James W. Rudge, Nui Inthalaphone, Rebecca Pavlicek, Phimpha Paboriboune, Bruno Flaissier, Chou Monidarin, Nicolas Steenkeste, Viengmon Davong, Manivanh Vongsouvath, K. A. Bonath, Melinda Messaoudi, Mitra Saadatian-Elahi, Paul Newton, Hubert Endtz, David Dance, Glaucia Paranhos Baccala, Valentina Sanchez Picot

by James W. Rudge, Nui Inthalaphone, Rebecca Pavlicek, Phimpha Paboriboune, Bruno Flaissier, Chou Monidarin, Nicolas Steenkeste, Viengmon Davong, Manivanh Vongsouvath, K. A. Bonath, Melinda Messaoudi, Mitra Saadatian-Elahi, Paul Newton, Hubert Endtz, David Dance, Glaucia Paranhos Baccala, Valentina Sanchez Picot Respiratory diseases are a major contributor to morbidity and mortality in many tropical countries, including Lao PDR. However, little has been published regarding viral or bacterial pathogens that can contribute to influenza-like illness (ILI) in a community setting. We report on the results of a community-based surveillance that prospectively monitored the incidence of ILI and its causative pathogens in Vientiane capital in Lao PDR. A cohort of 995 households, including 4885 study participants, were followed-up between May 2015 and May 2016. Nasopharyngeal swabs, throat swabs, and sputum specimens were collected from ILI cases identified through active case-finding. Real-Time PCR was used to test nasopharyngeal swabs for 21 respiratory pathogens, while throat and sputum samples were subjected to bacterial culture. Generalized linear mixed models were used to assess potential risk factors for associations with ILI. In total, 548 episodes of ILI were reported among 476 (9.7%) of the study participants and 330 (33.2%) of the study households. The adjusted estimated incidence of ILI within the study area was 10.7 (95%CI: 9.4–11.9) episodes per 100 person-years. ILI was significantly associated with age group (p

Rindra Randremanana, Voahangy Andrianaivoarimanana, Birgit Nikolay, Beza Ramasindrazana, Juliette Paireau, Quirine Astrid ten Bosch, Jean Marius Rakotondramanga, Soloandry Rahajandraibe, Soanandrasana Rahelinirina, Fanjasoa Rakotomanana, Feno M Rakotoarimanana, Léa Bricette Randriamampionona, Vaoary Razafimbia, Mamy Jean De Dieu Randria, Mihaja Raberahona, Guillain Mikaty, Anne-Sophie Le Guern, Lamina Arthur Rakotonjanabelo, Charlotte Faty Ndiaye, Voahangy Rasolofo, Eric Bertherat, Maherisoa Ratsitorahina,

This predominantly urban plague epidemic was characterised by a large number of notifications in two major urban areas and an unusually high proportion of pneumonic forms, with only 23% having one or more positive laboratory tests. Lessons about clinical and biological diagnosis, case definition, surveillance, and the logistical management of the response identified in this epidemic are crucial to improve the response to future plague outbreaks.

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.

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.…

Agard, M. J., Ozer, E. A., Morris, A. R., Piseaux, R., Hauser, A. R.

Microbial competition is most often studied at the genus or species level, but interstrain competition has been less thoroughly examined. Klebsiella pneumoniae is an important pathogen in the context of hospital-acquired pneumonia, and a better understanding of strain competition in the lungs could explain why some strains of this bacterium are more frequently isolated from pneumonia patients than others. We developed a barcode-free method called "StrainSeq" to simultaneously track the abundance of ten K. pneumoniae strains in a murine pneumonia model. We demonstrate that one strain (KPPR1) repeatedly achieved a marked numerical dominance 20 hours post-inoculation during pneumonia but did not exhibit a similar level of dominance in in vitro mixed-growth experiments. The emergence of a single dominant strain was also observed with a second respiratory pathogen, Acinetobacter baumannii, indicating that the phenomenon was not unique to K. pneumoniae. When KPPR1 was removed from the inoculum, a second strain emerged to achieve high numbers in the lungs, and when KPPR1 was introduced into the lungs one hour after the other nine strains, it no longer exhibited a dominant phenotype. Our findings indicate that certain strains of K. pneumoniae have the ability to outcompete others in the pulmonary environment and cause severe pneumonia, and that a similar phenomenon occurs with A. baumannii. In the context of the pulmonary microbiome, inter-strain competitive fitness may be another factor that influences the success and spread of certain lineages of these hospital-acquired respiratory pathogens.…

Wozniak, J. E., Band, V. I., Conley, A., Rishishwar, L., Burd, E. M., Satola, S. W., Hardy, D., Tsay, R., Farley, M. M., Jacob, J. T., Dumyati, G., Jordan, I. K., Weiss, D. S.

The convergence of hypervirulence and multidrug-resistance in Klebsiella pneumoniae is a significant concern. We report the first screen for hypermucoviscosity, a trait associated with increased virulence, using a US surveillance collection of carbapenem-resistant K. pneumoniae. We identified one hypermucoviscous isolate, encoding the KPC-3 carbapenemase among numerous resistance genes. The strain further exhibited colistin heteroresistance undetected by diagnostics. This convergence of diverse resistance mechanisms and increased virulence underscores the need for enhanced K. pneumoniae surveillance.…

Ludden C, Moradigaravand D, Jamrozy D, et al.

AbstractKlebsiella pneumoniae is a human, animal and environmental commensal and a leading cause of nosocomial infections, which are often caused by multi-resistant strains that are challenging to treat. We conducted a One Health evaluation of putative sources of K. pneumoniae that are carried by, and infect hospital patients. This combined data from a six-month study on two haematology wards at Addenbrooke’s Hospital, Cambridge, in 2015 to isolate K. pneumoniae from stool, blood and the environment, and a cross-sectional survey of K. pneumoniae from 29 livestock farms, 97 meat products, the hospital sewer and 20 municipal wastewater treatment plants in the East of England between 2014 and 2015. K. pneumoniae was isolated from stools of 17/149 (11%) patients and 18/922 swabs of their environment, together with one patient bloodstream infection during the study and 4 others over a 24-month period. Each patient carried one or more lineages that was unique to them, but two broad environmental contamination events and patient-environmental transmission were identified. K. pneumoniae was isolated from cattle and poultry, hospital sewage and 12/20 wastewater plants. There was low genetic relatedness between isolates from patients/their hospital environment versus isolates from elsewhere. Identical genes encoding cephalosporin resistance were carried by isolates from different reservoirs, but were carried on different plasmids by isolates from patients/their environment versus elsewhere. We identified no patient-to-patient transmission and no evidence for livestock as a source of K. pneumoniae infecting humans, but our findings reaffirm the importance of the hospital environment as a source of K. pneumoniae associated with serious human infection.

Abstract Background Indoleamine 2, 3-dioxygenase (IDO) is a key enzyme in the degradation of tryptophan (Trp) to kynurenine (Kyn). We measured IDO activity as the Kyn to Trp ratio, and investigated whether IDO could be used to assess prognosis of acquired immune deficiency Sydrome (AIDS) patients with pneumocystis pneumonia (PCP). Methods The Kyn and Trp concentration were measured by UPLC-MS/MS in plasma samples. A total of 49 AIDS-PCP patients were included in the analysis. Clinical characteristics and Kyn/Trp ratio were compared between survivors and non-survivors. Results Kyn/Trp ratio was significantly lower after anti-PCP treatment in AIDS patients with PCP (P  300 mmHg (P = 0.007). Kyn/Trp ratio, D-dimer and CRP showed much higher AUC for predicting death of AIDS-PCP patients. Kyn/Trp ratio was useful for predicting the mortality of AIDS-PCP due to a significantly higher Kyn/Trp ratio in the non-survivors (P = 0.002). And the high Kyn/Trp ratio group had higher mortality rate than low Kyn/Trp group (32.1% vs. 9.1%, respectively, p = 0.024). Conclusion Activation of the kynurenine pathway is associated with the severity and fatal outcomes of AIDS patients with pneumocystis pneumonia.…

Abstract Background Enterobacterales are among the most common causes of bacterial infections in the community and among hospitalized patients, and multidrug-resistant (MDR) strains have emerged as a major threat to human health. Resistance to third-generation cephalosporins is typical of MDRs, being mainly due to the production of extended spectrum β-lactamases or AmpC-type β-lactamases. Objective The objective of this paper is to review the epidemiological impact, diagnostic issues and treatment options with AmpC producers. Findings AmpC enzymes encoded by resident chromosomal genes (cAmpCs) are produced by some species (e.g., Enterobacter spp., Citrobacter freundii, Serratia marcescens), while plasmid-encoded AmpCs (pAmpCs) can be encountered also in species that normally do not produce cAmpCs (e.g., Salmonella enterica, Proteus mirabilis, Klebsiella pneumoniae and Klebsiella oxytoca) or produce them at negligible levels (e.g., Escherichia coli). Production of AmpCs can be either inducible or constitutive, resulting in different resistance phenotypes. Strains producing cAmpCs in an inducible manner (e.g., Enterobacter spp.) usually appear susceptible to third-generation cephalosporins, which are poor inducers, but can easily yield mutants constitutively producing the enzyme which are resistant to these drugs (which are good substrates), resulting in treatment failures. pAmpCs are usually constitutively expressed. Production of pAmpCs is common in community-acquired infections, while cAmpC producers are mainly involved in healthcare-associated infections. Conclusions To date, there is no conclusive evidence about the most appropriate treatment for AmpC-producing Enterobacterales. Carbapenems are often the preferred option, especially for severe infections in which adequate source control is not achieved, but cefepime is also supported by substantial clinical evidences as an effective carbapenem-sparing option.…

Abstract Background Until now, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MP) infection among adult patients has been low, and severe MP pneumonia due to a macrolide-resistant strain has seldom been reported. Here, we describe a rare case of severe life-threatening MP pneumonia due to a macrolide-resistant strain in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid. Case presentation A 39-year-old apparently healthy woman complained of fever and productive cough. Three days after onset, she was admitted to a local general hospital. On admission, her vital signs were stable except for high-grade fever. The patient’s chest X-ray and chest computed tomography images revealed subsegmental consolidation in her right lower lobe. Treatment with ampicillin/sulbactam, and azithromycin were initiated under a clinical diagnosis of community-acquired pneumonia. After treatment initiation, her fever had not subsided, and the pulmonary lesion had extended to the entire lower lobe. Thus, treatment with prednisolone as steroid pulse therapy was initiated from clinical day 7. However, neither her symptoms nor her pulmonary lesion improved; therefore, she was transferred to our hospital for further examination and treatment. On admission (clinical day 14), her indirect hemagglutination titer for MP was elevated at 1:2560, and bronchoalveolar fluid examination yielded positive results for the mycoplasma antigen. Based on these clinical findings, we confirmed a case of severe life-threatening MP pneumonia. Since her respiratory condition was extremely severe, we initiated levofloxacin and tetracycline. Two days later (clinical day 16), her fever, malaise, and hypoxia resolved, and her pulmonary lesions had significantly improved. Further molecular identification yielded the DNA of MP from her bronchoalveolar fluid, and mutation of A2063G in the 23S rRNA gene was revealed. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain. Conclusion More awareness is needed on the emergence of macrolide-resistant MP infection in adults, because severe infection could develop despite initial treatment with macrolide and steroid therapy, which are generally considered as standard therapy for MP.…

Abstract Background Understanding the relationship between serotype epidemiology and antimicrobial susceptibility of Streptococcus pneumoniae is essential for the effective introduction of pneumococcal conjugate vaccines (PCVs) and control of antimicrobial-resistant pneumococci. Methods We conducted a community-based study in Nha Trang, central Vietnam, to clarify the serotype distribution and pattern of S. pneumoniae antimicrobial susceptibility in children under 5 years of age and to identify risk factors for carrying antimicrobial-resistant strains. Nasopharyngeal swabs collected from children with acute respiratory infections (ARIs) hospitalized between April 7, 2008, and March 30, 2009, and from healthy children randomly selected in July 2008 were subjected to bacterial culture. Minimum inhibitory concentrations (MICs) against S. pneumoniae were determined, and multiplex-polymerase chain reaction (PCR) serotyping assays were performed. Logistic regression was applied to identify risk factors. Results We collected 883 samples from 331 healthy children and 552 ARI cases; S. pneumoniae was isolated from 95 (28.7%) healthy children and 202 (36.6%) ARI cases. Age and daycare attendance were significantly associated with pneumococcal carriage. In total, 18.0, 25.8 and 75.6% of the isolates had high MICs for penicillin (≥4 μg/ml), cefotaxime (≥2 μg/ml) and meropenem (≥0.5 μg/ml), respectively. The presence of pneumococci non-susceptible to multiple beta-lactams was significantly associated with serotype 19F (Odds Ratio: 4.23) and daycare attendance (Odds Ratio: 2.56) but not ARIs, age or prior antimicrobial use. The majority of isolates non-susceptible to multiple beta-lactams (90%) were PCV13 vaccine serotypes. Conclusions S. pneumoniae serotype 19F isolates non-susceptible to multiple beta-lactams are widely prevalent among Vietnamese children. Vaccine introduction is expected to significantly increase drug susceptibility.…

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.…

Getachew Alemkere, Admasu Tenna, Ephrem Engidawork

by Getachew Alemkere, Admasu Tenna, Ephrem Engidawork Background Malpractice and excess use of antimicrobials have been associated with multiple costs, including the development of resistant bacteria, which has become a threat to the human health. The aim of this study, therefore, was to assess the antibiotic use practice and to identify predictors of hospital outcome to uncover targets for stewardship. Methods An Institution-based prospective observational study was performed from 9 April to 7 July 2014 in the internal medicine wards of Tikur Anbessa Specialized Hospital. Patients with suspected systemic bacterial infections during this period were strictly followed and data were abstracted using data abstraction format. Descriptive statistics and binary logistic regression were used for statistical analysis. Results About half of the attended patients had suspected systemic bacterial infections, in which pneumonia is the most common. Cephalosporins were the most widely prescribed class of drugs in all the wards. Initial antibiotics were empiric in almost all of the cases. About 28% of the ward and 59% of the ICU patients died during the in-hospital stay. The mean length of stay (LoS) was 18.5+12.2 in the wards and 8.9+4.9 days in the ICU. Whilst digestive disease (AOR = 6.94, 95% CI: 2.24, 21.49), different signs and symptoms of disease (AOR = 2.43, 95% CI: 1.30, 4.56), sepsis (AOR = 2.59, 95% CI: 1.12, 5.99) and vancomycin use (AOR = 2.60, 95% CI: 1.30, 5.21) were independent positive predictors, antibiotic days (> 10) (AOR = 0.37, 95% CI: 0.20, 0.70) was a negative predictor for mortality. On the other hand, hospital-acquired infection (AOR = 3.01, 95% CI: 1.05, 8.62), beyond the median antibiotic days (> 10) (AOR = 4.05, 95% CI: 1.96, 8.37) and agent days beyond 21 days (AOR = 2.18, 95% CI: 1.01–4.68) were independently associated with prolonged LoS. Conclusion Generally, this observation entails an appropriate infection management and antimicrobial use policy. Any future policy should better start by addressing cases like pneumonia, and sepsis and drugs like cephalosporins.…

Arends, S. J. R., Rhomberg, P. R., Cotroneo, N., Rubio, A., Flamm, R. K., Mendes, R. E.

The antimicrobial activity of tebipenem and other carbapenem agents were tested in vitro against a set of recent clinical isolates responsible for urinary tract infection (UTI), as well as a challenge set. Isolates were tested by reference broth microdilution and included Escherichia coli (101 isolates), Klebsiella pneumoniae (208 isolates), and Proteus mirabilis (103 isolates) species. Within each species tested, tebipenem showed equivalent MIC50/90 values when compared to meropenem (E. coli, MIC50/90 ≤0.015/0.03 mg/L; K. pneumoniae, MIC50/90 0.03/0.06 mg/L; and P. mirabilis MIC50/90 0.06/0.12 mg/L) and consistently displayed MIC90 values 8-fold lower than imipenem. Tebipenem and meropenem (MIC50, 0.03 mg/L) showed equivalent MIC50 results against wild-type, AmpC-, and/or extended-spectrum β-lactamase (ESBL)-producing isolates. Tebipenem also displayed MIC50/90 values 4- to 8-fold lower than imipenem against the challenge set. All carbapenem agents were less active (MIC50, ≥8 mg/L) against isolates carrying carbapenemase genes. These data confirm the in vitro activity of the orally available agent tebipenem against prevalent UTI Enterobacteriaceae species, including those producing ESBLs and/or plasmid AmpC enzymes.…

Ambrose, P. G., VanScoy, B. D., Luna, B. M., Yan, J., Ulhaq, A., Nielsen, T., Rudin, S., Hujer, K., Bonomo, R., Actis, L., Skaar, E., Spellberg, B.

There has been a renewed interest in combining traditional small-molecule antimicrobial agents with non-traditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates, with ciprofloxacin minimum inhibitory concentrations (MIC) values ranging from 0.08 to 32 mg/L. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC:MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered, prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone (R2 = 0.64) and ciprofloxacin in combination with apotransferrin (R2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density, across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC:MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log10 CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log10 CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of bactericidal effect and suppress the growth rate of drug-resistant subpopulations.…

Ziegler, Katherine M.; Haywood, Jonathan D.; Sontag, Marci K.; Mourani, Peter M.

Objectives: We sought to compare the performance of the 2008 Centers for Disease Control and Prevention Pediatric criteria for ventilator-associated pneumonia, the 2013 Adult Ventilator-Associated Condition criteria, the new Draft Pediatric Ventilator-Associated Condition criteria, and physician-diagnosed ventilator-associated pneumonia in a cohort of PICU patients. Design: Secondary analysis of a previously conducted prospective observational study. Setting: PICU within a tertiary care children’s hospital between April 1, 2010, and April 1, 2011. Patients: Patients between 31 days and 18 years old, mechanically ventilated via endotracheal tube for more than 72 hours and no limitations of care. Interventions: None. Measurements and Main Results: Ventilator-associated pneumonia criteria applied in real time and ventilator-associated condition criteria applied retrospectively. Outcomes assessed between cases and noncases within criteria. Of the 133 eligible participants, 24 (18%) had ventilator-associated pneumonia by 2008 Pediatric criteria and 27 (20%) by physician diagnosis. Sixteen (12%) and 10 (8%) had ventilator-associated condition by 2013 Adult and Draft Pediatric criteria, respectively. We found significant overlap between cases identified with 2008 Pediatric criteria and physician diagnosis (p = 0.549), but comparisons between the other definitions revealed that the newer criteria identify different patients than previous Centers for Disease Control and Prevention ventilator-associated pneumonia criteria and physician diagnosis (p < 0.01). Although 20 participants were diagnosed with ventilator-associated pneumonia by 2008 Pediatric criteria and physician diagnosis, only three participants were identified by all four criteria. Three subjects uniquely identified by the Draft Pediatric criteria were noninfectious in etiology. Cases identified by all criteria except Draft Pediatric had higher ratios of actual ICU length of stay to Pediatric Risk of Mortality III-adjusted expected length of stay compared with noncases. Conclusions: The Draft Pediatric criteria identify fewer and different patients than previous ventilator-associated pneumonia criteria or physician diagnosis, potentially missing patients with preventable harms, but also identified patients with potentially preventable noninfectious respiratory deteriorations. Further investigations are required to maximize the identification of patients with preventable harms from mechanical ventilation. New address for Dr. Sontag: Center for Public Health Innovation at CI International, Littleton, CO 80120. 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 grant from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute R01HL124103; NIH/National Center for Advancing Translational Sciences Colorado Clinical Translational Sciences Award grant number UL1 TR001082. This project was supported by NIH/National Center for Research Resources Colorado Clinical & Translational Science Institute grant number UL1 RR025780. Its contents are the authors’ sole responsibility and do not necessarily represent official NIH views. Ms. Ziegler’s institution received funding from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01HL124103 and NIH/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical Translational Sciences Award (CTSA) grant number UL1 TR001082. Ms. Ziegler and Drs. Sontag and Mourani received support for article research from the NIH. Dr. Sontag’s institution received funding from NHLBI/NIH, Maternal Child Health Bureau of the Health Resources and Services Administration, and the Cystic Fibrosis Foundation, and she received funding from Research Triangle Institute (External Advisory Board for the Early Check Study). Dr. Mourani’s institution received funding from NHLBI/NIH and NCATS/NIH. Dr. Haywood disclosed that he does not have any potential conflicts of interest. This work was performed at the following institutions: Children’s Hospital Colorado, Aurora, CO and the University of Colorado Denver, Aurora, CO. Corresponding Author: Katie.Ziegler@ucdenver.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Evangelia-Theophano Piperaki, Leonidas S. Tzouvelekis, Vivi Miriagou, George L. Daikos

Carbapenem-resistant Acinetobacter baumannii (CRAB) has gained global notoriety as a critically important nosocomial pathogen. It mostly affects debilitated patients causing pneumonia and bloodstream infections with high mortality rates. Difficulties in treating CRAB infections stem from a formidable resistance profile that leaves available a few antibiotics of uncertain efficacy such as colistin and tigecycline. Despite the relentless attempts to improve therapeutic approaches (as depicted in colistin-oriented randomized clinical trials and the numerous observational studies), progress is still limited.

Levy C, Varon E, Ouldali N, et al.

AbstractBackgroundPneumococcal conjugate vaccine (PCV) implementation has led to a sharp decrease in invasive pneumococcal disease (IPD) due to the reduction in PCV serotypes (VTs). We aimed to describe the changes in the spectrum of IPD and its clinical presentations after PCV13 implementation.MethodsThis prospective, hospital-based, active surveillance involved 130 pediatric wards and microbiology departments throughout France. We analyzed IPD cases from 2011 to 2016 for which a pneumococcal isolate was sent to the National Reference Center for Pneumococci for serotyping. Clinical data recorded were medical history, vaccination status, type of IPD, clinical features and short-term evolution.ResultsAmong 1082 IPDs cases, we observed a 35.3% decrease (95%CI [29.2;41.8]) and the median age shifted from 38.3 months to 23.7 months (p =0.007). The change in IPD type was mostly due to a reduction in bacteremic pneumonia frequency (from 42.1% to 19.1%, p

Mendes, R. E., Castanheira, M., Woosley, L. N., Stone, G. G., Bradford, P. A., Flamm, R. K.

REPRISE was a pathogen-directed (ceftazidime-resistant) Phase 3 prospective, open-label, randomized, multicenter trial that evaluated the efficacy, safety, and tolerability of ceftazidime-avibactam (CAZ-AVI) and best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal (cIAI) and complicated urinary tract infections (cUTI). This study characterized the β-lactamase content of ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa recovered during the baseline visits of patients enrolled in REPRISE. Ceftazidime had MIC90 results of >64 μg/mL against baseline Enterobacteriaceae and P. aeruginosa. blaCTX-M variants were the most common β-lactamase found in Escherichia coli (detected in 94.3% of all E. coli) and Klebsiella pneumoniae (91.2%), whereas Proteus mirabilis often carried plasmid AmpC (66.7%). blaKPC (6), blaNDM-1 (3), blaOXA-48 (3), and blaVIM (2) were detected in 4.9% (14/284) of Enterobacteriaceae. Overall, clinical cure rates against the Enterobacteriaceae were 91.2% and 90.8% for the CAZ-AVI and BAT groups, respectively, or 92.5% and 92.9% in the subset of patients infected with isolates harboring blaCTX-M. Among patients with baseline isolates carrying AmpC genes (pAmpC and/or overexpression of the intrinsic AmpC) showed clinical cure rates of 80.0% and 89.5% for CAZ-AVI and BAT arms, respectively. Favorable microbiological responses were generally lower than clinical cure rates in both arms, but CAZ-AVI (80.0–85.0%) showed microbiological response rates consistently higher than BAT (57.9–64.3%) among patients with non-carbapenemase-producing Enterobacteriaceae. Lower microbiological response rates (50.0%) were found in patients with carbapenemase producers from both arms. This study expands on efficacy data analysis of CAZ-AVI among patients infected with ceftazidime-resistant pathogens, especially blaCTX-M-carrying isolates, and although clinical cure rates for CAZ-AVI and BAT were similar, eradication rates for CAZ-AVI were higher than BAT.…

Wang, Y.-C., Tang, H.-L., Liao, Y.-C., Chiou, C.-S., Chen, Y.-T., Chiang, M.-K., Lu, M.-C., Lai, Y.-C.

The endemic spread of carbapenemase-producing Klebsiella pneumoniae in Taiwan has become problematic (1)....…

Abstract Background Pyogenic liver abscess (PLA) in the elderly is insufficiently elucidated. A few studies attempted to investigate the role of age in PLA have yielded controversial results. The purpose of this study was to explore the possible differences in the comorbidity, microbiological characteristics and clinical course between elderly and young PLA patients. Methods The clinical data of 332 adult PLA patients who received treatment at our hospital from January 2010 to December 2016 were collected. The demographic data, etiologies, comorbidities, clinical features, laboratory results, imaging findings, microbiological characteristics, choices of treatment and clinical outcomes were analyzed. Results Eighty-two (24.7%) patients were older than 65 years. Comorbidities including hypertension, diabetes mellitus, and cholelithiasis were more frequently found in older patients. Elderly PLA patients were more likely to present with atypical symptoms and signs on admission. The laboratory abnormalities and imaging findings were similar between the two groups. Klebsiella pneumonia was the most common pathogen on pus culture in both groups. There were no statistically significant differences in choices of treatment, PLA-related complications and length of in-hospital stay between the two groups. And there was no in-hospital mortality. Conclusions The clinical characteristics were similar in young and elderly PLA patients. However, elderly PLA patients were more likely to have underlying diseases and tended to have atypical presentations. Physicians need to be vigilant when encounter possible elderly patients with PLA. However, older PLA patients had comparable outcomes as their younger counterparts. With effective treatment, both elderly and young PLA patients can be cured.…

Rizk, M. L., Bhavnani, S. M., Drusano, G., Dane, A., Eakin, A. E., Guina, T., Jang, S. H., Tomayko, J. F., Wang, J., Zhuang, L., Lodise, T. P.

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens" to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry and government. This and the accompanying mini-review on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this mini-review include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.…

Xu, J., Li, S.-Y., Almeida, D. V., Tasneen, R., Barnes-Boyle, K., Converse, P. J., Upton, A. M., Mdluli, K., Fotouhi, N., Nuermberger, E. L.

Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure TB in BALB/c mice compared to the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to BMZ resulted in a 1 log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to BMZ alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 vs. 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.…

Rodgers, A. M., McCrudden, M. T. C., Courtenay, A. J., Kearney, M.-C., Edwards, K. L., Ingram, R. J., Bengoechea, J., Donnelly, R. F.

Using a murine model of Klebsiella pneumoniae bacterial infection, we demonstrate that gentamicin dissolving microarray patches, applied to murine ears, could control K. pneumoniae infection. Mice treated with microarray patches had reduced bacterial burden in the nasal associated lymphoid tissue and lungs, in comparison to their untreated counterparts. This proof of concept study represents the first published data on the in vivo delivery of the antibiotic gentamicin, via dissolving microarray patches resulting in control of bacterial infection.…

Following publication of the original article [1],…

Holloway, A. J., Yu, J., Arulanandam, B. P., Milligan, G. N., Eaves-Pyles, T. D.

We have identified recombinant human cystatin 9 (rCST9) and C (rCSTC) as a combination, immunotherapeutic treatment against multi-drug resistant (MDR) New Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae (Kp). We evaluated the lasting protection of rCST9/rCSTC treatment against MDR NDM-1 Kp pneumonia. Results showed that rCST9/rCSTC treatment modulated endogenous serum biomarkers, cystatin 9 and C and amyloid A, associated with poor patient outcomes and provided prophylactic and long-term protection in a murine model of pneumonia.…

Abstract Purpose In this multicentre, retrospective, matched cohort study we aimed to evaluate the outcomes of neutropenic fever cases that were treated with daptomycin or a glycopeptide (vancomycin or teicoplanin). Methods Data and outcomes of adult (aged > 18-years old) patients with neutropenic fever [(1) without clinical and radiological evidence of pneumonia, (2) who were treated with daptomycin or a glycopeptide (teicoplanin or vancomycin) for any reason and for at least 72 h] were extracted from the hospital databases. Matching was performed with all of the three following criteria: (1) underlying disease, (2) reason for starting daptomycin or glycopeptide (microbiologic evidence vs. microbiologic evidence, clinical infection vs. clinical infection and empirical therapy vs. empirical therapy) and (3) neutropenic status. Results Overall 128 patients [(69/123) (56.1%) in the daptomycin cohort (D) and 59/123 (48%) in the glycopeptide cohort (G)] had a resolution of fever at the end of 72 h antibiotic treatment (p = 0.25). There was no significant difference in cured, improved and (cured + improved) rates between (D) and (G) cohorts as well as fever of unknown origin cases or microbiologically confirmed infections or clinically defined infections subgroups (p > 0.05). There was also no significant difference (p > 0.05), in terms of persistent response in the (D) versus (G) cohorts, Conclusions These findings suggest that although not better, daptomycin efficacy is comparable to vancomycin if used as empiric therapy in the treatment of adult febrile neutropenia. We conclude that daptomycin may be used at least as a salvage therapy alternative to glycopeptides in the treatment of adult febrile neutropenia cases. A large, randomized-controlled trial may further consolidate the evidence related to this question.…

Aline Wolfensberger, Werner Jakob, Mirjam Faes Hesse, Stefan P. Kuster, Angela H. Meier, Peter W. Schreiber, Lauren Clack, Hugo Sax

Conducting manual surveillance of non-ventilator-associated hospital-acquired pneumonia (nvHAP) using ECDC (European Centre for Disease Prevention and Control) surveillance criteria is very resource intensive. We developed and validated a semi-automated surveillance system for nvHAP, and describe nvHAP incidence and etiology at our hospital.

Abstract Background A novel method, termed loop-mediated isothermal amplification (LAMP), was developed by Notomi et al. (2000). Individually published results have been reported that this technology has been successfully applied to the detection of a variety of pathogens. However, the overall diagnostic accuracy of LAMP for Mycoplasma pneumoniae (MP) remains unclear. A meta-analysis was therefore performed to review the accuracy of LAMP for Mycoplasma pneumoniae. Methods Cochrane Library and PubMed were systematically searched and checked for studies using LAMP for detecting mycoplasma pneumoniae. We used PCR as a reference standard to evaluate the quality of the studies eligible for inclusion in the meta-analysis. Then, the data from the studies were extracted by two independent assessors. Meta-DiSc 1.4 software was utilized to test the heterogeneity of sensitivity (SEN), specificity (SP), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnosis odds ratio (DOR). The pooled analysis results were plotted, and the summary receiver operating characteristic (SROC) curve was plotted by calculating the area under the curve (AUC). Generated pooled summary estimates (95% CIs) were calculated for the overall accuracy, and a bivariate meta-regression model was used for the meta-analysis. Results Seven studies with nine fourfold tables were included in this meta-analysis. The pooled SEN and SPE for diagnosing Mycoplasma pneumoniae were 0.90 (95% CI: 0.87–0.93) and 0.98 (95% CI: 0.96–0.99), respectively. The PLR was 31.25 (95% CI: 14.83–65.87), NLR 0.10 (95% CI: 0.05–0.22), DOR 399.32 (95% CI: 172.01–927.00), and AUC 0.9892. Conclusions In conclusion, compared with PCR, LAMP is a valuable alternative method for Mycoplasma pneumoniae diagnosis in clinic with high sensitivity and specificity. However, more evidence is required to confirm that LAMP can fully replace other methods in the clinical diagnosis of MP.…

Bian, X., Liu, X., Chen, Y., Chen, D., Li, J., Zhang, J.

Background: Colistin-based combination therapy has become an important strategy to combat the carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal dosage regimen selection for the combination with the maximum efficacy is challenging.Method: Checkerboard assay was employed to evaluate the synergy of colistin in combination with meropenem, rifampicin, fosfomycin and minocycline against nine carbapenem-resistant A. baumannii (Minimum inhibitory concentration of meropenem [MICMEM]≥32 mg/L) isolated from Chinese hospital-acquired pneumonia (HAP) patients. Static time-kill assay, in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model and semi-mechanistic PK/PD modeling were conducted to predict and validate the synergistic effect of the most efficacious combination.Results: Both checkerboard and static time-kill assays demonstrated superior synergistic effect of colistin-meropenem combination against all CRAB isolates. In the in vitro PK/PD model, the dosage regimen of 2 g meropenem daily via 3-h infusion combined with steady-state 1 mg/L colistin effectively suppressed the bacterial growth at 24 h with 2-log10 decrease, compared to the initial inocula against two CRAB isolates. The semi-mechanistic PK/PD model predicted that more than 2 mg/L colistin combined with meropenem (2 g, 3-h infusion) was required to achieve the killing below the limit of detection (

Verrall A, Schneider M, Alisjahbana B, et al.

AbstractIntroductionA proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed ‘early clearance’.MethodsIndonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post-recruitment. Blood cell populations and ex-vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive.ResultsAmong 1347 case contacts, 317 were early clearers and 116 converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae.ConclusionsEarly clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

Abstract Background Patients with pneumonia who are elderly or severely ill are at a particularly high risk of mortality. This post hoc retrospective analysis of data from two Phase III studies evaluated early improvement outcomes in subgroups of high-risk patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP, excluding ventilator-associated pneumonia [VAP]). Methods One study included hospitalised CAP patients randomised to ceftobiprole or ceftriaxone ± linezolid treatment. The other study included HAP patients, who were randomised to ceftobiprole or ceftazidime plus linezolid treatment. The primary outcome was rate of early clinical response (Day 3 in CAP and Day 4 in HAP patients). Additional outcome measures included clinical cure at a test-of-cure visit, 30-day all-cause mortality and safety. Results The overall high-risk group comprised 398 CAP patients and 307 HAP patients with risk factors present at baseline. The rate of early response was numerically higher in ceftobiprole-treated patients vs comparator-treated patients in the following high-risk groups: CAP patients aged ≥75 years (16.3% difference, 95% confidence interval [CI]: 1.8, 30.8); CAP patients with COPD (20.1% difference, 95% CI: 8.8, 31.1); all high-risk HAP patients (12.5% difference, 95% CI: 3.5, 21.4); HAP patients with >10 baseline comorbidities (15.3% difference, 95% CI: 0.3, 30.4). Conclusions Previous studies show that ceftobiprole is an efficacious therapy for patients with pneumonia who are at high risk of poor outcomes. This post hoc analysis provides preliminary evidence that ceftobiprole treatment may have advantages over other antibiotics in terms of achieving early improvement in high-risk patients with HAP (excluding VAP) and in some subgroups of high-risk CAP patients. Trial registration NCT00210964: registered September 21, 2005; NCT00229008: registered September 29, 2005; NCT00326287: registered May 16, 2006.…

James Samwel Ngocho, Best Magoma, Gaudencia Alois Olomi, Michael Johnson Mahande, Sia Emmanueli Msuya, Marien Isaäk de Jonge, Blandina Theophil Mmbaga

by James Samwel Ngocho, Best Magoma, Gaudencia Alois Olomi, Michael Johnson Mahande, Sia Emmanueli Msuya, Marien Isaäk de Jonge, Blandina Theophil Mmbaga Background Despite the widespread implementation of the pneumococcal conjugate vaccine, Streptococcus pneumoniae remains the leading cause of severe pneumonia associated with mortality among children less than 5 years of age worldwide, with the highest mortality rates recorded in Africa and Asia. However, information on the effectiveness and prevalence of vaccine serotypes post-roll out remains scarce in most African countries. Hence, this systematic review aimed to describe what is known about the decline of childhood invasive pneumococcal disease post-introduction of the pneumococcal conjugate vaccine in Africa. Methods This systematic review included articles published between 2009 and 2018 on the implementation of the pneumococcal conjugate vaccine in Africa. We searched PubMed, Scopus and African Index Medicus for articles in English. Studies on implementation programmes of pneumococcal conjugate vaccine 10/13, with before and after data from different African countries, were considered eligible. The review followed the procedures published in PROSPERO (ID = CRD42016049192). Results In total, 2,280 studies were identified through electronic database research, and only 8 studies were eligible for inclusion in the final analysis. Approximately half (n = 3) of these studies were from South Africa. The overall decline in invasive pneumococcal disease ranged from 31.7 to 80.1%. Invasive pneumococcal diseases caused by vaccine serotypes declined significantly, the decline ranged from 35.0 to 92.0%. A much higher decline (55.0–89.0%) was found in children below 24 months of age. Of all vaccine serotypes, the relative proportions of serotypes 1, 5 and 19A doubled following vaccine roll out. Interpretation Following the introduction of the pneumococcal conjugate vaccine, a significant decline was observed in invasive pneumococcal disease caused by vaccine serotypes. However, data on the effectiveness in this region remain scarce, meriting continued surveillance to assess the effectiveness of pneumococcal vaccination to improve protection against invasive pneumococcal disease.…

Zhi Ruan, Qingyang Sun, Huiqiong Jia, Chenyun Huang, Weili Zhou, Xinyou Xie, Jun Zhang

Reiko Shimbashi, Bin Chang, Yoshinari Tanabe, Hiroaki Takeda, Hiroshi Watanabe, Tetsuya Kubota, Kei Kasahara, Kengo Oshima, Junichiro Nishi, Takaya Maruyama, Koji Kuronuma, Jiro Fujita, Tatsuki Ikuse, Yuki Kinjo, Motoi Suzuki, Anusak Kerdsin, Tomoe Shimada, Munehisa Fukusumi, Keiko Tanaka-Taya, Tamano Matsui, Tomimasa Sunagawa, Makoto Ohnishi, Kazunori Oishi, and the Adult IPD Study Group

by Reiko Shimbashi, Bin Chang, Yoshinari Tanabe, Hiroaki Takeda, Hiroshi Watanabe, Tetsuya Kubota, Kei Kasahara, Kengo Oshima, Junichiro Nishi, Takaya Maruyama, Koji Kuronuma, Jiro Fujita, Tatsuki Ikuse, Yuki Kinjo, Motoi Suzuki, Anusak Kerdsin, Tomoe Shimada, Munehisa Fukusumi, Keiko Tanaka-Taya, Tamano Matsui, Tomimasa Sunagawa, Makoto Ohnishi, Kazunori Oishi, and the Adult IPD Study Group Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013–March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An emergence of IPD caused by serotype 12F was identified during May 2015–March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential.

Abstract Background Despite World Health Organization recommendations, in many countries young children are not targeted for influenza vaccination. To help inform influenza vaccination policy, we examined the occurrence and burden of influenza in healthy children aged 6 to 35 months using data from a recent phase III placebo-controlled influenza vaccine trial conducted in countries in the Northern and Southern Hemispheres. Methods This was an analysis of data from participants included in the placebo arm of a phase III clinical trial in healthy children aged 6 to 35 months (EudraCT no. 2013–001231-51). Included children had never been vaccinated for influenza and were observed for one influenza season. Outcome measures included the occurrence of influenza-like illness (ILI), laboratory-confirmed influenza, virus types/subtypes, severe symptoms and complications of confirmed influenza, and healthcare use associated with confirmed influenza. Results Data from 2210 participants were analysed. ILI was reported for 811 participants (36.7%). Of these, 255 participants (31.4%) had 263 virologically confirmed episodes of influenza. The overall influenza attack rate was 11.5%. The most common influenza virus detected was A(H3N2) (40.7%), followed by B/Yamagata (23.6%), A(H1N1) (18.6%), and B/Victoria (8.0%). Grade 3 fever was reported in 24.3% of confirmed episodes, acute lower respiratory infection in 8.7%, acute otitis media in 6.1%, and pneumonia in 1.9%. In most influenza episodes (93.2%), antipyretics, analgesics, or non-steroidal anti-inflammatory drugs were taken. Antibiotics were prescribed for 41.4% of influenza episodes. More than half of the influenza episodes (57.0%) resulted in outpatient visits. Influenza resulted in overnight hospitalisation in 1.1% of episodes. Conclusions Influenza is associated with a significant burden of disease in healthy children. This analysis also revealed that antibiotics continue to be frequently used for young children with influenza. Trial registration EudraCT no. 2013–001231-51.…

Abstract Background To determine the epidemiology and risk factors for nosocomial infection (NI) in the Respiratory Intensive Care Unit (RICU) of a teaching hospital in Northwest China. Methods An observational, prospective surveillance was conducted in the RICU from 2013 to 2015. The overall infection rate, distribution of infection sites, device-associated infections and pathogen in the RICU were investigated. Then, the logistic regression analysis was used to test the risk factors for RICU infection. Results In this study, 102 out of 1347 patients experienced NI. Among them, 87 were device-associated infection. The overall prevalence of NI was 7.57% with varied rates from 7.19 to 7.73% over the 3 years. The lower respiratory tract (43.1%), urinary tract (26.5%) and bloodstream (20.6%) infections accounted for the majority of infections. The device-associated infection rates of urinary catheter, central catheter and ventilator were 9.8, 7.4 and 7.4 per 1000 days, respectively.The most frequently isolated pathogens were Staphylococcus aureus (20.9%), Klebsiella pneumoniae (16.4%) and Pseudomonas aeruginosa (10.7%). Multivariate analysis showed that the categories D or E of Average Severity of Illness Score (ASIS), length of stay (10–30, 30–60, ≥60 days), immunosuppressive therapy and ventilator use are the independent risk factors for RICU infection with an adjusted odds ratio (OR) of 1.65 (95% CI: 1.15~2.37), 5.22 (95% CI: 2.63~10.38)), 2.32 (95% CI: 1.19~4.65), 8.93 (95% CI: 3.17~21.23), 31.25 (95% CI: 11.80~63.65)) and 2.70 (95% CI: 1.33~5.35), respectively. Conclusion A relatively low and stable rate of NI was observed in our RICU through year 2013–2015. The ASIS-D、E, stay ≥10 days, immunosuppressive therapy and ventilator use are the independent risk factors for RICU infection.…

Buchwald A, Tamboura B, Tennant S, et al.

AbstractIntroductionFew studies describe the Respiratory Syncytial Virus (RSV) burden in African populations, and most have utilized hospital-based surveillance. In Mali, no community-based studies exist of the incidence or epidemiology of RSV infection. This study provides the first estimates of RSV incidence in Mali. MethodsIn a cohort of infants enrolled in a clinical trial of maternal influenza vaccination, we estimate incidence of RSV-associated febrile illness in the first six months of life, and identify risk factors for RSV infection and progression to severe disease. Infants (N = 1,871) were followed from birth to six months of age and visited weekly to detect pneumonia and influenza-like illness. Baseline covariates were explored as risk factors for RSV-febrile illness and RSV-pneumonia or hospitalization. ResultsIncidence of RSV-illness was estimated at 536.8 per 1,000 person-years, and 86% (131/153) of RSV-illness episodes were positive for RSV B. RSV-illness was most frequent in the fifth month of life and associated with having older mothers, and lower parity. The incidence of RSV-associated hospitalizations was 45.6 per 1,000 person-years. Among infants with RSV-illness, males were more likely to be hospitalized. The incidence of RSV-pneumonia was 29 cases per 1,000 person-years.DiscussionIn the first six months of life, Malian infants have a high incidence of RSV illness, primarily caused by RSV B. Prevention of early RSV will require passive protection via maternal immunization in pregnancy. Mali is the first country where RSV B had been identified as the dominant subtype, with potential implications for vaccine development.

Abstract Background The etiology and epidemiology of acute otitis media (AOM) are poorly understood in China. This study aimed to describe the etiology of AOM and the phenotypic and molecular characteristics of AOM-causing Streptococcus pneumoniae (S.pneumoniae) recovered from Chinese children. Methods A retrospective study was conducted to enrol patients younger than 18 years diagnosed as AOM. Middle ear fluid specimens were collected then cultured for bacterial pathogens. All S.pneumoniae isolates were tested for antibiotic susceptibility, serotypes, virulence genes, antibiotic resistant determinants and sequence types. Results The dominant otopathogen among AOM children was S.pneumoniae (54.4%). Among S.pneumoniae isolates, there were 97.3, 97.3 and 75.7% isolates resistant to erythromycin, tetracycline and trimethoprim-sulfamethoxazole, respectively. There was 72.8% S.pneumoniae with multidrug resistance. The dominant sequence types (STs) were ST271 and ST320, whereas the prevailing serotypes were 19F and 19A. The 7-valent and 13-valent pneumococcal conjugate vaccine (PCV) coverage among AOM children were 73.0 and 94.6%, respectively. Additionally, we found that CC271 expressed more of mef(A/E) (P 

Abstract Background Surgical site infection (SSI) is the foremost infection in the overall patient population, affecting up to 66% of operated patients and with a frequency up to nine times more than in developed countries. This study aimed to determine the rate, associated factors of surgical site infection, and identification of causative agents and their antimicrobial susceptibility in surgical ward of Wachemo University Nigist Eleni Mohamed Memorial Hospital (WUNEMMH), Southern Ethiopia. Method Prospective cohort study involving 255 patients who underwent surgical procedure in WUNEMMH from January 1 to September 1, 2017. We extracted data from medical chart, operational and anesthesia note by direct observation and interviewer administered semi-structured questionnaire which was validated. We collected wound specimens and processed it based on standard operating procedure, and disc-diffusion antibiotic susceptibility test was done. Data analysis was done using SPSS version 22.0. Factors significantly associated were identified using logistic regression model at P-value

Flamm, R. K., Rhomberg, P. R., Lindley, J. M., Sweeney, K., Ellis-Grosse, E. J., Shortridge, D.

The effect of combining fosfomycin with various antimicrobial agents was evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate 30 gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-calcoaceticus complex, and 20 Enterobacteriaceae. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with β-lactams. Two isolates of Pseudomonas aeruginosa, 2 Klebsiella pneumoniae, and 1 Acinetobacter baumannii-calcoaceticus complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.…

Ying Xu, Lu Jin, Ning liu, Xuemei Luo, Danjiang Dong, Jian Tang, Yan Wang, Yong You, Yang Liu, Ming Chen, Zhuxi Yu, Yingying Hao, Qin Gu

Abstract Background Bacillus cereus is a gram-positive rod bacterium that is responsible for food poisoning. It is naturally widely distributed, and thus often contaminates cultures. Although it is rarely considered responsible, it can cause serious infections under certain conditions. However, lethal infections, especially in immunocompetent patients, are rare. Case presentation A healthy 60-year-old man developed community-acquired B. cereus pneumonia and alveolar hemorrhage unveiled by abrupt chest pain and hemoptysis with no other advance symptoms. B. cereus induced silent alveolar destruction without any local or systemic inflammatory response. Although the lesion resembled lung anthrax, there was no evidence of Bacillus anthracis toxin. Conclusions Some isolates of B. cereus can cause anthrax-like fulminant necrotizing pneumonia in immunocompetent patients. If this type of B. cereus were used as a means of bioterrorism, it may be quite difficult to recognize as bioterrorism. We should keep B. cereus in mind as a potential pathogen of fulminant human infectious disease.…

Gingras, H., Patron, K., Bhattacharya, A., Leprohon, P., Ouellette, M.

Two whole genome screening approaches are described for studying the mode of action and the mechanisms of resistance to trimethoprim (TMP) in the Gram positive Streptococcus pneumoniae. The gain of function approach (Int-Seq) relies on a genomic library of DNA fragments integrated into a fucose-inducible cassette. The second approach leading to both gain and loss of function mutations is based on chemical mutagenesis coupled to next-generation sequencing (Mut-Seq). Both approaches pointed at the drug target dihydrofolate reductase (DHFR) as a major resistance mechanism to TMP. Resistance was achieved by dhfr overexpression either through the addition of fucose (Int-Seq) or by mutations upstream of the gene (Mut-Seq). Three type of mutations increased expression by disrupting a predicted Rho-independent terminator upstream of dhfr. Known and novel DHFR mutations were also detected by Mut-Seq and these were functionally validated for TMP resistance. The two approaches also suggested that an increase in the metabolic flux from purine synthesis to GTP and then to folate can modulate the susceptibility to TMP. We finally provide evidence for a novel role of the ABC transporter PatAB in TMP susceptibility. Our genomic screens highlighted novel aspects on the mode of action and resistance mechanisms to antibiotics.…

Galani Irene, Antoniadou Anastasia, Karaiskos Ilias, Kontopoulou Κostantina, Giamarellou Helen, Souli Maria

We characterized the first ceftazidime-avibactam-resistant KPC-producing-Klebsiella pneumoniae clinical isolate detected in Greece, before the introduction of ceftazidime-avibactam in clinical practice.

Shi T, Denouel A, Tietjen A, et al.

AbstractPneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8–8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9–1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Santiago Ewig, Martin Kolditz, Mathias W. Pletz, James Chalmers

There is an ongoing controversy on the role of the HCAP label in the treatment of patients with pneumonia.

Abstract Background Extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) represent a major problem in the management of nosocomial infections. However, ESBL-PE are not systematically monitored in African countries. The aim of this study was to determine ESBL-PE prevalence in patients from three hospitals in N’Djamena, the capital city of Chad, and to characterize the genetic origin of the observed resistance. Methods From January to March 2017, 313 non-duplicate isolates were recovered from various clinical specimens obtained from 1713 patients in the three main hospitals of N’Djamena. Bacterial species were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Susceptibility to 28 antibiotics was tested using the disk diffusion method on Müller-Hinton agar, and ESBL production was confirmed with the double-disc synergy test. The most prevalent ESBL genes associated with the observed resistance were detected using multiplex PCR followed by double-stranded DNA sequencing. Results Among the 313 isolates, 197 belonged to the Enterobacteriaceae family. The overall ESBL-PE prevalence was 47.72% (n = 94/197), with a higher rate among inpatients compared with outpatients (54.13% vs. 34.37%). ESBL-PE prevalence was highest in older patients (≥60 years of age). E. coli was the most common ESBL-producer organism (63.8%), followed by K. pneumoniae (21.2%). ESBL-PE were mainly found in urine samples (75%). The CTX-M-1 group was dominant (96.7% of the 94 ESBL-PE isolates, CTX-M-15 enzyme), followed by the CTX-M-9 group (4.1%). 86% of resistant isolates harbored more than one ESBL-encoding gene. ESBL production was also associated with the highest levels of resistance to non-β-lactam drugs. Conclusions The prevalence of ESBL-PE harboring resistant genes encoding ESBLs of the CTX-M-1 group was high (48%) among clinical isolates of three main hospitals in Chad, suggesting an alarming spread of ESBL-PE among patients.…

Tomas-Paul Cusack, Elizabeth A. Ashley, Clare L. Ling, Sayaphet Rattanavong, Tamalee Roberts, Paul Turner, Tri Wangrangsimakul, David A.B. Dance

We investigated the impact of breakpoint discrepancies between CLSI and EUCAST on susceptibility interpretation of clinical isolates at the Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos and performed a literature search to compare our findings to published reports. Zone diameters for first-line antimicrobial agents tested against non-duplicate clinical isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in 2017 were interpreted separately using EUCAST 2018 and CLSI 2018 breakpoints and greement measured.