Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm.

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

Spatio-temporal brain invasion pattern of Streptococcus pneumoniae and dynamic changes in the cellular environment in bacteremia-derived meningitis.

Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by a neuroinflammatory response and the deleterious action of bacterial toxins in the brain. However, little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with the presence of pneumococci closely associated to the microvasculature. In the hippocampus, the invasion provoked microglial activation, while the neurogenic niche showed increased proliferation and migration of neuroblasts. Our results indicate that, even before the outbreak of symptoms, the bacterial load throughout the brain is high and causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.

Intestinal colonization regulates systemic anti-commensal immune sensitivity and hyperreactivity.

Healthy host-microbial mutualism with our intestinal microbiota relies to a large degree on compartmentalization and careful regulation of adaptive mucosal and systemic anti-microbial immune responses. However, commensal intestinal bacteria are never exclusively or permanently restricted to the intestinal lumen and regularly reach the systemic circulation. This results in various degrees of commensal bacteremia that needs to be appropriately dealt with by the systemic immune system. While most intestinal commensal bacteria, except for pathobionts or opportunistic pathogen, have evolved to be non-pathogenic, this does not mean that they are non-immunogenic. Mucosal immune adaptation is carefully controlled and regulated to avoid an inflammatory response, but the systemic immune system usually responds differently and more vigorously to systemic bacteremia. Here we show that germ-free mice have increased systemic immune sensitivity and display anti-commensal hyperreactivity in response to the addition of a single defined T helper cell epitope to the outer membrane porin C (OmpC) of a commensal Escherichia coli strain demonstrated by increased E. coli-specific T cell-dependent IgG responses following systemic priming. This increased systemic immune sensitivity was not observed in mice colonized with a defined microbiota at birth indicating that intestinal commensal colonization also regulates systemic, and not only mucosal, anti-commensal responses. The observed increased immunogenicity of the E. coli strain with the modified OmpC protein was not due to a loss of function and associated metabolic changes as a control E. coli strain without OmpC did not display increased immunogenicity.

Whole-Genome Sequencing Reveals Differences among Kingella kingae Strains from Carriers and Patients with Invasive Infections.

As a result of the increasing use of sensitive nucleic acid amplification tests, Kingella kingae is being recognized as a common pathogen of early childhood, causing medical conditions ranging from asymptomatic oropharyngeal colonization to bacteremia, osteoarthritis, and life-threatening endocarditis. However, the genomic determinants associated with the different clinical outcomes are unknown. Employing whole-genome sequencing, we studied 125 international K. kingae isolates derived from 23 healthy carriers and 102 patients with invasive infections, including bacteremia (n = 23), osteoarthritis (n = 61), and endocarditis (n = 18). We compared their genomic structures and contents to identify genomic determinants associated with the different clinical conditions. The mean genome size of the strains was 2,024,228 bp, and the pangenome comprised 4,026 predicted genes, of which 1,460 (36.3%) were core genes shared by >99% of the isolates. No single gene discriminated between carried and invasive strains; however, 43 genes were significantly more frequent in invasive isolates, compared to asymptomatically carried organisms, and a few showed a significant differential distribution among isolates from skeletal system infections, bacteremia, and endocarditis. The gene encoding the iron-regulated protein FrpC was uniformly absent in all 18 endocarditis-associated strains but was present in one-third of other invasive isolates. Similar to other members of the Neisseriaceae family, the K. kingae differences in invasiveness and tropism for specific body tissues appear to depend on combinations of multiple virulence-associated determinants that are widely distributed throughout the genome. The potential role of the absence of the FrpC protein in the pathogenesis of endocardial invasion deserves further investigation. IMPORTANCE The wide range of clinical severities exhibited by invasive Kingella kingae infections strongly suggests that isolates differ in their genomic contents, and strains associated with life-threatening endocarditis may harbor distinct genomic determinants that result in cardiac tropism and severe tissue damage. The results of the present study show that no single gene discriminated between asymptomatically carried isolates and invasive strains. However, 43 putative genes were significantly more frequent among invasive isolates than among pharyngeal colonizers. In addition, several genes displayed a significant differential distribution among isolates from bacteremia, skeletal system infections, and endocarditis, suggesting that the virulence and tissue tropism of K. kingae are multifactorial and polygenic, depending on changes in the allele content and genomic organization. Further analysis of these putative genes may identify genomic determinants of the invasiveness of K. kingae and its affinity for specific body tissues and potential targets for a future protective vaccine.

Breaking the Gingival Barrier in Periodontitis.

The break of the epithelial barrier of gingiva has been a subject of minor interest, albeit playing a key role in periodontal pathology, transitory bacteraemia, and subsequent systemic low-grade inflammation (LGI). The significance of mechanically induced bacterial translocation in gingiva (e.g., via mastication and teeth brushing) has been disregarded despite the accumulated knowledge of mechanical force effects on tight junctions (TJs) and subsequent pathology in other epithelial tissues. Transitory bacteraemia is observed as a rule in gingival inflammation, but is rarely observed in clinically healthy gingiva. This implies that TJs of inflamed gingiva deteriorate, e.g., via a surplus of lipopolysaccharide (LPS), bacterial proteases, toxins, Oncostatin M (OSM), and neutrophil proteases. The inflammation-deteriorated gingival TJs rupture when exposed to physiological mechanical forces. This rupture is characterised by bacteraemia during and briefly after mastication and teeth brushing, i.e., it appears to be a dynamic process of short duration, endowed with quick repair mechanisms. In this review, we consider the bacterial, immune, and mechanical factors responsible for the increased permeability and break of the epithelial barrier of inflamed gingiva and the subsequent translocation of both viable bacteria and bacterial LPS during physiological mechanical forces, such as mastication and teeth brushing.

Clinical and Microbiological Characteristics of Recurrent Escherichia coli Bacteremia.

The causative agents of recurrent Escherichia coli bacteremia can be genetically identical or discordant, but the differences between them remain unclear. This study aimed to explore these differences, with regard to their clinical and microbiological features. Patients were recruited from a Japanese tertiary teaching hospital based on blood culture data and the incidence of recurrent E. coli bacteremia. We compared the patients' clinical and microbiological characteristics between the two groups (those with identical or discordant E. coli bacteremia) divided by the result of enterobacterial repetitive intergenic consensus PCR. Among 70 pairs of recurrent E. coli bacteremia strains, 49 pairs (70%) were genetically identical. Patients with genetically identical or discordant E. coli bacteremia were more likely to have renal failure or neoplasms, respectively. The virulence factor (VF) scores of genetically identical E. coli strains were significantly higher than those of genetically discordant strains, with the prevalence of eight VF genes being significantly higher in genetically identical E. coli strains. No significant differences were found between the two groups regarding antimicrobial susceptibility and biofilm formation potential. This study showed that genetically identical E. coli bacteremia strains have more VF genes than genetically discordant strains in recurrent E. coli bacteremia. IMPORTANCE Escherichia coli causes bloodstream infection, although not all strains are pathogenic to humans. In some cases, this infection reoccurs, and several reports have described the clinical characteristics and/or molecular microbiology of recurrent Escherichia coli bacteremia. However, these studies focused on patients with specific characteristics, and they included cases caused by microorganisms other than Escherichia coli. Hence, little is known about the pathogenicity of Escherichia coli isolated from the recurrent one. The significance of our study is in evaluating the largest cohorts to date, as no cohort studies have been conducted on this topic.

Antimicrobial Susceptibility Trends and Risk Factors for Antimicrobial Resistance in Pseudomonas aeruginosa Bacteremia: 12-Year Experience in a Tertiary Hospital in Korea.

BACKGROUND: Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) have been on the rise worldwide, and delayed active antimicrobial therapy is associated with high mortality. However, few studies have evaluated increases in P. aeruginosa infections with antimicrobial resistance and risk factors for such antimicrobial resistance in Korea. Here, we analyzed changes in antimicrobial susceptibility associated with P. aeruginosa bacteremia and identified risk factors of antimicrobial resistance. METHODS: The medical records of patients with P. aeruginosa bacteremia who were admitted to a tertiary hospital between January 2009 and October 2020 were retrospectively reviewed. Antibiotic resistance rates were compared among the time periods of 2009-2012, 2013-2016, and 2017-2020 and between the intensive care unit (ICU) and non-ICU setting. Empirical antimicrobial therapy was considered concordant, if the organism was susceptible to antibiotics in vitro, and discordant, if resistant. RESULTS: During the study period, 295 patients with P. aeruginosa bacteremia were identified. The hepatobiliary tract (26.8%) was the most common primary site of infection. The rates of carbapenem-resistant P. aeruginosa (CRPA), MDRPA, and extensively drug-resistant P. aeruginosa (XDRPA) were 24.7%, 35.9%, and 15.9%, respectively. XDRPA showed an increasing trend, and CRPA, MDRPA, and XDRPA were also gradually increasing in non-ICU setting. Previous exposure to fluoroquinolones and glycopeptides and urinary tract infection were independent risk factors associated with CRPA, MDRPA, and XDRPA. Previous exposure to carbapenems was an independent risk factor of CRPA. CRPA, MDRPA, and XDRPA were associated with discordant empirical antimicrobial therapy. CONCLUSION: The identification of risk factors for antimicrobial resistance and analysis of antimicrobial susceptibility might be important for concordant empirical antimicrobial therapy in patients with P. aeruginosa bacteremia.

Melioidosis: Laboratory Investigations and Association with Patient Outcomes.

Melioidosis is an infection caused by the bacterium Burkholderia pseudomallei. The most common presentation is bacteremia occurring in 38-73% of all patients, and the mortality rate ranges from 9% to 42%. Although there is abundant data representing risk factors for infection and patient outcomes, there is limited information regarding laboratory investigations associated with bacteremia and mortality. We assessed a range of baseline and diagnostic investigations and their association with patient outcomes in a retrospective cohort study in Townsville, Australia. 124 patients' medical and laboratory records were reviewed between January 1, 1997 and December 31, 2020. Twenty-seven patients died and 87 patients were bacteremic. The presence of lymphopenia (< 1.5 × 109 cells/L) was the highest risk for bacteremia (relative risk [RR] 2.2; 95% CI: 1.3-3.7, P < 0.001). Factors associated with mortality included lymphopenia, (RR: 1.4; 95% CI: 1.2-1.6, P = 0.004); uremia (RR: 1.7; 95% CI: 1.1-2.5, P = 0.03); and an elevated international normalized ratio (RR: 1.5; 95% CI: 1.2-2.0, P = 0.006). Median incubation to positive blood culture result was 28 hours with 15/82 (18%) positive in ≤ 24 hours. For serological testing during admission only 53/121 (44%) were indirect hemagglutination assay positive, 67/120 (56%) enzyme immunoassay IgG positive, and 23/89 (26%) IgM positive. Simple baseline investigations at time of presentation may be used to stratify patients at high risk for both bacteremia and mortality. This information can be used as a decision aid for early intensive management.

Pathogen clonal expansion underlies multiorgan dissemination and organ-specific outcomes during murine systemic infection.

The dissemination of pathogens through blood and their establishment within organs lead to severe clinical outcomes. However, the within-host dynamics that underlie pathogen spread to and clearance from systemic organs remain largely uncharacterized. In animal models of infection, the observed pathogen population results from the combined contributions of bacterial replication, persistence, death, and dissemination, each of which can vary across organs. Quantifying the contribution of each these processes is required to interpret and understand experimental phenotypes. Here, we leveraged STAMPR, a new barcoding framework, to investigate the population dynamics of extraintestinal pathogenic Escherichia coli, a common cause of bacteremia, during murine systemic infection. We show that while bacteria are largely cleared by most organs, organ-specific clearance failures are pervasive and result from dramatic expansions of clones representing less than 0.0001% of the inoculum. Clonal expansion underlies the variability in bacterial burden between animals, and stochastic dissemination of clones profoundly alters the pathogen population structure within organs. Despite variable pathogen expansion events, host bottlenecks are consistent yet highly sensitive to infection variables, including inoculum size and macrophage depletion. We adapted our barcoding methodology to facilitate multiplexed validation of bacterial fitness determinants identified with transposon mutagenesis and confirmed the importance of bacterial hexose metabolism and cell envelope homeostasis pathways for organ-specific pathogen survival. Collectively, our findings provide a comprehensive map of the population biology that underlies bacterial systemic infection and a framework for barcode-based high-resolution mapping of infection dynamics.

Infectious diseases specialist consultation in Staphylococcus lugdunensis bacteremia.

BACKGROUND: Commensal coagulase negative Staphylococcus lugdunensis may cause severe bacteremia (SLB) and complications. Treatment of SLB is not fully established and we wanted to evaluate if infectious diseases specialist consultation (IDSC) would improve management and prognosis. METHODS: Multicenter retrospective study of SLB patients followed for 1 year. Patients were stratified according to bedside (formal), telephone (informal) or lack of IDSC within 7 days of SLB diagnosis. RESULTS: Altogether, 104 SLB patients were identified: 24% received formal bedside and 52% informal telephone IDSC whereas 24% were managed without any IDSC. No differences in demographics, underlying conditions or severity of illness were observed between the groups. Patients with bedside IDSC, compared to telephone IDSC or lack of IDSC, had transthoracic echocardiography more often performed (odds ratio [OR] 4.00; 95% confidence interval [CI] 1.31-12.2; p = 0.012) and (OR 16.0; 95% CI, 4.00-63.9; P<0.001). Bedside IDSC was associated with more deep infections diagnosed compared to telephone IDSC (OR, 7.44; 95% CI, 2.58-21.4; p<0.001) or lack of IDSC (OR, 9.56; 95% CI, 2.43-37.7; p = 0.001). The overall mortality was 7%, 10% and 17% at 28 days, 90 days and 1 year, respectively. Considering all prognostic parameters, patients with IDSC, compared to lack of IDSC, had lower 90 days and 1 year mortality (OR, 0.11; 95% CI, 0.02-0.51; p = 0.005) and (OR, 0.22; 95% CI, 0.07-0.67; p = 0.007). CONCLUSION: IDSC may improve management and outcome of Staphylococcus lugdunensis bacteremia.

Simple indictor of increased blood culture contamination rate by detection of coagulase-negative staphylococci.

Coagulase-negative staphylococci (CoNS) are the most frequent contaminating bacteria; therefore, we aimed to investigate an indicator of CoNS to predict the increase in blood culture contamination rate (ConR). We performed a retrospective study of selected patients, who underwent blood culture testing. Contamination was defined as the presence of either one of two or more sets of skin-resident bacteria, except for cases with a low likelihood of contamination based on clinical aspects. We calculated the monthly ConR [(total number of contaminated cases per month)/(total number of blood culture sets collected per month) × 100] and analysed the ConR prediction ability using the following four indicators: the number of CoNS-positive sets of blood cultures, cases with at least one CoNS-positive blood culture set, cases with only one CoNS-positive blood culture set, and cases of contamination by CoNS. Cases with CoNS-positive blood cultures correlated with ConR (r = 0.85). Although the area under the receiver operating characteristic curve for the number of cases with ConR ≥ 2.5 differed significantly from that of the number of cases contaminated by CoNS, the negative predictive value was high, reaching up to 95.5% (95% confidential interval 87.3-99.1). The number of CoNS-positive cases could help predict an increase in ConR ≥ 2.5.

Krueppel-Like Factor 4 Expression in Phagocytes Regulates Early Inflammatory Response and Disease Severity in Pneumococcal Pneumonia.

The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early pro-inflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia.

Biofilm microbiome in extracorporeal membrane oxygenator catheters.

Despite the formation of biofilms on catheters for extracorporeal membrane oxygenation (ECMO), some patients do not show bacteremia. To elucidate the specific linkage between biofilms and bacteremia in patients with ECMO, an improved understanding of the microbial community within catheter biofilms is necessary. Hence, we aimed to evaluate the biofilm microbiome of ECMO catheters from adults with (n = 6) and without (n = 15) bacteremia. The microbiomes of the catheter biofilms were evaluated by profiling the V3 and V4 regions of bacterial 16s rRNA genes using the Illumina MiSeq sequencing platform. In total, 2,548,172 reads, with an average of 121,341 reads per sample, were generated. Although alpha diversity was slightly higher in the non-bacteremic group, the difference was not statistically significant. In addition, there was no difference in beta diversity between the two groups. We found 367 different genera, of which 8 were present in all samples regardless of group; Limnohabitans, Flavobacterium, Delftia, Massilia, Bacillus, Candidatus, Xiphinematobacter, and CL0-1 showed an abundance of more than 1% in the sample. In particular, Arthrobacter, SMB53, Neisseria, Ortrobactrum, Candidatus Rhabdochlamydia, Deefgae, Dyella, Paracoccus, and Pedobacter were highly abundant in the bacteremic group. Network analysis indicated that the microbiome of the bacteremic group was more complex than that of the non-bacteremic group. Flavobacterium and CL0.1, which were abundant in the bacteremic group, were considered important genera because they connected different subnetworks. Biofilm characteristics in ECMO catheters varied according to the presence or absence of bacteremia. There were no significant differences in diversity between the two groups, but there were significant differences in the community composition of the biofilms. The biofilm-associated community was dynamic, with the bacteremic group showing very complex network connections within the microbiome.

Factors associated with severe sepsis in diarrheal adults and their outcome at an urban hospital, Bangladesh: A retrospective analysis.

BACKGROUND: To describe factors associated with severe sepsis in diarrheal adults and their outcomes and offender in blood and stool to understand their interplay as clinical features of sepsis and severe diarrhea often overlap. METHODS AND RESULTS: We used this retrospective chart analysis employing an unmatched case-control design to study critically ill diarrheal adults aged ≥18 years treated in ICU of Dhaka hospital, icddr,b between January 2011 to December 2015. Of 8,863 in-patient diarrheal adults, 350 having severe sepsis were cases and an equal number of randomly selected non-septic patients were the controls. Cases died significantly more (14.9% vs 4.6%, p = <0.001) than controls. 69% of the cases progressed to septic shock. In logistic regression analysis, steroid intake, ileus, acute kidney injury (AKI), metabolic acidosis, and hypocalcemia were significantly associated with severe sepsis in diarrheal adults (all, p<0.05). 12% of cases (40/335) had bacteremia. Streptococcus pneumoniae [9 (22.5%)] was the single most common pathogen and gram-negatives [27 (67.5%)] were prevailing as a group. CONCLUSION: Diarrheal adults who had ileus, AKI, metabolic acidosis, hypocalcemia, and also took steroids were found to have an association with severe sepsis. Strikingly, gram-negative were the predominant bacteria among the diarrheal adults having severe sepsis.

Eggerthella lenta bacteremia successfully treated with ceftizoxime: case report and review of the literature.

Eggerthella lenta is a normal human microflora that is anaerobic, non-sporulating, and Gram positive. However, an increasing number of studies have shown that it could also be an important pathogen for humans, even causing life-threatening infection under certain conditions. However, understanding its pathogenic mechanism and treatment options still need to be improved; more clinical data are needed to explore it further. In this article, we report a case of ceftizoxime-cured E. lenta bacteremia and review the recent literature to provide more clinical data for the diagnosis of E. lenta bacteremia. Our report suggests that the frequency of E. lenta bacteremia is increased in patients with hematologic or solid organ cancer, diabetes mellitus and also in those with appendicitis.

Baseline iron status and presence of anaemia determine the course of systemic Salmonella infection following oral iron supplementation in mice.

BACKGROUND: Iron deficiency anaemia (IDA) is a major health concern. However, preventive iron supplementation in regions with high burden of infectious diseases resulted in an increase of infection related morbidity and mortality. METHODS: We fed male C57BL/6N mice with either an iron deficient or an iron adequate diet. Next, they received oral iron supplementation or placebo followed by intraperitoneal infection with Salmonella Typhimurium (S.Tm). FINDINGS: We found that mice with IDA had a poorer clinical outcome than mice on an iron adequate diet. Interestingly, iron supplementation of IDA mice resulted in higher bacterial burden in organs and shortened survival. Increased transferrin saturation and non-transferrin bound iron in the circulation together with low expression of ferroportin facilitated the access of the pathogen to iron and promoted bacterial growth. Anaemia, independent of iron supplementation, was correlated with reduced neutrophil counts and cytotoxic T cells. With iron supplementation, anaemia additionally correlated with increased splenic levels of the cytokine IL-10, which is suggestive for a weakened immune control to S.Tm infection. INTERPRETATION: Supplementing iron to anaemic mice worsens the clinical course of bacterial infection. This can be traced back to increased iron delivery to bacteria along with an impaired anti-microbial immune response. Our findings may have important implications for iron supplementation strategies in areas with high endemic burden of infections, putting those individuals, who potentially profit most from iron supplementation for anaemia, at the highest risk for infections. FUNDING: Financial support by the Christian Doppler Laboratory for Iron Metabolism and Anemia Research.

Clinical features and outcome of Aeromonas sobria bacteremia in pediatric and adult patients with hematologic malignancies: A single-center retrospective study in Peru.

BACKGROUND: Previous studies have found that healthcare-associated bacteremia (HAB) by Aeromonas species is associated with mortality. However, there is limited data on this outcome in patients with hematologic malignancies. This study aimed to identify the clinical features of patients with malignant hematologic diseases diagnosed with Aeromonas sobria bacteremia and to evaluate whether the type of bacteremia, community-acquired bacteremia (CAB) or HAB, is associated with mortality. METHODS: We retrospectively reviewed the clinical records of pediatric and adult patients between January 2000 and December 2017. Clinical characteristics were compared between CAB and HAB. Additionally, we stratified based on age group. Survival outcomes were assessed with Kaplan-Meier curves and a multivariate Cox regression analysis. RESULTS: A total of 37 patients (median age 24 years) were identified; 23 (62%) had HAB and 14 (38%) had CAB. Overall, the most common presenting symptom was abdominal pain (41%). Acute lymphoblastic leukemia (n = 12/15, 80%) and acute myeloid leukemia (n = 8/22, 36%) were the primary hematologic malignancies in pediatric and adult patients, respectively. CAB patients had worse overall survival (OS) rates at 30 days in all (43% versus HAB 91%, p = 0.006) and adult patients (30% versus HAB 92%, p = 0.002). Cox regression analysis found that quick Sequential Organ Failure Assessment and CAB were statistically significant factors associated with mortality. Low antimicrobial-resistant was noted, except for ciprofloxacin (n = 5/37, 14%). CONCLUSION: Our study found a worse OS among patients with hematologic malignancies and CAB by Aeromonas sobria. Our results suggest that patients with CAB present with a worse disease severity. These findings should aid clinicians to determine the survival prognosis in this population.

Crystalline ruthenium polypyridine nanoparticles: a targeted treatment of bacterial infection with multifunctional antibacterial, adhesion and surface-anchoring photosensitizer properties.

Photodynamic antibacterial therapy employs nanocomposites as an alternative to traditional antibiotics for the treatment of bacterial infections. However, many of these antibacterial materials are less effective towards bacteria than traditional drugs, either due to poor specificity or antibacterial activity. This can result in needless and excessive drug use in treatments. This paper describes a multifunctional drug delivery nanoparticle (MDD-NP), Sph-Ru-MMT@PZ, based on the nanostructured-form of [Ru(bpy)2dppz] (PF6)2 (Sph-Ru), which has adhesive properties towards its microbial targets as well as surface-anchoring photosensitizer effects. The design and construction of MDD-NP is based on the adhesive properties of the outer layers of montmorillonite (MMT), which allows Sph-Ru-MMT@PZ to successfully reach its bacterial target; the outer layer of the E. coli. In addition, under 670 nm red irradiation therapy (R-IT), the surface-anchoring properties use the photosensitizer phthalocyanine zinc (PZ) to destroy the bacteria by producing reactive oxygen species (ROS) which causes cell lysis of E. coli. More importantly, Sph-Ru-MMT@PZ has no fluorescence response to live E. coli with intact cell membranes but selectively stained and demonstrated fluorescence during membrane damage of early-stage cells as well as exposure of nuclear materials at late-stage of cell lysis. Sph-Ru-MMT@PZ showed beneficial and synergistic anti-infective effects in vivo by inhibiting the E. coli infection-induced inflammatory response and eventually promoting wound healing in mice. This new strategy for high precision antibacterial therapy towards specific targets, provides an exciting opportunity for the application of multifunctional nanocomposites towards microbial infections.

Impact of initial vancomycin pharmacokinetic/pharmacodynamic parameters on the clinical and microbiological outcomes of methicillin-resistant Staphylococcus aureus bacteremia in children.

Optimal vancomycin exposure is important to minimize treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We aimed to analyze the impact of initial vancomycin pharmacokinetic/pharmacodynamic (PK/PD) parameters, including the initial vancomycin C trough and the area under the curve (AUC)/minimal inhibitory concentration (MIC) on the outcomes of pediatric MRSA bacteremia. The study population consisted of hospitalized children aged between 2 months and 18 years with MRSA bacteremia, in whom C trough was measured at least one time within the time period of January 2010 to March 2018. Demographic profiles, underlying diseases, and clinical/microbiological outcomes were abstracted retrospectively. During the study period, 73 cases of MRSA bacteremia occurred in children with a median age of 12.4 months. Severe clinical outcomes leading to intensive care unit stay and/or use of mechanical ventilation occurred in 47.5% (35/73); all-cause 30-day mortality was 9.7% (7/72). The median dosage of vancomycin was 40.0 mg/kg/day. There was a weak linear relationship between C trough and the corresponding AUC/MIC (r = 0.235). ROC curves for achieving an AUC/MIC of 300 suggested that the initial C trough at 10 µg/mL could be used as a cut-off value with a sensitivity of 90.5% and a specificity of 44%. Although persistent bacteremia at 48-72 hours after vancomycin administration was observed more frequently when the initial C trough was < 10 µg/mL and initial AUC/MIC was < 300, initial AUC/MIC < 300 was the only risk factor associated with persistent bacteremia at 48-72 hours (adjusted OR 3.05; 95% CI, 1.07-8.68). Initial C trough and AUC/MIC were not associated with 30-day mortality. Although there was a weak relationship between C trough and AUC/MIC, initial AUC/MIC < 300 could be used as a predictor of persistent MRSA bacteremia at 48-72 hours. Further prospective data on optimal vancomycin dosing are necessary to improve clinical and microbiological outcomes in pediatric MRSA bacteremia.

Hypoalbuminemia as Surrogate and Culprit of Infections.

Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile. In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications.