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Gregory, A. E., van Schaik, E. J., Russell-Lodrigue, K., Fratzke, A., Samuel, J. E.
Coxiella burnetii, the etiological agent of Q fever, is a Gram-negative bacterium transmitted to humans by inhalation of contaminated aerosols. Acute Q fever is often self-limiting, presenting as a febrile illness that can result in atypical pneumonia. In some cases, Q fever becomes chronic leading to endocarditis that can be life threatening. Formalin-inactivated whole cell vaccine (WCV) confers long-term protection but has significant side-effects when administered to pre-sensitized individuals. Designing new vaccines against C. burnetii remains a challenge and requires the use of clinically relevant modes of transmission in appropriate animal models. We have developed a safe and reproducible C. burnetii aerosol challenge in three different animal models to evaluate the effects of pulmonary acquired infection. Using a MicroSprayer® Aerosolizer, BL/6 mice and Hartley guinea pigs were infected intratracheally with C. burnetii NMI and demonstrated susceptibility, determined by measuring bacterial growth in the lungs and subsequent dissemination to the spleen. Histologic analysis of lung tissue showed significant pathology associated with disease, which was more severe in guinea pigs. Infection using large particle aerosol (LPA) delivery was further confirmed in non-human primates, which developed fever and pneumonia. We also demonstrate that vaccinating mice and guinea pigs with WCV prior to LPA challenge is capable of eliciting protective immunity that significantly reduces splenomegaly and bacterial burden in spleen and lung tissues. These data suggest these models can have appreciable value using the LPA delivery system to study pulmonary Q fever pathogenesis as well as designing vaccine countermeasures to C. burnetii aerosol transmission.
Darpo, B., Xue, H., Tanaka, S. K., Tzanis, E.
Omadacycline, an aminomethylcycline, is a once-daily intravenous (i.v.) and oral antibiotic that is approved in the United States for treatment of adults with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. In this thorough QT study, the effects of a therapeutic (100 mg i.v.) and a supratherapeutic (300 mg i.v.) dose of omadacycline on the electrocardiogram were studied, with placebo and moxifloxacin as negative and positive controls. Omadacycline at these doses had no effect on the QTc interval. The largest mean placebo-corrected change-from-baseline QTcS (placebo-corrected QTcS) was 1.7 ms (90% confidence interval [CI], 0.06 to 3.30) and 2.6 ms (90% CI, 0.55 to 4.67), observed at 20 min and 2 h after the start of the infusion of 100 mg and 300 mg, respectively. Assay sensitivity was demonstrated with moxifloxacin, which caused clear prolongation of QTcS with the largest mean placebo-corrected QTcS of 9.8 ms at 1.5 and 2 h. With a linear exposure–response model, the estimated slope of the concentration–QTcS relationship was very shallow: 0.0007 ms per ng/ml (90% CI, 0.0000 to 0.0014). An effect on placebo-corrected QTcS exceeding 10 ms can be excluded at omadacycline concentrations in plasma up to ~8 μg/ml. Omadacycline had no effect on cardiac conduction (PR and QRS intervals), but caused an increase in heart rate of 16.8 beats per minute at 35 min after the 100-mg dose and 21.6 beats per minute at 50 min after the 300-mg dose.
Bacteria of the Achromobacter genus, more particularly xylosoxidans species, are responsible for various healthcare associated infections (HAI) which are increasingly described since the last decade. Cystic fibrosis (CF) patients are considered as potential reservoirs in hospitals. We performed a retrospective study to estimate the frequencies of Achromobacter spp. HAI among patients from French West Indies, to determine characteristics of infected patients and establish a possible link between CF and infections.
All adults with at least one Achromobacter spp. positive sample and infection criteria in accordance with European official definitions of HAI, hospitalized in University Hospital of Martinique from 2006 to 2016 for more than 48 h, were included. Patient clinical features, immune status and underlying diseases were obtained from medical files. A list of CF patients was given by clinicians.
Antibiotic-susceptibility profiles of the strains were determined using an automated method.
Mean incidence density was 0.038/1000 days of hospitalization. Achromobacter spp. HAI evolved as an endemic situation with a low but pretty much stable incidence rate over the 11-year observation period. An epidemic peak was noticed in 2013. Among the 66 included patients, 56.1% were immunocompetent and no one had CF. Pneumonia and bacteraemia were the two main HAI. Among the 79 isolated strains, 92.4% were resistant to at least 1 major antibiotic and 16.4% met the definition of multidrug-resistant bacteria.
This microorganism, little known in our country because of the scarcity of CF patients, represents a threat for both immunosuppressed and immunocompetent patients and a therapeutic challenge because of its high resistance.
Due to the importance of Chronic obstructive pulmonary disease (COPD) as the fourth cause of mortality worldwide and the lack of studies evaluating the prevalence of bacterial infections in disease exacerbation, this systematic review and meta-analysis was performed to determine the prevalence rate of bacterial infections in COPD patients.
PubMed, ISI Web of Science, and Scopus databases were systematically searched for population-based prevalence studies (1980–2018). MeSH terms for “Bacterial infections” and “AECOPD” were used as search keywords. The selected studies were filtered according to the inclusion and exclusion criteria. Fixed and random-effects models were used for estimation of summary effect sizes. Between-study heterogeneity, as well as publication bias, were calculated.
Finally, 118 out of 31,440 studies were selected. The overall estimation of the prevalence of bacterial infection was 49.59% [95% confidence interval (CI) 0.4418–0.55]. The heterogeneity in estimating the pooled prevalence of bacterial infections was shown in the studies (Cochran Q test: 6615, P
Maarten van den Berge, Huib AM Kerstjens
The efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) has been the subject of much debate. Additionally, their use has been associated with adverse events such as pneumonia. Therefore, identification of patients with COPD who are most likely to benefit from ICS, with reduced likelihood of adverse events, is important, even more so with the advent of triple therapy.
The Pneumonia Etiology Research for Child Health (PERCH) Study Group
In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes.
Meyer Sauteur P.
diagnosisGram stainMycoplasma pneumoniaesputumStreptococcus pneumoniae
Contreras, D. A., Fitzwater, S. P., Nanayakkara, D. D., Schaenman, J., Aldrovandi, G. M., Garner, O. B., Yang, S.
We report here a fatal case of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in a renal transplant patient without travel history in the past year, from whom 2 genetically different CRKP (ST14 and ST2497) strains carrying the same plasmids and anti-microbial resistance genes including blaNDM-1, blaOXA-232, blaCTX-M-15, armA and tet(D) were isolated from blood and abdominal cavity. The isolates were susceptible to colistin, tigecycline, eravacycline and cefiderocol, which was used to treat the CRKP in combination with ceftazidime/avibactam and polymyxin B and resulted in bacterial clearance. Despite the aggressive treatment, the patient died of ischemic colitis and multi-organ failure.
Ren H, Liu Y, Zhou J, et al.
AbstractBackgroundTrans-translation is a ribosome rescue system that plays an important role in bacterial tolerance to environmental stresses. It is absent in animals, making it a potential treatment target. However, its role in antibiotic tolerance in Pseudomonas aeruginosa remains unknown.MethodsThe role and activity of trans-translation during antibiotic treatment were examined with a trans-translation–deficient strain and a genetically modified trans-translation component gene, respectively. In vitro assays and murine infection models were used to examine the effects of suppression of trans-translation.ResultsWe found that the trans-translation system plays an essential role in P. aeruginosa tolerance to azithromycin and multiple aminoglycoside antibiotics. We further demonstrated that gentamicin could suppress the azithromycin-induced activation of trans-translation. Compared with each antibiotic individually, gentamicin and azithromycin combined increased the killing efficacy against planktonic and biofilm-associated P. aeruginosa cells, including a reference strain PA14 and its isogenic carbapenem-resistance oprD mutant, the mucoid strain FRD1, and multiple clinical isolates. Furthermore, the gentamicin-azithromycin resulted in improved bacterial clearance in murine acute pneumonia, biofilm implant, and cutaneous abscess infection models.ConclusionsCombination treatment with gentamicin and azithromycin is a promising strategy in combating P. aeruginosa infections.
Ana Helena A. Figueiredo, Matthijs C. Brouwer, Merijn W. Bijlsma, Arie van der Ende, Diederik van de Beek
Pneumonia is considered a focus of infection in patients presenting with community-acquired bacterial meningitis but the impact on disease course is unclear. The aim was to study presenting characteristics, clinical course and outcome of meningitis patients with co-existing pneumonia on admission.
Ribera, A., Benavent, E., El-Haj, C., Gomez-Junyent, J., Tubau, F., Rigo-Bonnin, R., Ariza, J., Murillo, O.
We compared the efficacies of meropenem alone and in combination with colistin against two strains of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, using an in vitro pharmacodynamic model that mimicked two different biofilm conditions. Meropenem in monotherapy achieved a remarkable efficacy (even a bactericidal effect) in all conditions, whereas colistin was almost inactive and resistance emerged. The addition of colistin to meropenem produced no relevant benefits in contrast with experiences with other microorganisms.
Poirel, L., Ortiz de la Rosa, J.-M., Richard, A., Aires-de-Sousa, M., Nordmann, P.
CTX-M-type extended-spectrum ß-lactamases (ESBL) are widespread among Enterobacterales worldwide. The most common variant is CTX-M-15 hydrolyzing ceftazidime at high rate, but sparing carbapenems. We identified here CTX-M-33, a point mutant derivative of CTX-M-15 (Asp to Ser substitution at Ambler position 109), exhibiting a low carbapenemase activity. ß-Lactamase CTX-M-33 was identified in a Klebsiella pneumoniae isolate belonging to ST405, lacking the outer membrane protein OmpK36, that was resistant to broad-spectrum cephalosporins and ß-lactam/ß-lactamase inhibitor combinations, and displayed a decreased susceptibility to carbapenems. Comparative hydrolytic activity assays showed that CTX-M-33 hydrolyzed ceftazidime at a lower level than CTX-M-15, but significantly hydrolyzed meropenem. In addition, CTX-M-33 showed higher Mutant Prevention Concentration values and wider mutant selection window in presence of meropenem, in accordance with its observed hydrolytic properties. We identified here the very first CTX-M enzyme possessing a weak carbapenemase activity, that may correspond to an emerging phenomenon when considering its possibility to evolve from the widespread ESBL CTX-M-15.
Detecting avian influenza virus has become an important public health strategy for controlling the emerging infectious disease.
The HIS (hospital information system) modified influenza surveillance system (ISS) and a newly built pneumonia surveillance system (PSS) were used to monitor the influenza viruses in Changsha City, China. The ISS was used to monitor outpatients in two sentinel hospitals and to detect mild influenza and avian influenza cases, and PSS was used to monitor inpatients in 49 hospitals and to detect severe and death influenza cases.
From 2005 to 2016, there were 3,551,917 outpatients monitored by the ISS system, among whom 126,076 were influenza-like illness (ILI) cases, with the ILI proportion (ILI%) of 3.55%. After the HIS was used, the reported incident cases of ILI and ILI% were increased significantly. From March, 2009 to September, 2016, there were 5,491,560 inpatient cases monitored by the PSS system, among which 362,743 were pneumonia cases, with a proportion of 6.61%. Among pneumonia cases, about 10.55% (38,260/362,743) of cases were severe or death cases. The pneumonia incidence increased each year in the city. Among 15 avian influenza cases reported from January, 2005 to September, 2016, there were 26.7% (4/15) mild cases detected by the HIS-modified ISS system, while 60.0% (9/15) were severe or death cases detected by the PSS system. Two H5N1 severe cases were missed by the ISS system in January, 2009 when the PSS system was not available.
The HIS was able to improve the efficiency of the ISS for monitoring ILI and emerging avian influenza virus. However, the efficiency of the system needs to be verified in a wider area for a longer time span in China.
We developed a clinical bedside tool to simultaneously estimate the probabilities of third-generation cephalosporin-resistant Enterobacteriaceae (3GC-R), carbapenem-resistant Enterobacteriaceae (CRE), and multidrug-resistant Pseudomonas aeruginosa (MDRP) among hospitalized adult patients with Gram-negative infections.
Data were obtained from a retrospective observational study of the Premier Hospital that included hospitalized adult patients with a complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP), or bloodstream infection (BSI) due to Gram-negative bacteria between 2011 and 2015. Risk factors for 3GC-R, CRE, and MDRP were ascertained by multivariate logistic regression, and separate models were developed for patients with community-acquired versus hospital-acquired infections for each resistance phenotype (N = 6). Models were converted to a singular user-friendly interface to estimate the probabilities of a patient having an infection due to 3GC-R, CRE, or MDRP when ≥ 1 risk factor was present.
Overall, 124,068 patients contributed to the dataset. Percentages of patients admitted for cUTI, cIAI, HAP/VAP, and BSI were 61.6, 4.6, 16.5, and 26.4%, respectively (some patients contributed > 1 infection type). Resistant infection rates were 1.90% for CRE, 12.09% for 3GC-R, and 3.91% for MDRP. A greater percentage of the resistant infections were community-acquired relative to hospital-acquired (CRE, 1.30% vs 0.62% of 1.90%; 3GC-R, 9.27% vs 3.42% of 12.09%; MDRP, 2.39% vs 1.59% of 3.91%). The most important predictors of having an 3GC-R, CRE or MDRP infection were prior number of antibiotics; infection site; infection during the previous 3 months; and hospital prevalence of 3GC-R, CRE, or MDRP. To enable application of the six predictive multivariate logistic regression models to real-world clinical practice, we developed a user-friendly interface that estimates the risk of 3GC-R, CRE, and MDRP simultaneously in a given patient with a Gram-negative infection based on their risk (Additional file 1).
We developed a clinical prediction tool to estimate the probabilities of 3GC-R, CRE, and MDRP among hospitalized adult patients with confirmed community- and hospital-acquired Gram-negative infections. Our predictive model has been implemented as a user-friendly bedside tool for use by clinicians/healthcare professionals to predict the probability of resistant infections in individual patients, to guide early appropriate therapy.
Lin, J., Lau, G. W.
Streptococcus pneumoniae (pneumococcus) causes multiple infectious diseases. The pneumococcal competence system facilitates genetic transformation, spreads antibiotic resistance and contributes to virulence. The DNA processing protein A (DprA) regulates the exit of pneumococcus from the competent state. Previously, we have shown that DprA is important in both bacteremia and pneumonia infections. Here, we examined the mechanisms of virulence attenuation in dprA. When compared to the parental wild-type D39, dprA enters the competent state when exposed to lower concentrations of the competence stimulating peptide CSP1. dprA overexpresses ComM, which delays cell separation after division. Additionally, dprA overexpresses allolytic factors LytA, CbpD and CibAB, and is more susceptible to detergent-triggered lysis. Disabling of the competent state-specific induction of ComM and allolytic factors compensated for the virulence loss in dprA, suggesting that overexpression of these factors contribute to virulence attenuation. Finally, dprA fails to down-regulate the expression of multiple competence-regulated genes, leading the excessive energy consumption. Collectively, these results indicate that inability to properly exit the competent state disrupts multiple cellular processes that cause virulence attenuation in dprA.
Carbapenem-resistant Enterobacteriaceae (CRE) represent an important global threat. The aim of this study is to describe the clinical course and outcomes of patients with CRE infections treated with ceftazidime-avibactam (CAZ-AVI) compared to patients treated with other agents.
A retrospective cohort study of patients with established CRE infections from January 2017 until August 2018 was conducted. All patients who received CAZ-AVI and all cultures with carbapenem-resistant isolates were screened. We compared patients who received CAZ-AVI for CRE infections with patients who received other agents.
A total of 38 consecutive patients with CRE infections were identified. Age and baseline comorbidities were similar between the two groups. The median time from admission to isolation of CRE culture was 22.5 days in the CAZ-AVI group and 17 days in the comparative group (P = 0.7). The incidence of CRE bacteremia was similar between the two groups: 7 patients (70%) in the CAZ-AVI group and 15 patients (53.6%) in the comparative group (P = 0.47). The most common type of CRE infections in both groups was hospital acquired pneumonia (HAP). Klebsiella pneumoniae was the predominant pathogen in both groups. A carbapenemase gene was detected in 35 (92%) patients; the OXA-48 gene was the predominant gene identified in 28 (74%) isolates. Eight out of ten patients in the CAZ-AVI group and fifteen out of twenty-eight in the comparative group achieved clinical remission (P = 0.14). After thirty days, all-cause mortality was observed in five patients in the CAZ-AVI group and 16 patients in the comparative group, accounting for 50 and 57% respectively.
In patients with established OXA-48-type CRE infection, CAZ-AVI is a reasonable alternative to standard therapy. These findings need to be confirmed in prospective studies.
Ping Zhang, Qiucheng Shi, Huangdu Hu, Bao Hong, Xueqing Wu, Xiaoxing Du, Murat Akova, Yunsong Yu
To investigate the activity of ceftazidime/avibactam (CAZ/AVI) against carbapenem-resistant Klebsiella pneumoniae (CRKP) and identify the resistance mechanisms before CAZ/AVI coming to Chinese market.
Macesic N, Nelson B, Mcconville T, et al.
AbstractBackgroundPolymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence.MethodsWe included 88 patients with PR K. pneumoniae from 2011–2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392).ResultsPolymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P < .001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P < .001). When clusters containing PR isolates in ≥2 patients were analyzed, 10/14 had multiple genetic events leading to PR.ConclusionsMolecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.
Matteo Bassetti, Elda Righi
Omadacycline is a newly developed, once-daily, oral and intravenous aminomethylcycline with a broad spectrum of activity.1 In 2018, the US Food & Drug Administration (FDA) approved omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia on the basis of the results of two phase 3 randomised controlled trials (RCTs).2,3
Rappo, U., Dunne, M. W., Puttagunta, S., Baldassarre, J. S., Su, S., Desai-Krieger, D., Inoue, M.
Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A Phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 hrs after 1500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%. ELF levels of dalbavancin exceeded the MIC90 of S. pneumoniae and S. aureus for ≥ 7 days.
Corbellino M, Kieffer N, Kutateladze M, et al.
AbstractIn July 2017, a patient presented colonization with a multi-drug resistant, carbapenemase (KPC-3)-producing Klebsiella pneumoniae isolate. A custom-made, lytic bacteriophage preparation was administered to the patient in December 2017, with subsequent eradication of the microorganism, and without adverse effects.
Theilacker C, Vyse A, Jodar L, et al.
Fan Jin, Xiao-hang Liu, Wen-can Chen, Zhang-ling Fan, Huan-ling Wang
Human metapneumovirus (HMPV) is an important respiratory pathogen that causes seasonal epidemics of acute respiratory illness and contributes significantly to childhood pneumonia. Current knowledge and understanding on its patterns of spread, prevalence and persistence in communities in low resource settings is limited.
We present findings of a molecular-epidemiological analysis of nasal samples from children
Noemi B. Hall, John M. Wood, A. Scott Laney, David J. Blackley
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 4, Page 518-518, August 15, 2019.
Candida albicans is an opportunistic pathogen, but since it also belongs to the normal fungal flora, positive sputum culture as the solely basis for the diagnosis of invasive Candida albicans pneumonia can easily lead to excessive antifungal therapy. Therefore, identification of a pneumonia biomarker might improve diagnostic accuracy.
A rabbit model was established by inoculating 5 × 107 cfu/mL C. albicans into the trachea of 20 rabbits with 20 rabbits as control group. Infection was monitored by chest thin-layer computed tomography (CT). 2 mL blood samples were collected daily during each infection and serum levels of potential biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Seven-day post-inoculation the rabbits were sacrificed by CO2 asphyxiation and lung tissue was histopathologically examined and blood was brought to culture. Data were statistically analyzed.
Infection became evident as early as day 3 post-inoculation. The levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble hemoglobin-haptoglobin scavenger receptor (sCD163), procalcitonin (PCT) and tumor necrosis factor-α (TNF-α) were elevated in the experimental group compared to the control (P 0.05). The dynamic curves of the levels of CRP, IL-6, IL-8, IL-10, SCD163 and TNF-α in both groups demonstrated a similar trend during infection but differences between the groups was observed only in the sTREM-1 levels. Receiver-operating characteristics (ROC) curve analysis showed that the sensitivity and specificity were 85 and 80% for sTREM-1 (cut-off value: 45.88 pg/mL) and 80 and 75% for SCD163 (cut-off value: 16.44 U/mL), respectively. The values of the area under the ROC curve (AUCROC) of sTREM-1 and SCD163 were 0.882 (95% CI: 0.922–0.976) and 0.814 (95% CI: 0.678–0.950), respectively. Other markers did not exhibit significant differences.
sTREM-1 and SCD163 might be suitable biomarkers for pneumonia.
Steck, P., Ritzmann, F., Honecker, A., Vella, G., Herr, C., Gaupp, R., Bischoff, M., Speer, T., Tschernig, T., Bals, R., Beisswenger, C.
Neutrophils contribute to lung injury in acute pneumococcal pneumonia. The interleukin 17 receptor E (IL-17RE) is the functional receptor for the epithelial-derived cytokine IL-17C which is known to mediate innate immune functions. The aim of this study was to investigate the contribution of IL-17RE/IL-17C to pulmonary inflammation in a mouse model of acute Streptococcus pneumoniae pneumonia. Numbers of neutrophils, the expression of the cytokine granulocyte-colony stimulating factor (G-CSF), and tumor necrosis factor α (TNF-α) were decreased in lungs of IL-17RE deficient (Il-17re-/-) mice infected with S. pneumoniae. Numbers of alveolar macrophages rapidly declined in both wild-type (WT) and Il-17re-/- mice and recovered 72 hours after infection. There were no clear differences in the elimination of bacteria and numbers of blood granulocytes between infected WT and Il-17re-/- mice. The fractions of granulocyte-monocyte progenitors (GMPs) were significantly reduced in infected Il-17re-/- mice. Numbers of neutrophils were significantly reduced in lungs of mice deficient for IL-17C 24 hours after infection with S. pneumoniae. These data indicate that the IL-17C/IL-17RE-axis promotes the recruitment of neutrophils without affecting the recovery of alveolar macrophages in the acute phase of S. pneumoniae lung infection.
Trevejo-Nunez, G., Elsegeiny, W., Aggor, F. E. Y., Tweedle, J. L., Kaplan, Z., Gandhi, P., Castillo, P., Ferguson, A., Alcorn, J. F., Chen, K., Kolls, J. K., Gaffen, S. L.
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide and IL-22 helps contain pneumococcal burden in lungs and extra pulmonary tissues. Administration of IL-22 increases hepatic complement 3, complement deposition on bacteria, and improves phagocytosis by neutrophils.The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22BP, encoded by Il22ra2-/-. To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined.Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22- dependent manner. Il22ra2-/- mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection compared to control mice. RNAseq analysis of infected Il22ra2-/- lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and DCs. Accordingly, we saw that macrophages from Il22ra2-/- mice displayed reduced of OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22-dependent. Furthermore, we showed that macrophages express IL-22Ra1 during pneumococcal infection and also that Il22ra2-/- macrophages rely more on the glycolytic pathway than WT controls.Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.
Vareille-Delarbre, M., Miquel, S., Garcin, S., Bertran, T., Balestrino, D., Evrard, B., Forestier, C.
Some respiratory infections have been associated with dysbiosis of the intestinal microbiota. The underlying mechanism is incompletely understood but crosstalk between intestinal microbiota and local immune cells could influence the immune response at distal mucosal sites. This has led to the concept of enhancing respiratory defences by modulating the intestinal microbiota with exogenous supplementation of beneficial strains. In this study, we examined the effect of Lactobacillus plantarum CIRM653 on the inflammatory response induced by the pathogen Klebsiella pneumoniae. Oral administration of L. plantarum CIRM653 to mice subsequently infected by K. pneumoniae via the nasal route i) reduced the pulmonary inflammation response, with decreased numbers of lung innate immune cells (macrophages, and neutrophils) and cytokines (KC, IL-6 and TNF-α) in the bronchoalveolar fluid and ii) induced an immunosuppressive Treg response in lungs. In vitro co-incubation of L. plantarum CIRM653 and K. pneumoniae with human dendritic cells and peripheral blood mononuclear cells resulted in decreased Th1 (IL-12p70; IFN-) and Th17 (IL-23, IL-17) and increased Treg (IL-10) cytokine levels compared to those observed with K. pneumoniae-infected cells. Neither K. pneumoniae nor L. plantarum CIRM653 had any effect on cytokine production by intestinal epithelial cells in vitro, but the induction of NF-B pathway and IL-8 and IL-6 production by K. pneumoniae in airway epithelial cells was significantly reduced when the pathogen was co-incubated with L. plantarum CIRM653. The remote IL-10-mediated modulation of K. pneumoniae inflammatory response by L. plantarum CIRM653 supports the concept of immunomodulation by beneficial bacteria through the gut-lung axis.
Flamm, R. K., Shortridge, D., Castanheira, M., Sader, H. S., Pfaller, M. A.
We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) collected during 2014 through 2018 from 87 U.S. medical centers spanning all nine census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against A. baumannii-A. calcoaceticus species complex, colistin was the most active agent exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptible. Minocycline ranked second in activity with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility >90%) against S. maltophilia: minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against B. cepacia complex: trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0%), meropenem (MIC50/90, 2/8 μg/ml; 89.1%) and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.
Kamonthip Rungrojcharoenkit, Wanitchaya Kittikraisak, Darunee Ditsungnoen, Sonja J. Olsen, Piyarat Suntarattiwong, Tawee Chotpitayasunondh, Chonticha Klungthong, In-Kyu Yoon, Fatimah S. Dawood, Stefan Fernandez, Louis Macareo, Kim A. Lindblade
Annual influenza epidemics cause between 3-5 million cases of severe illness and approximately 290,000 to 600,000 deaths globally (World Health Organization, 2018). Young children experience a high burden of influenza-associated illness, including hospital admissions for acute lower respiratory infection (ALRI) and pneumonia (Thompson et al., 2004; Neuzil et al., 2002; Poehling et al., 2006; Nair et al., 2011). Influenza virus infections also account for a substantial proportion of all pneumonia deaths of viral etiology in young children globally (Rudan et al., 2008),
Catherine R. Sears, Tobias Peikert, Jennifer D. Possick, Jarushka Naidoo, Mizuki Nishino, Sandip P. Patel, Philippe Camus, Mina Gaga, Edward B. Garon, Michael K. Gould, Andrew H. Limper, Philippe R. Montgrain, William D. Travis, M. Patricia Rivera
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 6, Page e31-e43, September 15, 2019.
We sought to assess reporting in China’s Pneumonia of Unknown Etiology (PUE) passive surveillance system for emerging respiratory infections and to identify ways to improve the PUE surveillance system’s detection of respiratory infections of public health significance.
From February 29–May 29, 2016, we actively identified and enrolled patients in two hospitals with acute respiratory infections (ARI) that met all PUE case criteria. We reviewed medical records for documented exposure history associated with respiratory infectious diseases, collected throat samples that were tested for seasonal and avian influenza, and interviewed clinicians regarding reasons for reporting or not reporting PUE cases. We described and analyzed the proportion of PUE cases reported and clinician awareness of and practices related to the PUE system.
Of 2619 ARI admissions in two hospitals, 335(13%) met the PUE case definition; none were reported. Of 311 specimens tested, 18(6%) were seasonal influenza virus-positive; none were avian influenza-positive.
Meder K, Jayasinghe S, Beard F, et al.
AbstractBackgroundUniversal pneumococcal conjugate vaccine (PCV) programs began in Indigenous Australian children in 2001 and all children in 2005, changing to PCV13 in 2011. We used laboratory data for invasive pneumococcal disease (IPD) and coded hospitalisations for non-invasive pneumococcal community acquired pneumonia (PnCAP) to evaluate long-term impact.MethodsAnnual incidence (per 100,000 population) was calculated for age-specific total IPD, PCV13-non7v serotypes and PnCAP by Indigenous status. Incidence in the pre-universal PCV7 (2002-2004), early-PCV7 (2005-2007), pre-PCV13 (2008-mid 2011) and post-PCV13 (mid 2011-2016) periods was used to calculate incidence rate ratios (IRRs).ResultsIn the total population, all-age incidence of IPD declined from 11.8 pre-PCV7 to 7.1 post-PCV13 (IRR 0.61, 95% CI 0.59-0.63) but for PnCAP declined
S. M. Michienzi et al.
Zhang Z, Zhao S, Lian D, et al.
AbstractBackgroundStreptococcus pneumonia meningitis (PM) is a major cause of childhood neurological deficits. Although the Notch1 signalling pathway regulates neurogenesis and neuroinflammation, we know little about its expression or influence on hippocampal neurogenesis and gliogenesis during PM.MethodsWe used immunofluorescence and western blots to detect Notch1 signalling expression during experimental PM. Through double-labelling immunofluorescence, we investigated proliferation and differentiation in the dentate gyrus (DG) in PM before and after treatment with exogenous Notch1 activator (Jagged1) and inhibitor (IMR-1).ResultsOur results showed that Notch1 was activated after 24 h in PM. Compared with the PBS control, Jagged1 increased the proliferation of neural stem cells and progenitor cells (NS/PCs) in DG. After 14 and 28 d of meningitis, astrocyte differentiation increased compared with control. Astrocyte differentiation was higher in the Jagged1 versus the PBS group. In contrast, IMR-1 increased neuronal differentiation but decreased astrocyte differentiation compared with DMSO treatment.ConclusionUnder PM, Notch1 signalling promotes NS/PC proliferation and astrocyte differentiation in DG, while decreasing neuronal differentiation. Transient activation of the Notch1 signalling pathway explains the reactive gliogenesis and limited neuronal differentiation observed in PM.
This Medical Letter review summarizes indications, dosing, and cost of Nuzyra, a semisynthetic tetracycline derivative, for once-daily intravenous and oral treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in adults
Behillil S, May F, Fourati S, et al.
AbstractIn a multicenter cohort study including 22 oseltamivir-treated patients with influenza A(H1N1)pdm09 acute respiratory distress syndrome, prevalence of the H275Y substitution in the neuraminidase, responsible for highly reduced sensitivity to oseltamivir, was 23%. Patients infected with the H275Y mutant virus had higher day-28 mortality than others (80% vs 12%; p=0.011).
Paiboonvong, T., Nosoongnoen, W., Sathirakul, K., Tangsujaritvijit, V., Kaemapairoj, J., Tragulpiankit, P., Montakantikul, P.
Sitafloxacin showed potent activity against various respiratory pathogens. Blood and BAL fluid samples were obtained from twelve subjects after a single oral dose of sitafloxacin 200 mg. The mean ± SD (median) maximum ratio of ELF to unbound plasma concentration was 1.02 ± 0.58 (1.33). The penetration ratio based on the mean and median AUC0-8 were 0.85 and 0.79 μg⋅h/mL, respectively. Sitafloxacin penetrates well into ELF in Thai critically ill patients with pneumonia.
Mueller, L., Masseron, A., Prod'Hom, G., Galperine, T., Greub, G., Poirel, L., Nordmann, P.
A novel KPC variant, KPC-41, was identified in a Klebsiella pneumoniae clinical isolate from Switzerland. This ß-lactamase possessed a three amino-acid insertion (Pro-Asn-Lys) located between amino acids 269 and 270 compared to the KPC-3 amino acid sequence. Cloning and expression of the blaKPC-41 gene in Escherichia coli, followed by determination of MIC values and kinetic parameters, showed that KPC-41, compared to KPC-3, has an increased affinity to ceftazidime and a decreased sensitivity to avibactam, leading to resistance to ceftazidime-avibactam once produced in K. pneumoniae. Furthermore, KPC-41 exhibited a drastic decrease of its carbapenemase activity. This report highlights that a diversity of KPC variants conferring resistance to ceftazidime-avibactam already circulate in Europe.
Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting.
This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts.
The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p
Doi Y, Van Duin D.
colistin resistanceKlebsiella pneumoniaecarbapenem-resistant Enterobacteriaceae
S. pneumoniae is the leading cause of community-acquired pneumonia in the solid organ transplant recipient (SOTR); nevertheless, the prevalence of colonization and of the colonizing/infecting serotypes has not been studied in this population. In this context, the aim of the present study was to describe the rate, characteristics, and clinical impact of S. pneumoniae nasopharyngeal carriage.
A prospective observational cohort of Solid Organ Transplant recipients (SOTR) was held at the University Hospital Virgen del Rocío, Seville, Spain with the aim to evaluate the S. pneumoniae colonization and the serotype prevalence in SOTR. Two different pharyngeal swabs samples from 500 patients were included in two different seasonal periods winter and spring/summer. Optochin and bile solubility tests were performed for the isolation of thew strains. Antimicrobial susceptibility studies (MICs, mg/l) of levofloxacin, trimethoprim-sulfamethoxazole, penicillin, amoxicillin, cefotaxime, ceftriaxone, erythromycin, azithromycin and vancomycin for each isolate were determined by E-test strips. Capsular typing was done by sequential multiplex PCR reactions. A multivariate logistic regression analysis of factors potentially associated with pneumococcal nasopharyngeal carriage and disease was performed.
Twenty-six (5.6%) and fifteen (3.2%) patients were colonized in winter and spring/summer periods, respectively. Colonized SOT recipients compared to non-colonized patients were more frequently men (79.5% vs. 63.1%, P
Keith C Meyer
Idiopathic interstitial pneumonias, especially idiopathic pulmonary fibrosis, are frequently accompanied by treatment-refractory, WHO group III pulmonary hypertension, and these patients are more likely to have a poor prognosis over time compared with patients whose disease course is not complicated by pulmonary hypertension.1 Although the antifibrotic agents pirfenidone and nintedanib substantially improve lung function decline in patients with idiopathic pulmonary fibrosis and might benefit patients with non-idiopathic forms of pulmonary fibrosis, the search for a beneficial agent that ameliorates the pulmonary hypertension that can arise in patients with idiopathic interstitial pneumonia has yet to find an effective pharmacotherapy.
Evans R. Fernández Pérez, David Sprunger, Pailin Ratanawatkul, Lisa A. Maier, Tristan J. Huie, Jeffrey J. Swigris, Joshua J. Solomon, Michael Mohning, Rebecca C. Keith, Kevin K. Brown
American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 4, Page 518-519, August 15, 2019.
Steven D Nathan, Jürgen Behr, Harold R Collard, Vincent Cottin, Marius M Hoeper, Fernando J Martinez, Tamera J Corte, Anne M Keogh, Hanno Leuchte, Nesrin Mogulkoc, Silvia Ulrich, Wim A Wuyts, Zhen Yao, Francis Boateng, Athol U Wells
In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP.
Incidence of the opportunistic infection Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant patients ranges from 5 to 15% with a mortality of up to 38%.
We present a liver transplant recipient who developed hypoxemic respiratory failure related to PJP soon after treatment for allograft rejection. His presentation was preceded by severe hypercalcemia of 14.6 mg/dL and an ionized calcium of 1.7 mmol/L which remained elevated despite usual medical management and eventually required renal replacement therapy. As approximately 5% of PJP cases have granulomas, here we review the role of pulmonary macrophages and inflammatory cytokines in the pathophysiology of granuloma-mediated hypercalcemia. We also discuss the interpretation of our patient’s laboratory studies, response to medical therapy, and clinical risk factors which predisposed him to PJP.
It is important for clinicians to consider PJP as an etiology of granulomatous pneumonia and non-parathyroid hormone mediated hypercalcemia in chronically immunosuppressed organ transplant recipients for timely diagnosis and management.
Guarana, M., Nucci, M., Nouer, S. A.
Empiric antibiotic therapy with a betalactam is standard of care in febrile neutropenia (FN), and is given to prevent early death. The addition of vancomycin is recommended in certain circumstances but the quality of evidence is low, reflecting the lack of clinical data. In order to characterize the epidemiology of early death and shock in FN, we reviewed all episodes of FN from 2003 to 2017 at University Hospital, Federal University of Rio de Janeiro, and looked at factors associated with shock at first fever and early death (within 3 days from first fever) by univariate and multivariate analyses. Among 1305 episodes of FN, shock occurred in 42 episodes (3.2%) and early death in 15 (1.1%). Predictors of shock were bacteremia due to Escherichia coli (odds ratio [OR] 8.47, 95% confidence interval [95% CI] 4.08 – 17.55, p
Ogawa H, Kitsios G, Iwata M, et al.
AbstractBackgroundThe clinical role of sputum Gram stain (SGS) in community-acquired pneumonia (CAP) diagnosis remains controversial. A 1996 meta-analysis of the diagnostic accuracy of SGS reported heterogeneous results. To update the available evidence, we performed a systematic review and a Bayesian standard and latent-class model meta-analysis.MethodsWe searched MEDLINE, Embase, and Cochrane Central by August 23, 2018 to identify studies reporting on the diagnostic accuracy, yield (percentage of patients with any pathogen(s) correctly identified by SGS), and clinical outcomes of SGS in adult patients with CAP. Two reviewers extracted the data. We quantitatively synthesized the diagnostic accuracy and yield, and descriptively analyzed other outcomes.ResultsTwenty-four studies with 4,533 patients were included. The methodological and reporting quality of the included studies was limited. When good-quality sputum specimens were selected, SGS had a summary sensitivity of 0.69 (95% credible intervals [CrI], 0.56–0.80) and specificity of 0.91 (CrI, 0.83–0.96) for detecting Streptococcus pneumoniae, and a sensitivity of 0.76 (CrI, 0.60–0.87) and specificity of 0.97 (CrI, 0.91–0.99) for Haemophilus influenzae. Adjusted analyses accounting for imperfect reference standards provided higher specificity estimates than the unadjusted analyses. Bacterial pathogens were identified in 73% (CrI, 26–96%) of good-quality specimens, and 36% (CrI, 22–53%) of all specimens regardless of quality. Evidence on other bacteria was sparse.ConclusionsSGS was highly specific to diagnose S. pneumoniae and H. influenzae infections in patients with CAP. With good-quality specimens, SGS can provide clinically actionable information for pathogen-directed antibiotic therapies.
Bae, D.-W., Jung, Y.-E., An, Y. J., Na, J.-H., Cha, S.-S.
ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica, and Escherichia coli. ACC-1-producing bacteria are susceptible to cefoxitin whereas they are resistant to oxyimino cephalosporins. Here, we depict crystal structures of apo ACC-1, adenylylated ACC-1, and acylated ACC-1 complexed with cefotaxime and cefoxitin. ACC-1 has noteworthy structural alterations in the R2-loop, the - loop, and the Phe119-loop along the active-site rim. The adenylate covalently bonded to the nucleophilic serine reveals a tetrahedral phosphorus mimicking the deacylation transition state. Cefotaxime in ACC-1 has a proper conformation for the substrate-assisted catalysis in that its C4 carboxylate and N5 nitrogen are adequately located to facilitate the deacylation reaction. In contrast, cefoxitin in ACC-1 has a distinct conformation in which those functional groups cannot contribute to catalysis. Furthermore, the orientation of the deacylating water relative to the acyl carbonyl group in ACC-1 is unfavorable for nucleophilic attack.
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
False-negative Results of Human Immunodeficiency Virus (HIV) Rapid Testing in HIV Controllers
21.09.2019Clinical Infectious Diseases Advance Access
Resistance of Influenza Virus to Antiviral Medications
20.09.2019Clinical Infectious Diseases Advance Access
Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study
20.09.2019Clinical Infectious Diseases Advance Access
Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes
20.09.2019Clinical Infectious Diseases Advance Access
Reply to Krahn and Sebastiani
20.09.2019Clinical Infectious Diseases Advance Access
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