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Acinetobacter baumannii is a Gram-negative opportunistic pathogen and a leading cause of ventilator-associated pneumonia. Murine models of A. baumannii lung infection allow researchers to experimentally assess A. baumannii virulence and host response. Intranasal administration of A. baumannii models acute lung infection. This chapter describes the methods to test A. baumannii virulence in a murine model of lung infection, including assessing the competitive index of a bacterial mutant and the associated inflammatory responses.
Acinetobacter baumannii is an important nosocomial pathogen capable of causing wound infections, pneumonia, and bacteremia. During infection, A. baumannii must acquire Zn to survive and colonize the host. Vertebrates have evolved mechanisms to sequester Zn from invading pathogens by a process termed nutritional immunity. One of the most upregulated genes during Zn starvation encodes a putative cell wall-modifying enzyme which we named ZrlA. We found that inactivation of zrlA diminished growth of A. baumannii during Zn starvation. Additionally, this mutant strain displays increased cell envelope permeability, decreased membrane barrier function, and aberrant peptidoglycan muropeptide abundances. This altered envelope increases antibiotic efficacy both in vitro and in an animal model of A. baumannii pneumonia. These results establish ZrlA as a crucial link between nutrient metal uptake and cell envelope homeostasis during A. baumannii pathogenesis, which could be targeted for therapeutic development.
Copyright © 2019 Vanderbilt University Medical Center. Published by Elsevier Inc. All rights reserved.
Background - Streptococcus pneumoniae is considered the leading bacterial cause of pneumonia in adults. Yet, it was not commonly detected by traditional culture-based and conventional urinary testing in a recent multicenter etiology study of adults hospitalized with community-acquired pneumonia (CAP). We used novel serotype-specific urinary antigen detection (SSUAD) assays to determine whether pneumococcal cases were missed by traditional testing.
Methods - We studied adult patients hospitalized with CAP at 5 hospitals in Chicago and Nashville (2010-2012) and enrolled in the Etiology of Pneumonia in the Community (EPIC) study. Traditional diagnostic testing included blood and sputum cultures and conventional urine antigen detection (ie, BinaxNOW). We applied SSUAD assays that target serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) to stored residual urine specimens.
Results - Among 1736 patients with SSUAD and ≥1 traditional pneumococcal test performed, we identified 169 (9.7%) cases of pneumococcal CAP. Traditional tests identified 93 (5.4%) and SSUAD identified 76 (4.4%) additional cases. Among 14 PCV13-serotype cases identified by culture, SSUAD correctly identified the same serotype in all of them. Cases identified by SSUAD vs traditional tests were similar in most demographic and clinical characteristics, although disease severity and procalcitonin concentration were highest among those with positive blood cultures. The proportion of pneumonia cases caused by serotypes exclusively covered by PCV13 was not significantly different between the first and second July-June study periods (6.4% vs 4.0%).
Conclusions - Although restricted to the detection of only 13 serotypes, SSUAD testing substantially increased the detection of pneumococcal pneumonia among adults hospitalized with CAP.
Loss of secretory IgA is common in the small airways of patients with chronic obstructive pulmonary disease and may contribute to disease pathogenesis. Using mice that lack secretory IgA in the airways due to genetic deficiency of polymeric Ig receptor (pIgR mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45 cells in the lungs, as well as an increase in total neutrophils, in pIgR mice compared with wild-type controls. This increase in neutrophils in pIgR mice was associated with elastin degradation in the alveolar compartment and around small airways, along with increased collagen deposition in small airway walls. Neutrophil depletion using anti-Ly6G antibodies or treatment with broad-spectrum antibiotics inhibited development of both emphysema and small airway remodeling, suggesting that airway bacteria provide the stimulus for deleterious neutrophilic inflammation in this model. Exogenous bacterial challenge using lysates prepared from pathogenic and nonpathogenic bacteria worsened neutrophilic inflammation and lung remodeling in pIgR mice. This phenotype was abrogated by antiinflammatory therapy with roflumilast. Together, these studies support the concept that disruption of the mucosal immune barrier in small airways contributes to chronic obstructive pulmonary disease progression by allowing bacteria to stimulate chronic neutrophilic inflammation, which, in turn, drives progressive airway wall fibrosis and emphysematous changes in the lung parenchyma.
Importance - β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches.
Objective - To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia.
Design, Setting, and Participants - We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children's hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017.
Main Outcomes and Measures - We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients' length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up.
Results - Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the Etiology of Pneumonia in the Community Study with radiographically confirmed pneumonia in the study period; 1019 (71.9%) received β-lactam monotherapy and 399 (28.1%) received β-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving β-lactam monotherapy and combination therapy (median, 55 vs 59 hours; adjusted hazard ratio, 0.87; 95% CI, 0.74-1.01). The propensity-matched cohort (n = 560, 39.5%) showed similar results. There were also no significant differences between treatment groups for the secondary outcomes.
Conclusions and Relevance - Empirical macrolide combination therapy conferred no benefit over β-lactam monotherapy for children hospitalized with community-acquired pneumonia. The results of this study elicit questions about the routine empirical use of macrolide combination therapy in this population.
BACKGROUND AND OBJECTIVES - National guidelines recommend blood cultures for children hospitalized with presumed bacterial community-acquired pneumonia (CAP) that is moderate or severe. We sought to determine the prevalence of bacteremia and characterize the microbiology and penicillin-susceptibility patterns of positive blood culture results among children hospitalized with CAP.
METHODS - We conducted a cross-sectional study of children hospitalized with CAP in 6 children's hospitals from 2007 to 2011. We included children 3 months to 18 years of age with discharge diagnosis codes for CAP using a previously validated algorithm. We excluded children with complex chronic conditions. We reviewed microbiologic data and classified positive blood culture detections as pathogens or contaminants. Antibiotic-susceptibility patterns were assessed for all pathogens.
RESULTS - A total of 7509 children hospitalized with CAP were included over the 5-year study period. Overall, 34% of the children hospitalized with CAP had a blood culture performed; 65 (2.5% of patients with blood cultures; 95% confidence interval [CI]: 2.0%-3.2%) grew a pathogen. accounted for 78% of all detected pathogens. Among detected pathogens, 50 (82%) were susceptible to penicillin. Eleven children demonstrated growth of an organism nonsusceptible to penicillin, representing 0.43% (95% CI: 0.23%-0.77%) of children with blood cultures obtained and 0.15% (95% CI: 0.08%-0.26%) of all children hospitalized with CAP.
CONCLUSIONS - Among children without comorbidities hospitalized with CAP in a non-ICU setting, the rate of bacteremia was low, and isolated pathogens were usually susceptible to penicillin. Blood cultures may not be needed for most children hospitalized with CAP.
Copyright © 2017 by the American Academy of Pediatrics.
Background - Recent trials suggest procalcitonin-based guidelines can reduce antibiotic use for respiratory infections. However, the accuracy of procalcitonin to discriminate between viral and bacterial pneumonia requires further dissection.
Methods - We evaluated the association between serum procalcitonin concentration at hospital admission with pathogens detected in a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia. Systematic pathogen testing included cultures, serology, urine antigen tests, and molecular detection. Accuracy of procalcitonin to discriminate between viral and bacterial pathogens was calculated.
Results - Among 1735 patients, pathogens were identified in 645 (37%), including 169 (10%) with typical bacteria, 67 (4%) with atypical bacteria, and 409 (24%) with viruses only. Median procalcitonin concentration was lower with viral pathogens (0.09 ng/mL; interquartile range [IQR], <0.05-0.54 ng/mL) than atypical bacteria (0.20 ng/mL; IQR, <0.05-0.87 ng/mL; P = .05), and typical bacteria (2.5 ng/mL; IQR, 0.29-12.2 ng/mL; P < .01). Procalcitonin discriminated bacterial pathogens, including typical and atypical bacteria, from viral pathogens with an area under the receiver operating characteristic (ROC) curve of 0.73 (95% confidence interval [CI], .69-.77). A procalcitonin threshold of 0.1 ng/mL resulted in 80.9% (95% CI, 75.3%-85.7%) sensitivity and 51.6% (95% CI, 46.6%-56.5%) specificity for identification of any bacterial pathogen. Procalcitonin discriminated between typical bacteria and the combined group of viruses and atypical bacteria with an area under the ROC curve of 0.79 (95% CI, .75-.82).
Conclusions - No procalcitonin threshold perfectly discriminated between viral and bacterial pathogens, but higher procalcitonin strongly correlated with increased probability of bacterial pathogens, particularly typical bacteria.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: firstname.lastname@example.org.
Background - Lower procalcitonin (PCT) concentrations are associated with reduced risk of bacterial community-acquired pneumonia (CAP) in adults, but data in children are limited.
Methods - We analyzed serum PCT concentrations from children hospitalized with radiographically confirmed CAP enrolled in the Centers for Disease Control and Prevention's Etiology of Pneumonia in the Community (EPIC) Study. Blood and respiratory specimens were tested using multiple pathogen detection methods for typical bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus), atypical bacteria (Mycoplasma pneumoniae and Chlamydophila pneumoniae), and respiratory viruses. Multivariable regression was used to assess associations between PCT concentrations and etiology and severity.
Results - Among 532 children (median age, 2.4 years; interquartile range [IQR], 1.0-6.3), patients with typical bacteria had higher PCT concentrations (±viruses; n = 54; median, 6.10; IQR, 0.84-22.79 ng/mL) than those with atypical bacteria (±viruses; n = 82; median, 0.10; IQR, 0.06-0.39 ng/mL), viral pathogens only (n = 349; median, 0.33; IQR, 0.12-1.35 ng/mL), or no pathogen detected (n = 47; median, 0.44; IQR, 0.10-1.83 ng/mL) (P < .001 for all). No child with PCT <0.1 ng/mL had typical bacteria detected. Procalcitonin <0.25 ng/mL featured a 96% negative predictive value (95% confidence interval [CI], 93-99), 85% sensitivity (95% CI, 76-95), and 45% specificity (95% CI, 40-50) in identifying children without typical bacterial CAP.
Conclusions - Lower PCT concentrations in children hospitalized with CAP were associated with a reduced risk of typical bacterial detection and may help identify children who would not benefit from antibiotic treatment.
© The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: email@example.com.
OBJECTIVES - Six recently published algorithms classify pneumonia patients presenting from the community into high- and low-risk groups for resistant bacteria. Our objective was to compare performance of these algorithms for identifying patients infected with bacteria resistant to traditional community-acquired pneumonia antibiotics.
METHODS - This was a retrospective study of consecutive adult patients diagnosed with pneumonia in an emergency department and subsequently hospitalized. Each patient was classified as high or low risk for resistant bacteria according to the following algorithms: original health care-associated pneumonia (HCAP) criteria, Summit criteria, Brito and Niederman strategy, Shorr model, Aliberti model, and Shindo model. The reference for comparison was detection of resistant bacteria, defined as methicillin-resistant Staphylococcus aureus or Gram-negative bacteria resistant to ceftriaxone or levofloxacin.
RESULTS - A total of 614 patients were studied, including 36 (5.9%) with resistant bacteria. The HCAP criteria classified 304 (49.5%) patients as high risk, with an area under the receiver operating characteristic curve (AUC) of 0.63 (95% confidence interval [CI] = 0.54 to 0.72), sensitivity of 0.69 (95% CI = 0.52 to 0.83), and specificity of 0.52 (95% CI = 0.48 to 0.56). None of the other algorithms improved both sensitivity and specificity or significantly improved the AUC. Compared to the HCAP criteria, the Shorr and Aliberti models classified more patients as high risk, resulting in higher sensitivity and lower specificity. The Shindo model classified fewer patients as high risk, with lower sensitivity and higher specificity.
CONCLUSIONS - All algorithms for identification of resistant bacteria included in this study had suboptimal performance to guide antibiotic selection. New strategies for selecting empirical antibiotics for community-onset pneumonia are necessary.
© 2015 by the Society for Academic Emergency Medicine.