Clinical and bacteriological features and prognosis of ascitic fluid infection in Chinese patients with cirrhosis

Clinical and bacteriological features and prognosis of ascitic fluid infection in Chinese... Background: Spontaneous bacterial peritonitis (SBP) and bacterascites (BA) represent frequent and serious complications in cirrhosis patients with ascites. However, few detailed data are available regarding the clinical and bacteriological feature of SBP or BA patients in China. Methods: We retrospectively analyzed bacteriological and clinical characteristics of patients with SBP and BA at Beijing 302 Hospital in China from January 2012 to December 2015. Results: A total of 600 patients with SBP (n = 408) or BA (n = 192) were enrolled. Patients with BA appeared to have a less severe clinical manifestation and lower mortality rate than patients with SBP. Gram-negative bacteria formed the majority of pathogens in SBP (73.9%) and BA (55.8%) cases. Higher ascitic fluid polymorphonuclear leucocytes (PMN) count and hepatocellular carcinoma were independent risk factors for BA episode progressing to SBP. The concentration of blood urea nitrogen (BUN) was independent risk factor for 30-day mortality of BA patients. For patients with SBP, the independent risk factors for 30-day mortality were age, Model for End-Stage Liver Disease (MELD) score, septic shock and hepatocellular carcinoma. Patients with third-generation cephalosporin or carbapenems resistant infection had a significantly lower survival probability. There were significant differences in clinical characteristics and outcome among the major bacteria. Multivariate analysis showed that patients infected with Klebsiella spp. had higher hazard ratio of 30-day mortality. Conclusion: Our study reported the bacteriological and clinical characteristics of patients with SBP and BA. Higher ascitic fluid PMN count and hepatocellular carcinoma were found to be independent risk factors for BA episode progressed to SBP. Outcome of ascitic fluid infection in patients with cirrhosis was influenced by the type of bacteria and antimicrobial susceptibility. Keywords: Cirrhosis, Spontaneous bacterial peritonitis, Bacterascites, Causative pathogens, Mortality, Risk factor * Correspondence: bcm2003@sina.com; geno0109@vip.sina.com Nian-zhi Ning, Tao Li and Ju-ling Zhang contributed equally to this work. Clinical Diagnostic Center, Beijing 302 Hospital, No. 100 Western 4th Middle Ring Road, Beijing 100039, China The State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No.20 Dongda Street, Fengtai District, Beijing 100071, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ning et al. BMC Infectious Diseases (2018) 18:253 Page 2 of 11 Background Methods Cirrhotic patients with ascites usually face poor out- Setting and study design comes, especially if infections such as spontaneous This study was conducted at Beijing 302 Hospital, bacterial peritonitis (SBP) develop [1]. Prompt and which is the largest liver disease hospital in China. appropriate empirical antibiotic therapy must be initi- The hospital’s database holds records of clinical ated immediately after the diagnosis of SBP to cover histories, disease manifestations, physical and labora- the most commonly isolated bacteria [2]. Previous tory findings, and treatments of admitted patients. studies showed that gram-negative bacteria, mainly Bacteriology laboratory files and patient characteristics Enterobacteriaceae, were major causative organisms of were reviewed to identify all cases with positive ascitic fluid infection [3, 4]. Third generation cephalo- ascitic fluid cultures in cirrhotic patients hospitalized sporins are the first line antibiotics to treat spontan- in our institution from January 1, 2012 to December eous bacterial peritonitis; however, it was showed that 31, 2015. Patients with secondary peritonitis were ex- the initial treatment with cefotaxime, one of the most cluded from the study. Patients with a positive culture commonly used cephalosporins, failed more frequently for common skin contaminants (coagulase-negative than expected [5]. It maybeexplained bythe change staphylococci, corynebacteria, propionibacteria,and of causative pathogen profile and the emergence of Bacillus spp.) were also excluded. antibiotic-resistant pathogens. In recent years, several studies have reported changes in the epidemiology of Definitions causative bacteria in SBP. Enterococcus spp. was in- The diagnosis of cirrhosis was based on clinical, bio- creasingly recognized as an important pathogen of chemical, histological and/or radiological findings. A ascitic fluid infection for patients with cirrhosis. diagnostic paracentesis was performed in all patients as Reuken et al. confirmed a profound increase in the recommended by European Association for the Study of frequency of Enterococcal infection from 11% to 35% the Liver (EASL) [2]. SBP was diagnosed when (a) ascitic between 2000 and 2011 in a German tertiary center fluid polymorphonuclear leucocytes (PMN) count ≥250 [6]. Piroth et al. found that Enteroccocci were iso- cells/μL, (b) ascitic fluid culture was positive; (c) there lated in 24% of ascitic fluid infection episodes, and was no evident intra-abdominal surgically treatable in 48% from patients receiving quinolone prophylaxis source for infection [2, 14]. The diagnosis of BA was in four French hospitals [7]. The emergence and made when (a) the ascitic fluid PMN count < 250 spread of multi-drug resistant bacteria such as cells/μL, (b) ascitic fluid culture was positive; (c) methicillin-resistant Staphylococcus aureus (MRSA), there was no evident intra-abdominal surgically extended-spectrum beta-lactamases (ESBL)-producing treatable source for infection [2, 15]. Fever, chills, Enterobacteriaceae and Carbapenemase producing abdominal pain and abdominal tenderness were (KPC) Klebsiella pneumonia are also of great con- considered symptoms of peritonitis [15]. Severity of cern since they may be associated with higher mor- cirrhosis was assessed at the time of the SBP or BA tality rate [8]. In recent years, an increased diagnosis using the Model for End-Stage Liver Disease prevalence of multi-drug resistant bacteria in SBP (MELD) score [16]. Nosocomial infection was defined as cases was reported [9, 10]. an infection that occurred > 48 h after admission to the Liver diseases affect ~ 300 million people in China, hospital [17]. and the incidence of liver cirrhosis has increased during recent years because of the low awareness of the perni- ciousness of liver diseases and low treatment rate for Microbiological methods these patients [11]. Some studies have described the Ascitic fluid samples were extracted and inoculated into pathogens profile and drug resistance of SBP in cirrhotic bottles at the patient’s bedside by aseptic manipulation patients in China [12, 13]. However, those studies were and cultured with BacT/Alert 240 automated blood cul- limited by being single-center study and failed to investi- ture system (BioMérieux France). White blood cell gate the characteristics and outcome of SBP. Thus, more (WBC) and PMN were counted by Sysmex automatic timely and comprehensive studies on bacteriological and cell analyzer XT-4000 (SYSMEX, Japan). Microorganism clinical characteristics of SBP and BA in China are identification was performed using the VITEK-II auto necessary. microbe system (BioMérieux France). Isolated pathogens In this study, we aimed at assessing the possible were tested for antimicrobial susceptibility using the changes in bacteria etiology of SBP and BA, the risk fac- disk-diffusion method and minimum inhibitory concen- tors of 30-day mortality and the differences in clinical tration testing. Antimicrobial susceptibility was judged characteristics and prognosis among patients with differ- according to guidelines of the Clinical and Laboratory ent causative pathogens. Standards Institute (CLSI) [18]. Ning et al. BMC Infectious Diseases (2018) 18:253 Page 3 of 11 Empirical antibiotic therapy Statistical analysis Third-generation cephalosporins (TGC), such as cefo- Quantitative variables were given as the mean ± standard de- taxime, were used as empirical therapy antibiotic in viation or the median (interquartile range). Student’s t test our hospital. Empirical antibiotic therapy initiated im- or Mann–Whitney U-test was used to compare continuous mediately on all patients with ascitic PMN count variables, and the x test or Fisher’sexact test wasusedto ≥250 cells/μL, without the results of ascitic fluid cul- compare categorical variables. Statistical differences among ture. Bacterascites patients exhibit signs of systemic several groups were analyzed using one-way ANOVA or the inflammation are also treated with cefotaxime. Other- nonparametric Kruskal-Wallis test, as appropriate. Risk fac- wise, the bacterascites patient should undergo a sec- tors for SBP development were determined by multivariate ond paracentesis when culture results come back binary logistic regression including significant univariate positive. Patients in whom the repeat PMN count is predictors (p < 0.05) using stepwise backward elimination. ≥250/μL would be treated for SBP. Carbapenems were The life-table method was used to compare survival prob- used in all severe patients with septic shock. Paracen- ability for patients according to different variables. A Cox tesis was performed repeatedly 2–3 days after initi- proportional hazard model analysis was carried out to iden- ation of antibiotic therapy to determine leukocyte and tify independent predictors of 30-day mortality for every epi- PMN counts in ascitic fluid. sode, defining death as the main event. Variables with p <0. Fig. 1 Flowchart of patient enrollment in the study. Abbreviation: AF, ascitic fluid; SBP, spontaneous bacterial peritonitis; BA, bacterascites; PMN, polymorphonuclear leucocytes Ning et al. BMC Infectious Diseases (2018) 18:253 Page 4 of 11 Table 1 Clinical and laboratory data of cirrhotic patients with BA and SBP Total (n = 600) BA (n = 192) SBP (n = 408) p Sex (male) 465 (77.5%) 144 (75%) 321 (78.7%) 0.314 Age (yr) 53.9 ± 11.9 55.7 ± 12.1 53.1 ± 11.6 0.011 Presentation of symptoms 458 (76.3%) 118 (61.5%) 340 (83.3%) < 0.001 Nosocomial infection 287 (47.8%) 84 (43.8%) 203 (49.8%) 0.17 MELD score 19.7 ± 9.5 16.3 ± 7.9 21.4 ± 9.8 < 0.001 Days in hospital 13 (7–19) 13 (7–18) 13 (7–19) 0.732 Days between admission and onset of infection 2 (0–9) 2 (0–6) 2 (0–10) 0.03 Causes of cirrhosis Hepatitis B 370 (61.7%) 105 (54.7%) 265 (65%) 0.016 Hepatitis C 59 (9.8%) 24 (12.5%) 35 (8.6%) 0.132 Biliary 22 (3.7%) 7 (3.6%) 15 (3.7%) 0.985 Alcoholic 90 (15%) 37 (19.3%) 53 (13%) 0.044 Others 59 (9.8%) 19 (9.9%) 40 (9.8%) 0.972 Serum features ALT(U/L) 35.0 (21.0–64.0) 30.0 (20.0–48.0) 38.0 (21.0–71.8) 0.001 AST(U/L) 60.0 (37.0–105.8) 53.0 (33.0–86.0) 65.5 (39.0–111.8) 0.004 Prealbumin(mg/L) 47.2 ± 25.8 55.3 ± 23.9 43.4 ± 25.8 < 0.001 Prothrombin time(S) 18.1 (15.0–22.6) 54.5 (40.2–68.0) 41.8 (26.0–57.7) < 0.001 BUN(mmol/L) 8.0 (5.1–13.2) 6.4 (4.8–9.9) 8.9 (5.4–14.4) < 0.001 Serum PMN(cells/μL) 5.4 (3.0–8.6) 4.0 (2.4–6.4) 6.2 (3.6–9.8) < 0.001 Serum WBC(cells/μL) 6.9 (4.3–10.5) 5.4 (3.4–8.3) 7.7 (5.1–11.6) < 0.001 Creatinine (μmol/L) 97.5 (78.0–138.8) 90.0 (70.2–111.8) 105.0 (82.0–157.0) < 0.001 Total protein(g/L) 55.0 (49.0–61.0) 56.0 (51.0–63.0) 54.0 (48.0–60.0) 0.001 Total bilirubin (μmol/L) 82.4 (35.9–233.4) 51.5 (30.0–144.3) 107.9 (42.7–260.0) < 0.001 Ascitic features Ascitic PMN(cells/μL) 799.5 (53.1–5405.8) 22.9 (5.6–71.3) 3099.9 (720.2–7873.0) < 0.001 Ascitic WBC(cells/μL) 1241.0 (253.3–6565.0) 169.0 (90.3–310.8) 3850.5 (1119.3–9826.8) < 0.001 Hepatocellular carcinoma 175 (29.2%) 49 (25.5%) 126 (30.9%) 0.178 Hepatic encephalopathy 203 (33.8%) 58 (30.2%) 145 (35.5%) 0.198 Septic shock 108 (18%) 19 (9.9%) 89 (21.8%) < 0.001 Upper gastrointestinal bleeding 114 (19%) 34 (17.7%) 80 (19.6%) 0.580 Diabetes mellitus 101 (16.8%) 37 (19.3%) 64 (15.7%) 0.274 30-day mortality 131 (21.8%) 26 (13.5%) 105 (25.7%) 0.001 Abbreviation: SBP spontaneous bacterial peritonitis, BA bacterascites, MELD Model for End-Stage Liver Disease, WBC white blood cell, PMN polymorphonuclear leukocytes, ALT alanine transarninase, AST aspartate aminotransferase, Bun blood urea nitrogen P:compared between BA and SBP. P-values < 0.05 are indicated in bold 05 in the univariate analysis were candidates for multivariate diagnostic paracentesis. Ascitic fluid culture in blood analysis and non-significant factors were removed by a back- culture bottles was positive in 13.0% (n = 1088) of pa- ward selection process. All tests were two-tailed and p <0. tients. The flowchart for patient enrollment was shown 05 were considered to be statistically significant. IBM SPSS in Fig. 1, and only 600 ascitic fluid infection episodes Statistics 19.0 was used for statistical analyses. (408 SBP and 192 BA) were identified in patients with cirrhosis and enrolled in this study (Fig. 1). Laboratory Results and clinical features at the time of diagnostic paracen- General characteristics and clinical presentation tesis were given in Table 1. Serum laboratory data During the study period (January 1, 2012 to December (alanine transaminase/ALT, aspartate aminotransferase/ 31, 2015), a total of 8365 patients were subjected to AST, prealbumin, BUN, creatinine, total protenin, total Ning et al. BMC Infectious Diseases (2018) 18:253 Page 5 of 11 bilirubin, erythrocytes/WBC, PMN and prothrombin treating gram-positive pathogen infections because of time) and ascitic features (WBC and PMN) of SBP were the low resistant rates. Nine Acinetobacter baumannii significantly higher than that of BA (p< 0.01). In add- strains were multidrug resistant. Multidrug resistant itional, septic shock was more common in patients with pathogens were associated with high 30-day mortality SBP (p< 0.01). There were no significant differences in rate. Our data showed that patients infected with multi- the percentage of nosocomial episodes between SBP and drug resistant Acinetobacter spp. had significantly higher BA. 30-day mortality compared to patients infected with sus- ceptible Acinetobacter spp. (100% vs. 11.1%, respectively, Bacteriological characteristics and impact of drug p < 0.001, Fig. 2b). Survival curves shows that patients resistance on mortality infected with TGC-resistant bacteria had a significantly Among the 600 patients, 554 patients had monobacterial lower survival probability than those with TGC- infection and the other 46 had polybacterial infection. susceptible bacteria (p= 0.001, Fig. 2c). Also, there was a Thus, a total of 656 pathogens were isolated from these significantly lower survival probability for patients in- patients and shown in Table 2. Gram-negative bacteria, fected with carbapenem–resistant organisms than it was accounting for 68.1% of pathogens in total, were more in carbapenem-susceptible cases (p< 0.001, Fig. 2d). common than gram-positive bacteria. The major Levofloxacin-resistant organisms were not associated pathogens identified were Escherichia coli (n = 267, 40. with greater mortality than levofloxacin-susceptible ones 7%), Streptococcus spp. (n = 110, 16.8%), Klebsiella spp. (p= 0.092, Fig. 2e). (n = 87, 13.3%), Enterococcus spp. (n = 66, 10.1%), Coagu- lase-positive staphylococci (n = 25, 3.8%), Enterobacter Risk factors for BA progressing to SBP spp. (n = 20, 3.0%) and Acinetobacter spp. (n = 18, 2.7%). For 187 of 237 cases with ascitic fluid PMN counts < 250 In total, these 7 types of pathogens account for 90.4% (n cells/μL at the first paracentesis, a follow-up paracentesis = 593) of the causative bacteria. The antimicrobial sus- was performed when culture results come back positive. ceptibility of these bacteria was shown in Fig. 2a. Nearly In our hospital, if BA patient exhibited symptoms of peri- half of Escherichia coli (49.4%) were resistant to TGC, tonitis, the patient would be treated with empirical anti- on the contrary, most of Klebsiella spp. isolates were biotic immediately. The development of BA between the sensitive to TGC. Vancomycin was a reliable agent for first and second paracentesis (usually 2–3 days) was of Table 2 Types of bacteria isolated from cultures of ascitic fluid in patients with cirrhosis Isolates no.(%) of isolates Total (n = 656) BA (n = 208) SBP (n = 448) P Gram-negative organisms Total 447 (68.1%) 116 (55.8%) 331 (73.9%) < 0.001 Escherichia coli 267 (40.7%) 71 (34.1%) 196 (43.8%) 0.020 Klebsiella spp. 87 (13.3%) 20 (9.6%) 67 (15.0%) 0.061 Enterobacter spp. 20 (3.0%) 5 (2.4%) 15 (3.3%) 0.513 Acinetobacter spp. 18 (2.7%) 5 (2.4%) 13 (2.9%) 0.716 Aeromonas spp. 9 (1.4%) 2 (1.0%) 7 (1.6%) 0.726 Citrobacter spp. 8 (1.2%) 3 (1.4%) 5 (1.1%) 0.713 Serratia spp. 7 (1.1%) 2 (1.0%) 5 (1.1%) 1.000 Burkholderia spp. 5 (0.8%) 3 (1.4%) 2 (0.4%) 0.333 Pseudomonas spp. 8 (1.2%) 1 (0.5%) 7 (1.6%) 0.446 Other 18 (4.0%) 4 (1.9%) 14 (3.1%) – Gram-positive organisms Total 209 (31.9%) 92 (44.2%) 117 (26.1%) < 0.001 Streptococcus spp. 110 (16.8%) 47 (22.6%) 63 (14.1%) 0.006 Enterococcus spp. 66 (10.1%) 29 (13.9%) 37 (8.3%) 0.024 Coagulase-positive staphylococci 25 (3.8%) 11 (5.3%) 14 (3.1%) 0.178 Kocuria spp. 3 (0.5%) 1 (0.5%) 2 (0.4%) 1.000 Other 5 (0.8%) 4 (1.9%) 1 (0.2%) – P:compared between isolates collected from BA and SBP. P-values < 0.05 are indicated in bold Ning et al. BMC Infectious Diseases (2018) 18:253 Page 6 of 11 Fig. 2 Drug resistance of major bacteria and impact of antibiotic resistance on mortality. (a) Resistance to antibiotics among seven major isolates. * Enterococcus spp. is naturally resistant to third-generation cephalosporins (TGC). TZP, piperacillin/tazobactam. (b) Effect of multi-drug resistance on patient mortality with respect to Acinetobacter spp. A.h.: Acinetobacter haemolyticus; A.l.: Acinetobacter lwoffii. (c, d, e) 30-day survival curve for patients with positive ascites culture according to third-generation cephalosporin, carbapenem or levofloxacin resistance (p= 0.004, < 0.001 and = 0.092, respectively) concern. Thus, potential risk factors for BA progressing to them. Multivariate analysis, including the variables asso- SBP were identified (Table 3). Results showed that devel- ciated with mortality by univariate analysis, showed that opment of BA was associated with the severity degree of the concentration of BUN was independent risk factor liver diseases (MELD score, p < 0.001), serum PMN (p =0. for 30-day mortality of BA patients (Table 4). For pa- 002), ascitic PMN (p = 0.002), presentation of fever (p =0. tients with SBP, the independent risk factors for 30-day 036) and serious complications (hepatocellular carcinoma mortality were age, MELD score, septic shock and hepa- and septic shock, p = 0.035 and 0.014, respectively). In tocellular carcinoma (Table 5). multivariate analysis, only the presentation of hepatocellu- lar carcinoma (OR = 3.047, 95% CI:1.161–7.997, p =0.024) Impact of isolate type on clinical characteristics and mortality and higher ascitic PMN count (OR = 1.007, 95% CI: 1. To study the impact of isolate type on clinical characteris- 001–1.013, p = 0.023) remained independent predictors tics and mortality, we limited the analysis to patients with for BA progressing to SBP. monobacterial ascitic fluid infections. Clinical characteris- tics of patients infected with different types of bacteria Risk factors for 30-day mortality of patients with BA and SBP were shown in (Additional file 1): Table S1. There were The 30-day mortality of patients with SBP was signifi- significant differences in clinical characteristics among the cantly higher than that of BA (25.7% vs. 13.5%, p =0. seven types of bacterial infection, for example the percent- 001) (Table 1). We studied independent risk factors of age of peritonitis symptoms, several clinical complications, 30-day mortality in BA and SBP respectively, and found type of peritonitis (SBP), nosocomial infection, serum and that independent risk factors were different between ascitic features, MELD score and days between admission Ning et al. BMC Infectious Diseases (2018) 18:253 Page 7 of 11 Table 3 Risk factors for BA episodes progressing to SBP Progress to SBP No progress to Univariate analysis Multivariate analysis (n = 45) SBP (n = 142) P Odds ratio (95% CI) P Odds ratio (95% CI) Sex (male) 37 (82.2%) 108 (76.1%) 0.390 0.687 (0.292–1.616) –– Age (yr) 52.4 ± 9.2 55.4 ± 12.5 0.144 0.979(0.951–1.007) –– Nosocomial infection 23 (51.1%) 57 (40.1%) 0.197 1.559 (0.795–3.059) –– MELD score 23.0 ± 10.7 16.3 ± 7.4 < 0.001 1.089 (1.046–1.133) 0.503 1.036 (0.934–1.149) Days between admission 3(0–7.5) 1 (0–6) 0.239 1.018 (0.989–1.048) –– and onset of infection Fever 30 (66.7%) 69 (48.6%) 0.036 2.116 (1.049–4.268) 0.053 2.533 (0.986–6.505) Chills 4 (8.9%) 11 (7.7%) 0.806 1.162 (0.351–3.846) –– Abdominal pain 15(33.3%) 34 (23.9%) 0.214 1.588(0.765–3.295) –– ALT(U/L) 42.0 (24.0–106.0) 30.0 (20.0–49.0) 0.011 1.005 (1.001–1.009) 0.326 1.004 (0.996–1.011) AST(U/L) 70.0 (42.0–135.5) 52.5 (33.0–88.5) 0.030 1.003(1.000–1.005) 0.602 1.001(0.996–1.006) Prealbumin(mg/L) 41.3 ± 22.7 56.1 ± 24.8 0.001 0.973 (0.957–0.989) 0.224 0.986 (0.965–1.008) Prothrombin time(S) 19.2 (15.7–31.1) 16.3 (14.1–19.3) < 0.001 1.078 (1.034–1.125) 0.118 1.064 (0.984–1.149) Bun(mmol/L) 8.6 (5.5–13.9) 6.6 (4.8–11.5) 0.074 1.039 (0.996–1.083) –– Serum PMN(cells/μL) 4.9 (2.8–9.8) 4.2 (2.4–6.6) 0.002 1.12 (1.042–1.205) 0.161 1.641 (0.822–3.277) Serum WBC(cells/μL) 6.1 (4.0–11.8) 5.4 (3.6–8.5) 0.006 1.096 (1.027–1.17) 0.223 0.671 (0.353–1.275) Serum creatinine (μmol/L) 105.0 (82.0–159.0) 88.5 (70.8–113.5) 0.15 1.003 (0.999–1.006) –– Total protein(g/L) 56.0 (50.0–61.0) 55.0 (50.0–63.0) 0.679 0.997 (0.983–1.011) –– Total bilirubin (μmol/L) 98.5 (43.9–311.4) 51.9 (32.4–140.2) 0.018 1.002 (1.000–1.005) 0.36 0.998 (0.994–1.002) Ascitic PMN(cells/μL) 64.7 (21.7–141.7) 24.0 (5.3–74.8) 0.002 1.008 (1.003–1.013) 0.029 1.007 (1.001–1.013) Ascitic WBC(cells/μL) 257.0(114.5–370.0) 161.0 (91.8–302.8) 0.529 1.000(0.999–1.002) –– hepatocellular carcinoma 20 (44.4%) 39 (27.5%) 0.035 2.113 (1.056–4.229) 0.024 3.047 (1.161–7.997) hepatic encephalopathy 16(35.6%) 43(30.3%) 0.508 1.27(0.626–2.577) –– septic shock 12(26.7%) 16 (11.3%) 0.014 2.864 (1.235–6.639) 0.799 0.851 (0.246–2.949) Gastrointestinal haemorrhage 11 (24.4%) 29 (20.4%) 0.567 1.261 (0.57–2.786) –– diabetes mellitus 7 (15.6%) 28(19.7%) 0.534 0.75 (0.303–1.856) –– P-values < 0.05 and corresponding Odds ratio are indicated in bold and onset of infection (p< 0.01). To investigate the impact China, and it permits statistical comparison and risk fac- of isolate type on the 30-day mortality, Cox proportional tor analysis for prognosis of SBP and BA. hazard model was used to control confounding variables, Nearly half (47.8%) of the ascitic fluid infection were such as MELD score, defining isolate type as dummy vari- nosocomial-acquired. It could be explained in part by able (Table 6 and Additional file 1: Table S2). In univariate that patients enrolled in this study underwent frequent analysis, patients infected with Acinetobacter spp., Klebsi- hospitalization before they were admitted to our depart- ella spp. and Enterococcus spp. had higher hazard ratios of ment and experienced long hospital stays. Previous stud- 30-day mortality compared to those infected with Escheri- ies also reported high nosocomial infection rates in chia coli. Multivariate analysis showed that only patients those patients [4, 19]. High rate of nosocomial-acquired infected with Klebsiella spp. had higher hazard ratio of SBP was not a common in China. Li et al. found that 30-day mortality compared to those with Escherichia coli nearly two-thirds of SBP in cirrhotic patients was (Table 6). community-acquired in a hospital located in Zhejiang province of China [12]. Discussion In comparison with the data base of SBP, little data for In this study, we retrospectively investigated the clinical BA is available. Previous researches indicated that many of and bacteriological characteristics of 600 SBP and BA patients with BA indeed were symptomatic and as a vari- patients, and studied the outcomes of these patients. To ant of spontaneous bacterial peritonitis [20, 21]. However, our knowledge, this is the most comprehensive and lar- the difference between BA and SBP is uncertain and con- gest dataset of patients with ascitic fluid infection from troversial because the lack of appropriate data sets and Ning et al. BMC Infectious Diseases (2018) 18:253 Page 8 of 11 Table 4 Risk factors for 30-day mortality in patients with BA Survivors Nonsurvivors Univariate analysis Multivariate analysis (n = 166) (n = 26) HR (95% Cl) P HR (95% Cl) p Age (yr) 55.3 ± 12.2 58.3 ± 11.6 1.022(0.991–1.055) 0.162 –– Sex (male) 125 (75.3%) 19 (73.1%) 1.152 (0.484–2.742) 0.750 –– Nosocomial infection 68 (41%) 16 (61.5%) 2.21 (1.000–4.884) 0.050 –– MELD score 14.7 ± 6.8 26.1 ± 7.7 1.153 (1.102–1.207) < 0.001 1.054 (0.988–1.125) 0.108 Days between admission 2(0–6) 4.5(0–17.3) 1.022 (1.002–1.042) 0.027 1.015 (0.986–1.045) 0.301 and onset of infection Symptoms of peritonitis 102 (61.4%) 16 (61.5%) 0.915 (0.414–2.022) 0.826 –– ALT(U/L) 28.0 (19.0–46.0) 45.5 (28.0–93.3) 1.003(1.000–1.006) 0.036 1.001(0.992–1.009) 0.861 AST(U/L) 50.0 (32.0–75.5) 88.0 (51.5–180.8) 1.003(1.001–1.005) 0.002 1.003(0.997–1.008) 0.308 Prealbumin(mg/L) 57.3 ± 24.2 42.6 ± 17.8 0.975 (0.957–0.993) 0.006 0.981 (0.958–1.004) 0.100 Bun(mmol/L) 5.9(4.7–9.1) 11.5 (7.7–15.5) 1.099 (1.055–1.143) < 0.001 1.1 (1.033–1.173) 0.003 Serum PMN (cells/μL) 3.6 (2.1–5.8) 6.5 (5.2–12.6) 1.219 (1.124–1.322) < 0.001 1.027 (0.926–1.14) 0.609 Total Protein(g/L) 57.0 (52.0–64.0) 51.0 (47.0–54.0) 0.979(0.957–1.001) 0.060 –– Ascitic PMN(cells/μL) 24.0 (6.5–69.0) 13.0 (3.2–115.0) 1.002 (0.996–1.008) 0.589 –– Hepatocellular carcinoma 42 (25.3%) 7 (26.9%) 1.056 (0.443–2.514) 0.903 –– Hepatic encephalopathy 39 (23.5%) 19 (73.1%) 6.442 (2.704–15.346) < 0.001 2.382 (0.849–6.679) 0.099 Septic shock 8 (4.8%) 11 (42.3%) 5.725 (2.614–12.536) < 0.001 2.247 (0.876–5.762) 0.092 Gastrointestinal haemorrhage 23 (13.9%) 11 (42.3%) 2.966 (1.361–6.466) 0.006 1.705 (0.655–4.438) 0.274 Diabetes mellitus 34 (20.5%) 3 (11.5%) 0.576 (0.1730–1.920) 0.369 –– P-values < 0.05 and corresponding HR are indicated in bold systematic analyses. In this retrospective study, we com- and SBP patients. The reason might be that SBP patients pared the clinical and bacteriological characteristics be- had higher MELD score and were thus sicker. tween SBP and BA. BA patients had lower 30-day Prognosis of patients with ascitic fluid infection was mortality and less severe liver diseases than SBP patients, influenced by bacterial antibiotic resistance. Our study as evidenced by a lower serum ALT and AST and lower suggested that resistant to TGC, which have been con- MELD scores, which is consistent with a previous report sidered as first-line treatment of SBP [14, 24], were asso- [21]. Symptoms of peritonitis, especially fever, and septic ciated with lower survival probability. This result is shock were less common in BA patients. In addition, consistent with previously studies [25–27]. Also, gram-positive organisms, such as Streptococcus and carbapenem-resistant gram-negative pathogen is a chal- Enterococcus, were more frequently found in BA than in lenge for treating peritonitis. Our study showed that SBP episodes. Our data also showed that hepatocellular carbapenem-resistance is associated with significantly carcinoma and higher ascitic PMN count were independ- lower 30-day survival probability (p < 0.01). Thus, this ent risk factors for BA episodes progressing to SBP. BA can be a life-threatening factor for cirrhotic patients with patients accompanied with hepatocellular carcinoma and ascitic fluid infection. higher ascitic PMN count thus should be optimal candi- Gram-positive pathogens were increasingly recognized dates for primary prophylaxis of SBP. as important causative bacteria in patients with SBP and Consistent with previous studies, we also found that BA [6, 7, 27, 28]. However, the impacts of those causa- MELD score [22], the presentation of hepatocellular car- tive bacteria on the outcome of patients with ascitic fluid cinoma [23] and presentation of septic shock [19] were infection are less well understood. Polymicrobial infec- independent risk factors for 30-day mortality at the time tion would be a confounding factor in studying the im- of SBP diagnosis. However, only the concentration of pact of isolate type on characteristic and outcome of BUN were identified as independent predictive factor of ascitic fluid infection. For instance, previous study have 30-day mortality in patients with BA. To our knowledge, shown that Enterococci were of low virulence and were this is the first study to identify the independent risk factors often found as a secondary invader in polymicrobial in- of 30-day mortality in patients with BA. The independent fections and the clinical relevance of enterococcal peri- risk factors of 30-day mortality were different between BA tonitis is subject of debate [29]. Thus, we limited our Ning et al. BMC Infectious Diseases (2018) 18:253 Page 9 of 11 Table 5 Risk factors for 30-day mortality in patients with SBP Survivors Nonsurvivors Univariate analysis Multivariate analysis (n = 303) (n = 105) HR (95% Cl) P HR (95% Cl) p Age(yr) 52.1 ± 11.5 55.9 ± 11.7 1.025 (1.008–1.041) 0.003 1.021 (1.003–1.04) 0.022 Sex (male) 245 (80.9%) 76 (72.4%) 1.326 (0.864–2.035) 0.196 –– Nosocomial infection 134 (44.2%) 69 (65.7%) 2.311 (1.544–3.46) < 0.001 1.577 (0.946–2.627) 0.081 MELD score 18.7 ± 8.4 29.1 ± 9.5 1.1 (1.078–1.122) < 0.001 1.067 (1.04–1.095) < 0.001 Days between admission 2(0–7) 8(1–18.5) 1.028 (1.016–1.039) < 0.001 1.015 (0.999–1.032) 0.07 and onset of infection Symptoms of peritonitis 259 (85.5%) 81 (77.1%) 0.672 (0.426–1.06) 0.088 –– ALT(U/L) 36 (21–63) 57 (25–150.5) 1.001 (1–1.001) 0.002 1.001 (1.000–1.002) 0.310 AST(U/L) 59 (37–100) 95 (48–202.5) 1(1–1.001) < 0.001 1.000 (1.000–1.001) 0.728 Prealbumin(mg/L) 46.8 ± 25.9 33.7 ± 22.9 0.98 (0.971–0.989) < 0.001 0.999 (0.989–1.009) 0.791 Bun(mmol/L) 8 (5.1–11.9) 13.3 (8.1–20.8) 1.061 (1.043–1.078) < 0.001 0.998(0.977–1.019) 0.824 Serum PMN (cells/μL) 5.8 (3.5–9.2) 7.5 (3.8–12.2) 1.061 (1.032–1.091) < 0.001 1.001(0.97–1.034) 0.931 Total Protein(g/L) 55 (49–60) 51 (44–57.5) 0.979(0.967–0.991) 0.001 1.002 (0.988–1.016) 0.778 Ascitic PMN(cells/μL) 2760 (741.4–7821) 3717.2 (660.9–8356) 1 (1–1) 0.241 –– Hepatocellular carcinoma 83 (27.4%) 43 (41%) 1.874 (1.268–2.771) 0.002 1.755 (1.14–2.703) 0.011 Hepatic encephalopathy 80 (26.4%) 65 (61.9%) 3.282 (2.213–4.866) < 0.001 1.533(0.972–2.42) 0.066 Septic shock 24 (7.9%) 65 (61.9%) 7.624 (5.135–11.321) < 0.001 4.169 (2.599–6.686) < 0.001 Gastrointestinal haemorrhage 47 (15.5%) 33 (31.4%) 2.02 (1.337–3.05) 0.001 1.243 (0.798–1.936) 0.337 Diabetes mellitus 48 (15.8%) 16 (15.2%) 1.044 (0.613–1.778) 0.875 –– P-values < 0.05 and corresponding HR are indicated in bold analysis to patients with monobacterial peritonitis when infection in multivariate analysis. Patients accompanied investigating the impact of isolate type on clinical charac- with Klebsiella spp. peritonitis seem to be associated with teristics and mortality. Reuken et al. also limited their poorer prognosis even though those bacteria were less re- analysis to monobacterial peritonitis and found that en- sistant against frequently used antimicrobial. terococcal SBP patients had a poorer prognosis than non- There were limitations in our study. First, our study enterococcal SBP [6]. In our study, we only observed was limited by being a single-center retrospective study. higher hazard ratio of 30-day mortality in patients infected However, our hospital is a referral center for liver disease with Acinetobacter spp., Klebsiella spp. and Enterococcus in the capital of China and many patients come from spp. compared to those infected with Escherichia coli in different regions of the country. Compared with a previ- univariate analysis. After adjusting for clinical parameters, ous report [12], there were similar pathogen profiles and however, only Klebsiella spp. infection (HR = 1.888, drug resistance in the two hospitals in China. The major 95%Cl, 1.092–3.265, p = 0.024) showed higher hazard ratio pathogens in both hospitals were E. coli, K. pneumoniae, of 30-day mortality compared to that of Escherichia coli Enterococcus spp. and S. aureus. Furthermore, the Table 6 Hazard ratios (HRs) for 30-day mortality of different types of bacteria against reference strains Bacteria Univariate analysis Multivariate analysis HR (95%Cl) P HR (95%Cl) p Escherichia coli Ref Ref Coagulase-positive staphylococci 0.298 (0.041–2.161) 0.231 0.399 (0.054–2.929) 0.367 Acinetobacter spp. 3.881 (1.654–9.108) 0.002 0.805 (0.306–2.118) 0.665 Enterobacter spp. 2.385 (0.944–6.025) 0.066 1.537 (0.572–4.131) 0.394 Klebsiella spp. 2.092 (1.264–3.46) 0.004 1.888 (1.092–3.265) 0.024 Enterococcus spp. 2.842 (1.644–4.911) < 0.001 0.964 (0.513–1.813) 0.911 Streptococcus spp. 0.551 (0.259–1.171) 0.121 0.95 (0.437–2.066) 0.896 Note: HRs were analyzed by using proportional hazards Cox regression model. In multivariate analysis, HR was adjusted for clinical parameters. Only the major monobacteria were included in analysis. Detailed information was shown in Table S2. P-values < 0.05 and corresponding HR are indicated in bold Ning et al. BMC Infectious Diseases (2018) 18:253 Page 10 of 11 resistant rate of gram-negative bacteria against TGC was Availability of data and materials All data generated or analysed during this study are included in this published both approximately 40%. Thus, to a lesser extent, our article [and its Additional file 1]. data may be representative in SBP patients in China. Second, patients with culture-negative SBP (ascitic Ethics approval and consent to participate PMN ≥ 250 cells/μl and a negative culture result) were The study was reviewed and approved by the Beijing 302 Hospital Research Ethics Committee. The Beijing 302 Hospital Research Ethics Committee waived not included in this study. Thus, our findings, such as the need for written informed consent from the participants due to the de- independent risk factors of 30-day mortality in patients identified secondary data analyzed in this study. with SBP, could not be applied to those patients. Competing interests The authors declare that they have no competing interests. Conclusions In conclusion, there were significant differences be- tween BA and SBP regarding clinical and bacterial Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published characteristics and 30-day mortality. Presentation of maps and institutional affiliations. hepatocellular carcinoma and higher ascitic PMN count were independent risk factors for BA progres- Author details The State Key Laboratory of Pathogen and Biosecurity, Beijing sing to SBP. The concentration of BUN were identi- Institute of Microbiology and Epidemiology, No.20 Dongda Street, fied as independent predictive factors of 30-day Fengtai District, Beijing 100071, China. Clinical Diagnostic Center, mortality in patients with BA. For patients with SBP, Beijing 302 Hospital, No. 100 Western 4th Middle Ring Road, Beijing 100039, China. Research Center for Biological Therapy, Institute of the independent risk factors for 30-day mortality were Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China. age, MELD score, septic shock and hepatocellular car- cinoma. The Klebsiella spp. related peritonitis is of Received: 8 August 2017 Accepted: 17 April 2018 concern, because those infections are associated with poorer outcome. Strict infection control must be im- References plemented to control the spread of third-generation 1. Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, cephalosporin or carbapenem-resistant pathogens. Burroughs AK: Infections in patients with cirrhosis increase mortality four- fold and should be used in determining prognosis. Gastroenterology 2010, 139(4):1246–1256, 1256.e1241–1245. Additional file 2. European Association for the Study of the L. 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ALT: Alanine transaminase;; AST: Aspartate aminotransferase;; 5. Angeloni S, Leboffe C, Parente A, Venditti M, Giordano A, Merli M, Riggio O. BA: Bacterascites;; BUN: Blood urea nitrogen;; MELD: End-Stage Liver Disease;; Efficacy of current guidelines for the treatment of spontaneous bacterial PMN: Polymorphonuclear;; SBP: Spontaneous bacterial peritonitis;; TGC: Third- peritonitis in the clinical practice. World J Gastroenterol. 2008;14(17):2757–62. generation cephalosporins; WBC: White blood cell; 6. Reuken PA, Pletz MW, Baier M, Pfister W, Stallmach A, Bruns T. Emergence of spontaneous bacterial peritonitis due to enterococci - risk factors and outcome in a 12-year retrospective study. Aliment Pharmacol Ther. 2012; Acknowledgments 35(10):1199–208. We thank LetPub (www.letpub.com) for its linguistic assistance during the 7. Piroth L, Pechinot A, Di Martino V, Hansmann Y, Putot A, Patry I, Hadou T, preparation of this manuscript. Jaulhac B, Chirouze C, Rabaud C, et al. 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Eur J Clin Microbiol Infect Dis. 2004;23(2):73–7. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Infectious Diseases Springer Journals

Clinical and bacteriological features and prognosis of ascitic fluid infection in Chinese patients with cirrhosis

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Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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Abstract

Background: Spontaneous bacterial peritonitis (SBP) and bacterascites (BA) represent frequent and serious complications in cirrhosis patients with ascites. However, few detailed data are available regarding the clinical and bacteriological feature of SBP or BA patients in China. Methods: We retrospectively analyzed bacteriological and clinical characteristics of patients with SBP and BA at Beijing 302 Hospital in China from January 2012 to December 2015. Results: A total of 600 patients with SBP (n = 408) or BA (n = 192) were enrolled. Patients with BA appeared to have a less severe clinical manifestation and lower mortality rate than patients with SBP. Gram-negative bacteria formed the majority of pathogens in SBP (73.9%) and BA (55.8%) cases. Higher ascitic fluid polymorphonuclear leucocytes (PMN) count and hepatocellular carcinoma were independent risk factors for BA episode progressing to SBP. The concentration of blood urea nitrogen (BUN) was independent risk factor for 30-day mortality of BA patients. For patients with SBP, the independent risk factors for 30-day mortality were age, Model for End-Stage Liver Disease (MELD) score, septic shock and hepatocellular carcinoma. Patients with third-generation cephalosporin or carbapenems resistant infection had a significantly lower survival probability. There were significant differences in clinical characteristics and outcome among the major bacteria. Multivariate analysis showed that patients infected with Klebsiella spp. had higher hazard ratio of 30-day mortality. Conclusion: Our study reported the bacteriological and clinical characteristics of patients with SBP and BA. Higher ascitic fluid PMN count and hepatocellular carcinoma were found to be independent risk factors for BA episode progressed to SBP. Outcome of ascitic fluid infection in patients with cirrhosis was influenced by the type of bacteria and antimicrobial susceptibility. Keywords: Cirrhosis, Spontaneous bacterial peritonitis, Bacterascites, Causative pathogens, Mortality, Risk factor * Correspondence: bcm2003@sina.com; geno0109@vip.sina.com Nian-zhi Ning, Tao Li and Ju-ling Zhang contributed equally to this work. Clinical Diagnostic Center, Beijing 302 Hospital, No. 100 Western 4th Middle Ring Road, Beijing 100039, China The State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No.20 Dongda Street, Fengtai District, Beijing 100071, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ning et al. BMC Infectious Diseases (2018) 18:253 Page 2 of 11 Background Methods Cirrhotic patients with ascites usually face poor out- Setting and study design comes, especially if infections such as spontaneous This study was conducted at Beijing 302 Hospital, bacterial peritonitis (SBP) develop [1]. Prompt and which is the largest liver disease hospital in China. appropriate empirical antibiotic therapy must be initi- The hospital’s database holds records of clinical ated immediately after the diagnosis of SBP to cover histories, disease manifestations, physical and labora- the most commonly isolated bacteria [2]. Previous tory findings, and treatments of admitted patients. studies showed that gram-negative bacteria, mainly Bacteriology laboratory files and patient characteristics Enterobacteriaceae, were major causative organisms of were reviewed to identify all cases with positive ascitic fluid infection [3, 4]. Third generation cephalo- ascitic fluid cultures in cirrhotic patients hospitalized sporins are the first line antibiotics to treat spontan- in our institution from January 1, 2012 to December eous bacterial peritonitis; however, it was showed that 31, 2015. Patients with secondary peritonitis were ex- the initial treatment with cefotaxime, one of the most cluded from the study. Patients with a positive culture commonly used cephalosporins, failed more frequently for common skin contaminants (coagulase-negative than expected [5]. It maybeexplained bythe change staphylococci, corynebacteria, propionibacteria,and of causative pathogen profile and the emergence of Bacillus spp.) were also excluded. antibiotic-resistant pathogens. In recent years, several studies have reported changes in the epidemiology of Definitions causative bacteria in SBP. Enterococcus spp. was in- The diagnosis of cirrhosis was based on clinical, bio- creasingly recognized as an important pathogen of chemical, histological and/or radiological findings. A ascitic fluid infection for patients with cirrhosis. diagnostic paracentesis was performed in all patients as Reuken et al. confirmed a profound increase in the recommended by European Association for the Study of frequency of Enterococcal infection from 11% to 35% the Liver (EASL) [2]. SBP was diagnosed when (a) ascitic between 2000 and 2011 in a German tertiary center fluid polymorphonuclear leucocytes (PMN) count ≥250 [6]. Piroth et al. found that Enteroccocci were iso- cells/μL, (b) ascitic fluid culture was positive; (c) there lated in 24% of ascitic fluid infection episodes, and was no evident intra-abdominal surgically treatable in 48% from patients receiving quinolone prophylaxis source for infection [2, 14]. The diagnosis of BA was in four French hospitals [7]. The emergence and made when (a) the ascitic fluid PMN count < 250 spread of multi-drug resistant bacteria such as cells/μL, (b) ascitic fluid culture was positive; (c) methicillin-resistant Staphylococcus aureus (MRSA), there was no evident intra-abdominal surgically extended-spectrum beta-lactamases (ESBL)-producing treatable source for infection [2, 15]. Fever, chills, Enterobacteriaceae and Carbapenemase producing abdominal pain and abdominal tenderness were (KPC) Klebsiella pneumonia are also of great con- considered symptoms of peritonitis [15]. Severity of cern since they may be associated with higher mor- cirrhosis was assessed at the time of the SBP or BA tality rate [8]. In recent years, an increased diagnosis using the Model for End-Stage Liver Disease prevalence of multi-drug resistant bacteria in SBP (MELD) score [16]. Nosocomial infection was defined as cases was reported [9, 10]. an infection that occurred > 48 h after admission to the Liver diseases affect ~ 300 million people in China, hospital [17]. and the incidence of liver cirrhosis has increased during recent years because of the low awareness of the perni- ciousness of liver diseases and low treatment rate for Microbiological methods these patients [11]. Some studies have described the Ascitic fluid samples were extracted and inoculated into pathogens profile and drug resistance of SBP in cirrhotic bottles at the patient’s bedside by aseptic manipulation patients in China [12, 13]. However, those studies were and cultured with BacT/Alert 240 automated blood cul- limited by being single-center study and failed to investi- ture system (BioMérieux France). White blood cell gate the characteristics and outcome of SBP. Thus, more (WBC) and PMN were counted by Sysmex automatic timely and comprehensive studies on bacteriological and cell analyzer XT-4000 (SYSMEX, Japan). Microorganism clinical characteristics of SBP and BA in China are identification was performed using the VITEK-II auto necessary. microbe system (BioMérieux France). Isolated pathogens In this study, we aimed at assessing the possible were tested for antimicrobial susceptibility using the changes in bacteria etiology of SBP and BA, the risk fac- disk-diffusion method and minimum inhibitory concen- tors of 30-day mortality and the differences in clinical tration testing. Antimicrobial susceptibility was judged characteristics and prognosis among patients with differ- according to guidelines of the Clinical and Laboratory ent causative pathogens. Standards Institute (CLSI) [18]. Ning et al. BMC Infectious Diseases (2018) 18:253 Page 3 of 11 Empirical antibiotic therapy Statistical analysis Third-generation cephalosporins (TGC), such as cefo- Quantitative variables were given as the mean ± standard de- taxime, were used as empirical therapy antibiotic in viation or the median (interquartile range). Student’s t test our hospital. Empirical antibiotic therapy initiated im- or Mann–Whitney U-test was used to compare continuous mediately on all patients with ascitic PMN count variables, and the x test or Fisher’sexact test wasusedto ≥250 cells/μL, without the results of ascitic fluid cul- compare categorical variables. Statistical differences among ture. Bacterascites patients exhibit signs of systemic several groups were analyzed using one-way ANOVA or the inflammation are also treated with cefotaxime. Other- nonparametric Kruskal-Wallis test, as appropriate. Risk fac- wise, the bacterascites patient should undergo a sec- tors for SBP development were determined by multivariate ond paracentesis when culture results come back binary logistic regression including significant univariate positive. Patients in whom the repeat PMN count is predictors (p < 0.05) using stepwise backward elimination. ≥250/μL would be treated for SBP. Carbapenems were The life-table method was used to compare survival prob- used in all severe patients with septic shock. Paracen- ability for patients according to different variables. A Cox tesis was performed repeatedly 2–3 days after initi- proportional hazard model analysis was carried out to iden- ation of antibiotic therapy to determine leukocyte and tify independent predictors of 30-day mortality for every epi- PMN counts in ascitic fluid. sode, defining death as the main event. Variables with p <0. Fig. 1 Flowchart of patient enrollment in the study. Abbreviation: AF, ascitic fluid; SBP, spontaneous bacterial peritonitis; BA, bacterascites; PMN, polymorphonuclear leucocytes Ning et al. BMC Infectious Diseases (2018) 18:253 Page 4 of 11 Table 1 Clinical and laboratory data of cirrhotic patients with BA and SBP Total (n = 600) BA (n = 192) SBP (n = 408) p Sex (male) 465 (77.5%) 144 (75%) 321 (78.7%) 0.314 Age (yr) 53.9 ± 11.9 55.7 ± 12.1 53.1 ± 11.6 0.011 Presentation of symptoms 458 (76.3%) 118 (61.5%) 340 (83.3%) < 0.001 Nosocomial infection 287 (47.8%) 84 (43.8%) 203 (49.8%) 0.17 MELD score 19.7 ± 9.5 16.3 ± 7.9 21.4 ± 9.8 < 0.001 Days in hospital 13 (7–19) 13 (7–18) 13 (7–19) 0.732 Days between admission and onset of infection 2 (0–9) 2 (0–6) 2 (0–10) 0.03 Causes of cirrhosis Hepatitis B 370 (61.7%) 105 (54.7%) 265 (65%) 0.016 Hepatitis C 59 (9.8%) 24 (12.5%) 35 (8.6%) 0.132 Biliary 22 (3.7%) 7 (3.6%) 15 (3.7%) 0.985 Alcoholic 90 (15%) 37 (19.3%) 53 (13%) 0.044 Others 59 (9.8%) 19 (9.9%) 40 (9.8%) 0.972 Serum features ALT(U/L) 35.0 (21.0–64.0) 30.0 (20.0–48.0) 38.0 (21.0–71.8) 0.001 AST(U/L) 60.0 (37.0–105.8) 53.0 (33.0–86.0) 65.5 (39.0–111.8) 0.004 Prealbumin(mg/L) 47.2 ± 25.8 55.3 ± 23.9 43.4 ± 25.8 < 0.001 Prothrombin time(S) 18.1 (15.0–22.6) 54.5 (40.2–68.0) 41.8 (26.0–57.7) < 0.001 BUN(mmol/L) 8.0 (5.1–13.2) 6.4 (4.8–9.9) 8.9 (5.4–14.4) < 0.001 Serum PMN(cells/μL) 5.4 (3.0–8.6) 4.0 (2.4–6.4) 6.2 (3.6–9.8) < 0.001 Serum WBC(cells/μL) 6.9 (4.3–10.5) 5.4 (3.4–8.3) 7.7 (5.1–11.6) < 0.001 Creatinine (μmol/L) 97.5 (78.0–138.8) 90.0 (70.2–111.8) 105.0 (82.0–157.0) < 0.001 Total protein(g/L) 55.0 (49.0–61.0) 56.0 (51.0–63.0) 54.0 (48.0–60.0) 0.001 Total bilirubin (μmol/L) 82.4 (35.9–233.4) 51.5 (30.0–144.3) 107.9 (42.7–260.0) < 0.001 Ascitic features Ascitic PMN(cells/μL) 799.5 (53.1–5405.8) 22.9 (5.6–71.3) 3099.9 (720.2–7873.0) < 0.001 Ascitic WBC(cells/μL) 1241.0 (253.3–6565.0) 169.0 (90.3–310.8) 3850.5 (1119.3–9826.8) < 0.001 Hepatocellular carcinoma 175 (29.2%) 49 (25.5%) 126 (30.9%) 0.178 Hepatic encephalopathy 203 (33.8%) 58 (30.2%) 145 (35.5%) 0.198 Septic shock 108 (18%) 19 (9.9%) 89 (21.8%) < 0.001 Upper gastrointestinal bleeding 114 (19%) 34 (17.7%) 80 (19.6%) 0.580 Diabetes mellitus 101 (16.8%) 37 (19.3%) 64 (15.7%) 0.274 30-day mortality 131 (21.8%) 26 (13.5%) 105 (25.7%) 0.001 Abbreviation: SBP spontaneous bacterial peritonitis, BA bacterascites, MELD Model for End-Stage Liver Disease, WBC white blood cell, PMN polymorphonuclear leukocytes, ALT alanine transarninase, AST aspartate aminotransferase, Bun blood urea nitrogen P:compared between BA and SBP. P-values < 0.05 are indicated in bold 05 in the univariate analysis were candidates for multivariate diagnostic paracentesis. Ascitic fluid culture in blood analysis and non-significant factors were removed by a back- culture bottles was positive in 13.0% (n = 1088) of pa- ward selection process. All tests were two-tailed and p <0. tients. The flowchart for patient enrollment was shown 05 were considered to be statistically significant. IBM SPSS in Fig. 1, and only 600 ascitic fluid infection episodes Statistics 19.0 was used for statistical analyses. (408 SBP and 192 BA) were identified in patients with cirrhosis and enrolled in this study (Fig. 1). Laboratory Results and clinical features at the time of diagnostic paracen- General characteristics and clinical presentation tesis were given in Table 1. Serum laboratory data During the study period (January 1, 2012 to December (alanine transaminase/ALT, aspartate aminotransferase/ 31, 2015), a total of 8365 patients were subjected to AST, prealbumin, BUN, creatinine, total protenin, total Ning et al. BMC Infectious Diseases (2018) 18:253 Page 5 of 11 bilirubin, erythrocytes/WBC, PMN and prothrombin treating gram-positive pathogen infections because of time) and ascitic features (WBC and PMN) of SBP were the low resistant rates. Nine Acinetobacter baumannii significantly higher than that of BA (p< 0.01). In add- strains were multidrug resistant. Multidrug resistant itional, septic shock was more common in patients with pathogens were associated with high 30-day mortality SBP (p< 0.01). There were no significant differences in rate. Our data showed that patients infected with multi- the percentage of nosocomial episodes between SBP and drug resistant Acinetobacter spp. had significantly higher BA. 30-day mortality compared to patients infected with sus- ceptible Acinetobacter spp. (100% vs. 11.1%, respectively, Bacteriological characteristics and impact of drug p < 0.001, Fig. 2b). Survival curves shows that patients resistance on mortality infected with TGC-resistant bacteria had a significantly Among the 600 patients, 554 patients had monobacterial lower survival probability than those with TGC- infection and the other 46 had polybacterial infection. susceptible bacteria (p= 0.001, Fig. 2c). Also, there was a Thus, a total of 656 pathogens were isolated from these significantly lower survival probability for patients in- patients and shown in Table 2. Gram-negative bacteria, fected with carbapenem–resistant organisms than it was accounting for 68.1% of pathogens in total, were more in carbapenem-susceptible cases (p< 0.001, Fig. 2d). common than gram-positive bacteria. The major Levofloxacin-resistant organisms were not associated pathogens identified were Escherichia coli (n = 267, 40. with greater mortality than levofloxacin-susceptible ones 7%), Streptococcus spp. (n = 110, 16.8%), Klebsiella spp. (p= 0.092, Fig. 2e). (n = 87, 13.3%), Enterococcus spp. (n = 66, 10.1%), Coagu- lase-positive staphylococci (n = 25, 3.8%), Enterobacter Risk factors for BA progressing to SBP spp. (n = 20, 3.0%) and Acinetobacter spp. (n = 18, 2.7%). For 187 of 237 cases with ascitic fluid PMN counts < 250 In total, these 7 types of pathogens account for 90.4% (n cells/μL at the first paracentesis, a follow-up paracentesis = 593) of the causative bacteria. The antimicrobial sus- was performed when culture results come back positive. ceptibility of these bacteria was shown in Fig. 2a. Nearly In our hospital, if BA patient exhibited symptoms of peri- half of Escherichia coli (49.4%) were resistant to TGC, tonitis, the patient would be treated with empirical anti- on the contrary, most of Klebsiella spp. isolates were biotic immediately. The development of BA between the sensitive to TGC. Vancomycin was a reliable agent for first and second paracentesis (usually 2–3 days) was of Table 2 Types of bacteria isolated from cultures of ascitic fluid in patients with cirrhosis Isolates no.(%) of isolates Total (n = 656) BA (n = 208) SBP (n = 448) P Gram-negative organisms Total 447 (68.1%) 116 (55.8%) 331 (73.9%) < 0.001 Escherichia coli 267 (40.7%) 71 (34.1%) 196 (43.8%) 0.020 Klebsiella spp. 87 (13.3%) 20 (9.6%) 67 (15.0%) 0.061 Enterobacter spp. 20 (3.0%) 5 (2.4%) 15 (3.3%) 0.513 Acinetobacter spp. 18 (2.7%) 5 (2.4%) 13 (2.9%) 0.716 Aeromonas spp. 9 (1.4%) 2 (1.0%) 7 (1.6%) 0.726 Citrobacter spp. 8 (1.2%) 3 (1.4%) 5 (1.1%) 0.713 Serratia spp. 7 (1.1%) 2 (1.0%) 5 (1.1%) 1.000 Burkholderia spp. 5 (0.8%) 3 (1.4%) 2 (0.4%) 0.333 Pseudomonas spp. 8 (1.2%) 1 (0.5%) 7 (1.6%) 0.446 Other 18 (4.0%) 4 (1.9%) 14 (3.1%) – Gram-positive organisms Total 209 (31.9%) 92 (44.2%) 117 (26.1%) < 0.001 Streptococcus spp. 110 (16.8%) 47 (22.6%) 63 (14.1%) 0.006 Enterococcus spp. 66 (10.1%) 29 (13.9%) 37 (8.3%) 0.024 Coagulase-positive staphylococci 25 (3.8%) 11 (5.3%) 14 (3.1%) 0.178 Kocuria spp. 3 (0.5%) 1 (0.5%) 2 (0.4%) 1.000 Other 5 (0.8%) 4 (1.9%) 1 (0.2%) – P:compared between isolates collected from BA and SBP. P-values < 0.05 are indicated in bold Ning et al. BMC Infectious Diseases (2018) 18:253 Page 6 of 11 Fig. 2 Drug resistance of major bacteria and impact of antibiotic resistance on mortality. (a) Resistance to antibiotics among seven major isolates. * Enterococcus spp. is naturally resistant to third-generation cephalosporins (TGC). TZP, piperacillin/tazobactam. (b) Effect of multi-drug resistance on patient mortality with respect to Acinetobacter spp. A.h.: Acinetobacter haemolyticus; A.l.: Acinetobacter lwoffii. (c, d, e) 30-day survival curve for patients with positive ascites culture according to third-generation cephalosporin, carbapenem or levofloxacin resistance (p= 0.004, < 0.001 and = 0.092, respectively) concern. Thus, potential risk factors for BA progressing to them. Multivariate analysis, including the variables asso- SBP were identified (Table 3). Results showed that devel- ciated with mortality by univariate analysis, showed that opment of BA was associated with the severity degree of the concentration of BUN was independent risk factor liver diseases (MELD score, p < 0.001), serum PMN (p =0. for 30-day mortality of BA patients (Table 4). For pa- 002), ascitic PMN (p = 0.002), presentation of fever (p =0. tients with SBP, the independent risk factors for 30-day 036) and serious complications (hepatocellular carcinoma mortality were age, MELD score, septic shock and hepa- and septic shock, p = 0.035 and 0.014, respectively). In tocellular carcinoma (Table 5). multivariate analysis, only the presentation of hepatocellu- lar carcinoma (OR = 3.047, 95% CI:1.161–7.997, p =0.024) Impact of isolate type on clinical characteristics and mortality and higher ascitic PMN count (OR = 1.007, 95% CI: 1. To study the impact of isolate type on clinical characteris- 001–1.013, p = 0.023) remained independent predictors tics and mortality, we limited the analysis to patients with for BA progressing to SBP. monobacterial ascitic fluid infections. Clinical characteris- tics of patients infected with different types of bacteria Risk factors for 30-day mortality of patients with BA and SBP were shown in (Additional file 1): Table S1. There were The 30-day mortality of patients with SBP was signifi- significant differences in clinical characteristics among the cantly higher than that of BA (25.7% vs. 13.5%, p =0. seven types of bacterial infection, for example the percent- 001) (Table 1). We studied independent risk factors of age of peritonitis symptoms, several clinical complications, 30-day mortality in BA and SBP respectively, and found type of peritonitis (SBP), nosocomial infection, serum and that independent risk factors were different between ascitic features, MELD score and days between admission Ning et al. BMC Infectious Diseases (2018) 18:253 Page 7 of 11 Table 3 Risk factors for BA episodes progressing to SBP Progress to SBP No progress to Univariate analysis Multivariate analysis (n = 45) SBP (n = 142) P Odds ratio (95% CI) P Odds ratio (95% CI) Sex (male) 37 (82.2%) 108 (76.1%) 0.390 0.687 (0.292–1.616) –– Age (yr) 52.4 ± 9.2 55.4 ± 12.5 0.144 0.979(0.951–1.007) –– Nosocomial infection 23 (51.1%) 57 (40.1%) 0.197 1.559 (0.795–3.059) –– MELD score 23.0 ± 10.7 16.3 ± 7.4 < 0.001 1.089 (1.046–1.133) 0.503 1.036 (0.934–1.149) Days between admission 3(0–7.5) 1 (0–6) 0.239 1.018 (0.989–1.048) –– and onset of infection Fever 30 (66.7%) 69 (48.6%) 0.036 2.116 (1.049–4.268) 0.053 2.533 (0.986–6.505) Chills 4 (8.9%) 11 (7.7%) 0.806 1.162 (0.351–3.846) –– Abdominal pain 15(33.3%) 34 (23.9%) 0.214 1.588(0.765–3.295) –– ALT(U/L) 42.0 (24.0–106.0) 30.0 (20.0–49.0) 0.011 1.005 (1.001–1.009) 0.326 1.004 (0.996–1.011) AST(U/L) 70.0 (42.0–135.5) 52.5 (33.0–88.5) 0.030 1.003(1.000–1.005) 0.602 1.001(0.996–1.006) Prealbumin(mg/L) 41.3 ± 22.7 56.1 ± 24.8 0.001 0.973 (0.957–0.989) 0.224 0.986 (0.965–1.008) Prothrombin time(S) 19.2 (15.7–31.1) 16.3 (14.1–19.3) < 0.001 1.078 (1.034–1.125) 0.118 1.064 (0.984–1.149) Bun(mmol/L) 8.6 (5.5–13.9) 6.6 (4.8–11.5) 0.074 1.039 (0.996–1.083) –– Serum PMN(cells/μL) 4.9 (2.8–9.8) 4.2 (2.4–6.6) 0.002 1.12 (1.042–1.205) 0.161 1.641 (0.822–3.277) Serum WBC(cells/μL) 6.1 (4.0–11.8) 5.4 (3.6–8.5) 0.006 1.096 (1.027–1.17) 0.223 0.671 (0.353–1.275) Serum creatinine (μmol/L) 105.0 (82.0–159.0) 88.5 (70.8–113.5) 0.15 1.003 (0.999–1.006) –– Total protein(g/L) 56.0 (50.0–61.0) 55.0 (50.0–63.0) 0.679 0.997 (0.983–1.011) –– Total bilirubin (μmol/L) 98.5 (43.9–311.4) 51.9 (32.4–140.2) 0.018 1.002 (1.000–1.005) 0.36 0.998 (0.994–1.002) Ascitic PMN(cells/μL) 64.7 (21.7–141.7) 24.0 (5.3–74.8) 0.002 1.008 (1.003–1.013) 0.029 1.007 (1.001–1.013) Ascitic WBC(cells/μL) 257.0(114.5–370.0) 161.0 (91.8–302.8) 0.529 1.000(0.999–1.002) –– hepatocellular carcinoma 20 (44.4%) 39 (27.5%) 0.035 2.113 (1.056–4.229) 0.024 3.047 (1.161–7.997) hepatic encephalopathy 16(35.6%) 43(30.3%) 0.508 1.27(0.626–2.577) –– septic shock 12(26.7%) 16 (11.3%) 0.014 2.864 (1.235–6.639) 0.799 0.851 (0.246–2.949) Gastrointestinal haemorrhage 11 (24.4%) 29 (20.4%) 0.567 1.261 (0.57–2.786) –– diabetes mellitus 7 (15.6%) 28(19.7%) 0.534 0.75 (0.303–1.856) –– P-values < 0.05 and corresponding Odds ratio are indicated in bold and onset of infection (p< 0.01). To investigate the impact China, and it permits statistical comparison and risk fac- of isolate type on the 30-day mortality, Cox proportional tor analysis for prognosis of SBP and BA. hazard model was used to control confounding variables, Nearly half (47.8%) of the ascitic fluid infection were such as MELD score, defining isolate type as dummy vari- nosocomial-acquired. It could be explained in part by able (Table 6 and Additional file 1: Table S2). In univariate that patients enrolled in this study underwent frequent analysis, patients infected with Acinetobacter spp., Klebsi- hospitalization before they were admitted to our depart- ella spp. and Enterococcus spp. had higher hazard ratios of ment and experienced long hospital stays. Previous stud- 30-day mortality compared to those infected with Escheri- ies also reported high nosocomial infection rates in chia coli. Multivariate analysis showed that only patients those patients [4, 19]. High rate of nosocomial-acquired infected with Klebsiella spp. had higher hazard ratio of SBP was not a common in China. Li et al. found that 30-day mortality compared to those with Escherichia coli nearly two-thirds of SBP in cirrhotic patients was (Table 6). community-acquired in a hospital located in Zhejiang province of China [12]. Discussion In comparison with the data base of SBP, little data for In this study, we retrospectively investigated the clinical BA is available. Previous researches indicated that many of and bacteriological characteristics of 600 SBP and BA patients with BA indeed were symptomatic and as a vari- patients, and studied the outcomes of these patients. To ant of spontaneous bacterial peritonitis [20, 21]. However, our knowledge, this is the most comprehensive and lar- the difference between BA and SBP is uncertain and con- gest dataset of patients with ascitic fluid infection from troversial because the lack of appropriate data sets and Ning et al. BMC Infectious Diseases (2018) 18:253 Page 8 of 11 Table 4 Risk factors for 30-day mortality in patients with BA Survivors Nonsurvivors Univariate analysis Multivariate analysis (n = 166) (n = 26) HR (95% Cl) P HR (95% Cl) p Age (yr) 55.3 ± 12.2 58.3 ± 11.6 1.022(0.991–1.055) 0.162 –– Sex (male) 125 (75.3%) 19 (73.1%) 1.152 (0.484–2.742) 0.750 –– Nosocomial infection 68 (41%) 16 (61.5%) 2.21 (1.000–4.884) 0.050 –– MELD score 14.7 ± 6.8 26.1 ± 7.7 1.153 (1.102–1.207) < 0.001 1.054 (0.988–1.125) 0.108 Days between admission 2(0–6) 4.5(0–17.3) 1.022 (1.002–1.042) 0.027 1.015 (0.986–1.045) 0.301 and onset of infection Symptoms of peritonitis 102 (61.4%) 16 (61.5%) 0.915 (0.414–2.022) 0.826 –– ALT(U/L) 28.0 (19.0–46.0) 45.5 (28.0–93.3) 1.003(1.000–1.006) 0.036 1.001(0.992–1.009) 0.861 AST(U/L) 50.0 (32.0–75.5) 88.0 (51.5–180.8) 1.003(1.001–1.005) 0.002 1.003(0.997–1.008) 0.308 Prealbumin(mg/L) 57.3 ± 24.2 42.6 ± 17.8 0.975 (0.957–0.993) 0.006 0.981 (0.958–1.004) 0.100 Bun(mmol/L) 5.9(4.7–9.1) 11.5 (7.7–15.5) 1.099 (1.055–1.143) < 0.001 1.1 (1.033–1.173) 0.003 Serum PMN (cells/μL) 3.6 (2.1–5.8) 6.5 (5.2–12.6) 1.219 (1.124–1.322) < 0.001 1.027 (0.926–1.14) 0.609 Total Protein(g/L) 57.0 (52.0–64.0) 51.0 (47.0–54.0) 0.979(0.957–1.001) 0.060 –– Ascitic PMN(cells/μL) 24.0 (6.5–69.0) 13.0 (3.2–115.0) 1.002 (0.996–1.008) 0.589 –– Hepatocellular carcinoma 42 (25.3%) 7 (26.9%) 1.056 (0.443–2.514) 0.903 –– Hepatic encephalopathy 39 (23.5%) 19 (73.1%) 6.442 (2.704–15.346) < 0.001 2.382 (0.849–6.679) 0.099 Septic shock 8 (4.8%) 11 (42.3%) 5.725 (2.614–12.536) < 0.001 2.247 (0.876–5.762) 0.092 Gastrointestinal haemorrhage 23 (13.9%) 11 (42.3%) 2.966 (1.361–6.466) 0.006 1.705 (0.655–4.438) 0.274 Diabetes mellitus 34 (20.5%) 3 (11.5%) 0.576 (0.1730–1.920) 0.369 –– P-values < 0.05 and corresponding HR are indicated in bold systematic analyses. In this retrospective study, we com- and SBP patients. The reason might be that SBP patients pared the clinical and bacteriological characteristics be- had higher MELD score and were thus sicker. tween SBP and BA. BA patients had lower 30-day Prognosis of patients with ascitic fluid infection was mortality and less severe liver diseases than SBP patients, influenced by bacterial antibiotic resistance. Our study as evidenced by a lower serum ALT and AST and lower suggested that resistant to TGC, which have been con- MELD scores, which is consistent with a previous report sidered as first-line treatment of SBP [14, 24], were asso- [21]. Symptoms of peritonitis, especially fever, and septic ciated with lower survival probability. This result is shock were less common in BA patients. In addition, consistent with previously studies [25–27]. Also, gram-positive organisms, such as Streptococcus and carbapenem-resistant gram-negative pathogen is a chal- Enterococcus, were more frequently found in BA than in lenge for treating peritonitis. Our study showed that SBP episodes. Our data also showed that hepatocellular carbapenem-resistance is associated with significantly carcinoma and higher ascitic PMN count were independ- lower 30-day survival probability (p < 0.01). Thus, this ent risk factors for BA episodes progressing to SBP. BA can be a life-threatening factor for cirrhotic patients with patients accompanied with hepatocellular carcinoma and ascitic fluid infection. higher ascitic PMN count thus should be optimal candi- Gram-positive pathogens were increasingly recognized dates for primary prophylaxis of SBP. as important causative bacteria in patients with SBP and Consistent with previous studies, we also found that BA [6, 7, 27, 28]. However, the impacts of those causa- MELD score [22], the presentation of hepatocellular car- tive bacteria on the outcome of patients with ascitic fluid cinoma [23] and presentation of septic shock [19] were infection are less well understood. Polymicrobial infec- independent risk factors for 30-day mortality at the time tion would be a confounding factor in studying the im- of SBP diagnosis. However, only the concentration of pact of isolate type on characteristic and outcome of BUN were identified as independent predictive factor of ascitic fluid infection. For instance, previous study have 30-day mortality in patients with BA. To our knowledge, shown that Enterococci were of low virulence and were this is the first study to identify the independent risk factors often found as a secondary invader in polymicrobial in- of 30-day mortality in patients with BA. The independent fections and the clinical relevance of enterococcal peri- risk factors of 30-day mortality were different between BA tonitis is subject of debate [29]. Thus, we limited our Ning et al. BMC Infectious Diseases (2018) 18:253 Page 9 of 11 Table 5 Risk factors for 30-day mortality in patients with SBP Survivors Nonsurvivors Univariate analysis Multivariate analysis (n = 303) (n = 105) HR (95% Cl) P HR (95% Cl) p Age(yr) 52.1 ± 11.5 55.9 ± 11.7 1.025 (1.008–1.041) 0.003 1.021 (1.003–1.04) 0.022 Sex (male) 245 (80.9%) 76 (72.4%) 1.326 (0.864–2.035) 0.196 –– Nosocomial infection 134 (44.2%) 69 (65.7%) 2.311 (1.544–3.46) < 0.001 1.577 (0.946–2.627) 0.081 MELD score 18.7 ± 8.4 29.1 ± 9.5 1.1 (1.078–1.122) < 0.001 1.067 (1.04–1.095) < 0.001 Days between admission 2(0–7) 8(1–18.5) 1.028 (1.016–1.039) < 0.001 1.015 (0.999–1.032) 0.07 and onset of infection Symptoms of peritonitis 259 (85.5%) 81 (77.1%) 0.672 (0.426–1.06) 0.088 –– ALT(U/L) 36 (21–63) 57 (25–150.5) 1.001 (1–1.001) 0.002 1.001 (1.000–1.002) 0.310 AST(U/L) 59 (37–100) 95 (48–202.5) 1(1–1.001) < 0.001 1.000 (1.000–1.001) 0.728 Prealbumin(mg/L) 46.8 ± 25.9 33.7 ± 22.9 0.98 (0.971–0.989) < 0.001 0.999 (0.989–1.009) 0.791 Bun(mmol/L) 8 (5.1–11.9) 13.3 (8.1–20.8) 1.061 (1.043–1.078) < 0.001 0.998(0.977–1.019) 0.824 Serum PMN (cells/μL) 5.8 (3.5–9.2) 7.5 (3.8–12.2) 1.061 (1.032–1.091) < 0.001 1.001(0.97–1.034) 0.931 Total Protein(g/L) 55 (49–60) 51 (44–57.5) 0.979(0.967–0.991) 0.001 1.002 (0.988–1.016) 0.778 Ascitic PMN(cells/μL) 2760 (741.4–7821) 3717.2 (660.9–8356) 1 (1–1) 0.241 –– Hepatocellular carcinoma 83 (27.4%) 43 (41%) 1.874 (1.268–2.771) 0.002 1.755 (1.14–2.703) 0.011 Hepatic encephalopathy 80 (26.4%) 65 (61.9%) 3.282 (2.213–4.866) < 0.001 1.533(0.972–2.42) 0.066 Septic shock 24 (7.9%) 65 (61.9%) 7.624 (5.135–11.321) < 0.001 4.169 (2.599–6.686) < 0.001 Gastrointestinal haemorrhage 47 (15.5%) 33 (31.4%) 2.02 (1.337–3.05) 0.001 1.243 (0.798–1.936) 0.337 Diabetes mellitus 48 (15.8%) 16 (15.2%) 1.044 (0.613–1.778) 0.875 –– P-values < 0.05 and corresponding HR are indicated in bold analysis to patients with monobacterial peritonitis when infection in multivariate analysis. Patients accompanied investigating the impact of isolate type on clinical charac- with Klebsiella spp. peritonitis seem to be associated with teristics and mortality. Reuken et al. also limited their poorer prognosis even though those bacteria were less re- analysis to monobacterial peritonitis and found that en- sistant against frequently used antimicrobial. terococcal SBP patients had a poorer prognosis than non- There were limitations in our study. First, our study enterococcal SBP [6]. In our study, we only observed was limited by being a single-center retrospective study. higher hazard ratio of 30-day mortality in patients infected However, our hospital is a referral center for liver disease with Acinetobacter spp., Klebsiella spp. and Enterococcus in the capital of China and many patients come from spp. compared to those infected with Escherichia coli in different regions of the country. Compared with a previ- univariate analysis. After adjusting for clinical parameters, ous report [12], there were similar pathogen profiles and however, only Klebsiella spp. infection (HR = 1.888, drug resistance in the two hospitals in China. The major 95%Cl, 1.092–3.265, p = 0.024) showed higher hazard ratio pathogens in both hospitals were E. coli, K. pneumoniae, of 30-day mortality compared to that of Escherichia coli Enterococcus spp. and S. aureus. Furthermore, the Table 6 Hazard ratios (HRs) for 30-day mortality of different types of bacteria against reference strains Bacteria Univariate analysis Multivariate analysis HR (95%Cl) P HR (95%Cl) p Escherichia coli Ref Ref Coagulase-positive staphylococci 0.298 (0.041–2.161) 0.231 0.399 (0.054–2.929) 0.367 Acinetobacter spp. 3.881 (1.654–9.108) 0.002 0.805 (0.306–2.118) 0.665 Enterobacter spp. 2.385 (0.944–6.025) 0.066 1.537 (0.572–4.131) 0.394 Klebsiella spp. 2.092 (1.264–3.46) 0.004 1.888 (1.092–3.265) 0.024 Enterococcus spp. 2.842 (1.644–4.911) < 0.001 0.964 (0.513–1.813) 0.911 Streptococcus spp. 0.551 (0.259–1.171) 0.121 0.95 (0.437–2.066) 0.896 Note: HRs were analyzed by using proportional hazards Cox regression model. In multivariate analysis, HR was adjusted for clinical parameters. Only the major monobacteria were included in analysis. Detailed information was shown in Table S2. P-values < 0.05 and corresponding HR are indicated in bold Ning et al. BMC Infectious Diseases (2018) 18:253 Page 10 of 11 resistant rate of gram-negative bacteria against TGC was Availability of data and materials All data generated or analysed during this study are included in this published both approximately 40%. Thus, to a lesser extent, our article [and its Additional file 1]. data may be representative in SBP patients in China. Second, patients with culture-negative SBP (ascitic Ethics approval and consent to participate PMN ≥ 250 cells/μl and a negative culture result) were The study was reviewed and approved by the Beijing 302 Hospital Research Ethics Committee. The Beijing 302 Hospital Research Ethics Committee waived not included in this study. Thus, our findings, such as the need for written informed consent from the participants due to the de- independent risk factors of 30-day mortality in patients identified secondary data analyzed in this study. with SBP, could not be applied to those patients. Competing interests The authors declare that they have no competing interests. Conclusions In conclusion, there were significant differences be- tween BA and SBP regarding clinical and bacterial Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published characteristics and 30-day mortality. Presentation of maps and institutional affiliations. hepatocellular carcinoma and higher ascitic PMN count were independent risk factors for BA progres- Author details The State Key Laboratory of Pathogen and Biosecurity, Beijing sing to SBP. The concentration of BUN were identi- Institute of Microbiology and Epidemiology, No.20 Dongda Street, fied as independent predictive factors of 30-day Fengtai District, Beijing 100071, China. Clinical Diagnostic Center, mortality in patients with BA. For patients with SBP, Beijing 302 Hospital, No. 100 Western 4th Middle Ring Road, Beijing 100039, China. Research Center for Biological Therapy, Institute of the independent risk factors for 30-day mortality were Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China. age, MELD score, septic shock and hepatocellular car- cinoma. The Klebsiella spp. related peritonitis is of Received: 8 August 2017 Accepted: 17 April 2018 concern, because those infections are associated with poorer outcome. Strict infection control must be im- References plemented to control the spread of third-generation 1. Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, cephalosporin or carbapenem-resistant pathogens. Burroughs AK: Infections in patients with cirrhosis increase mortality four- fold and should be used in determining prognosis. Gastroenterology 2010, 139(4):1246–1256, 1256.e1241–1245. Additional file 2. European Association for the Study of the L. 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BMC Infectious DiseasesSpringer Journals

Published: Jun 4, 2018

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