Simon Portsmouth, David van Veenhuyzen, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Peter Tenke, Tsutae Den Nagata

Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing.

Rima A Moghnieh, Zeina A Kanafani, Hussam Z Tabaja, Sima L Sharara, Lyn S Awad, Souha S Kanj

No uniformly organised collection of data regarding antimicrobial resistance has occurred in the countries of the Arab League. 19 countries of the Arab League have published data for antimicrobial susceptibility for the WHO priority organisms, and seven of 14 of these organisms are included in this Review (Escherichia coli, Klebsiella spp, Pseudomonas aeruginosa, Acinetobacter baumannii, Salmonella spp, Staphylococcus aureus, and Streptococcus pneumoniae). Although E coli and Klebsiella spp resistance to third-generation cephalosporins is common in all countries, with prevalence reaching more than 50% in Egypt and Syria, carbapenem resistance is emerging, albeit with a prevalence of less than 10%.

Salvatore Maurizio Maggiore, Mariangela Battilana, Luca Serano, Flavia Petrini

The periextubation period represents a crucial moment in the management of critically ill patients. Extubation failure, defined as the need for reintubation within 2–7 days after a planned extubation, is associated with prolonged mechanical ventilation, increased incidence of ventilator-associated pneumonia, longer intensive care unit and hospital stays, and increased mortality. Conventional oxygen therapy is commonly used after extubation. Additional methods of non-invasive respiratory support, such as non-invasive ventilation and high-flow nasal therapy, can be used to avoid reintubation.

Ji Soo Choi, Sang Hoon Lee, Ah Young Leem, Joo Han Song, Song Yee Kim, Kyung Soo Chung, Ji Ye Jung, Young Ae Kang, Young Sam Kim, Joon Chang, Moo Suk Park

by Ji Soo Choi, Sang Hoon Lee, Ah Young Leem, Joo Han Song, Song Yee Kim, Kyung Soo Chung, Ji Ye Jung, Young Ae Kang, Young Sam Kim, Joon Chang, Moo Suk Park Background Pneumocystis jirovecii pneumonia (PCP) is often fatal in human immunodeficiency (HIV)-negative patients and typically presents with respiratory insufficiency. Predicting treatment failure is challenging. This study aimed to identify prognostic factors and examine PCP polymerase chain reaction (PCR)-negative conversion in non-HIV PCP patients with respiratory failure. Method We retrospectively enrolled 81 non-HIV patients diagnosed with and treated for PCP with respiratory failure in the intensive care unit at a tertiary hospital over a 3-year period. PCP was diagnosed via nested PCR-mediated detection of Pneumocystis jirovecii in induced sputum samples, endotracheal aspirates, and bronchoalveolar lavage fluids. PCP PCR was performed weekly to check for negative conversion. Results The overall survival rate was 35.8%. Seventy-four patients (91.3%) required mechanical ventilation, and 6 (7.4%) required high-flow nasal oxygen treatment. The PCP PCR-negative conversion rate was 70.5% (survivors, 97%; non-survivors, 63.5%); the median time to conversion was 10 (7.0–14.0) days. On univariate analysis, the APACHE II score (p < 0.001), renal failure requiring renal replacement therapy (p = 0.04), PCP PCR-negative conversion (p = 0.003), and the PaO2/FiO2 ratio (first 24 hours) (p < 0.001) significantly correlated with mortality. On multivariate analysis, PCP PCR-negative conversion (hazard ratio, 0.433; 95% confidence interval, 0.203–0.928; p = 0.031) and the PaO2/FiO2 ratio (first 24 hours) (hazard ratio, 0.988; 95% confidence interval, 0.983–0.993; p < 0.001) independently predicted prognosis. Conclusions Determination of PCP PCR-negative conversion and PaO2/FiO2 ratios may help physicians predict treatment failure and mortality in non-HIV PCP patients with respiratory failure.…

Abstract This opinion article deals with the diagnostic clinical challenges faced by clinicians or health care workers in malaria-endemic areas when a severely sick child presents to the clinic with fever, coma or respiratory distress. Indeed, the coexistence of malaria with other severe infections like meningitis, invasive bacterial infection or pneumonia makes appropriate treatment allocation a matter of life and death. The use of biomarkers has been proposed as a potential solution to this problem. The arrival of high-throughput technologies allowed thousands of molecules (transcripts, proteins and metabolites) to be been screened in clinical samples from large cohorts of well/characterised patients. The major aim of these studies was to identify biomarkers that inform important decisions: should this child be referred to hospital? Should antibiotics, anti-malarials, or both, be administered? There is a large discrepancy between the number of biomarker discovery studies published and the number of biomarkers that have been clinically validated, let alone implemented. This article reflects on the many opportunities and obstacles encountered in biomarker research in malaria-endemic areas.…

Ibn Saied, Wafa; Mourvillier, Bruno; Cohen, Yves; Ruckly, Stephane; Reignier, Jean; Marcotte, Guillaume; Siami, Shidasp; Bouadma, Lila; Darmon, Michael; de Montmollin, Etienne; Argaud, Laurent; Kallel, Hatem; Garrouste-Orgeas, Maité; Soufir, Lilia; Schwebel, Carole; Souweine, Bertrand; Glodgran-Toledano, Dany; Papazian, Laurent; Timsit, Jean-François; on behalf of the OUTCOMEREA Study Group

Objectives: To investigate the respective impact of ventilator-associated pneumonia and ICU–hospital-acquired pneumonia on the 30-day mortality of ICU patients. Design: Longitudinal prospective studies. Setting: French ICUs. Patients: Patients at risk of ventilator-associated pneumonia and ICU–hospital-acquired pneumonia. Interventions: The first three episodes of ventilator-associated pneumonia or ICU–hospital-acquired pneumonia were handled as time-dependent covariates in Cox models. We adjusted using the case-mix, illness severity, Simplified Acute Physiology Score II score at admission, and procedures and therapeutics used during the first 48 hours before the risk period. Baseline characteristics of patients with regard to the adequacy of antibiotic treatment were analyzed, as well as the Sequential Organ Failure Assessment score variation in the 2 days before the occurrence of ventilator-associated pneumonia or ICU–hospital-acquired pneumonia. Mortality was also analyzed for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species(ESKAPE) and P. aeruginosa pathogens. Measurements and Main Results: Of 14,212 patients who were admitted to the ICUs and who stayed for more than 48 hours, 7,735 were at risk of ventilator-associated pneumonia and 9,747 were at risk of ICU–hospital-acquired pneumonia. Ventilator-associated pneumonia and ICU–hospital-acquired pneumonia occurred in 1,161 at-risk patients (15%) and 176 at-risk patients (2%), respectively. When adjusted on prognostic variables, ventilator-associated pneumonia (hazard ratio, 1.38 (1.24–1.52); p < 0.0001) and even more ICU–hospital-acquired pneumonia (hazard ratio, 1.82 [1.35–2.45]; p < 0.0001) were associated with increased 30-day mortality. The early antibiotic therapy adequacy was not associated with an improved prognosis, particularly for ICU–hospital-acquired pneumonia. The impact was similar for ventilator-associated pneumonia and ICU–hospital-acquired pneumonia mortality due to P. aeruginosa and the ESKAPE group. Conclusions: In a large cohort of patients, we found that both ICU–hospital-acquired pneumonia and ventilator-associated pneumonia were associated with an 82% and a 38% increase in the risk of 30-day mortality, respectively. This study emphasized the importance of preventing ICU–hospital-acquired pneumonia in nonventilated patients. The members of the OUTCOMEREA Network are listed in the supplementary appendix (Supplemental Digital Content 6, http://links.lww.com/CCM/E185). 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). The OUTCOMEREA research network entirely funded the study. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: timsit@bch.aphp.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Elie Azoulay

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1519-1526, December 15, 2018. …

Hsu C, Chang I, Hsieh P, et al.

AbstractKlebsiella pneumoniae is an important human pathogen causing hospital-acquired and community-acquired infections. Systemic K. pneumoniae infections may be preceded by gastrointestinal colonization, but the basis of this bacterium’s interaction with the intestinal epithelium remains unclear. Here, we report that the K. pneumoniae Sap (sensitivity to antimicrobial peptides) transporter contributes to bacterial–host cell interactions and in vivo virulence. Gene deletion showed that sapA is required for the adherence of a K. pneumoniae blood isolate to intestinal epithelial, lung epithelial, urinary bladder epithelial, and liver cells. The ΔsapA mutant was deficient for translocation across intestinal epithelial monolayers, macrophage interactions, and induction of proinflammatory cytokines. In a mouse gastrointestinal infection model, ΔsapA yielded significantly decreased bacterial loads in liver, spleen and intestine, reduced liver abscess generation, and decreased mortality. These findings offer new insights into the pathogenic interaction of K. pneumoniae with the host gastrointestinal tract to cause systemic infection.

Chan, W.-Y., Entwisle, C., Ercoli, G., Ramos-Sevillano, E., McIlgorm, A., Cecchini, P., Bailey, C., Lam, O., Whiting, G., Green, N., Goldblatt, D., Wheeler, J. X., Brown, J. S.

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes, and has led to non-vaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp, thought to be immune adjuvants). Proteomics and immunoblots demonstrated that compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognised protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including non-pneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonised after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, whilst passive transfer of rabbit serum from MAV vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat-shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.…

Jingtao Cui, Wenjuan Yan, Hongjie Xie, Shaoxia Xu, Qiaofeng Wang, Weihong Zhang, Anping Ni

by Jingtao Cui, Wenjuan Yan, Hongjie Xie, Shaoxia Xu, Qiaofeng Wang, Weihong Zhang, Anping Ni Background Chlamydia pneumoniae (C. pneumoniae) is an obligate intracellular bacterium and a human pathogen that causes respiratory infectious diseases. More than 50% of the adult population worldwide was once infected with C. pneumoniae, but investigations into this topic are insufficient in mainland China. Methods Anti-C. pneumoniae IgG and IgM antibodies were detected using micro-immunofluorescence test in serum samples of patients visiting Peking Union Medical College Hospital between 2008 and 2017 for routine medical purposes, and the aim of this retrospective study was to analyze the test results. Results Among 12,050 serum specimens tested for anti-C. pneumoniae IgG and IgM antibodies, the overall prevalence of anti-C. pneumoniae IgG antibodies was 86.6%, 87.2% for men and 86.0% for women. Adult men (>20 years) were found to have a significantly higher prevalence of anti-C. pneumoniae IgG than women (χ2 = 30.32, P = 0.000). 3 to 5 years old patients were observed to have the lowest prevalence of anti-C. pneumoniae IgG, 42.8%, then increased with age, reaching the highest level of 98.6% in patients over 70 years of age. In the 10,434 specimens with C. pneumoniae IgG antibodies, the total geometric mean titer (GMT) for C. pneumoniae IgG was 45.71. Although GMTs were found to be significantly higher among all men than among all women (t = 5.916, P = 0.000), sex difference actually began in patients over 40 years of age and increased in the elderly. In the total 12,050 specimens, 1.2% had anti-C. pneumoniae IgM, 3.3% had anti-C. pneumoniae IgG with titers equal to or greater than 1:512; 0.39% had ≥4-fold increasing titers of antibodies in acute and convalescent phase paired samples, and 4.4% were finally confirmed to have acute antibodies against C. pneumoniae. 6 to 10 years old patients were found to have the highest rate of both IgM antibodies (3.9%) and acute antibodies (6.2%) against C. pneumoniae. Acute antibodies against C. pneumoniae were found to be more frequent in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD, 14.0%, χ2 = 20.43, P = 0.000), patients with pneumonia (7.8%, χ2 = 51.87, P = 0.000) and patients with acute respiratory tract infection (12.3%, χ2 = 60.91, P = 0.000) than among all patients (4.4%). Both anti-C. pneumoniae IgG and IgM antibodies should be tested for acute antibodies against C. pneumoniae as testing for either alone will underestimate by a maximum of two-thirds the incidence of acute antibodies against C. pneumoniae. Conclusions More than 86% of Chinese patients on an average were once infected with C. pneumoniae. Adult men had both a higher prevalence and higher levels of antibodies than women. 6 to10 year old patients were found to have the most frequent acute infection of C. pneumoniae. C. pneumoniae is associated with AECOPD, pneumonia and acute respiratory tract infection. Anti-C. pneumoniae IgG and IgM should be tested simultaneously to avoid underestimation of acute antibodies against C. pneumoniae.…

Abstract Background Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described. Methods A systematic literature review and meta-analysis was performed to examine this relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections. Results Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting [C& SR]), there was an increased risk of mortality (odds ratio [OR], 1.60 [95% CI, 1.25–2.50]). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 [95% CI, 1.27–2.44]). Conclusions Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli.…

Juttukonda, L. J., Green, E. R., Lonergan, Z. R., Heffern, M. C., Chang, C. J., Skaar, E. P.

Acinetobacter baumannii is a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms, A. baumannii isolates are commonly multi-drug resistant and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistant A. baumannii as a ‘critical priority’ for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover mechanisms used by A. baumannii to survive stresses encountered during infection in order to identify new drug targets. In this study, we identified hydrogen peroxide (H2O2) as a stressor produced in the lung during A. baumannii infection using in vivo imaging and defined OxyR as a transcriptional regulator of the H2O2 stress response. Upon exposure to H2O2, A. baumannii differentially transcribes several hundred genes. However, transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in A. baumannii genetically inactivated for the transcriptional regulator oxyR. Moreover, inactivation of oxyR in both antimicrobial-susceptible and multi-drug-resistant A. baumannii strains impairs growth in the presence of H2O2. OxyR is a direct regulator of katE and ahpF1, which encode the major H2O2-degrading enzymes in A. baumannii, as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, an oxyR mutant is less fit than wild-type A. baumannii during infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive H2O2 stress encountered during infection.…

Norihiko Inoue, Kiyohide Fushimi

Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic

by Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic After three national point prevalence studies (PPS) of healthcare associated infections (HAI) conducted in Serbian acute care hospitals using US (CDC/NHSN) surveillance definitions, Serbia is about to switch to European (ECDC) criteria for the purpose of the fourth HAI PPS. The aim of this study was to compare the US and the European HAI definitions in Serbian trauma intensive care unit (ICU). Prospective surveillance was performed at two surgical-trauma ICUs of the Emergency department of Clinical Center of Serbia. HAIs were prospectively diagnosed by experienced clinician and epidemiologists using both types of HAI definitions simultaneously. The level of agreement between two case definitions was assessed by Cohen’s kappa statistic (k). Of 406 patients, 107 (26.3%) acquired at least one HAI (total of 107 according to US definitions and 141 according to European criteria). For microbiologically confirmed pneumonia agreement was k = 0.99 (95% CI, 0.96–1.00) and for clinically defined k = 0.86 (95% CI, 0.58–1.00). Agreement for bloodstream infections (BSI) was 0.79 (CI 95%, 0.70–0.89). When secondary BSI was excluded from the European classification, (30.9% of all BSI), concordance was k = 1.00 and when microbiologically confirmed catheter related BSI were reported separately as recommended by latest ECDC protocol update, (20.0% of all BSI), concordance was 0.60 (CI 95%, 0.41–0.80). No agreement was found between CLABSI and CRI while slight agreement was found when compared CLABSI and CRI3 (k = 0.11; 95%CI, 0.0–0.22). Agreement for overall UTI was moderate (k = 0.66; 95%CI, 0.53–0.79) while for microbiologically-confirmed symptomatic UTI was perfect (k = 1.00). For CAUTI good agreement was observed (k = 0.77; 95%CI, 0.34–1.0). Microbiological confirmation of PN and UTI should be stimulated and comparison of BSI should be done with emphasis on whether secondary BSI is included.

Dong, N., Liu, L., Zhang, R., Chen, K., Xie, M., Chan, E. W. C., Chen, S.

Completed sequences of three plasmids from a carbapenem-resistant, hypervirulent Klebsiella pneumoniae isolate, SH9, were obtained. In addition to the a pLVPK-like virulence-conferring plasmid (pVir-CR-HvKP_SH9), the two MDR plasmids (pKPC-CR-HvKP4_SH9 and pCTX-M-CR-HvKP4_SH9) were predicted to originate from a single pKPC-CR-HvKP4-like multi-replicon plasmid through homologous recombination. Interestingly, blaKPC-2 gene was detectable in five tandem repeats exhibiting the format of a NTEKPC-Id-like transposon (IS26-Tn3-ISKpn8-blaKPC-2-ISKpn6-korC-orf-IS26). The data suggested the important role of DNA recombination on mediating active plasmid evolution.…

Meyer Sauteur, P. M., de Bruijn, A. C. J. M., Graca, C., Tio-Gillen, A. P., Estevao, S. C., Hoogenboezem, T., Hendriks, R. W., Berger, C., Jacobs, B. C., van Rossum, A. M. C., Huizinga, R., Unger, W. W. J.

Antibody responses to Mycoplasma pneumoniae (Mp) correlate with pulmonary Mp clearance. However, Mp-specific IgG antibodies can cross-react with the myelin glycolipid galactocerebroside (GalC) and cause neurologic disorders. We assessed whether anti-glycolipid antibody formation is part of the physiological immune response to Mp. We show that antibodies against Mp-proteins and –glycolipids arise in serum of Mp-infected children and mice. Although antibodies to Mp-glycolipids were mainly IgG, anti-GalC antibodies were only of IgM. B-1a cells, shown to aid in protection against pathogen-derived glycolipids, are lacking in Bruton tyrosine kinase (Btk)-deficient mice. Mp-infected Btk-deficient mice developed Mp-specific IgG responses to Mp-proteins but not to Mp-glycolipids, including GalC. The equal recovery from Mp infection in Btk-deficient as wild-type mice suggests that pulmonary Mp clearance is predominantly mediated by IgG reactive with Mp-proteins and that Mp-glycolipid-specific IgG or IgM is not essential. These data will guide development of Mp-targeting vaccines avoiding induction of neurotoxic antibodies.…

Helio S. Sader, Robert K. Flamm, Jennifer M. Streit, Cecilia G. Carvalhaes, Rodrigo E. Mendes

Abstract Background The aim was to evaluate the value of organ-specific weighted incidence antibiogram (OSWIA) percentages for bacterial susceptibilities of Gram-negative bacteria (GNB) collected from intra-abdominal infections (IAIs) during SMART 2010–2014. Methods We retrospectively calculated the OSWIA percentages that would have been adequately covered by 12 common antimicrobials based on the bacterial compositions found in the appendix, peritoneum, colon, liver, gall bladder and pancreas. Results The ESBL positive rates were 65.7% for Escherichia coli, 36.2% for Klebsiella pneumoniae, 42.9% for Proteus mirabilis and 33.1% for Klebsiella oxytoca. Escherichia coli were mainly found in the appendix (76.8%), but less so in the liver (32.4%). Klebsiella pneumoniae constituted 45.2% of the total liver pathogenic bacteria and 15.2–20.8% were found in 4 other organs, except the colon and appendix (

Tamma, P. D., Fan, Y., Bergman, Y., Pertea, G., Kazmi, A., Lewis, S., Carroll, K. C., Schatz, M. C., Timp, W., Simner, P. J.

Objective: Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. We sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole genome sequencing in predicting AST results.Methods: Using a cohort of 40 clinical isolates (21 carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae, 10 non-carbapenemase-producing carbapenem resistant K. pneumoniae, and 9 carbapenem-susceptible K. pneumoniae), three separate sequencing and analysis pipelines were performed: (1) a real-time Nanopore analysis approach identifying acquired AMR genes, (2) an assembly-based Nanopore approach identifying acquired AMR genes and chromosomal mutations, and (3) an approach using short read correction of Nanopore assemblies. The short read correction of Nanopore assemblies served as the reference standard to determine the accuracy of Nanopore sequencing results.Results: With the real-time analysis approach, full annotation of acquired AMR genes occurred within 8 hours of subcultured isolates. Assemblies sufficient for full resistance gene and single nucleotide polymorphism annotation were available within 14 hours from subcultured isolates. The overall agreement of genotypic results and anticipated AST results for the 40 K. pneumoniae isolates was 77% (range 30-100%) and 92% (range 80-100%) for the real-time approach and the assembly approach, respectively. Evaluating the patients contributing the 40 isolates, the real-time approach and assembly approach could shorten the median time to effective antibiotic therapy by 20 hours and 26 hours, respectively, compared to standard AST.Conclusions: Nanopore sequencing offers a rapid approach to both accurately identify resistance mechanisms as well as predict AST results for K. pneumoniae isolates. Bioinformatics improvements enabling real-time alignment coupled with rapid extraction and library preparation will further enhance the accuracy and workflow of the Nanopore real-time approach.…

Viriyakosol, S., Kapoor, M., Okamoto, S., Covel, J., Soltow, Q. A., Trzoss, M., Shaw, K. J., Fierer, J.

Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis, and C. posadasii that are endemic in the southwestern US and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extra-pulmonary sites of infection are very difficult to treat and often require life-long azole therapy. APX001A is the first in a new class of broad spectrum antifungal agents which inhibit Gwt1, an enzyme which is required for localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once-daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, two hours after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001 and APX2097-treated mice survived significantly longer than control and fluconazole treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.…

Hu, Y., Liu, Y., Coates, A.

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae is prevalent and extremely difficult to treat. Reusing existing drugs and rejuvenating the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here we investigated in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae including extended-spectrum beta-lactamase (ESBL), New Delhi metallo-beta-lactamase 1 (NDM) or the mobilized colistin resistance (mcr-1) producing strains. Minimum inhibitory concentration was determined using the broth microdilution method. The combinatory effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. Fractional inhibitory concentration index from checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae, respectively, 100% of NDM-1-producing strains and 92% of mcr-1 producing E. coli. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In the murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. AZT and colistin combination poses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.…

Lee J. Quinton

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 10, Page 1246-1248, November 15, 2018. …

E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld

by E. Vonesh, K. L. Gooch, V. Khangulov, C. R. Schermer, K. M. Johnston, S. M. Szabo, J. S. Rumsfeld For managing overactive bladder (OAB), mirabegron, a β3 adrenergic receptor agonist, is typically used as second-line pharmacotherapy after antimuscarinics. Therefore, patients initiating treatment with mirabegron and antimuscarinics may differ, potentially impacting associated clinical outcomes. When using observational data to evaluate real-world safety and effectiveness of OAB treatments, residual bias due to unmeasured confounding and/or confounding by indication are important considerations. Falsification analysis, in which clinically irrelevant endpoints are tested as a reference, can be used to assess residual bias. The objective in this study was to compare baseline cardiovascular risk among OAB patients by treatment, and assess the presence of residual bias via falsification analysis of OAB patients treated with mirabegron or antimuscarinics, to determine whether clinically relevant comparisons across groups would be feasible. Linked electronic health record and claims data (Optum/Humedica) for OAB patients in the United States from 2011–2015 were available, with index defined as first date of OAB treatment during this period. Unadjusted characteristics were compared across groups at index and propensity-matching conducted. Falsification endpoints (hepatitis C, shingles, community-acquired pneumonia) were compared between groups using odds ratios (ORs) and 95% confidence intervals (CI). The study identified 10,311 antimuscarinic- and 408 mirabegron-treated patients. Mirabegron patients were predominantly older males, with more comorbidities. The analytic sample included 1,188 antimuscarinic patients propensity-matched to 396 mirabegron patients; after matching, no significant baseline differences remained. Estimates of falsification ORs were 0.7 (CI:0.3–1.7) for shingles, 1.5 (CI:0.3–8.2) for hepatitis C, 0.8 (CI:0.4–1.8) and 0.9 (CI:0.6–1.4) for pneumonia. While propensity matching successfully balanced observed covariates, wide CIs prevented definitive conclusions regarding residual bias. Accordingly, further observational comparisons by treatment group were not pursued. In real-world analysis, bias-detection methods could not confirm that differences in cardiovascular risk in patients receiving mirabegron versus antimuscarinics were fully adjusted for, precluding clinically relevant comparisons across treatment groups.

Abstract Background Adenoviruses (AdV) are non-enveloped, double-stranded DNA viruses with multiple serotypes, which cause a variety of end-organ disease in both immunocompetent and immunocompromised individuals. Some adenoviruses can become latent in the mucosa-associated lymphoid tissue (e.g. adenoids and tonsils), with the potential to reactivate sporadically, leading to upper or lower respiratory tract infection and disease. Bronchiolitis Obliterans (BO) is a rare chronic lung disorder which usually follows a severe insult to the respiratory tract. In children, it is a complication of severe infections (as post-infectious BO), typically manifesting after a severe respiratory infection, in previously healthy pre-school children. Symptoms and signs of air trapping (hyperinflated chest, expiratory wheeze) with persistent oxygen requirement are characteristic. The presence of the unusual mosaic tetrasomy 9p genotype in this case, despite standard cidofovir therapy for persistent or chronic adenovirus infection, may have impacted on the child’s long-term clinical outcomes. Case presentation We present a case of persistent AdV B3 infection in a 14-month old boy with mosaic tetrasomy 9p, which persisted for 10 weeks, resulting in radiologically-confirmed BO, requiring cidofovir to control the persistent AdV B3 infection and standard therapy with pulsed steroids. We argue that in the presence of the mosaic tetrasomy 9p, earlier antiviral therapy may have decreased the severity of BO, as this mutation is known to be associated with some degree of immune dysregulation. Conclusions Adenovirus infections are common in children and may persist as latent infections, with subsequent reactivations during loss of immune control, related to systemic illness arising from other causes. In chronic, reactivated AdV infection with pneumonia, BO is a recognised complication. However, in this case, with the presence of the mosaic tetrasomy 9p mutation, earlier antiviral therapy may have reduced such longer term complications, due to the immune dysregulatory nature of this mutation.…

Pfaller, M. A., Flamm, R. K., Mendes, R. E., Streit, J. M., Smart, J. I., Hamed, K. A., Duncan, L. R., Sader, H. S.

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that is approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates from hospitalized patients in the United States in 2016 that caused serious infections including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates that were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an ESBL phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). Against Haemophilus influenzae and Moraxella catarrhalis, 99.6% of all isolates were inhibited at ≤1 mg/L of ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among the Enterobacteriaceae, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activity against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive and Gram-negative pathogens that cause serious infections.…

Johannes G. Liese, Christoph Schoen, Mark van der Linden, Lisa Lehmann, David Goettler, Sabrina Keller, Anna Maier, Florian Segerer, Markus A. Rose, Andrea Streng

Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community- acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunisation for infants.

Wuerth, K., Lee, A. H. Y., Falsafi, R., Gill, E. E., Hancock, R. E. W.

Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multi-drug resistance are becoming more prevalent. Here we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo. IDR-1002 significantly reduced the bacterial burden in the bronchoalveolar lavage fluid (BALF) as well as MCP-1 in the BALF and serum, KC in the serum, and IL-6 in the BALF. RNA-Seq was conducted on lungs and whole blood and the effects of P. aeruginosa, IDR-1002, or the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results show that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.…

Abstract Background Bacterial co-infection of patients suffering from influenza pneumonia is a key element that increases morbidity and mortality. The occurrence of Acinetobacter baumannii co-infection in patients with avian influenza A (H7N9) virus infection has been described as one of the most prevalent bacterial co-infections. However, the clinical and laboratory features of this entity of H7N9 and A. baumannii co-infection have not been systematically investigated. Methods We collected clinical and laboratory data from laboratory-confirmed H7N9 cases co-infected by A. baumannii. H7N9 patients without bacterial co-infection and patients with A. baumannii-related pneumonia in the same hospital during the same period were recruited as controls. The antibiotic resistance features and the corresponding genome determinants of A. baumannii and the immune responses of the patients were tested through the respiratory and peripheral blood specimens. Results Invasive mechanical ventilation was the most significant risk factor for the nosocomial A. baumannii co-infection in H7N9 patients. The co-infection resulted in severe clinical manifestation which was associated with the dysregulation of immune responses including deranged T-cell counts, antigen-specific T-cell responses and plasma cytokines. The emergence of genome variations of extensively drug-resistant A. baumannii associated with acquired polymyxin resistance contributed to the fatal outcome of a co-infected patient. Conclusions The co-infection of H7N9 patients by extensively drug-resistant A. baumannii with H7N9 infection is an important issue which deserves attention. The dysfunctions of immune responses were associated with the co-infection and were correlated with the disease severity. These data provide useful reference for the diagnosis and treatment of H7N9 infection.…

Falcone, M., Russo, A., Shindo, Y., Farcomeni, A., Pieralli, F., Cangemi, R., Liu, J., Xia, J., Okumura, J., Sano, M., Jones, C., Vannucchi, V., Mancone, M., Micek, S., Xu, F., Violi, F., Kollef, M.

Objectives. While the inflammatory response to severe pneumonia is paramount in reining in and resolving the infection, the excessive inflammation can lead to deleterious effects. We theorized that patients with severe community-acquired pneumonia (CAP), treated with macrolides and aspirin, would receive benefit beyond conventional antibiotic therapy.Methods. An observational study was conducted on patients with severe CAP. All patients were admitted to 5 teaching hospitals (in Italy, USA, Japan, and China), and data were gathered from their electronic medical records. Severe pneumonia was defined according to ATS/IDSA criteria. Patients were divided in 4 groups: 1) Aspirin only (ASG), 2) Macrolides only (MG), 3) combination Aspirin + Macrolides (ASMG), or 4) neither (NASMG). Survival among the 4 groups was evaluated after adjustment for confounders, and after weighting by propensity score.Results. A total of 1295 patients were included in the analysis. There were 237 (18.3%) patients in the ASG, 294 (22.7%) in the MG, 148 (11.4%) in the ASMG, and 616 (47.6%) in the NASMG. Mortality at 30 days was 15.5% in the ASMG, compared to 28.2% of the NASMG, 23.8% of the MG, and 21.1% of the ASG. After propensity score analysis, receipt of aspirin plus macrolide (Hazard Ratio 0.71, 95% Confidence Interval 0.58-0.88, p=0.002) was associated with higher 30-day survival.Conclusions. This is a hypothesis generating a study in which data suggest that combination of aspirin plus a macrolide improves 30-day survival of patients with severe CAP. Further randomized studies will need to be undertaken to confirm this phenomenon.…

Kazuki Hatayama, Nobuyuki Nosaka, Mutsuko Yamada, Masato Yashiro, Yosuke Fujii, Hirokazu Tsukahara, Keyue Liu, Masahiro Nishibori, Akihiro Matsukawa, Tsuneo Morishima

Abstract Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury (ALI) due to excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti‐inflammatory effect of anti‐high‐mobility group box‐1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti‐HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine‐week‐old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post‐infection (dpi). The anti‐HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti‐HMGB1 mAb significantly improved survival rate whereas the anti‐HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti‐HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti‐HMGB1 with conventional anti‐influenza therapy might be useful against severe influenza virus infection. This article is protected by copyright. All rights reserved.

Rania Abu Seir, Kifaya Azmi, Ayob Hamdan, Hanan Namouz, Fuad Jaar, Hanaa Jaber, Carmit Rubin, Dafna Doron, Galia Rahav, Ziad Abdeen, Gili Regev-Yochay

by Rania Abu Seir, Kifaya Azmi, Ayob Hamdan, Hanan Namouz, Fuad Jaar, Hanaa Jaber, Carmit Rubin, Dafna Doron, Galia Rahav, Ziad Abdeen, Gili Regev-Yochay Background Pneumococcal conjugate vaccines (PCVs), PCV10 and PCV13, are currently used in different countries. We have previously reported the effectiveness of PCV7, following its introduction in Israel and before PCVs were introduced in Palestine. Here, we extended the study and compared the initial impact of PCV10 to that of PCV7/13. Methods Four cross-sectional surveys of S. pneumoniae carriage among children…

Girlich, D., Naas, T., Dortet, L.

The dissemination of carbapenemase-producing Enterobacteriaceae (CPE), has led to the increased use of colistin, which resulted in the emergence of colistin-resistant Enterobacteriaceae worldwide. One of the most threatening scenarios is the dissemination of colistin-resistance in CPE, particularly the plasmid-encoded resistance MCR. Thus, it becomes now mandatory to possess reliable media to screen for colistin-resistant Gram-negative isolates, especially Enterobacteriaceae. In this study we evaluated the performances of the Superpolymyxin™medium (ELITechGroup) and the CHROMID® Colistin R (bioMérieux) to screen for colistin-resistant Enterobacteriaceae from spiked rectal swabs. Stools were spiked with a total of 94 enterobacterial isolates (Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Enterobacter cloacae), including 53 colistin-resistant isolates. ESwabs™(Copan Diagnostics) were then inoculated with those spiked fecal suspensions and proceed as recommended by both manufacturers. The sensitivity of detection colistin-resistant Enterobacteriaceae were of 86.8% [95% confidence interval (CI95) 74.0 – 94.0] using both the Superpolymyxin™medium and the CHROMID® Colistin R plates. Surprisingly, the isolates that were not detected were not the same for both media. The specificities were high for both media, at 97.9% [CI95 = 87.3% - 99.9%] for Superpolymyxin™medium and 100% [CI95 = 90.4% - 100%] for the CHROMID® Colistin R medium. Both commercially-available media, CHROMID® Colistin R and Superpolymyxin™, provide a useful tool to screen for colistin-resistant Enterobacteriaceae from patient samples (rectal swabs) regardless of the level and mechanism of colistin resistance.…

Abstract Background Uganda has sought to address leading causes of childhood mortality: malaria, pneumonia and diarrhoea, through integrated community case management (iCCM). The success of this approach relies on community health worker (CHW) assessment and referral of sick children to a nearby health centre. This study aimed to determine rates of referral completion in an iCCM programme in rural Uganda. Methods This was a prospective observational study of referrals made by CHWs in 8 villages in rural western Uganda. All patient referrals by CHWs were tracked and health centre registers were reviewed for documentation of completed referrals. Caregivers of referred patients were invited to complete a survey 2–3 weeks after the referral with questions on the CHW visit, referral completion, and the patient’s clinical condition. Results Among 143 total referrals, 136 (94%) caregivers completed the follow-up survey. Reasons for visiting the CHW were fever/malaria in 111 (82%) cases, cough in 61 (45%) cases, and fast/difficult breathing in 25 (18%) cases. Overall, 121 (89%) caregivers reported taking the referred child for further medical evaluation, of whom 102 (75% overall) were taken to the local public health centre. Ninety per cent of reported referral visits were confirmed in health centre documentation. For the 34 caregivers who did not complete referral at the local health centre, the most common reasons were improvement in child’s health, lack of time, ease of going elsewhere, and needing to care for other children. Referrals were slightly more likely to be completed on weekdays versus weekends (p = 0.0377); referral completion was otherwise not associated with child’s age or gender, caregiver age, or caregiver relationship to child. One village had a lower rate of referral completion than the others. Improvement in the child’s health was not associated with completed referral or timing of the referral visit. Conclusions A high percentage of children referred to the health centre through iCCM in rural Uganda completed the referral. Barriers to referral completion included improvement in the child’s health, time and distance. Interestingly, referral completion at the health centre was not associated with improvement in the child’s health. Barriers to referral completion and clinical management at all stages of referral linkages warrant further study.…

Andreia N. Horácio, Catarina Silva-Costa, Elísia Lopes, Mário Ramirez, José Melo-Cristino, on behalf of the Portuguese Group for the Study of Streptococcal Infections

by Andreia N. Horácio, Catarina Silva-Costa, Elísia Lopes, Mário Ramirez, José Melo-Cristino, on behalf of the Portuguese Group for the Study of Streptococcal Infections Non-invasive pneumococcal pneumonia (NIPP) is a frequent cause of morbidity and mortality worldwide. The 13-valent pneumococcal conjugate vaccine (PCV13) was included in the national immunization program of children living in Portugal in 2015. Until then, PCV7 (since late 2001) and PCV13 (since early 2010) were given through the private market. We determined the serotype distribution and antimicrobial susceptibility of isolates causing adult NIPP in 2012–2015 and compared the results with previously published data (2007–2011). There were 50 serotypes among the 1435 isolates. The most common were serotypes: 3 (14%), 11A (8%), 19F (6%), 23A (5%), 6C (5%), 19A (4%), 23B (4%), 9N (4%) and non-typable isolates (4%). When considering data since the availability of PCV13 for children in the private market, the proportion of PCV13 serotypes declined from 44.0% in 2010 to 29.7% in 2015 (p < 0.001), mainly due to early decreases in the proportions of serotypes 3 and 19A. In contrast, during the same period, PCV7 serotypes (11.9% in 2012–2015) and the serotypes exclusive of the 23-valent polysaccharide vaccine (26.0% in 2012–2015), remained relatively stable, while non-vaccine types increased from 27.0% in 2010 to 41.9% in 2015 (p

Ines Brini, Naila Hannachi, Aida Guerrero, Dorothea Orth‐Höller, Sana Bhiri, Britta Schiela, Dorothee Holm‐von Laer, Jalel Boukadida, Heribert Stoiber

Abstract Background This study aimed to characterize the epidemiology of pathogenic respiratory agents in patients aged 0‐12 months and hospitalized for acute respiratory infections in Tunisia between 2013 and 2014. Methods A total of 20 pathogens including viruses, Mycoplasma pneumoniae, and Streptococcus pneumoniae, were detected using molecular sensitive assays and their associations with patient’s demographic data and season were analyzed. Results Viral infectious agents were found in 449 (87.2%) of 515 specimens. Dual and multiple infectious agents were detected in 31.4% and 18.6% of samples, respectively. Viral infection was predominant in the pediatric environment (90.8%, p

Kunze-Szikszay, Nils; Walliser, Karoline; Luther, Jakob; Cambiaghi, Barbara; Reupke, Verena; Dullin, Christian; Vautz, Wolfgang; Bremmer, Felix; Telgheder, Ursula; Zscheppank, Cornelia; Quintel, Michael; Perl, Thorsten

Objectives: The detection of microbial volatile organic compounds or host response markers in the exhaled gas could give an earlier diagnosis of ventilator-associated pneumonia. Gas chromatography-ion mobility spectrometry enables noninvasive, rapid, and sensitive analysis of exhaled gas. Using a rabbit model of ventilator-associated pneumonia we determined if gas chromatography-ion mobility spectrometry is able to detect 1) ventilator-associated pneumonia specific changes and 2) bacterial species-specific changes in the exhaled gas. Design: Experimental in vivo study. Setting: University research laboratory. Subjects: Female New Zealand White rabbits. Interventions: Animals were anesthetized and mechanically ventilated. To induce changes in the composition of exhaled gas we induced ventilator-associated pneumonia via endobronchial instillation of either Escherichia coli group (n = 11) or Pseudomonas aeruginosa group (n = 11) after 2 hours of mechanical ventilation. In a control group (n = 11) we instilled sterile lysogeny broth endobronchially. Measurements and Main Results: Gas chromatography-ion mobility spectrometry gas analysis, CT scans of the lungs, and blood samples were obtained at four measurement points during the 10 hours of mechanical ventilation. The volatile organic compound patterns in the exhaled gas were compared and correlated with ventilator-associated pneumonia severity. Sixty-seven peak areas showed changes in signal intensity in the serial gas analyses. The signal intensity changes in 10 peak regions differed between the groups. Five peak areas (P_648_36, indole, P_714_278, P_700_549, and P_727_557) showed statistically significant changes of signal intensity. Conclusions: This is the first in vivo study that shows the potential of gas chromatography-ion mobility spectrometry for early detection of ventilator-associated pneumonia specific volatile organic compounds and species differentiation by noninvasive analyses of exhaled gas. 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 a young investigators grant provided by the Medical Faculty of the Georg-August-University Göttingen. Dr. Kunze-Szikszay’s institution received funding from Medical Faculty of the Georg-August-University Göttingen, and he received support for article research from Medical Faculty of the Georg-August-University Göttingen. Dr. Perl received funding from Humedics, The37°Company, and MSD Sharp and Dohme GmbH (Haar, Germany). The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at the University Medical Centre of Göttingen, Göttingen, Germany. For information regarding this article, E-mail: nkunze@gwdg.de Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pecora, N., Zhao, X., Nudel, K., Hoffmann, M., Li, N., Onderdonk, A. B., Yokoe, D., Brown, E., Allard, M., Bry, L.

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM carrying strains of E. coli and E. cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3114-bp region containing the blaNDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed broad capacity for blaNDM transmission by conjugation, transposition, and complex inter-plasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naïve strains to acquire multi- and extensively-drug resistance profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization, to inform clinical decisions to prevent further spread.…

Joon Young Song, Ji Yun Noh, Jin Soo Lee, Seong-Heon Wie, Young Keun Kim, Jacob Lee, Hye Won Jeong, Shin Woo Kim, Sun Hee Lee, Kyung-Hwa Park, Won Suk Choi, Hee Jin Cheong, Woo Joo Kim

by Joon Young Song, Ji Yun Noh, Jin Soo Lee, Seong-Heon Wie, Young Keun Kim, Jacob Lee, Hye Won Jeong, Shin Woo Kim, Sun Hee Lee, Kyung-Hwa Park, Won Suk Choi, Hee Jin Cheong, Woo Joo Kim Background Influenza and pneumonia are leading causes of morbidity and mortality among the elderly. Although vaccination is a main strategy to prevent these infectious diseases, concerns remain with respect to vaccine effectiveness. Methods During three influenza seasons (2014–2015, 2015–2016 and 2016–2017), we evaluated the effectiveness of the influenza and pneumococcal vaccines against pneumonia and acute exacerbation of cardiopulmonary diseases among the elderly aged ≥65 years with influenza-like illness (ILI). Demographic and clinical data were collected prospectively. Results Among 2,119 enrolled cases, 1,302 (61.4%) and 871 (41.1%) received the influenza vaccine and 23-valent pneumococcal polysaccharide vaccine (PPV23), respectively. During an A/H3N2-dominant season with poor influenza vaccine effectiveness (2014–2015 season), neither the influenza vaccine nor PPV23 showed significant effectiveness against pneumonia or acute exacerbation of cardiopulmonary diseases. During seasons with good influenza vaccine effectiveness (2015–2016 and 2016–2017 seasons), the influenza vaccine was effective in preventing pneumonia, but PPV23 was not. In particular, the influenza vaccine was effective in preventing acute exacerbation of heart diseases (75.0%) during the A/H1N1-dominant 2015–2016 season. Conclusion The influenza vaccine was effective in preventing pneumonia only during vaccine-matched seasons with good effectiveness against circulating influenza viruses. In addition, the influenza vaccine was cardio-protective during a vaccine-matched A/H1N1-dominant season.…

Abstract Background Environmental disinfection with continuously antimicrobial surfaces could offer superior control of surface bioburden. We sought to decide the efficacy of photocatalyst antimicrobial coating in reducing methicillin-resistant Staphylococcus aureus (MRSA) acquisition in high incidence setting. Methods We performed prospective cohort study involving patients hospitalized in medical intensive care unit. A titanium dioxide-based photocatalyst was coated on high touch surfaces and walls. Five months of pre-intervention data were compared with five months of post-intervention data. The incidence rates of multidrug-resistant organism acquisition and the rates of hospital-acquired blood stream infection, pneumonia, urinary tract infection, and Clostridium difficile–associated diseases were compared using Cox proportional hazards regression analysis. Results In total, 621 patients were included. There was significant decrease in MRSA acquisition rate after photocatalyst coating (hazard ratio, 0.37; 95% confidence interval, 0.14–0.99; p = 0.04). However, clinical identification of vancomycin-resistant Enterococcus spp. and multidrug-resistant Acinetobacter baumannii did not decrease significantly. The hazard of contracting hospital-acquired pneumonia during the intervention period compared to baseline period was 0.46 (95% confidence interval, 0.23–0.94; p = 0.03). Conclusions In conclusion, MRSA rate was significantly reduced after photocatalyst coating. We provide evidence that photocatalyst disinfection can be an adjunctive measure to control MRSA acquisition in high-incidence settings. Trial registration ISRCTN Registry (ISRCTN31972004). Registered retrospectively on November 19, 2018.…

Spaulding A, Watson D, Dreyfus J, et al.

AbstractBackgroundBloodstream infections (BSIs) cause significant morbidity and mortality in children. Recent pediatric epidemiological data may inform prevention strategies and empiric antimicrobial therapy selection.MethodsWe conducted a retrospective cohort study from 2009–2016 utilizing demographic and microbiology data on inpatients

Abstract Background Despite the use of pneumococcal vaccines, indigenous populations are consistently disproportionately affected by invasive pneumococcal disease (IPD). With recent changes in Ontario’s provincial pneumococcal vaccination program, we sought to evaluate the epidemiology and burden of IPD in northwestern Ontario (NWO) Canada – a region that contains a substantial (19.2%) indigenous population. Methods We retrospectively reviewed all adult cases of IPD that were reported to the Thunder Bay District Health Unit, in Thunder Bay, Ontario, Canada, over a 10-year period (2006–2015). Patients admitted to the Thunder Bay Regional Health Sciences Centre with IPD had their charts reviewed to abstract clinical data. Statistical analysis, including incidence rates of IPD, was performed. Results Two hundred sixty-two cases of IPD occurred over the 10-year observation period and clinical data was available for 182 cases. Fifty-three of 182 (29.1%) patients were indigenous. 73 of 182 (40.1%) of patients were immunocompromised. Indigenous patients with IPD were more likely to be immunocompromised than non-indigenous patients (p 

Norosoa Harline Razanajatovo, Julia Guillebaud, Aina Harimanana, Soatiana Rajatonirina, Elisoa Hariniaina Ratsima, Zo Zafitsara Andrianirina, Hervé Rakotoariniaina, Todisoa Andriatahina, Arnaud Orelle, Rila Ratovoson, Judickaelle Irinantenaina, Dina Arinalina Rakotonanahary, Lovasoa Ramparany, Frédérique Randrianirina, Vincent Richard, Jean-Michel Heraud

by Norosoa Harline Razanajatovo, Julia Guillebaud, Aina Harimanana, Soatiana Rajatonirina, Elisoa Hariniaina Ratsima, Zo Zafitsara Andrianirina, Hervé Rakotoariniaina, Todisoa Andriatahina, Arnaud Orelle, Rila Ratovoson, Judickaelle Irinantenaina, Dina Arinalina Rakotonanahary, Lovasoa Ramparany, Frédérique Randrianirina, Vincent Richard, Jean-Michel Heraud Background Few comprehensive data exist regarding the epidemiology of severe acute respiratory infections (SARI) in low income countries. This study aimed at identifying etiologies and describing clinical features of SARI-associated hospitalization in Madagascar. Methods It is a prospective surveillance of SARI in 2 hospitals for 3 years. Nasopharyngeal swabs, sputum, and blood were collected from SARI patients enrolled and tested for viruses and bacteria. Epidemiological and clinical information were obtained from case report forms. Results Overall, 876 patients were enrolled in the study, of which 83.1% (728/876) were tested positive for at least one pathogen. Viral and bacterial infections occurred in 76.1% (667/876) and 35.8% (314/876) of tested samples, respectively. Among all detected viruses, respiratory syncytial virus (RSV) was the most common (37.7%; 348/924) followed by influenza virus A (FLUA, 18.4%; 170/924), rhinovirus (RV, 13.5%; 125/924), and adenovirus (ADV, 8.3%; 77/924). Among bacteria, Streptococcus pneumoniae (S. pneumoniae, 50.3%, 189/370) was the most detected followed by Haemophilus influenzae type b (Hib, 21.4%; 79/370), and Klebsiella (4.6%; 17/370). Other Streptococcus species were found in 8.1% (30/370) of samples. Compared to patients aged less than 5 years, older age groups were significantly less infected with RSV. On the other hand, patients aged more than 64 years (OR = 3.66) were at higher risk to be infected with FLUA, while those aged 15–29 years (OR = 3.22) and 30–64 years (OR = 2.39) were more likely to be infected with FLUB (influenza virus B). Conclusion The frequency of influenza viruses detected among SARI patients aged 65 years and more highlights the need for health authorities to develop strategies to reduce morbidity amongst at-risk population through vaccine recommendation. Amongst young children, the demonstrated burden of RSV should guide clinicians for a better case management of children. These findings reveal the need to develop point-of-care tests to avoid overuse of antibiotics and to promote vaccine that could reduce drastically the RSV hospitalizations.…

Socorro Lupisan, Akira Suzuki, Noel Macalalad, Rutchie Egos, Lydia Sombrero, Michiko Okamoto, Clyde Dapat, Melisa Mondoy, Hazel Galang, Vicente Francisco Froilan Zeta, Flora de la Pena, Vicente Romano, Remigio Olveda, Hitoshi Oshitani

K. Wagner, F. Imkamp, V.P. Pires, P.M. Keller

Rapid detection of macrolide resistance-associated mutations in Mycoplasma pneumoniae is crucial for effective antimicrobial treatment. In this study, we evaluated the Lightmix® Mycoplasma macrolide assay for the detection of point mutations at nucleotide position 2063 and 2064 in the 23S rRNA gene of M. pneumoniae that confer macrolide resistance.

Ana Paula Cassiolato, Samanta Cristine Grassi Almeida, Ana Lúcia Andrade, Ruth Minamisava, Maria Cristina de Cunto Brandileone

by Ana Paula Cassiolato, Samanta Cristine Grassi Almeida, Ana Lúcia Andrade, Ruth Minamisava, Maria Cristina de Cunto Brandileone Background In 2010, a ten–valent pneumococcal conjugate vaccine (PCV10) was introduced in the routine infant national immunization program in Brazil. Invasive pneumococcal disease (IPD) caused by serotype 19A (Spn19A) increased after the introduction of PCVs in several countries. We compared the frequency, antimicrobial resistance and molecular patterns of invasive Spn19A strains before and after PCV10 introduction in Brazil using data from the national laboratory-based surveillance. Methods We analyzed invasive Spn19A strains isolated from 2005–2009 (pre-PCV10 period), 2011–2015 and 2016–2017 (post-PCV10 periods). Antimicrobial susceptibility was performed for all Spn19A strains, and multilocus sequence typing (MLST) was performed for strains isolated in the age groups…

Eby J.

Hospital acquired pneumoniaVentilator associated pneumoniaClinical endpointClinical outcomePatient-reported outcomenon-inferiorityantimicrobial drug development…

Barton S, Murray R, Lillycrop K, et al.

AbstractBackgroundFucosyltransferase 2 (FUT2) controls the production of digestive and respiratory epithelia of histo-blood group antigens involved in the attachment of pathogens. The aim of our study was to relate FUT2 variants to reported gastrointestinal and respiratory illnesses in infancy.MethodsIn the Southampton Women’s Survey, FUT2 genetic variants (single-nucleotide polymorphisms [SNPs] rs601338 and rs602662) were genotyped in 1831 infants and related to infant illnesses, after adjustment for sex, breastfeeding duration, and potential confounders.ResultsFor FUT2 SNP rs601338, the risk ratios for ≥1 bout of diarrhea during ages 6–12 months and ages 12–24 months per additional risk (G) allele were 1.23 (95% confidence interval [CI], 1.08–1.4; P = .002) and 1.41 (95% CI, 1.24–1.61; P = 1.7 × 10−7), respectively; the risk ratio for ≥1 diagnosis of a lower respiratory illness (ie, pneumonia or bronchiolitis) during ages 12–24 months per additional G allele was 2.66 (95% CI, 1.64–4.3; P = .00007). Similar associations were found between rs602662 and gastrointestinal and respiratory illnesses, owing to the high linkage disequilibrium with rs601338 (R2 = 0.92). Longer breastfeeding duration predicted a lower risk of diarrhea, independent of infant FUT2 genotype.ConclusionsWe confirmed that FUT2 G alleles are associated with a higher risk of infant gastrointestinal illnesses and identified novel associations with respiratory illnesses. FUT2 locus variants need consideration in future studies of gastrointestinal and respiratory illnesses among infants.

Sakamoto, N., Akeda, Y., Sugawara, Y., Takeuchi, D., Motooka, D., Yamamoto, N., Laolerd, W., Santanirand, P., Hamada, S.

We report here the K. pneumoniae strains carrying chromosomal blaNDM-1 in Thailand. The genomes of these two isolates include a 160-kbp insertion containing blaNDM-1, which is almost identical to that in the IncHI1B-like plasmid. Further analysis indicated that IS5-mediated intermolecular transposition and Tn3-transposase-mediated homologous recombination resulted in the integration of blaNDM-1 into the chromosome from an IncHI1B-like plasmid. The spread of this type of carbapenem-resistant Enterobacteriaceae may threaten public health and warrants further monitoring.…

Paula Espinal, Elisabetta Nucleo, Mariasofia Caltagirone, Vittoria Mattioni Marchetti, Miriam R. Fernandes, Valeria Biscaro, Roberto Rigoli, Alessandra Carattoli, Roberta Migliavacca, Laura Villa

Genomic characterization of the internationally spread Sequence Type 16 carbapenem resistant Klebsiella pneumoniae…

Abstract Background There is no consensus on the most accurate combination of diagnostic criteria to define community acquired pneumonia (CAP). We describe inclusion criteria in randomized controlled trials (RCT) of CAP and assess their performance for the diagnosis of formally identified CAP. Methods RCTs related to CAP recorded on ClinicalTrials.gov were analysed. Due to high heterogeneity, we divided close CAP inclusion criteria into patterns (i.e. combinations of inclusion criteria). To assess their diagnostic performances, these CAP definition patterns were applied to a reference population of 319 suspected CAP patients, in whom the CAP diagnosis had been confirmed (n = 163) or excluded (n = 156) by an adjudication committee after a systematic thoracic CT-scan and a 28-day follow-up period. Results In the 47 RCTs included in the analysis, 42 different CAP inclusion criteria combinations were identified and 8 patterns created. This heterogeneity was not explained either by the trials’ methodology or by their objectives. When applied to the reference population, the performance ranges of the 8 definition patterns were 9.8–56.4% for sensitivities, 56.4 97.4% for specificities, 63.6 83.6% for positive predictive values and 50.8–66.7% for negative predictive values. None of the CAP definitions had both sensitivity and specificity superior to 65%. Depending on the CAP definition, the rate of included patients without CAP (“false positives”) ranged from 1 to 21%. Conclusions CAP diagnostic criteria within RCTs are heterogeneous, which may have far-reaching consequences on validity of RCT results.…