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.

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%.

Catherine Cordonnier, Sigrun Einarsdottir, Simone Cesaro, Roberta Di Blasi, Malgorzata Mikulska, Christina Rieger, Hugues de Lavallade, Giuseppe Gallo, Thomas Lehrnbecher, Dan Engelhard, Per Ljungman, European Conference on Infections in Leukaemia group

Infection is a main concern after haemopoietic stem cell transplantation (HSCT) and a major cause of transplant-related mortality. Some of these infections are preventable by vaccination. Most HSCT recipients lose their immunity to various pathogens as soon as the first months after transplant, irrespective of the pre-transplant donor or recipient vaccinations. Vaccination with inactivated vaccines is safe after transplantation and is an effective way to reinstate protection from various pathogens (eg, influenza virus and Streptococcus pneumoniae), especially for pathogens whose risk of infection is increased by the transplant procedure.

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.

Paul E Marik

Glucocorticoids have been used as adjunctive therapy in patients with sepsis and septic shock for more than four decades. The rationale for the use of glucocorticoids is that this class of drugs downregulates the proinflammatory response and limits the anti-inflammatory response while preserving innate immunity. Between 1976 and 2017, 22 randomised placebo-controlled trials have been published evaluating the benefit of glucocorticoids in patients with community-acquired pneumonia, sepsis, and septic shock.

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.…

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.

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.…

Abstract Background Pseudomonas aeruginosa is an unusual pathogen in community-acquired pneumonia, especially in previously healthy adults, but often indicates poor prognosis. Case presentation We report a previously healthy patient who developed severe community-acquired pneumonia (CAP) caused by P. aeruginosa. He deteriorated to septic shock and multiple organ dysfunction syndrome (MODS) quickly, complicated by secondary hematogenous central nervous system (CNS) infection. After 1 month of organ support and antipseudomonal therapy, he had significant symptomatic improvement and was discharged from hospital. During treatment, the pathogen developed resistance to carbapenems quickly and the antibiotic regimen was adjusted accordingly. Conclusions According to our case and related literature review, we conclude that more attention should be paid to community-acquired Pseudomonas aeruginosa pneumonia, because of its rapid progression and poor prognosis.…

Abstract Background Tumor necrosis factor-α (TNF-α) antagonists, most of which are monoclonal antibodies, became a widespread treatment for autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, psoriasis, psoriatic arthritis, hidradenitis suppurativa and uveitis. Their use is based on the blockage of TNF-α, which plays an important role in granulomas formation, development of phagosomes, activation and differentiation of macrophages, immune response against viral pathogens. The multiple adverse effects of TNF-α inhibition have been identified, including a two-to four-fold increased risk of active tuberculosis and other granulomatous conditions and an increased occurrence of some other serious bacterial, fungal and certain viral infections. Case presentation A 34-year-old male patient with disseminated varicella and pneumonitis was admitted to our hospital. The diagnosis of varicella was established serologically by enzyme immunoassay (EIA) and by polymerase chain reaction confirmation of the virus in vesicular fluid. The patient has been receiving adalimumab and methotrexate for the last 3 years due to ankylosing spondylitis and was seropositive to varicella zoster virus prior to the introduction of TNF-α antagonists. Acyclovir was administered for 10 days with the resolution of clinical illness and radiological signs of pneumonitis. Conclusion Due to the use of biological agents, particularly TNF-α inhibitors, as a well-established therapy for some autoimmune diseases, new potential adverse events can be expected in the future and we wanted to point out one of them. To our knowledge this is the first case of recurrent disseminated varicella in a patient taking TNF-α antagonists.…

Puzniak, L., DePestel, D. D., Srinivasan, A., Ye, G., Murray, J., Merchant, S., DeRyke, C. A., Gupta, V.

Background: Pseudomonas aeruginosa (PsA) is an important pathogen associated with significant morbidity and mortality. US guidelines for hospital-acquired and ventilator-associated pneumonia recommend the use of two antipseudomonal drugs for high-risk patients to ensure ≥95% of patients receive active empiric therapy. We evaluated the utility of combination antibiograms in identifying optimal PsA drug regimens.Methods: We conducted a retrospective cross-sectional analysis of antimicrobial susceptibility of all non-duplicate PsA blood and respiratory isolates collected between October 1, 2016 and September 30, 2017 from 304 US hospitals in the BD Insights Research Database. Combination antibiograms were used to determine in vitro antimicrobial susceptibility rates for potential PsA combination regimens consisting of a backbone antibiotic (extended-spectrum cephalosporin, carbapenem, or piperacillin/tazobactam) plus an aminoglycoside or fluoroquinolone.Results: Single agent susceptibility rates for the 11,701 non-duplicate PsA isolates ranged from 72.7% for fluoroquinolones to 85.0% for piperacillin/tazobactam. Susceptibility rates were higher for blood versus respiratory isolates (P < 0.05). Antibiotic combinations resulted in increased susceptibility rates, but did not achieve the goal of 95% antibiotic coverage. Adding an aminoglycoside resulted in higher susceptibility rates than adding a fluoroquinolone; piperacillin/tazobactam plus an aminoglycoside had the highest susceptibility rate (93.3%). Intensive care unit (ICU) isolates generally had lower susceptibility rates than non-ICU isolates.Conclusions: Commonly-used antipseudomonal drugs, either alone or in combination, do not achieve 95% coverage against US hospital PsA isolates, suggesting that new drugs are needed to attain this goal. Local institutional use of combination antibiograms has the potential to optimize empiric therapy of difficult-to-treat pathogens.…

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.

Abstract Background The roll out of antiretroviral therapy (ART) in Sub-Saharan Africa led to a decrease in mortality. Few studies have documented the causes of deaths among patients on long term antiretroviral therapy in Sub-Saharan Africa. Our objective was to describe the causes of death among patients on long term ART in Sub-Saharan Africa. Methods We used data from a prospective cohort of ART naïve patients receiving care and treatment at the Infectious Diseases Institute in Kampala, Uganda. Patients were followed up for 10 years. All deaths were recorded and possible causes established using verbal autopsy. Deaths were grouped as HIV-related (ART toxicities, any opportunistic infections (OIs) and HIV-related malignancies) and non-HIV related deaths while some remained unknown. We used Kaplan Meier survival methods to estimate cumulative incidence and rates of mortality for all causes of death. Results Of the 559, (386, 69%) were female, median age 36 years (IQR: 21–44), 89% had WHO clinical stages 3 and 4, and median CD4 count at ART initiation was 98 cells/μL (IQR: 21–163). A total of 127 (22.7%) deaths occurred in 10 years. The HIV related causes of death (n = 70) included the following; Tuberculosis 17 (24.3%), Cryptococcal meningitis 10 (15.7%), Kaposi’s Sarcoma 7(10%), HIV related toxicity 6 (8.6%), HIV related anemia 5(7.1%), Pneumocystis carinii Pneumonia (PCP) 5 (7.1%), HIV related chronic diarrhea 4 (5.7%), Non-Hodgkin Lymphoma 3 (4.3%), Herpes Zoster 2 (2.8%), other 10 (14.3%). The non-HIV related causes of death (n = 20) included non-communicable diseases (diabetes, hypertension, stroke) 6 (30%), malaria 3 (15%), pregnancy-related death 2 (10%), cervical cancer 2 (10%), trauma 1(5%) and others 6 (30%). Conclusion Despite the higher rates of deaths from OIs in the early years of ART initiation, we observed an emergence of non-HIV related causes of morbidity and mortality. It is recommended that HIV programs in resource-limited settings start planning for screening and treatment of non-communicable diseases.…

Decraene, V., Phan, H. T. T., George, R., Wyllie, D. H., Akinremi, O., Aiken, Z., Cleary, P., Dodgson, A., Pankhurst, L., Crook, D. W., Lenney, C., Walker, A. S., Woodford, N., Sebra, R., Fath-Ordoubadi, F., Mathers, A. J., Seale, A. C., Guiver, M., McEwan, A., Watts, V., Welfare, W., Stoesser, N., Cawthorne, J., the TRACE Investigators Group

Carbapenem-resistant Enterobacteriaceae (CRE) are a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli (KPC-EC) outbreak and wider CRE incidence trends over eight years in the Central Manchester Foundation NHS Trust (CMFT), UK, to determine the impact of Infection Prevention and Control measures.Bacteriology and patient administration data (2009 to 2017) were linked; a subset of CMFT/regional KPC-EC isolates (n=268) was sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n=184,539 screens), environmental sampling, enhanced cleaning, and ward closure/plumbing replacement. Segmented regression of time trends of CRE detections was used to evaluate the impact of interventions on CRE incidence.Genomic analysis (n=268 isolates) identified spread of a KPC-EC outbreak clone (ST216, strain-A; n=125) amongst patients and the environment, particularly on two cardiac wards (W3/W4), despite control measures. ST216 strain-A had caused an antecedent outbreak, and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae. CRE acquisition incidence declined after W3/W4 closure and plumbing replacement, suggesting an environmental contribution. However, W3/W4 wastewater sites were rapidly re-colonised with CRE and patient CRE acquisitions recurred, albeit at lower rates.Patient relocation and plumbing replacement were associated with control of a clonal KPC-EC outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and persistence of blaKPC in E. coli, including pathogenic lineages, is a concern.…

Xi Zeng, Hao Gu, Yan Cheng, Ke-Ran Jia, Dong Liu, Yue Yuan, Zhi-Fu Chen, Liu-Sheng Peng, Quan-Ming Zou, Yun Shi

Acinetobacter baumannii can cause severe nosocomial and community-acquired pneumonia. To study the pathogenesis of A. baumannii and develop new treatments, appropriate mouse models are needed. Most of reported mouse models of pulmonary A. baumannii infection are non-lethal or require mice immunosuppression to enhance infection. These models are not suitable for studying host immune response or evaluating immunotherapies.

Elie Azoulay

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

McIntosh K.

Abstract…

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.…

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.

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.…

Prendki Virginie, Huttner Benedikt, Marti Christophe, Mamin Aline, Fubini Pietro Elias, Meynet Marie-Pierre, Scheffler Max, Montet Xavier, Janssens Jean-Paul, Reny Jean-Luc, Kaiser Laurent, Garin Nicolas, Stirnemann Jérôme

NCT02467192…

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

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.…

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.…

Abstract Purpose We studied the incidence, morbidity and mortality of all patients presenting in our teaching hospital with proven influenza virus and/or respiratory syncytial virus (RSV) infection during the influenza epidemic season 2018 which was characterized by a predominant incidence of influenza virus B type B of the Yamagata line. Methods In the fall of 2017, specific precaution measures in addition to standard measures were implemented, including standardized testing for influenza virus A,B and RSV by multiplex PCR of pharyngeal swabsData from all consecutive patients were analyzed retrospectively. Results Overall 651 patients were examined for the presence of influenza virus and RSV; 214 patients had influenza virus A (n = 36), B (n = 152), and/or RSV (n = 30), including four patients with dual infection. 86% of cases had influenza virus (80% B), and 14% RSV infection. N = 23 cases were treated as outpatients. The rate of acute viral respiratory infections (influenza virus and RSV) was 191 of 2776 (6.9%) admissions to medical wards. Of n = 191 hospitalized cases, n = 44 cases (20.6%) had nosocomial infection. Viral infections were associated with a high morbidity (pneumonia 28.5%, mortality 4.7%). Independent predictors of prolonged hospitalization were the presence of pneumonia, NIV and renal complications, and independent predictors of pneumonia were age ≥ 65 years, bedridden status and CRP ≥ 2.9 mg/dL. Conclusions The rate of nosocomial cases was high despite established precaution measures. RSV was associated with morbidity and mortality comparable to influenza. Pneumonia remains the main complication of acute viral respiratory infections, and antimicrobial treatment should include both antiviral as well as antibacterial agents.…

Abstract Introduction A woman infected by carbapenem-resistant Klebsiella pneumoniae is reported in this study. Case report Tigecycline and meropenem combination was used, and indeed, in vitro checkerboard synergy test confirmed the antagonism between the two antibiotics. Thus, meropenem was ceased and single high-dose tigecycline was successful against the infection. Subsequent experiments showed that the isolates of the KPC-2-producing K. pneumoniae ST11 clone caused the infection. Conclusion Therefore, tigecycline and meropenem combination should be used with caution.…

Paukner, S., Gelone, S. P., Arends, S. J. R., Flamm, R. K., Sader, H. S.

Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for in vitro activity against a global collection of pathogens commonly causing CABP (n=8595) from the 2015–2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against pathogens commonly Streptococcus pneumoniae including multidrug resistant and extensively drug resistant strains (MIC50/90 for total and resistant subsets, 0.06/0.12 μg/mL; 100% inhibited at ≤1 μg/mL), Staphylococcus aureus including MRSA (both MIC50/90, 0.06/0.12 μg/mL; 99.8% and 99.6% inhibited at ≤1 μg/mL, respectively), Haemophilus influenzae (MIC50/90, 0.5/1 μg/mL; 93.8% inhibited at ≤1 μg/mL), and Moraxella catarrhalis (MIC50/90, 0.06/0.12 μg/mL; 100% inhibited at ≤0.25 μg/mL), and its activity was unaffected by resistance to other antibacterial classes.…

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

Carvalhaes, C. G., Huband, M. D., Reinhart, H. H., Flamm, R. K., Sader, H. S.

Omadacycline is a derivative of minocycline and the first agent of the aminomethylcycline class. A total of 3,282 organisms (one per patient) were consecutively collected from patients hospitalized in China (including Hong Kong) and Taiwan. Susceptibility testing was performed by broth microdilution methods in a central laboratory (JMI Laboratories). The collection included Gram-positive and Gram-negative organisms from patients with pneumonia, bloodstream, skin, community-acquired respiratory, and other infections. Omadacycline was very potent against Staphylococcus aureus (n=689; MIC50/90, 0.12/0.25 mg/L), including methicillin-resistant isolates (MRSA; n=299; MIC50/90, 0.12/0.5 mg/L), and had similar activity across geographic regions. Omadacycline was very active against Streptococcus pneumoniae (highest MIC, 0.25 mg/L), β-hemolytic streptococci (highest MIC, 1 mg/L), viridans group streptococci (highest MIC, 0.25 mg/L), and Enterococcus spp. (highest MIC, 0.5 mg/L) from all geographic regions. Overall, 53.8% of S. pneumoniae were penicillin-resistant (PRSPN; penicillin MIC, ≥2 mg/L) and 10.7% of enterococci (21.2% among E. faecium) were vancomycin-resistant (VRE). Omadacycline was active against Haemophilus influenzae (MIC50/90, 0.5/1 mg/L) regardless of β-lactamase production and was active against Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/L). Against Enterobacteriaceae, omadacycline was most active against Escherichia coli (MIC50/90, 1/2 mg/L), Klebsiella oxytoca (MIC50/90, 1/4 mg/L), and Enterobacter cloacae (MIC50/90, 2/4 mg/L). Omadacycline showed potent in vitro activity against Gram-positive and Gram-negative pathogens isolated from China and Taiwan, and retained activity against problem pathogens, such as MRSA, VRE, PRSPN, and extended-spectrum β-lactamase-producing E. coli. The observed MIC profile in Chinese isolates was very similar to that seen in the US and European surveillance studies.…

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 (

Barash, J. R., Castles, J. B., Arnon, S. S.

Infant botulism is an infectious intestinal toxemia that results from colonization of the infant large bowel by Clostridium botulinum (or rarely, by neurotoxigenic C. baratii or C. butyricum), with subsequent intraintestinal production and absorption of botulinum neurotoxin that then produces flaccid paralysis. The disease is often initially misdiagnosed as suspected sepsis or meningitis, diagnoses that require prompt empiric antimicrobial therapy. Antibiotics may also be needed to treat infectious complications of infant botulism, such as pneumonia or urinary tract infection. Clinical evidence suggests (see included case report) that broad-spectrum antibiotics that are eliminated by biliary excretion may cause progression of the patient’s paralysis by lysing C. botulinum vegetative cells in the large bowel lumen and thereby increasing the amount of botulinum neurotoxin available for absorption. The purpose of this antimicrobial susceptibility study was to identify an antimicrobial agent with little or no activity against C. botulinum that could be used to treat infant botulism patients initially diagnosed with suspected sepsis or meningitis, or who acquired secondary infections, without lysing C. botulinum. Testing of 12 antimicrobial agents indicated that almost all California infant botulism patient isolates are susceptible to most clinically utilized antibiotics and are also susceptible to newer antibiotics not previously tested against large numbers of C. botulinum patient isolates. No antibiotic with little or no activity against C. botulinum was identified. These findings reinforce the importance of promptly treating infant botulism patients with Human Botulism Immune Globulin (BIG-IV; BabyBIG®).…

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.…

Neill, Sarah; Dean, Nathan

Purpose of review Our purpose is to describe aspiration pneumonia/pneumonitis as a spectrum of infectious/noninfectious diseases affecting the lung. We summarize diagnosis, risk factors, treatment, and strategies for prevention of aspiration. Recent findings Aspiration is present in normal individuals, and disease manifestation depends on the chemical characteristics, frequency, and volume of inoculum. Anaerobes, though present, are no longer the predominant microbes isolated in aspiration pneumonia. Targets for preventing aspiration including improved oral hygiene and positional feeding have had mixed results. Patients diagnosed by clinicians with aspiration pneumonia experience greater morbidity and mortality than patients with community-acquired pneumonia. Summary Aspiration pneumonia and pneumonitis are part of the pneumonia continuum and share similarities in pathophysiology, microbiology, and treatment. Modern microbiology demonstrates that the lung is not sterile, and isolates in aspiration pneumonia frequently include aerobes or mixed cultures. Treatment for aspiration pneumonia should include antibiotic coverage for oral anaerobes, aerobes associated with community-acquired pneumonia, and resistant organisms depending on appropriate clinical context. Additional studies targeting prevention of aspiration and investigating the increased morbidity and mortality associated with aspiration pneumonia are warranted. Correspondence to Sarah Neill, MD, MPH, University of Utah, Division of Pulmonary and Critical Care Medicine, 26N. 1900 E, 701 Wintrobe, Salt Lake City, UT 84132, USA. Tel: +1 512 971 7176; e-mail: Sarah.Neill@hsc.utah.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Background Timely initiation of antibiotics within one hour of prescription is one of the recommended antibiotic stewardship interventions when managing patients with pneumonia in the emergency department. Effective implementation of this intervention depends on effective communication, a well-established coordination process and availability of resources. Understanding what may influence this aspect of care by using process mapping is an important component when planning for improvement interventions. The aim of the study was to identify factors that influence antibiotic initiation following prescription in the Adult Emergency and Trauma Centre of the largest referral hospital in Malawi. Methods We conducted a prospective observational case study using process mapping of two purposively selected adult pneumonia patients. One of the investigators CM observed the patient from the time of arrival at the triage area to the time he/she received initial dose of antibiotics. With purposively selected members of the clinical team; we used simple questions to analyze the map and identified facilitators, barriers and potential areas for improvement. Results Both patients did not receive the first dose of antibiotic within one hour of prescription. Despite the situation being less than ideal, potential facilitators to timely antibiotic initiation were: prompt assessment and triaging; availability of different expertise, timely first review by the clinician; and blood culture collected prior to antibiotic initiation. Barriers were: long waits, lack of communication/coordinated care and competency gap. Improvements are needed in communication, multidisciplinary teamwork, education and leadership/supervision. Conclusion Process mapping can have a significant impact in unveiling the system-related factors that influence timely initiation of antibiotics. The mapping exercise brought together stakeholders to evaluate and identify the facilitators and barriers. Recommendations here focused on improving communication, multidisciplinary team culture such as teamwork, good leadership and continuing professional development.…

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.…

Wadhera RK, Joynt Maddox KE, Wasfy JH, et al.

This cohort study examined the effects of the CMS’s Hospital Readmissions Reduction Program, which imposed financial penalties on hospitals with higher-than-expected readmission rates, on mortality among Medicare beneficiaries hospitalized with heart failure, acute myocardial infarction (AMI), or pneumonia.

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 Empirical antibiotic coverage for atypical pathogens in community-acquired pneumonia (CAP) has long been debated, mainly because of a lack of epidemiological data. We aimed to assess both testing for atypical pathogens and their prevalence in hospitalized patients with CAP worldwide, especially in relation with disease severity. Methods A secondary analysis of the GLIMP database, an international, multicentre, point-prevalence study of adult patients admitted for CAP in 222 hospitals across 6 continents in 2015, was performed. The study evaluated frequency of testing for atypical pathogens, including L. pneumophila, M. pneumoniae, C. pneumoniae, and their prevalence. Risk factors for testing and prevalence for atypical pathogens were assessed through univariate analysis. Results Among 3702 CAP patients 1250 (33.8%) underwent at least one test for atypical pathogens. Testing varies greatly among countries and its frequency was higher in Europe than elsewhere (46.0% vs. 12.7%, respectively, p 

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.…

Corinne Levy, Emmanuelle Varon, Naim Ouldali, Alain Wollner, Franck Thollot, François Corrard, Andreas Werner, Stéphane Béchet, Stéphane Bonacorsi, Robert Cohen

by Corinne Levy, Emmanuelle Varon, Naim Ouldali, Alain Wollner, Franck Thollot, François Corrard, Andreas Werner, Stéphane Béchet, Stéphane Bonacorsi, Robert Cohen After pneumococcal conjugate vaccine (PCV) implementation, the number of acute otitis media (AOM) episodes has decreased, but AOM still remains among the most common diagnoses in childhood. From 2% to 17% of cases of AOM feature spontaneous perforation of the tympanic membrane (SPTM). The aim of this study was to describe the bacteriological causes of SPTM 5 to 8 years years after PCV13 implementation, in 2010. From 2015 to 2018, children with SPTM were prospectively enrolled by 41 pediatricians. Middle ear fluid was obtained by sampling spontaneous discharge. Among the 470 children with SPTM (median age 20.8 months), no otopathogen was isolated for 251 (53.4% [95% CI 48.8%;58.0%]): 47.1% of infants and toddlers, 68.3% older children (p

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.…