Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study

The CIAO Study (“Complicated Intra-Abdominal infection Observational” Study) is a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012). Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 2,152 patients with a mean age of 53.8 years (range: 4–98 years) were enrolled in the study. 46.3% of the patients were women and 53.7% were men. Intraperitoneal specimens were collected from 62.2% of the enrolled patients, and from these samples, a variety of microorganisms were collectively identified. The overall mortality rate was 7.5% (163/2.152). According to multivariate analysis of the compiled data, several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission. Given the sweeping geographical distribution of the participating medical centers, the CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.


Introduction
Intra-abdominal infections (IAIs) include a wide spectrum of pathological conditions, ranging from uncomplicated appendicitis to fecal peritonitis.
In the event of complicated IAI [1], 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].

Study design
The aim of the CIAO Study was to describe the epidemiological, clinical, microbiological, and surgical treatment profiles of community-acquired and healthcareassociated complicated intra-abdominal infections (IAIs) based on data collected over a 6-month period (January-June 2012) from 68 medical institutions throughout Europe (see Figure 1).
Patients with either community-acquired or healthcareassociated complicated intra-abdominal infections (IAIs) were included in the study.
The center coordinator of each participating medical institution collected and compiled clinical data in an online case report database.
The collected data included the following: (i) patient and disease characteristics, i.e. patient demographic data, type of infection (nosocomial or community-acquired), severity criteria, and previous antibiotic therapy administered in the 7 days preceding surgery; (ii) origin of infection, surgical procedures performed, and antibiotic therapies administered; and (iii) microbiological data, i.e. identification of bacteria and microorganismal pathogens within the peritoneal fluid, the identification of yeasts (if present), and the antibiotic susceptibilities of bacterial isolates.
This observational study did not attempt to change or modify the laboratory or clinical practices of the participating physicians or their respective institutions, and it did not require informed consent or formal approval by an Ethics Committee.
A Scientific Committee was established to impartially assess the objectives, methodology, and overall scientific quality of the project.
The study was monitored by the coordination center, which processed and verified missing or unclear data submitted to the central database.
Statistical analysis was performed using STATA W statistical software.
Tables 1, 2 overviews the clinical findings and radiological assessments recorded upon patient admission.
Of 369 cases (17.1%) were attributable to post-operative infections. Anastomotic leaks were the most prevalent cause of post-operative infection. Of all post-operative infections, 40.2% resulted from colo-rectal leaks, 32.1% from upper gastro-intestinal leaks, 14.5% from biliary leaks, 11.2% from pancreatic leaks, and 1.9% from urinary leaks.
These specimens were obtained from 977 of the 1,701 patients presenting with community-acquired intraabdominal infections (57.4%).
Intraperitoneal specimens were collected from 362 (80.3%) of the remaining 451 patients with nosocomial intra-abdominal infections.
The major pathogens involved in intra-abdominal infections were found to be Enterobacteriaceae.
The aerobic bacteria identified in samples of peritoneal fluid are reported in Table 4.
In community-acquired IAIs, Extended-Spectrum Beta-Lactamase (ESBL)-producing Escherichia coli isolates comprised 10 There were 5 isolates of Klebsiella pneumoniae resistant to Carbapenems. All Carbapenem-resistant Klebsiella pneumoniae isolates were acquired in an intensive care setting.
Among the identified aerobic gram-negative isolates, there were 80 isolates of Pseudomonas aeruginosa, comprising 5.3% of all identified aerobic bacteria isolates (4.3% in patients with community-acquired infections versus 6.7% in patients with nosocomial infections).
The 3 Pseudomonas aeruginosa strains resistant to Carbapenems were also obtained from nosocomial infections.
Among the identified aerobic gram-positive bacteria, Enterococci (E. faecalis and E. faecium) were the most prevalent, representing 16% of all aerobic isolates, and were identified in 241 cases. 22 glycopeptide-resistant Enterococci were identified; 16 were glycopeptideresistant Enterococcus faecalis isolates and 6 were glycopeptide-resistant Enterococcus faecium isolates.
Although Enterococci were also present in communityacquired infections, they were far more prevalent in nosocomial infections.
Identified bacterial isolates from peritoneal fluid samples in both nosocomial and community-acquired IAIs are listed in Table 5.
Tests for anaerobes were conducted for 680 patients. 197 anaerobes were observed. The most frequently identified anaerobic pathogen was Bacteroides. 126 Bacteroides isolates were observed during the course of Identified anaerobic bacteria are reported in Table 6. Additionally, 138 Candida isolates were collectively identified (4.7%). 110 were Candida albicans and 28 were non-albicans Candida. 2 Candida albicans isolates and 7 non-albicans Candida isolates were resistant to Fluconazole (see Table 7).

Outcome
The overall mortality rate was 7.6% (163/2,152). 521 patients (24.2%) were admitted to the intensive care unit in the early recovery phase immediately following surgery.
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 (OR=2.6; 95%CI=1.8-3.5; p<0.0001).

Source control
Complicated intra-abdominal infections are an important source of patient morbidity and are frequently associated with poor clinical prognoses, particularly for patients in high-risk categories.
The CIAO Study has confirmed that acute appendicitis is the most common intra-abdominal condition requiring emergency surgery in Europe. Both open and laparoscopic appendectomies are viable treatment options for complicated appendicitis [4]. The laparoscopic appendectomy is a safe and effective means of surgical treatment for addressing complicated intra-abdominal infections, but open surgery still retains several clinical advantages, including a reduced probability of post-operative intraabdominal abscesses [5]. CIAO Study data indicate that the open approach was used in 55.1% of complicated appendicitis cases while the laparoscopic approach was performed in 39.8% of these cases.
For patients with periappendiceal abscesses, the proper course of surgical treatment remains a point of contention in the medical community. However, this contention notwithstanding, the most commonly employed treatment appears to be drainage with subsequent appendectomy [6].
Although guidelines for the management of intraabdominal infections commonly assert that patients with periappendiceal abscesses should be treated with percutaneous image-guided drainage, few patients underwent this procedure.
The laparoscopic versus open cholecystectomy debate has been extensively investigated in recent years. In the CIAO Study, the open cholecystectomy was the most common means of treating cholecystitis; 48.4% of patients with complicated cholecystitis underwent this procedure. By contrast, 118 patients (40.8%) underwent the laparoscopic procedure.
The optimal surgical management of colonic diverticular disease complicated by peritonitis remains a controversial issue in the medical community.
Hartmann's resection has historically been considered the procedure of choice for patients with generalized peritonitis and continues to be a safe and reliable technique for performing an emergency colectomy in the event of perforated diverticulitis, particularly in elderly patients with multiple co-morbidities [7][8][9][10].
More recently, however, reports have suggested that primary resection and anastomosis may be the optimum approach to addressing diverticulitis, even in the presence of diffuse peritonitis [11].
According to CIAO Study data, the Hartmann resection was the most frequently performed procedure to address complicated diverticulitis in Europe. 43.2% of patients underwent a Hartmann resection, and of these resections, the vast majority were open procedures (94.5% open compared to 5.5% laparoscopic). 54 of these patients (74%) underwent a Hartmann resection for generalized peritonitis, while the remaining 19 (26%) underwent the same procedure for localized peritonitis or abscesses.   22.5% of patients underwent colo-rectal resection to address complicated diverticulitis.

Microbiology
The significance of microbiological analysis of infected peritoneal fluid in community-acquired intra-abdominal infections has been debated in recent years.
Cultures from the site of infection should always be obtained for patients with nosocomial infections as well as for patients with community-acquired infections who are known to be at risk for drug-resistant strains. In these patients, causative pathogens and resistance patterns are unpredictable and always require cultures from the site of infection [4].
Bacterial cultures and analyses may be often clinically superfluous, particularly when the etiological agents are readily predictable [12]. However, some authors maintain that in-depth bacterial diagnosis has practical significance, even in low-risk patients with community-acquired IAIs. They argue that this analysis plays an important role in documenting epidemiological shifts in antimicrobial resistance patterns associated with community-acquired IAIs and in guiding individualized follow-up therapy. For high-risk patients with community-acquired IAIs or in the event of nosocomial IAIs, clinicians should always obtain cultures from the site of infection.
According to CIAO Study data, intraperitoneal specimens were collected from 62.2% of patients; these samples were obtained from 57.4% of patients with community-acquired IAIs and from 80.3% of patients with nosocomial IAIs.
In many clinical laboratories, species identification and susceptibility testing of anaerobic isolates are not routinely performed [13].
Of the total patients tested for aerobic microorganisms, 42.9% underwent tests for anaerobes.
The major pathogens involved in community-acquired intra-abdominal infections are Enterobacteriaceae, Streptococcus species, and certain anaerobes (particularly B. fragilis). Compared to community-acquired infections, nosocomial infections typically involved a broader spectrum of microorganisms, encompassing ESBL-producing Enterobacteriaceae, Enterococcus, Pseudomonas, and Candida species in addition to the Enterobacteriaceae, Streptococcus species, and anaerobes observed in community-acquired IAIs.
Antimicrobial resistance has become a major challenge complicating the treatment and management of intraabdominal infections.
The main resistance threat is posed by ESBLproducing Enterobacteriaceae, which are becoming increasingly common in community-acquired infections.
Many factors can increase the prevalence of ESBL activity in community-acquired intra-abdominal infections, including excessive use of antibiotics, residence in a long-term care facility, and recent hospitalization. Further, male patients and patients over the age of 65 appear to be particularly susceptible to ESBL-producing bacterial infections [14].
According to CIAO 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.
In addition to hydrolyzing Carbapenems, KPCproducing strains are also resistant to a variety of other antibiotics, and consequently, these infections pose a considerable challenge for clinicians in acute care situations.
KPC-producing bacteria are most common in nosocomial infections, particularly in patients with previous exposure to antibiotics [15]. 5 identified isolates of Klebsiella pneumoniae proved resistant to Carbapenems, and each was acquired in an intensive care setting.
The rate of Pseudomonas aeruginosa among aerobic isolates was 5.2%. There was no statistically significant difference in Pseudomonas prevalence between community-acquired and nosocomial IAIs.
Enterococci (E. faecalis and E. faecium) were identified in 15.7% of all aerobic isolates.
Although Enterococci were also identified in community-acquired infections, they were far more prevalent in nosocomial infections.
In the CIAO Study, 138 Candida isolates were observed among 1,890 total isolates (7.3%). Candida prevalence was significantly higher in the nosocomial IAI group than it was in the community-acquired IAI group.

Outcome
Of the 2,152 patients enrolled in the study, there were 163 deaths (7.6%).
According to univariate statistical analysis of the data, critical clinical condition of the patient upon hospital admission (defined by severe sepsis/septic shock) as well as critical clinical condition in the immediate postoperative period and ICU admission were all significant risk factors predictive of patient mortality. WBCs greater than 12,000 or less than 4,000 and core body temperatures greater than 38°C or less than 36°C by the third post-operative day were predictors of patient mortality. Among the various sources of infection, colonic non-diverticular perforations, complicated diverticulitis, and small bowel perforations correlated strongly 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.
According to stepwise multivariate analysis (PR=0.005 and PE=0.001), several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission.

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 CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.