Pediatric pneumonia death caused by community-acquired methicillin-resistant Staphylococcus aureus, Japan.
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ABSTRACT:
SUBMITTER: Ito T
PROVIDER: S-EPMC2600375 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A novel, methicillin-resistant [corrected] Staphylococcus aureus clone (Uruguay clone) with a non-multidrug-resistant phenotype caused a large outbreak, including 7 deaths, in Montevideo, Uruguay. The clone was distinct from the highly virulent community clone represented by strain MW2, although both clones carried Panton-Valentine leukocidin gene and cna gene.
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Project description:The use of macrolides against pneumonia has been reported to improve survival; however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM) and compared it with that of vancomycin (VCM) and daptomycin (DAP) in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection and then treated with AZM, VCM, or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (interleukin-6 [IL-6] and macrophage inflammatory protein-2 [MIP-2]) in bronchoalveolar lavage fluid or toxin expression levels (?-hemolysin [Hla] and staphylococcal protein A [Spa]) was observed following AZM treatment. In vitro, AZM suppressed the growth of MRSA in late log phase but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.
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Project description:Staphylococcus aureus is a major cause of both community- and healthcare-acquired pneumonias. Inducible costimulator (ICOS) is part of the CD28 family of proteins and is a target for immune checkpoint therapy. We found ICOS highly expressed on activated CD4 cells in response to S. aureus. In the absence of ICOS, mice had improved survival in a pneumonia model with the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 and significant reductions in bacterial burden in a nonlethal acute pneumonia model. Infected Icos-/- mice had major reductions in several proinflammatory cytokines, neutrophils, inflammatory monocytes, and eosinophils compared to infected wild-type mice, while there was improved expression of CD11c and macrophage receptor with collagenous structure on the surface of alveolar macrophages. Early during infection infected Icos-/- mice had increased numbers of alveolar macrophages and expression of several surface markers on alveolar macrophages and neutrophils. ICOS signaling also contributed to the pathogenesis of the airway pathogens Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus pneumoniae, and neutralizing antibody to ICOS led to improved clearance of S. aureus from the airway. Our results indicate that ICOS plays a significant role in orchestrating the innate immune response to S. aureus and other airway pathogens, and could be a potential immunomodulatory target to attenuate S. aureus-related immunopathology.
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Project description:The advent of methicillin-resistant Staphylococcus aureus (MRSA) and the frequent and excessive abuse of ventilators have made MRSA pneumonia an inordinate threat to human health. Appropriate antibacterial therapies are crucial, including the use of lysostaphin as an alternative to antibiotics. To explore the potential use of lysostaphin as a therapeutic agent for MRSA pneumonia, mice were intranasally infected with MRSA and then treated with recombinant lysostaphin (rLys; 45?mg/kg in the high-dose group and 1?mg/kg in the low-dose group) (0.33?mg/mL, 15?mg/mL), vancomycin (120?mg/kg) (40?mg/mL), or phosphate-buffered saline (PBS, negative control) 4?h after infection. Therapeutic efficacy was assessed by mouse survival, lung histopathology, bacterial density in the lungs, bodyweight, lung weight, temperature, white blood cells counts, lymphocytes counts, granulocytes counts, and monocytes counts. The mice treated with rLys showed lower mortality, less lung parenchymal damage, and lower bacterial density at metastatic tissue sites than mice treated with PBS or vancomycin. The overall mortality was 100%, 60%, 40%, and 60% for the control, vancomycin, high-dose rLys, and low-dose rLys groups, respectively. These findings indicate that, as a therapeutic agent for MRSA pneumonia, lysostaphin exerts profound protective effects in mice against the morbidity and mortality associated with S. aureus pneumonia.
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Project description:BackgroundCommunity-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a significant bacterial pathogen that poses considerable clinical and public health challenges. The majority of the CA-MRSA disease burden consists of skin and soft tissue infections (SSTI) not associated with significant morbidity; however, CA-MRSA also causes severe, invasive infections resulting in significant morbidity and mortality. The broad range of disease severity may be influenced by bacterial genetic variation.ResultsWe sequenced the complete genomes of 36 CA-MRSA clinical isolates from the predominant North American community acquired clonal type USA300 (18 SSTI and 18 severe infection-associated isolates). While all 36 isolates shared remarkable genetic similarity, we found greater overall time-dependent sequence diversity among SSTI isolates. In addition, pathway analysis of non-synonymous variations revealed increased sequence diversity in the putative virulence genes of SSTI isolates.ConclusionsHere we report the first whole genome survey of diverse clinical isolates of the USA300 lineage and describe the evolution of the pathogen over time within a defined geographic area. The results demonstrate the close relatedness of clinically independent CA-MRSA isolates, which carry implications for understanding CA-MRSA epidemiology and combating its spread.
| S-EPMC3598774 | biostudies-literature
Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile human pathogen that is associated with diverse types of infections ranging from benign colonization to sepsis. We postulated that MRSA must undergo specific genotypic and phenotypic changes to cause chronic pulmonary disease. We investigated how MRSA adapts to the human airway to establish chronic infection, as occurs during cystic fibrosis (CF). MRSA isolates from patients with CF that were collected over a 4-year period were analyzed by whole-genome sequencing, transcriptional analysis, and metabolic studies. Persistent MRSA infection was associated with staphylococcal metabolic adaptation, but not changes in immunogenicity. Adaptation was characterized by selective use of the tricarboxylic acid cycle cycle and generation of biofilm, a means of limiting oxidant stress. Increased transcription of specific metabolic genes was conserved in all host-adapted strains, most notably a 10,000-fold increase in fumC, which catalyzes the interconversion of fumarate and malate. Elevated fumarate levels promoted in vitro biofilm production in clinical isolates. Host-adapted strains preferred to assimilate glucose polymers and pyruvate, which can be metabolized to generate N-acetylglucosamine polymers that comprise biofilm. MRSA undergoes substantial metabolic adaptation to the human airway to cause chronic pulmonary infection, and selected metabolites may be useful therapeutically to inhibit infection.
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Project description:BackgroundBacterial pneumonia is a well described complication of influenza. In recent years, community-onset methicillin-resistant Staphylococcus aureus (cMRSA) infection has emerged as a contributor to morbidity and mortality in patients with influenza. Since the emergence and rapid dissemination of pandemic A(H1N1)2009 influenzavirus in April 2009, initial descriptions of the clinical features of patients hospitalized with pneumonia have contained few details of patients with bacterial co-infection.Methodology/principal findingsPatients with community-acquired pneumonia (CAP) caused by co-infection with pandemic A(H1N1)2009 influenzavirus and cMRSA were prospectively identified at two tertiary hospitals in one Australian city during July to September 2009, the period of intense influenza activity in our region. Detailed characterization of the cMRSA isolates was performed. 252 patients with pandemic A(H1N1)2009 influenzavirus infection were admitted at the two sites during the period of study. Three cases of CAP due to pandemic A(H1N1)2009/cMRSA co-infection were identified. The clinical features of these patients were typical of those with S. aureus co-infection or sequential infection following influenza. The 3 patients received appropriate empiric therapy for influenza, but inappropriate empiric therapy for cMRSA infection; all 3 survived. In addition, 2 fatal cases of CAP caused by pandemic A(H1N1)2009/cMRSA co-infection were identified on post-mortem examination. The cMRSA infections were caused by three different cMRSA clones, only one of which contained genes for Panton-Valentine Leukocidin (PVL).Conclusions/significanceClinicians managing patients with pandemic A(H1N1)2009 influenzavirus infection should be alert to the possibility of co-infection or sequential infection with virulent, antimicrobial-resistant bacterial pathogens such as cMRSA. PVL toxin is not necessary for the development of cMRSA pneumonia in the setting of pandemic A( H1N1) 2009 influenzavirus co-infection.
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Project description:UNLABELLED:Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. IMPORTANCE:With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection of strains of the S. aureus CC80 lineage. Our study determined that a single descendant of a PVL-positive methicillin-sensitive ancestor circulating in sub-Saharan Africa rose to become the dominant CA-MRSA clone in Europe, the Middle East, and North Africa. In the transition from a methicillin-susceptible lineage to a successful CA-MRSA clone, it simultaneously became resistant to fusidic acid, a widely used antibiotic for skin and soft tissue infections, thus demonstrating the importance of antibiotic selection in the success of this clone. This finding furthermore highlights the significance of horizontal gene acquisitions and underscores the combined importance of these factors for the success of CA-MRSA.
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Project description:Community-acquired infections caused by methicillin-resistant Staphylococcus aureus (MRSA) expressing the Panton-Valentine leukocidin (PVL) are rampant, but the contribution of PVL to bacterial virulence remains controversial. While PVL is usually viewed as a cytotoxin, at sublytic amounts it activates protective innate immune responses. A leukotoxic effect might predominate in high inoculum studies, whereas protective proinflammatory properties might predominate in settings with lower bacterial inocula that more closely mimic what initially occurs in humans. However, these protective effects might possibly be neutralized by antibodies to PVL, which are found in normal human sera and at increased levels following PVL(+) S. aureus infections. In a low-inoculum murine skin abscess model including a foreign body at the infection site, strains deleted for the pvl genes replicated more efficiently within abscesses than isogenic PVL(+) strains. Coinfection of mice at separate sites with isogenic PVL(+) and PVL(-) MRSA abrogated the differences in bacterial burdens, indicating a systemic effect on host innate immunity from production of PVL. Mice given antibody to PVL and then infected with seven different PVL(+) strains also had significantly higher bacterial counts in abscesses compared with mice given nonimmune serum. Antibody to PVL had no effect on MRSA strains that did not produce PVL. In vitro, antibody to PVL incapacitated PVL-mediated activation of PMNs, indicating that virulence of PVL(+) MRSA is enhanced by the interference of PVL-activated innate immune responses. Given the high rates of primary and recurring MRSA infections in humans, it appears that antibodies to PVL might contribute to host susceptibility to infection.
| S-EPMC2836673 | biostudies-literature
Project description:Staphylococcus aureus is the most common bacteria associated with the development of osteomyelitis in pediatric patients. Osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) can be difficult to safely and effectively treat. Vancomycin, linezolid, and clindamycin are commonly used to treat osteomyelitis caused by MRSA. While adult studies suggest intravenous (IV) daptomycin may by beneficial for the treatment of MRSA osteomyelitis, it is not Food and Drug Administration approved for use in pediatrics, and minimal data are available related to its use in this population. This case report describes the successful use of daptomycin (8 mg/kg/dose IV daily) combined with rifampin for 5 weeks, followed by 5 weeks of oral sulfamethoxazole/trimethoprim, for treatment of acute bilateral osteomyelitis caused by MRSA in an 8-year-old male. The patient did not initially respond to the combination of vancomycin plus rifampin and gentamicin, nor did he respond to ceftaroline treatment. After initiation of daptomycin, his fevers quickly subsided, his pain rapidly improved, and his inflammatory markers significantly decreased. While daptomycin was effective in this patient, additional research is needed to determine the true safety and efficacy of this drug for treatment of osteomyelitis caused by MRSA in pediatric patients.
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