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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.
Simon Portsmouth, David van Veenhuyzen, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Peter Tenke, Tsutae Den Nagata
Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing.
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.
Salvatore Maurizio Maggiore, Mariangela Battilana, Luca Serano, Flavia Petrini
The periextubation period represents a crucial moment in the management of critically ill patients. Extubation failure, defined as the need for reintubation within 2–7 days after a planned extubation, is associated with prolonged mechanical ventilation, increased incidence of ventilator-associated pneumonia, longer intensive care unit and hospital stays, and increased mortality. Conventional oxygen therapy is commonly used after extubation. Additional methods of non-invasive respiratory support, such as non-invasive ventilation and high-flow nasal therapy, can be used to avoid reintubation.
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.
Ji Soo Choi, Sang Hoon Lee, Ah Young Leem, Joo Han Song, Song Yee Kim, Kyung Soo Chung, Ji Ye Jung, Young Ae Kang, Young Sam Kim, Joon Chang, Moo Suk Park
by Ji Soo Choi, Sang Hoon Lee, Ah Young Leem, Joo Han Song, Song Yee Kim, Kyung Soo Chung, Ji Ye Jung, Young Ae Kang, Young Sam Kim, Joon Chang, Moo Suk Park
Background Pneumocystis jirovecii pneumonia (PCP) is often fatal in human immunodeficiency (HIV)-negative patients and typically presents with respiratory insufficiency. Predicting treatment failure is challenging. This study aimed to identify prognostic factors and examine PCP polymerase chain reaction (PCR)-negative conversion in non-HIV PCP patients with respiratory failure. Method We retrospectively enrolled 81 non-HIV patients diagnosed with and treated for PCP with respiratory failure in the intensive care unit at a tertiary hospital over a 3-year period. PCP was diagnosed via nested PCR-mediated detection of Pneumocystis jirovecii in induced sputum samples, endotracheal aspirates, and bronchoalveolar lavage fluids. PCP PCR was performed weekly to check for negative conversion. Results The overall survival rate was 35.8%. Seventy-four patients (91.3%) required mechanical ventilation, and 6 (7.4%) required high-flow nasal oxygen treatment. The PCP PCR-negative conversion rate was 70.5% (survivors, 97%; non-survivors, 63.5%); the median time to conversion was 10 (7.0–14.0) days. On univariate analysis, the APACHE II score (p < 0.001), renal failure requiring renal replacement therapy (p = 0.04), PCP PCR-negative conversion (p = 0.003), and the PaO2/FiO2 ratio (first 24 hours) (p < 0.001) significantly correlated with mortality. On multivariate analysis, PCP PCR-negative conversion (hazard ratio, 0.433; 95% confidence interval, 0.203–0.928; p = 0.031) and the PaO2/FiO2 ratio (first 24 hours) (hazard ratio, 0.988; 95% confidence interval, 0.983–0.993; p < 0.001) independently predicted prognosis. Conclusions Determination of PCP PCR-negative conversion and PaO2/FiO2 ratios may help physicians predict treatment failure and mortality in non-HIV PCP patients with respiratory failure.
This opinion article deals with the diagnostic clinical challenges faced by clinicians or health care workers in malaria-endemic areas when a severely sick child presents to the clinic with fever, coma or respiratory distress. Indeed, the coexistence of malaria with other severe infections like meningitis, invasive bacterial infection or pneumonia makes appropriate treatment allocation a matter of life and death. The use of biomarkers has been proposed as a potential solution to this problem. The arrival of high-throughput technologies allowed thousands of molecules (transcripts, proteins and metabolites) to be been screened in clinical samples from large cohorts of well/characterised patients. The major aim of these studies was to identify biomarkers that inform important decisions: should this child be referred to hospital? Should antibiotics, anti-malarials, or both, be administered? There is a large discrepancy between the number of biomarker discovery studies published and the number of biomarkers that have been clinically validated, let alone implemented. This article reflects on the many opportunities and obstacles encountered in biomarker research in malaria-endemic areas.
Pseudomonas aeruginosa is an unusual pathogen in community-acquired pneumonia, especially in previously healthy adults, but often indicates poor prognosis.
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.
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.
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.
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.
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.
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.
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.
Due to the use of biological agents, particularly TNF-α inhibitors, as a well-established therapy for some autoimmune diseases, new potential adverse events can be expected in the future and we wanted to point out one of them. To our knowledge this is the first case of recurrent disseminated varicella in a patient taking TNF-α antagonists.
Puzniak, L., DePestel, D. D., Srinivasan, A., Ye, G., Murray, J., Merchant, S., DeRyke, C. A., Gupta, V.
Background: Pseudomonas aeruginosa (PsA) is an important pathogen associated with significant morbidity and mortality. US guidelines for hospital-acquired and ventilator-associated pneumonia recommend the use of two antipseudomonal drugs for high-risk patients to ensure ≥95% of patients receive active empiric therapy. We evaluated the utility of combination antibiograms in identifying optimal PsA drug regimens.Methods: We conducted a retrospective cross-sectional analysis of antimicrobial susceptibility of all non-duplicate PsA blood and respiratory isolates collected between October 1, 2016 and September 30, 2017 from 304 US hospitals in the BD Insights Research Database. Combination antibiograms were used to determine in vitro antimicrobial susceptibility rates for potential PsA combination regimens consisting of a backbone antibiotic (extended-spectrum cephalosporin, carbapenem, or piperacillin/tazobactam) plus an aminoglycoside or fluoroquinolone.Results: Single agent susceptibility rates for the 11,701 non-duplicate PsA isolates ranged from 72.7% for fluoroquinolones to 85.0% for piperacillin/tazobactam. Susceptibility rates were higher for blood versus respiratory isolates (P < 0.05). Antibiotic combinations resulted in increased susceptibility rates, but did not achieve the goal of 95% antibiotic coverage. Adding an aminoglycoside resulted in higher susceptibility rates than adding a fluoroquinolone; piperacillin/tazobactam plus an aminoglycoside had the highest susceptibility rate (93.3%). Intensive care unit (ICU) isolates generally had lower susceptibility rates than non-ICU isolates.Conclusions: Commonly-used antipseudomonal drugs, either alone or in combination, do not achieve 95% coverage against US hospital PsA isolates, suggesting that new drugs are needed to attain this goal. Local institutional use of combination antibiograms has the potential to optimize empiric therapy of difficult-to-treat pathogens.
Ibn Saied, Wafa; Mourvillier, Bruno; Cohen, Yves; Ruckly, Stephane; Reignier, Jean; Marcotte, Guillaume; Siami, Shidasp; Bouadma, Lila; Darmon, Michael; de Montmollin, Etienne; Argaud, Laurent; Kallel, Hatem; Garrouste-Orgeas, MaitÃ©; Soufir, Lilia; Schwebel, Carole; Souweine, Bertrand; Glodgran-Toledano, Dany; Papazian, Laurent; Timsit, Jean-FranÃ§ois; on behalf of the OUTCOMEREA Study Group
To investigate the respective impact of ventilator-associated pneumonia and ICUâ€“hospital-acquired pneumonia on the 30-day mortality of ICU patients.
Longitudinal prospective studies.
Patients at risk of ventilator-associated pneumonia and ICUâ€“hospital-acquired pneumonia.
The first three episodes of ventilator-associated pneumonia or ICUâ€“hospital-acquired pneumonia were handled as time-dependent covariates in Cox models. We adjusted using the case-mix, illness severity, Simplified Acute Physiology Score II score at admission, and procedures and therapeutics used during the first 48 hours before the risk period. Baseline characteristics of patients with regard to the adequacy of antibiotic treatment were analyzed, as well as the Sequential Organ Failure Assessment score variation in the 2 days before the occurrence of ventilator-associated pneumonia or ICUâ€“hospital-acquired pneumonia. Mortality was also analyzed for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species(ESKAPE) and P. aeruginosa pathogens.
Measurements and Main Results:
Of 14,212 patients who were admitted to the ICUs and who stayed for more than 48 hours, 7,735 were at risk of ventilator-associated pneumonia and 9,747 were at risk of ICUâ€“hospital-acquired pneumonia. Ventilator-associated pneumonia and ICUâ€“hospital-acquired pneumonia occurred in 1,161 at-risk patients (15%) and 176 at-risk patients (2%), respectively. When adjusted on prognostic variables, ventilator-associated pneumonia (hazard ratio, 1.38 (1.24â€“1.52); p < 0.0001) and even more ICUâ€“hospital-acquired pneumonia (hazard ratio, 1.82 [1.35â€“2.45]; p < 0.0001) were associated with increased 30-day mortality. The early antibiotic therapy adequacy was not associated with an improved prognosis, particularly for ICUâ€“hospital-acquired pneumonia. The impact was similar for ventilator-associated pneumonia and ICUâ€“hospital-acquired pneumonia mortality due to P. aeruginosa and the ESKAPE group.
In a large cohort of patients, we found that both ICUâ€“hospital-acquired pneumonia and ventilator-associated pneumonia were associated with an 82% and a 38% increase in the risk of 30-day mortality, respectively. This study emphasized the importance of preventing ICUâ€“hospital-acquired pneumonia in nonventilated patients.
The members of the OUTCOMEREA Network are listed in the supplementary appendix (Supplemental Digital Content 6, http://links.lww.com/CCM/E185).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journalâ€™s website (http://journals.lww.com/ccmjournal).
The OUTCOMEREA research network entirely funded the study.
The authors have disclosed that they do not have any potential conflicts of interest.
For information regarding this article, E-mail: email@example.com
Copyright Â© by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Gregory, A. E., van Schaik, E. J., Russell-Lodrigue, K., Fratzke, A., Samuel, J. E.
Coxiella burnetii, the etiological agent of Q fever, is a Gram-negative bacterium transmitted to humans by inhalation of contaminated aerosols. Acute Q fever is often self-limiting, presenting as a febrile illness that can result in atypical pneumonia. In some cases, Q fever becomes chronic leading to endocarditis that can be life threatening. Formalin-inactivated whole cell vaccine (WCV) confers long-term protection but has significant side-effects when administered to pre-sensitized individuals. Designing new vaccines against C. burnetii remains a challenge and requires the use of clinically relevant modes of transmission in appropriate animal models. We have developed a safe and reproducible C. burnetii aerosol challenge in three different animal models to evaluate the effects of pulmonary acquired infection. Using a MicroSprayer® Aerosolizer, BL/6 mice and Hartley guinea pigs were infected intratracheally with C. burnetii NMI and demonstrated susceptibility, determined by measuring bacterial growth in the lungs and subsequent dissemination to the spleen. Histologic analysis of lung tissue showed significant pathology associated with disease, which was more severe in guinea pigs. Infection using large particle aerosol (LPA) delivery was further confirmed in non-human primates, which developed fever and pneumonia. We also demonstrate that vaccinating mice and guinea pigs with WCV prior to LPA challenge is capable of eliciting protective immunity that significantly reduces splenomegaly and bacterial burden in spleen and lung tissues. These data suggest these models can have appreciable value using the LPA delivery system to study pulmonary Q fever pathogenesis as well as designing vaccine countermeasures to C. burnetii aerosol transmission.
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
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.
The roll out of antiretroviral therapy (ART) in Sub-Saharan Africa led to a decrease in mortality. Few studies have documented the causes of deaths among patients on long term antiretroviral therapy in Sub-Saharan Africa. Our objective was to describe the causes of death among patients on long term ART in Sub-Saharan Africa.
We used data from a prospective cohort of ART naïve patients receiving care and treatment at the Infectious Diseases Institute in Kampala, Uganda. Patients were followed up for 10 years. All deaths were recorded and possible causes established using verbal autopsy. Deaths were grouped as HIV-related (ART toxicities, any opportunistic infections (OIs) and HIV-related malignancies) and non-HIV related deaths while some remained unknown. We used Kaplan Meier survival methods to estimate cumulative incidence and rates of mortality for all causes of death.
Of the 559, (386, 69%) were female, median age 36 years (IQR: 21–44), 89% had WHO clinical stages 3 and 4, and median CD4 count at ART initiation was 98 cells/μL (IQR: 21–163). A total of 127 (22.7%) deaths occurred in 10 years. The HIV related causes of death (n = 70) included the following; Tuberculosis 17 (24.3%), Cryptococcal meningitis 10 (15.7%), Kaposi’s Sarcoma 7(10%), HIV related toxicity 6 (8.6%), HIV related anemia 5(7.1%), Pneumocystis carinii Pneumonia (PCP) 5 (7.1%), HIV related chronic diarrhea 4 (5.7%), Non-Hodgkin Lymphoma 3 (4.3%), Herpes Zoster 2 (2.8%), other 10 (14.3%). The non-HIV related causes of death (n = 20) included non-communicable diseases (diabetes, hypertension, stroke) 6 (30%), malaria 3 (15%), pregnancy-related death 2 (10%), cervical cancer 2 (10%), trauma 1(5%) and others 6 (30%).
Despite the higher rates of deaths from OIs in the early years of ART initiation, we observed an emergence of non-HIV related causes of morbidity and mortality. It is recommended that HIV programs in resource-limited settings start planning for screening and treatment of non-communicable diseases.
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.
Xi Zeng, Hao Gu, Yan Cheng, Ke-Ran Jia, Dong Liu, Yue Yuan, Zhi-Fu Chen, Liu-Sheng Peng, Quan-Ming Zou, Yun Shi
Acinetobacter baumannii can cause severe nosocomial and community-acquired pneumonia. To study the pathogenesis of A. baumannii and develop new treatments, appropriate mouse models are needed. Most of reported mouse models of pulmonary A. baumannii infection are non-lethal or require mice immunosuppression to enhance infection. These models are not suitable for studying host immune response or evaluating immunotherapies.
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
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.
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.
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.
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: firstname.lastname@example.org
The authors report no conflicts of interest related to this work.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1519-1526, December 15, 2018.
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.
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.
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.
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.
Hsu C, Chang I, Hsieh P, et al.
AbstractKlebsiella pneumoniae is an important human pathogen causing hospital-acquired and community-acquired infections. Systemic K. pneumoniae infections may be preceded by gastrointestinal colonization, but the basis of this bacterium’s interaction with the intestinal epithelium remains unclear. Here, we report that the K. pneumoniae Sap (sensitivity to antimicrobial peptides) transporter contributes to bacterial–host cell interactions and in vivo virulence. Gene deletion showed that sapA is required for the adherence of a K. pneumoniae blood isolate to intestinal epithelial, lung epithelial, urinary bladder epithelial, and liver cells. The ΔsapA mutant was deficient for translocation across intestinal epithelial monolayers, macrophage interactions, and induction of proinflammatory cytokines. In a mouse gastrointestinal infection model, ΔsapA yielded significantly decreased bacterial loads in liver, spleen and intestine, reduced liver abscess generation, and decreased mortality. These findings offer new insights into the pathogenic interaction of K. pneumoniae with the host gastrointestinal tract to cause systemic infection.
Chan, W.-Y., Entwisle, C., Ercoli, G., Ramos-Sevillano, E., McIlgorm, A., Cecchini, P., Bailey, C., Lam, O., Whiting, G., Green, N., Goldblatt, D., Wheeler, J. X., Brown, J. S.
Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes, and has led to non-vaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp, thought to be immune adjuvants). Proteomics and immunoblots demonstrated that compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognised protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including non-pneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonised after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, whilst passive transfer of rabbit serum from MAV vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat-shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.
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.
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.
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.
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.
Jingtao Cui, Wenjuan Yan, Hongjie Xie, Shaoxia Xu, Qiaofeng Wang, Weihong Zhang, Anping Ni
by Jingtao Cui, Wenjuan Yan, Hongjie Xie, Shaoxia Xu, Qiaofeng Wang, Weihong Zhang, Anping Ni
Background Chlamydia pneumoniae (C. pneumoniae) is an obligate intracellular bacterium and a human pathogen that causes respiratory infectious diseases. More than 50% of the adult population worldwide was once infected with C. pneumoniae, but investigations into this topic are insufficient in mainland China. Methods Anti-C. pneumoniae IgG and IgM antibodies were detected using micro-immunofluorescence test in serum samples of patients visiting Peking Union Medical College Hospital between 2008 and 2017 for routine medical purposes, and the aim of this retrospective study was to analyze the test results. Results Among 12,050 serum specimens tested for anti-C. pneumoniae IgG and IgM antibodies, the overall prevalence of anti-C. pneumoniae IgG antibodies was 86.6%, 87.2% for men and 86.0% for women. Adult men (>20 years) were found to have a significantly higher prevalence of anti-C. pneumoniae IgG than women (Ï‡2 = 30.32, P = 0.000). 3 to 5 years old patients were observed to have the lowest prevalence of anti-C. pneumoniae IgG, 42.8%, then increased with age, reaching the highest level of 98.6% in patients over 70 years of age. In the 10,434 specimens with C. pneumoniae IgG antibodies, the total geometric mean titer (GMT) for C. pneumoniae IgG was 45.71. Although GMTs were found to be significantly higher among all men than among all women (t = 5.916, P = 0.000), sex difference actually began in patients over 40 years of age and increased in the elderly. In the total 12,050 specimens, 1.2% had anti-C. pneumoniae IgM, 3.3% had anti-C. pneumoniae IgG with titers equal to or greater than 1:512; 0.39% had â‰¥4-fold increasing titers of antibodies in acute and convalescent phase paired samples, and 4.4% were finally confirmed to have acute antibodies against C. pneumoniae. 6 to 10 years old patients were found to have the highest rate of both IgM antibodies (3.9%) and acute antibodies (6.2%) against C. pneumoniae. Acute antibodies against C. pneumoniae were found to be more frequent in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD, 14.0%, Ï‡2 = 20.43, P = 0.000), patients with pneumonia (7.8%, Ï‡2 = 51.87, P = 0.000) and patients with acute respiratory tract infection (12.3%, Ï‡2 = 60.91, P = 0.000) than among all patients (4.4%). Both anti-C. pneumoniae IgG and IgM antibodies should be tested for acute antibodies against C. pneumoniae as testing for either alone will underestimate by a maximum of two-thirds the incidence of acute antibodies against C. pneumoniae. Conclusions More than 86% of Chinese patients on an average were once infected with C. pneumoniae. Adult men had both a higher prevalence and higher levels of antibodies than women. 6 to10 year old patients were found to have the most frequent acute infection of C. pneumoniae. C. pneumoniae is associated with AECOPD, pneumonia and acute respiratory tract infection. Anti-C. pneumoniae IgG and IgM should be tested simultaneously to avoid underestimation of acute antibodies against C. pneumoniae.
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.
Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described.
A systematic literature review and meta-analysis was performed to examine this relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections.
Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting [C& SR]), there was an increased risk of mortality (odds ratio [OR], 1.60 [95% CI, 1.25–2.50]). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 [95% CI, 1.27–2.44]).
Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli.
Prendki Virginie, Huttner Benedikt, Marti Christophe, Mamin Aline, Fubini Pietro Elias, Meynet Marie-Pierre, Scheffler Max, Montet Xavier, Janssens Jean-Paul, Reny Jean-Luc, Kaiser Laurent, Garin Nicolas, Stirnemann Jérôme
Bacteria of the Achromobacter genus, more particularly xylosoxidans species, are responsible for various healthcare associated infections (HAI) which are increasingly described since the last decade. Cystic fibrosis (CF) patients are considered as potential reservoirs in hospitals. We performed a retrospective study to estimate the frequencies of Achromobacter spp. HAI among patients from French West Indies, to determine characteristics of infected patients and establish a possible link between CF and infections.
All adults with at least one Achromobacter spp. positive sample and infection criteria in accordance with European official definitions of HAI, hospitalized in University Hospital of Martinique from 2006 to 2016 for more than 48 h, were included. Patient clinical features, immune status and underlying diseases were obtained from medical files. A list of CF patients was given by clinicians.
Antibiotic-susceptibility profiles of the strains were determined using an automated method.
Mean incidence density was 0.038/1000 days of hospitalization. Achromobacter spp. HAI evolved as an endemic situation with a low but pretty much stable incidence rate over the 11-year observation period. An epidemic peak was noticed in 2013. Among the 66 included patients, 56.1% were immunocompetent and no one had CF. Pneumonia and bacteraemia were the two main HAI. Among the 79 isolated strains, 92.4% were resistant to at least 1 major antibiotic and 16.4% met the definition of multidrug-resistant bacteria.
This microorganism, little known in our country because of the scarcity of CF patients, represents a threat for both immunosuppressed and immunocompetent patients and a therapeutic challenge because of its high resistance.
Juttukonda, L. J., Green, E. R., Lonergan, Z. R., Heffern, M. C., Chang, C. J., Skaar, E. P.
Acinetobacter baumannii is a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms, A. baumannii isolates are commonly multi-drug resistant and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistant A. baumannii as a ‘critical priority’ for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover mechanisms used by A. baumannii to survive stresses encountered during infection in order to identify new drug targets. In this study, we identified hydrogen peroxide (H2O2) as a stressor produced in the lung during A. baumannii infection using in vivo imaging and defined OxyR as a transcriptional regulator of the H2O2 stress response. Upon exposure to H2O2, A. baumannii differentially transcribes several hundred genes. However, transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in A. baumannii genetically inactivated for the transcriptional regulator oxyR. Moreover, inactivation of oxyR in both antimicrobial-susceptible and multi-drug-resistant A. baumannii strains impairs growth in the presence of H2O2. OxyR is a direct regulator of katE and ahpF1, which encode the major H2O2-degrading enzymes in A. baumannii, as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, an oxyR mutant is less fit than wild-type A. baumannii during infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive H2O2 stress encountered during infection.
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).
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.
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).
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).
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.
Norihiko Inoue, Kiyohide Fushimi
Davide Mangioni, Giacomo Grasselli, Chiara Abbruzzese, Antonio Muscatello, Andrea Gori, Alessandra Bandera
Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic
by Olivera Djuric, Ljiljana Markovic-Denic, Bojan Jovanovic, Vesna Bumbasirevic
After three national point prevalence studies (PPS) of healthcare associated infections (HAI) conducted in Serbian acute care hospitals using US (CDC/NHSN) surveillance definitions, Serbia is about to switch to European (ECDC) criteria for the purpose of the fourth HAI PPS. The aim of this study was to compare the US and the European HAI definitions in Serbian trauma intensive care unit (ICU). Prospective surveillance was performed at two surgical-trauma ICUs of the Emergency department of Clinical Center of Serbia. HAIs were prospectively diagnosed by experienced clinician and epidemiologists using both types of HAI definitions simultaneously. The level of agreement between two case definitions was assessed by Cohen’s kappa statistic (k). Of 406 patients, 107 (26.3%) acquired at least one HAI (total of 107 according to US definitions and 141 according to European criteria). For microbiologically confirmed pneumonia agreement was k = 0.99 (95% CI, 0.96–1.00) and for clinically defined k = 0.86 (95% CI, 0.58–1.00). Agreement for bloodstream infections (BSI) was 0.79 (CI 95%, 0.70–0.89). When secondary BSI was excluded from the European classification, (30.9% of all BSI), concordance was k = 1.00 and when microbiologically confirmed catheter related BSI were reported separately as recommended by latest ECDC protocol update, (20.0% of all BSI), concordance was 0.60 (CI 95%, 0.41–0.80). No agreement was found between CLABSI and CRI while slight agreement was found when compared CLABSI and CRI3 (k = 0.11; 95%CI, 0.0–0.22). Agreement for overall UTI was moderate (k = 0.66; 95%CI, 0.53–0.79) while for microbiologically-confirmed symptomatic UTI was perfect (k = 1.00). For CAUTI good agreement was observed (k = 0.77; 95%CI, 0.34–1.0). Microbiological confirmation of PN and UTI should be stimulated and comparison of BSI should be done with emphasis on whether secondary BSI is included.
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.
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.
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Reply to Barner and Bruno-Murtha
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Resistance of Influenza Virus to Antiviral Medications
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Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study
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Hvad tænker Professor Thomas Benfield om"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvad mener Professor Niels Obel om artiklen"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
Hvad synes Professor Thomas Benfield om"Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial."?
Hvad mener Professor Morten Sodemann om artiklen"Evidence-based clinical guidelines for immigrants and refugees."?
Hvad mener Professor Niels Obel om artiklen"Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy."?
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