B. Davido, F. Bouchand, A. Dinh

We read with great interest the publication by Batard et al. [1] showing that the use of third-generation cephalosporins (3GC) was not associated with lower in-hospital mortality than amoxicillin/clavulanate (AC) in community-onset pneumonia. In an era of continuous emergence of resistance to antimicrobial agents, this is a hot topic, and therefore some points deserve to be discussed.

Rabab Rashwan, Julius F. Varano della Vergiliana, Sally M. Lansley, Hui Min Cheah, Natalia Popowicz, James C. Paton, Grant W. Waterer, Tiffany Townsend, Ian Kay, Jeremy S. Brown, Y. C. Gary Lee

by Rabab Rashwan, Julius F. Varano della Vergiliana, Sally M. Lansley, Hui Min Cheah, Natalia Popowicz, James C. Paton, Grant W. Waterer, Tiffany Townsend, Ian Kay, Jeremy S. Brown, Y. C. Gary Lee Pleural infection/empyema is common and its incidence continues to rise. Streptococcus pneumoniae is the commonest bacterial cause of empyema in children and among the commonest in adults. The mesothelium represents the first line of defense against invading microorganisms, but mesothelial cell responses to common empyema pathogens, including S. pneumoniae, have seldom been studied. We assessed mesothelial cell viability in vitro following exposure to common empyema pathogens. Clinical isolates of S. pneumoniae from 25 patients with invasive pneumococcal disease and three reference strains were tested. All potently induced death of cultured mesothelial cells (MeT-5A) in a dose- and time-dependent manner (>90% at 107 CFU/mL after 24 hours). No significant mesothelial cell killing was observed when cells were co-cultured with Staphylococcus aureus, Streptococcus sanguinis and Streptococcus milleri group bacteria. S. pneumoniae induced mesothelial cell death via secretory product(s) as cytotoxicity could be: i) reproduced using conditioned media derived from S. pneumoniae and ii) in transwell studies when the bacteria and mesothelial cells were separated. No excess cell death was seen when heat-killed S. pneumoniae were used. Pneumolysin, a cytolytic S. pneumoniae toxin, induced cell death in a time- and dose-dependent manner. S. pneumoniae lacking the pneumolysin gene (D39 ΔPLY strain) failed to kill mesothelial cells compared to wild type (D39) controls, confirming the necessity of pneumolysin in D39-induced mesothelial cell death. However, pneumolysin gene mutation in other S. pneumoniae strains (TIGR4, ST3 and ST23F) only partly abolished their cytotoxic effects, suggesting different strains may induce cell death via different mechanisms.

S. Omar Ali, Xiang Qing Yu, Gabriel J. Robbie, Yuling Wu, Kathryn Shoemaker, Li Yu, Antonio DiGiandomenico, Ashley E. Keller, Chuka Anude, Martha Hernandez-Illas, Terramika Bellamy, Judith Falloon, Filip Dubovsky, Hasan S. Jafri

MEDI3902 is a bivalent, bispecific human immunoglobulin G1κ monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and the Psl exopolysaccharide involved in P. aeruginosa colonization and tissue adherence. MEDI3902 is being developed for the prevention of nosocomial P. aeruginosa pneumonia in high-risk patients.

Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro

by Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro Background Group B Streptococcus (GBS) causes invasive infections in neonates and has been implicated as a cause of prelabour rupture of membranes, preterm delivery and stillbirths. The success of phase II trials of polyvalent polysaccharide GBS vaccines indicates that these infections are potentially preventable. Nigeria is the most populous country in Africa with one of the highest birth rates, one of the highest neonatal sepsis incidence rates and one of the highest mortality rates in the world. Therefore, before the possible introduction of preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine into Nigeria, it is vital that there is accurate data on the aetiology of neonatal sepsis and on the incidence of GBS neonatal sepsis in particular. The objective of this study was to determine the incidence and aetiology of neonatal sepsis in Nigeria with a focus on GBS sepsis and also to assess the potential impact of a GBS vaccine. Methods A literature search was conducted on the databases of African journals online, PubMed and Google Scholar for works conducted between 1987 to 2017. Case reports, reviews, and studies not stating specific culture methods or specific bacteria isolated were excluded. Data extracted included; incidence of neonatal sepsis, method of blood culture, blood volume, sample size, bacterial agents isolated and history of antibiotic use. PRISMA guidelines were followed and modified Down’s and Black criteria used to evaluate the quality of studies. Results A total of 5,114 studies were reviewed for neonatal sepsis out of which 24 consisting of a total of 2,280 cases were selected for final review. Nine studies met criteria for assessment of hospital based incidence of neonatal sepsis representing 31,305 hospital births. The incidence of neonatal sepsis was 18.2/1000 livebirths with range from 7-55/1000 livebirths while the GBS incidence was 0.06/1000 livebirths with range from 0-2/1000 live births. We discovered various limitations such as identification techniques that could result in underestimation of the true incidence of GBS sepsis. Pathogens such as Klebsiella pneumoniae and Staphylococcus aureus were more commonly isolated than GBS. Implications of key findings The hospital based incidence of neonatal sepsis was high at 18.2/1000 live births while that due to GBS was 0.06/1000 live births. The burden of neonatal sepsis, including that attributable to GBS is substantial and could be reduced by preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine. There is however very sparse meaningful data currently. Well planned prospective studies with larger sample sizes, more advanced isolation and identification techniques and those following up invasive disease cases for possible short and long term sequelae are needed—not only prior to possible introduction of the vaccine to determine the baseline epidemiology, but also thereafter to monitor its impact on the population. Strategies need to be developed to also reduce the morbidity and mortality attributable to other bacteria that have an incidence even greater than that of GBS.

Gros, Antoine; Dupuis, Claire; Ruckly, Stéphane; Lautrette, Alexandre; Garrouste-Orgeas, Maité; Gainnier, Marc; Forel, Jean-Marie; Marcotte, Guillaume; Azoulay, Elie; Cohen, Yves; Schwebel, Carole; Argaud, Laurent; de Montmollin, Etienne; Siami, Shidasp; Goldgran-Toledano,, Dany; Darmon, Michael; Timsit, Jean-Francois

Objectives: This study in critically ill patients with shock assessed the prognostic value of body weight variations occurring each day from day 3 to day 7 on the 30-day outcome in terms of mortality, occurrence of ventilator-associated pneumonia and of bedsore, and occurrence of length of stay . Design: Retrospective analysis of data. Multivariate subdistribution survival models were used at each day, from day 3 to day 7. The impact of body weight variations on length of stay was estimated through a multivariate negative binomial regression model. Setting: Prospective multicenter cohort study. Patients: Critically ill patients admitted in ICU with shock and requiring mechanical ventilation within 48 hours. Intervention: None. Measurements and Main Results: Two-thousand three-hundred seventy-four patients were included. Their median body weight variations increased from 0.4 kg (interquartile range, 0–4.8 kg) on day 3 to 3 kg (interquartile range, –0.4 to 8.2 kg) on day 7. Categories of body weight variations were defined depending on body weight variations interquartiles: weight loss, no weight gain, moderate and severe weight gain. A severe weight gain tended to be associated with death at days 5 and 6 (day 5: subdistribution hazard ratio, 1.27; 95% CI, 0.99–1.63; p = 0.06 and day 6: subdistribution hazard ratio, 1.43; 95% CI, 1.08–1.89; p = 0.01), a weight loss tended to be associated with bedsore, and a severe gain between at days 5 and 6 was associated with ventilator-associated pneumonia. Any body weight variations were associated with an increased length of stay. Conclusions: In survivors at day 3, body weight variations during the first days of ICU stay might be a clinically relevant tool to prevent weight gain but also for prognostication of 30-day mortality, occurrence of ventilator-associated pneumonia, and occurrence of prolonged ICU stay. Drs. Gros and Dupuis contributed equally to the article as co-first authors. Members of the OUTCOMEREA Study Group are listed in the Acknowledgments. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the OUTCOMEREA study group (Aulnay ss bois, France). Dr. Azoulay’s institution received research support from Alexion, Fisher & Payckle, Gilead, Jazz Pharma, Ablynx, and Astellas, and he received funding from lectures for Alexion, Gilead, Baxter, and Merck. Dr. Darmon received other support outside the submitted work from Merck (research grant, speaker fees, and support in organizing educational meetings), Astute medical (research grant), Astellas (speaker fees and support in organizing educational meetings), Bristol Myers Squibb (speaker fees), JazzPharma (support in organizing educational meetings), and Sanofi-Aventis (advisory board). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Jean-francois.timsit@aphp.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Multiplex real-time polymerase chain reaction assays have improved diagnostic sensitivity for a wide range of pathogens. However, co-detection of multiple agents and bacterial colonization make it difficult to distinguish between asymptomatic infection or illness aetiology. We assessed whether semi-quantitative microbial load data can differentiate between symptomatic and asymptomatic states for common respiratory pathogens. Methods We obtained throat and nasal swab samples from military trainees at two Thai Army barracks. Specimens were collected at the start and end of 10-week training periods (non-acute samples), and from individuals who developed upper respiratory tract infection during training (acute samples). We analysed the samples using a commercial multiplex respiratory panel comprising 33 bacterial, viral and fungal targets. We used random effects tobit models to compare cycle threshold (Ct) value distributions from non-acute and acute samples. Results We analysed 341 non-acute and 145 acute swab samples from 274 participants. Haemophilus influenzae type B was the most commonly detected microbe (77.4% of non-acute and 64.8% of acute samples). In acute samples, nine specific microbe pairs were detected more frequently than expected by chance. Regression models indicated significantly lower microbial load in non-acute relative to acute samples for H. influenzae non-type B, Streptococcus pneumoniae and rhinovirus, although it was not possible to identify a Ct-value threshold indicating causal etiology for any of these organisms. Conclusions Semi-quantitative measures of microbial concentration did not reliably differentiate between illness and asymptomatic colonization, suggesting that clinical symptoms may not always be directly related to microbial load for common respiratory infections.

Abstract Background Oxidative stress is a modifiable risk-factor in infection causing damage to human cells. As an adaptive response, cells catabolize Tyrosine to 3-Nitrotyrosine (Tyr-NO2) by nitrosylation. We investigated whether a more efficient reduction in oxidative stress, mirrored by a lowering of Tyrosine, and an increase in Tyr-NO2 and the Tyrosine/Tyr-NO2 ratio was associated with better clinical outcomes in patients with community-acquired pneumonia (CAP). Methods We measured Tyrosine and Tyr-NO2 in CAP patients from a previous randomized Swiss multicenter trial. The primary endpoint was adverse outcome defined as death or ICU admission within 30-days; the secondary endpoint was 6-year mortality. Results Of 278 included CAP patients, 10.4% experienced an adverse outcome within 30 days and 45.0% died within 6 years. After adjusting for the pneumonia Severity Index [PSI], BMI and comorbidities, Tyrosine nitrosylation was associated with a lower risk for short-term adverse outcome and an adjusted OR of 0.44 (95% CI 0.20 to 0.96, p = 0.039) for Tyr-NO2 and 0.98 (95% CI 0.98 to 0.99, p = 0.043) for the Tyrosine/Tyr-NO2 ratio. There were no significant associations for long-term mortality over six-years for Tyr-NO2 levels (adjusted hazard ratio 0.81, 95% CI 0.60 to 1.11, p = 0.181) and Tyrosine/Tyr-NO2 ratio (adjusted hazard ratio 1.00, 95% CI 0.99 to 1.00, p = 0.216). Conclusions Tyrosine nitrosylation in our cohort was associated with better clinical outcomes of CAP patients at short-term, but not at long term. Whether therapeutic modulation of the Tyrosine/Tyr-NO2 pathway has beneficial effects should be evaluated in future studies. Trial registration ISRCTN95122877. Registered 31 July 2006.

Dominika A. Kalkowska, Gert Jan Boender, Lidwien A. M. Smit, Christos Baliatsas, Joris Yzermans, Dick J. J. Heederik, Thomas J. Hagenaars

by Dominika A. Kalkowska, Gert Jan Boender, Lidwien A. M. Smit, Christos Baliatsas, Joris Yzermans, Dick J. J. Heederik, Thomas J. Hagenaars In a recent study of electronic health records (EHR) of general practitioners in a livestock-dense area in The Netherlands in 2009, associations were found between residential distance to poultry farms and the occurrence of community-acquired pneumonia (CAP). In addition, in a recent cross-sectional study in 2494 adults in 2014/2015 an association between CAP and proximity to goat farms was observed. Here, we extended the 2009 EHR analyses across a wider period of time (2009–2013), a wider set of health effects, and a wider set of farm types as potential risk sources. A spatial (transmission) kernel model was used to investigate associations between proximity to farms and CAP diagnosis for the period from 2009 to 2013, obtained from EHR of in total 140,059 GP patients. Also, associations between proximity to farms and upper respiratory infections, inflammatory bowel disease, and (as a control disease) lower back pain were analysed. Farm types included as potential risk sources in these analyses were cattle, (dairy) goats, mink, poultry, sheep, and swine. The previously found association between CAP occurrence and proximity to poultry farms was confirmed across the full 5-year study period. In addition, we found an association between increased risk for pneumonia and proximity to (dairy) goat farms, again consistently across all years from 2009 to 2013. No consistent associations were found for any of the other farm types (cattle, mink, sheep and swine), nor for the other health effects considered. On average, the proximity to poultry farms corresponds to approximately 119 extra patients with CAP each year per 100,000 people in the research area, which accounts for approximately 7.2% extra cases. The population attributable risk percentage of CAP cases in the research area attributable to proximity to goat farms is approximately 5.4% over the years 2009–2013. The most probable explanation for the association of CAP with proximity to poultry farms is thought to be that particulate matter and its components are making people more susceptible to respiratory infections. The causes of the association with proximity to goat farms is still unclear. Although the 2007–2010 Q-fever epidemic in the area probably contributed Q-fever related pneumonia cases to the observed additional cases in 2009 and 2010, it cannot explain the association found in later years 2011–2013.

Abstract Background Hypervirulent strains of Klebsiella pneumoniae are a recognized cause of a distinct invasive syndrome that results in pyogenic liver abscesses and metastatic complications, particularly in the Asia Pacific region. Reports of hypervirulent K.pneumoniae in Europe, the Americas and Australia indicate worldwide spread. We present a case of multi-focal osteomyelitis, a rarely described complication of hypervirulent K.pneumoniae in the medical literature. The prevalence of this condition in countries outside Asia may be expected to rise with increasing travel. Case presentation A 20-year-old Chinese man residing in Australia for 2 years presented with a 2-week history of gradually worsening leg pain preceded by 2 weeks of constitutional symptoms. Imaging with computerized axial tomography (CT) and other modalities revealed bilateral tibial lesions described as lattice-like linear lucencies involving the cortices with scalloping of the outer involved cortex. Cultures of tissue from a left tibial bone biopsy were positive cultures for K.pneumoniae. Whole-genome sequencing identified the isolate as K1 serotype ST23, a well-recognized hyper virulent strain capable of causing invasive disease. An abdominal CT revealed a 27x22mm liver abscess. The patient had no other metastatic manifestations of the disease, and responded to 6 weeks of intravenous ceftriaxone followed by 3 months of oral Ciprofloxacin. Conclusions Increased awareness of the manifestations and subsequent management of hyper virulent strains of K.pneumoniae by clinicians is important to assist early recognition and help minimize serious sequelae. Cases with overseas links, such as previous residence in the Asia Pacific area, are at higher risk for infection with the hyper virulent strain. This case highlights the need for clinicians to be able to recognize this important disease, especially in patients with the right epidemiological links, and to investigate and treat appropriately to prevent severe metastatic complications.

Abstract Background Klebsiella pneumoniae bloodstream infections (BSIs) occur with significant prevalence and high mortality worldwide. Antimicrobial resistance and virulence are two main factors participating in the pathogenicity of K. pneumoniae. Here we investigated the prevalence of blaKPC and virulence factors in K. pneumoniae isolated from patients with BSIs and their association with clinical outcome. Methods The clinical data of 285 K. pneumoniae BSI cases diagnosed from January 2013 to December 2015 in a Chinese university hospital were retrospectively evaluated. The “string test” was performed to identify hypermucoviscous K. pneumoniae (HMKP). blaKPC, rmpA, magA and serotype-specific genes were detected by PCR amplification. Finally, a Cox proportional hazards model was employed to determine the predictors of 14-day mortality. Results Of these isolates, the prevalence of blaKPC and rmpA were 33.3% (95/285) and 31.6% (90/285) respectively. 69 isolates (24.2%, 69/285) were HMKP. rmpA was strongly associated with HM phenotype. The KPC-producing KP and HMKP were almost non-overlapping and only three HMKP isolates harbored blaKPC. K1 (28, 40.6%) and K2 (22, 31.9%) were the most common serotypes in HMKP. 44.9% of HMKP BSIs had origin of biliary tract infection or liver abscess. The 14-day mortality was 100% in blaKPC+/HM+ subgroup (3/3), followed by blaKPC+/HM− (39/92, 42.4%), blaKPC−/HM+ (5/66, 7.6%) and blaKPC−/HM− (7/124, 5.6%). The 14-day cumulative survival was significantly different between blaKPC+ and blaKPC− subgroup (Log-rank p 

Abstract Background Bacterial meningitis is a life-threatening infection that remains a public health concern. Bacterial meningitis is commonly caused by the following species: Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes, Haemophilus influenzae and Escherichia coli. Here, we describe BMScan (Bacterial Meningitis Scan), a whole-genome analysis tool for the species identification of bacterial meningitis-causing and closely-related pathogens, an essential step for case management and disease surveillance. BMScan relies on a reference collection that contains genomes for 17 focal species to scan against to identify a given species. We established this reference collection by supplementing publically available genomes from RefSeq with genomes from the isolate collections of the Centers for Disease Control Bacterial Meningitis Laboratory and the Minnesota Department of Health Public Health Laboratory, and then filtered them down to a representative set of genomes which capture the diversity for each species. Using this reference collection, we evaluated two genomic comparison algorithms, Mash and Average Nucleotide Identity, for their ability to accurately and rapidly identify our focal species. Results We found that the results of Mash were strongly correlated with the results of ANI for species identification, while providing a significant reduction in run-time. This drastic difference in run-time enabled the rapid scanning of large reference genome collections, which, when combined with species-specific threshold values, facilitated the development of BMScan. Using a validation set of 15,503 genomes of our species of interest, BMScan accurately identified 99.97% of the species within 16 min 47 s. Conclusions Identification of the bacterial meningitis pathogenic species is a critical step for case confirmation and further strain characterization. BMScan employs species-specific thresholds for previously-validated, genome-wide similarity statistics compiled from a curated reference genome collection to rapidly and accurately identify the species of uncharacterized bacterial meningitis pathogens and closely related pathogens. BMScan will facilitate the transition in public health laboratories from traditional phenotypic detection methods to whole genome sequencing based methods for species identification.

Abstract Background Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. Methods We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. Results Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). Conclusions CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.

Ma, P., Laibinis, H. H., Ernst, C. M., Hung, D. T.

Carbapenem resistance is mainly mediated by carbapenemases or extended-spectrum β-lactamases (ESBL) plus loss of porins. However, we have identified a Klebsiella pneumoniae clinical isolate that contains neither carbapenemases nor ESBLs. Instead, we found that high-level expression of a novel blaOXA-10-derived β-lactamase gene, blaOXA-663, in conjunction with OmpK36 deficiency results in high-level carbapenem resistance. This finding demonstrates the combinatorial complexity of factors including β-lactamase activity, its expression levels, and porin activity that yield carbapenem resistance.

Hayden MK, Won SY.

Bloodstream infections due to Escherichia coli and Klebsiella pneumoniae are associated with significant morbidity, mortality, and financial costs. Resistance to third-generation cephalosporins is increasing in these species both in the community and in health care settings. The most common mechanism of third-generation cephalosporin resistance is production of an extended-spectrum β-lactamase (ESBL). These enzymes render E coli and K pneumoniae nonsusceptible to nearly all cephalosporins and penicillins. Carbapenems, such as meropenem, remain active and are considered preferred agents for treatment of bloodstream infections due to ESBL-producing organisms. However, treatment with carbapenems creates selective pressure for development of carbapenem resistance, which is arguably the greatest contemporary antibiotic resistance threat. Thus, there is intense interest both in the development of new antibiotics and in the reassessment of older antibiotics for use as carbapenem alternatives.

Benjamin E. Stephens, Meilinh Thi, Rahaf Alkhateb, Apeksha Agarwal, Francis E. Sharkey, Christopher Dayton and Gregory M. Anstead

Abstract. Murine typhus (MT) is an important cause of febrile illness in endemic areas, and there is an epidemiologic resurgence of this infection currently transpiring in Texas and California. Fatal cases and severe neurological complications are rare. A fatal case of MT in a middle-aged man is reported with a course culminating in multi-organ failure and refractory status epilepticus. An autopsy revealed hemorrhagic pneumonia, acute tubular necrosis, and ischemic necrosis in the liver, adrenals, and brain. We have also reviewed the neurologic complications of MT.

Becka, S. A., Zeiser, E. T., Barnes, M. D., Taracila, M. A., Nguyen, K., Singh, I., Sutton, G. G., LiPuma, J. J., Fouts, D. E., Papp-Wallace, K. M.

Burkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from Cystic Fibrosis. β-Lactam antibiotics are recommended as therapy for infections due to B. multivorans, which possesses two β-lactamase genes, blapenA and blaAmpC. PenA is a carbapenemase with a substrate profile similar to the Klebsiella pneumoniae carbapenemase (KPC); in addition, expression of PenA is inducible by β-lactams in B. multivorans. Herein, we characterize AmpC from B. multivorans ATCC 17616. AmpC possesses only 38-46% protein identity to non-Burkholderial AmpCs (e.g., PDC-1, CMY-2). Within 49 clinical isolates of B. multivorans, we identified 27 different AmpC variants. Some variants possessed single amino acid substitutions within critical active site motifs (-loop and R2 loop). Purified AmpC1 demonstrated minimal measurable catalytic activity towards β-lactams (i.e., nitrocefin and cephalothin). Moreover, avibactam was a poor inhibitor of AmpC1 (Ki app >600 μM) and the acyl-enzyme complex formation with AmpC1 was slow, likely due to lack of productive interactions with active site residues. Interestingly, immunoblotting using a polyclonal anti-AmpC antibody revealed that protein expression of AmpC1 was inducible in B. multivorans ATCC 17616 after growth in sub-inhibitory concentrations of imipenem (1 μg/ml). The AmpC is a unique inducible class C cephalosporinase that may play an ancillary role in B. multivorans compared to PenA, which is the dominant β-lactamase in B. multivorans ATCC 17616.

Friedrich MJ.

The deaths of children in developing countries from the leading bacterial causes of pneumonia and meningitis—Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib)—declined between 2000 and 2015, according to a recent report in the Lancet Global Health.

Gomes, A., Ferraz, R., Ficker, L., Collins, M. S., Prudencio, C., Cushion, M. T., Teixeira, C., Gomes, P.

The impact of Pneumocystis pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, auto-immune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both in vitro and in vivo, we now report the potent action of these compounds on Pneumocystis carinii, in vitro. Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding.

Abstract Background Despite the widespread availability of pneumococcal vaccines, rates of pneumococcal disease are disproportionately high in adults with chronic and immunocompromising conditions. This study investigated pneumococcal disease rates and associated resource utilization and costs in this group. Methods A retrospective, observational study was conducted using the Truven Health MarketScan® Commercial Claims and Encounters database. The study population was adults aged 19–64 years with continuous health plan enrollment for at least one year before and at least one day after January 1st 2012, 2013 and/or 2014. Medical conditions were identified using ICD-9-CM diagnosis codes and grouped into at-risk (chronic) and high-risk (immunocompromising) conditions. Pneumococcal disease was stratified into all-cause pneumonia (ACP) and invasive pneumococcal disease (IPD). Results Thirty-six million adults aged 19–64 years were included in the study. 17% had a condition that put them at increased risk for pneumococcal disease. Rates of ACP and IPD in adults with at-risk conditions were 3.6 and 4.6 times the rate in healthy adults, respectively, and 5.3 and 10.5 for adults with high-risk conditions. Risk was particularly high in adults with ≥2 medical conditions: rates of ACP and IPD were 8.1 and 10.6 times higher in adults with at-risk conditions than healthy adults and 6.3 and 13.4 times higher in adults with high-risk conditions, respectively. Resource use and costs were substantially higher per episode of ACP in at-risk and high-risk adults, with costs reaching $6,534 and $9,168, compared to $4,725 for healthy adults. Conclusions Pneumococcal disease rates in at-risk and high-risk adults are significantly higher than healthy adults leading to substantial economic burden.

Abstract To describe the characteristics of adult invasive H. influenzae disease, 34 patients diagnosed at a single tertiary center between 2004 and 2017 were analyzed in a retrospective case series study. The annual estimated incidence was 0.1 cases/100.000 inhabitants. Dominant source of infection was pneumonia accompanied by sepsis (62%) and caused by nontypeable strains (74%) with low ampicillin resistance (14%). Survival (94%) and complication rates were high (35%). Main empirical treatments were ceftriaxone or levofloxacine.

Abstract Background Patients with suspected Middle East respiratory syndrome coronavirus (MERS-CoV) infection should be hospitalized in isolation wards to avoid transmission. This suspicion can also lead to medical confusion and inappropriate management of acute respiratory syndrome due to causes other than MERS-CoV. Methods We studied the characteristics and outcome of patients hospitalized for suspected MERS-CoV infection in the isolation wards of two referral infectious disease departments in the Paris area between January 2013 and December 2016. Results Of 93 adult patients (49 male (52.6%), median age 63.4 years) hospitalized, 82 out of 93 adult patients had returned from Saudi Arabia, and 74 of them were pilgrims (Hajj). Chest X-ray findings were abnormal in 72 (77%) patients. The 93 patients were negative for MERS-CoV RT-PCR, and 70 (75.2%) patients had documented infection, 47 (50.5%) viral, 22 (23.6%) bacterial and one Plasmodium falciparum malaria. Microbiological analysis identified Rhinovirus (27.9%), Influenza virus (26.8%), Legionella pneumophila (7.5%), Streptococcus pneumoniae (7.5%), and non-MERS-coronavirus (6.4%). Antibiotics were initiated in 81 (87%) cases, with two antibiotics in 63 patients (67.7%). The median duration of hospitalization and isolation was 3 days (1–33) and 24 h (8–92), respectively. Time of isolation decreased over time (P 

The given names and family names of all authors were transposed in the original publication. The original article has been corrected.

Yousang Ko, Ho Young Lee, Yong Bum Park, Su Jin Hong, Jeong Hwan Shin, Seok Jin Choi, Changhwan Kim, So Young Park, Jin Young Jeong

by Yousang Ko, Ho Young Lee, Yong Bum Park, Su Jin Hong, Jeong Hwan Shin, Seok Jin Choi, Changhwan Kim, So Young Park, Jin Young Jeong Background Little is known about the correlation between microbiological yield and radiographic activity, on chest computed tomography (CT), in suspected pulmonary tuberculosis (PTB) cases, despite CT being widely used, clinically. Methods We used multicenter retrospective data, obtained from medical records, focusing on the diagnostic performance for definite PTB. We categorized patients into four groups, by radiographic activity: definitely active, probably active, indeterminate activity, and probably inactive. Results Of the 650 patients included, 316 had culture-confirmed PTB; 190 (29.2%), 323 (49.7%), 70 (10.8%), and 67 (10.3%) were classified into the definitely active, probably active, indeterminate activity, and probably inactive groups, respectively. The corresponding observed culture rates for CT radiographic activity were 61.6%, 60.7%, 4.3% and 0%, respectively. When not only culture rates but TB-PCR and histological results were taken into consideration as definite PTB, it showed 66.6%, 67.2%, 14.3%, and 0% of each CT radiographic activity, respectively. Regarding the diagnostic performance for definite PTB, radiographic activity displayed high sensitivity (97.1%, 95% confidence interval (CI), 94.6–98.5) and negative predictive values (92.7%, 95% CI, 86.6–96.2), considered definitely and probably active PTB. Apart from PTB, other etiologies, according to radiographic activity, were predominantly respiratory infections such as bacterial pneumonia and non-tuberculous mycobacterial infection. Conclusions Radiographic activity showed good diagnostic performance, and can be used easily in clinical practice. However, clinicians should consider other possibilities, because radiologic images do not confirm microbiological PTB.

Yanyun Jia , Yifang Liao , Lu Shao , Lulu Du , Bo Wang , Dongju Su

The first three cases of confirmed infection with the virus in China were documented between May 10 and May 15, 2009. Although the clinical characteristics of the H1N1 pneumonia were described in clinical reports, the therapy has few been described. Therefore, we report our experiences of 53 cases of the H1N1 pneumonia with treatment. We describe clinical characteristic of 53 patients who were hospitalized for laboratory‐confirmed H1N1 pneumonia at the 2nd Clinical College of Harbin Medical University. In addition, we measure the role of corticosteroid, mechanical ventilation, and non‐corticosteroid antiviral therapy in the management of pneumonia patients with novel H1N1 infection. Real‐time reverse‐transcriptase‐polymerase chain (RT‐PCR) testing was used to confirm infection. The outcome of therapy was compared in scores of PaO2 and CT. The data was statistical analyzed by the Shapiro‐Wilk, anova, Student‐Newman‐Keuls Test, and Kruskal‐Wallis Test. The most common symptoms were dyspnea. In moderate ill patients, the changes in the increased PaO2 were lower in the non‐corticosteroid antiviral therapy group than in the combination of corticosteroid and non‐corticosteroid antiviral therapy after 5 days’ therapy. The therapy protocol of non‐corticosteriod + mechanical ventilation played important role in the recovery of severe ill patients.

L’Huillier A, Ferreira V, Hirzel C, et al.

AbstractInfluenza is responsible for significant morbidity after transplantation. We evaluated Th1/Th2 cytokines and IL-10 levels during influenza infection in the post-transplant setting. Sera from 277 transplant recipients were analyzed at influenza diagnosis and 28 days later for IFN-γ, IL-4, IL-13 and IL-10. IL-13 levels were associated with protection against pneumonia and ICU admission, whereas the IFN-γ/IL-13 ratio and IL-10 levels were associated with an increased risk of pneumonia and ICU admission. This association was independent of viral load. A skewing of immune responses towards Th2 in transplant patients appears to confer protection from severe influenza infection, independently of viral load.

Kullaya, V., de Jonge, M. I., Langereis, J. D., van der Gaast - de Jongh, C. E., Büll, C., Adema, G. J., Lefeber, D., Cremers, A. J., Mmbaga, B. T., de Groot, P. G., de Mast, Q., van der Ven, A. J.

Platelets are increasingly recognized to play a role in the complications of Streptococcus pneumoniae infections. S. pneumoniae expresses neuraminidases, which may alter glycans on the platelet surface. In the present study, we investigated the capability of pneumococcal neuraminidase A (NanA) to remove sialic acid (desialylation) from the platelet surface, the consequences for the platelet activation status and reactivity, and the ability of neuraminidase inhibitors to prevent these effects. Our results show that soluble NanA induces platelet desialylation. Whereas desialylation itself did not induce platelet activation (P-selectin expression and platelet fibrinogen binding), platelets became hyper-reactive to ex vivo stimulation by adenosine diphosphate (ADP) and crosslinked collagen-related peptide (CRP-XL). Platelet aggregation with leukocytes also increased. These processes were dependent on the ADP-pathway as inhibitors of this pathway (apyrase and ticagrelor) abrogated platelet hyper-reactivity. Inhibition of NanA-induced platelet desialylation by neuraminidase inhibitors (e.g. oseltamivir acid) also prevented the platelet effects of NanA. Collectively, our findings show that soluble NanA can desialylate platelets leading to platelet hyper-reactivity which can be prevented by neuraminidase inhibitors.

Nicolas Hegerle, Myeongjin Choi, James Sinclair, Mohammed N. Amin, Morgane Ollivault-Shiflett, Brittany Curtis, Rachel S. Laufer, Surekha Shridhar, Jerod Brammer, Franklin R. Toapanta, Ian Alan Holder, Marcela F. Pasetti, Andrew Lees, Sharon M. Tennant, Alan S. Cross, Raphael Simon

by Nicolas Hegerle, Myeongjin Choi, James Sinclair, Mohammed N. Amin, Morgane Ollivault-Shiflett, Brittany Curtis, Rachel S. Laufer, Surekha Shridhar, Jerod Brammer, Franklin R. Toapanta, Ian Alan Holder, Marcela F. Pasetti, Andrew Lees, Sharon M. Tennant, Alan S. Cross, Raphael Simon Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) are important human pathogens that are associated with a range of infection types, including wound and disseminated infections. Treatment has been complicated by rising rates of antimicrobial resistance. Immunoprophylactic strategies are not constrained by antimicrobial resistance mechanisms. Vaccines against these organisms would be important public health tools, yet they are not available. KP surface O polysaccharides (OPS) are protective antigens in animal models of infection. Similarly, PA flagellin (Fla), the major subunit of the flagellar filament, is required for virulence and is a target of protective antibodies in animal models. We report herein the development of a combined KP and PA glycoconjugate vaccine comprised of the four most common KP OPS types associated with human infections (O1, O2, O3, O5), chemically linked to the two Fla types of PA (FlaA, FlaB). Conjugation of KP OPS to PA Fla enhanced anti-polysaccharide immune responses and produced a formulation that generated antibody titers to the four KP OPS types and both PA Fla antigens in rabbits. Passive transfer of vaccine-induced rabbit antisera reduced the bacterial burden and protected mice against fatal intravenous KP infection. Mice passively transferred with conjugate-induced antisera were also protected against PA infection after thermal injury with a FlaB-expressing isolate, but not a FlaA isolate. Taken together, these promising preclinical results provide important proof-of-concept for a broad spectrum human vaccine to prevent KP and PA infections.

J. Moon et al.

Abstract Background Legionellosis is a well-known cause of pneumonia. Primary cutaneous and subcutaneous infection caused by Legionella pneumophila is rare and the diagnosis is challenging. Case presentation A 38-year-old Thai woman with systemic lupus erythematosus and myasthenia gravis treated with prednisolone and azathioprine presented to our hospital with low-grade fever, diarrhea, and indurated skin lesions on both thighs. Initial examination showed plaques on both inner thighs. Magnetic resonance imaging showed myositis and swelling of the skin and subcutaneous tissue. Diagnosis of panniculitis due to L. pneumophila was carried out by histopathology, Gram stain, and 16S rRNA gene sequencing method of tissue biopsy from multiple sites on both thighs. Myocarditis was diagnosed by echocardiography. The final diagnosis was disseminated extrapulmonary legionellosis. Treatment comprised intravenous azithromycin for 3 weeks and the skin lesions, myositis and myocarditis resolved. Oral azithromycin and ciprofloxacin were continued for 3 months to ensure eradication of the organism. The patient’s overall condition improved. Conclusions To our knowledge, we report the first case of L. pneumophila infection manifesting with panniculitis, possible myositis, and myocarditis in the absence of pneumonia. The diagnosis of extrapulmonary Legionella infection is difficult, especially in the absence of pneumonia. A high index of suspicion and appropriate culture with special media or molecular testing are required. Initiation of appropriate treatment is critical because delaying therapy was associated with progressive infection in our patient.

Abstract Background Streptococcus pneumoniae is a commensal of the human upper respiratory tract and a major cause of morbidity and mortality worldwide. This paper presents the distribution of serotypes and antimicrobial resistance in commensal S. pneumoniae strains cultured from healthy carriers older than four years of age in nine European countries. Methods Nasal swabs from healthy persons (age between 4 and 107 years old) were obtained by general practitioners from each country from November 2010 to August 2011. Swabs were cultured for S. pneumoniae using a standardized protocol. Antibiotic resistance was determined for isolated S. pneumoniae by broth microdilution. Capsular sequencing typing was used to identify serotypes, followed by serotype-specific PCR assays in case of ambiguous results. Results Thirty-two thousand one hundred sixty-one nasal swabs were collected from which 937 S. pneumoniae were isolated. A large variation in serotype distribution and antimicrobial resistant serotypes across the participating countries was observed. Pneumococcal vaccination was associated with a higher risk of pneumococcal colonization and antimicrobial resistance independently of country and vaccine used, either conjugate vaccine or PPV 23). Conclusions Serotype 11A was the most common in carriage followed by serotypes 23A and 19A. The serotypes showing the highest resistance to penicillin were 14 followed by 19A. Serotype 15A showed the highest proportion of multidrug resistance.

Pu, Hong; Doig, Gordon S.; Heighes, Philippa T.; Allingstrup, Matilde J.

Objectives: To identify, appraise, and synthesize current evidence to determine whether early enteral nutrition alters patient outcomes from major burn injury. Data Sources: Medline, Embase, and the China National Knowledge Infrastructure were searched. The close out date was May 1, 2018. Study Selection: Early enteral nutrition was defined as a standard formula commenced within 24 hours of injury or admission to ICU or burn unit. Comparators included any form of nutrition support “except” early enteral nutrition. Only randomized controlled trials reporting patient-centered outcomes were eligible for inclusion. Data Extraction: The primary outcome was mortality. Gastrointestinal hemorrhage, sepsis, pneumonia, renal failure, and hospital stay were evaluated as secondary outcomes. Data Synthesis: Nine-hundred fifty-eight full-text articles were retrieved and screened. Seven randomized controlled trials enrolling 527 participants with major burn injury were included. Compared with all other types of nutrition support, early enteral nutrition significantly reduced mortality (odds ratio, 0.36; 95% CI, 0.18–0.72; p = 0.003; I2 = 0%). Early enteral nutrition also significantly reduced gastrointestinal hemorrhage (odds ratio, 0.21; 95% CI, 0.09–0.51; p = 0.0005; I2 = 0%), sepsis (odds ratio, 0.23; 95% CI, 0.11–0.48; p < 0.0001; I2 = 0%), pneumonia (odds ratio, 0.41; 95% CI, 0.21–0.81; p = 0.01; I2 = 63%), renal failure (odds ratio, 0.27; 95% CI, 0.09–0.82; p = 0.02; I2 = 32%), and duration of hospital stay (–15.31 d; 95% CI, –20.43 to –10.20; p < 0.00001; I2 = 0%). Conclusions: The improvements in clinical outcomes demonstrated in this meta-analysis are consistent with the physiologic rationale cited to support clinical recommendations for early enteral nutrition made by major clinical practice guidelines: gut integrity is preserved leading to fewer gastrointestinal hemorrhages, less infectious complications, a reduction in consequent organ failures, and a reduction in the onset of sepsis. The cumulative benefit of these effects improves patient survival and reduces hospital length of stay. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Pu’s Visiting Fellowship with the University of Sydney’s Northern Clinical School Intensive Care Research Unit was enabled by a grant from the National Leading Clinical Specialty Foundation for the Department of Critical Care Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China. Dr. Allingstrup reported receiving academic research grants from Fresenius Kabi Deutschland GmbH, Medinor A/S Denmark, and COSMED Srl, Rome, Italy and speakers honoraria from Fresenius Kabi A/S Denmark, Baxter Healthcare A/S Denmark and Nutricia A/S Denmark. Dr. Doig reported receiving academic research grants from Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland, and Nutricia Pharmaceutical (Wuxi) Ltd. China (lecture fees). Dr. Heighes has not disclosed any potential conflicts of interest. For information regarding this article, E-mail: gdoig@med.usyd.edu.au Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Harris PA, Tambyah PA, Lye DC, et al.

This noninferiority trial compares the effects of piperacillin-tazobactam vs meropenem on mortality in patients with bloodstream infection caused by ceftriaxone-nonsusceptible Escherichia coli or Klebsiella pneumoniae.

Abstract Background Community-acquired pneumonia (CAP) is a common condition with high mortality, morbidity and healthcare costs. This study aimed to determine whether clinical pathway (CP) implementation in different hospitals in China increased antibiotic compliance with the national CP in inpatients with CAP. Methods Chart reviews of CAP cases were conducted in 18 public hospitals from 3 different regions of China in 2015. Chi-square tests and the t-test were used to compare differences between hospitals that implemented CP (CP group) and those that did not (non-CP group). Multivariate logistic analysis was adopted to test whether CP implementation for CAP in hospitals affected their overall antibiotic use compliance rates with the national CP for CAP. Results The overall compliance rate with the national CP for inpatients with CAP was 43.69%. The compliance rates for timely initial antibiotic use, recommended antibiotic use and use of the recommended combination of antibiotics and the overall compliance rate were substantially higher in the CP group than in the non-CP group. A multivariate logistic model for overall compliance in inpatients with CAP showed that the hospitals in the CP group had greater overall compliance than those in the non-CP group (odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.16–2.71) after controlling for hospital and inpatient characteristics. Conclusion In China, the overall compliance rate with the national CP for inpatients with CAP was low, but inpatients with CAP in the hospitals in the CP group received antibiotics more concordantly with the national CP. Since adherence to evidence-based care has been shown to improve clinical outcomes, internal and external support from hospitals is required to facilitate CP implementation for inpatients with CAP. Additionally, governmental commitment, hospital input and population involvement are required to improve antibiotic utilization.

Tatsuya Tada, Kohei Uechi, Isamu Nakasone, Masashi Nakamatsu, Kazuhito Satou, Takashi Hirano, Teruo Kirikae, Jiro Fujita

Abstract Background Mycoplasma pneumoniae (M. pneumoniae) is a commonly causative pathogen for respiratory tract infections (RTIs) in humans. The epidemiological features of M. pneumoniae infections during post-epidemic, including age distribution and the seasonality of the patients, are not well investigated. Methods We retrospectively analyzed the clinical data of 7835 consecutive RTIs patients (3852 adults and 3983 children) who visited a teaching hospital, and defined an epidemic (2011–2013) and a post-epidemic period (2014–2016). M. pneumoniae was detected by fluorescence-quantatitive PCR in respiratory samples. Informed consent was obtained by all adults and the legal representatives of patients aged

Kunling Shen, Matthew Wasserman, Dongdong Liu, Yong-Hong Yang, Junfeng Yang, Greg F. Guzauskas, Bruce C. M. Wang, Betsy Hilton, Raymond Farkouh

by Kunling Shen, Matthew Wasserman, Dongdong Liu, Yong-Hong Yang, Junfeng Yang, Greg F. Guzauskas, Bruce C. M. Wang, Betsy Hilton, Raymond Farkouh Background The burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP). Objective To estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects. Methods We developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE. Results Scenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices. Discussion Initiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.

Charles S. Dela Cruz

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 2, Page 256-263, July 15, 2018.

Uyeki TM, Fowler RA, Fischer WA, II.

This Viewpoint reviews advances in the surveillance, diagnosis, and treatment of influenza since the 1918 pandemic, and identifies key clinical questions to address in advance of the next outbreak, including optimal treatment for hospitalized and critically ill patients and those with secondary bacterial pneumonia.

Abstract Background Increasing numbers of refractory or severe, even fatal, cases of Mycoplasma pneumoniae infections have been reported in recent years. Excessive inflammatory responses play a vital role in the pathogenesis of refractory M. pneumoniae pneumonia (RMPP). HMGB1 is an actively secreted cytokine produced by macrophages and other inflammatory cells that participates in various infectious diseases. The present study aimed to explore the role and clinical significance of HMGB1 in children with RMPP and the potential mechanism of HMGB1 expression. Methods Four hundred and fifty-two children diagnosed with M. pneumoniae pneumonia, including 108 children with RMPP, were enrolled from January 2013 to December 2015 at the Children’s Hospital of Soochow University. HMGB1, TNF-α, and IL-6 in peripheral blood from RMPP and non-RMPP (NRMPP) cases were detected by real-time PCR and ELISA. Lipid-associated membrane proteins (LAMPs) were extracted from live M. pneumoniae and prepared at different concentrations for stimulation of THP-1 cells. After coculture with LAMPs, HMGB1, TNF-α, IL-6, RAGE, TLR2, and TLR4 in THP-1 cells were detected by real-time PCR. Results Occurrences of cough, fever, and abnormal lung signs were more frequent in RMPP cases compared with NRMPP cases (all p 

Donghao Yu, Guangmei Zhang, Lingyu Gao, Wenbo Xu, Bin Cao

Zimmerman, L. I., Papin, J. F., Warfel, J., Wolf, R. F., Kosanke, S. D., Merkel, T. J.

Pertussis is a severe respiratory disease caused by Bordetella pertussis. The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, post-tussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under two months of age experience more severe disease with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases. The baboon model of pertussis provides the opportunity to evaluate the histopathology of severe, but non-fatal pertussis. The baboon model recapitulates the characteristic clinical signs of pertussis observed in humans including leukocytosis, paroxysmal coughing, mucus production, heavy colonization of the airway, and transmission of the bacteria between hosts. As in humans, the baboons demonstrate age-related differences in clinical presentation with younger animals experiencing more severe disease. We examined the histopathology of five to six-week old baboons with findings similar to those reported for fatal human infant cases. In juvenile baboons, we found that the disease is highly inflammatory and concentrated to the lungs with signs of disease that would typically be diagnosed as acute respiratory distress syndrome (ARDS) and bronchopneumonia. In contrast, no significant pathology was observed in the trachea. Histopathological changes in the trachea were limited to cellular infiltrates and mucus production. Immuno-histostaining revealed the bacteria localized to the surface of the ciliated epithelium in the conducting airways. Our observations provide important insights into the pathology of pertussis in typical, severe, but non-fatal pertussis cases in a very relevant animal model.

Mihaja Raberahona, Tiana Razafinambinintsoa, Volatiana Andriananja, Njaratiana Ravololomanana, Juliana Tongavelona, Rado Rakotomalala, Johary Andriamamonjisoa, Radonirina Lazasoa Andrianasolo, Rivonirina Andry Rakotoarivelo, Mamy Jean de Dieu Randria

by Mihaja Raberahona, Tiana Razafinambinintsoa, Volatiana Andriananja, Njaratiana Ravololomanana, Juliana Tongavelona, Rado Rakotomalala, Johary Andriamamonjisoa, Radonirina Lazasoa Andrianasolo, Rivonirina Andry Rakotoarivelo, Mamy Jean de Dieu Randria Background During the last few years, significant efforts have been made to improve access to antiretroviral therapy which led to dramatic reduction in AIDS-related events and mortality in HIV positive patients at the global level. However, current data in Africa suggested modest impact of widespread antiretroviral therapy scale-up especially regarding HIV-related hospitalization. In this study, we aimed to describe causes of hospitalization and factors associated with AIDS-defining events and inpatient mortality. Materials and methods A retrospective study was performed on medical records of HIV positive patients admitted for at least 24 hours in the Infectious Diseases Unit of the University Hospital Joseph Raseta Befelatanana Antananarivo. Cause of hospitalization was considered as the main diagnosis related to the symptoms at admission. Diagnostic criteria were based on criteria described in WHO guidelines. AIDS-defining events were defined as diseases corresponding to WHO stage 4 or category C of CDC classification. Results From 2010 to 2016, 236 hospital admissions were included. AIDS-defining events were the most frequent cause of hospitalization (61.9%) with an increasing trend during the study period. Tuberculosis (28.4%), pneumocystis pneumonia (11.4%), cerebral toxoplasmosis (7.2%) and cryptococcosis (5.5%) were the most frequent AIDS-defining events. Tuberculosis was also the most frequent cause of overall hospitalization. In multivariate analysis, recent HIV diagnosis (aOR = 2.0, 95% CI: 1.0–3.9), CD4…

Jones, A. K., Ranjitkar, S., Lopez, S., Li, C., Blais, J., Reck, F., Dean, C. R.

Twenty three K. pneumoniae (blaDHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/mL for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected from representative isolates. These had mutations in the chromosomal peptidoglycan recycling genes mpl or ampD. Pre-existing mpl mutations were also found in some of the clinical isolates examined and these had strongly upregulated expression of blaDHA-1.

Abstract Background The impact of different classes of microbial pathogens on mortality in severe community-acquired pneumonia is not well elucidated. Previous studies have shown significant variation in the incidence of viral, bacterial and mixed infections, with conflicting risk associations for mortality. We aimed to determine the risk association of microbial aetiologies with hospital mortality in severe CAP, utilising a diagnostic strategy incorporating molecular testing. Our primary hypothesis was that respiratory viruses were important causative pathogens in severe CAP and was associated with increased mortality when present with bacterial pathogens in mixed viral-bacterial co-infections. Methods A retrospective cohort study from January 2014 to July 2015 was conducted in a tertiary hospital medical intensive care unit in eastern Singapore, which has a tropical climate. All patients diagnosed with severe community-acquired pneumonia were included. Results A total of 117 patients were in the study. Microbial pathogens were identified in 84 (71.8%) patients. Mixed viral-bacterial co-infections occurred in 18 (15.4%) of patients. Isolated viral infections were present in 32 patients (27.4%); isolated bacterial infections were detected in 34 patients (29.1%). Hospital mortality occurred in 16 (13.7%) patients. The most common bacteria isolated was Streptococcus pneumoniae and the most common virus isolated was Influenza A. Univariate and multivariate logistic regression showed that serum procalcitonin, APACHE II severity score and mixed viral-bacterial infection were associated with increased risk of hospital mortality. Mixed viral-bacterial co-infections were associated with an adjusted odds ratio of 13.99 (95% CI 1.30–151.05, p = 0.03) for hospital mortality. Conclusions Respiratory viruses are common organisms isolated in severe community-acquired pneumonia. Mixed viral-bacterial infections may be associated with an increased risk of mortality.

Bi, D., Zheng, J., Li, J.-J., Sheng, Z.-K., Zhu, X., Ou, H.-Y., Li, Q., Wei, Q.

IncFIIK plasmids are associated with the acquisition and dissemination of multiple antimicrobial resistance in Klebsiella pneumoniae and often encountered in clinical isolates of this species. Since the phylogeny and evolution of IncFIIK plasmids remain unclear, herein we performed large-scale in silico typing and comparative analysis of these plasmids in publicly available bacterial/plasmid genomes. IncFIIK plasmids are prevalent in K. pneumoniae, as found in 69% sequenced genomes, covering 66% sequenced STs (sequence types), but sparse in other Enterobacteriaceae. IncFIIK replicons have three lineages. One IncFIIK allele could be found in distinct K. pneumoniae STs, highlighting the lateral genetic flow of IncFIIK plasmids. A set of 77 IncFIIK plasmids with full sequences were further analysed. A pool of 327 antibiotic resistance genes or remnants were annotated in 75.3% of these plasmids. Plasmid genome comparison reiterated that they often contain other replicons belonging to IncFIA, IncFIB, IncFIIYp, IncFIIpCRY, IncR, IncL and IncN groups and that they share a conserved backbone featuring an F-like conjugation module that has divergent components responsible for regulation and mating pair stabilization. Further epidemiological studies of IncFIIK plasmids are required due to sample bias of K. pneumoniae genomes in public database. This study provides insights into the evolution and structures of IncFIIK plasmids.

Xue, G., Crabb, D. M., Xiao, L., Liu, Y., Waites, K. B.

Levonadifloxacin (WCK 771) was evaluated against 68 type strains and clinical isolates of Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma pneumoniae and Ureaplasma species in comparison to moxifloxacin, levofloxacin, tetracycline and azithromycin or clindamycin. Levonadifloxacin MICs were ≤ 0.5 μg/ml for Mycoplasma genitalium. MIC90s (μg/ml) were 1 (Mycoplasma hominis), 0.125 (Mycoplasma pneumoniae) and 2 (Ureaplasma spp). Levonadifloxacin merits further study for treating infections caused by these organisms.

Blais, J., Lopez, S., Li, C., Ruzin, A., Ranjitkar, S., Dean, C. R., Leeds, J. A., Casarez, A., Simmons, R. L., Reck, F.

LYS228 is a novel monobactam with potent activity against Enterobacteriaceae. LYS228 is stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency against the majority of extended spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE) strains tested. Overall, LYS228 demonstrated potent activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates. Based upon MIC90 values, LYS228 (MIC90= 1 μg/mL) was ≥32-fold more active against these strains than were aztreonam, ceftazidime, ceftazidime/avibactam, cefepime, and meropenem. The MIC90 value for tigecyline was 4 μg/mL against the strains tested. Against Enterobacteriaceae isolates expressing ESBLs (N=37) or displaying carbapenem resistance (N=77), LYS228 had MIC90 values of 1 and 4 μg/mL, respectively.LYS228 exhibited potent bactericidal activity as indicated by low MBC to MIC ratios (≤4) against 97.4% (264/271) of the Enterobacteriaceae strains tested. In time-kill studies, LYS228 consistently achieved 3-log10 reduction in colony-forming units (CFU)/mL (≥99.9% killing) at concentrations ≥4X the MIC for E. coli and K. pneumoniae reference strains as well as isolates encoding TEM-1, SHV-1, CTX-M-14, CTX-M-15, KPC-2, KPC-3 and NDM-1 β-lactamases.

Monogue, M. L., Giovagnoli, S., Bissantz, C., Zampaloni, C., Nicolau, D. P.

Urinary tract infections (UTIs) are a tremendous burden to the healthcare system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multi-drug resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with in vitro activity against class A and class C β-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Herein, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem and nacubactam alone against 10 K. pneumoniae, E. coli, and E. cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM producing enzymes. Selected isolates had meropenem-nacubactam MICs between 1-8 μg/mL. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving ≥ 3 log reduction from 48h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed anti-bacterial properties, achieving > 1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam resistant isolates, meropenem-nacubactam demonstrated antibacterial kill upwards of 6 log10 CFU from 48h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in man against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed.

Sinead T. Loughran, Patrick A. Power, Paula T. Maguire, Samantha L. McQuaid, Paul J. Buchanan, Ingileif Jonsdottir, Robert W. Newman, Ruth Harvey, Patricia A. Johnson

by Sinead T. Loughran, Patrick A. Power, Paula T. Maguire, Samantha L. McQuaid, Paul J. Buchanan, Ingileif Jonsdottir, Robert W. Newman, Ruth Harvey, Patricia A. Johnson Importance Influenza virus is highly contagious and poses substantial public health problems due to its strong association with morbidity and mortality. Approximately 250,000–500,000 deaths are caused by seasonal influenza virus annually, and this figure increases during periods of pandemic infections. Most of these deaths are due to secondary bacterial pneumonia. Influenza-bacterial superinfection can result in hospitalisation and/or death of both patients with pre-existing lung disease or previously healthy individuals. The importance of our research is in determining that influenza and its component haemagglutinin has a direct effect on the classic pneumococcus induced pathways to IL-17A in our human ex vivo model.Our understanding of the mechanism which leaves people exposed to influenza infection during superinfection remain unresolved. This paper demonstrates that early infection of monocytes inhibits an arm of immunity crucial to bacterial clearance. Understanding this mechanism may provide alternative interventions in the case of superinfection with antimicrobial resistant strains of bacteria.

Raúl Méndez

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 3, Page 370-378, August 1, 2018.