Complicated intra-abdominal infections worldwide: the definitive data of the CIAOW Study

The CIAOW study (Complicated intra-abdominal infections worldwide observational study) is a multicenter observational study underwent in 68 medical institutions worldwide during a six-month study period (October 2012-March 2013). The study included patients older than 18 years undergoing surgery or interventional drainage to address complicated intra-abdominal infections (IAIs). 1898 patients with a mean age of 51.6 years (range 18-99) were enrolled in the study. 777 patients (41%) were women and 1,121 (59%) were men. Among these patients, 1,645 (86.7%) were affected by community-acquired IAIs while the remaining 253 (13.3%) suffered from healthcare-associated infections. Intraperitoneal specimens were collected from 1,190 (62.7%) of the enrolled patients. 827 patients (43.6%) were affected by generalized peritonitis while 1071 (56.4%) suffered from localized peritonitis or abscesses. The overall mortality rate was 10.5% (199/1898). According to stepwise multivariate analysis (PR = 0.005 and PE = 0.001), several criteria were found to be independent variables predictive of mortality, including patient age (OR = 1.1; 95%CI = 1.0-1.1; p < 0.0001), the presence of small bowel perforation (OR = 2.8; 95%CI = 1.5-5.3; p < 0.0001), a delayed initial intervention (a delay exceeding 24 hours) (OR = 1.8; 95%CI = 1.5-3.7; p < 0.0001), ICU admission (OR = 5.9; 95%CI = 3.6-9.5; p < 0.0001) and patient immunosuppression (OR = 3.8; 95%CI = 2.1-6.7; p < 0.0001).


Introduction
Intra-abdominal infections (IAIs) include a wide spectrum of pathological conditions, ranging from uncomplicated appendicitis to faecal peritonitis [1].
In the event of complicated IAI the infection proceeds beyond a singularly affected organ and causes either localized peritonitis (intra-abdominal abscesses) or diffuse peritonitis. Effectively treating patients with complicated intra-abdominal infections involves both source control and antimicrobial therapy [2,3].
In order to describe the epidemiological, clinical, microbiological, and surgical treatment profiles of complicated intra-abdominal infections (IAIs) in Europe, the World Society of Emergency Surgery (WSES) designed the CIAO Study (Complicated intra-abdominal infections observational study). The CIAO Study was conducted during 2012 across twenty European countries [4].
Given the interesting results of the CIAO Study, WSES designed a prospective observational study investigating the management of complicated intra-abdominal infections in a worldwide context.
The CIAOW study (Complicated intra-abdominal infections worldwide observational study) is a multicenter observational study underwent in 68 medical institutions worldwide during a six-month study period (October 2012-March 2013. In January 2013 the preliminary results (2-month study period) of the CIAOW study were published [5].
WSES presents the definitive data of the CIAOW Study.

Aim
The purpose of the study was to describe the clinical, microbiological, and treatment profiles of both communityand healthcare-acquired complicated IAIs in a worldwide context.
Patients older than 18 years with both communityacquired and healthcare-associated IAIs were included in the database.

Study population
The CIAOW study is a multicenter observational study underwent in 68 medical institutions worldwide. The study included patients undergoing surgery or interventional drainage to address complicated IAIs.
Medical institutions from each continent participated in the study. The geographical distribution of the participating centers are represented in Figure 1.

Study design
The study did not attempt to change or modify the laboratory or clinical practices of the participating physicians, and neither informed consent nor formal approval by an Ethics Committee were required.
The study met the standards outlined in the Declaration of Helsinki and Good Epidemiological Practices.
The study was monitored by the coordination center, which investigated and verified missing or unclear data submitted to the central database. This study was performed under the direct supervision of the board of directors of WSES.

Data collection
In each centre, the coordinator collected and compiled data in an online case report system. These data included the following: (i) patient and disease characteristics, i.e., demographic data, type of infection (community-or healthcare-acquired), severity criteria, previous curative antibiotic therapy administered in the 7 days preceding surgery; (ii) origin of infection and surgical procedures performed; and (iii) microbiological data, i.e., identification of bacteria and microbial pathogens within the peritoneal fluid, the presence of yeasts (if applicable), and the antibiotic susceptibilities of bacterial isolates.
The primary endpoints included the following: Clinical profiles of intra-abdominal infections Epidemiological profiles (epidemiology of the microorganisms isolated from intra-abdominal samples and these organisms' resistance to antibiotics) Management profiles

Results
Patients 2,020 cases were collected in the online case report system. 122 cases did not meet the inclusion criteria. 827 patients (43.6%) were affected by generalized peritonitis while 1071 (56.4%) suffered from localized peritonitis or abscesses.
296 patients (14.2%) were admitted in critical condition (severe sepsis/septic shock). Table 1, 2 overview the clinical findings and radiological assessments recorded upon patient admission.

Source control
The various sources of infection are outlined in Table 3  cholecystectomies, respectively. The remaining patients were treated with conservative methods (percutaneous drainage, non-operative treatment). Among the patients with complicated diverticulitis (106) the Hartmann resection was the most frequently performed procedure. 48 patients (45.3%) underwent a Hartmann resection. 31 of these patients (64.6%) underwent a Hartmann resection for generalized peritonitis, while the remaining 17 (35.6%) underwent the same procedure for localized peritonitis or abscesses. Colo-rectal resection was performed in 18 cases (17%) (5 with and 13 without protective stoma).
The remaining patients received conservative treatment (percutaneous drainage, non-operative treatment, surgical drainage and stoma). 4 patients underwent laparoscopic drainage.
These specimens were obtained from 977 of the 1,645 patients presenting with community-acquired intraabdominal infections (59.4%).
Intraperitoneal specimens were collected from 213 (84.2%) of the remaining 253 patients with nosocomial intra-abdominal infections.
The aerobic bacteria identified in intraoperative samples are reported In Table 4, 5.
The microorganisms isolated in subsequent samples from peritoneal fluid are reported in Table 6.
All the microorganisms isolated in both intraoperative and subsequent samples from peritoneal fluid are reported in Table 7.
The major pathogens involved in intra-abdominal infections were found to be Enterobacteriaceae.
Among the intra-operative isolates, Extended-Spectrum Beta-Lactamase (ESBL)-producing Escherichia coli isolates comprised 13.7% (75/548) of all Escherichia coli isolates, while ESBL-positive Klebsiella pneumoniae isolates represented 18.6% (26/140) of all Klebsiella pneumoniae isolates. ESBL-positive Enterobacteriaceae were more prevalent in patients with healthcare associated infections IAIs than they were in patients with community-acquired IAIs. ESBL-positive Escherichia coli isolates comprised  Among the microorganisms isolated in the intraoperative samples, there were 74 isolates of Pseudomonas aeruginosa, comprising 5.6% of all aerobic identified bacteria isolates.   Among all the microorganisms isolated in both intraoperative and subsequent samples from peritoneal fluid, there were 94 isolates of Pseudomonas aeruginosa, comprising 5.1% of all identified bacteria isolates.
The 2 Pseudomonas aeruginosa strains resistant to Carbapenems were also obtained from nosocomial infections.
Among all the aerobic gram-positive bacteria identified in the intraoperative samples, Enterococci (E. faecalis and E. faecium) were the most prevalent, representing 15.9% of all aerobic isolates, and were identified in 211 cases. Although Enterococci were also present in community-acquired infections, they were more prevalent in healthcare-associated infections (31.7%: 67/211).
Among all the microorganisms isolated in both intraoperative and subsequent samples from peritoneal fluid Enterococci were 237/1826 (12.9%).
Tests for anaerobes were conducted for 486 patients. Identified anaerobic bacteria from intra-operative specimens are reported in Table 8.
Among all the microorganisms isolated in both intraoperative and subsequent samples from peritoneal fluid, 141 anaerobes were observed. The most frequently identified anaerobic pathogen was Bacteroides. 108 Bacteroides isolates were observed during the course of the study.
In Table 9 are illustrated Candida spp. isolated in intraoperative specimens.
Among all the microorganisms isolated in both intraoperative and subsequent samples from peritoneal fluid, 117 Candida isolates were collectively identified (6%). 90 were Candida albicans and 27 were non-albicans Candida.

Outcome
The overall mortality rate was 10.5% (199/1898). 565 patients (29.8%) were admitted to the intensive care unit (ICU) in the early recovery phase immediately following surgery.
In the immediate post-operative clinical period 269 patients were critically ill (132 with septic shock, 137 with severe sepsis).
The setting of acquisition was also a variable found to be predictive of patient mortality (healthcare-associated infections: OR = 3.1; 95%CI = 2.2-4.5; p < 0.0001).

Discussion
The CIAOW Study confirmed that acute appendicitis is the most common intra-abdominal condition requiring emergency surgery worldwide. According to the WSES 2013 guidelines for management of intra-abdominal infections, both open and laparoscopic appendectomies are viable treatment options for complicated appendicitis [6]. CIAOW Study results indicate that the open approach was used in most patients and it was the most common approach in the patients with complicated appendicitis.
For patients with peri-appendiceal abscesses, the proper course of surgical treatment remains a point of contention in the medical community. Although guidelines for the management of intra-abdominal infections commonly assert that patients with peri-appendiceal abscesses should be treated with percutaneous imageguided drainage [5]. Percutaneous drainage with or without interval appendectomy to treat peri-appendiceal abscess results in fewer complications and shorter overall length of stay [6][7][8]. Data from CIAOW Study indicate that few patients underwent this procedure for a peri-appenceal abscess.
Laparoscopic cholecystectomy versus open cholecystectomy question for acute cholecystitis has been extensively investigated. Several studies showed that early laparoscopic cholecystectomy resulted in a significantly reduced length of stay, no major complications, and no significant difference in conversion rates when compared with initial antibiotic treatment and delayed laparoscopic cholecystectomy [9][10][11][12].
The open cholecystectomy was the most common means of treating complicated cholecystitis; 47.8% (133) of the patients with complicated cholecystitis underwent this procedure. By contrast, 36.7% (102) underwent a laparoscopic procedure.
The optimal surgical management of colonic diverticular disease complicated by peritonitis remains a controversial issue. Hartmann's resection has been considered the procedure of choice in patients with generalized peritonitis and remains a safe technique for emergency colectomy in perforated diverticulitis, especially in elderly patients with multiple co-morbidities [13]. More recently, some reports have suggested that primary resection and anastomosis is the preferred approach to diverticulitis, even in the presence of diffuse peritonitis [14,15].
According to CIAOW Study data, the Hartmann resection was the most frequently performed procedure to address both complicated diverticulitis and non-diverticular colonic perforations worldwide.
The significance of microbiological analysis of infected peritoneal fluid in community-acquired intra-abdominal infections has been debated in recent years.
Although the absence of impact of bacteriological cultures has been documented especially in appendicitis [16], in this era of the broad spread of resistant microorganisms such as nosocomial and community extended-spectrum b-lactamase (ESBL) Enterobacteriaceae, carbapenemase producing gram negatives, b lactamand vancomycin resistant enterococci (VRE), the threat of resistance is a source of major concern for clinicians. Therefore the results of the microbiological analyses have great importance for the therapeutic strategy of every patients.
According to CIAOW Study data, intraperitoneal specimens were collected from 62.7% of patients with complicated intra-abdominal infections. Intraperitoneal specimens were collected in 59.4% patients presenting with community-acquired intraabdominal infections.
Intraperitoneal specimens were collected from 84.2% of the patients with nosocomial intra-abdominal infections.
In many clinical laboratories, species identification and susceptibility testing of anaerobic isolates are not routinely performed. Tests for anaerobes were conducted for 486 patients.
The major pathogens involved in community-acquired intra-abdominal infections are Enterobacteriaceae, Streptococcus species, and certain anaerobes (particularly B. fragilis).
The main resistance threat in intra.-abdominal infections is posed by ESBL-producing Enterobacteriaceae, which are becoming increasingly common in communityacquired infections [17,18].
According to CIAOW Study data, ESBL producers were the most commonly identified drug-resistant microorganism involved in IAIs.
Recent years have seen an escalating trend of Klebsiella pneumoniae Carbapenemase (KPC) production, which continues to cause serious multidrug-resistant infections around the world. The recent emergence of Carbapenem-resistant Enterobacteriaceae is a major threat to hospitalized patients [19]. 5 identified isolates of Klebsiella pneumoniae proved resistant to Carbapenems.
Pseudomonas aeruginosa is one of the major nosocomial pathogens worldwide. It is intrinsically resistant to many drugs and is able to become resistant to virtually any antimicrobial agent.
The rate of Pseudomonas aeruginosa was 5.6% of all microorganisms isolated in the intra-operative samples. According to CIAOW study there was no significant difference between community and healthcare associate infections.
The 2 Pseudomonas aeruginosa strains resistant to Carbapenems were also obtained from nosocomial infections.
Enterococci are significant pathogens in intraabdominal infections. Among multidrug Gram positive bacteria, Enterococci remain a challenge. The evolution of antimicrobial resistance in these organisms poses enormous challenges for clinicians when faced with patients affected with Enterococcus infections. Enterococcus infections are difficult to treat because of both intrinsic and acquired resistance to many antibiotics.
Enterococci (E. faecalis and E. faecium) were the most common Gram positive aerobic isolates.
Although Enterococci were also identified in communityacquired infections, they were far more prevalent in nosocomial infections.
In the last years there has been a significant increase in the incidence of invasive infections due to Candida species.
Although the epidemiological role of Candida spp. in nosocomial peritonitis is not yet defined, the clinical role is significant, because Candida isolation is normally associated to a poor prognosis [20].
It is well known that patients with severe sepsis or septic shock may be complicated by high mortality rates. According to the CIAOW Study the overall mortality rate was 10.5% (199/1898).
29.8% of patients were admitted to the ICU in the early recovery phase immediately following surgery. In the immediate post-operative clinical period 269 patients were critically ill (132 with septic shock, 137 with severe sepsis).
The surgical treatment strategies following an initial emergency laparotomy have been debated in the last years.
The decision whether and when to perform a relaparotomy in secondary peritonitis is largely subjective and based on professional experience. Factors indicative of progressive or persistent organ failure during early postoperative follow-up are the best indicators for ongoing infection and associated positive findings at relaparotomy [21][22][23].
According to univariate statistical analysis of the data, septic shock and severe sepsis upon hospital admission were both predictive of patient mortality.
The setting of acquisition was also a variable found to be predictive of patient mortality (healthcare-associated infections).
Among the various sources of infection, colonic nondiverticular perforation, complicated diverticulitis, small bowel perforation and post-operative infections were significantly correlated with patient mortality.
Mortality rates did not vary to a statistically significant degree between patients who received adequate source control and those who did not. However, a delayed initial intervention (a delay exceeding 24 hours) was associated with an increased mortality rate.
The nature of the immediate post-operative clinical period was a significant predictor of mortality. Patients requiring ICU admission were also associated with increased mortality rates.
Also comorbidities were associated to patient mortality. According to stepwise multivariate analysis, several criteria were found to be independent variables predictive of mortality, including patient age, the presence of small bowel perforation, a delayed initial intervention (a delay exceeding 24 hours), ICU admission and patient immunosuppression.

Conclusion
Complicated intra-abdominal infections remain an important source of patient morbidity and are frequently associated with poor clinical prognoses, particularly for patients in high-risk categories.
Given the sweeping geographical distribution of the participating medical centers, the CIAOW Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections worldwide.