Invasive disease caused by Haemophilus influenzae in Sweden 1997–2009; evidence of increasing incidence and clinical burden of non‐type b strains

Introduction of a conjugated vaccine against encapsulated Haemophilus influenzae type b (Hib) has led to a dramatic reduction of invasive Hib disease. However, an increasing incidence of invasive disease by H. influenzae non‐type b has recently been reported. Non‐type b strains have been suggested to be opportunists in an invasive context, but information on clinical consequences and related medical conditions is scarce. In this retrospective study, all H. influenzae isolates ( n  =   410) from blood and cerebrospinal fluid in three metropolitan Swedish regions between 1997 and 2009 from a population of approximately 3 million individuals were identified. All available isolates were serotyped by PCR ( n  =   250). We observed a statistically significant increase in the incidence of invasive H. influenzae disease, ascribed to non‐typeable H. influenzae (NTHi) and encapsulated strains type f (Hif) in mainly individuals >60 years of age. The medical reports from a subset of 136 cases of invasive Haemophilus disease revealed that 48% of invasive NTHi cases and 59% of invasive Hif cases, respectively, met the criteria of severe sepsis or septic shock according to the ACCP/SCCM classification of sepsis grading. One‐fifth of invasive NTHi cases and more than one‐third of invasive Hif cases were admitted to intensive care units. Only 37% of patients with invasive non‐type b disease had evidence of immunocompromise, of which conditions related to impaired humoral immunity was the most common. The clinical burden of invasive non‐type b H. influenzae disease, measured as days of hospitalization/100 000 individuals at risk and year, increased significantly throughout the study period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87052/1/j.1469-0691.2010.03417.x.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/87052/2/CLM_3417_sm_FigS1.pd

Short Day–Mediated Cessation of Growth Requires the Downregulation of AINTEGUMENTALIKE1 Transcription Factor in Hybrid Aspen

Day length is a key environmental cue regulating the timing of major developmental transitions in plants. For example, in perennial plants such as the long-lived trees of the boreal forest, exposure to short days (SD) leads to the termination of meristem activity and bud set (referred to as growth cessation). The mechanism underlying SD–mediated induction of growth cessation is poorly understood. Here we show that the AIL1-AIL4 (AINTEGUMENTALIKE) transcription factors of the AP2 family are the downstream targets of the SD signal in the regulation of growth cessation response in hybrid aspen trees. AIL1 is expressed in the shoot apical meristem and leaf primordia, and exposure to SD signal downregulates AIL1 expression. Downregulation of AIL gene expression by SDs is altered in transgenic hybrid aspen plants that are defective in SD perception and/or response, e.g. PHYA or FT overexpressors. Importantly, SD–mediated regulation of growth cessation response is also affected by overexpression or downregulation of AIL gene expression. AIL1 protein can interact with the promoter of the key cell cycle genes, e.g. CYCD3.2, and downregulation of the expression of D-type cyclins after SD treatment is prevented by AIL1 overexpression. These data reveal that execution of SD–mediated growth cessation response requires the downregulation of AIL gene expression. Thus, while early acting components like PHYA and the CO/FT regulon are conserved in day-length regulation of flowering time and growth cessation between annual and perennial plants, signaling pathways downstream of SD perception diverge, with AIL transcription factors being novel targets of the CO/FT regulon connecting the perception of SD signal to the regulation of meristem activity

The Lipopolysaccharide from Capnocytophaga canimorsus Reveals an Unexpected Role of the Core-Oligosaccharide in MD-2 Binding

Capnocytophaga canimorsus is a usual member of dog's mouths flora that causes rare but dramatic human infections after dog bites. We determined the structure of C. canimorsus lipid A. The main features are that it is penta-acylated and composed of a “hybrid backbone” lacking the 4′ phosphate and having a 1 phosphoethanolamine (P-Etn) at 2-amino-2-deoxy-d-glucose (GlcN). C. canimorsus LPS was 100 fold less endotoxic than Escherichia coli LPS. Surprisingly, C. canimorsus lipid A was 20,000 fold less endotoxic than the C. canimorsus lipid A-core. This represents the first example in which the core-oligosaccharide dramatically increases endotoxicity of a low endotoxic lipid A. The binding to human myeloid differentiation factor 2 (MD-2) was dramatically increased upon presence of the LPS core on the lipid A, explaining the difference in endotoxicity. Interaction of MD-2, cluster of differentiation antigen 14 (CD14) or LPS-binding protein (LBP) with the negative charge in the 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) of the core might be needed to form the MD-2 – lipid A complex in case the 4′ phosphate is not present

The spread and clinical impact of ST14CC-PBP3 type IIb/A, a clonal group of non-typeable Haemophilus influenzae with chromosomally mediated β-lactam resistance-a prospective observational study

Objectives: Increasing incidences of non-typeable Haemophilus influenzae (NTHi) with β-lactam resistance mediated through mutations in penicillin-binding protein 3 (BLNAR or rPBP3) have been observed in the past decades. Recently, an rPBP3 NTHi sequence type (ST) 14 with PBP3 type IIb/A caused a disease outbreak in a nursing home in Sweden with severe outcomes, indicating increased bacterial virulence. In this prospective observational study, the epidemiology and clinical significance of the corresponding clonal group (ST14CC-PBP3IIb/A) in Skåne, Sweden was investigated. Methods: ST14CC-PBP3IIb/A isolates were identified through partial multilocus sequence typing and ftsI(PBP3 gene)-sequencing of prospectively collected H. influenzae from patients with respiratory tract or invasive infections (n=3262) in 2010-2012. Data on type of infection, hospitalization and outcomes were analysed, and the geographical distribution of isolates from different groups was investigated. Results: Isolates belonging to ST14CC-PBP3IIb/A constituted 26% (n=94/360) of respiratory tract rPBP3 NTHi. From mapping of patient addresses, a dynamic geographical spread was apparent during the study period. Furthermore, patients with infections by ST14CC-PBP3IIb/A isolates had higher hospitalization rates compared with patients infected with other rPBP3 NTHi (14/83 versus 21/255, p 0.025) and to a group of patients infected with susceptible NTHi (14/83 versus 13/191, p 0.010). ST14CC-PBP3IIb/A isolates constituted 25% (n=2/8) of invasive rPBP3 NTHi during the study period. Conclusions: Our investigation suggests that the ST14CC-PBP3IIb/A clonal group is associated with increased clinical virulence, resistance to several antimicrobial agents, and is persistent over time. We conclude that virulence varies between different NTHi, and that NTHi disease may be more dependent on bacterial factors than previously recognized

Decreased prevalence of Moraxella catarrhalis in addition to Streptococcus pneumoniae in children with upper respiratory tract infection after introduction of conjugated pneumococcal vaccine : a retrospective cohort study

Objectives: To study effects of the introduction of pneumococcal conjugate vaccines (PCV) on the interspecies dynamics of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in preschool children with respiratory tract infection. Methods: Nasopharyngeal samples from children aged ≤6 years with upper respiratory tract infection (n = 14 473) in South Sweden were analysed during 14 consecutive years, 5 years before and 9 years after PCV introduction. The yearly prevalence was calculated, and multivariate count regressions between prevalence and estimated yearly proportions of vaccinated children were performed. Associations between pneumococcal serotypes and the other pathogens were assessed. Results: When comparing the prevaccine period with the years after introduction, the prevalence of S. pneumoniae decreased by 65.2% (16.4 to 5.7 per 1000 individuals; p < 0.001), whereas M. catarrhalis and H. influenzae decreased by 52.1% (21.5 to 10.3 per 1000 individuals; p < 0.001) and 46.6% (13.6 to 7.3 per 1000 individuals; p < 0.001), respectively. In multivariate negative binomial regressions adjusted for yearly numbers of samples taken, S. pneumoniae and M. catarrhalis were significantly negatively associated with increasing vaccine coverage proportions (adjusted prevalence ratio (aPR) = 0.17; p < 0.001 and aPR = 0.48; p < 0.001, respectively), whereas H. influenzae (aPR = 0.75; p = 0.17) was not. In addition, the proportion of cultures positive for S. pneumoniae as well as M. catarrhalis was significantly lower in the postvaccine period compared to the prevaccine period, while this was not the case for H. influenzae. A significant positive association between certain PCV serotypes and simultaneous growth with M. catarrhalis was observed. Conclusions: After introduction of PCV, the prevalence of M. catarrhalis in addition to S. pneumoniae in children with respiratory tract infection decreased; this was also the case after adjusting for reduced numbers of samples taken. This may partly be attributed to a positive association between PCV serotypes and M. catarrhalis

Probiotics for intestinal decolonization of ESBL-producing Enterobacteriaceae : a randomized, placebo-controlled clinical trial

Objectives Infections with extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (EPE) are a major healthcare concern. Our goal was to investigate whether a probiotic mixture could be used for eradication therapy in patients with prolonged intestinal EPE carriage. Methods We performed a randomized, placebo-controlled, single-blinded clinical superiority trial in the south of Sweden between February 2017 and April 2019. Probiotic Vivomixx®, a mixture of 8 different living bacterial strains or placebo was given to adult outpatients intestinally colonized for at least 3 months with EPE. Patients with suspected active infections at the time of evaluation were excluded, and also those with immunosuppression, severe psychiatric disorder, drug abuse or dementia. Each patient in the probiotic arm was administered 2 sachets (9.0 × 1011 live bacteria) twice daily for 2 months. The primary outcome was intestinal EPE eradication at the end of the 1-year follow-up, as shown by 3 consecutive negative EPE rectal swabs during the follow-up year. The per protocol follow-up for all patients was 1, 3, 6 and 12 months after the initiation of the intervention. ClinicalTrials.gov Identifier: NCT03860415. Results In total, the target size of 80 patients were included. The median age was 68 years in both groups. The number of females in the probiotics group was 23 (58%) and in the placebo group 28 (70%). At the end of the trial, 12.5% (5 out of 40) of the patients in the probiotic group had achieved successful eradication of EPE, as defined by the primary outcome, in the intention to treat analysis. In the placebo group, 5% (2 out of 40) of the patients had achieved successful eradication of EPE (odds ratio 2.71; 95% confidence interval (CI), 0.49–14.9; p 0.24). Conclusions Successful EPE eradication was observed in very few individuals. This trial did not support Vivomixx® as being superior to placebo for intestinal decolonization in adult patients with chronic colonization of EPE, but was limited in power

Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia : a retrospective cohort study

Ineffective antimicrobial therapy of Pseudomonas aeruginosa bacteraemia increases mortality. Recent studies have proposed the use of antimicrobial combination therapy composed of a beta-lactam with either ciprofloxacin or tobramycin. To determine if combination therapy correlates to lower mortality and is superior compared to monotherapy, we investigated the effect of antimicrobial treatment regimens on 30-day mortality in a cohort with Pseudomonas aeruginosa bacteraemia. All cases of P. aeruginosa bacteraemia (n = 292) in southwest Skåne County, Sweden (years 2005–2010, adult population 361,112) and the whole county (2011–2012, 966,130) were identified. Available medical and microbiological records for persons aged 18 years or more were reviewed (n = 235). Antimicrobial therapy was defined as empiric at admission or definitive after culture results and was correlated to 30-day mortality in a multivariate regression model. The incidence and mortality rates were 8.0 per 100,000 adults and 22.9% (67/292), respectively. As expected, multiple comorbidities and high age were associated with mortality. Adequate empiric or definitive antipseudomonal treatment was associated with lower mortality than other antimicrobial alternatives (empiric p = 0.02, adj. p = 0.03; definitive p < 0.001, adj. p = 0.007). No difference in mortality was seen between empiric antipseudomonal monotherapy or empiric combination therapy. However, definitive combination therapy including ciprofloxacin correlated to lower mortality than monotherapy (p = 0.006, adj. p = 0.003), whereas combinations including tobramycin did not. Our results underline the importance of adequate antipseudomonal treatment. These data also suggest that P. aeruginosa bacteraemia should be treated with an antimicrobial combination including ciprofloxacin when susceptible