Epidemiological analysis of intra-abdominal infections in Italy from the Italian register of complicated intra-abdominal infections—the IRIS study: a prospective observational nationwide study

Abstract

Background

Intra-abdominal infections (IAIs) are common and severe surgical emergencies associated with high morbidity and mortality. In recent years, there has been a worldwide increase in antimicrobial resistance associated with intra-abdominal infections, responsible for a significant increase in mortality rates. To improve the quality of treatment, it is crucial to understand the underlying local epidemiology, clinical implications, and proper management of antimicrobial resistance, for both community- and hospital-acquired infections. The IRIS study (Italian Register of Complicated Intra-abdominal InfectionS) aims to investigate the epidemiology and initial management of complicated IAIs (cIAIs) in Italy.

Material and method

This is a prospective, observational, nationwide (Italy), multicentre study. approved by the coordinating centre ethic committee (Local Research Ethics Committee of Pisa (Prot n 56478//2019). All consecutively hospitalized patients (older than 16 years of age) with diagnosis of cIAIs undergoing surgery, interventional drainage or conservative treatment have been included.

Results

4530 patients included from 23 different Italian hospitals. Community Acquired infection represented the 70.9% of all the cases. Among appendicitis, we found that 98.2% of the cases were community acquired (CA) and 1.8% Healthcare-associated (HA) infections. We observed that CA represented the 94.2% and HA 5.8% of Gastro Duodenal perforation cases. The majority of HA infections were represented by colonic perforation and diverticulitis (28.3%) followed by small bowel occlusion (19%) and intestinal ischemia (18%). 27.8% of patients presented in septic shock. Microbiological Samples were collected from 3208 (70.8%) patients. Among 3041 intrabdominal sample 48.8% resulted positive. The major pathogens involved in intra-abdominal infections were found to be E.coli (45.6%). During hospital stay, empiric antimicrobial therapy was administered in 78.4% of patients. Amoxicillin/clavulanate was the most common antibiotic used (in 30.1% appendicitis, 30% bowel occlusion, 30.5% of cholecystitis, 51% complicated abdominal wall hernia, 55% small bowel perforation) followed by piperacillin/tazobactam (13.3% colonic perforation and diverticulitis, 22.6% cholecystitis, 24.2% intestinal ischemia, 28.6% pancreatitis). Empiric antifungal therapy was administered in 2.6% of patients with no sign of sepsis, 3.1% of patients with clinical sign of sepsis and 4.1% of patients with septic shock. Azoles was administered in 49.2% of patients that received empiric antifungal therapy. The overall mortality rate was 5.13% (235/4350). 16.5% of patients required ICU (748/4350). In accordance with mortality, it is important to highlight that 35.7% of small bowel perforation, 27.6% of colonic perforation and diverticulitis, 25.6% of intestinal ischemia and 24.6% of gastroduodenal complications required ICU.

Conclusion

Antibiotic stewardship programs and correct antimicrobial and antimycotic prescription campaigns are necessary to ulteriorly improve the adequacy of drug usage and reduce the resistances burden. This will help in improving the care and the cure of the next generations.

Background

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in emergency surgical units worldwide [1]. Complicated IAIs (cIAIs) are those ones passing the visceral peritoneal barrier (e.g., abscesses, perforations). The cornerstone of effective treatment of cIAIs includes early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using intravenous fluid therapy in critically ill patients [3,4,5,6]. Results from published clinical trials often may not be representative of the true morbidity and mortality rates of such severe infections. Guidelines helps in managing IAI but tailored management may differ according to local epidemiology [7].

The knowledge of the various bacteria epidemiology in the different regions is often impaired by the possibility to accrue data. Several data have been published about the topic enrolling patients from all around the world [8,9,10,11]. Dedicated studies as the present one may represent the starting point to diffuse the awareness about the necessity to improve knowledge about this important topic. National registries are needed, and they should be included in broader program such as the Web-based International Register of Emergency Surgery and Trauma (Wires-T). This will allow to accrue precise data with the possibility to sum or compare them.

In recent years, there has been a worldwide increase in infections caused by microorganisms resistant to multiple antimicrobial agents. This increase in antimicrobial resistance has been noted in both hospital and community settings. The increasing prevalence of multi-drug resistance is responsible for a significant increase in morbidity and mortality rates associated with intra-abdominal infections as well as a subsequent increase in overall healthcare costs [12,13,14]. Furthermore, a dramatic reduction in the development of new antibiotics effective against multidrug-resistant pathogens has further exacerbated the dilemma. Antibiotic stewardship program must be implemented at local and national base to optimize antibiotic usage and potentially reduce the overuse or misuse of antibiotics.

In fact, an antimicrobial-based approach in managing intra-abdominal infections always involves a delicate balance between the optimization of empirical therapy, which has been shown to improve clinical outcomes, and the reduction of excessive antimicrobial use, which has been proven to increase the rate of emergence of antimicrobial-resistant strains. To ulteriorly improve the quality of treatment a multidisciplinary approach (involving surgeon, infectious specialist, and intensive care specialist) is essential for the best management of such critical condition. It is crucial, moreover, that every clinician understand the underlying local epidemiology, clinical implications, and proper management of antimicrobial resistance, for both community- and hospital-acquired infections.

To the best of our knowledge, no previous studies have been designed and carried out with a purposely intention to investigate the Italian epidemiology of cIAIs. Furthermore, although previous studies analyzed prognostic factors in cIAIs [15,16,17,18,19,20], additional efforts should be made to identify further risk factors predictive of mortality in patients with cIAIs. Moreover, only few observational studies were published with the aim to investigate patient characteristics associated with a high risk of isolation of resistant pathogens from an intra-abdominal source [21,22,23,24]. The Italian Register of complicated Intra-abdominal InfectionS – the IRIS study aims to investigate the epidemiology and initial management of cIAIs in Italy.

Methods

The IRIS study (Italian Register of Complicated Intra-abdominal InfectionS) is a prospective, observational, nationwide (Italy), multicentre study. The Study has been approved by the coordinating centre ethic committee (Local Research Ethics Committee of Pisa (Prot n 56,478//2019).

Inclusion criteria

All consecutively hospitalized patients (older than 16 years of age) with diagnosis of cIAIs (defined as abdominal infections originating in an organ cavity, extending into the peritoneal space, and forming an abscess or peritonitis) undergoing surgery, interventional drainage or conservative treatment have been included in the study between May 1st, 2021 and April 31st, 2023.

Data collection

Data were accrued prospectively in on-line case report platform (www.clinicalregisters.org).

The following data have been collected for each patient:

Demographic data (Gender, age). Antimicrobial therapy administered within one month prior to surgery, comorbidities (primary or secondary immunodeficiency, solid or haematopoietic and lymphoid malignancy, severe cardiovascular disease, chronic dialysis, history of MDRO colonization/infection). Clinical findings upon admission, as fever (defined as core temperature > 38.0° C) or hypothermia (core temperature < 36.0° C), leucocytosis (white blood count [WBC] > 12,000 cells/ml) or leukopenia (WBC < 4000 cells/ml), presence of localized pain, diffuse pain, abdominal rigidity [25, 26]. Patient clinical condition at admission. Setting of infection acquisition: complicated IAIs will be classified as community- acquired (CA-cIAIs) or healthcare-acquired (HA-cIAIs). Complicated IAIs will be considered as HA-cIAIs in patients hospitalized for at least 48 h during the previous 90 days; or those residing in skilled nursing or long-term care facility during the previous 30 days; or those who have received intravenous therapy, wound care, or renal replacement therapy within the preceding 30 days. Radiological diagnosis (ultrasound, radiological and computer tomography findings). Source of infection (stomach or duodenum, gallbladder, small bowel, colon, appendix or other), and peritonitis diffusion (generalized or localized peritonitis/abscess). Source control (conservative treatment, operative or non-operative interventional procedures) and its adequacy, defining the latter one as the achievement to establish the cause of cIAIs and to control the origin of peritonitis. Pre-operative antimicrobial prophylaxis or therapy (type of antimicrobial(s) administered, dosage, duration). Antimicrobial therapy performed (type of antimicrobial(s) administered, dosage, duration), specifying if empirical therapy or guided by antibiogram(s) performed. Clavien-Dindo Score [27]. Infectious post-operative complications (tertiary peritonitis, surgical site infections, pneumonia, bacteraemia, sepsis). Length of ICU stay. Length of hospital stay (LOS). In-hospital mortality. Cultures will be performed on intra-operative samples of peritoneal fluid or purulent exudate/discrete abscesses. The decision to perform cultures is according to the discretion of the providers for each patient with cIAIs. Microbiological data: Isolated microorganisms will be classified according to the joint recommendations for epidemiologic studies from the European Centre for Disease Prevention and Control, and from the Centers for Disease Control and Prevention.

Microbiological data

Microbiological results to identify Gram-negative, Gram-positive and anaerobes bacteria, and fungi will be collected. Every hospital center determined antimicrobial susceptibilities of the isolated microorganisms according to its own procedures and criteria. Breakpoint guidelines used in antimicrobial susceptibility testing by each microbiology laboratory. All the microbiology laboratory used EUCAST guidelines [28, 29]. Isolated microorganisms will be classified according to the joint recommendations for epidemiologic studies from the European Centre for Disease Prevention and Control, and from the Centers for Disease Control and Prevention [30]. In our study, MDROs will be classified as follows: E.coli producing an extended-spectrum b-lactamase (ESBLp), E.coli resistant resistant to carbapenems, K. pneumoniae ESBLp, K. pneumoniae resistant to carbapenems, K. oxytoca ESBLp, K. oxytoca resistant to carbapenems, A. baumanii resistant to carbapenems, P. aeruginosa resistant to carbapenems, Methicillin-resistant Staphylococcus aureus (MRSA), E. faecalis resistant to vancomycin, E. faecium resistant to vancomycin, Bacteroides spp. resistant to metronidazole, Clostridium spp. resistant to metronidazole and C. albicans resistant to fluconazole.

Statistical analysis

All analyses were performed using R Statistical Software (v4.1.2; R Core Team 2021). Bar graph and were obtained via the ggplot2 R package (v3.4.4; Wickham 2016). Italy Maps was obtained via the ggplot2 R package (v3.4.4; Wickham 2016), the tidyverse R package (v2.0.0; Wickham et al. 2019), rnaturalearth R package (v3.4; Massicotte and South 2023).

Results

Centre contribution

We recruited a total of 4530 patients from 23 different Italian center. Centre contribution to database is shown in Fig. 1 according to regions; the region with the highest number of patients enrolled was Lombardy, which reported almost 1444 cases (31.8%) representing the most important contributor centre to database. Emilia Romagna recruited 894 cases (19.7%), followed by Toscana (641, 14.1%) and Veneto (389, 8.6%). No cases were reported from Liguria, Val d’Aosta, Trentino Alto Adige, Calabria, Molise, Abruzzo.

Fig. 1

Geographical distribution of centre contribution to IRIS study. Italy map, geographical distribution of center contribution to database, percentage of cases for each region. All analyses were performed using R Statistical Software (v4.1.2; R Core Team 2021). Italy Maps was obtained via the ggplot2 R package (v3.4.4; Wickham 2016), the tidyverse R package (v2.0.0; Wickham et al. 2019), rnaturalearth R package (v3.4; Massicotte and South 2023)

Demographic characteristics

Demographic characteristics of participants are shown in Table 1 according to Diagnosis. Community Acquired infection represented the 70.9% of all the cases and the predominant type of infection for all the diagnosis; 98.2% of appendicitis, 93.1% of cholecystitis, 71.7% of colonic perforation and diverticulitis, 94.2% of Gastroduodenal perforations and 91.6% of small bowel occlusion were community acquired Infections. Bar graph showing the number of cases of Community acquired and Healthcare Associated infection in accordance with type of diagnosis are presented in Fig. 2.

Table 1 Demographic characteristics and physiological status at presentation according to the type of diagnosis. (Data are presented as actual number (n), mean ± Standard deviation or percentage (%) where appropriate. F: Female; M: Male; ASA; American Society of Anaesthesiologists: Type of Infection, Community acquired “CA” vs Healthcare-associated “HA”: NA: not applicable.)

Fig. 2

Number of cases of community acquired (CA) and healthcare associated (HA) intra-abdominal infection (IAI) in accordance with type of diagnosis. Bar graph: number of cases of community acquired and healthcare associated infection in accordance with type of diagnosis. All analyses were performed using R Statistical Software (v4.1.2; R Core Team 2021). Bar graphs were obtained via the ggplot2 R package (v3.4.4; Wickham 2016). A: Appendicitis; BO: Bowel Occlusion; C: Cholecystitis; CPD; Colonic perforation and diverticulitis; CAWH: Complicated Abdominal Wall Hernia; GDP: Gastro Duodenal Perforations; GE: Gynaecological Emergencies; II: Intestinal Ischemia; P: Pancreatitis; SBP: Small bowel perforation

The septic status at presentation were sepsis in 33.5% and septic shock in 27.8% of patients. In details, patients with clinical signs of septic shock were 16.2% of Colonic perforation and diverticulitis, 12.7% of gastroduodenal complications, 22.6% of small bowel perforation and 23.1% of Intestinal Ischemia (Table 1).

Microbiology

Microbiological Samples were collected from 3208 (70.8%) patients (Table 2). 3041 (67%) were intrabdominal sample; 48.8% of intraabdominal samples resulted positive. In 50.4% of samples, we found that the intra-abdominal culture was associated with a positive blood stream sample (Table 2). The major pathogens involved in intra-abdominal infections were found to be E.coli (45.6%, as shown in Table 3). Only in 2.8% of the cases were collected both blood stream and intra-abdominal samples. In 0.9% of the cases only blood stream colures. Remarkably, in 29% of the cases microbiological samples were not collected. 3 Candida Glabrata and 142 Candida Albicans isolates were identified in Intraabdominal cultures. Even more, 29 non- albicans Candida and 6 non albicans candida resistant to fluconazole were found in the intra-abdominal cultures (Table 4).

Table 2 Microbiological sample and positive cultures

Table 3 Microbiological samples & Gram – and Gram +

Table 4 Microbiological samples & fungi

Antibiotic usage

Most of the patient (93.2%) did not take antimicrobial therapy before admission to the hospital (Table 5). During hospital stay, empiric antimicrobial therapy was administered in 78.4% of patients. The kind of empiric antibiotic administered were listed in Table 6. Amoxicillin/clavulanate was the most common antibiotic used (in 30.1% appendicitis, 30% bowel occlusion, 30.5% of cholecystitis, 51% complicated abdominal wall hernia, 55% small bowel perforation) followed by piperacillin/tazobactam (13.3% colonic perforation and diverticulitis, 22.6% cholecystitis, 24.2% intestinal ischemia, 28.6% pancreatitis). Empiric antifungal therapy was administered in 2.6% of patients with no sign of sepsis, 3.1% of patients with clinical sign of sepsis and 4.1% of patients with septic shock (Table 6). Azoles was administered in 49.2% of patients that received empiric antifungal therapy (Table 7).

Table 5 Diagnosis & antibiotic therapy

Table 6 Septic status empiric antifungal therapy

Table 7 Type of empiric antifungal therapy

Outcome

The overall mortality rate was 5.13% (235/4350). Remarkably, 16.7% of small bowel perforation, 10.2% of intestinal ischemia, 9.4% of gastroduodenal perforations and 9.2% of colonic perforation and diverticulitis died. 16.5% of patients required ICU (748/4350). In accordance with mortality, it is important to highlight that 35.7% of small bowel perforation, 27.6% of colonic perforation and diverticulitis, 25.6% of intestinal ischemia and 24.6% of gastroduodenal complications required ICU.

Discussion

IAIs are a diffuse cause of surgical emergencies all around the world [31]. They may encompass different grading of severity. From a mild self-limiting infection to a severe peritonitis associated to septic shock. Management of IAI must be multidisciplinary and several specialists should be involved.

In fact, despite the still high mortality, thanks to the multidisciplinary management, short-term survival from sepsis of abdominal origin has improved in recent years [32, 33]. However, as a result, there is a growing population of IAIs survivors, that unfortunately are now progressing into chronic critical illness with poorly defined long-term outcomes [34]. In fact, these patients may experience new symptoms, long-term disability, worsening of chronic health conditions, and increased risk for death following long hospitalization in healthcare facilities [35, 36].

Timely and, whenever possible, culture driven diagnosis, adequate source control, early and appropriate antimicrobial therapy, and expeditious physiological stabilization in critically ill patients are of paramount importance. Clinical, instrumental, and laboratory investigations should be proposed according to the clinical conditions with a step-up approach [37].

A very important issue at present is represented by the necessity to introduce the antibiotic stewardship concept and its implementation toward the reduction of antibiotic usage and misuse. This would warrant better strategies aiming to preserve antimicrobials effectiveness in next the years [38,39,40]. IAIs treatment encompass various combinations of strategies aiming to control the source, initiate empirical antimicrobial therapy as soon as possible and in the most severe cases hemodynamic support. A few strategies may be posed in action to contribute to restore the physiology aiming to expand the concept of source control beyond the mere surgical control of the source of infection. The therapeutical pressure variates according to the severity of the infection, to the physiologic deranging effects and to the patients baseline conditions [41, 42].

Present study aimed to obtain a picture of IAIs in Italy and their management. Up to now it represents the biggest cohort study about the topic ever realized in Italy. Even if few regions of the country have not enrolled patients into the register IRIS study covered the most part of the country. Thousands of patients with a well-balanced case mix have been enrolled. Interesting data about bacteria epidemiology and IAIs management have been obtained.

In general, one of the most impairing biases of the IAIs registries is the unbalanced enrollment of only some IAI and the prevalence of acute appendicitis over the other diseases. In present study the different infections are well-balanced, and the data are for the most of patients complete with a very small number of missing for the analyzed variables. This gave the opportunity to have a real-life picture of the cIAIs in Italy. Table 1 represents the distribution of the different cohorts of patients and all the presenting combination of IAIs are listed. The incidence of the different diseases in the different patients can be read and the known epidemiology of the several diseases is confirmed. Some diseases are mostly represented in young population, and some are more present in older people. In general, the surgical emergencies interest the people over the 5th decades of life apart from the acute appendicitis and gynecological emergencies.

The most part of infections fall under the classification of Community acquired infections (CA). This would mean that most of the bacteria would be sensible to the most of antimicrobials and for this reason easier to be treated. As already demonstrated, however, resistant bacteria are more frequent than expected in CA infections [43, 44]. The real incidence of resistances in CA bacteria is evolving and mostly unknown. Present study gives an overview of the different species isolated from cIAIs and the idea of which are the antimicrobials prescribing attitudes in Italy.

Table 2 shows how the different way to research for bacteria in surgical patients. One third of patients didn’t experience any kind of bacteria research. In many patients an intrabdominal culture was obtained with an overall positivity of 48.8%. Whenever the intra-abdominal culture was associated to a blood stream one the positivity was 50.4%. Blood stream culture alone showed a positivity of 17.5%. This data suggests associating in patients with cIAIs the intra-abdominal culture to the bloodstream to have the best possibilities of refining the antibiotic therapy. Table 3 shows the different isolated bacteria. As previously said resistant bacteria are variously mixed with the most of them isolated from the intra-abdominal cultures. To increase the antibiotic stewardship appropriateness bacteria isolation from intra-abdominal cavity is of paramount importance, better if with the association between peritoneal and blood samples.

Fungi as well are underestimated. They are unfrequently isolated as showed in Table 4. Whenever isolated, they showed a low percentage of resistances. As for bacteria, if the peritoneal and blood cultures are associated the research is more effective in isolating fungi.

Antimicrobics and antimycotics prescription is shown in Tables 5 and 6. The great variety of prescribed antimicrobials demonstrates ad antibiotic stewardship programs are largely needed in Italy. In fact, present data showed a great number of resistant bacteria in cIAIs. Many of the treated patients come from home. The number of resistant bacteria in community acquired infections is underestimated. Dedicated studies to improve knowledges about the source of resistances deriving from community acquired infections should be implemented. Lastly, last decades of antibiotic prescriptions policies brought worldwide to the number of resistances increasing year by year. Antibiotic stewardship programs implementation needs to be mandatory worldwide.

On one hand empiric antibiotic therapy was prescribed in 78.4% of patients with a median duration ranging from 5.9 to 12.9 days. Amoxicillin/clavulanate was the most common antibiotic used (in 30.1% appendicitis, 30% bowel occlusion, 30.5% of cholecystitis, 51% complicated abdominal wall hernia, 55% small bowel perforation) followed by piperacillin/tazobactam. (13.3% colonic perforation and diverticulitis, 22.6% cholecystitis, 24.2% intestinal ischemia, 28.6% pancreatitis). In general data showed as empiric antibiotic therapy is prescribed according to the severity of the disease and to the potential pathogens involved. Lastly, quinolones are generally not prescribed, and combination of molecules are reserved to those diseases that generally may present a multi bacteria aetiology.

On the other hand, however, many patients experienced empiric antimycotics prescription even in clinical conditions that generally don’t require them. Tables 6 and 7, in fact, suggest that, in general, a more appropriate prescription of antimycotics is urgently needed. Empiric antifungal therapy was administered in 2.6% of patients with no sign of sepsis, 3.1% of patients with clinical sign of sepsis and 4.1% of patients with septic shock (Table 6). Azoles was administered in 49.2% of patients that received empiric antifungal therapy (Table 7). In fact, several patients experience the use of azoles as front-line therapy, and this may be matter of debate. Antifungal as well as antibiotic prescribing attitude should be implemented. All clinicians must be aware about the necessity to know how to properly prescribe antibacterial therapies even in absence of infectious disease specialist support, as often happens in emergency settings.

Lastly ICU admission and mortality in all cIAIs is generally in the range described from the literature and for some diseases even lower demonstrating that cIAIs are well managed and treated.

Conclusion

Complicated intra-abdominal infections in Italy are a diffuse disease. The population affected is in general over the 5th decades of life and resistant bacteria are frequently involved. Community acquired infections represent the majority of the intra-abdominal infection cases, in particular appendicitis represented the main diagnosis among CA infection. Not surprisingly, the major pathogen involved in intra-abdominal infections was found to be E.coli. empiric antimicrobial therapy was administered in 78.4% of patients. Looking at the data, antibiotic stewardship programs and correct antimicrobial and antimycotic prescription campaigns are necessary to ulteriorly improve the adequacy of drug usage and reduce the resistances burden. This will help in improving the care and the cure of the next generations.