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

Pierre-François Laterre, Gwenhael Colin, Pierre-François Dequin, Thierry Dugernier, Thierry Boulain, Samareh Azeredo da Silveira, Frédéric Lajaunias, Antonio Perez, Bruno François

The nature of adverse events was consistent with the profile of the study population and CAL02 showed a promising safety profile and tolerability. However, the difference between high-dose and low-dose CAL02 could not be assessed in this study. Efficacy was in line with the expected benefits of neutralising toxins. The results of this study support further clinical development of CAL02 and provide a solid basis for a larger clinical study.

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.

Anne Paschke, Ulrich E Schaible, Wolfgang Hein

Legionnaires' disease, a type of legionellosis caused by Legionella pneumophila, can cause severe atypical bacterial pneumonia and Pontiac fever after inhalation of contaminated aerosols. The disease is severely underdiagnosed and underreported because of its non-specific symptoms and the low sensitivity of available diagnostic tests.1 In Germany, for example, the 600–900 cases reported per year are estimated to represent less than 5% of actual cases.2 In many countries, the disease is not even notifiable, and the sources of many outbreaks and almost all sporadic infections worldwide remain unidentified.

Mathias W Pletz, Michael Bauer, Axel A Brakhage

In The Lancet Infectious Diseases, Pierre-François Laterre and colleagues1 present the promising results of a first-in-human study of CAL02, a novel antitoxin liposomal agent administered as an adjunct to antibiotic therapy in severe community-acquired pneumococcal pneumonia. Two doses of CAL02 were administered, with a 24 h interval. CAL02 consists of a mixture of small, empty, uncoated unilamellar liposomes that act as traps for a broad panel of bacterial toxins known to be inserted in cellular membranes.

Geraint B Rogers

Acute lower respiratory tract infections (LRTIs) are a major source of early life morbidity and the principal infectious cause of infant mortality.1 A growing body of research suggests that the microbiome of the upper respiratory tract substantially influences the incidence and severity of LRTIs. The nasopharyngeal mucosa is the first line of defence against airborne pathogens. In addition to the mechanisms of host innate immunity, the commensal microbiota suppresses the expansion of populations of opportunistic pathogens that are common in the nasopharynx—including Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus—through a combination of competitive exclusion, suppression of virulence through direct inter-species interaction, and regulation of local immunity.

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.

Ann Danaiya Usher

Pneumococcal vaccination could become less costly for Gavi, The Vaccine Alliance, as a new, cheaper, alternative hits the market. Ann Danaiya Usher reports.

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 Botrytis species are well known fungal pathogens of various plants but have not been reported as human pathogens, except as allergenic precipitants of asthma and hypersensitivity pneumonitis. Case presentation The asymptomatic patient was referred because of a nodule revealed by chest X-ray. Computed tomography (CT) showed a cavitary nodule in the right upper lobe of the lung. He underwent wedge resection of the nodule, which revealed necrotizing granulomas and a fungus ball containing Y-shaped filamentous fungi, which was confirmed histopathologically. Culture of the specimen yielded white to grayish cotton-like colonies with black sclerotia. We performed multilocus gene sequence analyses including three single-copy nuclear DNA genes encoding glyceraldehyde-3-phosphate dehydrogenase, heat-shock protein 60, and DNA-dependent RNA polymerase subunit II. The analyses revealed that the isolate was most similar to Botrytis elliptica. To date, the pulmonary Botrytis sp. infection has not recurred after lung resection and the patient did not require any additional medication. Conclusions We report the first case of an immunocompetent patient with pulmonary Botrytis sp. infection, which has not recurred after lung resection without any additional medication. Precise evaluation is necessary for the diagnosis of pulmonary Botrytis infection because it is indistinguishable from other filamentous fungi both radiologically and by histopathology. The etiology and pathophysiology of pulmonary Botrytis infection remains unclear. Further accumulation and analysis of Botrytis cases is warranted.…

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.…

Rowe, H. M., Mann, B., Iverson, A., Poole, A., Tuomanen, E., Rosch, J. W.

Acute otitis media is one of the most common childhood infections worldwide. Currently licensed vaccines against the common otopathogen, Streptococcus pneumoniae, target the bacterial capsular polysaccharide and confer no protection against non-encapsulated strains or capsular types outside of vaccine coverage. Mucosal infections such as acute otitis media remain prevalent, even those caused by vaccine-covered serotypes. Here we report that a protein-based vaccine, a fusion construct of epitopes of CbpA to pneumolysin toxoid, confers effective protection against pneumococcal acute otitis media for non-PCV-13 serotypes and enhances protection for PCV-13 serotypes when co-administered with PCV-13. Having crossreactive epitopes, the fusion protein also induces potent antibody responses against non-typeable Haemophilus influenzae and S. pneumoniae, engendering protection against acute otitis media caused by emerging unencapsulated otopathogens. These data suggest that augmenting capsule-based vaccination with conserved, cross-reactive protein-based vaccines may broaden and enhance protection against acute otitis media.…

Derick Ansah, Jerusha Weaver, Beatriz Munoz, Evan M. Bloch, Christian L. Coles, Thomas Lietman and Sheila K. West

Abstract. Mass drug administration (MDA) for trachoma control using azithromycin has generated concern for the development of resistant organisms. However, the contribution from azithromycin available in local pharmacies has not been studied. In Kilosa district, Tanzania, MDA stopped over 4 years ago, and this study sought to determine the availability of azithromycin in local pharmacies and correlate it with azithromycin resistance in children born after MDA. A cross-sectional survey was conducted in 644 randomly selected hamlets in Kilosa district, in which the presence of a pharmacy and the availability of azithromycin and erythromycin were determined. In 30 randomly selected hamlets, a random sample of 60 children less than 5 years were tested for azithromycin-resistant Streptococcus pneumoniae (Spn) and Escherichia coli (Ec), from nasopharyngeal and rectal swabs, based on disk diffusion criteria. Only 26.6% of hamlets had a pharmacy. Azithromycin and erythromycin were available in 30.8% and 89.1% of pharmacies closest to the hamlets, respectively. In the 30 communities tested for resistance, the overall prevalence of azithromycin-resistant Spn isolates was 14%. Six of seven (87%) hamlets where azithromycin was available had resistant Spn, compared with 14 of 23 (61%) hamlets without availability. Similarly, six of seven (87%) hamlets where azithromycin was available had resistant Ec isolates compared with 21 of 23 (70%) hamlets without availability. However, the differences were not statistically significant (P = 0.46 and 0.49, respectively). The availability of azithromycin in pharmacies in the district was limited, and a strong correlation with azithromycin-resistant Spn or Ec was not observed.…

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.…

Konze, S. A., Abraham, W.-R., Goethe, E., Surges, E., Kuypers, M. M. M., Hoeltig, D., Meens, J., Vogel, C., Stiesch, M., Valentin-Weigand, P., Gerlach, G.-F., Buettner, F. F. R.

Actinobacillus pleuropneumoniae is a capnophilic pathogen of the porcine respiratory tract lacking enzymes of the oxidative branch of the tricarboxylic acid (TCA) cycle. We previously claimed that A. pleuropneumoniae instead uses the reductive branch in order to generate energy and metabolites. Here we show that bicarbonate and oxaloacetate supported anaerobic growth of A. pleuropneumoniae. Isotope mass spectrometry revealed heterotrophic fixation of carbon from stable isotope labeled bicarbonate by A. pleuropneumoniae which was confirmed by nano-scale secondary ion mass spectrometry at a single cell level. By gas chromatography-combustion-isotope ratio mass spectrometry we could further show that the labeled carbon atom is mainly incorporated into the amino acids aspartate and lysine, which are derived from the TCA metabolite oxaloacetate. We therefore suggest that carbon fixation occurs at the interface of glycolysis and the reductive branch of the TCA cycle. The heme precursor -aminolevulinic acid supported growth of A. pleuropneumoniae similar to bicarbonate implying that anaplerotic carbon fixation is needed for heme synthesis. However, deletion of potential carbon fixing enzymes including PEP-carboxylase (PEPC), PEP-carboxykinase (PEPCK), malic enzyme and oxaloacetate decarboxylase as well as various combinations thereof did not affect carbon fixation. Interestingly, generation of a deletion mutant lacking all four enzymes was not possible suggesting that carbon fixation in A. pleuropneumoniae is an essential metabolic pathway controlled by a redundant set of enzymes. A double deletion mutant lacking PEPC and PEPCK was not impaired in carbon fixation in vitro, but showed reduction of virulence in a pig infection model.…

Brennan, Alana T; Bonawitz, Rachael; Gill, Christopher J.; Thea, Donald M; Kleinman, Mary; Long, Lawrence; McCallum, Caitryn; Fox, Matthew P

Objective: Prior studies have demonstrated that HIV-exposed uninfected (HEU) infants and children experience morbidity and mortality at rates exceeding those of their HIV-unexposed uninfected (HUU) counterparts. We sought to summarize the association between HEU vs. HUU infants and children for the outcomes of diarrhea and pneumonia. Design: Meta-analysis. Methods: We reviewed studies comparing infants and children in the two groups for these infectious disease outcomes, in any setting, from 1993 to 2018 from six databases. Results: We included 12 studies, and 17,955 subjects total (n=5,074 (28.3%) HEU and n=12,881 (71.7%) HUU). Random effects models showed HEU infants and children had a 20% increase in the relative risk of acute diarrhea and a 30% increase in the relative risk of pneumonia when compared to their HUU counterparts. When stratifying by time since birth, we showed that HEU vs. HUU children had a 50% and 70% increased risk of diarrhea and pneumonia, respectively, in the first 6-months of life. Conclusion: We show an increased risk of diarrhea and pneumonia for HEU vs. HUU infants and children. Although we acknowledge, and commend, the immense public health success of prevention of mother-to-child transmission, we now have an enlarging population of children that appear to be vulnerable to not only death, but increased morbidity. We need to turn our attention to understanding the underlying mechanism and designing effective public health solutions. Further longitudinal research is needed to elucidate possible underlying immunological and/or sociological mechanisms that explain these differences in morbidity. Corresponding Author Details: Department of Global Health Boston University Crosstown Center, 3rd Floor, 801 Massachusetts Ave Boston, MA 02118 Phone: 617-414-1479, E-mail: abrennan@bu.edu The authors report no conflicts of interest related to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.…

Abstract Background Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab. Case presentation An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine. Conclusions We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.…

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.

Darpo, B., Xue, H., Tanaka, S. K., Tzanis, E.

Omadacycline, an aminomethylcycline, is a once-daily intravenous (i.v.) and oral antibiotic that is approved in the United States for treatment of adults with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. In this thorough QT study, the effects of a therapeutic (100 mg i.v.) and a supratherapeutic (300 mg i.v.) dose of omadacycline on the electrocardiogram were studied, with placebo and moxifloxacin as negative and positive controls. Omadacycline at these doses had no effect on the QTc interval. The largest mean placebo-corrected change-from-baseline QTcS (placebo-corrected QTcS) was 1.7 ms (90% confidence interval [CI], 0.06 to 3.30) and 2.6 ms (90% CI, 0.55 to 4.67), observed at 20 min and 2 h after the start of the infusion of 100 mg and 300 mg, respectively. Assay sensitivity was demonstrated with moxifloxacin, which caused clear prolongation of QTcS with the largest mean placebo-corrected QTcS of 9.8 ms at 1.5 and 2 h. With a linear exposure–response model, the estimated slope of the concentration–QTcS relationship was very shallow: 0.0007 ms per ng/ml (90% CI, 0.0000 to 0.0014). An effect on placebo-corrected QTcS exceeding 10 ms can be excluded at omadacycline concentrations in plasma up to ~8 μg/ml. Omadacycline had no effect on cardiac conduction (PR and QRS intervals), but caused an increase in heart rate of 16.8 beats per minute at 35 min after the 100-mg dose and 21.6 beats per minute at 50 min after the 300-mg dose.…

Abstract Background As technology progresses, several highly sensitive human immunodeficiency virus (HIV) screening kits are being researched and developed to quickly and efficiently identify serum HIV antibodies within the non-window period. In individuals who are HIV-seronegative, HIV infections that are not within a window period are rare. In such cases, all antibody detection methods will fail, and misdiagnosing these patients will have catastrophic consequences. Case presentation A 22-year-old male Chinese patient with diffuse exudative lesions in both lungs and initial symptoms of cough and dyspnoea was diagnosed with Pneumocystis jirovecii pneumonia (PJP) by aetiological examination, and the patient’s plasma CD4+ T-cell count was extremely low. In China, PJP is prevalent in HIV-infected individuals. Pneumocystis jirovecii (P. jirovecii) has a high colonisation rate in patients with HIV infections. This patient was naturally suspected of being an HIV patient; however, serum HIV antibody tests were negative using both an enzyme-linked immunosorbent assay (ELISA) and a latex agglutination assay, and HIV was not detected by western blotting. Subsequently, the plasma HIV viral load was found to be extremely high on two repeated plasma HIV RNA tests, thus confirming HIV-seronegative acquired immunodeficiency syndrome (AIDS) in this patient. With administration of effective anti-P. jirovecii treatment and highly active antiretroviral therapy (HAART) after diagnosis, the patient’s disease condition was rapidly controlled. Conclusion This is the second reported case in China of an HIV-seronegative AIDS patient. Such cases are also rare worldwide. Although HIV-seronegative HIV infections are rare, AIDS should be considered in immunodeficient patients with opportunistic infections, even if the test results are HIV-seronegative. Plasma HIV RNA testing is important for such patients.…

Singh, A. K., Curtiss, R., Sun, W.

In this study, a novel recombinant attenuated Yersinia pseudotuberculosis PB1+ strain (10069) engineered with yopK yopJ and asd triple mutations was used to deliver a Y. pestis fusion protein YopENt138-LcrV to Swiss Webster mice as a protective antigen against yersiniae infections. 10069 harboring the pYA5199 plasmid constitutively synthesize the YopENt138-LcrV fusion protein and secreted this protein via the Type 3 secretion system (T3SS) at 37°C and under calcium-deprived conditions. The attenuated 10069(pYA5199) strain was manifested by the establishment of controlled infection in different tissues without developing conspicuous signs of disease in histopathological analysis of microtome sections. A single-dose oral immunization of 10069(pYA5199) induced strong serum antibody titers (log10 mean value; 4.2), secretory IgA in bronchoalveolar lavage (BAL) of immunized mice, and Yersinia-specific CD4+ and CD8+ T cells producing high levels of TNF-α, IFN-, IL-2 as well as IL-17 in both lung and spleen of immunized mice, conferring comprehensive Th1- and Th2-mediated immune responses and protection against bubonic and pneumonic plague challenges with 80% and 90% survival, respectively. Mice immunized with 10069(pYA5199) also exhibited complete protection against lethal oral infections of Y. enterocolitica WA and Y. pseudotuberculosis PB1+. These findings indicated 10069(pYA5199) as an oral vaccine induces protective immunity to prevent bubonic and pneumonic plague as well as yersiniosis in mice and would be a promising oral vaccine candidate for protection against plague and yersiniosis for human and veterinary applications.…

Giordano, L., Fiori, B., D'Inzeo, T., Parisi, G., Liotti, F. M., Menchinelli, G., De Angelis, G., De Maio, F., Luzzaro, F., Sanguinetti, M., Posteraro, B., Spanu, T.

We directly tested 484 organisms from clinical (n = 310) and simulated (n = 174) positive blood cultures using the NG-Test CARBA 5 assay for carbapenemase-producing Enterobacterales detection. The assay identified all but four of the KPC (170/171), OXA-48-like (22/22), VIM (19/21), and NDM (14/15) producers with no false-positives. Among the clinical K. pneumoniae organisms tested, 122/123 KPC, 1/1 OXA-48-like, and 1/2 VIM producers were detected by the assay. Some VIM and NDM producers yielded scant but still readable bands with the assay. No organisms produced the IMPs that the assay was designed to detect.…

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.…

Canver, M. C., Satlin, M. J., Westblade, L. F., Kreiswirth, B. N., Chen, L., Robertson, A., Fauntleroy, K., Spina, M. L., Callan, K., Jenkins, S. G.

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health threat. We evaluated the in vitro activities of 19 antimicrobial agents including imipenem-relebactam against: a) 106 CRE bloodstream isolates that primarily expressed Klebsiella pneumoniae carbapenemase (KPC); and b) 20 OXA-48-like-expressing CRE isolates. Ninety-five percent of CRE bloodstream isolates were susceptible to imipenem-relebactam. In contrast to their comparable activity against KPC-producing CRE, ceftazidime-avibactam was more active in vitro against OXA-48-like CRE than imipenem-relebactam (90% susceptible vs. 15% susceptible).…

Perazella MA.

To the Editor A JAMA Diagnostic Test Interpretation article addressed the test characteristics of serum creatinine in critically ill patients with sepsis. The authors presented a patient with pneumonia and septic shock who developed acute kidney injury (AKI) on day 3. They discussed serum creatinine as a marker of glomerular filtration rate (GFR), noting the deficiencies of the test in patients who have received significant volume resuscitation. They noted that the biomarkers of kidney injury do not directly measure GFR, but neither does serum creatinine.

Davide Mangioni, Giacomo Grasselli, Chiara Abbruzzese, Antonio Muscatello, Andrea Gori, Alessandra Bandera

Abstract Background The point mutations in 23S rRNA gene of Mycoplasma pneumoniae (M. pneumoniae) can lead to high-level resistance to macrolides. This study aimed to evaluate allele-specific real-time PCR (ASPCR) to detect the resistance-related mutations located at positions A2063G and A2064G of 23S rRNA gene. Methods We detected 178 pharyngeal swab specimens and calculated the proportions of resistant and sensitive quasispecies using ASPCR assays. ASPCR assays can detect down to 10 copies of 23S rRNA gene and achieved sensitivities of

Julie A. Preston, Martin A. Bewley, Helen M. Marriott, A. McGarry Houghton, Mohammed Mohasin, Jamil Jubrail, Lucy Morris, Yvonne L. Stephenson, Simon Cross, David R. Greaves, Ruth W. Craig, Nico van Rooijen, Colin D. Bingle, Robert C. Read, Timothy J. Mitchell, Moira K. B. Whyte, Steven D. Shapiro, David H. Dockrell

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 1, Page 84-97, July 1, 2019. …

Silver, R. J., Paczosa, M. K., McCabe, A. L., Balada-Llasat, J.-M., Baleja, J. D., Mecsas, J.

The emergence of multi-drug resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and WT mice. The limited pool of amino acids in the lung did not change during infection and was insufficient for K. pneumoniae to overcome attenuating mutations in aroA, hisA, leuA, leuB, serA, serB, trpE and tyrA in WT and immunosuppressed mice. Deletion of aroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreased K. pneumoniae growth in the lungs. K. pneumoniae expressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants in K. pneumoniae yielded no mutations in aroA. Strikingly, glyphosate treatment of mice lowered the bacterial burden of 2 of 3 spontaneous glyphosate-resistant mutants and further lowered the burden of the less attenuated EPSP synthase catalytic mutant. Nine of 39 clinical isolate strains were resistant to glyphosate at levels comparable to those of selected resistant strains and none appeared more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential for K. pneumoniae infection are promising novel therapeutic targets.…

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.…

Wegene Borena, Simon Kruis, Maria Kitchen, Ninon Taylor, Martin Gisinger, Hannes Oberkofler, Heribert Stoiber, Robert Zangerle, Dorothee von Laer, Mario Sarcletti

Ureaplasma species (Ureaplasma spp.) are commonly considered to be part of the normal flora but are also capable of causing clinical illnesses. Among women they are responsible mainly for non-gonococcal urethritis and bacterial vaginosis. Serious complications may occur during pregnancy and after delivery with manifestations like chorioamnionitis, post-partum and post-abortal fever, congenital pneumonia, neonatal bacteremia and neonatal abscesses (Zhang et al.,2014; de Cordova et al., 2016).

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.…

Marimuthu, K., Ng, O. T., Cherng, B. P. Z., Fong, R. K. C., Pada, S. K., De, P. P., Ooi, S. T., Smitasin, N., Thoon, K. C., Krishnan, P. U., Ang, M., Chan, D. S. G., Kwa, A. L. H., Deepak, R. N., Chan, Y. K., Chan, Y. F. Z., Huan, X., Linn, K. Z., Tee, N. W. S., Tan, T. Y., Koh, T. H., Lin, R. T. P., Hsu, L. Y., Sengupta, S., Paterson, D. L., Perencevich, E., Harbarth, S., Teo, J., Venkatachalam, I., CaPES study group

Carbapenem-resistant Enterobacteriaceae (CRE) can be mechanistically classified into carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing carbapenem non-susceptible Enterobacteriaceae (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CNSE colonization and infection, we conducted a case-control study comparing patients with NCPCRE (cases) and patients with CPE (controls). Presence of carbapenemases was investigated with phenotypic tests followed by polymerase chain reaction (PCR) for predominant carbapenemase genes. We included 843 unique patients with first-episode CRE: 387 (45.9%) NCPCRE and 456 (54.1%) CPE. CPEs were mostly blaNDM (42.8%), blaKPC (38.4%), and blaOXA-48-like (12.1%). After adjusting for confounders and clustering at the institutional level, the odds of prior 30-day carbapenem exposure was three times higher among NCPCRE compared to CPE patients [lsqb]adjusted odds ratio (aOR), 3.16; 95% confidence interval (CI), 2.19-4.55; P

Parquet, M. d. C., Savage, K. A., Allan, D. S., Ang, M. T. C., Chen, W., Logan, S. M., Holbein, B. E.

Acinetobacter baumannii is a major cause of nosocomial infections especially hospital-acquired pneumonia. This bacterium readily acquires antibiotic resistance traits and therefore, new treatment alternatives are urgently needed. The virulence of A. baumannii linked to iron acquisition suggests a potential for new anti-infectives that target its iron acquisition. DIBI is a purpose-designed, iron-sequestering, anti-microbial that has shown promise for treating microbial infection. DIBI was investigated for its in vitro and in vivo activities against clinical A. baumannii isolates. DIBI was inhibitory for all isolates tested with very low MICs (2 μg/mL equivalent to 0.2 μM), i.e., at or below the typical antibiotic MICs reported for antibiotic sensitive strains. DIBI inhibition is Fe-specific and it caused an iron-restricted bacterial physiology which led to enhanced antibiotic killing by several discrete antibiotics. DIBI also strongly suppressed recovery growth of the surviving population following antibiotic exposure. A low intranasal dose (11 μmol/kg) of DIBI following intranasal challenge with hypervirulent ciprofloxacin (CIP)-resistant A. baumannii LAC-4, significantly reduced bacterial burdens in mice and DIBI also supressed the spread of the infection to the spleen. Treatment of infected mice with CIP alone (20mg/kg equivalent to 60 μmole/kg) was ineffective given LAC-4's CIP resistance but if combined with DIBI, the treatment efficacy improved significantly. Our evidence suggests that DIBI restricts host iron availability to A. baumannii growing in the respiratory tract, bolstering the host innate iron restriction mechanisms. DIBI has potential as a sole anti-infective or in combination with conventional antibiotics for the treatment of A. baumannii pneumonia.…

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.

Kubale J, Kuan G, Gresh L, et al.

AbstractBackgroundRespiratory syncytial virus (RSV) causes substantial morbidity and mortality among children worldwide, commonly through acute lower respiratory tract infections (ALRI). To assess the incidence of symptomatic RSV illness among young children, we conducted a prospective birth cohort study following children from 0-2 years of age in Managua, Nicaragua.MethodsChildren meeting the testing criteria (fever, history of fever, or severe respiratory symptoms [apnea, stridor, nasal flaring, wheezing, chest indrawing, and/or central cyanosis]), were tested for RSV infection using real-time reverse transcriptase-polymerase chain reaction. Acute lower respiratory infection was defined as diagnosis of pneumonia, bronchiolitis, bronchitis, or bronchial hyper-reactivity. Incidence was calculated, and 95% confidence intervals estimated using a Poisson distribution.ResultsA total of 833 children participated in the cohort, 289 (34.7%) had at least one episode of laboratory-confirmed RSV, and 156 (18.7%) of RSV-associated ALRI (RSV-ALRI). The incidence of symptomatic RSV was 248.1 cases per 1000 person-years (95% confidence interval [CI]: 223.2, 275.7). While infants aged 6-11 months had the highest incidence of symptomatic RSV (361.3/1000 person-years, 95% CI: 304.4, 428.8), infants

Abstract Background To detect carbapenemase-producing Gram-negative bacteria in bacterial laboratories at medical settings, a new immunochromatographic assay for New Delhi metallo-β-lactamases (NDMs) was developed. Methods The immunochromatographic assay for New Delhi metallo-β-lactamases producers was developed using rat monoclonal antibodies against NDMs. The assessment was performed using 350 isolates of Gram-negative bacteria, including Acinetobacter baumannii (51 isolates), Enterobacteriaceae (163 isolates), and Pseudomonas aeruginosa (136 isolates) obtained from 2015 to 2017 in medical settings in Myanmar. Of them, 302 isolates were resistant to carbapenems, including imipenem and/or meropenem. The blaNDM genes were identified by PCR and sequencing. Results Of the 350 clinical isolates tested, 164 (46.9%) (60 isolates of Escherichia coli, 51 isolates of Klebsiella pneumoniae, 25 isolates of Enterobacter cloacae, 23 isolates of P. aeruginosa, and 5 isolates of A. baumannii) were positive on this assay, and all the positive isolates harbored genes encoding NDM-1, − 4, − 5 and − 7. The remaining 186 (53.1%) isolates negative on the assay did not harbor genes encoding NDMs. The assay had a specificity of 100% and a sensitivity of 100%. The assessment revealed that more than 90% of carbapenem-resistant Enterobacteriaceae produced NDMs. Conclusions The immunochromatographic assay is an easy-to-use and reliable kit for detection of NDMs-producing Gram-negative bacteria. The assay revealed that NDM-producing Enterobacteriaceae isolates are wide-spread in medical settings in Myanmar.…

Echivard, Mathieu; Lichtenstein, Daniel A.; Lala, Adrian; Sanchez, Anais Perez; Girerd, Nicolas

Objectives: Lung ultrasound has shown increasing diagnostic value in many lung diseases and has become an efficient tool in the management of dyspnea. In the present case report, we describe a new ultrasound feature of potential interest. Data Sources: Clinical observation of a patient. Study Selection: Case report. Data Extraction: Data were extracted from medical records, after obtaining consent from the patient’s family. Illustrations were extracted from the imaging software and a video device. Data Synthesis: A 56-year-old man was admitted with pneumonia of adverse outcome. Lung ultrasound, a method increasingly considered as a bedside gold standard in critically ill patients due to its overwhelming advantages, was the only tool able to specify the lung injuries. We describe herein a distinctive sign unequivocally evoking a destructive process suggestive of pulmonary gangrene, a variant of the fractal sign combining a lung consolidation with an underlying heterogeneous free fluid. Conclusions: Lung ultrasound may help highlight pulmonary gangrene, a poorly-known disease, with this new ultrasonographic description. The next step will be to ascertain the relation between this new ultrasound feature and pulmonary gangrene and to assess how this bedside diagnosis could impact the prognosis of the disease. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Lichtenstein received funding from Novartis (board fees) and honoraria from Boehringer and Servier. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: m.echivard@neuf.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

M. Klompas

The CDC expanded the purview of safety surveillance for ventilated patients from ventilator-associated pneumonia (VAP) to ventilator-associated events (VAE) in 2013. CDC created VAE definitions to simplify surveillance, increase objectivity, and broaden prevention efforts. Many U.S. hospitals are conducting VAE surveillance but uptake beyond the U.S. has been limited. Review of recent publications suggest three major barriers to the adoption of VAE surveillance and prevention: 1) ongoing uncertainty about VAE and concern about its limited overlap with clinically-defined VAP, 2) a paucity of studies defining risk factors for VAEs and how best to prevent VAEs, and 3) lack of emphasis on VAE surveillance and prevention by regulatory agencies.

Abstract Background Bloodstream infections (BSI) are associated with high morbidity and mortality. This scenario worsens with the emergence of drug-resistant pathogens, resulting in infections which are difficult to treat or even untreatable with conventional antimicrobials. The aim of this study is to describe the epidemiological aspects of BSI caused by multiresistant gram-negative bacilli (MDR-GNB). Methods We conducted a laboratory-based surveillance for gram-negative bacteremia over a 1-year period. The bacterial isolates were identified by MALDI-TOF/MS and the antimicrobial susceptibility testing was performed by VITEK®2. Resistance genes were identified through PCR assays. Results Of the 143 patients, 28.7% had infections caused by MDR-GNB. The risk factors for MDR bacteremia were male sex, age ≥ 60, previous antimicrobial use, liver disease and bacteremia caused by K. pneumoniae. K. pneumoniae was the most frequently observed causative agent and had the highest resistance level. Regarding the resistance determinants, SHV, TEM, OXA-1-like and CTX-M-gp1 were predominant enzymatic variants, whereas CTX-M-gp9, CTX-M-gp2, KPC, VIM, GES, OXA-48-like, NDM and OXA-23-like were considered emerging enzymes. Conclusions Here we demonstrate that clinically relevant antibiotic resistance genes are prevalent in this setting. We hope our findings support the development of intervention measures by policy makers and healthcare professionals to face antibiotic resistance.…

Leith Greenslade, Amy Sarah Ginsburg

We welcome the announcement of the Africa Collaborative Initiative to Advance Diagnostics (AFCAD) by the Africa Centres for Disease Control and Prevention, as reported by Munyaradzi Makoni.1 However, there is a crucial omission in the list of AFCAD focus areas: pneumonia. Not only is pneumonia the leading infectious cause of mortality across Africa, but it is also the leading cause of all mortality, according to the latest Global Burden of Disease estimates.2 In 2017, pneumonia caused an estimated 695 000 deaths, compared with 543 000 deaths attributable to malaria, 529 000 deaths to HIV/AIDS, and 367 000 deaths to tuberculosis.

Rybitschka, Anja; Semmlack, Saskia; Kaplan, Peter W.; De Marchis, Gian Marco; Rüegg, Stephan; Marsch, Stephan; Sutter, Raoul

Objectives: Recommendations regarding nutrition during status epilepticus are lacking, and it is unclear whether restriction of calorie intake would result in beneficial effects or potential harm. We thus aimed to investigate associations between daily calorie intake and outcome in adult status epilepticus patients deriving from a 5-year cohort with a systematic and prospective collection of nutritional data. Design: Retrospective observational study. Setting: Medical ICUs at a tertiary academic medical care center. Patients: Consecutive patients with status epilepticus treated at the ICUs from 2012 to 2016 were included. Interventions: None. Measurements and Main Results: All patients with status epilepticus were monitored regarding nutrition support provided according to the guidelines. Relative risks of no return to baseline were estimated by Poisson regression with robust error variance and adjusted for potential confounders. Of 203 patients, 86 (42%) had return to baseline. Metabolic characteristics of patients with and without return to baseline did not differ. Patients without return to baseline received more calories and proteins per status epilepticus day, and increasing nutritional support was associated with ventilator-associated pneumonia (relative risk, 1.19; 95% CI, 1.09–1.28). Multivariable regression analysis revealed significant increases in relative risks for no return to baseline with every percent of days with nutrition (relative risk, 1.35; 95% CI, 1.05–1.74), with every 100 kcal (relative risk, 1.01; 95% CI, 1.002–1.01), and gram of protein intake (relative risk, 1.01; 95% CI, 1.001–1.01) per status epilepticus day, independent of potential confounders (including fatal etiology, duration and severity of status epilepticus, Charlson comorbidity index, and treatment with anesthetics). Conclusions: Our results indicate that increased calorie intake during status epilepticus is independently associated with unfavorable outcome. These findings require further validation and investigations into potential mediators, such as induction of ketogenesis, immunomodulating effects, and/or reduction of ICU-associated complications, such as infections. Drs. Rybitschka and Sutter planned the work, acquired and interpreted the data, and wrote the manuscript. Dr. Semmlack, Mr. Kaplan, Dr. De Marchis, Dr. Rüegg, and Dr. Marsch interpreted the data, revised the manuscript, and substantially contributed to the inaugural draft. All authors approved the final submitted version. Mr. Kaplan has provided unsponsored grand rounds, published books on EEG, status epilepticus, and epilepsy for which he received honoraria, has consulted for Cadwell, has been on the board of the ABCN, ICCN, and the ACNS. Dr. Semmlack disclosed government work. Mr. Kaplan has provided unsponsored grand rounds; published books on electroencephalography (EEG), status epilepticus, and epilepsy for which he received honoraria; has consulted for Cadwell; and has been on the board of the ABCN, ICCN, and the ACNS. Dr. De Marchis is supported by the Swiss National Science Foundation; Science Funds of the University Hospital Basel and University of Basel; Bangerter-Rhyner Foundation; the Swisslife Jubiläumsstiftung for Medical Research; the Swiss Neurological Society; the Fondazione Dr. Ettore Balli; De Quervain research grant; and the Thermo Fisher GmbH. He received travel honoraria by Bayer and speaker honoraria by Medtronic and BMS/Pfizer. Dr. Rüegg received unconditional research grants from UCB-pharma. He received honoraria from serving on the scientific advisory boards of Desitin, Eisai, GlaxoSmithKline (GSK), and UCB-pharma; travel grants from GSK, Janssen-Cilag, and UCB-pharma; and speaker fees from UCB-pharma and from serving as a consultant for Eisai, GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB-pharma. He does not hold any stocks of any pharmaceutical industries or manufacturers of medical devices. He received funding from Sandoz Switzerland; Novartis Oncology, Switzerland; Desitin GmbH, Switzerland; Editor Swiss EEG-Bulletin, support of UCB Switzerland and EGI USA Portland, currently Philips, Eindhoven, The Netherlands; and the Swiss Society of Clinical Neurophysiology and Swiss Neurological Society. He received funding from UCB-pharma, Novartis, and Swiss National Science Foundation Grants: grant number 320030_169379/1 and coapplicant for grants numbers 33CM30_125115/1 and 33CM30_140338/1; he disclosed that he is the president of the Swiss League against Epilepsy (no payments), Editor of EPILEPTOLOGIE (Journal of the Swiss League against Epilepsy) (no payments), and Editor of the Swiss EEG Bulletin (payments from UCB); he received honoraria from serving on the scientific advisory boards of Desitin, Eisai, GSK, and UCB-pharma; travel grants from GSK, Janssen-Cilag, and UCB-pharma; and speaker fees from UCB-pharma. Dr. Sutter received research grants from the Swiss National Foundation (No 320030_169379), the Research Fund of the University Basel, the Scientific Society Basel, and the Bangerter-Rhyner Foundation. He received personal grants from UCB-pharma and holds stocks from Novartis, Roche, and Johnson & Johnson. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at the University Hospital Basel, Basel, Switzerland. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. For information regarding this article, E-mail: raoul.sutter@usb.ch 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.

Abstract Background Spontaneous bacterial peritonitis (SBP) is a serious complication and common cause of death in patients with liver cirrhosis. This study was conducted to compare the microbiological characteristics, drug resistance, and treatment outcomes for nosocomial SBP and community-acquired SBP. Methods A retrospective study was performed on 334 patients with culture-positive SBP at Beijing Youan Hospital, China, between January 2012 and December 2016. The medical records for these patients were reviewed, and their clinical and laboratory data were analyzed. Results A total of 155 (46.4%) patients with nosocomial SBP and 179 (53.6%) with community-acquired SBP were included in this study. From the patients’ ascitic fluids, 334 pathogenic strains, including 178 Gram-negative bacterial strains, 138 Gram-positive bacterial strains and 18 other microbial strains were isolated. E. coli was the major pathogen (24.3%), followed by Klebsiella pneumoniae (12.0%) and Enterococcus faecium (10.5%). The proportion of Enterococcus was significantly higher in the patients with nosocomial SBP (6.1% vs. 27.7%, P