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1.
Front Immunol ; 13: 939213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936013

RESUMO

Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 108 CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections.


Assuntos
Bacteriemia , Sepse , Infecções Estafilocócicas , Animais , Bacteriemia/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Macrófagos Peritoneais , Camundongos , Camundongos Endogâmicos C57BL , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Sepse/microbiologia , Staphylococcus aureus/metabolismo , Receptor 4 Toll-Like
2.
BMC Infect Dis ; 22(1): 603, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35799130

RESUMO

BACKGROUND: Klebsiella pneumoniae strains have been divided into two major categories: classical K. pneumoniae, which are frequently multidrug-resistant and cause hospital-acquired infections in patients with impaired defenses, and hypervirulent K. pneumoniae, which cause severe community-acquired and disseminated infections in normal hosts. Both types of infections may lead to bacteremia and are associated with significant morbidity and mortality. The relative burden of these two types of K. pneumoniae among bloodstream isolates within the United States is not well understood. METHODS: We evaluated consecutive K. pneumoniae isolates cultured from the blood of hospitalized patients at Northwestern Memorial Hospital (NMH) in Chicago, Illinois between April 2015 and April 2017. Bloodstream isolates underwent whole genome sequencing, and sequence types (STs), capsule loci (KLs), virulence genes, and antimicrobial resistance genes were identified in the genomes using the bioinformatic tools Kleborate and Kaptive. Patient demographic, comorbidity, and infection information, as well as the phenotypic antimicrobial resistance of the isolates were extracted from the electronic health record. Candidate hypervirulent isolates were tested in a murine model of pneumonia, and their plasmids were characterized using long-read sequencing. We also extracted STs, KLs, and virulence and antimicrobial resistance genes from the genomes of bloodstream isolates submitted from 33 United States institutions between 2007 and 2021 to the National Center for Biotechnology Information (NCBI) database. RESULTS: Consecutive K. pneumoniae bloodstream isolates (n = 104, one per patient) from NMH consisted of 75 distinct STs and 51 unique capsule loci. The majority of these isolates (n = 58, 55.8%) were susceptible to all tested antibiotics except ampicillin, but 17 (16.3%) were multidrug-resistant. A total of 32 (30.8%) of these isolates were STs of known high-risk clones, including ST258 and ST45. In particular, 18 (17.3%) were resistant to ceftriaxone (of which 17 harbored extended-spectrum beta-lactamase genes) and 9 (8.7%) were resistant to meropenem (all of which harbored a carbapenemase genes). Four (3.8%) of the 104 isolates were hypervirulent K. pneumoniae, as evidenced by hypermucoviscous phenotypes, high levels of virulence in a murine model of pneumonia, and the presence of large plasmids similar to characterized hypervirulence plasmids. These isolates were cultured from patients who had not recently traveled to Asia. Two of these hypervirulent isolates belonged to the well characterized ST23 lineage and one to the re-emerging ST66 lineage. Of particular concern, two of these isolates contained plasmids with tra conjugation loci suggesting the potential for transmission. We also analyzed 963 publicly available genomes of K. pneumoniae bloodstream isolates from locations within the United States. Of these, 465 (48.3%) and 760 (78.9%) contained extended-spectrum beta-lactamase genes or carbapenemase genes, respectively, suggesting a bias towards submission of antibiotic-resistant isolates. The known multidrug-resistant high-risk clones ST258 and ST307 were the predominant sequence types. A total of 32 (3.3%) of these isolates contained aerobactin biosynthesis genes and 26 (2.7%) contained at least two genetic features of hvKP strains, suggesting elevated levels of virulence. We identified 6 (0.6%) isolates that were STs associated with hvKP: ST23 (n = 4), ST380 (n = 1), and ST65 (n = 1). CONCLUSIONS: Examination of consecutive isolates from a single center demonstrated that multidrug-resistant high-risk clones are indeed common, but a small number of hypervirulent K. pneumoniae isolates were also observed in patients with no recent travel history to Asia, suggesting that these isolates are undergoing community spread in the United States. A larger collection of publicly available bloodstream isolate genomes also suggested that hypervirulent K. pneumoniae strains are present but rare in the USA; however, this collection appears to be heavily biased towards highly antibiotic-resistant isolates (and correspondingly away from hypervirulent isolates).


Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Infecções por Klebsiella , Klebsiella pneumoniae , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Genômica , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/isolamento & purificação , Camundongos , Sepse/epidemiologia , Sepse/microbiologia , Estados Unidos/epidemiologia , beta-Lactamases/genética
3.
Lancet Glob Health ; 10(8): e1170-e1178, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35839815

RESUMO

BACKGROUND: Few population-level estimates of invasive neonatal infections have been reported from sub-Saharan Africa. We estimated the national incidence risk, aetiology, and pathogen antimicrobial susceptibility for culture-confirmed neonatal bloodstream infections and meningitis in South Africa. METHODS: We conducted a cross-sectional study of neonates (<28 days of life) admitted to neonatal or paediatric wards of 256 public sector health facilities in South Africa during 2014-19. Diagnostic pathology records from Jan 1, 2014, to Dec 31, 2019, were extracted from a national pathology data warehouse. A case was defined as a neonate with at least one positive blood or cerebrospinal fluid culture during a 14-day period. Incidence risk was calculated using annual numbers of registered livebirths. Among the causative pathogens identified, we calculated the proportion of cases attributed to each of them, as well as the rates of antibiotic susceptibility of Gram-positive and Gram-negative bacteria. FINDINGS: Among 43 438 records of positive cultures, there were 37 631 incident cases of neonatal infection with at least one pathogen isolated. The overall incidence risk of culture-confirmed infections was 6·0 per 1000 livebirths (95% CI 6·0-6·1). The incidence risk of late-onset sepsis (days 3-27 of life) was 4·9 per 1000 livebirths (4·9-5·0) and that of early-onset sepsis (days 0-2 of life) was 1·1 per 1000 livebirths (1·1-1·1); risk ratio 4·4 (95% CI 4·3-4·5). The cause of infection differed by syndrome, timing of infection onset, facility, and province, although Klebsiella pneumoniae (26%), Acinetobacter baumannii (13%), and Staphylococcus aureus (12%) were the dominant pathogens overall. Gram-negative bacteria had declining susceptibility to most antibiotics over the study period. INTERPRETATION: We found a high incidence risk of late-onset sepsis with provincial variations, predominance of K pneumoniae, and declining antibiotic susceptibility among Gram-negative bacteria. This national surveillance in an upper-middle-income country provides a baseline burden of neonatal infections against which the impact of future clinical and public health interventions can be measured. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Doenças Transmissíveis , Meningite , Sepse , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Estudos Transversais , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Recém-Nascido , Klebsiella pneumoniae , Meningite/epidemiologia , Sepse/microbiologia , África do Sul/epidemiologia
4.
Physiol Rep ; 10(11): e15290, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668576

RESUMO

Sepsis is a devastating disease with high morbidity and mortality and no specific treatments. The pathophysiology of sepsis involves a hyperinflammatory response and release of damage-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), from activated and dying cells. Purinergic receptors activated by ATP have gained attention for their roles in sepsis, which can be pro- or anti-inflammatory depending on the context. Current data regarding the role of ATP-specific purinergic receptor P2X7 (P2X7R) in vascular function and inflammation during sepsis are conflicting, and its role on the endothelium has not been well characterized. In this study, we hypothesized that the P2X7R antagonist AZ 10606120 (AZ106) would prevent endothelial dysfunction during sepsis. As proof of concept, we first demonstrated the ability of AZ106 (10 µM) to prevent endothelial dysfunction in intact rat aorta in response to IL-1ß, an inflammatory mediator upregulated during sepsis. Likewise, blocking P2X7R with AZ106 (10 µg/g) reduced the impairment of endothelial-dependent relaxation in mice subjected to intraperitoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. However, contrary to our hypothesis, AZ106 did not improve microvascular permeability or injury, lung apoptosis, or illness severity in mice subjected to CS. Instead, AZ106 elevated spleen bacterial burden and circulating inflammatory markers. In conclusion, antagonism of P2X7R signaling during sepsis appears to disrupt the balance between its roles in inflammatory, antimicrobial, and vascular function.


Assuntos
Receptores Purinérgicos P2X7 , Sepse , Trifosfato de Adenosina , Animais , Inflamação , Camundongos , Ratos , Sepse/microbiologia , Transdução de Sinais
5.
Antimicrob Resist Infect Control ; 11(1): 83, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35698179

RESUMO

BACKGROUND: Sepsis due to multidrug resistant (MDR) bacteria is a growing public health problem mainly in low-income countries. METHODS: A multicenter study was conducted between October 2019 and September 2020 at four hospitals located in central (Tikur Anbessa and Yekatit 12), southern (Hawassa) and northern (Dessie) parts of Ethiopia. A total of 1416 patients clinically investigated for sepsis were enrolled. The number of patients from Tikur Anbessa, Yekatit 12, Dessie and Hawassa hospital was 501, 298, 301 and 316, respectively. At each study site, blood culture was performed from all patients and positive cultures were characterized by their colony characteristics, gram stain and conventional biochemical tests. Each bacterial species was confirmed using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI TOF). Antimicrobial resistance pattern of bacteria was determined by disc diffusion. Logistic regression analysis was used to assess associations of dependent and independent variables. A p-value < 0.05 was considered as statistically significant. The data was analyzed using SPSS version 25. RESULTS: Among 1416 blood cultures performed, 40.6% yielded growth. Among these, 27.2%, 0.3% and 13.1%, were positive for pathogenic bacteria, yeast cells and possible contaminants respectively. Klebsiella pneumoniae (26.1%), Klebsiella variicola (18.1%) and E. coli (12.4%) were the most frequent. Most K. variicola were detected at Dessie (61%) and Hawassa (36.4%). Almost all Pantoea dispersa (95.2%) were isolated at Dessie. Rare isolates (0.5% or 0.2% each) included Leclercia adecarboxylata, Raoultella ornithinolytica, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia, Kosakonia cowanii and Lelliottia amnigena. Enterobacteriaceae most often showed resistance to ampicillin (96.2%), ceftriaxone (78.3%), cefotaxime (78%), cefuroxime (78%) and ceftazidime (76.4%). MDR frequency of Enterobacteriaceae at Hawassa, Tikur Anbessa, Yekatit 12 and Dessie hospital was 95.1%, 93.2%, 87.3% and 67.7%, respectively. Carbapenem resistance was detected in 17.1% of K. pneumoniae (n = 111), 27.7% of E. cloacae (n = 22) and 58.8% of Acinetobacter baumannii (n = 34). CONCLUSION: Diverse and emerging gram-negative bacterial etiologies of sepsis were identified. High multidrug resistance frequency was detected. Both on sepsis etiology types and MDR frequencies, substantial variation between hospitals was determined. Strategies to control MDR should be adapted to specific hospitals. Standard bacteriological services capable of monitoring emerging drug-resistant sepsis etiologies are essential for effective antimicrobial stewardship.


Assuntos
Antibacterianos , Sepse , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Escherichia coli , Etiópia/epidemiologia , Hospitais , Humanos , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Encaminhamento e Consulta , Sepse/microbiologia
6.
Mediators Inflamm ; 2022: 5026103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35677734

RESUMO

Sepsis-induced inflammatory response leads to intestinal damage and secondary bacterial translocation, causing systemic infections and eventually death. Emodin is a natural anthraquinone derivative in many plants with promising bioactivities. However, the effects and mechanisms of emodin on sepsis-induced intestinal dysfunctions have not been well clarified yet. We found that emodin treatment suppressed the inflammatory response in the intestines of septic mice. Intestinal barrier function was also improved by emodin through enhancing ZO-1 and occludin expression, which prevented the secondary translocation of Escherichia coli. By proteome microarray investigation, JNK2 was identified as a direct target of emodin. In vitro study also showed that emodin inhibited LPS-induced inflammatory response in intestinal epithelial cells. Nuclear factors including NF-κB and AP-1 were further identified as downstream effectors of JNK2. Bioinformatic analysis based on 16s rRNA gene sequencing illustrated that emodin treatment significantly increased the alpha- and beta-diversity of gut microbiota in septic mice. Moreover, data according to functional prediction showed that emodin decreased the abundance of potential pathogenic bacteria in gut. Our findings have shown that emodin treatment prevented inflammatory induced barrier dysfunction and decreased the potential pathogenicity of lumen bacteria, reducing the hazard of lumen bacterial translocation during sepsis.


Assuntos
Emodina , Microbioma Gastrointestinal , Mucosa Intestinal , Sepse , Animais , Emodina/uso terapêutico , Mucosa Intestinal/metabolismo , Lipopolissacarídeos , Camundongos , NF-kappa B/metabolismo , RNA Ribossômico 16S/metabolismo , Sepse/tratamento farmacológico , Sepse/microbiologia
7.
Front Immunol ; 13: 907461, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720383

RESUMO

Circadian rhythms affect the progression and severity of bacterial infections including those caused by Streptococcus pneumoniae, but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication of S. pneumoniae within splenic macrophages, we sought to investigate whether events within the spleen correlate with differential outcomes of invasive pneumococcal infection. Utilising murine invasive pneumococcal disease (IPD) models, here we report that infection during the murine active phase (zeitgeber time 15; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. This correlated with significantly higher pneumococcal burden within the spleen of active phase-infected mice at early time points compared to rest phase-infected mice. Whole-section confocal microscopy analysis of these spleens revealed that the number of pneumococci is significantly higher exclusively within marginal zone metallophilic macrophages (MMMs) known to allow intracellular pneumococcal replication as a prerequisite step to the onset of septicaemia. Pneumococcal clusters within MMMs were more abundant and increased in size over time in active phase-infected mice compared to those in rest phase-infected mice which decreased in size and were present in a lower percentage of MMMs. This phenomenon preceded significantly higher levels of bacteraemia alongside serum IL-6 and TNF-α concentrations in active phase-infected mice following re-seeding of pneumococci into the blood. These data greatly advance our fundamental knowledge of pneumococcal infection by linking susceptibility to invasive pneumococcal infection to variation in the propensity of MMMs to allow persistence and replication of phagocytosed bacteria. These findings also outline a somewhat rare scenario whereby the active phase of an organism's circadian cycle plays a seemingly counterproductive role in the control of invasive infection.


Assuntos
Infecções Pneumocócicas , Sepse , Animais , Macrófagos/microbiologia , Camundongos , Fagocitose , Infecções Pneumocócicas/microbiologia , Sepse/microbiologia , Streptococcus pneumoniae
8.
PLoS One ; 17(6): e0269385, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35737713

RESUMO

In low-resource settings, detection of healthcare-acquired outbreaks in neonatal units relies on astute clinical staff to observe unusual morbidity or mortality from sepsis as microbiological diagnostics are often absent. We aimed to generate reliable (and automated) early warnings for potential clusters of neonatal late onset sepsis using retrospective data that could signal the start of an outbreak in an NCU in Port au Prince, Haiti, using routinely collected data on neonatal admissions. We constructed smoothed time series for late onset sepsis cases, late onset sepsis rates, neonatal care unit (NCU) mortality, maternal admissions, neonatal admissions and neonatal antibiotic consumption. An outbreak was defined as a statistical increase in any of these time series indicators. We created three outbreak alarm classes: 1) thresholds: weeks in which the late onset sepsis cases exceeded four, the late onset sepsis rates exceeded 10% of total NCU admissions and the NCU mortality exceeded 15%; 2) differential: late onset sepsis rates and NCU mortality were double the previous week; and 3) aberration: using the improved Farrington model for late onset sepsis rates and NCU mortality. We validated pairs of alarms by calculating the sensitivity and specificity of the weeks in which each alarm was launched and comparing each alarm to the weeks in which a single GNB positive blood culture was reported from a neonate. The threshold and aberration alarms were the strongest predictors for current and future NCU mortality and current LOS rates (p<0.0002). The aberration alarms were also those with the highest sensitivity, specificity, negative predictive value, and positive predictive value. Without microbiological diagnostics in NCUs in low-resource settings, applying these simple algorithms to routinely collected data show great potential to facilitate early warning for possible healthcare-acquired outbreaks of LOS in neonates. The methods used in this study require validation across other low-resource settings.


Assuntos
Sepse Neonatal , Sepse , Atenção à Saúde , Haiti/epidemiologia , Hospitais , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Sepse Neonatal/diagnóstico , Sepse Neonatal/epidemiologia , Sepse Neonatal/microbiologia , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/epidemiologia , Sepse/microbiologia
9.
Mycopathologia ; 187(4): 397-404, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35661958

RESUMO

Opportunistic infections are serious complications in critically ill COVID-19 patients, especially co-infections with bacterial and fungal agents. Here we report a rare case of bloodstream co-infection by Trichosporon asahii, an emerging yeast, and Acinetobacterbaumannii, an opportunistic nosocomial pathogen, both multidrug resistant, in a tertiary hospital from southern Brazil. A review of the literature regarding similar cases is also included. Treatment with multiple antimicrobials failed, and the patient progressed to death four days after the diagnosis of bacteremia and fungemia.


Assuntos
COVID-19 , Coinfecção , Micoses , Sepse , Trichosporon , Antifúngicos/uso terapêutico , Basidiomycota , COVID-19/complicações , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Humanos , Micoses/diagnóstico , Sepse/microbiologia
10.
Int Immunopharmacol ; 109: 108907, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35691271

RESUMO

BACKGROUND: Sepsis is a life-threateningorgandysfunction caused by the cytokine storm induced by the severe bacterial infection. Excessive inflammatory responses are responsible for the lethal organ damage during the early stage of sepsis. Helminth infection and helminth-derived proteins have been identified to have the ability to immunomodulate the host immune system by reducing inflammation against inflammatory diseases. Trichinella spiralis cystatin (Ts-Cys) is a cysteine protease inhibitor with strong immunomodulatory functions on host immune system. Our previous studies have shown that excretory-secretory proteins of T. spiralis reduced sepsis-induced inflammation and Ts-Cys was able to inhibit macrophages to produce inflammatory cytokines. Whether Ts-Cys has a therapeutic effect on polymicrobial sepsis and related immunological mechanism are not yet known. METHODS: Sepsis was induced in BALB/c mice using cecal ligation and puncture (CLP), followed by intraperitoneal injection of 15 µg recombinant Ts-Cys (rTs-Cys). The therapeutic effect of rTs-Cys on sepsis was evaluated by observing the 72-hour survival rates of CLP-induced septic mice and the acute injury of lung and kidney through measuring the wet/dry weight ratio of lung, the levels of blood urea nitrogen (BUN) and creatinine (Cr) in sera and the tissue section pathology. The potential underlying mechanism was investigated using mouse bone marrow-derived macrophages (BMDMs) by observing the effect of rTs-Cys on LPS-stimulated macrophage polarization. The expression of genes associated with macrophage polarization in BMDMs and tissues of septic mice was measured by Western Blotting and qPCR. RESULTS: In this study, we demonstrated the treatment with rTs-Cys alleviated CLP-induced sepsis in mice with significantly reduced pathological injury in vital organs of lung and kidney and reduced mortality of septic mice. The further study identified that treatment with rTs-Cys promoted macrophage polarization from classically activated macrophage (M1) to alternatively activated macrophage (M2) phenotype via inhibiting TLR2/MyD88 signal pathway and increasing expression of mannose receptor (MR), inhibited pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and increased regulatory anti-inflammatory cytokines (IL-10 and TGF-ß) in sera and tissues (lung and kidney) of mice with polymicrobial sepsis. CONCLUSIONS: Our results demonstrated that rTs-Cys had a therapeutic effect on sepsis through activating regulatory macrophages possibly via suppressing TLR2/MyD88 signal pathway. We also identified that rTs-Cys-induced M2 macrophage differentiation was associated with increased expression of MR on the surface of macrophages. Our results underscored the importance of MR in regulating macrophages during the treatment with rTs-Cys, providing another immunological mechanism in which helminths and their derived proteins modulate the host immune system. The findings in this study suggest that rTs-Cys is a potential therapeutic agent for the prevention and treatment of sepsis and other inflammatory diseases.


Assuntos
Cistatinas , Sepse , Trichinella spiralis , Animais , Cistatinas/genética , Cistatinas/metabolismo , Cistatinas/uso terapêutico , Citocinas/metabolismo , Proteínas de Helminto , Inflamação , Macrófagos , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Sepse/tratamento farmacológico , Sepse/microbiologia , Receptor 2 Toll-Like/metabolismo
11.
PLoS Negl Trop Dis ; 16(5): e0010414, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35613181

RESUMO

Community-acquired bacterial bloodstream infections are caused by diverse pathogens with changing antimicrobial-resistance patterns. In low-middle income countries in Southeast Asia, where dengue fever is endemic and a leading cause of fever, limited information is available about bacterial bloodstream infections due to challenges of implementing a blood culture service. This study describes bacterial bloodstream pathogens and antimicrobial-resistance patterns in Metro Manila, the Philippines. We aimed to identify the proportion of patients with a positive blood culture, the bacteria isolated and their antimicrobial resistance patterns, and the clinical characteristics of these patients, in this dengue endemic area. We conducted a prospective observational study in a single hospital enrolling febrile patients clinically suspected of having a community-acquired bacterial bloodstream infection between 1st July 2015 and 30th June 2019. Each patient had a blood culture and additional diagnostic tests according to their clinical presentation. We enrolled 1315 patients and a significant positive blood culture was found in 77 (5.9%) including Staphylococcus aureus (n = 20), Salmonella enterica Typhi (n = 18), Escherichia coli (n = 16), Streptococcus pneumoniae (n = 3) and Burkholderia pseudomallei (n = 2). Thirty-four patients had meningococcal disease diagnosed by culture (n = 8) or blood PCR (n = 26). Additional confirmed diagnoses included leptospirosis (n = 177), dengue virus infection (n = 159) and respiratory diphtheria (n = 50). There were 79 (6.0%, 95%CI 4.8%-7.4%) patients who died within 28 days of enrollment. Patients with a positive blood culture were significantly more likely to die than patients with negative culture (15.2% vs 4.4%, P<0.01). Among S. aureus isolates, 11/20 (55%) were methicillin-resistant (MRSA) and ST30: USA1100 was dominant sequence type (88.9%). Antimicrobial-susceptibility was well preserved in S. enterica Typhi. Among hospitalized patients with clinically suspected community-acquired bacterial bloodstream infection in Metro Manila, the Philippines, 5.9% had a blood culture confirmed infection of whom 15.6% died. S. aureus, including a significant number of MRSA (USA1100 clones), S. enterica Typhi, E.coli and Neisseria meningitidis were frequently identified pathogens.


Assuntos
Bacteriemia , Infecções Comunitárias Adquiridas , Dengue , Salmonella enterica , Sepse , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Dengue/complicações , Farmacorresistência Bacteriana , Escherichia coli , Febre/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Filipinas/epidemiologia , Salmonella typhi , Sepse/microbiologia , Staphylococcus aureus
12.
Sci Rep ; 12(1): 8347, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35589773

RESUMO

Neonatal bloodstream infections (BSI) can lead to sepsis, with high morbidity and mortality, particularly in low-income settings. The high prevalence of third-generation cephalosporin-resistant organisms (3GC-RO) complicates the management of BSI. Whether BSI is linked to carriage of 3GC-RO, or to acquisition from the hospital environment is important for infection prevention and control, but the relationship remains unclear, especially in low-income settings. At a tertiary hospital in Mwanza, Tanzania, we screened neonatal blood and rectal samples from 200 neonates, and 400 (hospital) environmental samples. We used logistic regression to identify risk factors, and Kolmogorov-Smirnov tests and randomisation analyses to compare distributions of species and resistance patterns to assess potential routes of transmission. We found that BSIs caused by 3GC-RO were frequent (of 59 cases of BSI, 55 were caused by 3GC-RO), as was carriage of 3GC-RO, particularly Escherichia coli, Klebsiella pneumoniae, and Acinetobacter species. In the 28 infants with both a carriage and blood isolate, there were more (4 of 28) isolate pairs of the same species and susceptibility profile than expected by chance (p < 0.05), but most pairs were discordant (24 of 28). Logistic regression models found no association between BSI and carriage with either 3GC-RO or only 3GC-R K. pneumoniae. These analyses suggest that carriage of 3GC-RO is not a major driver of BSI caused by 3GC-RO in this setting. Comparison with environmental isolates showed very similar distributions of species and resistance patterns in the carriage, BSI, and the environment. These similar distributions, a high frequency of Acinetobacter spp. isolations, the lack of strong association between carriage and BSI, together with the high proportion of 3GC-RO in BSI all suggest that these neonates acquire multidrug-resistant carriage and blood isolates directly from the hospital environment.


Assuntos
Bacteriemia , Sepse , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/microbiologia , Bactérias , Cefalosporinas/farmacologia , Atenção à Saúde , Escherichia coli , Hospitais , Humanos , Lactente , Recém-Nascido , Klebsiella pneumoniae , Sepse/microbiologia , Tanzânia/epidemiologia
13.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35503431

RESUMO

Preterm infants are susceptible to bloodstream infection by coagulase-negative staphylococci (CONS) that can lead to sepsis. Glucose-rich parenteral nutrition is commonly used to support the infants' growth and energy expenditure but may exceed endogenous regulation during infection, causing dysregulated immune response and clinical deterioration. Using a preterm piglet model of neonatal CONS sepsis induced by Staphylococcus epidermidis (S. epidermidis) infection, we demonstrate the delicate interplay between immunity and glucose metabolism to regulate the host infection response. Circulating glucose levels, glycolysis, and inflammatory response to infection are closely connected across the states of tolerance, resistance, and immunoparalysis. Furthermore, high parenteral glucose provision during infection induces hyperglycemia, elevated glycolysis, and inflammation, leading to metabolic acidosis and sepsis, whereas glucose-restricted individuals are clinically unaffected with increased gluconeogenesis to maintain moderate hypoglycemia. Finally, standard glucose supply maintaining normoglycemia or pharmacological glycolysis inhibition enhances bacterial clearance and dampens inflammation but fails to prevent sepsis. Our results uncover how blood glucose and glycolysis control circulating immune responses, in turn determining the clinical fate of preterm infants infected with CONS. Our findings suggest further refinements of the current practice of parenteral glucose supply for preterm infants during infection.


Assuntos
Sepse , Infecções Estafilocócicas , Animais , Glucose , Glicólise , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Sepse/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/fisiologia , Suínos
14.
Int J Mol Sci ; 23(9)2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35562877

RESUMO

Polymicrobial sepsis is associated with worse patient outcomes than monomicrobial sepsis. Routinely used culture-dependent microbiological diagnostic techniques have low sensitivity, often leading to missed identification of all causative organisms. To overcome these limitations, culture-independent methods incorporating advanced molecular technologies have recently been explored. However, contamination, assay inhibition and interference from host DNA are issues that must be addressed before these methods can be relied on for routine clinical use. While the host component of the complex sepsis host-pathogen interplay is well described, less is known about the pathogen's role, including pathogen-pathogen interactions in polymicrobial sepsis. This review highlights the clinical significance of polymicrobial sepsis and addresses how promising alternative molecular microbiology methods can be improved to detect polymicrobial infections. It also discusses how the application of shotgun metagenomics can be used to uncover pathogen/pathogen interactions in polymicrobial sepsis cases and their potential role in the clinical course of this condition.


Assuntos
Coinfecção , Sepse , Coinfecção/diagnóstico , Coinfecção/microbiologia , Humanos , Metagenômica , Sepse/diagnóstico , Sepse/microbiologia
15.
J Infect Public Health ; 15(5): 586-588, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35500542

RESUMO

We report a case of congenital brucellosis subsequently associated with Klebsiella pneumoniae infection in a Saudi preterm neonate. A girl born with severe respiratory distress was admitted to a neonatal intensive care unit. Laboratory examinations revealed thrombocytopenia and slight leukocytosis. Her mother was a confirmed case of brucellosis. Initial blood culture confirmed the diagnosis of infection, and the baby was treated empirically with rifampicin, gentamicin, and ciprofloxacin. Follow-up revealed that her general condition was gradually improved. On day 27, the baby deteriorated, showing abdominal distension and signs of sepsis and requiring intubation. Rifampicin was replaced by amikacin. A septic workup showed a normal total leukocyte count, with 68.3% neutrophils, decreased platelet count, and increased C-reactive protein level. Blood culture and sensitivity testing reported multidrug-resistant K. pneumoniae susceptible to amikacin and resistance to gentamicin, ciprofloxacin, and beta-lactam antibiotics. The baby remains critically ill, showing a poor treatment response with rapid deterioration, and arrested on day 33. Concomitant bacterial infections might explain signs of sepsis and respiratory distress among neonates with congenital brucellosis. Accurate and early diagnosis, parental history, and adequate treatment are associated with the prognosis of congenital brucellosis and other related bacterial infections.


Assuntos
Brucelose , Coinfecção , Infecções por Klebsiella , Síndrome do Desconforto Respiratório , Sepse , Amicacina , Antibacterianos/uso terapêutico , Brucelose/complicações , Brucelose/diagnóstico , Brucelose/tratamento farmacológico , Ciprofloxacina , Coinfecção/tratamento farmacológico , Feminino , Gentamicinas/uso terapêutico , Humanos , Recém-Nascido , Infecções por Klebsiella/complicações , Infecções por Klebsiella/diagnóstico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Rifampina , Sepse/microbiologia
16.
Antimicrob Resist Infect Control ; 11(1): 73, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35590391

RESUMO

BACKGROUND: There is a paucity of data regarding blood culture utilization and antimicrobial-resistant (AMR) infections in low and middle-income countries (LMICs). In addition, there has been a concern for increasing AMR infections among COVID-19 cases in LMICs. Here, we investigated epidemiology of AMR bloodstream infections (BSI) before and during the COVID-19 pandemic in the Indonesian national referral hospital. METHODS: We evaluated blood culture utilization rate, and proportion and incidence rate of AMR-BSI caused by WHO-defined priority bacteria using routine hospital databases from 2019 to 2020. A patient was classified as a COVID-19 case if their SARS-CoV-2 RT-PCR result was positive. The proportion of resistance was defined as the ratio of the number of patients having a positive blood culture for a WHO global priority resistant pathogen per the total number of patients having a positive blood culture for the given pathogen. Poisson regression models were used to assess changes in rate over time. RESULTS: Of 60,228 in-hospital patients, 8,175 had at least one blood culture taken (total 17,819 blood cultures), giving a blood culture utilization rate of 30.6 per 1,000 patient-days. A total of 1,311 patients were COVID-19 cases. Blood culture utilization rate had been increasing before and during the COVID-19 pandemic (both p < 0.001), and was higher among COVID-19 cases than non-COVID-19 cases (43.5 vs. 30.2 per 1,000 patient-days, p < 0.001). The most common pathogens identified were K. pneumoniae (23.3%), Acinetobacter spp. (13.9%) and E. coli (13.1%). The proportion of resistance for each bacterial pathogen was similar between COVID-19 and non-COVID-19 cases (all p > 0.10). Incidence rate of hospital-origin AMR-BSI increased from 130.1 cases per 100,000 patient-days in 2019 to 165.5 in 2020 (incidence rate ratio 1.016 per month, 95%CI:1.016-1.017, p < 0.001), and was not associated with COVID-19 (p = 0.96). CONCLUSIONS: In our setting, AMR-BSI incidence and etiology were similar between COVID-19 and non-COVID-19 cases. Incidence rates of hospital-origin AMR-BSI increased in 2020, which was likely due to increased blood culture utilization. We recommend increasing blood culture utilization and generating AMR surveillance reports in LMICs to inform local health care providers and policy makers.


Assuntos
COVID-19 , Infecção Hospitalar , Sepse , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias , Hemocultura , COVID-19/epidemiologia , Infecção Hospitalar/microbiologia , Escherichia coli , Hospitais , Humanos , Indonésia/epidemiologia , Klebsiella pneumoniae , Pandemias , Encaminhamento e Consulta , SARS-CoV-2/genética , Sepse/microbiologia
17.
Emerg Microbes Infect ; 11(1): 1325-1334, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35475418

RESUMO

Owing to an increasing number of infections in adults, Lactococcus (L.) garvieae has gained recognition as an emerging human pathogen, causing bacteraemia and septicaemia. In September 2020, four paediatric onco-hematologic patients received a platelet concentrate from the same adult donor at Bambino Gesù Children's Hospital IRCCS, Rome. Three of four patients experienced L. garvieae sepsis one day after transfusion. The L. garvieae pediatric isolates and the donor's platelet concentrates were retrospectively collected for whole-genome sequencing and shot-gun metagenomics, respectively (Illumina HiSeq). By de novo assembly of the L. garvieae genomes, we found that all three pediatric isolates shared a 99.9% identity and were characterized by 440 common SNPs. Plasmid pUC11C (conferring virulence properties) and the temperate prophage Plg-Tb25 were detected in all three strains. Core SNP genome-based maximum likelihood and Bayesian trees confirmed their phylogenetic common origin and revealed their relationship with L. garvieae strains affecting cows and humans (bootstrap values >100 and posterior probabilities = 1.00). Bacterial reads obtained by the donor's platelet concentrate have been profiled with MetaPhlAn2 (v.2.7.5); among these, 29.9% belonged to Firmicutes, and 5.16% to Streptococcaceae (>97% identity with L. garvieae), confirming the presence of L. garvieae in the platelet concentrate transfusion. These data showed three episodes of sepsis for the first time due to a transfusion-associated transmission of L. garvieae in three pediatric hospitalized hematology patients. This highlights the importance to implement the screening of platelet components with new human-defined pathogens for ensuring the safety of blood supply, and more broadly, for the surveillance of emerging pathogens.


Assuntos
Lactococcus , Sepse , Teorema de Bayes , Criança , Farmacorresistência Bacteriana , Humanos , Lactococcus/classificação , Lactococcus/genética , Filogenia , Estudos Retrospectivos , Sepse/microbiologia
18.
Cytokine ; 154: 155876, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35405484

RESUMO

Tet methylcytosine dioxygenase 2 (Tet2) is an important enzyme in the demethylation of DNA. Recent evidence has indicated a role for Tet2 in the regulation of macrophage activation by lipopolysaccharide (LPS) and mice with a myeloid cell Tet2 deficiency showed enhanced lung inflammation upon local LPS administration. However, mice with a global Tet2 deficiency showed reduced systemic inflammation during abdominal sepsis. Here, we sought to determine the role of myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia. To this end we infected myeloid cell specific Tet2 deficient and control mice with two common gram-negative respiratory pathogens via the airways: Pseudomonas aeruginosa (PAK, causing acute infection that remains confined in the lungs) or Klebsiella pneumoniae (causing a gradually evolving pneumonia with subsequent dissemination and sepsis) and compared bacterial loads and host response parameters between mouse strains. Bone marrow derived macrophages from myeloid Tet2 deficient mice released more interleukin-6 than control macrophages upon stimulation with PAK or K. pneumoniae. However, bacterial loads did not differ between mouse strains upon infection with viable PAK or K. pneumoniae, and neither did cytokine levels or neutrophil recruitment. In addition, in the K. pneumoniae pneumosepsis model myeloid Tet2 deficiency did not affect systemic inflammation or organ injury. Together these data strongly argue against a role for myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia and pneumosepsis.


Assuntos
Proteínas de Ligação a DNA , Dioxigenases , Pneumonia Bacteriana , Sepse , Animais , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Inflamação , Klebsiella pneumoniae , Lipopolissacarídeos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides , Pneumonia Bacteriana/microbiologia , Sepse/microbiologia
20.
Pediatr Dev Pathol ; 25(4): 409-418, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35227107

RESUMO

PURPOSE AND CONTEXT: Streptococcal Infection (SI) is an important cause of pediatric death in children, yet limited reports exist on autopsy findings in fatal SI cases. METHOD: Case records (1997-2019) of SI with no pre-existing risk factors were reviewed and selected. Their clinical and pathological findings in the autopsy reports were analyzed. RESULTS: In our cohort of 38 cases based on bacterial culture results, SI was most commonly caused by Streptococcus pneumoniae (SPn; 45%) and Streptococcus pyogenes (SPy; 37%). 92% of decedents had some prodromal symptoms prior to terminal presentation. The clinical course was often rapid, with 89% found unresponsive, suddenly collapsing, or dying within 24 hours of hospital admission. 64% of deaths were attributed to sepsis, more frequently diagnosed in the SPy group than in the SPn group (71% vs 48%). Pneumonia was found in both SPn and SPy groups, whereas meningitis was exclusively associated with SPn. CONCLUSION: Our study shows fatal SI is most commonly caused by either SPn or SPy, both of which are frequently associated with prodromal symptoms, rapid terminal clinical course, and evidence of sepsis. Postmortem diagnosis of sepsis is challenging and should be correlated with clinical features, bacterial culture results, and autopsy findings.


Assuntos
Infecções Estreptocócicas , Autopsia , Causas de Morte , Criança , Humanos , Sintomas Prodrômicos , Sepse/diagnóstico , Sepse/microbiologia , Sepse/mortalidade , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/mortalidade , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pyogenes/isolamento & purificação
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