Epidemiology, Risk Factors, and Clinical Outcomes of Bloodstream Infection due to Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in Hematologic Malignancy: A Retrospective Study from Central South China.

Objective: To determine the epidemiology, risk factors, and prognosis of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bloodstream infections (BSIs) among hematology malignancy (HM) patients in China. Method: From January 2010 to June 2018, we retrospectively collected and analyzed the 449 HM patients with E. coli or K. pneumoniae BSIs from three leading hospitals in Hunan Province, China. Results: Two hundred four (45.4%) patients harbored ESBL-producing bacteremia. The proportion of ESBL-producing bacteremia increased significantly with the growth of the year, with a ratio of 34.47% in 2010-2014 to 54.7% in 2015-2018. Comparing with non-ESBL groups in HM patients, central venous catheter (odds ratio [OR] 1.717, p = 0.009), previous antibiotic exposure (OR 1.559, p = 0.035), and E. coli (OR 2.561, p ≤ 0.001) among ESBL groups were independent risk factors. No significant differences in 30-day mortality were tested in patients with BSI caused by ESBL-producing or non-ESBL-producing E. coli and K. pneumoniae (17.1% vs. 16.7%; p = 0. 893). The proportion of carbapenem used within 72 hours after the onset of bacteremia in two groups was high, which was routinely used as "last-resort drugs" in Gram-negative bacterial infections. Risk factors associated with 30-day mortality in HM patients with E. coli or K. pneumoniae bacteremia were myelodysplastic syndrome, incomplete remission of the disease, Multinational Association of Supportive Care in Cancer score <21, Pitt bacteremia score ≥4, Charlson comorbidity score >3, catheter insertion, use of vasopressors, and inappropriate antibiotics within 72 hours of BSI onset. Conclusions: The results of this study may provide some references for the whole process management of HM patients with BSIs.

Necrotizing fasciitis in haematological patients: a different scenario.

To describe and compare the characteristics of necrotizing fasciitis (NF) in patients with and without haematological malignancy. All adult patients diagnosed with NF and treated at our hospital were included (January 2010-March 2019). Diagnosis was based on intraoperative findings or consistent clinical/radiological characteristics, and patients were classified as group A (with haematological malignancy) or group B (without haematological malignancy). Student's t (quantitative), Fisher's exact (qualitative), and Kaplan-Meyer tests were used for the statistical analysis. The study included 29 patients: 8 in group A and 21 in group B. All haematological patients had severe neutropenia (0.2 [0.02-0.5] ×109 cells/L; p < 0.001) and positive blood cultures (100% vs. 61.9%; p = 0.04) at diagnosis. Gram-negative bacilli NF was more common in group A (87.5% vs. 9.5%; p = 0.001), predominantly due to Escherichia coli (50% vs. 9.5%; p = 0.056). Surgical treatment was less common in haematological patients (5 [62.5%] vs. 21 [100%]; p = 0.015). Overall, 9 (31%) patients died: 4 (50%) in group A and 5 (23.8%) in group B (p = 0.17). The univariate analysis showed that mortality tended to be higher (OR 3.2; 95%CI 0.57-17.7; p = 0.17) and to occur earlier (2.2 ± 2.6 vs. 14.2 ± 19.9 days; p = 0.13) in haematological patients. The LRINEC index > 6 did not predict mortality in either group. In our study, NF in patients with haematological malignancies was mainly due to Gram-negative bacilli, associated to high and early mortality rates. In our experience, the LRINEC scale was not useful for predicting mortality.

Weissella confusa DD_A7 pre-treatment to zebrafish larvae ameliorates the inflammation response against Escherichia coli O157:H7.

Increasing multidrug-resistant pathogenic bacterial contamination in the environment has become the leading cause of food poisoning, resulting in life-threatening conditions due to late detection and limited therapeutic options. Escherichia coli O157:H7 is one such pathogen which is severely affecting the environmental livestock and ultimately leads to human infection. In this context, probiotics could be a useful strategy to minimize the growth of pathogens, as they produce several antimicrobial compounds and shows an exclusive competitive behavior against the pathogens. Therefore, supplementation of probiotics is wieldy accepted in the field of agriculture for the maintenance of animal's health. Previously, we reported that W. confusa DD_A7 possesses anti-bacterial and immune-stimulatory activity in-vitro. Therefore, in the present study, we investigated the impact of oral-administration of DD_A7 powder against E. coli O157:H7. The 6 days post-fertilized zebrafish larvae were used to evaluate the pathogenicity of the microbe. 1 × 108 CFU/ml of E. coli O157:H7 effectively induced the inflammatory response in zebrafish larvae. Where 1 × 108 CFU/ml DD_A7 pre-treatment prolonged the survivability of zebrafish larvae and improved the immune response of zebrafish larvae against pathogenic infection. The antibacterial property of DD_A7 against the pathogen correlated with the significant reduction of oxidative stress and host inflammatory response, by inhibiting NF-κB and its downstream signaling pathway. The findings demonstrated the prophylactic activity of DD_A7 suggesting that its supplementation improved the host defense mechanism by reducing oxidative stress. The growth of pathogen was effectively suppressed in the DD_A7 pre-treated larvae and maintained a healthy gastrointestinal environment in the zebrafish model.

Effect of intranasal instillation of Escherichia coli on apoptosis of spleen cells in diet-induced-obese mice.

Splenic immune function was enhanced in diet-induced-obese (DIO) mice caused by Escherichia coli. The changes in spleen function on apoptosis were still unknown. Two hundred mice in groups Lean-E. coli and DIO-E. coli were intranasal instillation of E. coli. And another two hundred mice in groups Lean-PBS and DIO-PBS were given phosphate-buffered saline (PBS). Subsequently, spleen histology was analyzed. Then the rates of spleen cell (SC) apoptosis, and expression of the genes and proteins of Bcl-2, Bax, caspase-3 and caspase-9 were quantified in each group at 0 h (uninfected), 12 h, 24 h, and 72 h postinfection. The SC apoptosis rates of the DIO-E. coli groups were lower than those of the DIO-PBS groups at 12, 24 and 72 h (p < 0.05). Anti-apoptotic Bcl-2 expression gene and protein of the DIO-E. coli groups were higher than those of the DIO-PBS groups (p < 0.05). Gene expressions of pro-apoptotic Bax, caspase-3 and caspase-9 of the DIO-E. coli groups were lower than those of DIO-PBS groups at 12, 24 and 72 h (p < 0.05). The SC apoptosis rates of the Lean-E. coli groups were higher than those of the Lean- PBS groups at 12 h and 24 h (p < 0.05). Interestingly, the SC apoptosis rates in the DIO-E. coli groups were lower than those of the Lean-E. coli groups at 12 h (p < 0.05). In conclusion, our results suggested that the DIO mice presented stronger anti-apoptotic abilities than Lean mice in non-fatal acute pneumonia induced by E. coli infection, which is more conducive to protecting the spleen and improving the immune defense ability of the body.

Staphylococcus Aureus Osteomyelitis as an Inducer of Tolerance to Escherichia Coli Pyelonephritis: an Experimental Study.

The high incidence of osteomyelitis in vulnerable populations like those with multiple injuries or elderly undergoing joint arthroplasties generates the question what may be their responses to subsequent infection by high virulent isolates. Rabbits were subject to two operations at three week intervals; sham osteomyelitis and sham pyelonephritis (group S); sham osteomyelitis and Escherichia coli pyelonephritis (group P); and Staphylococcus aureus osteomyelitis and E. coli pyelonephritis (group OP). Survival was recorded; cytokine stimulation of circulating mononuclear cells (PBMCs) and tissue myeloperoxidase (MPO) activity and bacterial growth were monitored. In some experiments, dalbavancin treatment was given before pyelonephritis. Healthy PBMCs were pre-treated with bone homogenate, S. aureus or both. Mortality of groups S, P and OP after induction of pyelonephritis was 0%, 50% and 8.3% respectively. Tumour necrosis factor-alpha (TNFα) production by PBMCs was significantly lower in the OP group at 48 hours. E. coli bacterial load was similar in groups P and OP at death or sacrifice whereas the MPO activity of group OP was decreased. Production of TNFα was further decreased among dalbavancin treated rabbits; in these rabbits tissue MPO was increased. TNFα production decreased when healthy PBMCs pre-treated with bone homogenate, S. aureus (HKSA) or both were stimulated with E. coli (HKEC); production was further decreased in the presence of anti-TLR4 and anti-TLR9. It is concluded that staphylococcal osteomyelitis modulated the innate immune responses of the host leading to protection from death by highly virulent E. coli. Tolerance to TLR ligands is the most likely mechanism of action.

Effect of colibacillosis on the immune response to a rabbit viral haemorrhagic disease vaccine.

Viral haemorrhagic disease (VHD) and colibacillosis are common diseases in rabbits that cause economic losses worldwide. The effect of colibacillosis on the immune response of vaccinated rabbits against rabbit haemorrhagic disease virus (RHDV) was studied. Four groups (G1-G4) were included. G1 was the negative control group; G2 was the RHDV vaccine group; G3 was the E. coli-infected group; and G4 was the E. coli-infected + RHDV vaccine group. The E. coli infection and RHDV vaccination were simultaneously performed, with another previous infection, 3 days before vaccination. At 28 days post-vaccination (PV), the rabbits (G2-G4) were challenged intramuscularly with 0.5 ml of RHDV at a dose of 103 50% median lethal dose (LD50)/rabbit. The rabbits were observed for clinical signs, body weight gain and mortality rates. Tissue, blood, serum, and faecal samples and rectal swabs were collected at 3, 5, 7, 14, 21 and 28 days PV. Significant clinical signs and mortality and a decrease in BW were observed in the infected + RHDV vaccine group. On the 3rd day post-infection (PI), compared with all the other groups, the vaccinated group (G2) had significantly upregulated hepatic tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels; however, the infected + RHDV vaccine group had significantly higher intestinal levels of TNF-α and IL-6 than the other groups. Furthermore, E. coli infection in vaccinated rabbits led to immunosuppression, as shown by significant decreases (P < 0.05) in heterophil phagocytic activity, the CD4+/CD8+ ratio, and HI antibody responses to RHDV and a significant increase in the heterophil to lymphocyte (H/L) ratio. In conclusion, colibacillosis leads to immunosuppression involving a shift in the equilibrium of cytokines and reduced weight gain and mortality in vaccinated rabbits and could be a contributing factor in RHDV vaccination failure in rabbit farming.

Atorvastatin increases the production of proinflammatory cytokines and decreases the survival of Escherichia coli-infected mice.

To assess whether the immunosuppressive effects of atorvastatin outweigh its antibacterial ones in an infection, mice were infected with Escherichia coli and administered atorvastatin; survival rates were then monitored. Mice treated with atorvastatin post-infection showed a remarkable decrease in their survival rate. On the other hand, the higher the level of serum IFN-γ in the infected mice treated with atorvastatin, the lower was the survival rate. Levels of IL-4 were markedly depressed in all groups infected with E. coli and treated with atorvastatin. Since atorvastatin inhibits IFN-γ expression in the absence of bacterial infection, we examined whether bacterial lipopolysaccharide (LPS) was the element capable of overriding this inhibition. Mouse peripheral blood mononuclear cells were treated with atorvastatin and lipopolysaccharide ex vivo then proinflammatory (IFN-γ, TNFα, IL-6) and prohumoral/regulatory (IL-4, IL-13, IL-10) cytokine levels were analyzed in culture supernatants. While proinflammatory cytokine levels were decreased upon treatment with atorvastatin alone, their levels were markedly elevated by treatment with LPS, bacterial lysate or bacterial culture supernatant. On the other hand, atorvastatin exerted an inhibitory effect on production of the prohumoral/regulatory cytokines. Our data indicates that any consideration for statins as antimicrobial treatment should assess the possible adverse outcomes.

Análisis clínico y microbiológico de la sepsis grave y el choque séptico por Escherichia coli en Medellín, Colombia / Severe sepsis and septic shock by Escherichia coli, clinical and microbiological analysis in Medellin, Colombia

Resumen Introducción: Escherichia coli es causa frecuente de un amplio espectro de infecciones, desde una infeccion urinaria no complicada hasta la sepsis grave y el choque septico, asociadas con desenlaces de alto impacto como ingreso a UCI y mortalidad. Objetivos: Determinar las diferencias en mortalidad. ingreso a UCI/UCE, presencia de cepas BLEE y tratamiento antimicrobiano en pacientes con sepsis grave y choque séptico por E. coli, con o sin bacteriemia, asi como su variabilidad dependiendo del foco infeccioso. Material y Métodos: Análisis secundario de estudio de cohorte prospective multicéntrico. Resultados: De 458 pacientes que tenian infeccion por E. coli, 123 tenian aislamiento solo en hemocultivo, 222 solo en urocultivo y 113 en ambas muestras. El aislamiento solo en hemocultivo se asocio mayor frecuencia de ingreso a UCI (n = 63; 5,2%). mayor necesidad de ventilacion mecánica (n = 19; 15,5%), mayor mortalidad y estancia hospitalaria (n = 22; 18%; mediana de 12 dias, RIQ= 7-17, respectivamente), pero con menor presencia de cepas productoras de BLEE en comparacion con urocultivos y hemocultivo, urocultivo (n = 20; 17,7% y n = 46; 20,7%, respectivamente). Recibieron tratamiento antimicrobiano en las primeras 24 h 424 pacientes (92,6%), con mas frecuencia piperacilina/ tazobactam (n = 256,60,3%). La proporcion de pacientes tratados empiricamente con carbapenemicos vs no carbapenemicos fue similar en los tres grupos. Discusión: El foco infeccioso. sumado a factores de nesgo para cepas productoras de BLEE, son herramientas utiles para definir pronostico y tratamiento en esta población, debido a la variabilidad clínica y microbiologica en los distintos aislados. Conclusión: Los pacientes con aislamiento de E. coli solo en hemocultivo presentan con mayor frecuencia desenlaces desfavorables en comparación con los pacientes con E. coli en urocultivo, con o sin bacteriemia. Llama la atencion en nuestro medio la menor cantidad de cepas productoras de BLEE en los pacientes con solo hemocultivo positivo.

Background: Escherichia coli is a common cause of a broad spectrum of infections, from non-complicated urinary tract infection, to severe sepsis and septic shock, that are associated to high impact outcomes, such as ICU admission and mortality. Aims: To establish differences in mortality, ICU admission, ESBL positive strains and antibiotic treatment, between patients with E. coli related severe sepsis and septic shock, with or without bacteremia and its variability based on the source of infection. Method: Secondary data analysis of a multicentric prospective cohort study. Results: From 458 patients with E. coli isolation, 123 had E. coli exclusively in blood culture, 222 solely in urine culture, and 113 in both samples. Escherichia coli isolation exclusively in blood culture was associated with higher frequency of ICU admission (n = 63; 51.2%), higher rate of mechanical ventilation requirement (n = 19; 15.5%), higher mortality and longer hospital stay (n = 22; 18%; median of 12 days, IQR= 7 - 17, respectively); but with a lower occurrence of ESBL strains, compared to patients with positive urine culture and positive blood/urine cultures (n = 20; 17.7% and n = 46; 20.7%, respectively). 424 patients (92.6%) received antibiotic treatment in the first 24 hours. The most commonly prescribed was piperacilin/tazobactam (n = 256;60.3%). The proportion of patients empirically treated with carbapenems vs non-carbapenems was similar in the three groups. Discussion: The source of infection, associated with ESBL strains risk factors, are useful tools to define prognosis and treatment in this population, because of their clinical and microbiological variability. Conclusion: Patients with E. coli isolation exclusively in the blood culture had higher frequency of non-favorable outcomes in comparison to patients with E. coli in urine culture with or without bacteremia. Additionally, in our population patients with E. coli solely in blood culture have lower prevalence of ESBL positive strains.

Caspase-3-mediated GSDME activation contributes to cisplatin- and doxorubicin-induced secondary necrosis in mouse macrophages.

OBJECTIVE: Induction of secondary necrosis/pyroptosis contributes to the toxicity of chemotherapeutic drugs, in which gasdermin E (GSDME) plays critical roles. This study aimed to explore whether GSDME is involved in mediating the cytotoxic effects of cisplatin and doxorubicin on mouse macrophages. METHODS: RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) were treated with cisplatin or doxorubicin. Propidium iodide staining was used to assay necrosis, and immunoblotting was performed to detect protein expression. GSDME was knocked down by using small interfering RNA. Mice were injected intraperitoneally to evaluate toxicity to macrophages in vivo. Flow cytometry and immunofluorescence microscopy were adopted to analyse phenotypes of peritoneal cells. Cytokine levels were assayed by cytometric bead array. RESULTS: Both cisplatin and doxorubicin dose-dependently induced necrosis in mouse RAW 264.7 macrophages and BMDMs. Accompanying this, multiple caspases were activated, concomitant with the cleavage of poly (ADP-ribose) polymerase. Consistent with caspase-3 activation, GSDME was cleaved to generate its N-terminal fragment (GSDME-NT), thus leading to secondary necrosis/pyroptosis. Inhibition of caspase-3 significantly attenuated the generation of GSDME-NT concurrently with decreased necrosis in macrophages. GSDME knockdown also evidently decreased the necrosis in RAW 264.7 and BMDMs. Besides, cisplatin administration depleted peritoneal macrophages in mice, which was associated with caspase-3 activation and GSDME-NT generation. Consistent with the macrophage depletion, cisplatin administration significantly decreased survival of mice with bacterial infection. CONCLUSION: Chemotherapeutic cisplatin and doxorubicin exerted their cytotoxicity on macrophages partly by inducing caspase-3/GSDME-mediated secondary necrosis.

The Role of Iron in the Susceptibility of Neonatal Mice to Escherichia coli K1 Sepsis.

Sepsis from Escherichia coli expressing the K1 antigen is a leading cause of death in neonates. In a murine model, E. coli K1 grew rapidly in the peritoneal cavity of neonatal mice, causing fatal disease. In contrast, adult mice cleared the infection. Neonatal mice mounted a rapid and equivalent antimicrobial immune response compared to adult mice. Interestingly, peritoneal fluid from neonatal mice contained significantly more total iron than that of adult mice, which was sufficient to support enhanced E. coli growth. Transient iron overload in adult mice infected with E. coli resulted in 100% mortality. Maternal diet-induced mild iron deficiency decreased offspring peritoneal iron, decreased bacterial growth, and conferred protection against sepsis. Taken together, neonatal susceptibility to E. coli K1 sepsis is enhanced by a localized excess of peritoneal iron that allows for unchecked bacterial growth. Targeting this excess iron may provide a new therapeutic target in human patients.

Bloodstream infection with extended-spectrum beta-lactamase-producing Escherichia coli: The role of virulence genes.

BACKGROUND: Extraintestinal pathogenic Escherichia coli (ExPEC) strains hold the responsibility for the majority of E. coli infections. Numerous extraintestinal virulence factors (VFs) were possessed by ExPEC which are involved in the pathogenesis of infection. However, the effect of comorbidities or infection syndrome in the association of VFs and mortality remains inconclusive. METHOD: This study addressed whether specific sequence type (ST) and VFs of extended-spectrum beta-lactamase-producing E. coli (ESBL-EC) are associated with different outcomes in patients with bloodstream infection. 121 adults from southern Taiwan with ESBL-EC bloodstream infections were enrolled during a 6-year period. Demographic data, including infection syndromes, underlying disease and outcomes, were collected. The virulence factors in isolates were analyzed by PCR and multilocus sequence typing analyses were also performed. RESULT: Positivity for the virulence genes iha, hlyD, sat, iutA, fyuA, malX, ompT, and traT was associated with ST131 positivity (P < 0.05). Some ESBL-EC virulence genes associated with urinary tract infection (UTI) were revealed. Positivity for ST405 and the virulence genes iroN and iss were significantly associated with increased 30-day mortality (death within 30 days) on univariate analysis (P < 0.05). Independent risk factors of 30-day mortality in bacteremic patients with UTI included underlying chronic liver disease and malignancy. ST131 was borderline associated with 30-day mortality. Independent risk factors associated with 30-day mortality among bacteremic patients without UTI included comorbidities and iroN positivity. CONCLUSION: In bacteremic patients with UTI, and the ST131 clone was borderline associated with mortality. Positivity for the virulence gene iroN may be linked to mortality in bacteremic patients without UTI.

Colonic adenoma-associated Escherichia coli express specific phenotypes.

Specific Escherichia coli strains have been associated to colorectal cancer, while no data are available on genotypic and phenotypic features of E. coli colonizing premalignant adenomatous polyps and their pathogenic potential. This study was aimed at characterizing isolates collected from polyps and adjacent tissue in comparison with those from normal mucosa. From colonoscopy biopsies, 1500 E. coli isolates were retrieved and genotyped; 272 were characterized for phylogroup and major phenotypic traits (i.e., biofilm formation, motility, hemolysins, and proteases). Selected isolates were analyzed for extraintestinal pathogenic E. coli (ExPEC)-associated virulence genes and in vivo pathogenicity using Galleria mellonella. The majority of isolates collected from polyps were strong biofilm and poor protease producers, whereas those isolates from normal mucosa were highly motile, proteolytic and weak biofilm formers. Isolates from adjacent tissues shared features with those from both polyps and normal mucosa. Among selected E. coli isolates, ExPEC gene content/profile was variable and uncorrelated with the tissue of collection and larval mortality. Despite the heterogeneous virulence-gene carriage of the E. coli intestinal population, E. coli colonizing colonic adenomatous polyps express specific phenotypic traits that could represent an initial pathoadaptation to local environmental changes characterizing these lesions.

Carbapenem versus Cefepime or Piperacillin-Tazobactam for Empiric Treatment of Bacteremia Due to Extended-Spectrum-ß-Lactamase-Producing Escherichia coli in Patients with Hematologic Malignancy.

Infections with extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli are common in patients with hematologic malignancy. The utility of cefepime and piperacillin-tazobactam as empiric therapy for ESBL-producing E. coli bacteremia in patients with hematologic malignancy is largely unknown. We conducted a single-center, retrospective cohort review of 103 adult inpatients with leukemia and/or hematopoietic stem cell transplant (HCT) recipients with monomicrobial ESBL-producing E. coli bacteremia. No association between increased 14-day mortality and empiric treatment with cefepime (8%) or piperacillin-tazobactam (0%) relative to that with carbapenems (19%) was observed (P = 0.19 and P = 0.04, respectively). This observation was consistent in multivariate Cox proportional hazards models adjusted for confounding and an inverse probability of treatment-weighted (IPTW) Cox proportional hazards model. Both fever and persistent bacteremia were more common in patients treated empirically with cefepime or piperacillin-tazobactam. Empiric treatment with cefepime or piperacillin-tazobactam did not result in increased mortality relative to that with treatment with carbapenems in patients with hematologic malignancy and ESBL-producing E. coli bacteremia, although most patients were changed to carbapenems early in treatment. However, due to prolonged fever and persistent bacteremia, their role may be limited in this patient population.

Associated factors and clinical outcomes of bloodstream infection due to extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae during febrile neutropenia.

Patients with neutropenia are vulnerable to serious infections. During the last decade, increased prevalence of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae has affected immunocompromised patients. We conducted a single-center case-control study to evaluate factors associated with ESBL-positive bacteremia among neutropenic patients, and its clinical impact. The study included adult patients with hematologic or oncologic diseases diagnosed with ESBL-positive and ESBL-negative Escherichia coli or Klebsiella pneumoniae bacteremia during febrile neutropenia between January 2010 and October 2017 at the Shaare Zedek Medical Center, Jerusalem, Israel. Analyses included risk factors for ESBL-positive bacteremia, appropriateness of empiric antibiotics, mortality, length of stay, and intensive care unit (ICU) admission. Univariate and multivariate models were constructed. The cohort (80 patients), consisted of 54 ESBL-negative and 26 ESBL-positive Gram-negative bacteremia. Multivariate analysis suggested ESBL-positive bacteremia to be associated with long-term central venous catheter (CVC) (odds ratio (OR), 8.7; 95% confidence interval (CI), 1.6-48.1; P=0.01], index culture obtained 48 h post-admission (OR, 3.6; 95% CI, 1-12.3; P=0.04), and exposure to previous antimicrobial therapy (OR, 12.6; 95% CI, 2.1-74; P<0.01). There were no significant differences between groups with regard to length of stay, ICU admission, or mortality rates. Mortality was associated with high Pitt bacteremia score but not inappropriate empirical therapy. Previous antimicrobial therapy, long-term CVC, and hospital-acquired bacteremia were associated with ESBL bacteremia. Neutropenic patients with ESBL bacteremia have increased morality due to other factors than ESBL status. These findings should be validated in other centers and with larger populations.

Azithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis.

Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1ß, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

[Antibiotic Resistance and Risk Factors for Mortality of Blood Stream Infections (BSIs) with Escherichia coli in Patients with Hematological Malignancies].

OBJECTIVE: To analyze the risk factors for mortality of blood stream infections (BSIs) caused by Escherichia coli in the patients with hematological malignancies. METHODS: There were 110 Escherichia coli BSIs patients with hematological malignancies included in recent five years. Among them,77 cases had BSIs caused by extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli (ESBL-EC group),while 33 cases had BSIs with non-ESBL-producing Escherichia coli (non-ESBL-EC group). The antibiotic resistance and clinical features were compared between the two groups,and the risk factors for death within 30 d were analyzed. RESULTS: Less than 10% of the isolates were resistant to carbapenems and amikacin. Between ESBL-EC group and non-ESBL-EC group,the clinical symptoms,prior use of antibiotics or antifungal agents,risk factors for infection,30 d mortality rates were not significantly different (P>0.05). A logistic regression analysis confirmed that non remission of hematologic malignancies (odds ratio=9.575,95% confidence interval 1.546-59.312,P=0.015) and inappropriate initial antibiotic therapy (odds ratio=8.806,95% confidence interval 1.527-50.772, P=0.015) were independent risk factors for 30 d mortality. CONCLUSION: The use of effective antimicrobial treatment as early as possible could reduce the risk of death for hematological malignancies patients suffering Escherichia coli BSIs.

Invasive infection caused by Klebsiella pneumoniae is a disease affecting patients with high comorbidity and associated with high long-term mortality.

Klebsiella pneumoniae (KP) is after Escherichia coli (EC) the most common gram-negative species causing invasive infections. Herein, we analyzed risk factors and prognosis in invasive infections caused by KP versus EC, in an area with low antimicrobial resistance. Moreover, we compared antimicrobial resistance and relative prevalence of KP and EC (KP/EC-ratio) in different European countries, using EARS-Net data. Adult patients admitted to Karolinska University Hospital 2006-2012 with invasive infection caused by KP (n = 599) were matched regarding sex and age with patients infected by EC. The medical records were retrospectively reviewed. Comorbidity was adjusted for with multivariable analysis. European data were retrieved from the EARS-Net database. No differences were observed in 7- and 30-day mortality between the groups. The 90-day mortality was significantly higher in the KP cohort (26% versus 17%, p<0.001), but not after adjusting for comorbidity. Malignancy was seen in 53% of the patients with KP versus 38% with EC, OR 1.86 (1.34-2.58). A significant increase in the rate of ESBL-production was observed in EC, but not in KP. The KP/EC-ratio remained stable. In contrast, European data showed increasing percentages of isolates non-susceptible to third-generation cephalosporins in EC and KP, and increasing KP/EC-ratio. Invasive infection caused by KP is a disease affecting patients with high comorbidity and associated with high 90-d mortality. The stable KP/EC-ratio and low occurrence of antimicrobial resistance in data from Karolinska University Hospital compared to aggregate data from 20 EARS-Net countries could be related to absence of clonal spread of multidrug-resistant KP.

Combined Effects of M1 Muscarinic Acetylcholine Receptor Agonist TBPB and α7n-Acetylcholine Receptor Activator GTS-21 on Mouse Mortality and Blood Concentration of Proinflammatory Cytokines in Sepsis.

Experiments on random-bred albino mice showed that M1 muscarinic acetylcholine receptor agonist (TBPB) and α7n-acetylcholine receptor agonist (GTS-21) significantly reduced mortality of mice with experimental sepsis (intraperitoneally administration of E. coli) in 4 and 24 h after modeling by reducing blood concentration of proinflammatory cytokines TNF-α, IL-1ß, and IL-6. Combined treatment with TBPB and GTS-21 determined their additive effect.

Bacteraemia due to AmpC ß-lactamase-producing Escherichia coli in hospitalized cancer patients: risk factors, antibiotic therapy, and outcomes.

AmpC ß-lactamase-producing Escherichia coli (AmpC-EC) is one of the main antimicrobial resistant pathogens in patients with cancer. A cohort study was performed to evaluate the risk factors, antibiotic therapy, and outcomes of AmpC-EC bacteraemia in hospitalized cancer patients from September 2012 through December 2015. Two hundred forty-eight cases of E. coli bacteraemia were documented in cancer patients, 51 (20.6%) were caused by AmpC-EC and 197 (79.4%) were caused with non-AmpC-EC. Prior exposure to cephalosporins (OR 2.786; 95% CI: 1.094-7.091; P=0.032), carbapenems (OR 2.296; 95% CI: 1.054-5.004; P=0.036), and invasive procedures (OR 4.237; 95% CI: 1.731-10.37; P=0.002) were identified as independent risk factors for AmpC-EC. The time to positivity (TTP) of patients with AmpC-EC bacteraemia tended to be significantly shorter than that of non-AmpC-EC (8.33±2.18h versus 9.48±3.82h; P=0.006), and had a higher 30-day mortality rate in AmpC-EC compared with non-AmpC-EC (25.5% versus 12.2%; P=0.018). Metastasis (OR=2.778, 95% CI: 1.078-7.162; P=0.034), the presence of septic shock (OR=4.983, 95% CI: 1.761-14.10; P=0.002), and organ failure (OR=24.51 95% CI: 9.884-60.81; P<0.001) were independently associated with the overall mortality. The mortality rate showed a gradual increase when appropriate antibiotic therapy (AAT) was delayed more than 48h as determined by the trend test (P<0.001). In conclusion, this study showed that prevalence of AmpC-EC was high in hospitalized cancer patients of our area. Thus, it is necessary to apply appropriate therapeutic approaches and improve outcomes based on the analysis of risk factors for the acquisition of AmpC-EC.

Efficacy of mealworm and super mealworm larvae probiotics as an alternative to antibiotics challenged orally with Salmonella and E. coli infection in broiler chicks.

This study was conducted to evaluate dry mealworm (Tenebrio molitor) (DMLP) and super mealworm (Zophobas morio) (DSMLP) larvae probiotics as alternatives to antibiotics in broiler chicks. A total of 240 one-day old Ross 308 male broiler chicks were randomly assigned to three dietary treatments consisting of ten replications with eight birds each in a completely randomized design. The dietary treatments were, (i) control (basal diet), (ii) 0.4% DMLP (basal diet + 0.4% DMLP, DM basis), and (iii) 0.4% DSMLP (basal diet + 0.4% DSMLP, DM basis). On day one, 1 mL of mixed broth agar consisting of 2.4 × 107 cfu Salmonella enteritidis KCTC 2021 and 3.7 × 107 cfu Escherichia coli KCTC 2571 was injected orally into each chick. After one week, growth performance, immunity, mortality, internal organ weight, and cecal and fecal microbiota were investigated. Average daily gain ( ADG: ) and average daily feed intake (ADFI) increased, while feed conversion ratio (FCR) (g intake/g gain per bird) decreased in response to DMLP and DSMLP supplementation (P < 0.05). Additionally, mortality decreased (P < 0.05), while IgG and IgA levels increased following DMLP and DSMLP supplementation (P < 0.05). Internal organs remained unaffected, except for a reduced bursa of Fabricius weight in DSMLP supplementation (P < 0.05). Cecal E. coli and Salmonella contents were reduced in DMLP and DSMLP supplementation (P < 0.05), while fecal microbiota contents and pH of cecal and fecal digesta remained unaffected. In conclusion, dietary supplementation with DMLP and DSMLP increased ADG and IgG and IgA levels, while reducing FCR, mortality and cecal E. coli and Salmonella spp. CONTENTS: Thus, DMLP and DSMLP can be utilized as an alternative to antibiotics in broiler diets.