin in the Enterococcus group. Total antibiotic exposure, as measured by total antibiotic days and hospital length of stay were comparable between the two groups.

Outcomes

The impact of isolation of Enterococcus on the composite outcome and individual outcomes is shown in Table 4. Uni-variable analyses revealed no difference in either the composite or individual outcomes with only 15 occurrences of pre-specified outcomes within the Enterococcus group. Only one subject in the Enterococcus group died during the study time frame. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (OR 1.53 [95% CI = 0.78–3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71) when adjusted for baseline characteristics in a stepwise fashion. In addition, no association was found with the individual components of the composite outcome: SSI (OR 1.30 [95% CI = 0.47–3.62]; p = 0.61; c-statistic = 0.73) and recIAI, (OR 1.35 [95% CI = 0.63–2.91]; p = 0.44; c-statistic = 0.65). Parameters found to predict independently the composite outcome were as follows: biliary tree (OR 0.35 [95% CI = 0.13–0.92]; p = 0.03); hospital-acquired infection (OR 1.97 [95% CI = 1.10–3.52]; p = 0.02); and percutaneous drain (OR 0.59 [95% CI = 0.36–0.96]; p = 0.04). A sub-group analysis including patients with hospital-acquired or health-care–associated infections demonstrated no difference in the composite outcome (25% vs. 22.7%, p = 0.80) for the Enterococcus and no Enterococcus groups, respectively. The only parameter included from the dataset that predicted isolation of Enterococcus was the APACHE-II score (un-adjusted OR 1.07; p < 0.01).

Table 4.

Clinical Outcomes Stratified by Isolation of Enterococcus

Characteristic	Enterococcus (n = 50)	No Enterococcus (n = 468)	p
Composite outcome, no. (%)	15 (30.0)	98 (20.9)	0.14
Surgical site infection	5 (10.0)	35 (7.5)	0.53
Recurrent intra-abdominal infection	10 (20.0)	66 (14.1)	0.26
Death	1 (2.0)	4 (1.0)	0.40

Discussion

The present study demonstrates that isolation of Enterococcus from IAI did not affect treatment outcomes in patients receiving antimicrobial therapy and source control interventions for the treatment of IAIs. In addition, isolation of Enterococcus did not portend mortality. In light of these findings, an alternative treatment strategy may not be warranted for patients based on isolation of Enterococcus alone but in concert with other risk factors. Enterococcus spp. are commonly isolated bacteria from peri-operative cultures, with documented isolation in more than one-third of patients [3 –6]. The incidence of enterococcal isolation increases in post-operative and health-care–associated infections [8,11]. The occurrence of a post-operative infection predicts independently the isolation of Enterococcus along with increased age and APACHE II score, whereas appendiceal infections were a negative predictor for isolation of Enterococcus [7,8,12]. In the present study, the average age was the same between groups and similar to the Enterococcus not present group in Burnett et al. [8]. Within the cohort studied, the average APACHE II score for the Enterococcus and no Enterococcus group were 12.6 and 9.8, respectively. Again, this is similar to the subjects (APACHE II <12) in the prior studies who did not have Enterococcus isolated [8]. Within the studied cohort, the appendix was the site of infection 8%–15% of the time, which as noted above carries a lower incidence for isolating Enterococcus. Health-care–associated IAIs carry almost a four-fold increased risk of isolating Enterococcus relative to community-acquired infections [11]. More than 60% of the IAIs included in the current study originated in the community setting. Taken together, the demographics, site of infection, and disease severity distribution may account for the low number of Enterococcus isolates in the present study (n = 50; 10%). Of note, the current Surgical Infection Society guidelines recommend anti-enterococcal coverage for health-care–associated IAIs because of the increased potential for isolation of Enterococcus. However, our study demonstrated a similar percent of patients who did or did not have Enterococcus isolated within the health-care–associated IAI sub-group, with an overall consistent distribution of setting of acquisition regardless of isolation of Enterococcus. In addition, no difference in outcomes was observed in the subset of patients with hospital-acquired/health-care–associated IAIs.

Prior studies demonstrated that isolation of Enterococcus from peri-operative cultures results in treatment failure, primarily by occurrence or recurrence of intra-abdominal abscesses and non-surgical infections [8,13]. In contrast, Claridge et al. [3] showed no difference in treatment failure, non-infectious, and infectious complications when Enterococcus was isolated from non-appendiceal IAIs. Other underlying differences in treatment outcome definitions and patient characteristics between previous studies and ours may explain the discrepant results. In addition to treatment failures, several studies linked the isolation of Enterococcus from IAI cultures to increased mortality [7,14 –16], whereas others demonstrated no association with mortality [3,13]. Our study showed zero deaths in the Enterococcus group. Compared with the previous studies (mortality range, 7%–48%), the overall mortality rate of less than 1% in the STOP-IT cohort is substantially lower. This precludes generalizing the results of our study to higher risk patient populations (e.g., patients admitted to the intensive care unit, septic shock, etc.).

The necessity of empiric and directed antimicrobial coverage against Enterococcus continues to be debated. Despite its association with increased morbidity and mortality in a number of studies, adequate antimicrobial coverage of this organism may not improve outcomes [16] and in one study, was associated with increased mortality [14]; however, post-operative infection rates were reduced with adequate coverage [9]. Large randomized trials that used ertapenem, a carbapenem without Enterococcus activity [17], resulted in similar treatment efficacy for IAIs compared against piperacillin-tazobactam [6,12]. Post hoc analysis of subjects with Enterococcus isolated from three randomized controlled trials showed that treatment failures were predicted by presence of post-operative infection and advanced age, but coverage of Enterococcus did not affect treatment outcomes [12]. In addition, recent IAI trials that used novel antimicrobial combinations with limited activity against Enterococcus support the effectiveness of agents without directed activity against Enterococcus [18,19]. The majority of our sample received a regimen that had activity against Enterococci, which possibly affected treatment outcomes and may explain the equivalency demonstrated.

Discrepant results in treatment outcomes may be explained by the possibility that this organism serves more as a marker of disease severity un-related to its inherent pathogenic capabilities. Alternatively, enterococci may synergistically enhance the effect of other more problematic bacterial pathogens via pro-inflammatory means [20,21]. The possibility exists that the source control procedures alone drive treatment outcomes regardless of antimicrobial therapy. To this end, shorter antimicrobial courses were shown equivalent in the STOP-IT trial [10] and the presence of source control may have resulted in equivalent outcomes in patients with Enterococcus isolated.

Indiscriminate use of antimicrobial agents for the treatment of IAIs carries the potential to select for resistant pathogens supporting thoughtful and judicious use of the antimicrobial agents used to treat these infections [23]. Exposure to the broad-spectrum antimicrobial therapy for the treatment of IAIs alters gastrointestinal flora and favors the selection of more resistant pathogens [24 –26]. Acquisition of resistant gram-positive organisms increases length of hospital stay and predicts increased severity of IAIs [27]. In addition, the isolation of resistant pathogens predicts negatively de-escalation of antimicrobial agents possibly leading to prolonged antimicrobial exposure and associated untoward effects [28]. Shorter antimicrobial courses did not predict independently treatment failure in subjects with Enterococcus isolated. Reliance on source control and shorter antimicrobial courses regardless of the pathogen isolated serves to promote antimicrobial stewardship and reduces collateral antimicrobial damage.

The present study has several limitations. First, the construct of the post hoc analysis and reliance on a pre-populated database limits the ability to discern what role individual interventions played in the outcomes studied. For example, antibiotic prescriptions were recorded as a categorical parameter, given or not, without exact duration or timing of exposure. This prevents ascertaining whether prescribed antimicrobial agents were culture-directed based on isolation of Enterococcus or if provided as empiric coverage. This challenge also holds true for the timing of Enterococcus cultures. The database design precludes the study from determining whether the isolate affected the initial presentation or was a subsequent bystander. In addition, subjects were not randomly assigned to isolation of Enterococcus requiring multi-variable analysis to correct for non-randomized disposition of the subjects into two arbitrary groups. Second, the assumed effectiveness of antimicrobial therapy relies on global susceptibility rates, because antimicrobial susceptibly testing results were not reported. Third, the generalizability of the results is limited because the majority of the subjects presenting with community-acquired infections and all subjects receiving source control biased the population toward a lower risk population. As confirmed by the power analysis, the small number of subjects with Enterococcus isolated results in reduced power and increased chance of a type II error limiting the ability to determine the true effect of isolating Enterococcus from IAIs.

In conclusion, Enterococcus was not a more common pathogen in health-care–associated IAIs. Furthermore, it was not associated with an increased number or severity of complications of IAIs after adjustment for patient and infection characteristics, setting of acquisition, and treatment strategy. The current post hoc analysis demonstrates that antimicrobial therapy in tandem with adequate source control may not need to be altered based on the isolation of Enterococcus from IAI cultures. Larger studies would assist with further guideline development addressing this specific pathogen.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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