Peritoneal Infection Research Articles

Evaluation of LPRDA Pentapeptide for the Prevention and Treatment of Staphylococcus aureus Peritoneal Infection

Targeting virulence determinants is a promising approach to controlling S. aureus infections in the face of the global spread of antibiotic resistance. S. aureus-induced peritonitis often occurs in dialysis, implant and trauma patients. To develop novel prevention and treatment options for peritoneal infection, we investigated the oligopeptide sortase A inhibitor LPRDA as a non-conventional antibacterial that does not affect staphylococcal survival. Administration of LPRDA prior to S. aureus challenge reduced the bacterial load of internal organs and bacterial colonization of the abdominal cavity in animals. In addition, LPRDA inhibited α-hemolysin production in 80% of the 35 reference and clinical S. aureus strains tested. Consequent research of LPRDA interactions with cefazolin and vancomycin has demonstrated the potential for combined application of the antivirulent and antibiotic agents under study.

Eliminating Intracellular MRSA via Mannosylated Lipid-Coated Calcium Phosphate Nanoparticles.

Methicillin-resistant Staphylococcus aureus (MRSA) within cells proves exceptionally challenging to eradicate using conventional antimicrobials, resulting in recurring infections and heightened resistance. Herein, we reported an innovative mannosylated lipid-coated photodynamic/photothermal calcium phosphate nanoparticle (MAN-LCaP@ICG) for eradicating intracellular MRSA. The MAN-LCaP functioned as the vehicle for drug delivery, exhibiting preferential uptake by macrophages and facilitating the transport of ICG to intracellular pathogens. The MAN units integrated into MAN-LCaP@ICG could promote binding with MAN residuals on macrophage cells, as evidenced by cellular uptake assays using fluorescence microscopy and flow cytometry. Following its targeted accumulation, MAN-LCaP@ICG could enter into the cytoplasm and efficiently eradicate intracellular MRSA by a combination of the lysosome escape capability of CaP and the photodynamic and photothermal therapeutic effects of ICG. Furthermore, MAN-LCaP@ICG could kill MRSA more effectively than LCaP@ICG without MAN units or free ICG in a mouse peritoneal infection model. Therefore, MAN-LCaP@ICG provided a promising direction for human clinical application in combating intracellular infections.

The impact of shortening patient–doctor contact duration on early peritoneal dialysis-related infections

Early peritoneal dialysis (PD)-related infection is a severe complication. This study investigated the relationship between patient–doctor contact (PDC) duration and early PD-related infection. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea, incident dialysis patients receiving PD were divided into two groups based on PDC duration (< 15 min versus ≥ 15 min), which was defined as the duration a nephrologist typically spends with a patient receiving PD during each visit according to the facility practice pattern. Early risks of PD-related infections, such as peritonitis and catheter-related infection (onset within 3 and 12 months of PD), were compared to the PDC duration using Cox regression. The study included 276 patients (184 [66.7%] in the shorter PDC group [< 15 min] and 92 [33.3%] in the longer PDC group [≥ 15 min]). The average age did not differ between the groups. The incidences of 3- and 12-month PD-related infections were significantly lower in the longer PDC group than in the shorter PDC group (3 months: 1.1% versus 9.8%, P = 0.007; 12 months: 9.8% versus 23.4%, P = 0.007). Longer PDC was independently associated with a lower risk of PD-related infections at 3 and 12 months (3 months: adjusted hazard ratio [aHR], 0.11; 95% confidence interval [CI], 0.02–0.85, P = 0.034; 12 months: aHR, 0.43; 95% CI 0.19–0.99, P = 0.048). Overall, a longer PDC duration was associated with a significantly lower risk of early PD-related infection.

Bulk and single-cell RNA-seq analyses reveal canonical RNA editing associated with microglia homeostasis and its role in sepsis-associated encephalopathy

Previous studies have demonstrated the roles of both microglia homeostasis and RNA editing in sepsis-associated encephalopathy (SAE), yet their relationship remains to be elucidated. In this study, we analyzed bulk and single-cell RNA-seq (scRNA) datasets containing 107 brain tissue and microglia samples from mice with microglial depletion and repopulation to explore canonical RNA editing associated with microglia homeostasis and evaluate its role in SAE. Analysis of mouse brain RNA-Seq revealed hallmarks of microglial repopulation, including peak expressions of Apobec1 and Apobec3 at Day 5 of repopulation and dramatically altered B2m RNA editing. Significant time-dependent changes in brain RNA editing during microglial depletion and repopulation were primarily observed in synapse-related genes, such as Tbc1d24 and Slc1a2. ScRNA-Seq revealed heterogeneous RNA editing among microglia subpopulations and their distinct changes associated with microglia homeostasis. Moreover, repopulated microglia from lipopolysaccharide (LPS)-induced sepsis mice exhibited intensified up-regulation of Apobec1 and Apobec3, with distinct RNA editing responses to LPS, mainly involved in immune-related pathways. The hippocampus from sepsis mice induced by peritoneal contamination and infection showed upregulated Apobec1 and Apobec3 expression, and altered RNA editing in immune-related genes, such as B2m and Mier1, and nervous-related lncRNA Meg3 and Snhg11, both of which were repressed by microglial depletion. Furthermore, the expression of complement-related genes, such as C4b and Cd47, was substantially correlated with RNA editing activity in microglia homeostasis and SAE. Our study demonstrates canonical RNA editing associated with microglia homeostasis and provides new insights into its potential role in SAE.

6-Methoxyldihydrochelerythrine Chloride Inhibiting Intra and Extracellular Drug-Resistant Bacteria.

Vancomycin-resistant enterococcus (VRE) is a major nosocomial pathogen that exhibits enhanced infectivity due to its robust virulence and biofilm-forming capabilities. In this study, 6-methoxyldihydrochelerythrine chloride (6-MDC) inhibited the growth of exponential-phase VRE and restored VRE's sensitivity to vancomycin. 6-MDC predominantly suppressed the de novo biosynthetic pathway of pyrimidine and purine in VRE by the RNA-Seq analysis, resulting in obstructed DNA synthesis, which subsequently weakened bacterial virulence and impeded intracellular survival. Furthermore, 6-MDC inhibited biofilm formation, eradicated established biofilms, reduced virulence, and enhanced the host immune response to prevent intracellular survival and replication of VRE. Finally, 6-MDC reduced the VRE load in peritoneal fluid and cells significantly in a murine peritoneal infection model. This paper provides insight into the potential antimicrobial target of benzophenanthridine alkaloids for the first time.

Peritoneal infection after colorectal cancer surgery induces substantial alterations in postoperative protein levels: an exploratory study

PurposePeritoneal infection, due to anastomotic leakage, after resection for colorectal cancer have been shown to associate with increased cancer recurrence and mortality, as well as cardiovascsular morbidity. Alterations in circulating protein levels could help shed light on the underlying mechanisms, prompting this exploratory study of 64 patients operated for colorectal cancer with anastomosis.MethodsThirty-two cases who suffered a postoperative peritoneal infection were matched with 32 controls who had a complication-free postoperative stay. Proteins in serum samples at their first postoperative visit and at one year after surgery were analysed using proximity extension assays and enzyme-linked immunosorbent assays. Multivariate projection methods, adjusted for multiple testing, were used to compare levels between groups, and enrichment and network analyses were performed.ResultsSeventy-seven proteins, out of 270 tested, were differentially expressed at a median sampling time of 41 days postoperatively. These proteins were all normalised one year after surgery. Many of the differentially expressed top hub proteins have known involvement in cancer progression, survival, invasiveness and metastasis. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K-Akt) and transforming growth factor beta (TGF-β) signaling.ConclusionThese affected proteins and pathways could provide clues as to why patients with peritoneal infection might suffer increased cancer recurrence, mortality and cardiovascular morbidity.

Peritoneal dialysis-related infections in elderly patients.

This review outlines the epidemiology, characteristics, risk factors, and prognosis of peritoneal dialysis (PD)-related peritonitis, PD catheter-related infections, and the effects of assisted PD in elderly patients from the Japanese perspective. Based on the literature, the incidence of peritonitis is likely to be higher in elderly patients than in younger patients. The most frequent causative bacteria in elderly patients are Gram-positive bacteria, as in adult PD patients, most commonly due to transcatheter infection. However, elderly patients may have difficulty recognizing cloudy drainage fluid due to decreased visual acuity. Hypokalemia, the use of gastric acid suppressants, prophylactic antibiotic use before endoscopy, biocompatible fluids and hypoalbuminemia considered modifiable risk factors for peritonitis. However, the mechanism by which treatment of hypokalemia prevents peritonitis is unknown. Currently, the relationship between gastric acid suppression therapy and peritonitis in elderly patients is debatable, with no evidence to strongly recommend uniform discontinuation of gastric acid suppression therapy. Exit-site infection (ESI) is a major risk factor for the development of peritonitis, and appropriate prevention and management of ESI may reduce infection-related hospitalizations in PD patients. Currently, no randomized, controlled trials have verified the effectiveness of antibiotic application for ESI in Japan, but results from other countries are awaited. In assisted PD, it is extremely important that family members, caregivers, and nurses who support the procedure receive sufficient education and training from medical professionals familiar with PD. Early detection and treatment of PD-related infections are required because the risk of death increases in elderly patients.

Bacterial profile and antibiotic susceptibility patterns in patients with secondary peritonitis: a cross-sectional study in Uganda

IntroductionSecondary peritonitis is the second leading cause of sepsis worldwide. Drug resistance to peritoneal cavity bacterial infection remains a public health threat, especially in resource-limited settings in Africa, including Uganda. This study aimed to determine the antibacterial susceptibility patterns and factors associated with secondary peritonitis among patients with acute abdomen who underwent surgery at a Regional Referral Hospital in Uganda.MethodsThis was a cross-sectional study conducted at Hoima Regional Referral Hospital (HRRH) that enrolled 126 patients with acute abdomen. Clinical samples were aseptically collected at laparotomy from patients with secondary peritonitis for culture and sensitivity using standard Microbiological methods. Binary logistic regression was used to identify factors associated with secondary peritonitis among patients with acute abdomen.ResultsThe majority of the patients were males (61.9%) with a mean age of 37.9(SD ± 21.8). Secondary peritonitis was found in 57(45.2%) of the patients. Gram-negative bacteria were the most commonly isolated organisms with Escherichia coli (35.8%) and Klebsiella spp (17.0%) predominating. Imipenem 88.8%(8/9), Amikacin 88.8%(8/9), Ciprofloxacin 44.4%(4/9) and Gentamicin 44.4%(4/9) demonstrated sensitivity to the different isolated organisms at varying degrees. Being a male (AOR = 3.658; 95% CI = 1.570–8.519, p = 0.003) and presenting 3 days after onset of symptoms (AOR = 2.957; 95% CI = 1.232–7.099, p = 0.015) were independently associated with secondary peritonitis.ConclusionImipenem, Amikacin, Ciprofloxacin, and Gentamicin should be considered for empirical therapy in cases of secondary peritonitis. Patients, more especially males with abdominal pain should be encouraged to present early to the hospital to minimize progression to secondary peritonitis.

#784 Peritoneal dialysis-related infections by Kocuria kristinae: cases from a Mexican hospital

Abstract Background and Aims Kocuria species, gram-positive actinobacteria, are typically found in the environment, on human skin and as oral flora. These microorganisms are considered saprophytes and non-pathogenic. They rarely cause infections. Patients generally have some compromise due to underlying conditions, including solid tumors, hematologic malignancies, or metabolic disorders. There are few cases in the literature of peritoneal dialysis-associated peritonitis due to these germs. Reports of exit site infections or tunnel infections are even rarer or doesn't exist. Method Retrospective description of 4 cases of exit site and/or tunnel infections due to Kocuria kristinae over a 3-year period in a single center. Results Four cases of exit site infection were evaluated, with an average age of 63.2 ± 8.8 years. Half of the patients were diabetic. No patient had a history of peritoneal dialysis-related infection. The dialysis modality for all patients was CAPD (Continuous Ambulatory Peritoneal Dialysis). All patients presented symptoms of exit site infection, such as erythema and purulent discharge, but none of them had peritonitis. Three cases were treated with quinolones, and one received linezolid. One case received two antibiotic treatment regimens without an adequate response, and tunnel infection developed, required the removal of the dialysis catheter and a change in modality to HD (hemodialysis). Conclusion Exit site infections due to Kocuria are extremely rare. Despite the absence of specific management guidelines, the response to treatment is usually adequate. Due to the theoretical ability to produce biofilm, Kocuria infections should be considered a potential risk for recurrence and refractory disease. To our knowledge, there are no reports of exit site infections due to Kocuria.

#2650 A novel approach for exit site care reduces peritoneal dialysis catheter related infections

Abstract Background and Aims Peritoneal dialysis (PD) related infections, including peritonitis and catheter related infections, are associated with significant morbidity and technique failure. Various exit site care protocols are available, most allow to shower in running water after the exit site is well healed. Following an increase in exit site infections (ESI) in our dialysis unit, partially resulting from water derived organisms, we implemented a novel exit site care protocol. The protocol included complete avoidance of water exposure using stoma bag during shower; and change in antibiotic treatment from gentamycin to mupirocin. We aimed to evaluate its efficacy to decrease ESI episodes. Method A prospective single center trial. Study group included PD patients between June 2018 - May 2021 who implemented the new exit-site care protocol. They were compared to a historical control group that included all PD patients between January 2016 to May 2018. In the control group, exit-site care included a daily shower with a bactericidal cleanser containing chlorhexidine 4%, thereafter local gentamycin 0.1% was applied with sterile gauze dressing. In the study group, water exposure during daily wash was avoided using a stoma bag sealed around the catheter exit-site and the tubing. Thereafter, the exit-site was cleaned with a chlorhexidine 0.5%- alcohol 70% solution and local mupirocin 2% was applied with a sterile gauze cover. Primary outcome was catheter related infections, including ESI and tunnel infection. Secondary outcomes were peritonitis and technique loss. Results A total of 113 patients were included, 58 patients in control and 55 in study group. Mean follow up time was 13.28 ± 9.5 months in control and 16.4 12.7 months in study group. ESI rate was significantly lower in study group (0.11/patient year) compared to control group (0.71/ patient year), p&amp;lt;0.001. Time to first ESI was significantly longer in study group, χ² (1) = 25.104, p &amp;lt; 0.001 (Fig. 1). On multivariate logistic regression analysis confirmed the protective effect of the intervention on ESI risk (p &amp;lt;0.001). Longer PD vintage and active cancer predicted ESI (p = 0.01 and 0.02, respectively). There were no tunnel infections during study period compared to 3 episodes during control. Peritonitis rate was significantly lower in study group (0.19/patient years) compared to control group (0.40/patient years), p=0.011. There was no difference in time to first peritonitis episode between groups χ² (1)=2.32, p=0.128. Nine patients were lost to PD due to PD related infection in control group, compared to 5 in study group. Peritonitis related mortality occurred in one patient in control group. Conclusion Protection of exit site from water exposure in conjunction with local Mupirocin cream reduced significantly ESI and peritonitis episodes in peritoneal dialysis patients. This protocol may be more beneficial in areas of poor water quality.

Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus invivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.

Activation of TLR9 signaling suppresses the immunomodulating functions of CD55lo fibroblastic reticular cells during bacterial peritonitis.

Fibroblastic reticular cells (FRCs) are a subpopulation of stromal cells modulating the immune environments in health and disease. We have previously shown that activation of TLR9 signaling in FRC in fat-associated lymphoid clusters (FALC) regulate peritoneal immunity via suppressing immune cell recruitment and peritoneal resident macrophage (PRM) retention. However, FRCs are heterogeneous across tissues and organs. The functions of each FRC subset and the regulation of TLR9 in distinct FRC subsets are unknown. Here, we confirmed that specific deletion of TLR9 in FRC improved bacterial clearance and survival during peritoneal infection. Furthermore, using single-cell RNA sequencing, we found two subsets of FRCs (CD55hi and CD55lo) in the mesenteric FALC. The CD55hi FRCs were enriched in gene expression related to extracellular matrix formation. The CD55lo FRCs were enriched in gene expression related to immune response. Interestingly, we found that TLR9 is dominantly expressed in the CD55lo subset. Activation of TLR9 signaling suppressed proliferation, cytokine production, and retinoid metabolism in the CD55lo FRC, but not CD55hi FRC. Notably, we found that adoptive transfer of Tlr9 -/-CD55lo FRC from mesenteric FALC more effectively improved the survival during peritonitis compared with WT-FRC or Tlr9 -/-CD55hi FRC. Furthermore, we identified CD55hi and CD55lo subsets in human adipose tissue-derived FRC and confirmed the suppressive effect of TLR9 on the proliferation and cytokine production in the CD55lo subset. Therefore, inhibition of TLR9 in the CD55lo FRCs from adipose tissue could be a useful strategy to improve the therapeutic efficacy of FRC-based therapy for peritonitis.

Evidence-based care combined with chlorhexidine gluconate antimicrobial dressing in the prevention of peritoneal dialysis catheter-associated infections

To effectively prevent catheter-related infections during peritoneal dialysis (PD), we have applied evidence-based care (EBC) and chlorhexidine gluconate antimicrobial dressings (CHGAD) to the management of PD patients. CHGAD demonstrated good hygroscopic properties, effectively preventing the pooling of blood and exudate at the catheter outlet. Additionally, CHGAD could effectively inhibit the activity of G+ and G− bacteria, providing effective antibacterial effect on the wound. Furthermore, we found that CHGAD also exhibited good biocompatibility without affecting the activity of fibroblasts. Patients undergoing PD treatment were randomly assigned to either the control or EBC group. The control group received standard care while the EBC group received EBC along with CHGAD. Subsequently, we compared patient- and healthcare-related risk factors, treatment adherence, self-care, catheter infection rates, and satisfaction between the two groups. The results demonstrated that EBC effectively reduced risk factors for catheter infections by improving compliance rate of patients’ Hb, HbA1c, and Alb level, as well as hand hygiene compliance, dialysis water management, high-frequency contact table, disinfection and isolation, and catheter maintenance during dialysis. Furthermore, EBC improved patients’ treatment adherence, self-care ability, and participation in PD catheter management. The combination of EBC and CHGAD effectively reduced the incidence of catheter infections and improved patient satisfaction with care. Consequently, EBC combined with CHGAD shows significant potential in the management of catheter infections in PD patients and should be advocated in clinical practice.

Acute and Chronic Kidney Disease Worsen Outcomes in Experimental Sepsis.

Infection is a leading cause of morbidity in individuals with acute and chronic kidney disease (AKD, CKD). However, there is significant difficulty in modeling infection into an animal host with preexisting kidney disease. We report a novel method of peritoneal infection induced via cecal slurry inoculation deployed into mice with experimental aristolochic acid-induced AKD and CKD. AKD, CKD, and paired control mice were injected with sham, low, or higher doses of donor-recipient matched cecal slurry solution. Animal survival, sepsis severity, and change in glomerular filtration rate was tracked longitudinally throughout the study. Histology for kidney injury, flow cytometry, plasma cytokines, and evidence of indirect organ injury from sepsis were also assessed. Infected AKD mice experienced significantly heightened sepsis severity, with 100% mortality by 24 hours after high cecal slurry doses versus no mortality in control mice. Additionally, AKD mice receiving lower cecal slurry doses developed dramatically increased pro-inflammatory cytokines and persistent cytopenias. Infected CKD mice also had worse outcomes than paired CKD-controls, though less severe than in AKD mice. Interestingly, animals with AKD had worse outcomes than mice with CKD after any cecal slurry dose or time-point after inoculation, despite higher baseline kidney function and less uremic sequela. These data confirm that acute bacterial infection can be modeled in animals with established kidney disease; and suggest that the clinical state of kidney disease (AKD versus CKD) may influence host susceptibility to infection more than the degree of kidney failure alone.

Rare Cases of Ralstonia pickettii Blood Stream Infection in Hospitalized Patients with Uterus and Cervical Cancer Under Surgery and Blood Transfusion: A Case Report

Introduction: Ralstonia pickettii is a rare environmental gram-negative bacterium that causes nosocomial infection due to its robust quorum-sensing system and constitution of biofilm in medical equipment and hospital instruments. Objectives: According to various case reports, Ralstonia is associated with catheter-related bacteremia, pneumonia, osteomyelitis, hemoperitoneum infection, meningitis, neonatal sepsis, endocarditis, and peritoneal fluid infection after internal surgery. Methods: In this study, rare cases of nosocomial R. pickettii bloodstream infection were reported in hospitalized patients with uterus and cervical cancer with metastatic squamous cell carcinoma to the colon under surgery and blood transfusion. Results: A 46-year-old woman was admitted to the general surgery department of the target teaching hospital for the chief complaint of abdominal pain, nausea, and vomiting. Before admission, she was under hysterectomy, colectomy, colostomy, and chemotherapy three weeks ago. She received packed red blood cells twice during hospitalization and surgery. In addition, two consecutive blood cultures were positive for R. pickettii using the BD BACTEC™ FX Instruments and confirmation by bioMérieux API 20NE. According to antibiogram test reports, Meropenem (1gr/Q8h/IV) was prescribed, and fortunately, blood culture results were negative after 14 days. In addition, the patient received pantoprazole (I.V. 40 mg) and octreotide (100 mcg/mL) during hospitalization. Conclusions: R. pickettii is responsible for bloodstream infection and sepsis in cancer departments, especially during common surgical operations, and blood transfusions, especially for cancer patients. Hence, recognizing the source of infection can be helpful in appropriate infection control and successful treatment.

Estimates of antibiotic resistance in Italy and Western Europe in 2019: a MICROBE-based comparative analysis.

antimicrobial resistance (AMR) will cause 10 million deaths per year worldwide by 2050, with economic costs of up to 100 trillion dollars. Antibiotic resistance (ABR) constitutes the majority of this health threat. Globally, 1.27 million people died in 2019 as a direct result of ABR. One in 5 deaths occurred in children under five, and 6 bacterial pathogens accounted for more than 70% of ABR-associated deaths. to compare ABR estimates in terms of death and disability-adjusted life-years (DALYs) in 2019 in Italy and in Western Europe (WE) by grading the infectious syndromes and the bacterial pathogens involved, with the aim to identify the most urgent healthcare needs in Italy. the estimates of the burden of ABR in 2019 in WE and Italy, extracted from the Measuring Infectious Causes and Resistance Outcomes for Burden Estimation (MICROBE) tool by the Institute for Health Metrics and Evaluation (IHME; Seattle, USA), reported deaths and DALYs associated with 33 bacterial pathogens across 12 infectious syndromes, as well as deaths and DALYs associated with and attributable to ABR for 23 bacteria and 86 pathogen-drug combinations. The comparison between WE and Italy was performed in steps. First, among the 12 groups of infectious syndromes from the Global Burden of Diseases (GBD) study 2019, the most impacting in terms of deaths and DALYs were ranked based on the magnitude of rates, and the corresponding ABR-associated burden was reported. Then, the burden of the leading pathogens (bacteria, viruses, fungi, and polymicrobial infections) for all infectious syndromes was compared between the two areas. Death and DALY rates associated with ABR were reported for each bacterium, together with the percentage of ABR-attributable burden. Although it is known that Italy is one of the WE countries with the largest share of elderly, crude rates were reported instead of age-standardized rates, in order to quantify the actual burden of ABR in the two areas. Italy and Western Europe. death and DALYs rates per 100,000 inhabitants. the largest difference between ABR-associated death rates in the two areas was found for bloodstream infections (25.2 and 18.8 per 100,000 in Italy and WE, respectively), followed by peritoneal and abdominal infections (15.1 and 12.2 in Italy and WE, respectively). However, the percentages of deaths and DALYs attributable to ABR were always higher in Italy for all the infections considered. Regarding pathogens, Escherichia coli accounted for the greatest burden associated to ABR, in terms of both deaths and DALYs, in both areas. The highest ABR-attributable percentage of deaths was found for Acinetobacter baumannii (28.4% in WE and 31.9% in Italy), accounting also for the highest percentage of ABR-attributable DALYs (28.4% in WE and 31.7% in Italy). The pathogen-drug combination with the highest burden associated with AMR was Escherichia coli-Aminopenicillin, while the greatest AMR-attributable burden was found for Staphylococcus aureus-Methicillin (MRSA). On average, 55.4% of Escherichia coli was resistant to Aminopenicillin in WE, with Italy ranking third (67.6%). Nordic countries showed smaller values, with Sweden in last place (32.8%). The average percentage of MRSA in WE was 16%, with Italy exceeding it by more than 13 pointsConclusions: despite similar sepsis mortality rates in Italy and other WE countries, the proportion of ABR-associated and attributable deaths was higher in Italy. Targeted strategies aimed at reducing the circulation of bacteria and resistant microorganisms together with other interventions could lead to an overall reduction in deaths associated with ABR.

Loss of Mptx2 alters bacteria composition and intestinal homeostasis potentially by impairing autophagy

A recent single-cell survey of the small-intestinal epithelium suggests that mucosal pentraxin 2 (Mptx2) is a new Paneth cell marker, but its function and involved mechanism in the Paneth cell are still unknown. Therefore, we create Mptx2 knockout (Mptx2−/−) mice to investigate its precise effects on intestinal homeostasis using models of lipopolysaccharide (LPS), methicillin-resistant Staphylococcus aureus (MRSA) peritoneal infection, and dextran sulfate sodium (DSS)–induced intestinal injury and inflammation. We here find that Mptx2 is selectively expressed in Paneth cells in the small intestines of mice. Mptx2−/− mice have increased susceptibility to intestinal inflammation and injured. Mptx2 deficiency reduces Paneth cell count and expression of antimicrobial factors, leading to altered intestinal bacteria composition. Loss of Mptx2 aggravates MRSA infection–induced damage in the intestine while decreasing autophagy in Paneth cells. Mptx2−/− mice are more vulnerable to LPS-induced intestinal possibly due to inhibition of the autophagy/endoplasmic reticulum (ER) stress pathway. Mptx2−/− mice are susceptible to DSS-induced colitis that could be ameliorated by treatment with gentamicin or vancomycin antibiotics. In conclusion, Mptx2 is essential to maintain intestinal homeostasis potentially via regulation of autophagy in Paneth cells.

Preporuke za dijagnostički i terapijski pristup infekcija povezanih sa peritonealnom dijalizom

Introduction: Patients with end-stage renal disease who start active treatment with peritoneal dialysis have an increased risk of developing infections. Methods: This paper will present information from relevant professional/scientific sources regarding modern diagnostic and therapeutic modalities for the treatment of infections in patients on peritoneal dialysis. Topic: Infections associated with peritoneal dialysis are: peritoneal catheter exit site infections, tunnel infections and peritonitis. The symptoms of the mentioned infections vary from mild ones such as erythema and secretion at the exit point of the peritoneal catheter to pronounced symptomatology in the development of peritonitis accompanied by abdominal pain and elevated body temperature. The most common cause of peritonitis is infection of the exit site of the catheter, and the two main causes of infection are Staphylococcus aureus and Pseudomonas aeruginosa. If the existence of an infection is suspected, it is necessary to sample the dialysate for cytological examination and culture and to take a swab of the exit site of the catheter. Treatment begins with empiric antibiotic therapy, then it is corrected according to the antibiogram, and the exit site is treated locally with an antibiotic. If there is no therapeutic response after five days of intraperitoneal therapy in peritonitis, it is recommended to remove the catheter. Conclusion: According to the current guidelines of the International Society for Peritoneal Dialysis (ISPD), timely prevention of infections, diagnosis and treatment of peritoneal dialysis-related infections are necessary to prolong patient survival.

Metamizole outperforms meloxicam in sepsis: insights on analgesics, survival and immunomodulation in the peritoneal contamination and infection sepsis model.

Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and anti-inflammatory properties of two non-opioid analgesics. Adult C57BL/6J mice were intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry. Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1β compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups. Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model.

A loss of function mutation in SOCS2 results in increased inflammatory response of macrophages to TLR ligands and Staphylococcus aureus.

The role of suppressor of cytokine signaling (SOCS)2 in anti-infective bacterial immunity has been poorly investigated compared to other members of the SOCS family. We characterized the previously identified loss of function R96C point mutation of SOCS2 using a genome-edited mouse model that resumes the phenotype of Socs2 knockout mice. The response of macrophages to TLR-ligands and Staphylococcus aureus was examined. Conversely to previously published data using human monocyte-derived macrophages, the stimulation of bone-marrow-derived macrophages with various TLR ligands did not show any difference according to the SOCS2 variant. Upregulation of IL-6 and TNF-α pro-inflammatory cytokines production was only seen when the SOCS2 expression was promoted by the culture of macrophages in the presence of GM-CSF. Furthermore, we showed that the SOCS2 point mutation is associated with heightened STAT5 phosphorylation in a short time frame upon GM-CSF incubation. In mice, recruitment of neutrophil and F4/80int Ly6C+ inflammatory macrophage, as well as IFN-γ and IL-10 concentrations, are significantly increased upon S. aureus peritoneal infection. Altogether, these data support the idea that by lowering the pro-inflammatory environment, SOCS2 favors better control of bacterial burden during a systemic infection caused by S. aureus.