Application of mNGS in the Etiological Diagnosis of Thoracic and Abdominal Infection in Patients With End-Stage Liver Disease

BackgroundDespite the obvious advantages of metagenomic next-generation sequencing (mNGS) in etiological diagnosis of various infectious diseases, there are few reports on etiological diagnosis of suspected thoracic and abdominal infections in patients with end-stage liver disease (ESLD).MethodsSeventy-three ESLD patients were enrolled from January 2019 to May 2021 due to suspected complicated thoracic and abdominal infections with poor response to empirical anti-infective treatment. Pleural effusion and ascites samples of these patients were collected for mNGS detection and conventional pathogen culture. The application value of mNGS in etiological diagnosis of thoracic and abdominal infections in ESLD patients was finally evaluated.ResultsA total of 96 pathogens were detected using mNGS method, including 47 bacteria, 32 viruses, 14 fungi, 2 Mycobacterium tuberculosis, and 1 parasite. The positive rate of mNGS reached 42.5%, which was significantly higher than that of conventional culture method (21.9%) (p = 0.008). Considering neutrophil counts, the overall positive rate of bacteria detection of both methods in Polymorphonuclear Neutrophils (PMN) ≥250/mm3 group was 64.3% and in PMN <250/mm3 group was 23.7%. Compared with the final clinical diagnosis, the agreement rate of mNGS in patients with positive bacteria detection and with suspected positive bacteria detection was 78.6% (11/14) and 44.4% (8/18), respectively. In addition, the agreement rate of mNGS was 66.7% (4/6, respectively) in patients with positive and suspected fungal detection. Interestingly, of the 11 patients with fungal detection, 5 had alcoholic liver disease, accounting for 45.5% of all patients with alcoholic liver disease. We also detected 32 strains of viruses using mNGS, mainly cytomegalovirus (62.5%).ConclusionsThe mNGS method is a useful supplement to conventional culture methods, which performs a higher positive rate, higher sensitivity, and broader pathogen spectrum, especially for rare pathogens and those difficult to culture. For ESLD patients, mNGS has great prospects in early etiological diagnosis of thoracic and abdominal infections. In addition, the cutoff values for the diagnosis of bacterial infection (PMN ≥250/mm3) in the thoracic and abdominal cavities may need to be redefined.

Antibiotic Prophylaxis for Surgical Site Infection in General Surgery: Oncological Treatments and HIPEC

The procedure of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined surgical and oncological treatment for peritoneal carcinomatosis of various origins. Antibiotic prophylaxis is usually center-related and should be discussed together with the infectious disease specialist, taking into account the advanced oncologic condition of the patient, the complexity of surgery—often requiring multiorgan resections—and the risk of post-HIPEC neutropenia. The incidence of surgical site infection (SSI) after CRS and HIPEC ranges between 11 and 46%. These patients are also at high risk of postoperative abdominal infections and septic complications, and a bacterial translocation during HIPEC has been hypothesized. Many authors have proposed aggressive screening protocols and a high intra and postoperative alert, in order to minimize and promptly identify all possible infectious complications following CRS and HIPEC.

Errors in Diagnosing Infectious Diseases: A Physician Survey

Background: Infectious diseases are commonly missed or misdiagnosed. Errors in diagnosing infectious diseases not only affect the patient but also the community health.Objectives: To describe our investigation on the most common errors in diagnosing infectious diseases and their causes according to the physicians' reports.Methods: Between August 2018 and February 2019, specialist physicians and residents across Mashhad, Iran were invited to participate in a survey to report errors they had made or witnessed regarding the diagnosis of infectious diseases.Results: Overall, 465 cases were reported by 315 participants. The most common infectious diseases affected by diagnostic errors were upper respiratory tract infections (URTIs) (n = 69, 14.8%), tuberculosis (TB) (n = 66, 14.1%), pleuro-pulmonary infections (n = 54, 11.6%), central nervous system (CNS) infections (n = 51, 10.9%), and urinary tract infections (n = 45, 9.6%). Errors occurred most frequently in generating a diagnostic hypothesis (n = 259, 55/7%), followed by history taking (n = 200, 43%), and physical examination (n = 191, 41/1%). Errors related to the diagnosis of TB (odds ratio [OR]: 2.4, 95% confidence interval [CI]:0.9–5.7; P value: 0.047) and intra-abdominal infections (OR: 7.2, 95% CI: 0.9–53.8; P value: 0.02) were associated with more-serious outcomes.Conclusion: A substantial proportion of errors in diagnosing infectious diseases moderately or seriously affect patients' outcomes. URTIs, TB, and pleuropulmonary infections were the most frequently reported infectious diseases involved in diagnostic error while errors related to the diagnosis of TB and intraabdominal infections were more frequently associated with poor outcomes. Therefore, contagious and potentially life-threatening infectious diseases should always be considered in the differential diagnosis of patients who present with compatible clinical syndromes.

Antipseudomonal vs narrow-spectrum agents for the treatment of community-onset intra-abdominal infections

Background Antipseudomonal antibiotics are often used to treat community-acquired intra-abdominal infections (CA-IAI) despite common causative pathogens being susceptible to more narrow-spectrum agents. The purpose of this study was to compare treatment-associated complications in adult patients treated for CA-IAI with antipseudomonal versus narrow-spectrum regimens. Methods This retrospective cohort study included patients >18 years admitted for CA-IAI treated with antibiotics. The primary objective of this study was to compare 90-day treatment-associated complications between patients treated empirically with antipseudomonal versus narrow-spectrum regimens. Secondary objectives were to compare infection and treatment characteristics along with patient outcomes. Sub-group analyses were planned to compare outcomes of patients with low-risk and high-risk CA-IAI and patients requiring surgical intervention versus medically managed. Results A total of 350 patients were included: Antipseudomonal, n=204; Narrow-spectrum, n=146. There were no differences in 90-day treatment-associated complications between groups (Antipseudomonal 15.1% vs Narrow-spectrum 11.3%, p=0.296). Additionally, no differences were observed in hospital LOS, 90-day readmission, C. difficile, or mortality. In multivariate logistic regression, treatment with a narrow-spectrum regimen (OR 0.75 [95% C.I 0.39-1.45] was not independently associated with the primary outcome. No differences were observed in 90-day treatment-associated complications for patients with low-risk (Antipseudomonal 15% vs Narrow-spectrum 9.6%, p=0.154) or high-risk CA-IAI (Antipseudomonal 15.8% vs Narrow-spectrum 22.2%, p=0.588), or those who were surgically (Antipseudomonal 8.5% vs Narrow-spectrum 9.2%, p=0.877) or medically managed (Antipseudomonal 23.1 vs Narrow-spectrum 14.5, p=0.178). Conclusion Treatment-associated complications were similar among patients treated with antipseudomonal and narrow-spectrum antibiotics. Antipseudomonal therapy is likely unnecessary for most patients with CA-IAI.

An Alarming Mimicry of Intra-Abdominal Infections: Acute Appendiceal Diverticulitis

A 65-year-old woman presented with three days of colicky abdominal pain. Abdominal imaging illustrated small bowel enteritis, ascites in both paracolic gutters, and incidental hepatic steatosis. Although ascites fluid demonstrated high neutrophil count consistent with peritonitis and the patient received adequate antibiotics, she clinically deteriorated. Subsequent exploratory laparotomy revealed necrotic appendix and multiple intra-abdominal abscesses. Histopathology showed acute suppurative appendicitis with multiple other intact small diverticula, indicating likely perforation of inflamed appendiceal diverticula with subsequent abscess formation and abdominal peritonitis. This case highlights the importance of ascites fluid analysis and continued clinical correlation, especially in cases of rare entities with atypical presentations.

Revising Host Phenotypes of Sepsis Using Microbiology

Background: There is wide heterogeneity in sepsis in causative pathogens, host response, organ dysfunction, and outcomes. Clinical and biologic phenotypes of sepsis are proposed, but the role of pathogen data on sepsis classification is unknown.Methods: We conducted a secondary analysis of the Recombinant Human Activated Protein C (rhAPC) Worldwide Evaluation in Severe Sepsis (PROWESS) Study. We used latent class analysis (LCA) to identify sepsis phenotypes using, (i) only clinical variables (“host model”) and, (ii) combining clinical with microbiology variables (e.g., site of infection, culture-derived pathogen type, and anti-microbial resistance characteristics, “host-pathogen model”). We describe clinical characteristics, serum biomarkers, and outcomes of host and host-pathogen models. We tested the treatment effects of rhAPC by phenotype using Kaplan-Meier curves.Results: Among 1,690 subjects with severe sepsis, latent class modeling derived a 4-class host model and a 4-class host-pathogen model. In the host model, alpha type (N = 327, 19%) was younger and had less shock; beta type (N=518, 31%) was older with more comorbidities; gamma type (N = 532, 32%) had more pulmonary dysfunction; delta type (N = 313, 19%) had more liver, renal and hematologic dysfunction and shock. After the addition of microbiologic variables, 772 (46%) patients changed phenotype membership, and the median probability of phenotype membership increased from 0.95 to 0.97 (P < 0.01). When microbiology data were added, the contribution of individual variables to phenotypes showed greater change for beta and gamma types. In beta type, the proportion of abdominal infections (from 20 to 40%) increased, while gamma type patients had an increased rate of lung infections (from 50 to 78%) with worsening pulmonary function. Markers of coagulation such as d-dimer and plasminogen activator inhibitor (PAI)-1 were greater in the beta type and lower in the gamma type. The 28 day mortality was significantly different for individual phenotypes in host and host-pathogen models (both P < 0.01). The treatment effect of rhAPC obviously changed in gamma type when microbiology data were added (P-values of log rank test changed from 0.047 to 0.780).Conclusions: Sepsis host phenotype assignment was significantly modified when microbiology data were added to clinical variables, increasing cluster cohesiveness and homogeneity.

110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)