Controversies in nosocomial peritonitis

Introduction

Although recently very significant progress has been achieved in the diagnosis and treatment of intra-abdominal infections (IAI), such as nosocomial peritonitis, their management continues to represent a real challenge for specialists working in Intensive Care Units (ICUs) [1]. This situation can be explained, among other factors, by the difficulty in identifying the microorganisms responsible for the infection and, above all, by the growing number of pathogens resistant to commonly used antimicrobials [2]. Therefore, this document focuses on several aspects to optimize the current management of nosocomial peritonitis: changes in the epidemiology of causative microorganisms; measures to optimize antibiotic therapy, including reducing its duration; and advances in microbiological diagnosis.

Epidemiology

In numerous instances, complicated intra-abdominal infections (cIAI) are not monobacterial but polymicrobial, and the presence of multidrug-resistant (MDR) microorganisms that compromise the effectiveness of treatment is common. In the study by Labricciosa et al. [2], two or more pathogens were identified in 45.6% of peritoneal fluid samples from 1,986 patients with cIAI, with MDR organisms accounting for up to 9.8% of all isolates. Moreover, MDR organisms, with an incidence of 13.9%, were more frequently isolated in patients with nosocomial cIAI. This is relevant since healthcare-associated cIAI, together with prior antibiotic therapy within one week of surgery, severe cardiovascular disease, leukocyte counts <4,000/mL or >12,000/mL, and inadequate source control, represent five independent risk factors associated with MDR infection. The AbSeS study [3], conducted in 2,621 patients admitted to ICUs in 309 hospitals across 42 countries, diagnosed with community-acquired IAI (31.6%) or hospital-acquired IAI, either early (25%) or late (43.4%), reported a prevalence of antimicrobial-resistant microorganisms of 26.3%, with an overall mortality rate of 29.1%. Although no significant differences were observed in resistance prevalence depending on acquisition setting, late-onset nosocomial IAI, the presence of resistant microorganisms (methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, or Gram-negative bacteria producing extended-spectrum β-lactamases or resistant to carbapenems), and failure of source control, along with diffuse peritonitis, sepsis, septic shock, advanced age, liver failure, and heart failure, were identified as independent risk factors for mortality. Similarly, a post hoc analysis of 1,077 patients with confirmed secondary peritonitis from the AbSeS study [4], in which a total of 1,643 microorganisms were isolated. Mostly Gram-negative bacteria (48.5%), showed that inadequate empirical therapy was associated with isolation of Klebsiella spp., non-fermenting bacilli (Pseudomonas spp., Stenotrophomonas maltophilia, Acinetobacter spp.), Enterococcus faecium, E. faecalis, and Candida spp. Inadequate empirical therapy was observed more frequently in cases of antimicrobial resistance. Once again, septic shock (OR 3.08 [95% CI 1.42–7.00]), late-onset nosocomial peritonitis (OR 1.71 [95% CI 1.16–2.52]), and failure of source control evidenced by persistent inflammation on day 7 (OR 5.71 [95% CI 3.99–8.18]) were identified as factors associated with higher mortality. Finally, the study by De Pascale et al. [5] reported 283 nosocomial infections due to carbapenem-resistant Enterobacterales (CRE; incidence: 3.57 cases per 1,000 patient-days) and 138 due to carbapenem-resistant Pseudomonas aeruginosa (CRPA; incidence: 1.74 cases per 1,000 patient-days) in a total of 13,088 patients admitted to 20 ICUs in Italian hospitals during a 12-month period. In this case, empirical therapy directed at Gram-negative pathogens was inadequate in 59.2% of cases. While crude ICU mortality was 30.4%, mortality associated with CRE infections was significantly higher than in patients with CRPA (36.7% vs. 20.0%).

Improvement of treatment

In recent decades, many pathogens involved in cIAI have developed resistance to commonly used antibiotics, greatly limiting therapeutic options [6]. In this context, the combination of ceftazidime–avibactam plus metronidazole has demonstrated non-inferior efficacy and similar tolerability compared with meropenem in the treatment of MDR cIAI, making it an effective alternative to carbapenems for these infections [6]. Its efficacy is comparable in infections caused by both ceftazidime-susceptible and resistant pathogens, and its safety profile is consistent with that of ceftazidime monotherapy [6]. Treatment with imipenem/cilastatin/relebactam (500/500/250 mg) every 6 hours for 5–14 days has shown good efficacy and safety in the management of both cIAI and complicated urinary tract infections (cUTI), including those with secondary sepsis [7]. After completion of treatment, this combination was associated with a favorable clinical response in 85.7% of the microbiologically evaluable (ME) population with cIAI, as well as a favorable microbiological response in 100% of ME patients with cUTI [7]. All patients with sepsis achieved either a clinical or microbiological favorable response at the end of treatment [7]. The TANGO II study [8] confirmed the efficacy of meropenem–vaborbactam monotherapy in CRE infections, including cIAI. Compared with the best available therapy (polymyxins, carbapenems, aminoglycosides, tigecycline, or ceftazidime–avibactam), meropenem–vaborbactam achieved higher clinical cure rates (65.6% vs. 33.3% [95% CI 3.3–61.3]; p=0.03), lower 28-day all-cause mortality (15.6% vs. 33.3% [95% CI –44.7 to 9.3]), and lower nephrotoxicity (31.3% vs. 80% [95% CI –74.6 to –22.9]; p<0.001) [8]. Real-world studies have confirmed the good efficacy and safety of cefiderocol in cIAI caused by Gram-negative bacteria [9]. Clinical trials IGNITE 1 [10] and IGNITE 4 [11] demonstrated the non-inferiority of eravacycline (1 mg/kg every 12 h) compared with ertapenem (1 g every 24 h) (clinical cure: 86.8% vs. 87.6% [95% CI –7.1 to 5.5]) and meropenem (1 g every 8 h) (90.8% vs. 91.2% [95% CI –6.1 to 5.3]). The REVISIT study [12] confirmed the efficacy and safety of aztreonam–avibactam in patients with cIAI caused by Gram-negative bacteria, with clinical cure rates comparable to those of meropenem (76.4% vs. 74.0%). In the same vein, the management of intra-abdominal candidiasis (IAC) continues to be a major challenge in ICUs [13]. This can be explained, at least in part, by the highly deficient penetration of echinocandins into peritoneal fluid: anidulafungin 0.66–1.82 µg/mL (with the highest serum-to-peritoneal ratio, close to 30%), caspofungin 0.21–0.46 µg/mL, and micafungin 0.68–0.88 µg/mL. These concentrations are below the resistance selection threshold demonstrated in several studies, posing a potential risk of resistance in patients receiving prolonged echinocandin therapy and leading to suboptimal control of IAC [13]. Furthermore, an imaging mass spectrometry study in an animal model demonstrated a complete absence of tissue penetration with the standard micafungin dose as early as three hours after administration [13]. Therefore, it can be concluded that the use of echinocandins, although recommended in guidelines as standard therapy for candidemia, is ineffective for IAC. Such a recommendation may stem from the erroneous extrapolation of plasma penetration data to peritoneal fluid. Accordingly, based on the Italian Consensus on Antimicrobial Optimization [13], liposomal amphotericin B should be the empirical treatment of choice in high-risk IAC patients while awaiting the results of the 1,3-β-D-glucan test.

Advances in microbiological diagnosis

Culture-based diagnostic tests require around five days for pathogen identification and susceptibility results, which is why severe infections are often treated empirically with broad-spectrum antimicrobials [14]. This underscores the urgent need for rapid detection methods to allow earlier use of narrow-spectrum agents [14]. In this regard, the multiplex PCR system FilmArray^® (bioMérieux), validated for positive blood cultures, has demonstrated a high detection rate (90.5%) for causative microorganisms in peritoneal fluid and abscesses, with a detection limit ranging from 10² to 106 CFU/mL depending on the microorganism. That makes it a potentially rapid and affordable tool for bacterial identification in IAI [14]. However, it should not completely replace conventional microbiological methods [15]. Regarding IAC diagnosis, PCR testing of abdominal fluid has demonstrated the presence of various Candida species in a high proportion of cases, including those in which peritoneal 1,3-β-D-glucan revealed monofungal C. albicansi infection [13]. Combining serum 1,3-β-D-glucan <3.3 pg/mL and peritoneal fluid 1,3-β-D-glucan <45 pg/mL provides a negative predictive value of 100% for IAC [13], potentially guiding the discontinuation of antifungal therapy initiated intraoperatively or during the first hours of ICU stay when infection is suspected.

Reduction of antimicrobial treatment duration

Despite progress in IAI management, optimal treatment duration remains uncertain, currently set at 7–14 days [1]. Recent evidence suggests that 3–5 days may be sufficient for cure and for reducing the risk of resistance in patients with adequate source control. The STOP-IT trial [1] concluded that 4±1 days of antibiotic therapy achieved outcomes similar to 8±1 days in patients with adequate source control. Procalcitonin (PCT)-guided therapy has been shown to reduce treatment duration by 50% (5.1 ± 2.1 vs. 10.2 ± 3.7 days; p<0.001) in critically ill patients with secondary peritonitis, with no differences depending on the presence or absence of septic shock [16]. Although antifungal therapy for candidemia must continue for 14 days after the first negative blood culture, in invasive candidiasis without candidemia (such as IAC), treatment duration may be shortened depending on biomarker results, especially 1,3-β-D-glucan [13]. Specifically, a biomarker-based strategy combining 1,3-β-D-glucan, mannan (cutoff 125 pg/mL), and antimannan (cutoff 10 UA/mL) on days 0 and 4 reduced antifungal treatment to a median of 6 days compared with 13 days in the control group [13]. Funding None to declare.  Conflict of Interest The authors declare no conflict of interest. Author contributions  Writing—original draft preparation, E.M. and A.S.R.; writing—review and editing, E.M. and A.S.R. All authors have read and agreed to the published version of the manuscript

References

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