Next Article in Journal
Identification of a Novel FLNC Truncating Variant in Fetal Tetralogy of Fallot: A Case Report and Review of the Literature
Next Article in Special Issue
Cervicofacial Actinomycosis Presenting as a Fistulized Neck Mass During Pregnancy: A Case Report
Previous Article in Journal
Correction: Lee et al. Evaluation of the PowerChek™ Respiratory Virus Panel 1/2/3/4 for the Detection of 16 Respiratory Viruses: A Comparative Study with the Allplex™ Respiratory Panel Assay 1/2/3 and BioFire® Respiratory Panel 2.1 plus. Diagnostics 2025, 15, 2713
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Diagnostics
Volume 15
Issue 24
10.3390/diagnostics15243095
diagnostics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Evolving Microbiology and Antimicrobial Resistance in Peritonitis of Biliary Origin: An Evidence-Based Update of the Tokyo Guidelines (TG18) for Clinicians

by
Elena-Adelina Toma
1,2,
Octavian Enciu
1,2,*,
Gabriela Loredana Popa
1,3,
Valentin Calu
1,2,
Dumitru Cătălin Pîrîianu
1,2,
Andrei Ludovic Poroșnicu
1,2 and
Mircea Ioan Popa
1,4
1
Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
2
Surgery Department, Elias University Emergency Hospital, 050474 Bucharest, Romania
3
Parasitic Disease Department, Colentina Clinical Hospital, 050474 Bucharest, Romania
4
The “Cantacuzino” National Medico-Military Institute for Research and Development, 050474 Bucharest, Romania
*
Author to whom correspondence should be addressed.
Diagnostics 2025, 15(24), 3095; https://doi.org/10.3390/diagnostics15243095
Submission received: 11 November 2025 / Revised: 30 November 2025 / Accepted: 3 December 2025 / Published: 5 December 2025
(This article belongs to the Special Issue Multidisciplinary Diagnostic Approaches to Infectious Pathologies in Surgical Specialties)
Review Reports Versions Notes

Abstract

Background: Biliary peritonitis is a severe intra-abdominal emergency with high mortality. Effective management requires source control and appropriate antimicrobial therapy. Methods: This review synthesizes recent literature (2016–2025), as well as established guidelines recommendations on the evolving microbiology and antimicrobial resistance patterns in biliary tract infections, as data on biliary peritonitis is scarce and relatively heterogeneous. Results: The microbiological landscape is stratified by patient history. Community-acquired infections are typically caused by Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp. In contrast, healthcare-associated infections show a shift, with highly resistant pathogens such as Pseudomonas aeruginosa, and a tendency towards polymicrobial infections. The rise of multidrug-resistant (MDR) organisms, including extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, Carbapenem-Resistant Enterobacterales (CRE), and Vancomycin-Resistant Enterococci (VRE), is a critical challenge limiting therapeutic options. Resistance patterns vary geographically, necessitating the use of local data. Conclusions: This review argues for a paradigm shift from severity-based guidelines to a dual-axis model incorporating resistance risk factors (prior healthcare exposure, previous biliary interventions, a history of MDR infections). We propose a risk-stratified approach to empiric antibiotic selection, emphasizing microbiological diagnostics for therapy de-escalation. Future research should focus on prospective studies, novel antibiotics, and rapid diagnostics.

1. Introduction

1.1. The Clinical Challenge of Biliary Peritonitis

Biliary peritonitis, the inflammation of the peritoneum resulting from the leakage of bile into the abdominal cavity, represents a surgical emergency associated with substantial morbidity (between 20% and 30%) and a distressingly high mortality rate, which can range from 8% to 50%, especially in elderly patients or those with significant comorbidities [1,2,3]. The underlying etiologies are diverse, most commonly stemming from the perforation of the gallbladder due to severe acute cholecystitis, empyema, or gangrene [4]. Other causes include iatrogenic injury during procedures like cholecystectomy or endoscopic retrograde cholangiopancreatography (ERCP), and, less frequently, spontaneous rupture of the intrahepatic or extrahepatic biliary tree [4,5]. Such ruptures are often precipitated by elevated intraductal pressure from obstructing calculi or strictures [6,7].
The condition rapidly progresses to bacterial peritonitis as microorganisms from the infected biliary system contaminate the peritoneal space. This secondary bacterial infection is the principal driver of sepsis, systemic inflammatory response syndrome (SIRS), and adverse patient outcomes [5,8]. Compounding this issue, bile itself has been demonstrated to impair local host defense mechanisms, thereby creating a more permissive environment for bacterial proliferation and exacerbating the infectious process [9].

1.2. The Intersection of Pathophysiology and Microbiology

The clinical progression from a localized biliary tract infection (BTI), such as acute cholecystitis or cholangitis, to diffuse biliary peritonitis represents a pathological continuum [10]. Consequently, the microorganisms responsible for the initial BTI are the very same pathogens that seed the peritoneal cavity upon perforation or leakage [11]. This direct link makes a thorough understanding of the microbiology of cholecystitis and cholangitis fundamental to the effective management of biliary peritonitis. The pathophysiology is rooted in biliary stasis and obstruction, which disrupts the normal antegrade flow of bile and allows for the retrograde ascension of enteric microorganisms from the duodenum [12]. As intraductal pressure rises behind the obstruction, it not only compromises the integrity of the biliary epithelium but also facilitates the translocation of bacteria and their toxins into the systemic circulation and, in the event of rupture, into the peritoneal cavity [2,6,12].
This review operates on the principle that while “biliary peritonitis” is a clinical diagnosis describing a final common pathway, its microbiology is not a distinct entity. Instead, it is a direct reflection of its precursor conditions. The presence of bile salts in the peritoneum causes significant chemical peritonitis, which may impair local defenses and alter membrane permeability differently than in the biliary ducts. Furthermore, the bacterial load in perforation peritonitis is typically higher, and the polymicrobial nature of the infection may be more pronounced due to the sudden release of stagnant, infected bile into a large sterile cavity. Consequently, the pathogen spectrum and resistance behaviors observed in non-perforating BTIs may not be directly applicable to perforation-related peritonitis. Specifically, anaerobic co-infection may be more clinically relevant in peritonitis because of the hypoxic environment within an abscess or collection [12]. The relative scarcity of studies focusing exclusively on the microbiology of biliary peritonitis necessitates logical, evidence-based extrapolation from the far richer body of literature on the microbiology of acute cholecystitis and cholangitis. Still, findings should be interpreted with this distinction in mind. This approach is a limitation but can also be regarded as a necessary methodology for constructing a clinically useful tool.

1.3. The Rising Tide of Antimicrobial Resistance

The successful management of biliary peritonitis rests on two interdependent pillars: timely and adequate source control—achieved through surgical debridement, drainage, or percutaneous intervention—and the administration of appropriate antimicrobial therapy [13]. The latter is crucial for controlling sepsis and preventing further complications. However, the efficacy of empiric antibiotic regimens is increasingly jeopardized by the global crisis of antimicrobial resistance (AMR) [14]. Multiple studies have now established that the administration of inadequate initial antibiotic therapy in patients with severe biliary infections is an independent predictor of increased mortality [8,15].
The high mortality associated with biliary peritonitis can be conceptualized as a result of a synergistic, two-sided process. The first aspect is the chemical toxicity of bile, which causes direct tissue damage and, critically, impairs the peritoneum’s local immune defenses [9]. The second attack wave is the subsequent high-inoculum bacterial challenge from the contaminated bile. This combination, in which the host’s innate ability to contain the infection is already compromised, creates an ideal scenario for the development of fulminant sepsis. This dynamic underscores the importance of selecting an appropriate and effective empirical antibiotic from the outset, as the therapeutic window is narrow and the patient’s defenses are weakened.

2. Methodology

2.1. Study Design and Search Strategy

To ensure a comprehensive synthesis of current evidence, a structured literature search was conducted using the electronic databases PubMed/MEDLINE, Embase, Web of Science, Scopus, and Google Scholar. The search targeted articles published between 1 January 2016, and 31 December 2024. This search was extended to include articles published between 2004 and 2015, considering the scarcity of data regarding biliary peritonitis as a distinct entity. The primary search strategy employed combinations of the following Medical Subject Headings (MeSH) and keywords: “biliary peritonitis,” “acute cholangitis,” “acute cholecystitis,” “bile culture,” “antimicrobial resistance,” “multidrug resistance,” “ESBL,” “CRE,” and “VRE”.

2.2. Selection Criteria

The review prioritized peer-reviewed original research articles involving human subjects but also included case reports and limited case series, given the low number of articles specifically addressing biliary peritonitis. Inclusion criteria required that studies provide specific data on microbiological isolates from bile or peritoneal fluid and/or detailed antibiograms. Studies focusing exclusively on pediatric populations or animal models were excluded to maximize the generalizability of findings to adult clinical practice. Articles not available in English were also excluded.

2.3. Data Synthesis and Bias Minimization

Retrieved records were screened for relevance by title and abstract. Selected full-text articles were analyzed to extract data regarding pathogen frequency, resistance phenotypes, and genetic resistance mechanisms. Given the scarcity of studies specifically titled “biliary peritonitis,” data were stratified where possible between localized biliary infections (cholecystitis/cholangitis) and those complicated by perforation or bacteremia to infer trends relevant to peritonitis. To minimize selection bias, studies from diverse geographic regions (Europe, Asia, North America) were included to reflect global variations in resistance patterns.

3. The Microbiological Landscape of Biliary Tract Infections

The spectrum of pathogens causing BTIs, and by extension biliary peritonitis, is not uniform. It is heavily stratified by the patient’s clinical background, particularly the distinction between community-acquired infections and those associated with healthcare exposure or prior interventions.

3.1. The Classic Pathogens in Community-Acquired Biliary Infections

In patients presenting from the community without a recent history of hospitalization or biliary procedures, the responsible pathogens are typically enteric organisms originating from the gastrointestinal tract [16]. Gram-negative bacilli from the Enterobacteriaceae family (Order Enterobacterales) have historically been, and remain, the predominant isolates, identified in up to 70% of infections [17,18,19,20,21]. Escherichia coli is consistently identified as the most frequent pathogen. Numerous studies report its isolation in 25–40% of positive bile and blood cultures from patients with acute cholangitis or cholecystitis. Klebsiella pneumoniae is reliably the second most common Gram-negative organism, with a reported prevalence of 15% to 20% across various studies [22,23,24].
Gram-positive cocci, particularly Enterococcus species, are also key pathogens. Once considered by some to be mere colonizers, their pathogenic role is now firmly established, especially in more severe or complicated infections [22,25].
Other, less common but clinically significant isolates in community-acquired BTIs include Streptococcus spp., Enterobacter spp., Citrobacter freundii, Bacteroides fragilis, or Clostridioides spp. [22].

3.2. The Microbial Shift in Healthcare-Associated and Post-Intervention Settings

One of the most critical findings in the recent literature is the dramatic and predictable shift in the microbial flora of patients with healthcare-associated infections (HCAI) or a history of biliary system manipulation. Procedures such as ERCP with sphincterotomy, biliary stent placement, or prior cholecystectomy fundamentally alter the biliary environment, selecting for a different, more resistant cohort of pathogens [25,26].
This microbial evolution is not merely a change in species but reflects a fundamental alteration of the biliary resistome. Interventions like stenting introduce a foreign body that serves as a nidus for biofilm formation, an environment that favors intrinsically more resilient organisms [27]. Subsequent courses of antibiotics then exert powerful selective pressure, eliminating susceptible community flora (such as sensitive E. coli) and allowing these more resistant, biofilm-associated organisms to flourish. This process creates a dangerous cycle in which each medical interaction can enrich the biliary system with increasingly challenging bacteria.
In these high-risk patients, there is a significantly higher prevalence of:
•
Pseudomonas aeruginosa: While uncommon in community-acquired BTIs, its prevalence can surge to over 21% in post-cholecystectomy or post-ERCP patients, compared to less than 10% in those without such a history [24,28]. Admission to an intensive care unit (ICU) is another strong risk factor for isolation [29].
•
Enterococcus spp.: The frequency of enterococcal isolation increases markedly in patients with prior interventions. Studies have documented a prevalence of 32.4% in post-cholecystectomy patients and as high as 43.6% in patients with indwelling biliary stents [26,30]. The presence of a biliary drain and the total number of prior interventions are powerful predictors of enterococcal infection.
•
Other Enterobacterales (Klebsiella aerogenes, Serratia marcescens, Citrobacter freundii complex, Providencia spp., Morganella morganii): These organisms also show a significantly higher prevalence in patients with a history of cholecystectomy compared to those without previous biliary tract interventions [26,28,30] and are more common in those with biliary reconstructions [31].
Furthermore, polymicrobial infections are far more common in these settings, with some studies reporting that up to 78% of bile cultures grow multiple organisms, particularly in patients with indwelling devices, and that patients with cholangitis have multiple pathogens identified in bile cultures than those with acute cholecystitis [27,29,32]. One study reported that E. coli and E. faecium were most commonly found in mixed BTI, and these two types of bacteria also showed higher individual rates of AMR [20]. Over 10% of patients had three pathogens identified in their bile cultures, and in 2.39% of cases, four simultaneous bacterial infections were reported. The same study reported a two-fold increase in the proportion of polymicrobial BTI over five years, from 23.08% to 45.67%. Another study reported up to nine distinct microorganisms (including both bacteria and fungi) in one bile culture, with more than half of patients with polymicrobial BTI also having positive blood cultures with at least one bacterial strain present [29]. These findings underline the need for a more aggressive initial treatment in cases where post-interventional infections are likely, including supportive measures even in the absence of clinically evident organ dysfunction. Moreover, microbiological testing of explanted stents could provide important information regarding the current polymicrobial landscape, as multiple pathogens are often involved in biliary stent colonization in patients without cholangitis symptoms [33].

3.3. The Role of Anaerobic and Fungal Infections

Anaerobic bacteria, such as Bacteroides and Clostridium spp., are reported in less than 10% of BTI cases [32,34]. Their presence is particularly suspected in patients with hepatic abscesses, peritonitis, or a history of bilioenteric anastomosis (e.g., choledochojejunostomy), which allows for direct contamination by colonic flora [22,34].
Fungal pathogens, predominantly Candida spp., are isolated in less than 5% of community-acquired infections, while some series report a prevalence as high as 55% in patients with previous interventions [21,33,35,36]. Fungal biliary infection is often associated with specific risk factors, including prolonged or broad-spectrum antibiotic therapy, the presence of indwelling biliary stents, and underlying immunosuppression [33,35].

3.4. Etiology-Specific Microbiological Variations: Malignant Versus Benign Obstruction

Current evidence is inconclusive regarding distinct microbiological differences between patients with malignant biliary obstruction (MBO) and those with benign causes, such as choledocholithiasis (stones in the common bile duct or gallbladder). In almost half of patients with biliary tract obstruction, regardless of etiology, infection is present, with no association between type of obstruction and specific pathogens, except for one positive significant correlation between E. coli and gallstones, as reported by a single-center study [23]. While E. coli and Klebsiella spp. remain the most common isolates in both groups, pathogens involved in malignant obstruction may exhibit more resistance to cephalosporines or carbapenems in some cohorts [37]. The etiology of biliary tract obstruction is not a certain predictor of AMR, as reported by another study analyzing 568 patients with acute cholangitis [38]. However, malignant obstruction is reportedly a risk factor for higher mortality rates in patients with acute cholangitis [39].

4. Evolving Patterns of Antimicrobial Resistance

The selection of an effective empiric antibiotic regimen is complicated not just by the shifting spectrum of pathogens but, more critically, by the escalating rates of antimicrobial resistance among them. This trend threatens the efficacy of nearly all classes of antibiotics used to treat intra-abdominal infections.

4.1. The Proliferation of Extended-Spectrum β-Lactamase (ESBL)-Producing Enterobacteriaceae

Extended-spectrum β-lactamases (ESBLs) are enzymes, most commonly found in E. coli and K. pneumoniae, that hydrolyze and confer resistance to most penicillin and cephalosporin antibiotics, including third- and fourth-generation agents (e.g., ceftriaxone, cefepime) [40]. This renders many first-line empiric therapies for BTIs completely ineffective.
The global prevalence of ESBL-producing bacteria is increasing at an alarming rate in both community and healthcare settings [41,42]. A meta-analysis showed the global intestinal carriage rate in a community setting has increased eight times from the rates observed between 2003–2005 and those reported 2015–2018, while key risk factors for infection with an ESBL-producing organism include prior use of antibiotics (especially cephalosporins and fluoroquinolones), recent hospitalization, and residence in a long-term care facility [40,43]. In the context of biliary infections, the prevalence of ESBL-producing organisms exceeds 23% and increases the risk of cholangitis in patients with biliary obstruction, as concluded by a 2024 study [44]. Another investigation identified an ESBL prevalence of 13.9% in patients with both a prior sphincterotomy and an indwelling stent [33]. The most frequently identified ESBL resistance genes are usually blaCTX-M and blaTEM in E. coli, and blaTEM and blaSHV for Klebsiella spp. [44].

4.2. The Emergent Threat of Carbapenem-Resistant Gram-Negative Pathogens

Carbapenem antibiotics, such as meropenem and imipenem, have long served as the last line of defense against severe infections caused by ESBL-producing organisms. Consequently, the emergence and spread of Carbapenem-Resistant Enterobacterales (CRE) represents a grave public health crisis, leaving clinicians with few, if any, effective treatment options [45,46].
While still less common than ESBLs, the prevalence of CRE in biliary infections is rising and warrants significant concern. Recent studies have reported CRE rates ranging from 2.1% to 6.9% in cohorts of patients with cholangitis [44,47]. As with other forms of resistance, the prevalence is significantly higher in patients with a history of biliary stenting, patients with cancer, those with chronic kidney disease, and recent antibiotic treatment [31,47]. Klebsiella pneumoniae is the most frequently implicated CRE species in these infections, with the Klebsiella pneumoniae carbapenemase (KPC) enzyme being a predominant mechanism of resistance.
In recent years, carbapenem-resistant Acinetobacter baumannii has been identified in an increased number of cases, especially in patients who were immunocompromised and required ICU hospitalization. It showed an increased tendency towards multidrug resistance, with over half of the identified strains being carbapenem-resistant, carrying the blaOXA-23 gene, and requiring treatment with Colistin for effective management [48,49]. However, Colistin-resistant strains of Acinetobacter baumannii have been reported in recent years, through gene mutations or gene transfer, which has underlined the need for future development of new treatment strategies [50].
Pseudomonas aeruginosa exhibiting resistance to carbapenems has also been reported in BTI patients with severe concomitant acute pancreatitis, with drug resistance rates increasing over the last decade and currently reported at over 60% of cases [49,51].

4.3. Resistance in Gram-Positive Pathogens: The Case of Vancomycin-Resistant Enterococci (VRE)

Enterococcus species possess a high degree of both intrinsic and acquired antibiotic resistance. A baseline level of resistance is common, with at least one-third of enterococcal isolates from biliary cultures demonstrating resistance to ampicillin, a historically active agent [21].
The primary concern, however, is Vancomycin-Resistant Enterococci (VRE) infections, which have emerged in recent years in patients with acute cholecystitis and/or cholangitis, infections that are particularly problematic in healthcare-associated settings [52]. In patients with BTIs, antibiotic resistance is most often found in Enterococcus faecium and Enterococcus faecalis, but VRE prevalence can reach almost 90% in certain isolates, such as Enterococcus casselifavus [21,36]. VRE strains are rarely encountered in acute cholecystitis patients but have been reported in up to 15% of blood cultures from patients undergoing ERCP after cholecystectomy [28,38,53,54]. A known history of VRE colonization is a significant risk factor for isolating VRE from bile during an acute infection, as are previous invasive procedures, recent antibiotic use, and immunosuppressive therapies, highlighting the importance of reviewing a patient’s past microbiology data [28,55].
Table 1 presents these complex resistance phenotypes in their direct clinical implications, providing a concise reference for clinicians.

5. Implications for Antimicrobial Stewardship and Clinical Practice

The evolving microbiological and resistance landscape demands a more nuanced and risk-stratified approach to the management of biliary peritonitis and its precursor infections. A “one-size-fits-all” strategy is no longer viable.

5.1. Risk Stratification—The Key to Empiric Therapy

The initial choice of empiric antibiotic therapy should not be based solely on the clinical severity of the presentation. Timely antimicrobial intervention is paramount, because for each 30 min delay in delivering antibiotics, increased mortality by an odds ratio of 1.02, as reported by a prospective study of 356 patients [58].
The rapid but thorough risk assessment for the presence of MDR organisms should be a routine part of the initial patient evaluation. Key risk factors that should prompt consideration of broader-spectrum empiric coverage include [29,36,49]:
•
Healthcare-Associated Infection: Recent hospitalization (within 90 days), residence in a long-term care facility, or receiving outpatient healthcare (e.g., dialysis).
•
Prior Biliary Interventions: A history of cholecystectomy, ERCP (especially with sphincterotomy), or the presence of an indwelling biliary stent or drainage catheter.
•
Recent Antibiotic Use: Exposure to any antibiotic within the preceding 90 days, with particular concern for third-generation cephalosporins and fluoroquinolones.
•
Known Colonization with MDR Organisms: A documented history of colonization or infection with MRSA, VRE, ESBL-producing organisms, or CRE.
•
High Comorbidity Burden: A high Charlson Comorbidity Index (e.g., ≥5) has been associated with more resistant pathogens.
•
Critical Illness: Admission to an ICU setting.

5.2. Applying and Adapting Clinical Practice Guidelines

International guidelines, most notably the Tokyo Guidelines (TG18), provide an essential framework for management, but must be applied with flexibility and adapted to local resistance realities [11,59].
-
For Low-Risk Patients: In a patient presenting from the community with no identified risk factors for MDR organisms, a narrower-spectrum agent may still be appropriate for mild-to-moderate disease. Options with good biliary penetration and safety profiles include a penicillin/β-lactamase inhibitor (usually ampicillin–sulbactam) or a third-generation cephalosporin (especially ceftriaxone, as it exhibits increased levels of biliary excretion) in association with metronidazole in selected cases [60,61]. Fluoroquinolone-based therapy remains an option for patients with known allergies to other antibiotic classes, in association with metronidazole, but with limited efficacy in areas where E. coli has over 30% resistance rates in the community [59,61,62].
-
For High-Risk Patients: In any patient with one or more risk factors for MDR pathogens, broader empiric coverage is mandatory, regardless of the initial clinical severity. Piperacillin–tazobactam has traditionally been the workhorse in this scenario, but with resistance rates of Enterobacteriaceae now exceeding 20%, as well as high resistance rates of Acinetobacter spp. and Pseudomonas spp. in some high-risk populations, its reliability as a single agent is diminishing [63,64]. Cefmetazole has been suggested as an effective alternative for patients with ESBL-producing bacteria, with very good results [56,65]. Patients with severe disease or those with a very high suspicion of an ESBL or CRE infection (known CRE carrier, recent carbapenem use), initial empiric therapy with a carbapenem is warranted pending culture results, but physicians should be aware that meropenem has poorer biliary penetration in obstruction cases, compared to imipenem/cilastatin [59,61,66]. Critically ill patients at risk for Candida spp. infection warrants the addition of an antifungal drug, such as fluconazole or echinocandin [11].
The duration of antimicrobial treatments also needs to be adapted to each case, as a key tenet of antimicrobial stewardship is using the shortest effective duration of therapy and modulation of treatment length through close monitoring of C-reactive protein and procalcitonin [67]. A growing body of evidence suggests that for patients with adequately source-controlled biliary infections, shorter courses of antibiotics (3–7 days) are non-inferior to longer courses, and prompt surgical intervention may warrant discontinuation of antibiotherapy after source control, with good outcomes [68,69,70,71]. This practice is crucial for reducing selective pressure, minimizing side effects, and lowering healthcare costs, but close monitoring of outcomes is advisable, as these results of shorter-course therapies have been reported for patients with acute cholangitis or cholecystitis, and not for biliary peritonitis patients [66,70]. According to a review published in 2025 by Sartelli et al., for the Global Alliance for Infections in Surgery, the analysis of multiple trials and randomized controlled trials yielded the same results: in patients with adequate source control, a short course of antibiotics (four days) for patients with mild to moderate disease, while critically ill patients benefit from antimicrobial therapy lasting 7 to 8 days, with no improvement in any outcomes following prolonged therapy [72].

5.3. The Critical Role of Microbiological Diagnostics

In an era of rampant resistance, microbiological diagnostics are not an academic exercise; they are a cornerstone of effective and responsible antibiotic use. Obtaining bile and/or blood cultures as soon as possible in all patients with moderate-to-severe BTIs is strongly recommended [13,59]. The primary purpose of these cultures is to facilitate timely de-escalation of therapy or adapt the antimicrobial regimen to individual needs based on resistance profiles. Once a pathogen is identified and its susceptibilities are known, broad-spectrum empiric agents should be narrowed to the most effective, safest, and narrowest-spectrum drug possible [11,32]. This practice preserves broad-spectrum agents for when they are truly needed and minimizes the collateral damage to the patient’s microbiome. While blood cultures have lower sensitivity, a positive result is precise and clinically significant. Bile cultures have a higher diagnostic yield but may sometimes represent colonization rather than true infection, especially in patients with long-term stents [28,62]. Moreover, bile cultures may be positive even in patients who have already received antibiotic therapy and may help select patients for whom antifungal treatment is needed [24]. The concordance between bile and blood cultures is only partial, at less than 40%, and thus both should be collected when feasible [73].

5.4. Carbapenem-Sparing Strategies and Future Horizons

The preservation of carbapenems is a global public health priority. Strategies to avoid their overuse are vital. In high-risk patients with suspected resistant Gram-negative infections, newer β-lactam/β-lactamase inhibitor combinations, such as ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, or meropenem-vaborbactam, as well as new-generation cephalosporines such as cefiderocol, may have a role in treating confirmed ESBL-producing Enterobacteriaceae and certain CRE infections [74,75]. However, clinical data specifically for their use in biliary infections are still limited, and their use should be guided by infectious disease consultation.
The future of BTI management will likely involve the integration of rapid molecular diagnostics. Technologies such as multiplex PCR-based identification can indicate specific pathogens with high sensitivity and specificity, detect specific resistance genes (e.g., blaKPC, blaNDM, blaCTX-M) directly from bile or blood samples within hours rather than days, and could revolutionize empiric therapy, allowing for highly targeted treatment from the outset [76].
Table 2 synthesizes this review into an actionable clinical tool, providing risk-stratified empiric antibiotic recommendations.

6. Conclusions and Future Directions

6.1. Synthesis of Key Findings

Biliary peritonitis is a life-threatening sequela of common biliary diseases, and its management is increasingly complicated by antimicrobial resistance. This review of recent literature highlights several critical conclusions. First, the microbiology of biliary peritonitis is a direct extension of the primary BTI, and it is profoundly stratified by patient history. The traditional paradigm of community-acquired enteric Gram-negative pathogens is being supplanted in an increasing proportion of patients by a more complex, resistant flora characteristic of healthcare-associated infections, dominated by organisms like Pseudomonas aeruginosa, Enterococcus spp., and MDR bacteria. Second, resistance to nearly all classes of workhorse antibiotics—including third-generation cephalosporins, fluoroquinolones, and even piperacillin–tazobactam—is high and continues to increase globally. Third, the emergence of ESBL-producing Enterobacteriaceae as common pathogens and the rising threat of CRE and VRE in biliary infections pose a profound therapeutic challenge that demands a fundamental shift in clinical strategy. Empiric treatment based on clinical severity alone is no longer sufficient; it must be integrated with a robust assessment of a patient’s risk of harboring a resistant organism.

6.2. Identified Gaps in Current Knowledge

Despite the wealth of data on BTIs, several significant knowledge gaps remain, particularly concerning biliary peritonitis. There is a notable lack of prospective, multicenter studies that specifically analyze the microbiology, antimicrobial resistance patterns, and clinical outcomes of biliary peritonitis as a distinct clinical entity. Most current knowledge is extrapolated from studies on cholangitis and cholecystitis. The clinical impact and optimal management of fungal biliary infections, particularly those caused by Candida species, are not well defined. Moreover, while newer antibiotic agents with activity against MDR organisms (e.g., novel β-lactam/β-lactamase inhibitor combinations) are available, their efficacy, safety, and optimal place in the treatment of severe, resistant biliary infections require evaluation in dedicated clinical trials.

Author Contributions

Conceptualisation, E.-A.T., O.E., V.C. and G.L.P.; methodology, A.L.P. and E.-A.T.; software, A.L.P. and D.C.P.; validation, O.E., G.L.P. and V.C.; formal analysis, E.-A.T. and A.L.P.; data curation, O.E. and D.C.P.; writing—original draft preparation, E.-A.T.; writing—review and editing, E.-A.T., O.E. and M.I.P.; visualisation, G.L.P.; supervision, V.C. and M.I.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AMRAntimicrobial Resistance
BTIBiliary Tract Infection
CRECarbapenem-Resistant Enterobacteriaceae
ERCPEndoscopic Retrograde Cholangiopancreatography
ESBLExtended-Spectrum β-Lactamase
HCAIHealthcare-Associated Infection
ICUIntensive Care Unit
KPCKlebsiella pneumoniae Carbapenemase
MDRMultidrug-Resistant
SIRSSystemic Inflammatory Response Syndrome
TG18Tokyo Guidelines 2018
VREVancomycin-Resistant Enterococci

References

  1. Borghese, M.; Caramanico, L.; Anelli, L.; De Cesare, A.; Farrocco, G.; Spallone, G. Etiopathogenetic and physiopathological considerations on biliary peritonitis. Minerva Med. 1986, 77, 735–738. [Google Scholar] [PubMed]
  2. Lochan, R.; Joypaul, B.V. Bile peritonitis due to intra-hepatic bile duct rupture. World J. Gastroenterol. 2005, 11, 6728–6729. [Google Scholar] [CrossRef]
  3. Gabriele, R.; Bolognese, A.; De Toma, G.; Impara, L.; Conte, M.; Di Cello, P.; Forcione, A.R.; Izzo, P.; Nicolanti, V.; Pugliese, F.; et al. Analysis of variables predictive of severity in biliary peritonitis. Ann. Ital. Chir. 2012, 83, 445–449. [Google Scholar]
  4. Moriwaki, Y.; Sugiyama, M.; Mochizuki, Y.; Yamazaki, Y.; Suda, T.; Hasegawa, S.; Matsuda, G.; Karube, N.; Uchida, K.; Yamamoto, T. A pitfall of the diagnostic process of differentiating bile peritonitis from acute appendicitis. Hepatogastroenterology 2004, 51, 353–356. [Google Scholar]
  5. Gupta, V.; Chandra, A.; Gupta, V.; Patel, R.; Dangi, A.; Pai, A. Gallbladder perforation: A single-center experience in north India and a step-up approach for management. Hepatobiliary Pancreat. Dis. Int. 2022, 21, 168–174. [Google Scholar] [CrossRef]
  6. Hamura, R.; Haruki, K.; Tsutsumi, J.; Takayama, S.; Shiba, H.; Yanaga, K. Spontaneous biliary peritonitis with common bile duct stones: Report of a case. Surg. Case Rep. 2016, 2, 103. [Google Scholar] [CrossRef]
  7. Upadhyaya, V.D.; Kumar, B.; Singh, M.; Rudramani; Jaiswal, S.; Lal, R.; Gambhir, S.; Rohan, M. Spontaneous biliary peritonitis: Is bed side diagnosis possible? Afr. J. Paediatr. Surg. 2013, 10, 112–116. [Google Scholar] [CrossRef] [PubMed]
  8. Date, R.S.; Thrumurthy, S.G.; Whiteside, S.; Umer, M.A.; Pursnani, K.G.; Ward, J.B.; Mughal, M.M. Gallbladder perforation: Case series and systematic review. Int. J. Surg. 2012, 10, 63–68. [Google Scholar] [CrossRef]
  9. Sistrunk, J.R.; Nickerson, K.P.; Chanin, R.B.; Rasko, D.A.; Faherty, C.S. Survival of the Fittest: How Bacterial Pathogens Utilize Bile To Enhance Infection. Clin. Microbiol. Rev. 2016, 29, 819–836. [Google Scholar] [CrossRef]
  10. Stefanidis, D.; Sirinek, K.R.; Bingener, J. Gallbladder perforation: Risk factors and outcome. J. Surg. Res. 2006, 131, 204–208. [Google Scholar] [CrossRef] [PubMed]
  11. Fico, V.; La Greca, A.; Tropeano, G.; Di Grezia, M.; Chiarello, M.M.; Brisinda, G.; Sganga, G. Updates on Antibiotic Regimens in Acute Cholecystitis. Medicina 2024, 60, 1040. [Google Scholar] [CrossRef] [PubMed]
  12. Geier, A.; Fickert, P.; Trauner, M. Mechanisms of disease: Mechanisms and clinical implications of cholestasis in sepsis. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006, 3, 574–585. [Google Scholar] [CrossRef]
  13. Sartelli, M.; Chichom-Mefire, A.; Labricciosa, F.M.; Hardcastle, T.; Abu-Zidan, F.M.; Adesunkanmi, A.K.; Ansaloni, L.; Bala, M.; Balogh, Z.J.; Beltran, M.A.; et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J. Emerg. Surg. 2017, 12, 29. [Google Scholar] [CrossRef] [PubMed]
  14. Huston, J.M.; Barie, P.S.; Dellinger, E.P.; Forrester, J.D.; Duane, T.M.; Tessier, J.M.; Sawyer, R.G.; Cainzos, M.A.; Rasa, K.; Chipman, J.G.; et al. The Surgical Infection Society Guidelines on the Management of Intra-Abdominal Infection: 2024 Update. Surg. Infect. 2024, 25, 419–435. [Google Scholar] [CrossRef]
  15. de Miguel-Palacio, M.; Gonzalez-Castillo, A.M.; Membrilla-Fernandez, E.; Pons-Fragero, M.J.; Pelegrina-Manzano, A.; Grande-Posa, L.; Morera-Casaponsa, R.; Sancho-Insenser, J.J. Impact of empiric antibiotic therapy on the clinical outcome of acute calculous cholecystitis. Langenbecks Arch. Surg. 2023, 408, 345. [Google Scholar] [CrossRef]
  16. Zhao, J.; Wang, B.; Zhao, M.; Pan, X. Clinical and biochemical factors for bacteria in bile among patients with acute cholangitis. Eur. J. Gastroenterol. Hepatol. 2025, 37, 33–38. [Google Scholar] [CrossRef]
  17. Salvador, V.B.; Lozada, M.C.; Consunji, R.J. Microbiology and antibiotic susceptibility of organisms in bile cultures from patients with and without cholangitis at an Asian academic medical center. Surg. Infect. 2011, 12, 105–111. [Google Scholar] [CrossRef] [PubMed]
  18. Cozma, M.A.; Gaman, M.A.; Diaconu, C.C.; Berger, A.; Zerbib, F.; Mateescu, R.B. Microbial Profile and Antibiotic Resistance Patterns in Bile Aspirates from Patients with Acute Cholangitis: A Multicenter International Study. Antibiotics 2025, 14, 679. [Google Scholar] [CrossRef]
  19. Zhao, C.; Liu, S.; Bai, X.; Song, J.; Fan, Q.; Chen, J. A Retrospective Study on Bile Culture and Antibiotic Susceptibility Patterns of Patients with Biliary Tract Infections. Evid. Based Complement. Altern. Med. 2022, 2022, 9255444. [Google Scholar] [CrossRef]
  20. Zhang, H.; Cong, Y.; Cao, L.; Xue, K.; Qi, P.; Mao, Q.; Xie, C.; Meng, Y.; Cao, B. Variability of bile bacterial profiles and drug resistance in patients with choledocholithiasis combined with biliary tract infection: A retrospective study. Gastroenterol. Rep. 2024, 12, goae010. [Google Scholar] [CrossRef]
  21. Liu, T.; Li, M.; Tang, L.; Wang, B.; Li, T.; Huang, Y.; Xu, Y.; Li, Y. Epidemiological, clinical and microbiological characteristics of patients with biliary tract diseases with positive bile culture in a tertiary hospital. BMC Infect. Dis. 2024, 24, 1010. [Google Scholar] [CrossRef]
  22. Gomi, H.; Takada, T.; Hwang, T.L.; Akazawa, K.; Mori, R.; Endo, I.; Miura, F.; Kiriyama, S.; Matsunaga, N.; Itoi, T.; et al. Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis. J. Hepatobiliary Pancreat. Sci. 2017, 24, 310–318. [Google Scholar] [CrossRef]
  23. Tajeddin, E.; Sherafat, S.J.; Majidi, M.R.; Alebouyeh, M.; Alizadeh, A.H.; Zali, M.R. Association of diverse bacterial communities in human bile samples with biliary tract disorders: A survey using culture and polymerase chain reaction-denaturing gradient gel electrophoresis methods. Eur. J. Clin. Microbiol. Infect. Dis. 2016, 35, 1331–1339. [Google Scholar] [CrossRef]
  24. Weigand, S.; Kandulski, A.; Zuber-Jerger, I.; Scherer, M.; Werner, J.; Bornschein, J.; Weigand, K. The Presence and Significance of Bacteria and Fungi in Bile Aspirated During ERC-A Retrospective Analysis. Biomedicines 2025, 13, 1255. [Google Scholar] [CrossRef]
  25. Mussa, M.; Martinez Perez-Crespo, P.M.; Lopez-Cortes, L.E.; Retamar-Gentil, P.; Sousa-Dominguez, A.; Goikoetxea-Aguirre, A.J.; Reguera-Iglesias, J.M.; Leon Jimenez, E.; Fernandez-Natal, I.; Arminanzas-Castillo, C.; et al. Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: A Multicenter Cohort Study from the PROBAC Project. Microbiol. Spectr. 2022, 10, e0005122. [Google Scholar] [CrossRef]
  26. Miutescu, B.; Vuletici, D.; Burciu, C.; Bende, F.; Ratiu, I.; Moga, T.; Gadour, E.; Bratosin, F.; Tummala, D.; Sandru, V.; et al. Comparative Analysis of Antibiotic Resistance in Acute Cholangitis Patients with Stent Placement and Sphincterotomy Interventions. Life 2023, 13, 2205. [Google Scholar] [CrossRef] [PubMed]
  27. Vaishnavi, C.; Samanta, J.; Kochhar, R. Characterization of biofilms in biliary stents and potential factors involved in occlusion. World J. Gastroenterol. 2018, 24, 112–123. [Google Scholar] [CrossRef]
  28. Gromski, M.A.; Gutta, A.; Lehman, G.A.; Tong, Y.; Fogel, E.L.; Watkins, J.L.; Easler, J.J.; Bick, B.L.; McHenry, L.; Beeler, C.; et al. Microbiology of bile aspirates obtained at ERCP in patients with suspected acute cholangitis. Endoscopy 2022, 54, 1045–1052. [Google Scholar] [CrossRef] [PubMed]
  29. Reuken, P.A.; Torres, D.; Baier, M.; Loffler, B.; Lubbert, C.; Lippmann, N.; Stallmach, A.; Bruns, T. Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis. PLoS ONE 2017, 12, e0169900. [Google Scholar] [CrossRef]
  30. Miutescu, B.; Vuletici, D.; Burciu, C.; Bende, F.; Ratiu, I.; Moga, T.; Gadour, E.; Reddy, S.; Sandru, V.; Balan, G.; et al. Comparative Analysis of Microbial Species and Multidrug Resistance Patterns in Acute Cholangitis Patients with Cholecystectomy: A Single-Center Study. Diseases 2024, 12, 19. [Google Scholar] [CrossRef]
  31. Kuhara, Y.; Kitagawa, H.; Kaiki, Y.; Omori, K.; Shigemoto, N.; Akita, T.; Uemura, K.; Fukuma, S.; Takahashi, S.; Ohge, H. Microbiological Characteristics of Pathogens Isolated From Blood Cultures of Patients With Acute Cholangitis: Insights From Patients With Biliary-Enteric Anastomosis. J. Hepatobiliary Pancreat. Sci. 2025, 32, 766–776. [Google Scholar] [CrossRef]
  32. Gassiep, I.; Edwards, F.; Laupland, K.B. Epidemiology of biliary tract-associated bloodstream infections and adequacy of empiric therapy: An Australian population-based study. Eur. J. Clin. Microbiol. Infect. Dis. 2024, 43, 1753–1760. [Google Scholar] [CrossRef]
  33. Lubbert, C.; Wendt, K.; Feisthammel, J.; Moter, A.; Lippmann, N.; Busch, T.; Mossner, J.; Hoffmeister, A.; Rodloff, A.C. Epidemiology and Resistance Patterns of Bacterial and Fungal Colonization of Biliary Plastic Stents: A Prospective Cohort Study. PLoS ONE 2016, 11, e0155479. [Google Scholar] [CrossRef]
  34. Strohaker, J.; Wiegand, L.; Beltzer, C.; Konigsrainer, A.; Ladurner, R.; Meier, A. Clinical Presentation and Incidence of Anaerobic Bacteria in Surgically Treated Biliary Tract Infections and Cholecystitis. Antibiotics 2021, 10, 71. [Google Scholar] [CrossRef]
  35. Tridente, A.; Clarke, G.M.; Walden, A.; McKechnie, S.; Hutton, P.; Mills, G.H.; Gordon, A.C.; Holloway, P.A.H.; Chiche, J.D.; Bion, J.; et al. Patients with faecal peritonitis admitted to European intensive care units: An epidemiological survey of the GenOSept cohort. Intensive Care Med. 2014, 40, 202–210. [Google Scholar] [CrossRef] [PubMed]
  36. Chen, S.; Lai, W.; Song, X.; Lu, J.; Liang, J.; Ouyang, H.; Zheng, W.; Chen, J.; Yin, Z.; Li, H.; et al. The distribution and antibiotic-resistant characteristics and risk factors of pathogens associated with clinical biliary tract infection in humans. Front. Microbiol. 2024, 15, 1404366. [Google Scholar] [CrossRef] [PubMed]
  37. Miutescu, B.; Vuletici, D.; Burciu, C.; Turcu-Stiolica, A.; Bende, F.; Ratiu, I.; Moga, T.; Sabuni, O.; Anjary, A.; Dalati, S.; et al. Identification of Microbial Species and Analysis of Antimicrobial Resistance Patterns in Acute Cholangitis Patients with Malignant and Benign Biliary Obstructions: A Comparative Study. Medicina 2023, 59, 721. [Google Scholar] [CrossRef]
  38. Jeong, H.T.; Song, J.E.; Kim, H.G.; Han, J. Changing Patterns of Causative Pathogens over Time and Efficacy of Empirical Antibiotic Therapies in Acute Cholangitis with Bacteremia. Gut Liver 2022, 16, 985–994. [Google Scholar] [CrossRef] [PubMed]
  39. Tsou, Y.K.; Su, Y.T.; Lin, C.H.; Liu, N.J. Acute cholangitis: Does malignant biliary obstruction vs choledocholithiasis etiology change the clinical presentation and outcomes? World J. Clin. Cases 2023, 11, 6984–6994. [Google Scholar] [CrossRef]
  40. Pitout, J.D.; Laupland, K.B. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: An emerging public-health concern. Lancet Infect. Dis. 2008, 8, 159–166. [Google Scholar] [CrossRef]
  41. Doi, Y.; Park, Y.S.; Rivera, J.I.; Adams-Haduch, J.M.; Hingwe, A.; Sordillo, E.M.; Lewis, J.S., 2nd; Howard, W.J.; Johnson, L.E.; Polsky, B.; et al. Community-associated extended-spectrum beta-lactamase-producing Escherichia coli infection in the United States. Clin. Infect. Dis. 2013, 56, 641–648. [Google Scholar] [CrossRef] [PubMed]
  42. Cherian, J.P.; Cosgrove, S.E.; Haghpanah, F.; Klein, E.Y.; for the Centers for Disease Control and Prevention’s Prevention Epicenters Program and the Modeling Infectious Diseases in Healthcare Network. Risk-factor analysis for extended-spectrum beta-lactamase-producing Enterobacterales colonization or infection: Evaluation of a novel approach to assess local prevalence as a risk factor. Infect. Control Hosp. Epidemiol. 2023, 44, 1793–1800. [Google Scholar] [CrossRef]
  43. Bezabih, Y.M.; Sabiiti, W.; Alamneh, E.; Bezabih, A.; Peterson, G.M.; Bezabhe, W.M.; Roujeinikova, A. The global prevalence and trend of human intestinal carriage of ESBL-producing Escherichia coli in the community. J. Antimicrob. Chemother. 2021, 76, 22–29. [Google Scholar] [CrossRef] [PubMed]
  44. Alipour, S.; Harzandi, N.; Sadeghi, A.; Rabbani, A.; Houri, H. A worrisome prevalence of extended-spectrum beta-lactamase producers in patients with biliary obstruction and cholangitis: Phenotypic and molecular characterization of biliary Escherichia coli and Klebsiella pneumoniae isolates. Microb. Pathog. 2024, 197, 107026. [Google Scholar] [CrossRef] [PubMed]
  45. Logan, L.K.; Weinstein, R.A. The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace. J. Infect. Dis. 2017, 215, S28–S36. [Google Scholar] [CrossRef]
  46. Toh, H.S.; Chuang, Y.C.; Huang, C.C.; Lee, Y.L.; Liu, Y.M.; Ho, C.M.; Lu, P.L.; Liu, C.E.; Chen, Y.H.; Wang, J.H.; et al. Antimicrobial susceptibility profiles of Gram-negative bacilli isolated from patients with hepatobiliary infections in Taiwan: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2006–2010. Int. J. Antimicrob. Agents 2012, 40, S18–S23. [Google Scholar] [CrossRef]
  47. Li, K.; Jiang, S.; Fu, H.; Hao, Y.; Tian, S.; Zhou, F. Risk Factors and Prognosis of Carbapenem-Resistant Organism Colonization and Infection in Acute Cholangitis. Infect. Drug Resist. 2022, 15, 7777–7787. [Google Scholar] [CrossRef]
  48. Boral, B.; Unaldi, O.; Ergin, A.; Durmaz, R.; Eser, O.K.; Acinetobacter Study, G. A prospective multicenter study on the evaluation of antimicrobial resistance and molecular epidemiology of multidrug-resistant Acinetobacter baumannii infections in intensive care units with clinical and environmental features. Ann. Clin. Microbiol. Antimicrob. 2019, 18, 19. [Google Scholar] [CrossRef]
  49. Chen, S.; Shi, J.; Chen, M.; Ma, J.; Zeng, Z.; Wang, R.; Cui, Y.; Gao, X. Characteristics of and risk factors for biliary pathogen infection in patients with acute pancreatitis. BMC Microbiol. 2021, 21, 269. [Google Scholar] [CrossRef]
  50. Islam, M.M.; Jung, D.E.; Shin, W.S.; Oh, M.H. Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections. Pathogens 2024, 13, 1049. [Google Scholar] [CrossRef]
  51. Wu, Z.Y.; Wu, X.S.; Yao, W.Y.; Wang, X.F.; Quan, Z.W.; Gong, W. Pathogens’ distribution and changes of antimicrobial resistance in the bile of acute biliary tract infection patients. Zhonghua Wai Ke Za Zhi 2021, 59, 24–31. [Google Scholar] [CrossRef]
  52. Suh, S.W.; Choi, Y.S.; Choi, S.H.; Do, J.H.; Oh, H.C.; Kim, H.J.; Lee, S.E. Antibiotic selection based on microbiology and resistance profiles of bile from gallbladder of patients with acute cholecystitis. Sci. Rep. 2021, 11, 2969. [Google Scholar] [CrossRef]
  53. Stathopoulos, P.; Lerner, P.; Astheimer, P.; Breitling, L.P.; Zumblick, M.; Pararas, M.; Lohoff, M.; Gress, T.M.; Denzer, U.W. Endoscopic retrograde cholangiopancreatography-obtained bile culture in acute cholangitis: Retrospective analysis of bile cultures and risk factors in a tertiary care center. J. Gastroenterol. Hepatol. 2024, 39, 935–941. [Google Scholar] [CrossRef]
  54. Tascini, C.; Di Paolo, A.; Polillo, M.; Ferrari, M.; Lambelet, P.; Danesi, R.; Menichetti, F. Case report of a successful treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and MRSA/vancomycin-resistant Enterococcus faecium cholecystitis by daptomycin. Antimicrob. Agents Chemother. 2011, 55, 2458–2459. [Google Scholar] [CrossRef]
  55. Karasawa, Y.; Kato, J.; Kawamura, S.; Kojima, K.; Ohki, T.; Seki, M.; Tagawa, K.; Toda, N. Risk Factors for Acute Cholangitis Caused by Enterococcus faecalis and Enterococcus faecium. Gut Liver 2021, 15, 616–624. [Google Scholar] [CrossRef] [PubMed]
  56. Aoto, K.; Inose, R.; Kosaka, T.; Shikata, K.; Muraki, Y. Comparative effectiveness of cefmetazole versus carbapenems and piperacillin/tazobactam as initial therapy for bacteremic acute cholangitis: A retrospective study. J. Infect. Chemother. 2024, 30, 213–218. [Google Scholar] [CrossRef] [PubMed]
  57. Huang, X.M.; Zhang, Z.J.; Zhang, N.R.; Yu, J.D.; Qian, X.J.; Zhuo, X.H.; Huang, J.Y.; Pan, W.D.; Wan, Y.L. Microbial spectrum and drug resistance of pathogens cultured from gallbladder bile specimens of patients with cholelithiasis: A single-center retrospective study. World J. Gastrointest. Surg. 2022, 14, 1340–1349. [Google Scholar] [CrossRef] [PubMed]
  58. Barie, P.S.; Hydo, L.J.; Shou, J.; Larone, D.H.; Eachempati, S.R. Influence of antibiotic therapy on mortality of critical surgical illness caused or complicated by infection. Surg. Infect. 2005, 6, 41–54. [Google Scholar] [CrossRef]
  59. Gomi, H.; Solomkin, J.S.; Schlossberg, D.; Okamoto, K.; Takada, T.; Strasberg, S.M.; Ukai, T.; Endo, I.; Iwashita, Y.; Hibi, T.; et al. Tokyo Guidelines 2018: Antimicrobial therapy for acute cholangitis and cholecystitis. J. Hepatobiliary Pancreat. Sci. 2018, 25, 3–16. [Google Scholar] [CrossRef]
  60. Orda, R.; Berger, S.A.; Levy, Y.; Shnaker, A.; Gorea, A. Penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue in patients with acute cholecystitis. Dig. Dis. Sci. 1992, 37, 1691–1693. [Google Scholar] [CrossRef]
  61. Thabit, A.K. Antibiotics in the Biliary Tract: A Review of the Pharmacokinetics and Clinical Outcomes of Antibiotics Penetrating the Bile and Gallbladder Wall. Pharmacotherapy 2020, 40, 672–691. [Google Scholar] [CrossRef]
  62. Sokal, A.; Sauvanet, A.; Fantin, B.; de Lastours, V. Acute cholangitis: Diagnosis and management. J. Visc. Surg. 2019, 156, 515–525. [Google Scholar] [CrossRef]
  63. Oh, J.; Park, S.Y.; Lee, J.S.; Lee, S.H. Effect of restricting piperacillin/tazobactam prescription on rates of antimicrobial resistance in gram-negative bacteria and antibiotic consumption. Eur. J. Clin. Microbiol. Infect. Dis. 2023, 42, 53–60. [Google Scholar] [CrossRef] [PubMed]
  64. Edwards, T.; Heinz, E.; van Aartsen, J.; Howard, A.; Roberts, P.; Corless, C.; Fraser, A.J.; Williams, C.T.; Bulgasim, I.; Cuevas, L.E.; et al. Piperacillin/tazobactam-resistant, cephalosporin-susceptible Escherichia coli bloodstream infections are driven by multiple acquisition of resistance across diverse sequence types. Microb. Genom. 2022, 8, 000789. [Google Scholar] [CrossRef] [PubMed]
  65. Miyazaki, M.; Yamada, Y.; Matsuo, K.; Komiya, Y.; Uchiyama, M.; Nagata, N.; Takata, T.; Jimi, S.; Imakyure, O. Change in the Antimicrobial Resistance Profile of Extended-Spectrum beta-Lactamase-Producing Escherichia coli. J. Clin. Med. Res. 2019, 11, 635–641. [Google Scholar] [CrossRef]
  66. Ladsavong, T.S.; Brewer, B.R.; Rumbaugh, K.A. Antibiotic Prescribing Patterns and Risk Factors for Multidrug-Resistant Organisms in Critically Ill Surgical Patients with Intra-Abdominal Infections. Surg. Infect. 2025. [Google Scholar] [CrossRef]
  67. Slieker, J.C.; Aellen, S.; Eggimann, P.; Guarnero, V.; Schafer, M.; Demartines, N. Procalcitonin-Guided Antibiotics after Surgery for Peritonitis: A Randomized Controlled Study. Gastroenterol. Res. Pract. 2017, 2017, 3457614. [Google Scholar] [CrossRef] [PubMed]
  68. Grant, J.; Saux, N.L.; Members of the Antimicrobial Stewardship and Resistance Committee (ASRC) of the Association of Medical Microbiology and Infectious Disease (AMMI) Canada. Duration of antibiotic therapy for common infections. J. Assoc. Med. Microbiol. Infect. Dis. Can. 2021, 6, 181–197. [Google Scholar] [CrossRef]
  69. Masuda, S.; Imamura, Y.; Ichita, C.; Jinushi, R.; Kubota, J.; Kimura, K.; Makazu, M.; Sato, R.; Kako, M.; Kobayashi, M.; et al. Comparison of antimicrobial therapy termination in febrile and afebrile patients with acute cholangitis after drainage. Sci. Rep. 2024, 14, 17858. [Google Scholar] [CrossRef]
  70. Tinusz, B.; Szapary, L.; Paladi, B.; Tenk, J.; Rumbus, Z.; Pecsi, D.; Szakacs, Z.; Varga, G.; Rakonczay, Z., Jr.; Szepes, Z.; et al. Short-Course Antibiotic Treatment Is Not Inferior to a Long-Course One in Acute Cholangitis: A Systematic Review. Dig. Dis. Sci. 2019, 64, 307–315. [Google Scholar] [CrossRef]
  71. Giulea, C.; Enciu, O.; Birca, T.; Miron, A. Selective Intraoperative Cholangiography in Laparoscopic Cholecystectomy. Chirurgia 2016, 111, 26–32. [Google Scholar]
  72. Sartelli, M.; Palmieri, M.; Labricciosa, F.M. Antibiotics for Intra-Abdominal Infections: When, Which, How and How Long? Antibiotics 2025, 14, 1127. [Google Scholar] [CrossRef]
  73. Wang, C.; Yu, H.; He, J.; Li, M.; Zhang, L.; Xu, Y.; Gao, W.; Yang, X.; Guo, X.; Guo, Z. Comparative analysis of bile culture and blood culture in patients with malignant biliary obstruction complicated with biliary infection. J. Cancer Res. Ther. 2021, 17, 726–732. [Google Scholar] [CrossRef]
  74. Bianco, G.; Boattini, M.; Comini, S.; Iannaccone, M.; Casale, R.; Allizond, V.; Barbui, A.M.; Banche, G.; Cavallo, R.; Costa, C. Activity of ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol and comparators against Gram-negative organisms causing bloodstream infections in Northern Italy (2019–2021): Emergence of complex resistance phenotypes. J. Chemother. 2022, 34, 302–310. [Google Scholar] [CrossRef] [PubMed]
  75. Bittencourt, A.A.; Faustino, V.L.; Batista, P.M.; Leonel, L.P.; de Paula, M.D.N.; Polis, T.J. Activity of ceftolozane/tazobactam and comparators against gram-negative bacilli: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART—Brazil), 2018–2021. Braz. J. Infect. Dis. 2025, 29, 104497. [Google Scholar] [CrossRef] [PubMed]
  76. Nakamura, G.; Asai, K.; Watanabe, R.; Kuroda, M.; Shibahara, Y.; Teraoka, S.; Hagiwara, O.; Kakizaki, N.; Sato, J.; Watanabe, M.; et al. Multiplex PCR-based rapid pathogen identification in acute cholecystitis using the FilmArray BCID2 panel. Front. Microbiol. 2025, 16, 1687205. [Google Scholar] [CrossRef] [PubMed]
Table 1. Key resistance phenotypes and associated antimicrobial non-susceptibility in biliary pathogens.
Table 1. Key resistance phenotypes and associated antimicrobial non-susceptibility in biliary pathogens.
Resistance PhenotypeCommon PathogensKey Affected Antibiotics (Drugs Likely Ineffective)Representative Resistance RatesKey Citations
ESBL-producing EnterobacteriaceaeE. coli, K. pneumoniaePenicillins, Cephalosporins (all generations), AminoglycosidesPrevalence of 15–44% in high-risk BTI cohorts. Carbapenems are the treatment of choice, but resistance is growing.[23,24,46,56,57]
Carbapenem-Resistant Enterobacterales (CRE) and Gram-negative pathogensK. pneumoniae, E. coli, Acinetobacter baumannii, Pseudomonas aeruginosaAll Penicillins, Cephalosporins, Carbapenems Prevalence of 4.5–66% in high-risk BTI cohorts. Treatment is extremely difficult, often requiring combination therapy with Colistin and novel agents.[48,49,51]
Vancomycin-Resistant Enterococci (VRE)E. faecium > E. faecalisVancomycin, often AmpicillinPrevalence of 8–19% in high-risk BTI cohorts. Treatment options include Linezolid or Daptomycin.[23,24]
Table 2. Empiric antibiotic regimens for biliary infections based on severity and resistance risk.
Table 2. Empiric antibiotic regimens for biliary infections based on severity and resistance risk.
Mild-to-Moderate Severity (Tokyo Grade I/II)Severe/Septic Shock (Tokyo Grade III)
Low Resistance Risk (Community-acquired, no recent interventions/antibiotics, no recent hospitalization)First-line: Ceftriaxone OR Ampicillin/Sulbactam. Rationale: Covers common community pathogens (E. coli, Klebsiella). Considerations: Add Metronidazole if a bilioenteric anastomosis is present. Check local resistance rates for Ceftriaxone [74].First-line: Cefmetazole OR Piperacillin/Tazobactam. Rationale: Broader spectrum covering common pathogens plus some Pseudomonas and anaerobes. It can also cover ESBL-producing pathogens in areas with high community resistance rates. Considerations: Provides more reliable coverage than cephalosporins in sicker patients or in areas with higher ESBL-producers prevalence [56,65].
High Resistance Risk (Healthcare-associated, prior biliary intervention, recent antibiotics, known MDR colonization)First-line: Cefmetazole OR Piperacillin/Tazobactam OR Meropenem. Rationale: Necessary broad coverage for Pseudomonas, Enterococcus, and potentially resistant Enterobacterales. Considerations: Even with “mild” signs, the risk of a resistant pathogen is high. A carbapenem (Meropenem) may be considered if local piperacillin–tazobactam resistance is high (>15–20%) or if the patient is a known ESBL carrier [11,59,64].First-line: Meropenem OR Imipenem/Cilastatin. Rationale: Provides the broadest empiric coverage for ESBL-producers and most other resistant pathogens. Considerations: Add Linezolid/Daptomycin if the patient is a known VRE carrier or in a high-prevalence VRE setting. Consult infectious diseases for potential use of novel agents if CRE is highly suspected [11,59,61,64,66].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Toma, E.-A.; Enciu, O.; Popa, G.L.; Calu, V.; Pîrîianu, D.C.; Poroșnicu, A.L.; Popa, M.I. The Evolving Microbiology and Antimicrobial Resistance in Peritonitis of Biliary Origin: An Evidence-Based Update of the Tokyo Guidelines (TG18) for Clinicians. Diagnostics 2025, 15, 3095. https://doi.org/10.3390/diagnostics15243095

AMA Style

Toma E-A, Enciu O, Popa GL, Calu V, Pîrîianu DC, Poroșnicu AL, Popa MI. The Evolving Microbiology and Antimicrobial Resistance in Peritonitis of Biliary Origin: An Evidence-Based Update of the Tokyo Guidelines (TG18) for Clinicians. Diagnostics. 2025; 15(24):3095. https://doi.org/10.3390/diagnostics15243095

Chicago/Turabian Style

Toma, Elena-Adelina, Octavian Enciu, Gabriela Loredana Popa, Valentin Calu, Dumitru Cătălin Pîrîianu, Andrei Ludovic Poroșnicu, and Mircea Ioan Popa. 2025. "The Evolving Microbiology and Antimicrobial Resistance in Peritonitis of Biliary Origin: An Evidence-Based Update of the Tokyo Guidelines (TG18) for Clinicians" Diagnostics 15, no. 24: 3095. https://doi.org/10.3390/diagnostics15243095

APA Style

Toma, E.-A., Enciu, O., Popa, G. L., Calu, V., Pîrîianu, D. C., Poroșnicu, A. L., & Popa, M. I. (2025). The Evolving Microbiology and Antimicrobial Resistance in Peritonitis of Biliary Origin: An Evidence-Based Update of the Tokyo Guidelines (TG18) for Clinicians. Diagnostics, 15(24), 3095. https://doi.org/10.3390/diagnostics15243095

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop